**3. Hodgkin's lymphoma and HIV**

#### **3.1. Introduction and epidemiology**

298 Immunodeficiency

**Figure 1.** HIV seropositive and HIV seronegative patients with non-Hodgkin's Lymphoma from 1993

**Figure 2.** HIV seropositive and HIV seronegative patients with Hodgkin's Lymphoma from 1990 to

to 2008 seen at Chris Hani Baragwanath Academic Hospital

2011 seen at Chris Hani Baragwanath Academic Hospital

HL occurring in the setting of immunodeficiency (with particular reference to HIV/AIDS) is generally aggressive, presents with advanced stage disease, frequent constitutional ('B') symptoms, less favourable histology, more frequent bone marrow involvement and a poorer prognosis compared to immunocompetent individuals (17,18).

With the advent of HAART (highly active antiretroviral therapy), now referred to as cART (combination antiretroviral therapy), the AIDS related morbidity, particularly with respect to opportunistic infections has decreased and the survival of HIV/AIDS patients has increased (35,36). In the post cART era, ADCs (AIDS-defining cancers) continue to fall, but the rates of NADCs (non-AIDS defining cancers) such as HL, anal carcinoma, lung carcinoma and skin cancers are on the increase (37). With HL, there is a noticeably increasing relative risk of approximately 10 - 15 fold, compared with the general population (13-15,17,18,20-22).

Several epidemiological studies conducted in the last two decades, and summarised in the article by Carbone et al, 2009 (22) strongly support the evidence that HIV positive individuals have a higher risk of developing HL compared to their HIV negative counterparts. This is in contrast to HIV-NHL or HIV-Kaposi's sarcoma (where the incidence of the disease has decreased significantly after the introduction of cART). cART has allowed the use of standard therapeutic options to be delivered to seropositive patients in a more optimal manner, bringing about renewed optimism in the management of such patients. cART use is associated with higher CD4 T cell counts and enhanced immunity. Thus, despite the benefit of cART, which improves immunity and decreases the risk of opportunistic infections, there is a paradoxical increased risk of HL (22). The authors conclude that the improved CD4 T cell count that occurs post cART use, provides antiapoptotic pathways and mechanisms for immune escape by tumour cells, thus resulting in an increased risk of HL (22).

Hodgkin's Lymphoma and Human Immunodeficiency Virus Infection 301

RS cells of classical HL represent transformed B cells (post germinal center B cells) that originate from preapoptotic germinal center B cells. They express CD15 and CD30 as well as LMP-1 and display a BCL6-/CD138+/MUM1/IRF4+ (Interferon Regulatory Factor-4) phenotype (43,47,48). In addition, LMP2A and EBNA-1 may also contribute to the development of the RS cells and are expressed in the RS cells of this tumour (44,45). LMP2A may promote the survival of the 'crippled' germinal center B cells, thereby aiding in their

In general, HIV-seropositive patients with HL tend to have a more aggressive clinical course than their seronegative counterparts. The behaviour of the disease is different, and based on a number of studies (22,50-57), the following characteristics were noted: more frequent constitutional 'B' symptoms – 70-96%, more advanced stage disease (III and IV) – 74-92%, , more frequent involvement of extranodal sites – 17-62%, with bone marrow involvement being the most common extranodal site – 40-59%, followed by involvement of the liver – 17-40% and spleen – 20-30%. The vast majority (>80%) of the patients were males. The median age at presentation was approximately 34 years. The median CD4 count was mostly in the intermediate range of 240-306/μl (22,50-57). Compared to HIV negative HL, where nodular sclerosis is the dominant histological subtype, mixed cellularity is most commonly encountered in HIV-HL – 33-53% (17,22,34,56-57). Nodular sclerosis is the second most common histological subtype in HIV-HL – 24-31%. However, with more severe immunosuppression, nodular sclerosis becomes infrequent (38). There is also an increasing number of patients with lymphocyte depleted histology - 14-20% in HIV-HL (17,22,56-57).

