**The Role of Liver Transplantation in HIV Positive Patients**

Deepak Joshi and Kosh Agarwal

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/51556

### **1. Introduction**

258 Immunodeficiency

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#### **1.1. Burden of liver disease**

In developed countries, the management and treatment of HIV-1 infection was revolutionised after the introduction of combined anti-viral therapy (cART) in 1996. The major outcome was the reduction of AIDS and AIDS-related deaths (1). Such was the success of cART, that now more than 50% of deaths in HIV positive patients on cART are not directly related to HIV infection or AIDS (1-3). The D:A:D (data collection on adverse events of anti-HIV drugs) study demonstrated that liver disease had become the commonest cause of a non-AIDS related death overtaking cardiovascular disease (2). Given the similar transmission routes, unsurprisingly nearly two-thirds of deaths were secondary to chronic hepatitis C virus (HCV) infection, 17% secondary to chronic hepatitis B virus (HBV) infection and 3% due drug-induced liver injury related to cART (2). Other liver-related aetiologies amongst HIV positive individuals include alcohol, non-alcohol related liver disease (NAFLD), hepatocellular carcinoma (HCC) (Table 1). HIV positive patients present with the same clinical sequelae of chronic liver disease as their HIV negative counterparts but tend to present at a younger age but with a markedly reduced survival rate after the first episode of decompensation (4). In HIV-positive patients with compensated cirrhosis an increased mortality rate is associated with age > 50 years, MELD score > 11 and poor control of HIV disease (5).

#### **1.2. Viral aetiologies**

One third of patients with HIV infection are co-infected with chronic HCV, and the majority of deaths in HIV-positive patients with ESLD can be attributable to HCV infection(6). HCV is transmitted via contaminated blood or blood products. At-risk groups include

© 2012 Joshi and Agarwal, licensee InTech. This is an open access chapter 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. © 2012 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.

intravenous drug users, patients with haemophilia who were exposed to contaminated infusions of plasma derived factor VIII or X concentrate, men who have sex with men (MSM) and individuals who have sex with IVDUs (7). Vertical transmission is also possible and is more likely if the mother is HIV-positive. A more recent trend is the increase in the number of new cases of acute HCV in MSM who are HIV-positive acquired via sexual transmission (8, 9).

The Role of Liver Transplantation in HIV Positive Patients 261

HIV/HBV co-infection related – morbidity is considerably less when compared to HIV/HCV co-infected patients. This is due to the use of nucleoside and nucleotide reverse-transcriptase inhibitors (lamivudine, emtricitabine and tenofovir) that are used in cART regimens and

Given that co-infection with HBV and HCV are the leading causes of liver disease amongst HIV-positive patients, the incidence of hepatocellular carcinoma (HCC) is expected to rise and the MORTAVIC and French Mortalite studies have both demonstrated an increasing number of deaths attributable to HCC (6, 32). HIV-positive patients presenting with HCC are younger at presentation (52 versus 64 years, p<0.0001), are more likely to be symptomatic at presentation, have multiple tumours at presentation, and have advanced

Awareness of drug-induced liver injury or cART-induced hepatotoxicity is increasing. Deciding on the culprit drug is often difficult because of the use of combination therapies. Recognised patterns of liver injury include hypersensitivity, idiosyncratic hepatotoxicity, mitochondrial toxicity, an immune reconstitution syndrome and hepato-steatosis (34-38). Acute liver failure resulting from cART is uncommon. The development of non-cirrhotic portal hypertension (NCPH) secondary to cART in particular to didanosine is an emerging disease entity (39). The pathogenesis of NCPH appears to be linked to a pro-thrombotic state, an acquired protein S deficiency. The spectrum of histological findings include nodular regenerative hyperplasia, hepatoportal sclerosis, peri-portal fibrosis and sclerosing

