**Hematopoietic Stem Cell Transplantation in HIV Infected Patients**

Nitya Nathwani

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/52686

### **1. Introduction**

In the highly active antiretroviral therapy (HAART) era, the survival of HIV infected pa‐ tients has improved. Opportunistic infections and AIDS related syndromes in these individ‐ uals have declined (Palella et al, 1998). HIV infected individuals have an increased tendency to develop malignancy. These include a number of non-AIDS defining malignancies, as well as the AIDS defining malignancies which are Kaposi sarcoma, invasive cervical cancer and non-Hodgkin Lymphoma (NHL). Among the NHL group, the incidence of systemic NHL, CNS Lymphoma and primary effusion lymphoma are increased in this population. Malig‐ nancies continue to be an important cause of mortality in these individuals.

The incidence of NHL increases with progressive immunosuppression in HIV-infected pa‐ tients. The majority of these cases are intermediate or high-grade and almost all are diffuse large B cell (immunoblastic variant) or Burkitt-like lymphomas. The incidence of Hodgkin lymphoma (HL) is also increased in the HIV positive population (Bigar R et al, 2006) though it is not an AIDS defining illness. Acute myeloid leukemia may also occur with higher fre‐ quency in the setting of HIV infection (Grulich A et al, 2007). NHL and HL occurring in HIV infected individuals are characterized by an aggressive clinical course with an advanced stage at presentation (Levine AM, 2000).

In the pre-HAART era, the standard treatment for AIDS associated NHL was low dose che‐ motherapy. It was thought that they would be unable to tolerate intensive chemotherapy be‐ cause of the underlying immunodeficiency. Randomized trials of standard doses of combination chemotherapy versus reduced doses revealed inferior results in the standard dose arm due to increased hematologic toxicity and infections (Kaplan LD et al, 1997). In the post-HAART era, patients were treated more aggressively due to improved hematologic re‐ serve in patients on HAART. Patients are now treated similar to non HIV NHL patients.

© 2013 Nathwani; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Their remission rates and median survival with aggressive combination chemotherapy and HAART is similar to their HIV negative counterparts (Boue, F et al, 2006).

This thereby reduced the period of neutropenia and mucositis, which improved survival in

Hematopoietic Stem Cell Transplantation in HIV Infected Patients

http://dx.doi.org/10.5772/52686

59

This procedure has been the standard treatment for HIV negative patients with relapsed NHL since the landmark PARMA trial published by Philip et al in the New England Journal of Medicine (1995). In this trial, patients with relapsed chemosensitive aggressive NHL were treated with 2 cycles of DHAP (Dexamethasone, Cisplatin and Cytarabine) and if respon‐ sive, randomly assigned to receive either DHAP for 4 additional cycles or high dose chemo‐ therapy with BEAC (BCNU/Carmustine, Etoposide, Cytarabine and Cyclophosphamide) followed by ASCT, The results of this study revealed an overall survival (OS) benefit of 53 versus 32 percent (p= 0.038) in favor of the high dose chemotherapy arm. This approach has also been used in high risk patients who are in first remission (Haioun, C et al, 1997). Nonrandomized trials of this high risk group have demonstrated high rates of progression free survival (FPS). Similarly, trials of HIV negative patients with Hodgkin Lymphoma have shown that ASCT can provide long term PFS for patients with relapsed disease (Linch,

ASCT in HIV positive patients was pioneered by the French in the pre-HAART era (Ga‐ barre, J et al, 1996). The first patient was reported as a case study. He was a 40 year old male with HIV related NHL, receiving Zidovudine and Zalcitabine as antiretroviral treatment. He was treated with BEAM (BCNU, Etoposide, Cytarabine and Melphalan) chemotherapy for relapsed lymphoma followed by ASCT. His post-transplant course was complicated by sev‐ eral opportunistic infections including cytomegalovirus viremia, mycobacterium pneumo‐ nia and cryptosporidiosis. This report corroborated the fear that the immune impairment due to HIV augmented the infection risk. However, it also demonstrated that mobilizing stem cells and successful engraftment were feasible in this setting. In the post-HAART era, French investigators performed a study with fourteen patients with relapsed or refractory NHL. Eight patients died of which six deaths were from lymphoma. This study established that the mortality due to infection was substantially reduced, but that control of the underly‐ ing lymphoma remained the challenge (Gabarre et al, 2001). It set the stage for ASCT to be considered a feasible task in HIV patients, and revealed that infectious issues were manage‐

Other centers have described similar findings. The larger City of Hope study had patients with less advanced lymphoma and disqualified chemotherapy refractory patients (Krishnan A, et al, 2005). The initial series consisted of 20 patients with HL or NHL. All patients were on HAART. The majority of patients underwent CBV (cyclophosphamide, BCNU, Etopo‐ side) chemotherapy as conditioning. Engraftment times were comparable to HIV negative patients, median was 11 days. Despite efforts to continue HAART throughout the transplant period, only nine out of twenty were able to tolerate it. The remainder resumed it at a me‐ dian of two months following ASCT. The poor tolerance of HAART was due to either nau‐ sea or mucositis. Transplant related mortality was low, as was the incidence of opportunistic infections. No patient died of an opportunistic infection. Although the CD4 count did nadir

1993). All these studies were done in the HIV negative population.

able without apparent adverse consequences on the HIV infection.

**2.1. ASCT in HIV positive patients**

patients.

Consequently, more aggressive therapies such as high dose chemotherapy and stem cell transplantation have been explored in the HAART era with encouraging results. This chap‐ ter will go through autologous and allogeneic stem cell transplantation in HIV infected indi‐ viduals and also highlight some of the recent developments in the field.

### **2. Autologous Stem Cell Transplantation (ASCT)**

Autologous stem cell transplantation means transplantation with a person's own hemato‐ poietic stem cells which are harvested ahead of time and cryopreserved for later use. Pluri‐ potent hematopoietic stem cells are those which are capable of self renewal and of differentiation. These are the cells targeted for collection. The main advantage of this proce‐ dure is to enable the patient to receive myeloablative dose intense chemotherapy for a ma‐ lignancy that has demonstrated a dose response to chemotherapy. Stem cells collected from the peripheral blood after priming with G-CSF (Granulocyte Colony Stimulating Factor) are generally preferred to stem cells from the bone marrow due to shorter engraftment times, thereby reducing morbidity and mortality. Stem cell apheresis is an outpatient procedure where cells are collected through large volume apheresis over approximately 4-6 hours. These stem cells are either cryopreserved with DMSO directly or can be manipulated by methods such as CD34 positive selection and transduction prior to cryopreservation.

There are various preparative regimens used for stem cell transplantation in patients with hematologic malignancy. The ideal regimen should be able to eradicate the malignancy, have no mortality and manageable side effects or toxicity. Alas, no such treatments exist. There are several treatment regimens in use. Selection of high dose chemotherapy regimens is based upon the use of chemotherapeutic agents that have a dose response in the hemato‐ logic malignancy. In addition, drugs are chosen that have nonoverlapping toxicities save for the hematologic toxicity. For example in NHL, typical agents include Cyclophosphamide, Etoposide, Carmustine (BCNU) and melphalan. In Hodgkin lymphoma, frequently utilized preparative regimens include the CBV regimen with Cyclophosphamide, Carmustine (BCNU), and Etoposide (VP-16) and the BEAM regimen with Carmustine (BCNU), Etopo‐ side (VP-16), Cytarabine (Ara-C) and Melphalan.

Patients typically receive the conditioning regimen followed by infusion of thawed autolo‐ gous stem cells approximately 24- 48 hours post completion of chemotherapy. Thereafter en‐ sues a period of profound neutropenia, also often mucositis and GI toxicity such as nausea and diarrhea. During this period of neutropenia, the risk of infection is significantly in‐ creased. Hence patients are housed in hepa filtered rooms, and placed on low bacteria diets in addition to other infectious precautions. Nonetheless, fever and infection can be common. Mucositis is a risk factor for infection as it increases the likelihood of intermittent bacteremia from the GI tract. The use of peripheral blood progenitor cells harvested from apheresis in‐ stead of bone marrow stem cells led to a shortening of engraftment of white blood cell times. This thereby reduced the period of neutropenia and mucositis, which improved survival in patients.

This procedure has been the standard treatment for HIV negative patients with relapsed NHL since the landmark PARMA trial published by Philip et al in the New England Journal of Medicine (1995). In this trial, patients with relapsed chemosensitive aggressive NHL were treated with 2 cycles of DHAP (Dexamethasone, Cisplatin and Cytarabine) and if respon‐ sive, randomly assigned to receive either DHAP for 4 additional cycles or high dose chemo‐ therapy with BEAC (BCNU/Carmustine, Etoposide, Cytarabine and Cyclophosphamide) followed by ASCT, The results of this study revealed an overall survival (OS) benefit of 53 versus 32 percent (p= 0.038) in favor of the high dose chemotherapy arm. This approach has also been used in high risk patients who are in first remission (Haioun, C et al, 1997). Nonrandomized trials of this high risk group have demonstrated high rates of progression free survival (FPS). Similarly, trials of HIV negative patients with Hodgkin Lymphoma have shown that ASCT can provide long term PFS for patients with relapsed disease (Linch, 1993). All these studies were done in the HIV negative population.

### **2.1. ASCT in HIV positive patients**

Their remission rates and median survival with aggressive combination chemotherapy and

Consequently, more aggressive therapies such as high dose chemotherapy and stem cell transplantation have been explored in the HAART era with encouraging results. This chap‐ ter will go through autologous and allogeneic stem cell transplantation in HIV infected indi‐

Autologous stem cell transplantation means transplantation with a person's own hemato‐ poietic stem cells which are harvested ahead of time and cryopreserved for later use. Pluri‐ potent hematopoietic stem cells are those which are capable of self renewal and of differentiation. These are the cells targeted for collection. The main advantage of this proce‐ dure is to enable the patient to receive myeloablative dose intense chemotherapy for a ma‐ lignancy that has demonstrated a dose response to chemotherapy. Stem cells collected from the peripheral blood after priming with G-CSF (Granulocyte Colony Stimulating Factor) are generally preferred to stem cells from the bone marrow due to shorter engraftment times, thereby reducing morbidity and mortality. Stem cell apheresis is an outpatient procedure where cells are collected through large volume apheresis over approximately 4-6 hours. These stem cells are either cryopreserved with DMSO directly or can be manipulated by

methods such as CD34 positive selection and transduction prior to cryopreservation.

There are various preparative regimens used for stem cell transplantation in patients with hematologic malignancy. The ideal regimen should be able to eradicate the malignancy, have no mortality and manageable side effects or toxicity. Alas, no such treatments exist. There are several treatment regimens in use. Selection of high dose chemotherapy regimens is based upon the use of chemotherapeutic agents that have a dose response in the hemato‐ logic malignancy. In addition, drugs are chosen that have nonoverlapping toxicities save for the hematologic toxicity. For example in NHL, typical agents include Cyclophosphamide, Etoposide, Carmustine (BCNU) and melphalan. In Hodgkin lymphoma, frequently utilized preparative regimens include the CBV regimen with Cyclophosphamide, Carmustine (BCNU), and Etoposide (VP-16) and the BEAM regimen with Carmustine (BCNU), Etopo‐

Patients typically receive the conditioning regimen followed by infusion of thawed autolo‐ gous stem cells approximately 24- 48 hours post completion of chemotherapy. Thereafter en‐ sues a period of profound neutropenia, also often mucositis and GI toxicity such as nausea and diarrhea. During this period of neutropenia, the risk of infection is significantly in‐ creased. Hence patients are housed in hepa filtered rooms, and placed on low bacteria diets in addition to other infectious precautions. Nonetheless, fever and infection can be common. Mucositis is a risk factor for infection as it increases the likelihood of intermittent bacteremia from the GI tract. The use of peripheral blood progenitor cells harvested from apheresis in‐ stead of bone marrow stem cells led to a shortening of engraftment of white blood cell times.

HAART is similar to their HIV negative counterparts (Boue, F et al, 2006).

viduals and also highlight some of the recent developments in the field.

**2. Autologous Stem Cell Transplantation (ASCT)**

58 Current Perspectives in HIV Infection

side (VP-16), Cytarabine (Ara-C) and Melphalan.

ASCT in HIV positive patients was pioneered by the French in the pre-HAART era (Ga‐ barre, J et al, 1996). The first patient was reported as a case study. He was a 40 year old male with HIV related NHL, receiving Zidovudine and Zalcitabine as antiretroviral treatment. He was treated with BEAM (BCNU, Etoposide, Cytarabine and Melphalan) chemotherapy for relapsed lymphoma followed by ASCT. His post-transplant course was complicated by sev‐ eral opportunistic infections including cytomegalovirus viremia, mycobacterium pneumo‐ nia and cryptosporidiosis. This report corroborated the fear that the immune impairment due to HIV augmented the infection risk. However, it also demonstrated that mobilizing stem cells and successful engraftment were feasible in this setting. In the post-HAART era, French investigators performed a study with fourteen patients with relapsed or refractory NHL. Eight patients died of which six deaths were from lymphoma. This study established that the mortality due to infection was substantially reduced, but that control of the underly‐ ing lymphoma remained the challenge (Gabarre et al, 2001). It set the stage for ASCT to be considered a feasible task in HIV patients, and revealed that infectious issues were manage‐ able without apparent adverse consequences on the HIV infection.

Other centers have described similar findings. The larger City of Hope study had patients with less advanced lymphoma and disqualified chemotherapy refractory patients (Krishnan A, et al, 2005). The initial series consisted of 20 patients with HL or NHL. All patients were on HAART. The majority of patients underwent CBV (cyclophosphamide, BCNU, Etopo‐ side) chemotherapy as conditioning. Engraftment times were comparable to HIV negative patients, median was 11 days. Despite efforts to continue HAART throughout the transplant period, only nine out of twenty were able to tolerate it. The remainder resumed it at a me‐ dian of two months following ASCT. The poor tolerance of HAART was due to either nau‐ sea or mucositis. Transplant related mortality was low, as was the incidence of opportunistic infections. No patient died of an opportunistic infection. Although the CD4 count did nadir at 6 months, post-transplant follow up demonstrated that the underlying HIV disease did not deteriorate as a result of the transplant and the CD4 counts recovered to pre-transplant levels by one year in all patients. PFS and OS were 85%. The improved result compared to the French experience may be from selecting patients with less advanced disease and che‐ motherapy sensitive disease.

withdrawal rate before transplantation displays the obstacles in treating these aggressive

Hematopoietic Stem Cell Transplantation in HIV Infected Patients

http://dx.doi.org/10.5772/52686

61

The European Group for Blood and Marrow Transplantation conducted a retrospective, multicentre registry-based analysis of sixty eight patients from twenty institutions since 1999 (Balsalobre P et al, 2009). There were fifty patients with NHL and eighteen patients with HL. At the time of ASCT, sixteen patients were in first complete remission (CR1); forty four patients were in CR more than 1, partial remission, or chemotherapy-sensitive relapse; and eight patients had chemotherapy resistant disease. Most patients were treated with a chemotherapy based conditioning regimen (BEAM and variants). The median CD4 count at transplantation was 162 cells/micro litter, and eighty percent of patients had an HIV viral load under 200/mL. All patients engrafted at a median of eleven days, save one. The inci‐ dence of non relapse mortality (NRM) was 4.4% and 7.5% at 3 and 12 months, respectively. Three patients died from bacterial infection, two died of HIV related complications, and one patient died of an unknown cause while in CR. At a median follow-up of 32 months, pro‐ gression free survival and overall survival were 56.5% and 61% at three years, respectively. On multivariate analysis, chemotherapy resistant disease and not attaining complete remis‐ sion predicted poorer progression free survival and overall survival. This data indicates again similar to the HIV negative transplant setting, disease control with chemotherapy at

Two case control studies also demonstrated that HIV status does not impact ASCT out‐ comes for lymphoma. The European Group for Blood and Marrow Transplantation under‐ took a retrospective study of 106 patients (Diez-Martin et al, 2009) which included 53 HIVpositive lymphoma patients who underwent transplant with controls matched for histology, non-age adjusted IPI (International Prognostic Index), and disease status at transplant. There were 66 percent NHL and 34 percent HL patients. Both groups were similar, other than the higher percentage of males, mixed cellularity Hodgkin lymphoma and patients receiving granulocyte colony stimulating factor before engraftment, and a smaller fraction receiving total body irradiation based conditioning within the HIV lymphoma cohort. With median follow-up of 30 months, progression free survival was 61 percent for the HIV-lymphoma group and 56 percent for the control lymphoma group. Overall survival was 61.5 percent for HIV-positive patients and 70 percent for controls (p = NS). There was a trend towards delay in platelet engraftment after transplant in the HIV group. It is uncertain whether this result‐ ed from the more frequent granulocyte colony stimulating factor use in that cohort or to HAART therapy or to chronic HIV infection of the bone marrow. Incidence of relapse, over‐ all survival and progression free survival were comparable in both groups. In the first year following ASCT, there was an elevated, but statistically insignificant non relapse mortality in the HIV lymphoma group, primarily from early bacterial infections. This data suggested that in the HAART era, HIV infection should not preclude lymphoma patients from under‐ going ASCT. The authors recommended conscientious infection prophylaxis and vigilant

lymphomas.

the time of ASCT predicts a more favorable result.

immune recovery surveillance shortly following ASCT.

