20. End-stage liver disease, HIV and liver transplantation

José M. Miró, Fernando Agüero, Pablo Ruiz, Gonzalo Crespo, Alejandro Forner, Montserrat Laguno, Montserrat Tuset, Juan Ambrosioni, Anna Lligoña, Constantino Fondevila, Asuncion Moreno, Juan-Carlos García-Valdecasas, Antonio Rimola and the Hospital Clinic OLT in HIV Working Group

Introduction

The introduction of effective combined antiretroviral therapy (cART) changed HIV into a chronic disease with significant reductions in AIDS-related deaths and large increases in life expectancy (ART-CC 2008, Barre-Sinousi 2013). This has, however, been accompanied by a steady increase in liver-related morbidity and mortality due to coinfection with chronic hepatitis B (HBV) and hepatitis C (HCV) (Joshi 2011, Ioannou 2013). As a consequence, end-stage liver disease (ESLD) has become one of the main causes of death among people living with HIV who are coinfected with HCV or HBV (Smith 2014, Weber 2006, Weber 2013).

Hopefully, the burden of morbidity and mortality due to HCV coinfection will decrease with the uptake of the recently-introduced direct acting antivirals (DAAs). Meanwhile, the medical management of liver-related complications is essential, and liver transplantation (LT) remains the only therapeutic option for appropriate HIV positive candidates with end-stage liver disease (ESLD).

The aim of the present review is to give an overview presenting epidemiological data on ESLD and liver-related mortality in the setting of HIV and discussing the role of liver transplantation in this population.

End-stage liver disease in HIV positive patients

Magnitude of the problem and natural history

Of the approximately 35 million people living with HIV globally, between two and four million are chronically infected with HBV (Alter 2006) and around seven million have chronic HCV (Soriano 2010).

The prevalence of HCV and/or HBV coinfection varies considerably depending on the mode of HIV transmission and the geographical region (Peters 2014, Taylor 2012, Chew 2016, Klein 2016). Overall, the prevalence of HCV coinfection is 25% to 30% (Kim 2013, Peters 2014, Rockstroh 2005, Chew 2016) and of HBV coinfection around 5% to 20% (Konopnicki 2005, Soriano 2013). However, a number of reports have revealed changes in the epidemiological pattern (Ioannou 2013, Kim 2013, Taylor 2012). In Spain there was a significant decrease in prevalence of HCV/HIV coinfection, from 25.3% in 2004–2005 to 8.2% in 2010–2011 (Serrano-Villar 2015). This trend was consistently observed in all risk groups: PWID 92.4% to 81.4%; MSM, 4.7% to 2.6%; heterosexual men, 13.0% to 8.9%; and heterosexual women, 14.5% to 4.0%. Moreover, a decrease in prevalence from 35% to 25% in people with HCV/HIV coinfection was also observed in the US (Ioannou 2013).

It is well known that HIV has a deleterious effect on the natural history of HCV infection. HIV infection leads to higher HCV viraemia, decreased responsiveness to HCV therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV), accelerated rates of fibrosis, increased risk of developing decompensated cirrhosis and death, and a significant risk of developing hepatocellular carcinoma (HCC) (Chen 2014, Garcia-Samaniego 2001, Graham 2001, Gunthard 2014, Konerman 2014, Mohsen 2003, Poynard 2003, Sherman 2015, Rotman 2009, Operskalski 2011, Mastroianni 2014, Chew 2016, Klein 2016).

The mechanisms associated with accelerated fibrosis progression rates among people with HCV/HIV coinfection are not well understood, but multiple hypotheses have been proposed. These include a direct viral effect of HIV on hepatocytes and/or the stellate cells, microbial translocation and many immunologic alterations such as diminished HCV-specific T cell responses, immune activation, increased hepatocyte apoptosis and immunologic dysregulation, that promote hepatic fibrosis (Rotman 2009, Operskalski 2011, Lin 2013, Mastroianni 2014, Chen 2014, Mastroianni 2014, Sherman 2015, Chew 2016).

The prevalence of cirrhosis in people with HCV/HIV coinfection is 21% and 49% at 20 and 30 years following the acquisition of HCV infection, respectively (Thein 2008). The risk of cirrhosis development is two-fold higher in patients with HCV/HIV coinfecion patients to HCV monoinfection (Thein 2008). Additionally, patients with HCV/HIV coinfection who are on cART have a two-fold higher risk of fibrosis progression, if they have uncontrolled HIV replication (Cooper 2015). Indeed, a higher grade of fibrosis is associated with an increased rate of hepatic decompensation (Chen 2014, Limketkai 2013, Macias 2014, Berenguer 2015, Lo Re 2014, Macías 2013, Chen 2009, Branch 2012). To the contrary, those patients with HCV/HIV coinfection who achieve sustained virologic response of HCV infection with PEG-IFN and RBV have a higher probability of hepatic fibrosis regression (Casado 2013, Lissen 2006), as well as a lower risk of developing hepatic decompensation events and death (Berenguer 2012, Labarga 2015, Mira 2013, Berenguer 2014). It is expected that HCV-related morbidity and mortality will further decrease with the introduction of the interferon-free DAA regimens (Rockstroh 2015). The advent of these new agents has dramatically improved the treatment options of patients with coinfection, with SVR rates similar to those obtained in HCV monoinfection (EACS 2019, Shafran 2015, Sherman 2015, Arends 2015). Therefore, patients with HCV/HIV coinfection should be treated similar to HCV monoinfection (Sherman 2015, EACS 2019, Shafran 2015, Arends 2015, Karageorgopoulos 2015).

The effect of HCV on the progression of HIV is not well defined. Some studies however have observed a negative impact (Miller 2005, Grint 2014, Hua 2013).