Based on the Italian Cooperative Group on AIDS and Tumors (GICAT) study, in comparison with patients who were cART naive, patients receiving cART before the onset of HL are older, have less B symptoms, have higher leukocyte and neutrophil counts and have

In a recent review of 43 patients with HIV associated HL seen at CHBAH over a 2 year period (July 2008 – June 2010) a number of striking similarities and differences were noted when comparing this cohort with other published studies outside of Africa (17). The median age at presentation of 38 years was similar to other series. There was no striking male predominance. Conversely, the male to female ratio is almost equal at 1.1:1. All the patients had heterosexual acquisition of HIV. None of the patients acquired their HIV through intravenous drug use or homosexual contacts. This is different to other series where homosexuality and intravenous drug use are significant, documented risk groups (15,20,22,50,56,57). The presentation with advanced stage disease (82%), more frequent 'B' symptoms (93%), more frequent involvement of extranodal sites (bone marrow-38%; liver-45%; spleen-28%) and 'true' extranodal sites (17%) and the histological pattern of disease (mixed cellularity being the most common) is similar to that reported in the literature. The median CD4 count of 176/μl is generally lower, although there are series reported of HIV-HL with median CD4 counts of <200/μl (51). In this series 12/29 (41%) of the patients had

development (49).

a higher haemoglobin level (56).

**3.3. Clinical presentation and management** 

However, in contrast to this, a 20-year cohort study has shown that with the advent of antiretroviral therapy, ADCs (AIDS-defining cancers) continue to fall, but the rates of NADCs (non-AIDS defining cancers) are on the increase. The authors suggest that this increase appears to be more related to the aging of the HIV population (i.e. increased longevity allowing a greater risk of developing lymphoma) rather than the antiretroviral therapy and its effect on the CD4 T cell count (37).

#### **3.2. Pathogenesis**

Histologically, HL is characterized by a population of neoplastic Reed-Sternberg (RS) cells, which constitute <1-2% of the cellular component, admixed with a reactive, mixed inflammatory infiltrate of lymphocytes, plasma cells, eosinophils and histiocytes. Cytokines and chemokines are produced by either the RS cells or the reactive cells in the background micro-environment of the tissue. The cytokine production may explain the presence and maintenance of an impaired immune response, while the chemokines (cytokines with chemoattractant properties) play a role in leucocyte trafficking, attract chemokine receptor CCR4-expressing Th-2 cells and T regulatory cells, and allow a favourable environment for survival of RS cells (38-40). Cross talk between the RS cells and reactive cells mediated by cytokines such as IL-13, IL-17, IL-10, transforming growth factor-beta and chemokines principally CCL17 (thymus and activation-regulated chemokine, TARC) and CCL22 (macrophage-derived chemokine, MDC), lead to an environment where RS cells are able to proliferate, escape from apoptosis and survive host anti-tumour defense (38-40). The CD4+ T cells surrounding the neoplastic cells in HL are CD45RO+/CD45RA-/CD45RBdim, suggesting a memory Th2 phenotype (41).

HIV-associated immunosuppression is a state that permits the unchecked and uncontrolled proliferation of Epstein-Barr virus (EBV) infection. EBV has been implicated in the etiopathogenesis of classic HL, with a high frequency of EBV association (80-100%) noted in tissues of patients with HIV-HL (42,43). EBV transforming proteins, such as latent membrane protein-1 (LMP-1), is expressed in virtually all HIV-HL patients (43-45). The expression of EBV-LMP-1 is important in the pathogenesis of HIV-HL. LMP-1 expression by EBV-infected RS cells represents the principal mechanism for constitutive NF (nuclear factor) -κB activity, which confers an apoptosis resistant phenotype to the RS cells (43,45). EBV-immortalized B cells also produce CCL17 and CCL22 through LMP-1 mediated activation of NFκB (46).

RS cells of classical HL represent transformed B cells (post germinal center B cells) that originate from preapoptotic germinal center B cells. They express CD15 and CD30 as well as LMP-1 and display a BCL6-/CD138+/MUM1/IRF4+ (Interferon Regulatory Factor-4) phenotype (43,47,48). In addition, LMP2A and EBNA-1 may also contribute to the development of the RS cells and are expressed in the RS cells of this tumour (44,45). LMP2A may promote the survival of the 'crippled' germinal center B cells, thereby aiding in their development (49).