**Figure 1.** Median CD4 count trends during apheresis and after ASCT. Krishnan A et al. Blood 2005; 105:874-878 Blood: Journal of the American Society of Hematology by American Society of Hematology. Copyright 2009 Repro‐ duced with permission of AMERICAN SOCIETY OF HEMATOLOGY (ASH) in the format Journal via Copyright Clearance Center.

The Italian cooperative group on AIDS and tumors (GIGAT) reported the long term results on 50 patients with HIV and relapsed or refractory lymphoma (Re A, et al, 2009). Similar to the City of Hope study, only patients with chemotherapy sensitive disease were selected to proceed with peripheral stem cell collection. Forty-six patients were already on HAART, two started at the time of study enrollment, and two at the time of stem cell mobilization. A minimum CD4 count of 100 cells/micro liter prior to initiating chemotherapy was a prerequisite. There were no eligibility criteria for viral load and therefore the viral loads at study entry ranged considerably. Thirteen patients withdrew before stem cell collection. Among these, two withdrawals were from early toxic deaths, one patient refusal, and the remaining ten patients had chemotherapy refractory disease. Eventually, twenty seven pa‐ tients underwent ASCT. Of these, seven temporarily suspended HAART, some for similar reasons to the City of Hope experience with mucositis, and others for hepatotoxicity. All pa‐ tients received BEAM (Carmustine/BCNU, Etoposide, Cytarabine and Melphalan) as the conditioning regimen. Three year progression free survival for the patients who proceeded to transplant was also similar to the City of Hope experience at 76.3%. Multivariate analysis of prognostic factors for survival showed that bone marrow involvement, performance sta‐ tus less than 2, and CD4 count below 100 cells/micro liter were significant. No significant HIV-associated infections were noted. In those patients on effective HAART therapy, the in‐ fectious risk was similar to patients without HIV who underwent ASCT. The high patient withdrawal rate before transplantation displays the obstacles in treating these aggressive lymphomas.

at 6 months, post-transplant follow up demonstrated that the underlying HIV disease did not deteriorate as a result of the transplant and the CD4 counts recovered to pre-transplant levels by one year in all patients. PFS and OS were 85%. The improved result compared to the French experience may be from selecting patients with less advanced disease and che‐

**Figure 1.** Median CD4 count trends during apheresis and after ASCT. Krishnan A et al. Blood 2005; 105:874-878 Blood: Journal of the American Society of Hematology by American Society of Hematology. Copyright 2009 Repro‐ duced with permission of AMERICAN SOCIETY OF HEMATOLOGY (ASH) in the format Journal via Copyright Clearance

The Italian cooperative group on AIDS and tumors (GIGAT) reported the long term results on 50 patients with HIV and relapsed or refractory lymphoma (Re A, et al, 2009). Similar to the City of Hope study, only patients with chemotherapy sensitive disease were selected to proceed with peripheral stem cell collection. Forty-six patients were already on HAART, two started at the time of study enrollment, and two at the time of stem cell mobilization. A minimum CD4 count of 100 cells/micro liter prior to initiating chemotherapy was a prerequisite. There were no eligibility criteria for viral load and therefore the viral loads at study entry ranged considerably. Thirteen patients withdrew before stem cell collection. Among these, two withdrawals were from early toxic deaths, one patient refusal, and the remaining ten patients had chemotherapy refractory disease. Eventually, twenty seven pa‐ tients underwent ASCT. Of these, seven temporarily suspended HAART, some for similar reasons to the City of Hope experience with mucositis, and others for hepatotoxicity. All pa‐ tients received BEAM (Carmustine/BCNU, Etoposide, Cytarabine and Melphalan) as the conditioning regimen. Three year progression free survival for the patients who proceeded to transplant was also similar to the City of Hope experience at 76.3%. Multivariate analysis of prognostic factors for survival showed that bone marrow involvement, performance sta‐ tus less than 2, and CD4 count below 100 cells/micro liter were significant. No significant HIV-associated infections were noted. In those patients on effective HAART therapy, the in‐ fectious risk was similar to patients without HIV who underwent ASCT. The high patient

motherapy sensitive disease.

60 Current Perspectives in HIV Infection

Center.

The European Group for Blood and Marrow Transplantation conducted a retrospective, multicentre registry-based analysis of sixty eight patients from twenty institutions since 1999 (Balsalobre P et al, 2009). There were fifty patients with NHL and eighteen patients with HL. At the time of ASCT, sixteen patients were in first complete remission (CR1); forty four patients were in CR more than 1, partial remission, or chemotherapy-sensitive relapse; and eight patients had chemotherapy resistant disease. Most patients were treated with a chemotherapy based conditioning regimen (BEAM and variants). The median CD4 count at transplantation was 162 cells/micro litter, and eighty percent of patients had an HIV viral load under 200/mL. All patients engrafted at a median of eleven days, save one. The inci‐ dence of non relapse mortality (NRM) was 4.4% and 7.5% at 3 and 12 months, respectively. Three patients died from bacterial infection, two died of HIV related complications, and one patient died of an unknown cause while in CR. At a median follow-up of 32 months, pro‐ gression free survival and overall survival were 56.5% and 61% at three years, respectively. On multivariate analysis, chemotherapy resistant disease and not attaining complete remis‐ sion predicted poorer progression free survival and overall survival. This data indicates again similar to the HIV negative transplant setting, disease control with chemotherapy at the time of ASCT predicts a more favorable result.

Two case control studies also demonstrated that HIV status does not impact ASCT out‐ comes for lymphoma. The European Group for Blood and Marrow Transplantation under‐ took a retrospective study of 106 patients (Diez-Martin et al, 2009) which included 53 HIVpositive lymphoma patients who underwent transplant with controls matched for histology, non-age adjusted IPI (International Prognostic Index), and disease status at transplant. There were 66 percent NHL and 34 percent HL patients. Both groups were similar, other than the higher percentage of males, mixed cellularity Hodgkin lymphoma and patients receiving granulocyte colony stimulating factor before engraftment, and a smaller fraction receiving total body irradiation based conditioning within the HIV lymphoma cohort. With median follow-up of 30 months, progression free survival was 61 percent for the HIV-lymphoma group and 56 percent for the control lymphoma group. Overall survival was 61.5 percent for HIV-positive patients and 70 percent for controls (p = NS). There was a trend towards delay in platelet engraftment after transplant in the HIV group. It is uncertain whether this result‐ ed from the more frequent granulocyte colony stimulating factor use in that cohort or to HAART therapy or to chronic HIV infection of the bone marrow. Incidence of relapse, over‐ all survival and progression free survival were comparable in both groups. In the first year following ASCT, there was an elevated, but statistically insignificant non relapse mortality in the HIV lymphoma group, primarily from early bacterial infections. This data suggested that in the HAART era, HIV infection should not preclude lymphoma patients from under‐ going ASCT. The authors recommended conscientious infection prophylaxis and vigilant immune recovery surveillance shortly following ASCT.

infections in the HIV-positive group, with three cases of cytomegalovirus viremia, one case of adenovirus viremia, and one case of varicella infection. Disease free survival and overall survival were not significantly different between the two groups. The two year disease free survival for the HIV-positive NHL group was 76 percent and 56 percent for the HIV-nega‐ tive group. The overall survival for both groups was also similar at 75 percent notwithstand‐

Hematopoietic Stem Cell Transplantation in HIV Infected Patients

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63

**Figure 3.** Probability of overall survival by HIV status. Krishnan A, Palmer J, Zaia J, et al. Vol. 16, (September 2010), pp. 1302-08. "Reprinted From: HIV Status Does Not Affect the Outcome of Autologous Stem Cell Transplantation (ASCT) for Non-Hodgkin Lymphoma (NHL) Biology of Blood and Marrow Transplantation 16:1302-1308 (2010), with permis‐

Causes of death in the HIV-positive cohort were mostly from relapsed lymphoma, and not infection. Disease status at the time of transplant was the only clear predictor of outcome.

This data from the European Group for Blood and Marrow Transplantation (Balsalobre et al, 2009) and the City of Hope experience (Krishnan, et al, 2010) revealed better progres‐ sion free survival rates in the HIV-positive lymphoma patients compared to their HIV-neg‐ ative counterparts. This improved early outcome is interesting. Perhaps incorporating HAART in the regimen improves the result. Maybe transplant with high dose chemothera‐ py resets the clock on the immunologic effects of HIV, either by depleting the HIV reser‐ voir or by its alterations on the T cell reconstitution. Inherent genetic variability may also play a part. Homozygosity for the 32-bp CCR5 allele CCR-∆ 32 has been shown to confer resistance to HIV infection (Liu R et al, 1996). This same deletion may also offer defense against lymphoma development in HIV patients (Dean M et al, 1999). A trial in the Unit‐ ed States of ASCT for HIV lymphoma via the Bone Marrow Transplant Clinical Trials Net‐ work will prospectively analyze the genotypes and the CCR5 mutation to find its association with disease free survival. Correlative studies will also assess the pre and post-

ing a higher proportion of poor risk HIV positive NHL patients.

This single-institution series corroborates the European data.

sion from Elsevier"

transplant HIV viral reservoir.

**Figure 2.** Survival according to HIV infection status: positive versus negative. Diez-Martin JL et al. Blood 2009; 113:6011-6014 Blood: Journal of the American Society of Hematology by American Society of Hematology. Copyright 2009 Reproduced with permission of AMERICAN SOCIETY OF HEMATOLOGY (ASH) in the format Journal via Copyright Clearance Center

City of Hope undertook a retrospective matched case-control study (Krishnan, et al, 2010) to study long-term outcome in HIV positive NHL patients (cases) and HIV negative NHL pa‐ tients (controls). Twenty nine patients with HIV positive NHL were matched with HIV neg‐ ative NHL controls with respect to sex, time to ASCT, year of transplant, histology, age, disease status, number of prior regimens, and conditioning regimen. A higher ratio of HIV positive NHL patients had high grade disease versus the HIV negative NHL controls. There were mostly male patients in both groups. The median CD4 count at study entry was 153.5, and the viral load was 6500. All patients in the HIV cohort were on HAART at the time of transplant; however thirteen patients had to interrupt treatment. The median follow-up for HIV-positive NHL patients was 62.4 months, and 48.4 months for the HIV-negative NHL controls. The median time to neutrophil engraftment was comparable for both groups. Non relapse mortality was also comparable for the two groups. Infectious complications did dif‐ fer between the two groups, with more opportunistic infections occurring in the HIV-posi‐ tive cohort, however this did not affect survival. There were more opportunistic viral infections in the HIV-positive group, with three cases of cytomegalovirus viremia, one case of adenovirus viremia, and one case of varicella infection. Disease free survival and overall survival were not significantly different between the two groups. The two year disease free survival for the HIV-positive NHL group was 76 percent and 56 percent for the HIV-nega‐ tive group. The overall survival for both groups was also similar at 75 percent notwithstand‐ ing a higher proportion of poor risk HIV positive NHL patients.

**Figure 3.** Probability of overall survival by HIV status. Krishnan A, Palmer J, Zaia J, et al. Vol. 16, (September 2010), pp. 1302-08. "Reprinted From: HIV Status Does Not Affect the Outcome of Autologous Stem Cell Transplantation (ASCT) for Non-Hodgkin Lymphoma (NHL) Biology of Blood and Marrow Transplantation 16:1302-1308 (2010), with permis‐ sion from Elsevier"

Causes of death in the HIV-positive cohort were mostly from relapsed lymphoma, and not infection. Disease status at the time of transplant was the only clear predictor of outcome. This single-institution series corroborates the European data.

**Figure 2.** Survival according to HIV infection status: positive versus negative. Diez-Martin JL et al. Blood 2009; 113:6011-6014 Blood: Journal of the American Society of Hematology by American Society of Hematology. Copyright 2009 Reproduced with permission of AMERICAN SOCIETY OF HEMATOLOGY (ASH) in the format Journal via Copyright

City of Hope undertook a retrospective matched case-control study (Krishnan, et al, 2010) to study long-term outcome in HIV positive NHL patients (cases) and HIV negative NHL pa‐ tients (controls). Twenty nine patients with HIV positive NHL were matched with HIV neg‐ ative NHL controls with respect to sex, time to ASCT, year of transplant, histology, age, disease status, number of prior regimens, and conditioning regimen. A higher ratio of HIV positive NHL patients had high grade disease versus the HIV negative NHL controls. There were mostly male patients in both groups. The median CD4 count at study entry was 153.5, and the viral load was 6500. All patients in the HIV cohort were on HAART at the time of transplant; however thirteen patients had to interrupt treatment. The median follow-up for HIV-positive NHL patients was 62.4 months, and 48.4 months for the HIV-negative NHL controls. The median time to neutrophil engraftment was comparable for both groups. Non relapse mortality was also comparable for the two groups. Infectious complications did dif‐ fer between the two groups, with more opportunistic infections occurring in the HIV-posi‐ tive cohort, however this did not affect survival. There were more opportunistic viral

Clearance Center

62 Current Perspectives in HIV Infection

This data from the European Group for Blood and Marrow Transplantation (Balsalobre et al, 2009) and the City of Hope experience (Krishnan, et al, 2010) revealed better progres‐ sion free survival rates in the HIV-positive lymphoma patients compared to their HIV-neg‐ ative counterparts. This improved early outcome is interesting. Perhaps incorporating HAART in the regimen improves the result. Maybe transplant with high dose chemothera‐ py resets the clock on the immunologic effects of HIV, either by depleting the HIV reser‐ voir or by its alterations on the T cell reconstitution. Inherent genetic variability may also play a part. Homozygosity for the 32-bp CCR5 allele CCR-∆ 32 has been shown to confer resistance to HIV infection (Liu R et al, 1996). This same deletion may also offer defense against lymphoma development in HIV patients (Dean M et al, 1999). A trial in the Unit‐ ed States of ASCT for HIV lymphoma via the Bone Marrow Transplant Clinical Trials Net‐ work will prospectively analyze the genotypes and the CCR5 mutation to find its association with disease free survival. Correlative studies will also assess the pre and posttransplant HIV viral reservoir.