First, patients with HCV/HIV coinfection with active HCV replication have a significantly higher cART discontinuation rates due to toxicity than those who do not have HCV replication or who are not HCV-infected (Grint 2014). Second, patients with HCV/HIV coinfection patients who initiate cART develop virologic failure earlier than patients with HIV monoinfection (Hua 2013). Third, the CD4+ cell increase seems impaired in HCV/HIV coinfection compared to HIV monoinfection (Hua 2013, Miller 2005), and CD8 downregulation would be hampered by HCV/HIV coinfection (Zaegel-Faucher 2015).

In the early cART era, increased liver related morbidity and mortality was observed in numerous studies. From 1996 to 2009, the prevalence of decompensated cirrhosis increased from 2% to 6% in patients with HCV/HIV coinfection (Ioannou 2013). ESLD accounts for approximately 10% of deaths among people with HIV infection (Farahani 2017).

A French prospective multicentre study that followed 21,000 HIV positive patients (4,000 of whom were coinfected with HCV or HBV) reported that ESLD accounted for 23.7% of non-AIDS-related deaths (Rosenthal 2007). In this population, ESLD was fatal in 1.5% of patients in 1995, 6.6% in 1997, 14.3% in 2001, and 12.6% in 2003. In addition, 92.6% of patients who died from ESLD had chronic HCV. Another prospective study comprising  11 cohorts from Europe, the United States (US) and Australia included 23,500 HIV positive patients (22.5% were HCV positive) recorded 1,250 deaths (Weber 2006). Deaths related to AIDS were the most frequent (31.1%), while liver disease was the most frequent non-AIDS related cause of death (14.5%). Moreover, HCV was shown to be an independent predictor of liver-related death. It is worth noting that the overall and cause-specific mortality in HCV/HIV coinfection remained stable over the last years whereas a decrease in mortality was observed in HIV monoinfection (Berenguer 2012).

Clinical features of HIV-coinfected patients with ESLD

The clinical pattern of the different complications related to cirrhosis shows some differences in cART-treated HCV/HIV coinfection compared to HCV monoinfection (Lo Re 2014). Firstly, people with HCV/HIV coinfection receiving cART have a significantly higher rate of decompensation and mortality (33% versus 15%)  than patients with HCV monoinfection (Lo Re 2014).

Ascites is the most frequent event of hepatic decompensation ranging from 36% to 83% in HCV/HIV coinfection (Pineda 2005, Merchante 2006, Pineda 2009, Anderson 2013, Ioannou 2013, Lo Re 2014). The development of spontaneous bacterial peritonitis (SBP) is similar in both groups. SBP in HCV/HIV coinfection had a high incidence of Streptococcus pneumoniae exceeded only by Escherichia coli (Shaw 2006). In addition, variceal haemorrhage seems less common in HCV/HIV coinfection (Lo Re 2014, Pineda 2005).

Prognosis after hepatic decompensation

The mortality rate for patients with HCV/HIV coinfection with decompensated and compensated cirrhosis was 27/100 person-years and 4/100 person-years, respectively (López-Diéguez 2011). This high mortality impacts the survival rates after hepatic decompensation of these patients, which range from 50% to 66% in the first year (Merchante 2006, Murillas 2009, Pineda 2005, López-Diéguez 2011), 30% to 43% at three years (Merchante 2006, López-Diéguez 2011) and 25% to 30% at five years (Merchante 2006, Murillas 2009, Pineda 2005, López-Diéguez 2011). These survival rates are significantly lower than those observed in patients with HCV monoinfection. The median survival time after the hepatic decompensation is around 13–19 months in HCV/HIV coinfection (Merchante 2006, Murillas 2009, Pineda 2005), while in patients with HCV monoinfection it is 48 months (Pineda 2005).

Several risk factors for hepatic decompensation have been identified: advanced fibrosis stage at presentation (Macias 2014, Lo Re 2014), more advanced liver cirrhosis (Child-Turcotte-Pugh scale -CTP- > 5 points) (Pineda 2009), low CD4 cell count (< 300 cells/mm3), lack of past treatment against HCV (Pineda 2009), anaemia at baseline, and diabetes mellitus (Lo Re 2014). Factors independently associated with mortality in this population are the degree of hepatic fibrosis (Macias 2014), the severity of liver disease measured by the Model of End Stage Liver Disease (MELD) scale (Pineda 2005, Murillas 2009), a higher score on the CTP (Pineda 2005, Merchante 2006, López-Diéguez 2011) and CD4 cell count below 100 cells/mm3 (Merchante 2006, López-Diéguez 2011). Treatment with cART has a protective role in HCV/HIV coinfection slowing the progression of hepatic fibrosis (Cooper 2014, Anderson 2014, Merchante 2006, López-Diéguez 2011, Murillas 2009, Thorpe 2011). As a result, likelihood of liver decompensation is decreased by 30% by successful cART (Anderson 2014) and the probability of death after the first hepatic decompensation by 40% (Merchante 2006). By contrast, discontinuation of cART (López-Diéguez 2011) or a detectable serum HIV viral load may facilitate progression of fibrosis (Cooper 2014) and increase by more than three times the probability of death in these patients (Murillas 2009, Ingle 2014).

Mortality during the evaluation process for liver transplantation

High mortality rates among patients with HCV/HIV coinfection with ESLD waiting for LT have also been reported in observational studies. Indeed, episodes of decompensation are frequent among patients on LT waiting lists (Warren-Gash 2017). Overall mortality during the evaluation period prior to waiting list entry ranges from 25% (Maida 2005) to 43% (Ragni 2005, Tan-Tam 2014). In addition, once patients are enlisted, mortality on the waiting list may vary from 14% (Subramanian 2010, Tan-Tam 2014, Martel-Laferrière 2015) to 67% (Murillas 2009). Waiting list mortality was 14% in patients with HIV infection (n=167) and 11% in the control group without HIV (n=792) (p=0.30), with MELD score being the only variable independently associated with death (Subramanian 2010).