#### **3.3. Clinical presentation and management**

300 Immunodeficiency

an increased risk of HL (22).

**3.2. Pathogenesis** 

a memory Th2 phenotype (41).

activation of NFκB (46).

therapy and its effect on the CD4 T cell count (37).

of the disease has decreased significantly after the introduction of cART). cART has allowed the use of standard therapeutic options to be delivered to seropositive patients in a more optimal manner, bringing about renewed optimism in the management of such patients. cART use is associated with higher CD4 T cell counts and enhanced immunity. Thus, despite the benefit of cART, which improves immunity and decreases the risk of opportunistic infections, there is a paradoxical increased risk of HL (22). The authors conclude that the improved CD4 T cell count that occurs post cART use, provides antiapoptotic pathways and mechanisms for immune escape by tumour cells, thus resulting in

However, in contrast to this, a 20-year cohort study has shown that with the advent of antiretroviral therapy, ADCs (AIDS-defining cancers) continue to fall, but the rates of NADCs (non-AIDS defining cancers) are on the increase. The authors suggest that this increase appears to be more related to the aging of the HIV population (i.e. increased longevity allowing a greater risk of developing lymphoma) rather than the antiretroviral

Histologically, HL is characterized by a population of neoplastic Reed-Sternberg (RS) cells, which constitute <1-2% of the cellular component, admixed with a reactive, mixed inflammatory infiltrate of lymphocytes, plasma cells, eosinophils and histiocytes. Cytokines and chemokines are produced by either the RS cells or the reactive cells in the background micro-environment of the tissue. The cytokine production may explain the presence and maintenance of an impaired immune response, while the chemokines (cytokines with chemoattractant properties) play a role in leucocyte trafficking, attract chemokine receptor CCR4-expressing Th-2 cells and T regulatory cells, and allow a favourable environment for survival of RS cells (38-40). Cross talk between the RS cells and reactive cells mediated by cytokines such as IL-13, IL-17, IL-10, transforming growth factor-beta and chemokines principally CCL17 (thymus and activation-regulated chemokine, TARC) and CCL22 (macrophage-derived chemokine, MDC), lead to an environment where RS cells are able to proliferate, escape from apoptosis and survive host anti-tumour defense (38-40). The CD4+ T cells surrounding the neoplastic cells in HL are CD45RO+/CD45RA-/CD45RBdim, suggesting

HIV-associated immunosuppression is a state that permits the unchecked and uncontrolled proliferation of Epstein-Barr virus (EBV) infection. EBV has been implicated in the etiopathogenesis of classic HL, with a high frequency of EBV association (80-100%) noted in tissues of patients with HIV-HL (42,43). EBV transforming proteins, such as latent membrane protein-1 (LMP-1), is expressed in virtually all HIV-HL patients (43-45). The expression of EBV-LMP-1 is important in the pathogenesis of HIV-HL. LMP-1 expression by EBV-infected RS cells represents the principal mechanism for constitutive NF (nuclear factor) -κB activity, which confers an apoptosis resistant phenotype to the RS cells (43,45). EBV-immortalized B cells also produce CCL17 and CCL22 through LMP-1 mediated In general, HIV-seropositive patients with HL tend to have a more aggressive clinical course than their seronegative counterparts. The behaviour of the disease is different, and based on a number of studies (22,50-57), the following characteristics were noted: more frequent constitutional 'B' symptoms – 70-96%, more advanced stage disease (III and IV) – 74-92%, , more frequent involvement of extranodal sites – 17-62%, with bone marrow involvement being the most common extranodal site – 40-59%, followed by involvement of the liver – 17-40% and spleen – 20-30%. The vast majority (>80%) of the patients were males. The median age at presentation was approximately 34 years. The median CD4 count was mostly in the intermediate range of 240-306/μl (22,50-57). Compared to HIV negative HL, where nodular sclerosis is the dominant histological subtype, mixed cellularity is most commonly encountered in HIV-HL – 33-53% (17,22,34,56-57). Nodular sclerosis is the second most common histological subtype in HIV-HL – 24-31%. However, with more severe immunosuppression, nodular sclerosis becomes infrequent (38). There is also an increasing number of patients with lymphocyte depleted histology - 14-20% in HIV-HL (17,22,56-57).