The D:A:D study also highlighted that the prevalence of the metabolic syndrome has increased over the last decade from 19% in 2000-2001 to 42% in2006-2007 (43). This is likely to result in an increase in the prevalence of NAFLD, given that NAFLD is the hepatic manifestation of the metabolic syndrome. There is limited data available on the risk factors for NAFLD in HIV-positive patients but attention has focused on the role of cART because of its negative effects of insulin resistance, glucose metabolism and lipid metabolism. Central adiposity, male sex, low serum high-density lipoprotein levels, raised triglycerides levels and an increased ratio of alanine aminotransferase to aspartate aminotransferase have

Irrespective of liver aetiology, HIV-positive patients with liver disease need to be managed in a multi-disciplinary environment by an experienced HIV physician and Hepatologist. Given their rapid disease kinetic, HIV-positive patients with end stage liver disease (ESLD) need to be identified early. Specific guidelines for LT in HIV-positive patients evolved as our understanding of the specific issues faced by this cohort improves. Current US National

been suggested as risk factors for the development of NAFLD (44).

**1.4. Selection criteria for liver transplantation** 

have both anti-HIV and anti-HBV activity.

disease compared to HIV-negative patients (31, 33).

**1.3. Non-viral aetiologies** 

portal venopathy (40-42).

HIV infection clearly affects HCV-related liver disease. The combination of HIV/HCV coinfection is associated with a reduced rate of spontaneous HCV RNA clearance and therefore an increased likelihood of developing chronic HCV infection (10). Once HCV infection is established then a more rapid fibrosis progression rate is evident (11). The development of cirrhosis tends to occur on average 15 years earlier than in HCV monoinfected individuals (12). Predictors of fibrosis progression include detectable HIV viraemia, low CD4+ counts, baseline necro-inflammatory activity on liver biopsy and increased alcohol consumption (>50g per day) (13, 14). HIV/HCV co-infected patients have a poorer survival following the first episode of decompensation; median estimated survival of only 13 months (4). Mechanisms for this accelerated fibrosis rate appear to be multi-factorial and include a weaker adaptive immune response of CD8+ cells, the increased number of the profibrogenic CD8+ cells and relative reduction in CD4+ cells, the presence of insulin resistance and reduction of interleukin – 10 expression(15-19, 19, 20). The HIV virus cannot enter hepatocytes directly but it can upregulate pro-fibrotic pathways e.g. transforming growth factor B-1 which further activates hepatic stellate cells (10).

Treatment of HCV in patients with HIV is more difficult compared to HCV-monoinfected patients and is associated with an increased side-effect profile. At present pegylated interferon and ribavirin are the only licensed medications for the treatment of HCV in HIV/HCV co-infected patients. Compared to HCV mono-infected patients, end-of-treatment (29-62%) and sustained virological response rates (SVR) are inferior (17-35%) (21-26). The use of the newer protease inhibitors in the treatment of HCV in HIV-positive patients has only been limited to the trial arena. Preliminary data from the 110 Phase 2 study demonstrate similar outcomes to monoinfection with 74% SVR 12 in telaprevir triple therapy group (n=38) vs 45% standard of care (n=22); with no breakthrough in HIV RNA and similar side effect profile to monoinfection treated with telaprevir.

HIV-positive patients commonly exhibit evidence of previous HBV infection, whereas 10% of the HIV-positive population have evidence of chronic HBV infection (27). Vertical transmission of HBV remains the most common route of infection worlwide, whilst sexual transmission and percutaneous transmission is more likely in Europe and North America (28, 29). HIV-positive patients that contract HBV infection are less likely to clear the virus, a quarter of patients will develop chronic HBV infection, especially those with low CD4+ cell counts (30). HIV/HBV co-infected patients also have increased HBV DNA viral loads compared to HBV mono-infected patients, which also translates into an increased risk of developing HCC (31).