For these reasons, physicians attending HIC/HCV coinfection patients with cirrhosis should closely follow and evaluate them for LT after the first clinical decompensation or upon the development of HCC. Both prevention and effective treatment of these complications might improve the likelihood of survival until LT (EACS 2019, Martel-Laferrière 2013, Tsochatzis 2012).

Management of complications of cirrhosis

The management of complications of cirrhosis (portal hypertension, ascites, gastrointestinal bleeding, encephalopathy, SBP, HCC, and hepatorenal syndrome) is basically the same as for the HIV negative population and is reviewed elsewhere (Forner 2018, Gines 2012, Jalan 2014, EACS 2019, Martel-Laferriere 2013, Liou 2014, Spengler 2011, Harrison 2016, EASL 2018).

Cirrhotic HIV positive patients should receive cART because it has been shown to be beneficial by reducing complications and mortality (Cooper 2014, Anderson 2014, Merchante 2006, López-Diéguez 2011, Murillas 2009, Thorpe 2011). Some antiretroviral drugs (ARVs) should be adjusted according to liver function and the use of others is not recommended in cases of cirrhosis (e.g., stavudine, didanosine, zidovudine – are all now very rarely used) (EACS 2019, Martin-Laferrière 2014, University of Liverpool 2020).

Lifestyle factors and drugs that may accelerate the progression of liver disease, such as hepatotoxic drugs (e.g., didanosine, nonsteroidal anti-inflammatory drugs), alcohol, tobacco, cannabis should be assessed and discontinuation is strongly recommended wherever possible. In some studies, smoking has been linked to more severe fibrosis in patients with chronic HCV (Tsochatzis 2009) and may also increase necroinflammation, irrespective of alcohol consumption (Hezode 2003). Alcohol consumption was higher in patients with HCV/HIV coinfection who died from ESLD (92%) (Rosenthal, 2007, Cooper 2005). Study results assessing the effect of smoking cannabis on liver fibrosis are controversial (Brunet 2013, Hezode 2008, Ishida 2008, Liu 2014).

Vaccination status should be evaluated in the assessment period prior to transplantation and vaccines should be updated according to national schedules (Blumberg 2019)

HCV/HBV management

Several treatments for HBV and HCV infection are currently available. Indications for HCV treatment are identical to those in patients with HCV monoinfection (EASL 2018, EACS 2019, Sherman 2015, AASLD-IDSA 2019).

The main objective of antiviral HCV treatment is to achieve SVR at the time of LT in order to minimise the risk of HCV recurrence posttransplant. HCV eradication reduces the rate of decompensation and might diminish the risk of HCC (EACS 2019).

Treatment of chronic HCV with PEG-IFN+RBV is contraindicated in patients with decompensated liver disease. Safety regarding this regimen in HCV/HIV coinfection is a concern (Mauss 2004). Hepatic decompensation was observed in HCV/HIV coinfected patients with advanced cirrhosis, and its incidence was 10.4% (14/134). Six of these 14 patients (43%) died as a result of hepatic decompensation. Antiretroviral treatment with didanosine identified as a risk factor. In contrast, no hepatic decompensation was noted in patients with HCV/HIV coinfection without cirrhosis.

The introduction of DAAs has also changed the standard of care for patients with advanced liver cirrhosis, resulting in substantial improvement in HCV cure rates (Campos-Varela 2015, EACS 2019, EASL 2018, Sherman 2015, AASLD-IDSA 2019). IFN-free regimens with fewer side effects, high efficacy and shorter treatment durations are now standard treatment options for difficult-to-treat patients (see chapters 15 and 19). In fact, IFN-free regimens are the only sensible option in HCV/HIV-coinfected patients due to their virological efficacy, ease of use, safety and tolerability. In addition, adherence to DAAs in patients with HCV/HIV coinfection is high and comparable to that in HCV monoinfection (Townsend 2016). HCV/HIV coinfected patients with ESLD waiting for LT can be treated before transplantation, although the benefit for these patients is not clearly established (EASL 2018). Furthermore, the widespread use of DAAs and its high therapeutic efficacy in high income countries can impact on the number and type of indications of LT, decreasing notably ESLD due to HCV infection (Figure 1). All this implies that in the future the indications of transplantation for decompensated cirrhosis by HCV will be substantially reduced.

Drug-drug interactions between DAAs and ARVs should be assessed before initiating therapy Karageorgopoulos 2014, Kiser 2013, Sherman 2015, El-Sherif 2015, MacBrayne 2016, EACS 2019). As this is an extremely rapidly evolving area, consultation of up-to-date databases on drug interactions is mandatory. The interactions of the antivirals used for the treatment of HCV can be found on some well established websites  (University of Liverpool 2020, Toronto General Hospital’s Hepatitis C Drug Information Web site 2017, EACS 2019).

HIV has a negative impact on the progression chronic HBV by increasing HBV replication, reducing the rate of spontaneous clearance of HBeAg and increasing the risk of developing cirrhosis (Thio 2009). Since ongoing HBV replication is a contraindication for LT and only patients without HBV viraemia are accepted for LT, treatment of HBV should be a priority. HIV positive patients with chronic HBV can be treated with lamivudine (or emtricitabine) and tenofovir-DF (TDF) as part of their antiretroviral therapy (Saag 2018, EACS 2019). Due to its high stability against the development of HBV resistance TDF is the standard treatment for HBV in coinfected patients. Entecavir is an alternative to TDF in addition to fully suppresive cART in selected cases (Saag 2018, EACS 2019). In cohort studies, after five years of continuous treatment, HBeAg seroconversion was achieved in 21% of patients with HIV/HBV coinfection treated with lamivudine, 50% in the group on TDF and in 57% in those receiving TDF/emtricitabine (Saag 2018, Kosi 2012). Moreover, most patients withHIV/HBV coinfection achieved complete suppression of HBV replication with TDF-based HBV therapy despite high baseline viraemia (see Chapter 14).