Based on the Italian Cooperative Group on AIDS and Tumors (GICAT) study, in comparison with patients who were cART naive, patients receiving cART before the onset of HL are older, have less B symptoms, have higher leukocyte and neutrophil counts and have a higher haemoglobin level (56).

In a recent review of 43 patients with HIV associated HL seen at CHBAH over a 2 year period (July 2008 – June 2010) a number of striking similarities and differences were noted when comparing this cohort with other published studies outside of Africa (17). The median age at presentation of 38 years was similar to other series. There was no striking male predominance. Conversely, the male to female ratio is almost equal at 1.1:1. All the patients had heterosexual acquisition of HIV. None of the patients acquired their HIV through intravenous drug use or homosexual contacts. This is different to other series where homosexuality and intravenous drug use are significant, documented risk groups (15,20,22,50,56,57). The presentation with advanced stage disease (82%), more frequent 'B' symptoms (93%), more frequent involvement of extranodal sites (bone marrow-38%; liver-45%; spleen-28%) and 'true' extranodal sites (17%) and the histological pattern of disease (mixed cellularity being the most common) is similar to that reported in the literature. The median CD4 count of 176/μl is generally lower, although there are series reported of HIV-HL with median CD4 counts of <200/μl (51). In this series 12/29 (41%) of the patients had newly diagnosed HIV at the time of the diagnosis of HL. In 62% of the patients, the duration of the diagnosis of HIV (including new patients was < 1 year). Only 45% of the patients were on antiretroviral therapy at diagnosis of HL, compared to 71-80% in other series (22,56,57). A further striking difference is the high proportion of patients with Tuberculosis in this series – 59% (38% with active disease and 21% with past, documented disease). The high prevalence of tuberculosis may be a reflection of the more severe immunosuppression in the patients, the delay in diagnosis of HIV and hence the absence of antiretroviral therapy use at diagnosis and the very common occurrence of tuberculosis in the general population. The presence of tuberculosis, often in a disseminated fashion, has an adverse impact on the clinical outcome of the patients. In general, the outcome of the HIV-HL patients was less favourable than the HIV seronegative patients (17).

Hodgkin's Lymphoma and Human Immunodeficiency Virus Infection 303

myelosuppression, potential drug-drug interactions of the antiretrovirals and anti-infectives with chemotherapy, the advanced and widespread nature of the disease at presentation and the preponderance of less favourable histological subtypes. Treatment approaches include vigorous supportive care (HAART, antivirals, antifungals, neutrophil-stimulating growth

Chemotherapy regimens for HIV-HL such as EBV, EBVP, ABVD and MOPP/ABV hybrid are feasible and can be delivered with concomitant cART. The AIDS Clinical Trials Group (ACTG) treated 21 patients with ABVD for 4-6 cycles with G-CSF support. Antiretroviral therapy was not used. The complete remission rate (CR) was 43% with a median overall survival of 18 months (59). In a more recent Spanish study (GESIDA – Groupo de Estudia de SIDA), 62 patients with HIV-HL received the standard, full-dose ABVD and cART with 87% of the patients achieving a CR. The 5-year overall survival (OS) and event-free survival (EFS) probabilities were 76 and 71% respectively. The immunological response to HAART had a positive impact on OS (p=0.002) and EFS (p=0.001) (60). Use of cART substantially improves the overall survival in HIV associated HL. This is due to a decrease in the incidence of opportunistic infections, the ability to deliver more appropriate and aggressive chemotherapy on schedule and to the less aggressive presentation of lymphoma in patients on cART, in comparison with those lymphomas that arise in patients who never received cART (50-53). In the study of Hentrich et al, 2006, 34/59 patients receiving cART (n=34) had a significantly better 2-year overall survival than those not receiving cART (74% versus 30%, p<0.001) (61). The advent of cART also allows for more aggressive treatment options such as VEBEP (62), BEACOPP (63), Stanford V (64) and the use of high-dose chemotherapy and autologous stem cell transplantation (ASCT) in selected patients (65,66). However, in general, response rates and cure rates are lower than in HIV seronegative patients, despite the substantial progress made in the last decade. The challenge at present is to optimise the use of standard approaches as used in HIV negative HL. Once this is established, evaluation