#### **2.2. Immune recovery post transplant**

An Italian study (Simonelli et al, 2010) prospectively evaluated 33 lymphoma patients of whom 24 were HIV positive and nine were HIV-negative. All patients had relapsed or re‐ fractory disease and both groups were given similar high dose chemotherapy and ASCT protocols. The study compared the immunological baseline features in the two groups. The study showed that front line chemotherapy resulted in immunodepression in the general population, which qualitatively differs from that observed in HIV-infected patients. HIVpositive patients had higher CD8+ T cell counts and inverted ratios of CD4+ cells to CD8+ cells than HIV-negative patients. There were no significant differences in the CD4+ cell com‐ partment and thymic reservoir, between the groups. The authors attributed this finding to good control of HIV-RNA levels from ongoing HAART therapy. The initial differences in the dynamics of immune recovery between the populations also diminished with longer fol‐ low-up. Specifically, the CD8+ subpopulation, together with CD56+ NK cells quickly recov‐ ered in both groups of patients, leading, to a reversal of the ratio of CD4+ cells to CD8+ cells in the HIV-negative patients for up to two years following transplantation. In the HIV-in‐ fected population, high dose chemotherapy produced a different immune incompetence compared with conventional chemotherapy, which primarily impacted the CD4+ T cell sub‐ set without significantly affecting the CD4/CD8 ratio. In the first three months post ASCT, significantly more infectious episodes occurred in the HIV-positive group. The authors dem‐ onstrated that HIV-positive patients with early post-transplant infections had significantly lower CD4+ T cell counts during the third month post ASCT, compared with HIV-negative patients without infections. There was no difference in the frequency of infection or the dy‐ namics of CD4+ T cell reconstitution beyond three months post ASCT. Overall, the study showed that high dose chemotherapy and ASCT in HIV-infected lymphoma patients does not worsen initial immune impairment or enhance viral replication or peripheral HIV reser‐ voir in the long term. The temporary elevation in the incidence of early infectious events in the HIV-positive group may be related to an arrest in the CD4+ T cell count increment dur‐ ing the first three months post ASCT. There were no significant changes in the HIV DNA levels during the follow-up period, with values at 24 months significantly lower than those at baseline.

when compared with patients with lower levels (HR, 8.33, 95% CI 0.99 - 70.06, p=0.05). At the time of publication, of the 22 patients, 14 (63.6%) were still alive, of which 13 were in remission and one relapsed; 8 (36.5%) died, of which 6 deaths were from relapsed lympho‐ ma and 2 were from opportunistic infections. Of note, baseline HIV DNA levels were signifi‐ cantly different between alive and deceased patients. Results from this study established HIV DNA as an valuable additional tool to optimize and tailor therapy, and also predict

Hematopoietic Stem Cell Transplantation in HIV Infected Patients

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65

**Figure 4.** Kaplan–Meier curve showing survival according to baseline HIV DNA levels (*n* = 19) Bortolin MT, Zanussi S, Talamini R, et al. *AIDS Research and Human Retroviruses*. Vol. 26, No. 2, (2010), pp. 245-251. " The publisher for this

Allogeneic transplantation refers to hematopoietic stem cells which come from an HLA matched donor. Allogeneic transplants typically have a higher morbidity and mortality than autologous transplants mostly due to infection or graft versus host disease. The 'graft' refers to the transplanted hematopoietic stem cells transplanted from the donor (sibling or match‐ ed unrelated donor) and the 'host' refers to the patient. In graft versus host disease, the do‐ nor's immune cells attack the recipient's organs. Virtually any organ can be affected, but frequently affected organs include the skin, liver and gut. Graft versus host disease (GVHD) is a major impediment to the success of bone marrow transplantation. Treatment and pre‐ vention of GVHD includes immunosuppressive medications and sometimes steroids. The incidence of chronic graft versus host disease (that occurring after 100 days post transplant)

treatment outcome in these patients.

copyrighted material is Mary Ann Liebert, Inc. publishers."

**3. Allogeneic transplantation**

It is well-recognized that HIV persists at low levels in peripheral blood mononuclear cells, mostly in infected resting CD4+ T cells which constitute a stable reservoir for HIV, even when viral replication is well controlled with antiretroviral therapy. Analysis of HIV-1 DNA (HIV DNA) (Koelsch, KK et al, 2008) in peripheral blood mononuclear cells is therefore an accessible virological marker for estimating HIV infection. Bortolin's study of 22 patients with HIV associated relapsed or refractory lymphomas treated with salvage high dose che‐ motherapy followed by ASCT looked at the kinetics of the predictive value of HIV DNA. HIV DNA was measured by real-time PCR in the peripheral blood mononuclear cells. At baseline, HIV DNA was found to be associated with HIV-1 RNA (HIV RNA), but not with CD4 counts. HIV RNA load was under control throughout follow-up, while HIV DNA lev‐ els were nearly always detectable. The overall survival analysis demonstrated that patients with higher HIV DNA levels at baseline had a higher and nearly significant risk of death when compared with patients with lower levels (HR, 8.33, 95% CI 0.99 - 70.06, p=0.05). At the time of publication, of the 22 patients, 14 (63.6%) were still alive, of which 13 were in remission and one relapsed; 8 (36.5%) died, of which 6 deaths were from relapsed lympho‐ ma and 2 were from opportunistic infections. Of note, baseline HIV DNA levels were signifi‐ cantly different between alive and deceased patients. Results from this study established HIV DNA as an valuable additional tool to optimize and tailor therapy, and also predict treatment outcome in these patients.

**Figure 4.** Kaplan–Meier curve showing survival according to baseline HIV DNA levels (*n* = 19) Bortolin MT, Zanussi S, Talamini R, et al. *AIDS Research and Human Retroviruses*. Vol. 26, No. 2, (2010), pp. 245-251. " The publisher for this copyrighted material is Mary Ann Liebert, Inc. publishers."

### **3. Allogeneic transplantation**

**2.2. Immune recovery post transplant**

64 Current Perspectives in HIV Infection

at baseline.

An Italian study (Simonelli et al, 2010) prospectively evaluated 33 lymphoma patients of whom 24 were HIV positive and nine were HIV-negative. All patients had relapsed or re‐ fractory disease and both groups were given similar high dose chemotherapy and ASCT protocols. The study compared the immunological baseline features in the two groups. The study showed that front line chemotherapy resulted in immunodepression in the general population, which qualitatively differs from that observed in HIV-infected patients. HIVpositive patients had higher CD8+ T cell counts and inverted ratios of CD4+ cells to CD8+ cells than HIV-negative patients. There were no significant differences in the CD4+ cell com‐ partment and thymic reservoir, between the groups. The authors attributed this finding to good control of HIV-RNA levels from ongoing HAART therapy. The initial differences in the dynamics of immune recovery between the populations also diminished with longer fol‐ low-up. Specifically, the CD8+ subpopulation, together with CD56+ NK cells quickly recov‐ ered in both groups of patients, leading, to a reversal of the ratio of CD4+ cells to CD8+ cells in the HIV-negative patients for up to two years following transplantation. In the HIV-in‐ fected population, high dose chemotherapy produced a different immune incompetence compared with conventional chemotherapy, which primarily impacted the CD4+ T cell sub‐ set without significantly affecting the CD4/CD8 ratio. In the first three months post ASCT, significantly more infectious episodes occurred in the HIV-positive group. The authors dem‐ onstrated that HIV-positive patients with early post-transplant infections had significantly lower CD4+ T cell counts during the third month post ASCT, compared with HIV-negative patients without infections. There was no difference in the frequency of infection or the dy‐ namics of CD4+ T cell reconstitution beyond three months post ASCT. Overall, the study showed that high dose chemotherapy and ASCT in HIV-infected lymphoma patients does not worsen initial immune impairment or enhance viral replication or peripheral HIV reser‐ voir in the long term. The temporary elevation in the incidence of early infectious events in the HIV-positive group may be related to an arrest in the CD4+ T cell count increment dur‐ ing the first three months post ASCT. There were no significant changes in the HIV DNA levels during the follow-up period, with values at 24 months significantly lower than those

It is well-recognized that HIV persists at low levels in peripheral blood mononuclear cells, mostly in infected resting CD4+ T cells which constitute a stable reservoir for HIV, even when viral replication is well controlled with antiretroviral therapy. Analysis of HIV-1 DNA (HIV DNA) (Koelsch, KK et al, 2008) in peripheral blood mononuclear cells is therefore an accessible virological marker for estimating HIV infection. Bortolin's study of 22 patients with HIV associated relapsed or refractory lymphomas treated with salvage high dose che‐ motherapy followed by ASCT looked at the kinetics of the predictive value of HIV DNA. HIV DNA was measured by real-time PCR in the peripheral blood mononuclear cells. At baseline, HIV DNA was found to be associated with HIV-1 RNA (HIV RNA), but not with CD4 counts. HIV RNA load was under control throughout follow-up, while HIV DNA lev‐ els were nearly always detectable. The overall survival analysis demonstrated that patients with higher HIV DNA levels at baseline had a higher and nearly significant risk of death

Allogeneic transplantation refers to hematopoietic stem cells which come from an HLA matched donor. Allogeneic transplants typically have a higher morbidity and mortality than autologous transplants mostly due to infection or graft versus host disease. The 'graft' refers to the transplanted hematopoietic stem cells transplanted from the donor (sibling or match‐ ed unrelated donor) and the 'host' refers to the patient. In graft versus host disease, the do‐ nor's immune cells attack the recipient's organs. Virtually any organ can be affected, but frequently affected organs include the skin, liver and gut. Graft versus host disease (GVHD) is a major impediment to the success of bone marrow transplantation. Treatment and pre‐ vention of GVHD includes immunosuppressive medications and sometimes steroids. The incidence of chronic graft versus host disease (that occurring after 100 days post transplant) is up to 80% in recipients of allogeneic peripheral blood stem cells. On the other hand, allo‐ geneic transplant has the advantage of lower rates of relapse due to the 'clean graft' as well as the immunologic effects of the donor graft, the so called graft versus tumor effect. These immunologic effects could be potentially even more beneficial in the treatment of HIV infec‐ tion if the attendant risks of the procedure in the HIV infected patient could be overcome.

phylaxis. HAART was continued with adjustments to prevent drug interactions. The HIV RNA remained undetectable and no HIV associated infections were noted. The first patient died of GVHD. The second patient remained alive at the time of publication, more than 180 days following transplant. It is notable that both patients' donor cells expressed wild-type CCR5 co receptor, and not the CCR∆32 allele which is linked with resistance to HIV infec‐ tion. Reconstitution of CD4+ and CD8+ subsets was in accordance with other nonmyeloabla‐ tive transplants. New HIV-1 specific CD8+ T cell responses were produced after transplant. The gradual loss of detectable proviral DNA in the patient who achieved full donor chimer‐ ism suggests that the reservoir of latently infected lymphocytes died out after transplanta‐

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67

Larger studies are needed to determine if the benefits of allogeneic transplant can be pre‐ served in the myeloablative setting with its accompanying elevated morbidity and mortali‐ ty. The largest series was a retrospective study of thirty patients with various hematologic malignancies transplanted between 1987 and 2003 from the European Group for Blood and Marrow Transplantation (Gupta V, et al, 2007). Treatment related mortality at 100 days was 46 percent. There was a striking difference in survival in patients transplanted after 1996 af‐ ter availability of HAART. Prior to 1996, only two out of twenty two patients survived, but after 1996, four out of eight patients survived. This study revealed that reduction of trans‐ plant related mortality and control of HIV infection together are imperative in carrying out

Allogeneic hematopoietic stem cell transplantation has the exciting prospect of controlling the HIV infection. HIV-1 enters host cells by binding to a CD4 receptor and then interacting with either CCR5 or the CXC chemokine receptor (CXCR4). Homozygosity for a 32-bp dele‐ tion (delta 32) in the CCR5 allele confers natural resistance to infection with CCR5 tropic HIV strains (R5 HIV) because of the lack of CCR5 cell-surface expression. (Dean M et al,

A case report from Germany by Hutter et al (2009) published in the *New England Journal of Medicine* described a 40 year old patient with a ten year history of HIV who underwent allo‐ geneic stem cell transplantation (SCT) in February 2007 for relapsed acute myelogenous leu‐ kemia from an HLA-matched unrelated donor who was homozygous for the CCR5 delta 32 allele. HAART was given until the day prior to transplantation. The patient relapsed at day 332 and was treated with a second transplant from the same donor after reinduction therapy with cytarabine and gemtuzumab along with single dose total body irradiation. There was no viral rebound twenty months after transplantation and discontinuation of antiretroviral therapy. Tissue sites, such as the intestines, serve as reservoirs, and were looked at to detect the HIV virus despite the absence of viremia. In this patient, the rectal biopsy performed at 159 days after transplant did reveal that CCR5-producing macrophages were still present in the intestinal mucosa, which demonstrated they had not yet been replaced by the new im‐

tion. This study alluded to the dual benefits of allogeneic transplantation.

successful allogeneic transplants in this population.

1996 as cited in Allers et al, 2011)

**4. Allogeneic transplantation for HIV infection**

Allogeneic stem cell transplantation (alloSCT) is more difficult than ASCT in HIV infected individuals due to the need for chronic immunosuppression in an already immunosup‐ pressed individual. Solid organ transplantation set the stage for allogeneic stem cell trans‐ plantation in that solid organ transplant patients also need chronic immunosuppression. There have been several published reports of solid-organ transplantation in HIV positive pa‐ tients who are receiving HAART, which demonstrated that, in most cases, HIV infection does not affect the outcome of transplantation. Drug interactions were handled by requisite dose adjustments. The underlying HIV infection was controlled provided patients remained on antiretroviral therapy. (Ragni MV et al, 1999; Prachalias AA et al, 2001; Kuo PC, 2001; Gow PJ & Mutimer D, 2001 as cited in Halpern et al, 2002). Some solid organ transplant cen‐ ters regard HIV patients akin to other high risk patients, for example, diabetics, or the elder‐ ly (Persad G et al, 2008).

The literature on allogeneic transplantation in HIV positive patients is considerably more limited than ASCT. Experience with ASCT in HIV-positive patients has shown that HIV in‐ fection did not impede engraftment provided myelosuppressive medications like azidothy‐ midine were avoided. Therefore, in the allogeneic field, comparable engraftment times were expected. Allogeneic transplantation data indicates the rate of immune reconstitution after transplant is related to the type of conditioning regimen, HLA compatibility of the donor and host, and the occurrence of GVHD. In an allogeneic transplant with an HIV negative recipient, T lymphocyte recovery occurs by thirty days following transplant, although ini‐ tially with primarily CD8+ T cells (Keever, CA et al, 1989). CD4+ cell recovery often takes up to six months.

Early reports of allogeneic transplant were in the pre-HAART period. Holland et al (1989) at Johns Hopkins published a case of a forty one year old male with HIV lymphoma who re‐ ceived a conditioning regimen consisting of total body irradiation and Cyclophosphamide followed by allogeneic bone marrow transplantation. Prior to the transplant, he was given high dose azidothymidine and following the transplant, he was given a lower dose. There was no significant regimen-related toxicity, and he engrafted at day seventeen, but there‐ after died of lymphoma at day forty seven. At autopsy, no evidence of HIV, either by cul‐ ture, or PCR was found in tissue specimens. Although the result was poor, this early report demonstrated the achievability of the procedure and raised the intriguing question, could allogeneic transplant be a route to treat HIV infection.

Woolfrey et al (2008) published a series of two HIV-positive patients who received nonmye‐ loablative transplants at the Fred Hutchinson Research Center. They received conditioning with Fludarabine and 200 cGy total body irradiation. They got HLA-matched peripheral blood stem cells, one from a sibling and the other from an unrelated donor. Post-transplan‐ tation cyclosporine and mycophenolatemofetil were given for graft versus host disease pro‐ phylaxis. HAART was continued with adjustments to prevent drug interactions. The HIV RNA remained undetectable and no HIV associated infections were noted. The first patient died of GVHD. The second patient remained alive at the time of publication, more than 180 days following transplant. It is notable that both patients' donor cells expressed wild-type CCR5 co receptor, and not the CCR∆32 allele which is linked with resistance to HIV infec‐ tion. Reconstitution of CD4+ and CD8+ subsets was in accordance with other nonmyeloabla‐ tive transplants. New HIV-1 specific CD8+ T cell responses were produced after transplant. The gradual loss of detectable proviral DNA in the patient who achieved full donor chimer‐ ism suggests that the reservoir of latently infected lymphocytes died out after transplanta‐ tion. This study alluded to the dual benefits of allogeneic transplantation.