Combined antiretroviral therapy (cART)

Effective cART has been associated with improved clinical outcomes in patients with advanced liver fibrosis and chronic HBV and HCV (Anderson 2013, Limketkai 2012, Lopez-Dieguez 2011, Pineda 2007, Thorpe 2011). In contrast, permanent discontinuation of cART was associated with an increased risk of fibrosis progression (Thorpe 2011), a higher risk of first hepatic decompensation and poorer survival rate (Lopez-Dieguez 2011).

cART should be carefully planned in persons with HIV and ESLD. In general, cART should follow the current guidelines (Saag 2018, EACS 2019). However, some ARVs may be contraindicated in cirrhotic patients (e.g., didanosine, nevirapine), and in advanced liver cirrhosis dosing should be adjusted according to the degree of hepatic impairment in particular for HIV protease inhibitors (University of Liverpool 2020, Wyles 2005). In addition, liver function must be closely monitored for signs of hepatotoxicity (Sherman 2015). Due to their pharmacokinetic characteristics, integrase inhibitors offer advantages in these patients. Raltegravir (RAL) has demonstrated adequate serum levels, without dose adjustment and was well tolerated in patients with decompensated liver cirrhosis stage C on the CPT scale (Barau 2014, Hernández-Novoa 2014). Dolutegravir has a higher barrier to resistance than RAL and also has the advantage of once-daily administration (Blumberg 2019).

Therapeutic drug monitoring may be useful for efavirenz and protease inhibitors. In addition, atazanavir (and the no-longer used indinavir) can increase unconjugated bilirubin levels by inhibiting UDP-glucuronyltransferase. As total bilirubin is a component of both the Child-Turcotte-Pugh and MELD scores both drugs can affect the score.

Other important pharmacokinetic/pharmacodynamic interactions may exist between ARVs and HCV drugs. cART should be selected or modified to suit the HCV treatment. Fatal lactic acidosis and acute pancreatitis have been described with the concomitant use of ribavirin and didanosine. Zidovudine and stavudine should also be avoided in patients treated with ribavirin due to an increased risk of hematological and neurological toxicities, respectively (Saag 2018, Sherman 2015).

The use of cobicistat-based regimens, efavirenz, etravirine, nevirapine, ritonavir, and any HIV protease inhibitor, boosted or not by ritonavir, is not recommended in HIV positive patients receiving simeprevir (EACS 2019, Sherman 2015). Indeed, simeprevir can only be used with the following ARV drugs: raltegravir, rilpivirine, maraviroc, enfuvirtide, tenofovir, emtricitabine, lamivudine, and abacavir (AASLD-IDSA 2019, Sherman 2015, EASL 2018). The daily dose of daclatasvir should be adjusted in patients receiving atazanavir or efavirenz. On the contrary, no drug-drug interaction has been reported between sofosbuvir and ARVs.

Finally, given the speed with which new ARV and HCV drugs will debut, new interactions may be relevant and physicians should regularly consult updated databases on drug-drug interactions (University of Liverpool 2020).

Hepatocellular carcinoma in HIV positive patients

HCC prevalence (Ioannou 2013) and incidence (Merchante 2013, Sahasrabuddhe 2012) have steadily increased among individuals with HIV/AIDS over the past decades. In addition, the contribution of HCC to liver-related mortality in patients with HCV/HIV coinfection has significantly increased from 5% in 1995 to 25% in 2005 (Rosenthal 2009) and 40% in 2010 (Rosenthal 2015).

HCC occurs at a younger age in patients with HIV (Dika 2016); some studies have suggested that HCC might have a faster and worse outcome in HCV/HIV coinfection than in HCV monoinfection (Berretta 2011, Puoti 2004, Vibert 2011). However, other reports have failed to demonstrate lower survival rates in HCV/HIV coinfection (Brau 2007, Lim 2012). The comparison between studies may be misleading because of limited sample size, differences in study design and patient characteristics.

Although HIV positive patients with HBV or HCV coinfection should be systematically screened for HCC (Dika 2016) there is evidence that HCC screening is far from optimal in this population (Jain 2007, Beauchamp 2013, Hearn 2015). The proportion of patients with HIV/HBV coinfection undergoing HCC screening was significantly lower than observed in patients with HBV monoinfection (36% vs 81%) (Hearn 2015). These results are similar to those observed in a previous study (Jain 2007) in which abdominal ultrasound was performed in only 36% (130/357) of HIV/HBV coinfected patients during a four year period (1999–2003). More recently, a Canadian study showed that over a third of patients with HCV/HIV coinfection with cirrhosis were not screened for the presence of HCC by ultrasound (Beauchamp 2013).

Survival can be improved if HCC is diagnosed in the setting of a screening programme (Berretta 2011). However, so far no data from larger studies on cost-effectiveness of screening for HCC in cirrhotic patients with HIV/HBV coinfection are available (Joshi 2011, Gelu-Simeon 2014). These data do exist for HCV and HBV monoinfections.

Of note, HCC as indication for LT in HIV/HCV coinfected patients has shown an increase in recent years (Figure 1). The widespread use of DAAs and the consequent decrease of ESLD due to HCV infection may be the underlying factors of this fact.

Evaluation process for liver transplantation in HIV positive patients

The involvement of a multidisciplinary team with expertise in the different areas is vital when assessing HIV positive patients who are coinfected for LT (Miro 2007, Joshi 2011, Blumberg 2013). These teams should consist of members from the LT unit (from the medical and surgical areas), infectious disease specialists, and experts in the field of mental health and addictions and social workers (Miró 2007). The evaluation process to determine if an HIV positive patient is a suitable candidate usually lasts between seven and ten months (Martel-Laferriére 2015). HIV positive patients have a significantly lower probability of being listed than those who are HIV negative (18% versus 42%, respectively). The most common reason for not listing HIV positive patients is a lack of sufficient severity of liver disease (23%) (Martel-Laferriére 2015). The presence of HCC and a higher score on the MELD scale in HIV positive patients being evaluated for LT are factors independently associated with listing (Martel-Laferriére 2015).