HIV is associated with an increased risk of developing HL, a risk that has not lessened despite the introduction and benefit of cART. HL is now being regarded among the most common NADCs, which have clearly increased in the post cART era. The association from being largely coincidental (overlapping and similar age group for both HL and HIV) may now be increasingly causal, with the most plausible explanation being attributed to the

The recognition of an increasing trend of HIV-HL in resource-poor settings needs to be further highlighted, so that early diagnosis, early recourse to cART and appropriate supportive therapy and specific therapy such as chemotherapy can be administered to

Therapy of HIV associated HL entails using the same therapeutic approaches as in seronegative HL, including standard chemotherapy regimens such as ABVD, and in the

factors), together with standard multiagent chemotherapy.

of experimental and newer therapies should follow.

pathogenetic role of Epstein Barr virus infection.

**4. Conclusion** 

improve survival.

In another local study from CHBAH, covering a fifteen period from 1990 to 2004, the clinical characteristics of 163 patients with Hodgkin's lymphoma are reviewed (58). Table 2 depicts the differences between the HIV seropositive and HIV seronegative patients in this study.


**Table 2.** Clinical characteristics of HIV seropositive and HIV seronegative patients seen over a fifteen year period (1990 - 2004) at Chris Hani Baragwanath Academic Hospital (adapted from Fazel, 2012)

Based on the findings of this study, HIV seronegative patients compared to HIV seropositive patients have more advanced stage disease, a higher frequency of mixed cellularity subtype, a slightly higher risk of tuberculosis and 'true' extranodal disease and a poorer response to treatment (58).

The management of HIV-HL is challenging because of the frequency of infections, likelihood of organ dysfunction due to HIV, more frequent involvement of the bone marrow, increased myelosuppression, potential drug-drug interactions of the antiretrovirals and anti-infectives with chemotherapy, the advanced and widespread nature of the disease at presentation and the preponderance of less favourable histological subtypes. Treatment approaches include vigorous supportive care (HAART, antivirals, antifungals, neutrophil-stimulating growth factors), together with standard multiagent chemotherapy.

Chemotherapy regimens for HIV-HL such as EBV, EBVP, ABVD and MOPP/ABV hybrid are feasible and can be delivered with concomitant cART. The AIDS Clinical Trials Group (ACTG) treated 21 patients with ABVD for 4-6 cycles with G-CSF support. Antiretroviral therapy was not used. The complete remission rate (CR) was 43% with a median overall survival of 18 months (59). In a more recent Spanish study (GESIDA – Groupo de Estudia de SIDA), 62 patients with HIV-HL received the standard, full-dose ABVD and cART with 87% of the patients achieving a CR. The 5-year overall survival (OS) and event-free survival (EFS) probabilities were 76 and 71% respectively. The immunological response to HAART had a positive impact on OS (p=0.002) and EFS (p=0.001) (60). Use of cART substantially improves the overall survival in HIV associated HL. This is due to a decrease in the incidence of opportunistic infections, the ability to deliver more appropriate and aggressive chemotherapy on schedule and to the less aggressive presentation of lymphoma in patients on cART, in comparison with those lymphomas that arise in patients who never received cART (50-53). In the study of Hentrich et al, 2006, 34/59 patients receiving cART (n=34) had a significantly better 2-year overall survival than those not receiving cART (74% versus 30%, p<0.001) (61). The advent of cART also allows for more aggressive treatment options such as VEBEP (62), BEACOPP (63), Stanford V (64) and the use of high-dose chemotherapy and autologous stem cell transplantation (ASCT) in selected patients (65,66). However, in general, response rates and cure rates are lower than in HIV seronegative patients, despite the substantial progress made in the last decade. The challenge at present is to optimise the use of standard approaches as used in HIV negative HL. Once this is established, evaluation of experimental and newer therapies should follow.