Larger studies are needed to determine if the benefits of allogeneic transplant can be pre‐ served in the myeloablative setting with its accompanying elevated morbidity and mortali‐ ty. The largest series was a retrospective study of thirty patients with various hematologic malignancies transplanted between 1987 and 2003 from the European Group for Blood and Marrow Transplantation (Gupta V, et al, 2007). Treatment related mortality at 100 days was 46 percent. There was a striking difference in survival in patients transplanted after 1996 af‐ ter availability of HAART. Prior to 1996, only two out of twenty two patients survived, but after 1996, four out of eight patients survived. This study revealed that reduction of trans‐ plant related mortality and control of HIV infection together are imperative in carrying out successful allogeneic transplants in this population.

### **4. Allogeneic transplantation for HIV infection**

is up to 80% in recipients of allogeneic peripheral blood stem cells. On the other hand, allo‐ geneic transplant has the advantage of lower rates of relapse due to the 'clean graft' as well as the immunologic effects of the donor graft, the so called graft versus tumor effect. These immunologic effects could be potentially even more beneficial in the treatment of HIV infec‐ tion if the attendant risks of the procedure in the HIV infected patient could be overcome. Allogeneic stem cell transplantation (alloSCT) is more difficult than ASCT in HIV infected individuals due to the need for chronic immunosuppression in an already immunosup‐ pressed individual. Solid organ transplantation set the stage for allogeneic stem cell trans‐ plantation in that solid organ transplant patients also need chronic immunosuppression. There have been several published reports of solid-organ transplantation in HIV positive pa‐ tients who are receiving HAART, which demonstrated that, in most cases, HIV infection does not affect the outcome of transplantation. Drug interactions were handled by requisite dose adjustments. The underlying HIV infection was controlled provided patients remained on antiretroviral therapy. (Ragni MV et al, 1999; Prachalias AA et al, 2001; Kuo PC, 2001; Gow PJ & Mutimer D, 2001 as cited in Halpern et al, 2002). Some solid organ transplant cen‐ ters regard HIV patients akin to other high risk patients, for example, diabetics, or the elder‐

The literature on allogeneic transplantation in HIV positive patients is considerably more limited than ASCT. Experience with ASCT in HIV-positive patients has shown that HIV in‐ fection did not impede engraftment provided myelosuppressive medications like azidothy‐ midine were avoided. Therefore, in the allogeneic field, comparable engraftment times were expected. Allogeneic transplantation data indicates the rate of immune reconstitution after transplant is related to the type of conditioning regimen, HLA compatibility of the donor and host, and the occurrence of GVHD. In an allogeneic transplant with an HIV negative recipient, T lymphocyte recovery occurs by thirty days following transplant, although ini‐ tially with primarily CD8+ T cells (Keever, CA et al, 1989). CD4+ cell recovery often takes up

Early reports of allogeneic transplant were in the pre-HAART period. Holland et al (1989) at Johns Hopkins published a case of a forty one year old male with HIV lymphoma who re‐ ceived a conditioning regimen consisting of total body irradiation and Cyclophosphamide followed by allogeneic bone marrow transplantation. Prior to the transplant, he was given high dose azidothymidine and following the transplant, he was given a lower dose. There was no significant regimen-related toxicity, and he engrafted at day seventeen, but there‐ after died of lymphoma at day forty seven. At autopsy, no evidence of HIV, either by cul‐ ture, or PCR was found in tissue specimens. Although the result was poor, this early report demonstrated the achievability of the procedure and raised the intriguing question, could

Woolfrey et al (2008) published a series of two HIV-positive patients who received nonmye‐ loablative transplants at the Fred Hutchinson Research Center. They received conditioning with Fludarabine and 200 cGy total body irradiation. They got HLA-matched peripheral blood stem cells, one from a sibling and the other from an unrelated donor. Post-transplan‐ tation cyclosporine and mycophenolatemofetil were given for graft versus host disease pro‐

allogeneic transplant be a route to treat HIV infection.

ly (Persad G et al, 2008).

66 Current Perspectives in HIV Infection

to six months.

Allogeneic hematopoietic stem cell transplantation has the exciting prospect of controlling the HIV infection. HIV-1 enters host cells by binding to a CD4 receptor and then interacting with either CCR5 or the CXC chemokine receptor (CXCR4). Homozygosity for a 32-bp dele‐ tion (delta 32) in the CCR5 allele confers natural resistance to infection with CCR5 tropic HIV strains (R5 HIV) because of the lack of CCR5 cell-surface expression. (Dean M et al, 1996 as cited in Allers et al, 2011)

A case report from Germany by Hutter et al (2009) published in the *New England Journal of Medicine* described a 40 year old patient with a ten year history of HIV who underwent allo‐ geneic stem cell transplantation (SCT) in February 2007 for relapsed acute myelogenous leu‐ kemia from an HLA-matched unrelated donor who was homozygous for the CCR5 delta 32 allele. HAART was given until the day prior to transplantation. The patient relapsed at day 332 and was treated with a second transplant from the same donor after reinduction therapy with cytarabine and gemtuzumab along with single dose total body irradiation. There was no viral rebound twenty months after transplantation and discontinuation of antiretroviral therapy. Tissue sites, such as the intestines, serve as reservoirs, and were looked at to detect the HIV virus despite the absence of viremia. In this patient, the rectal biopsy performed at 159 days after transplant did reveal that CCR5-producing macrophages were still present in the intestinal mucosa, which demonstrated they had not yet been replaced by the new im‐ mune system. Although these long-lasting cells from the host can be viral reservoirs even after transplantation, HIV-1 DNA was not found in his rectal mucosa. Immunologic studies showed a loss of anti-HIV virus specific interferon gamma producing T cells. This indicated that HIV antigenic stimulation was not present post transplant. His viral load continued to be undetectable despite the presence of non-CCR5 tropic X4 virus variants. After nearly two years of follow-up, the patient's CD4 cell count normalized with all cells exhibiting the ho‐ mozygous CCR5-deleted gene. This observation is notable because homozygosity for CCR5 delta 32 deletion is related to high but not complete resistance to HIV-1.

evaluation of leukoencephalopathy. This study also looked at 10 HIV negative stem cell transplant controls and 15 HIV negative healthy controls, 5 of whom underwent colonosco‐ py as a cancer preventive examination. It was found that CD4+ T cell reconstitution in‐ creased continuously and, after two years reached levels within the normal range of age matched healthy patients. There was 100 percent donor chimerism, which was shown by ab‐ sent CCR5 expression. Among the CD4+ T cells, there were more activated effector memory cells and less naïve cells when compared with healthy controls. CD4+ T cell reconstitution also occurred in the gut mucosa of the reported patient, similar to the stem cell transplant control patients, with cells exclusively derived from the donor hematopoietic system. There was more than a twofold increase in mucosal CD4+ T cells in the transplant patients com‐ pared to healthy controls, which demonstrates that conditioning and transplant elicits the

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**Figure 6.** The mucosal immune system has been efficiently repopulated with donor-derived CD4+ T cells. (A) Immuno‐ histochemical quantification of CD4+ T cells in colon tissue of the CR5Δ32/Δ32 SCT patient, SCT control patients (27 ± 9 months after transplantation), and healthy control patients. The horizontal lines denote the median values of each group. Allers K, Hütter G, Hofmann J, et al. *Blood.* Vol. 117, No. 10, (March 2011), pp. 2790-2799. Blood: journal of the American Society of Hematology by American Society of Hematology. Copyright 2009 Reproduced with permission of

HIV RNA and DNA were not detected in the peripheral blood or biopsy specimens ob‐ tained from various tissues. These biopsies revealed that tissue macrophages were ultimate‐ ly replaced by donor-derived macrophages without CCR5 expression (Parker and Sereti, 2011). The T cells of the reported patient do not express normal levels of CXCR4 and appear vulnerable to X4-tropic HIV. HIV specific antibodies declined over time, with only envelope

The study suggests that CCR5∆32/∆32 SCT has probably led to a cure of HIV infection in this patient. However it remains difficult to conclusively demonstrate eradication of HIV and its latent reservoirs, and the chance of resurgence of lingering X4 strains which survived the chemotherapy and radiation, leading to X4 HIV rebound still exists. Host-originating

AMERICAN SOCIETY OF HEMATOLOGY (ASH) in the format Journal via Copyright Clearance Center

antibodies being detectable at the time of publication.

enrichment of HIV target cells in the gut mucosal immune system.

**Figure 5.** Clinical Course and HIV-1 Viremia. Hütter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. *The New England Journal of Medicine,* Vol. 360, No. 7, (February 2009) pp. 692-8. Permission granted. Copyright MMS

Allers et al (2011) published an article involving the same patient with extended follow-up, which reveals that he had remained off HAART and had no evidence of HIV disease for 45 months after the transplant. During his treatment course, he underwent multiple colonos‐ copies with biopsies to rule out GVHD, in addition to a liver biopsy and brain biopsy for evaluation of leukoencephalopathy. This study also looked at 10 HIV negative stem cell transplant controls and 15 HIV negative healthy controls, 5 of whom underwent colonosco‐ py as a cancer preventive examination. It was found that CD4+ T cell reconstitution in‐ creased continuously and, after two years reached levels within the normal range of age matched healthy patients. There was 100 percent donor chimerism, which was shown by ab‐ sent CCR5 expression. Among the CD4+ T cells, there were more activated effector memory cells and less naïve cells when compared with healthy controls. CD4+ T cell reconstitution also occurred in the gut mucosa of the reported patient, similar to the stem cell transplant control patients, with cells exclusively derived from the donor hematopoietic system. There was more than a twofold increase in mucosal CD4+ T cells in the transplant patients com‐ pared to healthy controls, which demonstrates that conditioning and transplant elicits the enrichment of HIV target cells in the gut mucosal immune system.

mune system. Although these long-lasting cells from the host can be viral reservoirs even after transplantation, HIV-1 DNA was not found in his rectal mucosa. Immunologic studies showed a loss of anti-HIV virus specific interferon gamma producing T cells. This indicated that HIV antigenic stimulation was not present post transplant. His viral load continued to be undetectable despite the presence of non-CCR5 tropic X4 virus variants. After nearly two years of follow-up, the patient's CD4 cell count normalized with all cells exhibiting the ho‐ mozygous CCR5-deleted gene. This observation is notable because homozygosity for CCR5

**Figure 5.** Clinical Course and HIV-1 Viremia. Hütter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. *The New England Journal of Medicine,* Vol. 360, No. 7, (February 2009) pp.

Allers et al (2011) published an article involving the same patient with extended follow-up, which reveals that he had remained off HAART and had no evidence of HIV disease for 45 months after the transplant. During his treatment course, he underwent multiple colonos‐ copies with biopsies to rule out GVHD, in addition to a liver biopsy and brain biopsy for

692-8. Permission granted. Copyright MMS

delta 32 deletion is related to high but not complete resistance to HIV-1.

68 Current Perspectives in HIV Infection

**Figure 6.** The mucosal immune system has been efficiently repopulated with donor-derived CD4+ T cells. (A) Immuno‐ histochemical quantification of CD4+ T cells in colon tissue of the CR5Δ32/Δ32 SCT patient, SCT control patients (27 ± 9 months after transplantation), and healthy control patients. The horizontal lines denote the median values of each group. Allers K, Hütter G, Hofmann J, et al. *Blood.* Vol. 117, No. 10, (March 2011), pp. 2790-2799. Blood: journal of the American Society of Hematology by American Society of Hematology. Copyright 2009 Reproduced with permission of AMERICAN SOCIETY OF HEMATOLOGY (ASH) in the format Journal via Copyright Clearance Center

HIV RNA and DNA were not detected in the peripheral blood or biopsy specimens ob‐ tained from various tissues. These biopsies revealed that tissue macrophages were ultimate‐ ly replaced by donor-derived macrophages without CCR5 expression (Parker and Sereti, 2011). The T cells of the reported patient do not express normal levels of CXCR4 and appear vulnerable to X4-tropic HIV. HIV specific antibodies declined over time, with only envelope antibodies being detectable at the time of publication.

The study suggests that CCR5∆32/∆32 SCT has probably led to a cure of HIV infection in this patient. However it remains difficult to conclusively demonstrate eradication of HIV and its latent reservoirs, and the chance of resurgence of lingering X4 strains which survived the chemotherapy and radiation, leading to X4 HIV rebound still exists. Host-originating CD4+ T cells appear to be totally removed from the immune system; however tissue macro‐ phages are practically resistant to conditioning and less susceptible to the cytopathic effects of HIV infection, making them resilient viral reservoirs (Swingler S et al, 2007). One of the most promising findings of this report was the demonstration that later in the course of im‐ mune reconstitution, host-originating macrophages became undetectable in the GI mucosa by both phenotypic and genotypic analysis. These findings suggest that the replacement of host tissue cells with donor derived cells has reduced the size of the viral reservoir during the course of the immune reconstitution, which consequently had reduced the risk of HIV rebound over time.

tients with HIV-related lymphomas. Similar to well controlled diabetes, well controlled HIV infection does not significantly increase the risk of infections following ASCT if a program of adequate surveillance and prophylaxis is used. Allogeneic stem cell transplantation re‐ mains a more difficult task, is still in its infancy, and lacks larger studies. The Hutter and Allers experience of allogeneic SCT with a CCR5 negative donor has given a name and face to the cure of HIV. The task of finding more feasible options for the enormousglobal popula‐

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[1] Allers, K., Hütter, G., Hofmann, J., et al., & (2011, . (2011). Evidence for the cure of HIV infection by CCR5 (Delta) 32 (Delta) 32 stem cell transplantation.Blood. March

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[3] Biggar, R., Jaffe, E., Goedert, J., et al. (2006). Hodgkin Lymphoma and immunodefi‐ ciency in persons with HIV/AIDS. BloodDecember 2006, , 108(12), 3786-3791.

[4] Bortolin, M. T., Zanussi, S., Talamini, R., et al. (2010). Predictive value of HIV Type 1 DNA levels on overall survival in HIV-related lymphoma patients treated with highdose chemotherapy (HDC) plus autologous stem cell transplantation (ASCT). *AIDS*

[5] Boue, F., Gabarre, J., Gisselbrecht, C., et al. (2006). Phase II trial of CHOP Plus Rituxi‐ mab in Patients With HIV\_Associated Non-Hodgkin's Lymphoma. Journal of Clini‐

[6] Dean, M., Jacobson, L. P., Mc Farlane, G., et al. (1999). Reduced risk of AIDS lympho‐ ma in individuals heterozygous for the CCR5-DELTA32 mutation. Cancer Research‐

[7] Díez-Martín, J. L., Balsalobre, P., Re, A., et al. (2009). Comparable survival between

gous peripheral blood stem cell transplantation. *Blood*. 113. June 2009), (23),

non-Hodgkin and Hodgkin lymphoma patients undergoing autolo‐

tion living with HIV remains.

City of Hope National Medical Center, Duarte, USA

2011), , 117(10), 2790-2799.

2009), , 27(13), 2192-2198.

August 1999), , 3561-2564.

and HIV-

HIV+

6011-6014.

*Research and Human Retroviruses*, 26(2), 245-251.

cal Oncology.September 2006) , 24(25), 4123-4128.