Donor evaluation

Finally, the pre-LT donor evaluation should follow the same criteria as for the general population (Miro 2007).

The use of deceased HCV positive donors for HCV/HIV co-infected recipients showed inferior results in the NIH trial (Terrault 2012) of LT in HIV-infected individuals. However, it should be reassessed in future in both LT and KT in HIV-infected recipients due to the good preliminary results in KT in HIV-uninfected individuals, where pre- and post-transplant HCV treatment with DAAs was safe and prevented chronic HCV-infection in HCV D+/R- kidney transplant recipients (Miro 2019).

In the United States (and also in Spain), federal law banned HIV D+/R+ transplantation in 1984, but it was revised with the HIV Organ Policy Equity (HOPE) Act in 2013 (Fishman 2016, Blumberg 2019), allowing HIV D+/R+ transplants in research trials.  Multicenter national trials investigating the practice of HIV D+/R+ deceased-donor kidney and liver transplantation (NCT02602262, NCT03500315) are underway. In other countries, HIV D+/R+ liver transplant experience is limited to a few case reports without unusual complications.  These could be suitable approaches to mitigate the current organ shortage for this population (Richterman 2015, Miro 2019).

Liver transplant (LT) in HIV positive patients

HIV infection per seis not a contraindication for LT (Miro 2007, Blumberg 2019, Miro 2014). Indeed, LT is the only therapeutic option for appropriate HIV positive candidates with ESLD. The evaluation of LT candidates with HIV infection prior to being listed should be based on three main criteria: A) the degree of liver disease, B) the status of HIV infection, and, C) other criteria (psychiatric and drug use evaluation).

Liver disease criteria

The criteria are basically the same as for the HIV negative population. Briefly, they are acute liver failure, ascites with other factors associated with poor outcome such as CPT >7 points or MELD score >12 points, refractory ascites, hepatorenal syndrome, malnourishment or history of SBP, encephalopathy in patients with poor liver function (CPT >7 points), variceal bleeding that is difficult to manage with standard therapy and/or associated with poor liver function, hepatopulmonary syndrome and the development of HCC fitting the Milan criteria (one lesion ≤5 cm or no more than three tumour nodules ≤ 3 cm, in the absence of macroscopic vascular invasion or extrahepatic disease).

A new indication for LT in HIV positive patients was described in a French study (Tateo 2008). Three patients underwent LT due to nodular regenerative hyperplasia. LT is the only therapeutic option in cases of severe portal hypertension caused by nodular regenerative hyperplasia, and disease does not seem to recur after LT (Sultanik 2013).

HIV criteria

Most LT groups from Europe and North America use similar HIV criteria. These are summarised in Table 1 (Blumberg 2019, Morabito 2016, Miro 2005, O’Grady 2005).

Clinical criteria

Some authors are in favour of waving exclusion criteria for some OIs that can be effectively treated and prevented, such as tuberculosis, candidiasis, and Pneumocystis jirovecii pneumonia (Neff 2004, Radecke 2005, Roland 2004). In fact, the US NIH has updated the inclusion criteria and only untreatable diseases continue to be exclusion criteria for LT (e.g., progressive multifocal leukoencephalopathy, chronic cryptosporidiosis, multidrug-resistant systemic fungal infections, primary CNS lymphoma, and visceral Kaposi’s sarcoma) (Blumberg 2019).

Immunological criteria

All groups agree that the CD4+ T lymphocyte count should be above 100 cells/mm³ for LT (Neff 2004, Roland 2004). This figure is lower than that for kidney transplantation (CD4 >200 cells/mm³), because patients with cirrhosis often have lymphopenia due to hypersplenism, which leads to a lower absolute CD4 cell count, despite high CD4 cell percentages and good virologic control of HIV. In Spain, Italy, and the US, the CD4 cell count must be greater than 200 cells/mm³ in patients with previous OIs (Blumberg 2019, Morabito 2016, Miro 2005).

In Italy (Grossi 2012) and the UK (O’Grady 2005), the CD4 cut-off is 200 cells/mm³, unless patients have decompensated cirrhosis or portal hypertension; in this situation, the CD4 cell count threshold is 100 cells/mm³.

Virologic criteria

The essential criterion for LT is that the patient must have the option of effective, safe and long-lasting cART during the posttransplant period (Fung 2004, Neff 2004). The best situation is stable cART before transplantation with undetectable HIV viral load by ultrasensitive techniques (<50 copies/mL). Currently, cART is recommended for all HIV positive adults (Saag 2018). However, in the limited number of patients in which the benefit of initiating cART is not clear (e.g., elite controllers), it is unknown whether and when (pretransplant or posttransplant) it would be beneficial to initiate cART in order to reach an undetectable HIV plasma viral load. The proportion of HIV positive patients are not admitted on the LT waiting list for reasons related to their HIV (e.g., history of OIs or uncontrolled HIV infection) may vary between 6% and 10% (Martel-Laferriére 2015, Gelu-Simeon 2015).

Other criteria

To be included on the LT waiting list, HIV positive people must have had a favourable psychiatric evaluation. Psychiatric problems are the reasons for contraindication against LT in 3% of HIV positive LT candidates (Gelu-Simeon 2015).

Patients who use recreational or injecting drugs should not be placed on the waiting list. In Spain, patients must undergo a two-year period without using heroin and cocaine (Miro 2005), and six months with no consumption of other drugs (e.g., cannabis, alcohol). A recent paper reported that 13% of those HIV positive LT candidates were not enlisted due to active drinking (Gelu-Simeon 2015).