HIV/HBV co-infection related – morbidity is considerably less when compared to HIV/HCV co-infected patients. This is due to the use of nucleoside and nucleotide reverse-transcriptase inhibitors (lamivudine, emtricitabine and tenofovir) that are used in cART regimens and have both anti-HIV and anti-HBV activity.

Given that co-infection with HBV and HCV are the leading causes of liver disease amongst HIV-positive patients, the incidence of hepatocellular carcinoma (HCC) is expected to rise and the MORTAVIC and French Mortalite studies have both demonstrated an increasing number of deaths attributable to HCC (6, 32). HIV-positive patients presenting with HCC are younger at presentation (52 versus 64 years, p<0.0001), are more likely to be symptomatic at presentation, have multiple tumours at presentation, and have advanced disease compared to HIV-negative patients (31, 33).

#### **1.3. Non-viral aetiologies**

260 Immunodeficiency

transmission (8, 9).

developing HCC (31).

intravenous drug users, patients with haemophilia who were exposed to contaminated infusions of plasma derived factor VIII or X concentrate, men who have sex with men (MSM) and individuals who have sex with IVDUs (7). Vertical transmission is also possible and is more likely if the mother is HIV-positive. A more recent trend is the increase in the number of new cases of acute HCV in MSM who are HIV-positive acquired via sexual

HIV infection clearly affects HCV-related liver disease. The combination of HIV/HCV coinfection is associated with a reduced rate of spontaneous HCV RNA clearance and therefore an increased likelihood of developing chronic HCV infection (10). Once HCV infection is established then a more rapid fibrosis progression rate is evident (11). The development of cirrhosis tends to occur on average 15 years earlier than in HCV monoinfected individuals (12). Predictors of fibrosis progression include detectable HIV viraemia, low CD4+ counts, baseline necro-inflammatory activity on liver biopsy and increased alcohol consumption (>50g per day) (13, 14). HIV/HCV co-infected patients have a poorer survival following the first episode of decompensation; median estimated survival of only 13 months (4). Mechanisms for this accelerated fibrosis rate appear to be multi-factorial and include a weaker adaptive immune response of CD8+ cells, the increased number of the profibrogenic CD8+ cells and relative reduction in CD4+ cells, the presence of insulin resistance and reduction of interleukin – 10 expression(15-19, 19, 20). The HIV virus cannot enter hepatocytes directly but it can upregulate pro-fibrotic pathways e.g. transforming growth

Treatment of HCV in patients with HIV is more difficult compared to HCV-monoinfected patients and is associated with an increased side-effect profile. At present pegylated interferon and ribavirin are the only licensed medications for the treatment of HCV in HIV/HCV co-infected patients. Compared to HCV mono-infected patients, end-of-treatment (29-62%) and sustained virological response rates (SVR) are inferior (17-35%) (21-26). The use of the newer protease inhibitors in the treatment of HCV in HIV-positive patients has only been limited to the trial arena. Preliminary data from the 110 Phase 2 study demonstrate similar outcomes to monoinfection with 74% SVR 12 in telaprevir triple therapy group (n=38) vs 45% standard of care (n=22); with no breakthrough in HIV RNA

HIV-positive patients commonly exhibit evidence of previous HBV infection, whereas 10% of the HIV-positive population have evidence of chronic HBV infection (27). Vertical transmission of HBV remains the most common route of infection worlwide, whilst sexual transmission and percutaneous transmission is more likely in Europe and North America (28, 29). HIV-positive patients that contract HBV infection are less likely to clear the virus, a quarter of patients will develop chronic HBV infection, especially those with low CD4+ cell counts (30). HIV/HBV co-infected patients also have increased HBV DNA viral loads compared to HBV mono-infected patients, which also translates into an increased risk of

factor B-1 which further activates hepatic stellate cells (10).

and similar side effect profile to monoinfection treated with telaprevir.