**Author details**

Nitya Nathwani

**References**

### **5. Gene therapy and the future**

Gooley et al (2010) reported impressive decreases in allogeneic transplantation-related mor‐ tality. Nevertheless, the risk of allogeneic SCT is inappropriately high to recommend it in the absence of an underlying malignancy that requires it as therapy. It cannot be proposed as a treatment strategy for the bulk of HIV-infected patients who can live long healthy lives with the use of HAART. Homozygosity for the delta 32 mutation is only found in a minority of the population, so it is not feasible to find such HLA-matched donors for the majority of patients. Preferably, one would aspire to integrate the benefits of transplantation of cells with the CCR5 mutation without the hazards of allogeneic SCT. One potential way to ach‐ ieve this would be to transplant autologous stem cells that were genetically modified to be CCR5 negative. We have performed two trials at the City of Hope using this approach. The most recent employed a lentivirus-based system to transduce stem cells with a combination of three forms of anti-HIV RNA. This incorporated RNA1 in the form of a short-hairpin RNA targeted to an exon in HIV-1 tat/rev, a decoy for the HIV tat reactive element and a ribozyme that targets the host cell CCR5 chemokine receptor. Krishnan et al (2008) reported four patients with AIDS-related lymphoma transplanted with autologous lentiviral-trans‐ duced modified stem cells and unmanipulated stem cells following high-dose chemothera‐ py. All patients engrafted and exhibited low levels of genetically modified cells. Future trials will address how to augment engraftment of the genetically modified stem cells. Further plans are for planned interruption of HAART which would further demonstrate the func‐ tionality of these genetically modified cells. It is likely that an amalgamation of approaches with an aim to limit CD4 T cell targets and target viral reservoirs may be necessary to ach‐ ieve a cure.

### **6. Conclusion**

In the HAART era, the barrier of HIV infection as an obstacle to transplant has been broken. The role of ASCT has been well established in the HIV negative population for the treatment of relapsed or high-risk lymphoma. Numerous studies have now shown that ASCT can be safely performed in HIV-positive patients, and that it may lead to durable remissions in pa‐ tients with HIV-related lymphomas. Similar to well controlled diabetes, well controlled HIV infection does not significantly increase the risk of infections following ASCT if a program of adequate surveillance and prophylaxis is used. Allogeneic stem cell transplantation re‐ mains a more difficult task, is still in its infancy, and lacks larger studies. The Hutter and Allers experience of allogeneic SCT with a CCR5 negative donor has given a name and face to the cure of HIV. The task of finding more feasible options for the enormousglobal popula‐ tion living with HIV remains.

### **Author details**

CD4+ T cells appear to be totally removed from the immune system; however tissue macro‐ phages are practically resistant to conditioning and less susceptible to the cytopathic effects of HIV infection, making them resilient viral reservoirs (Swingler S et al, 2007). One of the most promising findings of this report was the demonstration that later in the course of im‐ mune reconstitution, host-originating macrophages became undetectable in the GI mucosa by both phenotypic and genotypic analysis. These findings suggest that the replacement of host tissue cells with donor derived cells has reduced the size of the viral reservoir during the course of the immune reconstitution, which consequently had reduced the risk of HIV

Gooley et al (2010) reported impressive decreases in allogeneic transplantation-related mor‐ tality. Nevertheless, the risk of allogeneic SCT is inappropriately high to recommend it in the absence of an underlying malignancy that requires it as therapy. It cannot be proposed as a treatment strategy for the bulk of HIV-infected patients who can live long healthy lives with the use of HAART. Homozygosity for the delta 32 mutation is only found in a minority of the population, so it is not feasible to find such HLA-matched donors for the majority of patients. Preferably, one would aspire to integrate the benefits of transplantation of cells with the CCR5 mutation without the hazards of allogeneic SCT. One potential way to ach‐ ieve this would be to transplant autologous stem cells that were genetically modified to be CCR5 negative. We have performed two trials at the City of Hope using this approach. The most recent employed a lentivirus-based system to transduce stem cells with a combination of three forms of anti-HIV RNA. This incorporated RNA1 in the form of a short-hairpin RNA targeted to an exon in HIV-1 tat/rev, a decoy for the HIV tat reactive element and a ribozyme that targets the host cell CCR5 chemokine receptor. Krishnan et al (2008) reported four patients with AIDS-related lymphoma transplanted with autologous lentiviral-trans‐ duced modified stem cells and unmanipulated stem cells following high-dose chemothera‐ py. All patients engrafted and exhibited low levels of genetically modified cells. Future trials will address how to augment engraftment of the genetically modified stem cells. Further plans are for planned interruption of HAART which would further demonstrate the func‐ tionality of these genetically modified cells. It is likely that an amalgamation of approaches with an aim to limit CD4 T cell targets and target viral reservoirs may be necessary to ach‐

In the HAART era, the barrier of HIV infection as an obstacle to transplant has been broken. The role of ASCT has been well established in the HIV negative population for the treatment of relapsed or high-risk lymphoma. Numerous studies have now shown that ASCT can be safely performed in HIV-positive patients, and that it may lead to durable remissions in pa‐

rebound over time.

70 Current Perspectives in HIV Infection

ieve a cure.

**6. Conclusion**

**5. Gene therapy and the future**

Nitya Nathwani

City of Hope National Medical Center, Duarte, USA

### **References**


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[21] Krishnan, A., Molina, A., Zaia, J., et al. (2005). Durable Remissions with autologous stem cell transplantation for high-risk HIV associated lymphomas. BloodJanuary

[22] Krishnan, A., Palmer, J., Zaia, J., et al. (2010). HIV status does not affect the outcome of autologous stem cell transplantation (ASCT) for Non-Hodgkin Lymphoma (NHL). Biology of Blood and Marrow TransplantationSeptember 2010), , 16, 1302-1308. [23] Krishnan, A., Zaia, J. A., Rossi, J., et al. (2008). First in Human Engraftment of Anti HIV lentiviral vector gene modified CD 34+ peripheral blood progenitor cells in the

[24] Levine AM.(2000). Acquired immunodeficiency Syndrome-Related Lymphoma: Clin‐

[25] Linch, D. C., Goldstone, A. H., Mc Millan, A., et al. (1993). Dose intensification with autologous bone marrow transplantation in relapsed and resistant Hodgkin's dis‐ ease: results of a BNLI randomized trial. The Lancet. April 1993), , 341(8852),

[26] Liu, R., Paxton, W., Choe, S., et al. (1996). Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cel‐

[27] Palella FJ, Delaney KM, Moorman AC, et al.(1998). Declining morbidity and mortali‐ ty among patients with advanced human immunodeficiency virus infection. The

[28] Parker, R. ., Sereti, I., & (2011, . (2011). The power of 1 in HIV therapeutics.Blood.

[29] Persad, G. C., Little, R. F., & Grady, C. (2008). Including persons with HIV infection in cancer clinical trials. Journal of Clinical Onoclogy, March 2008), , 26(7), 1027-1032. [30] Philip, T., Guglielmi, C., Hagenbeek, A., et al. (1995). Autologous bone marrow trans‐ plantation as compared with salvage chemotherapy in relapses of chemotherapysensitive non-Hodgkin's lymphoma. The New England Journal of Medicine.

[31] Re, A., Michieli, M., Casari, S., et al. (2009). High-dose therapy and autologous pe‐ ripheral blood stem cell transplantation as salvage treatment for AIDS-related lym‐ phoma: long-term results of the Italian Cooperative Group on AIDS and Tumors (GICAT) study with analysis of prognostic factors. BloodAugust 2009), , 114(7),

[32] Simonelli, C., Zanussi, S., Pratesi, C., et al. (2010). Immune recovery after autologous stem cell transplantation is not different for HIV-infected versus HIV-uninfected pa‐

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[8] Forman SJ, Blume KG, Thomas ED,(1994). Bone Marrow Transplantation.Blackwell

[9] Gabarre, J., Choquet, S., Azar, N., et al. (2001). High Dose Chemotherapy with autol‐ ogous stem cell transplantation for HIV associated lymphoma: A single center report

[10] Gabarrre, J., Leblond, V., Sutton, L., et al. (1996). Autologous bone Marrow trans‐ plantation in relapsed HIV related Non-Hodgkin's lymphoma. Bone Marrow Trans‐

[11] Gooley TA, Chien JW, Pergam SA, et al(2010). Reduced mortality after allogeneic hematopoietic-cell transplantation. The New England Journal of MedicineNovember

[12] Grulich AE, Leeuwen MT, Falster MO, et al.(2007). Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-

[13] Gupta, V., Tomblyn, M., Pederson, T., et al. (2007). Allogeneic hematopoietic stem cell transplantation in HIV-positive patients with malignant and non-malignant dis‐ orders: a report from the center for international blood and marrow transplant re‐ search (CIBMTR). Biology of Blood and Marrow TransplantationSupplement,

[14] Haioun, C., Lepage, E., Gisselbrecht, C., et al. (1997). Benefit of autologous bone mar‐ row transplantation over sequential chemotherapy in poor risk aggressive non-Hodgkin's lymphoma: Updated results of the Prospective Study LNH87-2. Journal of

[15] Halpern SD, Ubel PA &Caplan AL(2002). Solid Organ Transplantation in HIV infect‐ ed patients. The New England Journal of MedicineJuly 2002), , 347(4), 284-287.

[16] Holland, H. K., Saral, R., Rossi, J. J., et al. (1989). Allogeneic bone marrow transplan‐ tation, zidovudine and human immunodeficiency virus type 1 (HIV-1) infection. An‐

[17] Hütter, G., Nowak, D., Mossner, M., et al. (2009). Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. The New England Journal of Medicine‐

[18] Kaplan, LD, Strauss DJ, Testa, MA et al.(1997). Low-Dose Compared with Standard-Dose m-BACOD Chemotherapy for Non-Hodgkin's Lymphoma Associated with Human Immunodeficiency Virus Infection.The New England Journal of Medi‐

[19] Keever, Small. T. N., Flomenberg, N., et al. (1989). Immune Reconstitution following bone marrow transplantation: Comparison of recipients of T cell depleted marrow with recipients of conventional marrow grafts. BloodApril 1989) , 73(5), 1340-1350.

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72 Current Perspectives in HIV Infection

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on 14 patients. Blood 2001; 98: Abstract # 2092


tients with relapsed or refractory lymphoma. Clinical Infectious DiseasesJune 2010) , 1672-1679.

**Section 2**

**HIV Screening**


**Section 2**

### **HIV Screening**

tients with relapsed or refractory lymphoma. Clinical Infectious DiseasesJune 2010) ,

[33] Swingler, S., Mann, A. M., Zhou, J., et al. (2007). Apoptotic killing of HIV-1 infected macrophages is subverted by the viral envelope glycoprotein. PLoS PathogensSep‐

[34] Woolfrey, A. E., Malhotra, U., Harrington, Rd., et al. (2008). Generation of HIV-1 spe‐ cific CD8+ cell responses following allogeneic hematopoietic cell transplantation.

1672-1679.

74 Current Perspectives in HIV Infection

tember 2007), , 3(9), 1281-1290.

Blood, October 2008), , 112(8), 3484-3487.

**Chapter 4**

**Screening for HIV Infection in Pregnancy**

screening of their patients during annual exams and prenatal visits.

**1.1. Screening for HIV infection during prenatal care**

Approximately 100 to 200 infants annually in the United States are infected with HIV (CDC, 2007). Most were born to mothers who were unaware of their infected HIV status or who did not receive preventative services during their pregnancy to reduce transmission rates. Therefore, in 2006, the CDC updated its guidelines for screening of various populations for HIV, including pregnant women. Obstetricians and gynecologists are ideally suited to such

Screening only patients who reported risk factors for the HIV infection will miss many in‐ fected women. Therefore, the current recommendation is for implementation of universal opt-out screening for HIV as early in pregnancy as possible (Branson et al., 2006). In this uni‐ versal opt-out screening method, a patient is informed that HIV testing will be performed as a routine part of her prenatal care, unless she declines testing. She should be given written or oral information about HIV, including an explanation of the infection, the meaning of positive or negative test results, and measures that can be used to reduce perinatal transmis‐ sion. She should also be given the opportunity to ask further questions. However, no in‐ formed consent is required. If a patient declines screening, this should be documented in the medical record, and screening should be offered at subsequent prenatal visits (Branson et al., 2006; ACOG, 2008). Retesting is recommended with each new pregnancy. Although these are the recommendations endorsed by the CDC and ACOG, healthcare providers must be aware of the laws regarding screening in their own states, which may differ from the above guidelines. Further information on state HIV testing laws can be obtained from state

> © 2013 Dola et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Chi Dola, Maga Martinez, Olivia Chang and

Additional information is available at the end of the chapter

Amanda Johnson

**1. Introduction**

http://dx.doi.org/10.5772/54551

and local health departments.

### **Screening for HIV Infection in Pregnancy**

Chi Dola, Maga Martinez, Olivia Chang and Amanda Johnson

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54551

### **1. Introduction**

Approximately 100 to 200 infants annually in the United States are infected with HIV (CDC, 2007). Most were born to mothers who were unaware of their infected HIV status or who did not receive preventative services during their pregnancy to reduce transmission rates. Therefore, in 2006, the CDC updated its guidelines for screening of various populations for HIV, including pregnant women. Obstetricians and gynecologists are ideally suited to such screening of their patients during annual exams and prenatal visits.

#### **1.1. Screening for HIV infection during prenatal care**

Screening only patients who reported risk factors for the HIV infection will miss many in‐ fected women. Therefore, the current recommendation is for implementation of universal opt-out screening for HIV as early in pregnancy as possible (Branson et al., 2006). In this uni‐ versal opt-out screening method, a patient is informed that HIV testing will be performed as a routine part of her prenatal care, unless she declines testing. She should be given written or oral information about HIV, including an explanation of the infection, the meaning of positive or negative test results, and measures that can be used to reduce perinatal transmis‐ sion. She should also be given the opportunity to ask further questions. However, no in‐ formed consent is required. If a patient declines screening, this should be documented in the medical record, and screening should be offered at subsequent prenatal visits (Branson et al., 2006; ACOG, 2008). Retesting is recommended with each new pregnancy. Although these are the recommendations endorsed by the CDC and ACOG, healthcare providers must be aware of the laws regarding screening in their own states, which may differ from the above guidelines. Further information on state HIV testing laws can be obtained from state and local health departments.

© 2013 Dola et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Chou et al, estimated that the number needed to screen (NNS) in an area with 0.15% preva‐ lence would be between 3,500 to 12,170 to prevent 1 case of perinatally-acquired HIV infec‐ tion. In a high risk area with a prevalence of 5%, the NNS would be from 105 to 365 to prevent 1 case of perinatally-acquired infection (Chou et, 2005).

risk behaviors or is infected with HIV, or women who have had a new or more than one

Studies indicate that between 40 and 85 percent of infants infected with HIV are born to mothers whose HIV infection status is unknown prior to delivery (ACOG, 2008). If a woman without documentation of HIV status presents to labor and delivery, opt-out rapid HIV test‐ ing should be performed at time of her initial presentation. A positive result should prompt immediate treatment with antiretroviral prophylaxis without awaiting the result of confir‐ matory testing. If subsequent confirmatory testing shows the woman to be HIV negative, treatment may be discontinued. Similarly, if a woman has an unknown HIV status in the postpartum period, her infant should be tested by rapid screening. Antiretroviral treatment should be initiated with a positive result, as the benefits of such treatment are maximized when started within 48 hours of delivery (ACOG, 2008; Rahangdale & Cohan, 2008). Again,

The above recommendation for prenatal screening for HIV infection is summarized in

Initial prenatal care visit Enzyme immunoassay (ELISA) Western blot or immunofluorescent

Rapid HIV antibody screening test. Western blot or IFA testing

for acquisition of HIV infection

**2. Evidences supporting the effectiveness of current interventions to**

Research in HIV infection reported several key factors in the transmission of the virus from the mother to the infant. The risk factors for transmission can be divided into: virologic/ immunologic, maternal health status/behavior, and obstetrical factors (McGowan et al, 2000). High maternal plasma HIV-1 viral load, low maternal CD4 T-lymphocyte count, mul‐ tidrug-resistant HIV genotype will increase the transmission rate. Certain maternal behavior (illicit drug use, cigarette smoking, breast feeding) or maternal health status (increased base‐

antibody (IFA) testing

Western blot or IFA testing

Screening for HIV Infection in Pregnancy http://dx.doi.org/10.5772/54551 79

**Timing Screening test Confirmatory Test**

**Table 1.** CDC and ACOG recommendation for screening for HIV infection during pregnancy.

**decrease mother-to-child transmission of HIV infection**

sexual partner during their pregnancy)

**•** Women with signs or symptoms of acute HIV infection

**1.3. Screening of women with undocumented HIV status**

treatment may be stopped if confirmatory testing is negative.