Patients who are on stable methadone maintenance are accepted for transplantation and can continue opioid maintenance after transplantation (Jiao 2010). Finally, as with other transplant candidate, HIV positive patients must have an appropriate degree of social stability in order to ensure adequate care in the posttransplant period. Around 20% of HIV positive patients who are not enlisted for LT due to psychosocial reasons such as lack of family/social support or toxic consumption (Martel-Laferriére 2015, Gelu-Simeon 2015).

Outcome of LT in HIV positive patients

Overall, mid- and long-term survival rates of HIV positive LT recipients are comparable to HIV negative patients, except for HCV/HIV coinfection. Survival rates in patients with HCV/HIV coinfection is lower compared to HCV monoinfected LT recipients (Table 2) (see below) (Coffin 2010, Duclos-Vallee 2008, Miro 2012, Terrault 2012, Locke 2016). However, with the high HCV eradication rates currently seen with DAAs, life expectancy in HCV-HIV LT recipients should be the same as in HIV negative recipients.

Most patients-maintained HIV viral suppression with good immunological status after LT (Miro 2015). Moreover, case reports of HIV positive LT recipients receiving organs from HIV positive deceased donors have been promising (Calmy 2016, Hathorn 2016). Studies under the HOPE Act (Fishman 2016) will provide more robust evidence in the coming years.

Complications after LT in HIV positive patients

After LT, patients and medical staff responsible for their care face a complex clinical setting (Miro 2007, Miro 2015). Patients should continue cART while immunosuppressive agents and antibiotic prophylaxis for OIs are also needed. Additionally, some patients will receive treatment for posttransplant complications such as de novo diabetes mellitus or arterial hypertension. Patients who are receiving methadone treatment can restart after LT. As a general rule, HIV positive patients should follow the same recommendations of care as any other LT recipient (Lucey 2013).

People living with HIV have not shown an increased risk of post-operative complications or a higher incidence of OIs or tumours than HIV negative patients (Harbell 2013, Miro 2015, Samuel 2008).

Infectious complications

Posttransplant infections are a major cause of morbidity and mortality in LT recipients who are HIV positive (Miro 2015). However, incidence and aetiology of infections in HIV positive patients during the early posttransplant period are similar to those reported in HIV negative patients (Miro 2015). A high rate of severe non-opportunistic (43%) and opportunistic (11%) infections in a cohort of 84 patients with HCV/HIV coinfection who underwent LT has been reported (Moreno 2012): bacterial infections occurred in 38 patients (45%), CMV infections in 21 (25%), uncomplicated herpes virus infections in 13 (15%), and fungal infections in 16 patients (19%, 7 invasive cases). A pretransplant MELD score >15, history of category C AIDS-defining events and non-tacrolimus-based immunosuppressive regimens were factors independently associated with severe infections.

A French study found that 37% (40/109) of HIV positive LT recipients developed at least one infection during the first year after transplantation (Teicher 2015). Most were respiratory bacterial infections (45%) followed by those affecting the biliary tract (20%). Three patients developed CMV disease (colitis, pneumonia and hepatitis) and four developed an opportunistic infection (two oesophageal candidiasis, one lymph node tuberculosis and one atypical mycobacterial infection). The mortality associated with infections was 21% (9/43). A MELD score > 17 points at the time of LT was associated with a two-fold higher risk of developing severe infections posttransplantation (Teicher 2015).

Other complications

A high incidence of posttransplant hepatic artery thrombosis (HAT) (12%, 3/24) was observed in one small cohort (Cherian 2012), while in HIV negative people, HAT is reported in about 4.4% (Bekker 2009). However, this finding was not confirmed in two other cohorts: the first including 32 patients (none of whom presented with HAT) (Gastaca 2012) and the second including 125 HIV positive liver recipients which reported six (5%) cases of HAT (Harbell 2013). Larger studies are needed in order to obtain more robust data on this relevant complication.

The risk of recurrent or de novo malignancy after solid organ transplantation in HIV positive patients is low (Nissen 2012). After a median follow-up of 2.8 years posttransplant, 12 out of 125 (9.6%) liver recipients developed 14 malignancies: 11 de novo malignancies (nine skin cancer, one Kaposi's sarcoma and one lymphoma) and three recurrences of pre-LT malignancy: two HCC and one cholangiocarcinoma (Nissen 2012).

Aseptic osteonecrosis in three (12.5%) out of 24 patients who underwent LT has been reported (Cocchi 2012). The incidence of this complication should be analysed in future research.

Pharmacokinetic interactions in the posttransplant period

Clinical management in the posttransplant period is complex, and handling pharmacokinetic interactions is challenging (Primeggia 2013).

Efavirenz is an inducer of CYP3A4, while ritonavir-boosted HIV protease inhibitors (PIs) are CYP3A4 inhibitors. Ritonavir and a new selective CYP3A inhibitor without intrinsic anti-HIV activity, cobicistat, have a potent inhibitory effect (Deeks 2013). This fact has a considerable impact on patient management (Frassetto 2013). Subjects taking concomitant ritonavir- or cobicistat-boosted ARVs (e.g., PIs, elvitegravir) will require rapid and significant dose adjustments of both calcineurin inhibitors and mTOR inhibitors (Deeks 2013, Frassetto 2013). In the presence of HIV PIs, the increase in the ciclosporin exposure could be two- to four-fold (AUC) and for tacrolimus more than ten-fold. With a combination of an HIV PI plus efavirenz, the interaction is complex and needs to be closely monitored. Nevirapine has no significant effect on calcineurin inhibitor pharmacokinetics (Frassetto 2013).