### **4. Conclusion**

302 Immunodeficiency

newly diagnosed HIV at the time of the diagnosis of HL. In 62% of the patients, the duration of the diagnosis of HIV (including new patients was < 1 year). Only 45% of the patients were on antiretroviral therapy at diagnosis of HL, compared to 71-80% in other series (22,56,57). A further striking difference is the high proportion of patients with Tuberculosis in this series – 59% (38% with active disease and 21% with past, documented disease). The high prevalence of tuberculosis may be a reflection of the more severe immunosuppression in the patients, the delay in diagnosis of HIV and hence the absence of antiretroviral therapy use at diagnosis and the very common occurrence of tuberculosis in the general population. The presence of tuberculosis, often in a disseminated fashion, has an adverse impact on the clinical outcome of the patients. In general, the outcome of the HIV-HL patients was less

In another local study from CHBAH, covering a fifteen period from 1990 to 2004, the clinical characteristics of 163 patients with Hodgkin's lymphoma are reviewed (58). Table 2 depicts the differences between the HIV seropositive and HIV seronegative patients in this study.

> 61% 17% 22%

> 27% 19%

> 38% 8%

**Table 2.** Clinical characteristics of HIV seropositive and HIV seronegative patients seen over a fifteen year period (1990 - 2004) at Chris Hani Baragwanath Academic Hospital (adapted from Fazel, 2012)

Based on the findings of this study, HIV seronegative patients compared to HIV seropositive patients have more advanced stage disease, a higher frequency of mixed cellularity subtype, a slightly higher risk of tuberculosis and 'true' extranodal disease and a

The management of HIV-HL is challenging because of the frequency of infections, likelihood of organ dysfunction due to HIV, more frequent involvement of the bone marrow, increased

42% 41% 13%

23% 17%

57% 21%

HIV Status Seropositive Seronegative Total Number of Patients = 163 47 (29%) 116 (71%) Median Age (Range) in Years 30 (13-59) 29 (13-87) M:F Ratio 1.8:1 1.2:1 CD4 Count at Presentation (/ul) 186 (32-769) N/A 'B' Symptoms 77% 78% Advanced Stage (III & IV) Disease 78% 67% 'True' Extranodal Disease 13% 12%

favourable than the HIV seronegative patients (17).

Histological Subtype: Mixed Cellularity Nodular Sclerosis

Treatment Response Complete Response Partial Response

poorer response to treatment (58).

Other

Tuberculosis Prevalence Active Disease

HIV is associated with an increased risk of developing HL, a risk that has not lessened despite the introduction and benefit of cART. HL is now being regarded among the most common NADCs, which have clearly increased in the post cART era. The association from being largely coincidental (overlapping and similar age group for both HL and HIV) may now be increasingly causal, with the most plausible explanation being attributed to the pathogenetic role of Epstein Barr virus infection.

The recognition of an increasing trend of HIV-HL in resource-poor settings needs to be further highlighted, so that early diagnosis, early recourse to cART and appropriate supportive therapy and specific therapy such as chemotherapy can be administered to improve survival.

Therapy of HIV associated HL entails using the same therapeutic approaches as in seronegative HL, including standard chemotherapy regimens such as ABVD, and in the salvage setting, autologous stem cell transplantation in selected patients. In general, the prognosis and overall survival still remains poorer in HIV-HL compared to HIV negative HL. Importantly, the concomitant use of anti-retroviral agents has allowed for the delivery of full-dose and dose-intensive chemotherapy given on schedule, as well as prophylaxis against certain opportunistic infections such as Pneumocystis jirovecii pneumonia, and the liberal use of growth factors (granulocyte colony stimulating factor) and other supportive measures, constitutes an important aspect of supportive therapy and has contributed to an improvement in prognosis. The early recognition and treatment of tuberculosis cannot be overemphasized in settings where tuberculosis is endemic. Newer specific treatment approaches for HL may become necessary in the future to improve survival. However, for the present, HIV-associated HL appears to be on the increase and remains an emerging and ongoing challenge.

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