Third trimester of pregnancy Repeat ELISA in women at **high risk**

table 1.

status

At time of labor and delivery for women with undocumented HIV

At this time, both conventional and rapid screening tests for HIV are available to the health‐ care provider. Conventional testing consists of a screening test with an enzyme immunoas‐ say (ELISA), followed by confirmatory testing of a positive result with Western blot or immunofluorescent antibody (IFA) testing. The sensitivity and specificity of this method of testing is greater than 99%. False positive results are rare even in the setting with low preva‐ lence. Final results may not be available for several days to weeks. With rapid testing, a blood or saliva test for HIV antibodies is performed, and the results are often available with‐ in an hour. Confirmatory testing of a preliminary positive result is still required before a di‐ agnosis of HIV can be made. A negative result with either the conventional or rapid screening test indicates a woman does not have HIV, and no further testing is needed, un‐ less one suspects the patient was recently infected with HIV but has not produced an anti‐ body response to the virus (ACOG, 2008; Rahangdale & Cohan, 2008). If the initial screening test is positive, but the confirmatory test is negative, the patient should be considered not infected, and no further testing is necessary.

#### **1.2. Rescreening in the third trimester**

Studies from several countries have demonstrated that pregnant women seem to be at in‐ creased risk for acquisition of HIV over their non-pregnant counterparts (Moodley et al., 2009; Gray et al., 2005; Sansom et al., 2003). Theories for this range from behavioral actions of the woman or her partner that put her at increased risk, to physiologic changes associated with pregnancy, including changes to the genital tract mucosa to changes in cellular immun‐ ity that may lead to increased susceptibility to HIV with pregnancy. Evidence has demon‐ strated that the rate of seroconversion during pregnancy may be as high as 2 to 3 percent in some areas (Moodley et al., 2009; Gray et al., 2005; Sansom et al., 2003). A study by Sansom, *et al* demonstrated that in a population with an HIV incidence of approximately 1 in 1000 person-years, the cost of repeat testing was offset by the savings in medical costs for preven‐ tion of an infected infant (Sansom et al., 2003). For the above reasons, repeat HIV testing is recommended in certain populations in the third trimester, preferably before 36 weeks ges‐ tation (Branson et al., 2006; ACOG, 2008). These populations include:


risk behaviors or is infected with HIV, or women who have had a new or more than one sexual partner during their pregnancy)

**•** Women with signs or symptoms of acute HIV infection

Chou et al, estimated that the number needed to screen (NNS) in an area with 0.15% preva‐ lence would be between 3,500 to 12,170 to prevent 1 case of perinatally-acquired HIV infec‐ tion. In a high risk area with a prevalence of 5%, the NNS would be from 105 to 365 to

At this time, both conventional and rapid screening tests for HIV are available to the health‐ care provider. Conventional testing consists of a screening test with an enzyme immunoas‐ say (ELISA), followed by confirmatory testing of a positive result with Western blot or immunofluorescent antibody (IFA) testing. The sensitivity and specificity of this method of testing is greater than 99%. False positive results are rare even in the setting with low preva‐ lence. Final results may not be available for several days to weeks. With rapid testing, a blood or saliva test for HIV antibodies is performed, and the results are often available with‐ in an hour. Confirmatory testing of a preliminary positive result is still required before a di‐ agnosis of HIV can be made. A negative result with either the conventional or rapid screening test indicates a woman does not have HIV, and no further testing is needed, un‐ less one suspects the patient was recently infected with HIV but has not produced an anti‐ body response to the virus (ACOG, 2008; Rahangdale & Cohan, 2008). If the initial screening test is positive, but the confirmatory test is negative, the patient should be considered not

Studies from several countries have demonstrated that pregnant women seem to be at in‐ creased risk for acquisition of HIV over their non-pregnant counterparts (Moodley et al., 2009; Gray et al., 2005; Sansom et al., 2003). Theories for this range from behavioral actions of the woman or her partner that put her at increased risk, to physiologic changes associated with pregnancy, including changes to the genital tract mucosa to changes in cellular immun‐ ity that may lead to increased susceptibility to HIV with pregnancy. Evidence has demon‐ strated that the rate of seroconversion during pregnancy may be as high as 2 to 3 percent in some areas (Moodley et al., 2009; Gray et al., 2005; Sansom et al., 2003). A study by Sansom, *et al* demonstrated that in a population with an HIV incidence of approximately 1 in 1000 person-years, the cost of repeat testing was offset by the savings in medical costs for preven‐ tion of an infected infant (Sansom et al., 2003). For the above reasons, repeat HIV testing is recommended in certain populations in the third trimester, preferably before 36 weeks ges‐

**•** Women living in areas with a high incidence of HIV/AIDs, including the 20 states with

**•** Women who receive their healthcare in facilities where at least 1 in 1000 women screened

**•** Women who engage in high-risk behavior that puts them at risk for HIV acquisition (in‐ jection drug use, exchange of sex for drugs or money, diagnosis of another sexually trans‐ mitted infection in the past year, a sex partner who engages in injection drug use or high-

tation (Branson et al., 2006; ACOG, 2008). These populations include:

the highest incidence among women of child-bearing age

prevent 1 case of perinatally-acquired infection (Chou et, 2005).

infected, and no further testing is necessary.

**1.2. Rescreening in the third trimester**

78 Current Perspectives in HIV Infection

for HIV are found to be infected

#### **1.3. Screening of women with undocumented HIV status**

Studies indicate that between 40 and 85 percent of infants infected with HIV are born to mothers whose HIV infection status is unknown prior to delivery (ACOG, 2008). If a woman without documentation of HIV status presents to labor and delivery, opt-out rapid HIV test‐ ing should be performed at time of her initial presentation. A positive result should prompt immediate treatment with antiretroviral prophylaxis without awaiting the result of confir‐ matory testing. If subsequent confirmatory testing shows the woman to be HIV negative, treatment may be discontinued. Similarly, if a woman has an unknown HIV status in the postpartum period, her infant should be tested by rapid screening. Antiretroviral treatment should be initiated with a positive result, as the benefits of such treatment are maximized when started within 48 hours of delivery (ACOG, 2008; Rahangdale & Cohan, 2008). Again, treatment may be stopped if confirmatory testing is negative.

The above recommendation for prenatal screening for HIV infection is summarized in table 1.


**Table 1.** CDC and ACOG recommendation for screening for HIV infection during pregnancy.

### **2. Evidences supporting the effectiveness of current interventions to decrease mother-to-child transmission of HIV infection**

Research in HIV infection reported several key factors in the transmission of the virus from the mother to the infant. The risk factors for transmission can be divided into: virologic/ immunologic, maternal health status/behavior, and obstetrical factors (McGowan et al, 2000). High maternal plasma HIV-1 viral load, low maternal CD4 T-lymphocyte count, mul‐ tidrug-resistant HIV genotype will increase the transmission rate. Certain maternal behavior (illicit drug use, cigarette smoking, breast feeding) or maternal health status (increased base‐ line weight or malnutrition or vitamin A deficiency) can increase the rate of mother-to-child transmission. Some obstetrical factors (vaginal delivery, prolonged rupture of membrane, fetal scalp electrode placement, chorioamnionitis, perineal lacerations, prematurity) can in‐ crease the vertical transmission rate (McGowan et al, 2000).

neonatal prophylaxis alone in a mother who did not receive antiretroviral prophylaxis thera‐

Screening for HIV Infection in Pregnancy http://dx.doi.org/10.5772/54551 81

A meta-analysis of 15 prospective cohort studies by the International Perinatal HIV Group (The International Perinatal HIV Group, 1999) included 8,533 mother-neonate pairs. Vertical HIV transmission was reduced by 50% when the mode of delivery was elective cesarean delivery. The effect of both antiretroviral therapy prophylaxis and ce‐ sarean delivery further reduced HIV transmission by 87 percent when compared with other modes of delivery (either vaginal delivery or non-elective cesarean delivery) and no antiretroviral therapy. However, in women who received HAART and achieved low HIV viral load levels (defined as less than 1,000 copies/ mL), current data is in‐ sufficient to determine whether elective cesarean delivery would offer further risk re‐ duction. ACOG concluded that scheduled cesarean delivery should be discussed and recommended for HIV-infected women whose HIV-1 RNA viral load exceeds 1,000 copies/mL. Scheduled cesarean delivery was recommended as early as 38 weeks gesta‐ tion to reduce the risk of labor or of prematurely ruptured membranes (ACOG, 1999).

Breastfeeding was associated with an HIV transmission rate of 14% to 16% based on the re‐ sults of two meta-analyses of observational studies (Dunn et al, 1992, John et al, 2001). A re‐ view of the literature did not reveal any randomized, controlled trials evaluating the HIV transmission rate associated with breastfeeding in the United States. A large, prospective co‐ hort study in Italy included 3,770 babies and concluded that HIV infection rates were signifi‐ cantly higher in babies who were breastfed after the authors adjusted for other factors, including antiretroviral use (adjusted odds ratio, 10.20 [CI, 2.73 to 38.11]) (Arch Pediatr Ado‐

In a study in Africa, women who breastfed and did not receive antiretroviral therapy had a probability of transmitting the HIV infection of 36.7% (CI, 29.4% to 44.0%) at 24 months and an infant mortality rate of 24.4% (CI, 18.2% to 30.7%). Those who formula fed their babies had a transmission probability of 20.5% (CI, 14.0% to 27.0%) and an infant mortality rate of

As a result, in many countries, including the United States where formula feeding is readily available and inexpensive, breastfeeding is not recommended for infants of HIV-infected

We will next explore the potential risks as the results of prenatal HIV screening and the po‐ tential harms of the recommended interventions to reduce perinatal transmission of HIV in‐

**3. Potential harms/risks as the result of prenatal HIV screening**

py was less effective in preventing HIV infection (Taha et al, 2003).

**2.2. Scheduled cesarean delivery**

**2.3. Avoidance of breastfeeding**

lesc Med., 2002, Chou et al, 2005).

women (WHO, 2000).

fection (Table 2).

20.0% (CI, 14.4% to 25.6%) (Nduati et al, 2000).

Other reports on perinatal transmission of HIV infection suggested that approximately 70% of the infections transmitted to the infant during the labor and delivery process; only 30% of the cases occurred during the antepartum period (Kourtis et al, 2006). Current interventions to prevent perinatal transmission of HIV infection included: prophylaxis therapy with anti‐ retroviral medication, scheduled cesarean delivery and avoidance of breast feeding. These interventions resulted in decreasing transmission rate to 2% (Cooper et al, 2002). We will ex‐ amine the evidence supporting these interventions.

### **2.1. Prophylaxis with antiretroviral agents**

The Pediatric AIDS Clinical Trials Group (PACTG) 076 conducted a randomized controlled study and in 1994 published its landmark results demonstrating a reduction in perinatal HIV transmission by two-third with the antiretroviral medication Zidovudine (ZDV). HIVinfected mothers in the study group received a three-part regimen of antiretroviral medica‐ tion. They received ZDV during pregnancy, intravenous ZDV during labor, and their infant received ZDV orally for 6 weeks (Conner et al, 1994). This trial reported a decrease in trans‐ mission rate from 26% in the placebo group to 8% in those patients who received ZDV. Later in the year of 1994, FDA approved the use of ZDV for reducing perinatal HIV transmission and the U.S. Public Health Service Task Force (USPHSTF) and CDC published their recom‐ mendations for the administration of this regimen in an effort to reduce mother-to-child transmission of the HIV infection (CDC, 2006).

In the late 1990s, additional antiretroviral medications were developed and the combined use of three or more of these drugs was found to greatly inhibit viral replication and allow improvement of the immune system. The combination of these medications was known as highly active antiretroviral therapy (HAART). In 1998, USPHSTF and CDC issued recom‐ mendation regarding HAART: pregnant women should receive HAART if they required the treatment for their disease status and all HIV-infected pregnant women should be offered HAART. USPHSTF and CDC at that time acknowledged that the benefits and risks to the fetus are uncertain (CDC, 1998). Four large U.S. and European cohort studies all concluded that regimens with two or more antiretroviral drugs were more effective than the one-drug regimen for reducing vertical transmission of the HIV infection (Cooper et al, 2002, Arch Pe‐ diatr Adolesc Med 2002, Clin Infect Dis *2005*, Mandelbrot et al, 2001).

For women diagnosed late in pregnancy and were not able to receive a full course of antire‐ troviral treatment, a short course of antenatal treatment, although less effective, also was proven to decrease perinatal transmission (Lallemant et al, 2000, Shaffer et al, 1999, Petra study 2002, Wiktor et al, 1999, Dabis et al, 1999, Chou et al, 2005). There was some reduction in the HIV infection transmission even when treatment was abbreviated to only antiretrovi‐ ral regimen during labor (Moodley et al, 2003, Taha et al, 2003, Guay et al, 1999). However, neonatal prophylaxis alone in a mother who did not receive antiretroviral prophylaxis thera‐ py was less effective in preventing HIV infection (Taha et al, 2003).

#### **2.2. Scheduled cesarean delivery**

line weight or malnutrition or vitamin A deficiency) can increase the rate of mother-to-child transmission. Some obstetrical factors (vaginal delivery, prolonged rupture of membrane, fetal scalp electrode placement, chorioamnionitis, perineal lacerations, prematurity) can in‐

Other reports on perinatal transmission of HIV infection suggested that approximately 70% of the infections transmitted to the infant during the labor and delivery process; only 30% of the cases occurred during the antepartum period (Kourtis et al, 2006). Current interventions to prevent perinatal transmission of HIV infection included: prophylaxis therapy with anti‐ retroviral medication, scheduled cesarean delivery and avoidance of breast feeding. These interventions resulted in decreasing transmission rate to 2% (Cooper et al, 2002). We will ex‐

The Pediatric AIDS Clinical Trials Group (PACTG) 076 conducted a randomized controlled study and in 1994 published its landmark results demonstrating a reduction in perinatal HIV transmission by two-third with the antiretroviral medication Zidovudine (ZDV). HIVinfected mothers in the study group received a three-part regimen of antiretroviral medica‐ tion. They received ZDV during pregnancy, intravenous ZDV during labor, and their infant received ZDV orally for 6 weeks (Conner et al, 1994). This trial reported a decrease in trans‐ mission rate from 26% in the placebo group to 8% in those patients who received ZDV. Later in the year of 1994, FDA approved the use of ZDV for reducing perinatal HIV transmission and the U.S. Public Health Service Task Force (USPHSTF) and CDC published their recom‐ mendations for the administration of this regimen in an effort to reduce mother-to-child

In the late 1990s, additional antiretroviral medications were developed and the combined use of three or more of these drugs was found to greatly inhibit viral replication and allow improvement of the immune system. The combination of these medications was known as highly active antiretroviral therapy (HAART). In 1998, USPHSTF and CDC issued recom‐ mendation regarding HAART: pregnant women should receive HAART if they required the treatment for their disease status and all HIV-infected pregnant women should be offered HAART. USPHSTF and CDC at that time acknowledged that the benefits and risks to the fetus are uncertain (CDC, 1998). Four large U.S. and European cohort studies all concluded that regimens with two or more antiretroviral drugs were more effective than the one-drug regimen for reducing vertical transmission of the HIV infection (Cooper et al, 2002, Arch Pe‐

For women diagnosed late in pregnancy and were not able to receive a full course of antire‐ troviral treatment, a short course of antenatal treatment, although less effective, also was proven to decrease perinatal transmission (Lallemant et al, 2000, Shaffer et al, 1999, Petra study 2002, Wiktor et al, 1999, Dabis et al, 1999, Chou et al, 2005). There was some reduction in the HIV infection transmission even when treatment was abbreviated to only antiretrovi‐ ral regimen during labor (Moodley et al, 2003, Taha et al, 2003, Guay et al, 1999). However,

diatr Adolesc Med 2002, Clin Infect Dis *2005*, Mandelbrot et al, 2001).

crease the vertical transmission rate (McGowan et al, 2000).

amine the evidence supporting these interventions.