Raltegravir (RAL), which is mainly metabolised by uridine diphosphate glucuronyltransferase, is not a substrate of CYP450 and can safely be used in HIV positive LT recipients (Barau 2014, Tricot 2009). A study enrolling 13 HIV positive solid organ transplantation recipients (eight liver and five kidney) on RAL, reported a lack of significant interaction between RAL and calcineurin inhibitors (Tricot 2009). These findings were later confirmed in a cohort of 16 HIV positive solid organ transplant recipients (Mirò 2013). Therefore, the combination of two nucleos(t)ide reverse transcriptase inhibitors (TDF/emtricitabine or abacavir/lamivudine) plus RAL is probably the cART regimen of choice in transplant recipients. The introduction of dolutegravir (and probably bictegravir), which shares the same metabolic pathway and has shown superior virological efficacy over RAL, will be another option to safely treat LT recipients (Cahn 2013, Castellino 2013, Waki 2011). Furthermore, previous reports have mentioned the hypothetical anti-rejection and antifibrotic properties of the CCR5 inhibitor maraviroc (Haim-Boukobza 2013, Macias 2012). These findings remain preliminary and the results of larger studies in humans are necessary to confirm these interesting effects.

In addition, telaprevir and boceprevir (HCV PIs that are no longer used) increase the drug levels of ciclosporin and tacrolimus to a magnitude similar to that seen with HIV protease inhibitors. Management of drug-drug interactions is a challenging issue and is even more complex given the higher incidence of chronic kidney disease observed in these patients (Bahirwani 2014).

Finally, since this is an extremely rapidly evolving area, consultation of up-to-date databases on drug interactions is mandatory. The interactions of the antivirals used for the treatment of HCV can be found on the following websites:

• https://www.hep-druginteractions.org
• https://app.hivclinic.ca
• https://www.hivmedicationguide.com

as well as in the product labels.

Immunosuppression and rejection in HIV positive LT recipients

The optimal immunosuppressive regimen in HIV positive LT recipients is currently not known. However, HIV positive coinfected patients undergoing LT usually receive the same immunosuppressive regimens used in LT recipients without HIV (Miro 2007, Miro 2015). In general, the most commonly used immunosuppressive regimen combines a calcineurin inhibitor with corticosteroids. Findings from the two major LT cohorts (Miro 2012, Terrault 2012) confirm that individuals with HCV/HIV coinfection are more likely to have acute rejection than those with HCV monoinfection. A 38% acute rejection rate was reported in HIV coinfection compared to 20% in HIV negative patients (p<0.001) (Miro 2012).

This higher rate of acute rejection may be due to difficulties in achieving adequate serum levels of immunosuppressant agents due to drug-drug interactions between ARVs and calcineurin inhibitors. In addition, a higher rate of misinterpretation of acute rejection (mainly versus recurrent HCV infection) cannot be ruled out in HCV/HIV coinfection (Terrault 2012).

HCV recurrence after LT

For those patients with replicating HCV, the recurrence of HCV is universal after LT, regardless of HIV status. The impact of this fact on the post-LT outcome of these patients has dramatically change since the advent of DAAs.

Pre-DAAs era

Recurrence of HCV in patients with HCV/HIV coinfection was more severe and occurs earlier (Antonini 2011, Castells 2006) than in HCV monoinfected patients in the era of PEG-IFN plus RBV due to the low rate of SVR, impacting on mid-term survival of HIV positive LT recipients (de Vera 2006).

The three major nationwide cohorts of LT recipients with HCV/HIV coinfection (France, Spain and the US) showed, uniformly, that post-LT survival rates are lower than those of HCV monoinfected patients (Table 2) (Duclos-Valeè 2008, Miro 2012, Terrault 2012). Survival rates vary from 76% to 88% in the first year, 60% to 62% at three years, and 51% to 54% at five years in patients with HCV/HIV coinfection. On the other hand, HCV monoinfected patients have survival rates of 90% to 92%, 70% to 76% and 71% to 81% in the first, third- and fifth-year post-LT, respectively. HIV was independently associated with mortality (Miro 2012, Terrault 2012). Other risk factors for death were HCV genotype 1 and a higher donor risk index (DRI) (Miro 2012). By contrast, the absence of HCV replication was associated with a significantly lower risk of death at five years (HR 0.23) (Mirò 2012).

Several studies have explored the effectiveness of treatment of HCV recurrence after LT with PEG-IFN plus RBV (Castells 2015, Duclos-Vallee 2011, Terrault 2014). They consistently found a very low SVR rate. HIV infection, donor age >60 years, HCV genotype 1 or 4 and severe histological hepatitis were identified as risk factors for virologic failure (Castells 2015). The main results are summarised in Table 4. The US (Terrault 2014) and Spanish (Castells 2015) cohort studies showed an SVR of only 10% in patients with genotype 1. In the Spanish study, a 59% rate of SVR was obtained in patients with genotypes 2/3 compared with only 7% in patients with genotype 1/4.

DAA era

At the beginning of the era of DAAs, HIV positive patients were not included in most studies in the setting of LT (Campos-Varela 2015) and data on the efficacy of these drugs in this clinical scenario was derived from case reports (Antonini 2015, Borentain 2014). However, current evidence confirms the high efficacy of DAAs in the setting of LT recipients with HCV/HIV coinfection (Campos-Varela 2016, Londoño 2016, Grant 2016, Fagiuoli 2016, Castells 2017, Manzardo 2018,) (Table 4). Most of these patients were treated with sofosbuvir plus ledipasvir with/without ribavirin. Indeed, SVR at 12 weeks is similar in LT recipients both with and without HIV infection (Manzardo 2018). The conclusion from these studies is that IFN-free regimens for post LT HCV recurrence in HIV positive individuals were highly effective and well tolerated, with results comparable to HCV monoinfection. In fact, current guidelines recommend DAAs regimens as the only options in HCV/HIV-coinfected patients after LT because of their virological efficacy, safety and tolerability (EASL 2018). Therefore, the post-transplant HCV recurrence and its fearful consequences seen until a few years ago in the PEG-IFN plus RBV era have disappeared with DAA treatment due to the high rate of virus eradication.