Awareness of drug-induced liver injury or cART-induced hepatotoxicity is increasing. Deciding on the culprit drug is often difficult because of the use of combination therapies. Recognised patterns of liver injury include hypersensitivity, idiosyncratic hepatotoxicity, mitochondrial toxicity, an immune reconstitution syndrome and hepato-steatosis (34-38). Acute liver failure resulting from cART is uncommon. The development of non-cirrhotic portal hypertension (NCPH) secondary to cART in particular to didanosine is an emerging disease entity (39). The pathogenesis of NCPH appears to be linked to a pro-thrombotic state, an acquired protein S deficiency. The spectrum of histological findings include nodular regenerative hyperplasia, hepatoportal sclerosis, peri-portal fibrosis and sclerosing portal venopathy (40-42).

The D:A:D study also highlighted that the prevalence of the metabolic syndrome has increased over the last decade from 19% in 2000-2001 to 42% in2006-2007 (43). This is likely to result in an increase in the prevalence of NAFLD, given that NAFLD is the hepatic manifestation of the metabolic syndrome. There is limited data available on the risk factors for NAFLD in HIV-positive patients but attention has focused on the role of cART because of its negative effects of insulin resistance, glucose metabolism and lipid metabolism. Central adiposity, male sex, low serum high-density lipoprotein levels, raised triglycerides levels and an increased ratio of alanine aminotransferase to aspartate aminotransferase have been suggested as risk factors for the development of NAFLD (44).

#### **1.4. Selection criteria for liver transplantation**

Irrespective of liver aetiology, HIV-positive patients with liver disease need to be managed in a multi-disciplinary environment by an experienced HIV physician and Hepatologist. Given their rapid disease kinetic, HIV-positive patients with end stage liver disease (ESLD) need to be identified early. Specific guidelines for LT in HIV-positive patients evolved as our understanding of the specific issues faced by this cohort improves. Current US National

Institutes of Health multi-center trial guidelines for LT in HIV positive patients with chronic liver disease are listed in Table 2. UK guidelines have similar requirements.

The Role of Liver Transplantation in HIV Positive Patients 263

contra-indications include multidrug resistant HIV, resistant fungal infections, chronic intestinal cryptosporidiosis, progressive multi-focal leukoencephalopathy and central

Standard surgical techniques with conventional arterial, venous and biliary anastomosis are recommended. One concern highlighted is the possible risk of transmission of HIV to the surgical team. The risk of HIV however is low and is substantially lower than the risk of transmission of HBV and HCV (50). In the event of HIV exposure, current regimens provide effective prophylaxis (51). As HIV infection is associated with a pro-thrombotic state, concerns have been raised regarding an increased risk of vascular complications post transplantation (52). Recent data from our Institution demonstrated an increased an increased incidence of hepatic artery thrombosis compared to HIV negative patients (12% vs. 3.2%, p=0.016) (53). Given the increased pro-thrombotic risk, the introduction of prophylactic subcutaneous heparin (5000 units every 8 hours) is recommended once the international normalised ration (INR) is below 1.5 and the platelet count is greater than 50 x

Immunosuppression should be tailored to the individual taking into account aetiology of liver disease, renal function, risk factors for the metabolic syndrome and specifically to HIV patients the possible interactions with combined anti-viral therapy (cART) medications. Dual immunosuppression with calcineurin inhibitors (CNIs) and cortico-steroids is recommended post-LT. Target trough levels in the first 3 months should be the same as HIV negative patients (cyclosporin, 100-250 ng/ml; tacrolimus, 8-10ng/ml). Utilising data from HCV mono-infected patients post-LT, rapid withdrawal of cortico-steroids should be avoided due to the association of a more severe recurrence of HCV (54). We therefore recommend that prednisolone, which is usually commenced at 20mg daily, be withdrawn by a slow taper at 3 months. Anti-fungal prophylaxis (fluconazole 50mg daily) should be given for a minimum of 3 months post-LT. Episodes of acute cellular rejection (ACR) should also be managed as one would in HIV negative patients namely moderate-severe episodes be treated with a 3-day course of intravenous methylprednisolone (1g daily). Consideration of the introduction of mycophenalate mofetil (MMF) after the 2nd episode of ACR is