**2.1. Prophylaxis with antiretroviral agents**

80 Current Perspectives in HIV Infection

transmission of the HIV infection (CDC, 2006).

A meta-analysis of 15 prospective cohort studies by the International Perinatal HIV Group (The International Perinatal HIV Group, 1999) included 8,533 mother-neonate pairs. Vertical HIV transmission was reduced by 50% when the mode of delivery was elective cesarean delivery. The effect of both antiretroviral therapy prophylaxis and ce‐ sarean delivery further reduced HIV transmission by 87 percent when compared with other modes of delivery (either vaginal delivery or non-elective cesarean delivery) and no antiretroviral therapy. However, in women who received HAART and achieved low HIV viral load levels (defined as less than 1,000 copies/ mL), current data is in‐ sufficient to determine whether elective cesarean delivery would offer further risk re‐ duction. ACOG concluded that scheduled cesarean delivery should be discussed and recommended for HIV-infected women whose HIV-1 RNA viral load exceeds 1,000 copies/mL. Scheduled cesarean delivery was recommended as early as 38 weeks gesta‐ tion to reduce the risk of labor or of prematurely ruptured membranes (ACOG, 1999).

#### **2.3. Avoidance of breastfeeding**

Breastfeeding was associated with an HIV transmission rate of 14% to 16% based on the re‐ sults of two meta-analyses of observational studies (Dunn et al, 1992, John et al, 2001). A re‐ view of the literature did not reveal any randomized, controlled trials evaluating the HIV transmission rate associated with breastfeeding in the United States. A large, prospective co‐ hort study in Italy included 3,770 babies and concluded that HIV infection rates were signifi‐ cantly higher in babies who were breastfed after the authors adjusted for other factors, including antiretroviral use (adjusted odds ratio, 10.20 [CI, 2.73 to 38.11]) (Arch Pediatr Ado‐ lesc Med., 2002, Chou et al, 2005).

In a study in Africa, women who breastfed and did not receive antiretroviral therapy had a probability of transmitting the HIV infection of 36.7% (CI, 29.4% to 44.0%) at 24 months and an infant mortality rate of 24.4% (CI, 18.2% to 30.7%). Those who formula fed their babies had a transmission probability of 20.5% (CI, 14.0% to 27.0%) and an infant mortality rate of 20.0% (CI, 14.4% to 25.6%) (Nduati et al, 2000).

As a result, in many countries, including the United States where formula feeding is readily available and inexpensive, breastfeeding is not recommended for infants of HIV-infected women (WHO, 2000).

### **3. Potential harms/risks as the result of prenatal HIV screening**

We will next explore the potential risks as the results of prenatal HIV screening and the po‐ tential harms of the recommended interventions to reduce perinatal transmission of HIV in‐ fection (Table 2).


always be well prepared to provide the appropriate emotional support for a possibility of

Screening for HIV Infection in Pregnancy http://dx.doi.org/10.5772/54551 83

Women tested positive for HIV infection can experience significant problems with discrimi‐ nation from their partner, social ostracization from their family and members of the com‐ munity (Provisional Committee on Pediatric AIDS, 1995, Samson et al, 1998). They were found to have higher anxiety and depression scores and many women fear abandonment or abuse, therefore, did not disclose their HIV status to their friend or families. (Lester, 1995) although no increased risk for intimate partner violence was noted according to one cohort

Data on consequences of false-positive HIV infection diagnoses in pregnant women are mainly anecdotal as reported by Sheon et al. The potential risks from false-positive results included: elective termination of pregnancy, anxiety, social discrimination and relationship

False positive results from rapid HIV testing during labor result in 4 women receiving un‐

Efforts continue to increase our knowledge of the potential teratogenic effects of the antiretrovi‐ ral agents administered in pregnancy. The Antiretroviral Pregnancy Registry Steering Commit‐ tee published their recent report of antiretroviral exposures during pregnancy from January 1989 through July 2007. They did not identify an increased risk of birth defects in those exposed to any of the antiretroviral therapy in the first trimester. The risk of birth defects among women exposed to antiretroviral therapy in first trimester was 2.8 per 100 live births, which is not differ‐ ent from the risk of birth defects in women exposed to these agents in the second or third trimes‐ ter (2.6 per 100 live births), nor the CDC's reported background rate of birth defects of 2.72 per

Four retrospective reports associated Sustiva (Efavirenz) with neural tube defects in infants born of mothers exposed to this medication in the first trimester (Bardeguez, 2009). There are discrepant results with regard to mitochondrial toxicity and disorders in children ex‐ posed in utero to antiretroviral therapy. Two deaths believed to be due to mitochondrial dis‐ order were reported in children exposed in utero to nucleoside analogues (in specific, a combination of Zidovudine and Lamivudine regimen) (Blanche et al, 1999). However, Euro‐ pean Collaborative report and systematic review of U.S. cohorts reports did not find evi‐ dence of clinical symptoms, or deaths due to mitochondrial dysfunction among HIV-

Of infants exposed in utero to Zidovudine who were followed at 4 years to 6 years of life. The re‐ ports were reassuring. Normal growth, cognitive, and developmental function were noted in these infants at 4 years old. They did not sustain any tumors or deaths from cancer at 6 years old.

necessary antiretroviral prophylaxis out of 4,849 women tested (Bulterys et al, 2004).

abnormal result (Katz, 2000).

study (Koenig et al, 2002, Chou et al, 2005)

**4.1. Potential teratogenic effects of ART**

problems with their partner (Sheon et al, 1994, Chou et al, 2005).

**4. Risks of Antiretroviral Therapy (ART) to fetus**

100 live births (www.APRegistry.com, 2007, Bardeguez, 2009).

negative infants exposed to antiretroviral agents in utero (Bardeguez, 2009).

**Table 2.** Potential harms / risks from prenatal screening and strategic interventions to decrease perinatal transmission of HIV infection:

According to Katz, prenatal screening for HIV in pregnancy aims to test a presumably healthy population to discover asymptomatic women who are actually infected with HIV infection. These pregnant women might not have or perceive that they have risk factors for the HIV infection. This is different than the usual situation when a woman acknowledges her risk for the infection and requests the screening test. Most women would agree to be screened as they believe that they are doing everything they can for the health for their baby but they might not realize the full implication of a positive HIV test result on their lives. In some instances, they do not perceive that they are at risk for the infection and thus could be quite unprepared to receive the positive diagnosis. This could result in adverse effect on their emotional health, their pregnancy, and the family. Thus health care provider should always be well prepared to provide the appropriate emotional support for a possibility of abnormal result (Katz, 2000).

Women tested positive for HIV infection can experience significant problems with discrimi‐ nation from their partner, social ostracization from their family and members of the com‐ munity (Provisional Committee on Pediatric AIDS, 1995, Samson et al, 1998). They were found to have higher anxiety and depression scores and many women fear abandonment or abuse, therefore, did not disclose their HIV status to their friend or families. (Lester, 1995) although no increased risk for intimate partner violence was noted according to one cohort study (Koenig et al, 2002, Chou et al, 2005)

Data on consequences of false-positive HIV infection diagnoses in pregnant women are mainly anecdotal as reported by Sheon et al. The potential risks from false-positive results included: elective termination of pregnancy, anxiety, social discrimination and relationship problems with their partner (Sheon et al, 1994, Chou et al, 2005).

False positive results from rapid HIV testing during labor result in 4 women receiving un‐ necessary antiretroviral prophylaxis out of 4,849 women tested (Bulterys et al, 2004).

### **4. Risks of Antiretroviral Therapy (ART) to fetus**

### **4.1. Potential teratogenic effects of ART**

**Maternal risks Fetal risks**

Potential risk for elective termination

Risks of neural tube defects with Sustive (Efavirenz) with first trimester

? Potential risk of mitochondrial

A trend toward higher risk of respiratory distress syndrome among neonates born by cesarean section (when compared to those born via

Inconsistent data regarding increasing risk for preterm birth and low-birth

toxicity and disorder

vaginal delivery)

of pregnancy

exposure.

weight

**Prenatal screening**

82 Current Perspectives in HIV Infection

Screened positive Discrimination from their partner

Screened falsely positive Anxiety

**Interventions to decrease perinatal**

Scheduled cesarean delivery at 38

**transmission**

weeks

of HIV infection:

friends

and friend

during labor

ART prophylaxis Hepatic toxicity and hypersensitivity

Social ostracization from family and

Abandonment and abuse from family

Unnecessary antiretroviral prophylaxis

Post-operative morbidities, including: postpartum fever, hemorrhage, endometritis, urinary tract infection.

**Table 2.** Potential harms / risks from prenatal screening and strategic interventions to decrease perinatal transmission

According to Katz, prenatal screening for HIV in pregnancy aims to test a presumably healthy population to discover asymptomatic women who are actually infected with HIV infection. These pregnant women might not have or perceive that they have risk factors for the HIV infection. This is different than the usual situation when a woman acknowledges her risk for the infection and requests the screening test. Most women would agree to be screened as they believe that they are doing everything they can for the health for their baby but they might not realize the full implication of a positive HIV test result on their lives. In some instances, they do not perceive that they are at risk for the infection and thus could be quite unprepared to receive the positive diagnosis. This could result in adverse effect on their emotional health, their pregnancy, and the family. Thus health care provider should

Anxiety and depression

Social discrimination Relationship problems

reaction (with Nevirapine) Development of drug resistance Gestational diabetes (with combination therapy including

protease inhibitors)

Efforts continue to increase our knowledge of the potential teratogenic effects of the antiretrovi‐ ral agents administered in pregnancy. The Antiretroviral Pregnancy Registry Steering Commit‐ tee published their recent report of antiretroviral exposures during pregnancy from January 1989 through July 2007. They did not identify an increased risk of birth defects in those exposed to any of the antiretroviral therapy in the first trimester. The risk of birth defects among women exposed to antiretroviral therapy in first trimester was 2.8 per 100 live births, which is not differ‐ ent from the risk of birth defects in women exposed to these agents in the second or third trimes‐ ter (2.6 per 100 live births), nor the CDC's reported background rate of birth defects of 2.72 per 100 live births (www.APRegistry.com, 2007, Bardeguez, 2009).

Four retrospective reports associated Sustiva (Efavirenz) with neural tube defects in infants born of mothers exposed to this medication in the first trimester (Bardeguez, 2009). There are discrepant results with regard to mitochondrial toxicity and disorders in children ex‐ posed in utero to antiretroviral therapy. Two deaths believed to be due to mitochondrial dis‐ order were reported in children exposed in utero to nucleoside analogues (in specific, a combination of Zidovudine and Lamivudine regimen) (Blanche et al, 1999). However, Euro‐ pean Collaborative report and systematic review of U.S. cohorts reports did not find evi‐ dence of clinical symptoms, or deaths due to mitochondrial dysfunction among HIVnegative infants exposed to antiretroviral agents in utero (Bardeguez, 2009).

Of infants exposed in utero to Zidovudine who were followed at 4 years to 6 years of life. The re‐ ports were reassuring. Normal growth, cognitive, and developmental function were noted in these infants at 4 years old. They did not sustain any tumors or deaths from cancer at 6 years old.

### **4.2. Association between ART and preterm birth and low-birth weight**

Inconsistent results were noted among the reports studying the effects of combination antire‐ troviral therapy on two obsterics outcomes: preterm birth and low birth-weight. Lorenzi et al in 1998 first reported the association between combination antiretroviral therapy with preterm birth in a retrospective Swiss study of 30 women (Lorenzi et al, 1998). Subsequently, other Euro‐ pean studies reported a similar association between combination antiretroviral therapy and preterm birth (The European Collaborative Study (ECS) andSwiss Mother + Child HIV Cohort Study (Mo-CHiV), 2000, Grosch-Woerner et al, 2008). However, this association was not found in U.S. studies until a recent study by Cotter et al. The authors prospectively collected the data from 1990 through 2002 on 999 women receiving antiretroviral regimen during pregnancy. They concluded that women who received combination therapy that included a protease inhib‐ itor had an increased risk of preterm delivery (Cotter et al, 2006).

morbidities. Most studies report that HIV-infected women are at higher risk for post-opera‐ tive complications, mostly infectious, than the uninfected women (Coll et al., 2002; Grubert el al., 1999; Vimercati et al., 2000). The rate of complications is higher in those with severe

Screening for HIV Infection in Pregnancy http://dx.doi.org/10.5772/54551 85

Read et al conducted a largest prospective observational study which included 1,186 HIV-infected women from The Women and Infants Transmission Study. The authors evaluated the postpartum morbidity among these infected women according to their mode of delivery. When compared to women who delivered vaginally, women who un‐ derwent scheduled cesarean delivery had an increased rate of postpartum fever (14.3%), hemorrhage (7.1%), endometritis (5.4%), urinary tract infection (5.4%), and any postpar‐

**7. Potential neonatal risks from scheduled cesarean delivery at 38 weeks**

In the absence of medical or obstetrical indications, ACOG recommends against sched‐ uled cesarean delivery at less than 39 weeks of gestation, due to the increased risk of respiratory morbidity in the neonate born prior to this gestational age (ACOG, 2001). Neonatal morbidity is high even among those neonates born via cesarean delivery a few days younger than 39 weeks (Tita et al, 2011). However, both ACOG and U.S. Public Health Service recommend scheduled cesarean delivery at 38 weeks for HIV-in‐ fected women with viral load greater than 1,000 copies/ml (ACOG, 2001; Public Health Service Task Force, 2010). The scheduled cesarean delivery date is set at one week ear‐ lier than the usually required gestational age of 39 weeks to avoid onset of spontane‐ ous labor and rupture of membranes which could increase perinatal transmission of HIV. Livingston et al and the IMPACT Protocol 1025 Study Group evaluated the risk of neonatal respiratory distress syndrome according to the mode of delivery and gesta‐ tional age at delivery. They reported that the mode of delivery was not associated with respiratory distress syndrome. However, there was a trend toward a higher risk of respiratory distress syndrome among neonates delivered by either elective or nonelective cesarean section when compared to those delivered vaginally. Two out of 227 neonates born via scheduled cesarean delivery at 38 weeks gestation had respiratory

Current evidence supports prenatal HIV screening. The benefits from screening appear to outweight the small risks / harms to the fetus and mothers from the treatment interventions which significantly reduce perinatal-acquired HIV infection. We concluded the chapter by discussing the obstacles to the HIV prenatal screening and prevention interventions. Prena‐

immunodeficiency (Jamieson et al., 2007).

tum morbidity (26.7%) (Read et al, 2001).

distress syndrome (Livingston et al., 2010).

**8. Conclusion**

**gestation**

In a largest analysis to date, Tuomola et al did not find an increased rate of premature birth or low birth-weight infants among 2,123 HIV infected pregnant women from seven clinical studies who received combination ART and gave birth from 1990 through 1998.

### **5. Risks of ART to mothers**

A large prospective study evaluating the rates of maternal toxicity, pregnancy complica‐ tions, and peripartum morbidity among HIV-infected pregnant women receiving prenatal care and ART concluded that adverse events were rare. Gestational diabetes was noted to be highest among women who received combination therapy including protease inhibitors ei‐ ther before or during first trimester (Watts et al, 2004). Reports of potential risks of hepatic toxicity and hypersensitivity reaction were noted in pregnant women receiving the drug Ne‐ virapine (Bardeguez, 2009).