HBV recurrence after LT

Cohorts of patients with HIV/HBV coinfection are not as large as those with HCV/HIV coinfection. The outcome of LT is much better, as effective control of HBV replication with anti-HBV hyperimmune globulin and HBV polymerase inhibitors is almost always possible (Coffin 2010, Tateo 2009). Probably due to the low incidence of HBV recurrence, survival rates in the short and medium term in HIV/HBV coinfection LT recipients are similar to those observed in HBV monoinfected LT recipients. A French study that included 13 patients with HIV/HBV coinfection revealed 100% graft and patient survival after a mean follow-up of 32 months (Tateo, 2009). Consistent with these findings, a US study enrolling 22 patients with HIV/HBV coinfection and 20 HBV monoinfected patients reported a cumulative patient and graft survival at three years of 85% in the HIV/HBV-coinfected patients and 100% in the HBV-monoinfected group (p=0.08).

Hepatocellular carcinoma

Preliminary data from case series showed satisfactory outcomes in people with HIV coinfection undergoing LT for HCC (Di Benedetto 2006, Di Benedetto 2008). In 2011, a French study (Vibert 2011) observed a trend towards a higher drop-out rate HIV positive patients with hepatitis B or C compared to HIV negative controls (5/21, 23% versus 7/64, 10%, respectively; p=0.08). From the time of enlisting, the survival rates at one and three years were 81% and 55% in the HIV positive group versus 91% and 82% in the HIV negative group (p=0.005). Moreover, the rate of HCC recurrence was two times higher in the HIV positive group than in the control group (30% versus 15%) (Vibert 2011). In contrast, an Italian study (Di Benedetto 2013) enrolling 30 HIV positive and 125 HIV negative LT recipients with HCC, observed that the proportion of HCC recurrence was two-fold higher in patients without HIV infection (2/30, 7% versus 18/125, 14%, respectively, p=0.15). Moreover, survival rates at one and three years after LT were similar (77% and 65% versus 86% and 70%, respectively. These two studies have two significant limitations: small sample sizes and limited follow-up periods.

A Spanish report (Agüero 2016) compared the outcome of 74 HIV negative patients undergoing LT for HCC with those of 222 LT recipients without HIV infection. There were no statistical differences regarding the baseline characteristics of tumours in both groups. Survival rates at one, three, and five years for HIV positive versus HIV negative patients were 88% versus 90%, 78% versus 78%, and 67% versus 73% (p=0.779), respectively. HCV infection (HR 7.90) and maximum nodule diameter >3 cm in the explanted liver (HR 1.72) were independently associated with mortality in the whole series. HCC recurrence occurred in 12 HIV positive patients (16%) and 32 HIV negative patients (14%), with a probability of 4% versus 5% at one year, 18% versus 12% at three years, and 20% versus 19% at five years. Microscopic vascular invasion (HR 3.40) was the only factor independently associated with HCC recurrence. HIV infection had no impact on recurrence of HCC or survival after LT. These results support the indication of LT in HIV positive patients with HCC.

In addition, a Spanish study (Agüero 2017) showed that the incidence and the histopathological features of incidental HCC in HCV infected LT recipients being HIV positive or HIV negative were similar. Post-LT survival was, however, lower in HIV positive patients, probably because of a more aggressive HCV recurrence.

Liver retransplantation

Currently, in patients without HIV infection, liver retransplantation (re-LT) accounts for approximately 10% of all liver transplants (Pfitzmann 2007, Reese 2009). Overall post-retransplant patient survival rate is between 15% and 20% lower than the primary LT survival rate (Carrion 2010). This lower survival is of concern due to the significant shortage of available organs.

In HIV positive patients, the frequency of re-LT is similar to the observed LT recipients without HIV infection (6%) (Gastaca 2012, Agüero 2016). Overall survival rates at one and three years after re-LT for HIV positive (n=14) and HIV negative (n=157) patients were 50% versus 72% and 42% versus 64%, respectively (p=0.16).

A prospective international study which enrolled 37 HIV positive patients undergoing re-LT found similar results (Agüero 2016). Five-year survival probability in patients with a positive HCV RNA (n=22) at re-LT was 30% compared to 80% in patients with negative HCV RNA (n=10) (p=0.025). HCV recurrence was the main cause of death (7/22 cases, 32%). Therefore, the indication for re-LT in people with HCV/HIV coinfection with active HCV replication at time of re-LT should be reassessed in the setting of the widespread use of new DAAs.

Conclusions

ESLD is an increasingly frequent clinical scenario in the setting of HIV coinfection with either HCV or HBV.

Early diagnosis of ESLD complications is particularly important and should be actively monitored and treated. In general terms, the management of ESLD in HIV positive patients should be the same as in those who are HIV negative.

Physicians caring for ESLD patients should follow them prospectively and promptly evaluate them for LT after the first clinical decompensation of liver disease.

LT is a life-saving procedure in this population and is safe and effective in patients with HBV infection. However, the recurrence of HCV infection in HIV positive patients can affect both graft and patient survival in the medium and long term. However due to the availability of effective and interferon free DAA regimen this scenario is currently undergoing a rapid change.

The members of the Hospital Clinic OLT in HIV Working Group are: JM Miró, F. Agüero, J. Ambrosioni, G. Crespo, P. Ruiz, A Forner, M Laguno, M. Londoño, JL Blanco, D. Nicolas, J Mallolas, M Tuset, M. Martinez-Rebollar, M Monras, A Ligoña, J Blanch, P. Ruiz, D Paredes, M. Brunet, J Fuster, C Fontdevila, JC García-Valdecasas, JM Gatell, A Moreno, A Rimola, (Hospital Clinic – IDIBAPS - CIBERehd, University of Barcelona, Barcelona).

Dr. F. Aguero is currently working at Preventive Medicine Department, University Hospital of Bellvitge, University of Barcelona, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.

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