Both tacrolimus and cyclosporin are metabolised via the P450 cytochrome. In addition, nonnucleoside reverse-transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs), which are commonly part of cART regimens, are also metabolised by the same pathway, therefore increasing the risk of drug – drug interactions. NNRTIs (e.g. efavirenz) decrease serum CNI concentrations by induction of the P450 cytochrome whilst PIs (e.g. ritonavir and lopinavir) are inducers resulting in increased CNI concentrations (55). We have used tacrolimus doses as low as 1mg per week in certain individuals. Raltegravir, a novel HIV-1 integrase inhibitor, is not metabolised via the P450 cytochrome and has been used successfully post transplantation in combination with nucleoside reverse-transcriptase inhibitors and

nervous system lymphoma.

109 cells/L.

recommended.

**2. Post liver transplantation** 

The Model for End-Stage Liver Disease (MELD) score has been adopted by transplant centers across Europe and North America to ensure the appropriate allocation of organs to those at the highest risk of death (45). Although MELD has been well validated in the HIVnegative patients, there have been mixed reports on its sensitivity in HIV-positive patients with ESLD (46). One prospective study reported similar MELD scores at the initial LT assessment for HIV-positive and HIV negative patients despite those with HIV having a significantly shorter cumulative survival time (880 versus 1427 days, p=0.04) (47). Another observation made by the same study was that the MELD score did not differentiate between survivors and non-survivors (13 versus 15, p = 0.6). Two more recent studies, both prospective, however have suggested that the MELD score may actually be a sensitive predictor of patient outcome (47, 48). Multivariate analysis of predictive factors of mortality demonstrated that the MELD score was independently associated with death (HR per 5-U increase 1.53, p<0.001). The MELD score also remained predictive of death on subgroup analysis of HIV/HCV patients (without HCC) and on comparison with HIV negative historical controls, the mortality rates were significantly higher for HIV-positive patients in each MELD category (48). In the second study, which matched 167 HIV-positive patients with 792 HIV-negative patients the baseline MELD score was the only significant predictor of pre-LT mortality in HIV-positive patients after controlling for CD4+ counts and HIV RNA levels (47).

Optimal control of HIV disease is an important prerequisite for HIV-positive patients undergoing consideration for LT. In patients with portal hypertension, splenic sequestration of T lymphocytes can lead to a fall in the CD4+ T cell count. In such cases a CD4+ cell count > 100 cells/uL is acceptable. A fall in the CD4+ cell count can also be precipitated by the use of pegylated interferon. In our opinion, CD4+ T cell percentages may represent a more sensitive indicator of immune reconstitution in HIV-positive patients with portal hypertension. HIV-positive patients undergoing evaluation for LT also require an undetectable HIV viral load (< 50 copies/mL) except for those that presently acutely. The inability to achieve an undetectable HIV RNA viral load before LT has been associated with an increased mortality rate (HR 3.5, p<0001)(48). In addition to good therapeutic options available in the pre-transplant period, HIV-positive patients require future cART options based upon their previous regimens and HIV phenol- genotype resistance testing. It is not inconceivable that certain HIV-positive patients may not be able to tolerate cART medications pre-LT due to brittle liver synthetic function. This group should not be automatically excluded from LT as long as HIV control is deemed possible post LT by the multidisciplinary team. cART intolerance post-LT, however has been identified as an important predictor of survival (49).

A thorough knowledge of past opportunistic infections is required. A distant history of an opportunistic infection in a patient that was not taking cART is not a contraindication to LT unless there is no effective treatment available for possible recurrence post-LT. Absolute contra-indications include multidrug resistant HIV, resistant fungal infections, chronic intestinal cryptosporidiosis, progressive multi-focal leukoencephalopathy and central nervous system lymphoma.