Another valid concern is the potential development of drug resistance when ART was ad‐ ministered to the mother for a short period during pregnancy. Drug resistance was noted in 20 – 69% of women who received only intrapartum prophylaxis with single-dose nevira‐ pine. This could decrease the choice of medications for these women should they later need treatment for their disease. Although, there are reports that this observed resistance dis‐ solved over time. (Bardeguez, 2009). Limited exposure to zidovudine alone did not alter ma‐ ternal disease progression, time until development of AIDS or death, or development of genotypic zidovudine resistance (Bardeguez et al, 2003).

### **6. Potential maternal risks from scheduled cesarean delivery**

Cesarean deliveries could result in significant complications when compared to vaginal de‐ livery even for HIV-negative women (Allen et al., 2003; Makoha et al., 2004). HIV-infected women with an immunodeficient state could potentially at risk for post-operative infectious morbidities. Most studies report that HIV-infected women are at higher risk for post-opera‐ tive complications, mostly infectious, than the uninfected women (Coll et al., 2002; Grubert el al., 1999; Vimercati et al., 2000). The rate of complications is higher in those with severe immunodeficiency (Jamieson et al., 2007).

Read et al conducted a largest prospective observational study which included 1,186 HIV-infected women from The Women and Infants Transmission Study. The authors evaluated the postpartum morbidity among these infected women according to their mode of delivery. When compared to women who delivered vaginally, women who un‐ derwent scheduled cesarean delivery had an increased rate of postpartum fever (14.3%), hemorrhage (7.1%), endometritis (5.4%), urinary tract infection (5.4%), and any postpar‐ tum morbidity (26.7%) (Read et al, 2001).

### **7. Potential neonatal risks from scheduled cesarean delivery at 38 weeks gestation**

In the absence of medical or obstetrical indications, ACOG recommends against sched‐ uled cesarean delivery at less than 39 weeks of gestation, due to the increased risk of respiratory morbidity in the neonate born prior to this gestational age (ACOG, 2001). Neonatal morbidity is high even among those neonates born via cesarean delivery a few days younger than 39 weeks (Tita et al, 2011). However, both ACOG and U.S. Public Health Service recommend scheduled cesarean delivery at 38 weeks for HIV-in‐ fected women with viral load greater than 1,000 copies/ml (ACOG, 2001; Public Health Service Task Force, 2010). The scheduled cesarean delivery date is set at one week ear‐ lier than the usually required gestational age of 39 weeks to avoid onset of spontane‐ ous labor and rupture of membranes which could increase perinatal transmission of HIV. Livingston et al and the IMPACT Protocol 1025 Study Group evaluated the risk of neonatal respiratory distress syndrome according to the mode of delivery and gesta‐ tional age at delivery. They reported that the mode of delivery was not associated with respiratory distress syndrome. However, there was a trend toward a higher risk of respiratory distress syndrome among neonates delivered by either elective or nonelective cesarean section when compared to those delivered vaginally. Two out of 227 neonates born via scheduled cesarean delivery at 38 weeks gestation had respiratory distress syndrome (Livingston et al., 2010).

### **8. Conclusion**

**4.2. Association between ART and preterm birth and low-birth weight**

itor had an increased risk of preterm delivery (Cotter et al, 2006).

genotypic zidovudine resistance (Bardeguez et al, 2003).

**6. Potential maternal risks from scheduled cesarean delivery**

**5. Risks of ART to mothers**

84 Current Perspectives in HIV Infection

virapine (Bardeguez, 2009).

Inconsistent results were noted among the reports studying the effects of combination antire‐ troviral therapy on two obsterics outcomes: preterm birth and low birth-weight. Lorenzi et al in 1998 first reported the association between combination antiretroviral therapy with preterm birth in a retrospective Swiss study of 30 women (Lorenzi et al, 1998). Subsequently, other Euro‐ pean studies reported a similar association between combination antiretroviral therapy and preterm birth (The European Collaborative Study (ECS) andSwiss Mother + Child HIV Cohort Study (Mo-CHiV), 2000, Grosch-Woerner et al, 2008). However, this association was not found in U.S. studies until a recent study by Cotter et al. The authors prospectively collected the data from 1990 through 2002 on 999 women receiving antiretroviral regimen during pregnancy. They concluded that women who received combination therapy that included a protease inhib‐

In a largest analysis to date, Tuomola et al did not find an increased rate of premature birth or low birth-weight infants among 2,123 HIV infected pregnant women from seven clinical

A large prospective study evaluating the rates of maternal toxicity, pregnancy complica‐ tions, and peripartum morbidity among HIV-infected pregnant women receiving prenatal care and ART concluded that adverse events were rare. Gestational diabetes was noted to be highest among women who received combination therapy including protease inhibitors ei‐ ther before or during first trimester (Watts et al, 2004). Reports of potential risks of hepatic toxicity and hypersensitivity reaction were noted in pregnant women receiving the drug Ne‐

Another valid concern is the potential development of drug resistance when ART was ad‐ ministered to the mother for a short period during pregnancy. Drug resistance was noted in 20 – 69% of women who received only intrapartum prophylaxis with single-dose nevira‐ pine. This could decrease the choice of medications for these women should they later need treatment for their disease. Although, there are reports that this observed resistance dis‐ solved over time. (Bardeguez, 2009). Limited exposure to zidovudine alone did not alter ma‐ ternal disease progression, time until development of AIDS or death, or development of

Cesarean deliveries could result in significant complications when compared to vaginal de‐ livery even for HIV-negative women (Allen et al., 2003; Makoha et al., 2004). HIV-infected women with an immunodeficient state could potentially at risk for post-operative infectious

studies who received combination ART and gave birth from 1990 through 1998.

Current evidence supports prenatal HIV screening. The benefits from screening appear to outweight the small risks / harms to the fetus and mothers from the treatment interventions which significantly reduce perinatal-acquired HIV infection. We concluded the chapter by discussing the obstacles to the HIV prenatal screening and prevention interventions. Prena‐ tal screening for HIV infection and implementation of Protocol 076 were lauded as a major public health success story and resulted in a significant decline in the number of children infected with HIV from their mother. However, in the United States, there are still about 100–200 infants born every year with perinatally acquired HIV infection (CDC, 2007). Lack of prenatal care remains one of the obstacles to prevention of perinatal transmission of HIV. In the United States about 5 to 10% of women do not pursue prenatal care or receive insuffi‐ cient care (Kogan et al., 1998). HIV infected women, in particular, often do not receive pre‐ natal care. In New York City, 50% of women infected with HIV who delivered in at a municipal hospital did not receive prenatal care (Minkoff et al., 1990). Of the HIV-infected women surveyed in Philadelphia, only one third reported adequate prenatal care, and 20% did not receive any care (Turner et al., 1996).

Lastly, not only obstetricians and gynecologists need to follow the CDC and ACOG guidelines in providing opt-out prenatal screening for HIV they must receive appropri‐ ate training for pre and post screening counseling and must ensure patient confiden‐ tiality. More importantly, at every screening they must be prepared for positive results: they must be compassionate toward those tested positive and must have re‐ sources available for their emotional support beyond providing the standard medical

Screening for HIV Infection in Pregnancy http://dx.doi.org/10.5772/54551 87

Department of Obstetrics and Gynecology, Tulane University School of Medicine, New

[1] Allen, V. M, Connell, O, Liston, C. M, & Baskett, R. M. T.F. ((2003). Maternal morbidi‐ ty associated with cesarean deliverywithout labor compared with spontaneous onset

[2] American College of Obstetricians and Gynecologists. ACOG Committee Opinion Routine Human Immunodeficiency Virus Screening. Obstetrics and Gynecology

[3] American College of Obstetricians and Gynecologists. ACOG Committee Opinion Prenatal and Perinatal Human Immunodeficiency Virus Testing: Expanded Recom‐

[4] American College of Obstetricians and GynecologistsACOG committee opinion # 234. Scheduled cesarean delivery and the prevention of vertical transmission of HIV

[5] Bardeguez, A. D, Shapiro, D. E, Mofenson, L. M, Coombs, R, Frenkel, L. M, Fowler, M. G, et al. Effect of cessation of zidovudine prophylaxis to reduce vertical transmis‐ sion on maternal HIV disease progression and survival. J Acquir Immune Defic

[6] Brabin, L. (2002). Interactions of the Female Hormonal Environment, Susceptibility to Viral Infections, and Disease Progression. *AIDS Patient Care and STDs*, 211 EOF-221

mendations. Obstetrics and Gynecology (2008). , 112: 739-742.(418)

interventions to decrease vertical transmission.

\*Address all correspondence to: cdola@tulane.edu

(2008). , 112: 401-403.(411)

infection. May, (2000).

Syndr (2003). , 32, 170-81.

EOF.

, Maga Martinez, Olivia Chang and Amanda Johnson

of labor at term. Obstet Gynecol 2003; , 102, 477-82.

**Author details**

Orleans, Louisiana, USA

Chi Dola\*

**References**

Even more worrisome, at the Medical Center of Louisiana in New Orleans, LA, 50% of the HIV-infected parturients who did not have prenatal care but presented to the hospital for labor and delivery did not disclose their HIV status to their physicians (CDC, 2004). Could it be because the HIV-infected women did not know of the available interventions that they put their infants at risk for the infection?

Several authors attempt to understand why HIV-infected women opted out of prenatal care and available interventions to decrease vertical transmission. Rothpletz-Puglia et al solicited opinions from a group of HIV-negative women about the process of prenatal HIV screening. The authors reported that fear was a big factor for declining testing. The women are afraid to find out they are HIV-infected. They are frightened to discover a partner's infidelity. They are fearful of being judged by their health care provider or of being denied medical care if they tested positive (Rothpletz-Puglia et al, 2001).

Lancioni et al. reported that HIV-infected women did not participate in prenatal care be‐ cause they fear disclosing their status to their caretakers and being judged by them for con‐ tinuing the pregnancy (Lancioni et al., 1999). In a recent report by Lindau et al, HIV-infected women who were interviewed were aware of the benefits of prophylaxis treatment yet most received insufficient or no prenatal care. They knew of their HIV infection diagnosis but most did not disclose their status to their caretaker when they presented for delivery at hos‐ pitals capable of providing prophylaxis treatment. They attributed health care providers' lack of sensitivity, violations of confidentiality, disdain for HIV infection and substance abuse as reasons for their non-participation in prenatal care, avoidance of treatment for HIV infection, and non-disclosure of their HIV status. Denial and fear were other barriers to HIV prophylaxis treatment (Lindau, 2006).

We agreed with Lindau et al that may be what is needed to further reduce perinatal trans‐ mission beyond the conventional models for prevention is to understand the HIV-infected women's point of view, their fears and concerns and to eliminate the disrespect treatment as perceived by them from the health care providers. It is hope that we can create a medical environment where these women will be confident of our compassion and care to disclose their status and to want to seek prenatal care and HIV prophylaxis treatment (Lindau, 2006).

Lastly, not only obstetricians and gynecologists need to follow the CDC and ACOG guidelines in providing opt-out prenatal screening for HIV they must receive appropri‐ ate training for pre and post screening counseling and must ensure patient confiden‐ tiality. More importantly, at every screening they must be prepared for positive results: they must be compassionate toward those tested positive and must have re‐ sources available for their emotional support beyond providing the standard medical interventions to decrease vertical transmission.

### **Author details**

tal screening for HIV infection and implementation of Protocol 076 were lauded as a major public health success story and resulted in a significant decline in the number of children infected with HIV from their mother. However, in the United States, there are still about 100–200 infants born every year with perinatally acquired HIV infection (CDC, 2007). Lack of prenatal care remains one of the obstacles to prevention of perinatal transmission of HIV. In the United States about 5 to 10% of women do not pursue prenatal care or receive insuffi‐ cient care (Kogan et al., 1998). HIV infected women, in particular, often do not receive pre‐ natal care. In New York City, 50% of women infected with HIV who delivered in at a municipal hospital did not receive prenatal care (Minkoff et al., 1990). Of the HIV-infected women surveyed in Philadelphia, only one third reported adequate prenatal care, and 20%

Even more worrisome, at the Medical Center of Louisiana in New Orleans, LA, 50% of the HIV-infected parturients who did not have prenatal care but presented to the hospital for labor and delivery did not disclose their HIV status to their physicians (CDC, 2004). Could it be because the HIV-infected women did not know of the available interventions that they

Several authors attempt to understand why HIV-infected women opted out of prenatal care and available interventions to decrease vertical transmission. Rothpletz-Puglia et al solicited opinions from a group of HIV-negative women about the process of prenatal HIV screening. The authors reported that fear was a big factor for declining testing. The women are afraid to find out they are HIV-infected. They are frightened to discover a partner's infidelity. They are fearful of being judged by their health care provider or of being denied medical care if

Lancioni et al. reported that HIV-infected women did not participate in prenatal care be‐ cause they fear disclosing their status to their caretakers and being judged by them for con‐ tinuing the pregnancy (Lancioni et al., 1999). In a recent report by Lindau et al, HIV-infected women who were interviewed were aware of the benefits of prophylaxis treatment yet most received insufficient or no prenatal care. They knew of their HIV infection diagnosis but most did not disclose their status to their caretaker when they presented for delivery at hos‐ pitals capable of providing prophylaxis treatment. They attributed health care providers' lack of sensitivity, violations of confidentiality, disdain for HIV infection and substance abuse as reasons for their non-participation in prenatal care, avoidance of treatment for HIV infection, and non-disclosure of their HIV status. Denial and fear were other barriers to HIV

We agreed with Lindau et al that may be what is needed to further reduce perinatal trans‐ mission beyond the conventional models for prevention is to understand the HIV-infected women's point of view, their fears and concerns and to eliminate the disrespect treatment as perceived by them from the health care providers. It is hope that we can create a medical environment where these women will be confident of our compassion and care to disclose their status and to want to seek prenatal care and HIV prophylaxis treatment (Lindau, 2006).

did not receive any care (Turner et al., 1996).

86 Current Perspectives in HIV Infection

put their infants at risk for the infection?

they tested positive (Rothpletz-Puglia et al, 2001).

prophylaxis treatment (Lindau, 2006).

Chi Dola\* , Maga Martinez, Olivia Chang and Amanda Johnson

\*Address all correspondence to: cdola@tulane.edu

Department of Obstetrics and Gynecology, Tulane University School of Medicine, New Orleans, Louisiana, USA

### **References**


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92 Current Perspectives in HIV Infection


**Chapter 5**

**Human Immunodeficiency**

**Virus Testing Algorithm in**

**Resource Limiting Settings**

Teddy Charles Adias and Osaro Erhabor

http://dx.doi.org/10.5772/53675

services is being advocated globally.

to HIV testing (PAHO, 2008).

general population and Cost of testing (WHO, 2004).

**1. Introduction**

Additional information is available at the end of the chapter

Testing and counseling for human immunodeficiency virus (HIV) is now recognized as a priority in national HIV programs because it is the gateway to HIV/AIDS prevention, care, treatment, and support interventions. In order to ensure access to HIV testing for large pop‐ ulations and to facilitate access to antiretroviral treatment in the context of the World Health Organization's universal access strategy, radical scaling up of HIV testing and counseling

The use of HIV rapid tests will facilitate this in many settings, particularly in services in which the people most likely to benefit from knowing their HIV status can be reached. These Settings include diagnostic and treatment services for tuberculosis and sexually trans‐ mitted infections; services linked to the prevention of mother-to-child transmission of HIV; the management of occupational and non-occupational exposures to HIV; at voluntary counseling and testing (VCT) sites; in remote areas where the creation and maintenance of a laboratory infrastructure is not possible; and where hard-to-reach populations have access

To date, HIV testing strategies has clear objective for diagnosis, surveillance and transfusion safety. The need for appropriate selection of testing platforms and protocol had also varied from setting to setting. In general, four criteria had underpinned the choice of most appro‐ priate test or combination of tests for any given setting and depend on: General goal for test‐ ing, Diagnostic indices of sensitivity and specificity, Prevalence of HIV infection in the

and reproduction in any medium, provided the original work is properly cited.

© 2013 Adias and Erhabor; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**Chapter 5**
