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Liver transplantation in HIV/HCV co-infected patients remains difficult: strategies to get these patients to earlier transplantation are needed
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Are HIV-infected patients candidates for liver transplantation?
Hepatology May 2008
Didier Samuel123, Rainer Weber4, Peter Stock5, Jean-Charles Duclos-Vallee123, Norah Terrault6
1 INSERM, U785, Villejuif F-94800, France
2 Universite Paris-Sud, Faculte de Medecine, Orsay F-91400, France
3 AP-HP Hopital Paul Brousse, Villejuif F-94800, France
4 Division of Infectious Diseases, University Hospital, CH-8091 Zurich, Switzerland
5 Department of Surgery, University of California, San Francisco, USA
6 Department of Medicine, University of California, San Francisco, USA
10. Conclusions and "What do we not know?" (D. Samuel)
Short-term outcomes for HBV/HIV co-infected patients are excellent. Prevention of HBV recurrence can be achieved with combination HBIG and nucleos/tide analogues. HIV disease does not appear to be adversely affected by transplantation, at least in the short-term. Control of HBV replication prior to transplantation is important to minimize the risk of recurrence but a requirement for an undetectable HBV DNA level may be too restrictive. Rather, the decision to transplant patients with HBV/HIV infection with detectable HBV DNA should be influenced by the level of HBV DNA, the likelihood of achieving viral suppression with anti-HBV agents (i.e. absence of a multidrug-resistant HBV) and the availability of HBIG for prophylaxis. Studies in HBV monoinfected patients indicate combination high-dose HBIG and antivirals can effectively prevent recurrence in viremic patients and this approach needs to be tested in HBV/HIV co-infected patients also.
Outcomes for HCV/HIV co-infected patients are more variable but poorer than HCV-monoinfected patients and non-HCV-infected transplant recipients [51]. With a 5-year survival of 50% or lower in most series, there is clearly a need to examine critically the factors contributing to worse outcomes and adjust practices accordingly. Divergent center-specific results limit interpretation of results, but one predictor of reduced survival is consistently seen. Patients with high MELD scores do poorly. This emphasizes the need to develop strategies to get these patients to transplantation earlier Jules: I said this years ago). Optimization of donor (age, steatosis) and perioperative factors (cold ischemia time) may also reduce the severity of HCV recurrence and since recurrent HCV disease is a leading cause of graft loss, factors known to influence disease progression in HCV-monoinfected patients need to be considered in patient management. Clearly an absence of effective antivirals is the major limitation. Additional agents, specifically protease and polymerase inhibitors with activity against HCV, will be predicted to significantly affect the outcomes of HCV/HIV transplant recipients. Until such drugs are available, however, alternative treatment paradigms need to be examined including pre-transplant therapy, preemptive therapy, (early and prior to histologic recurrence) or maintenance therapy.
In conclusion, this overview shows that excellent results of liver transplantation in HIV/HBV co-infected patients can be achieved. It shows as well that liver transplantation in HIV/HCV co-infected patients remains difficult. However, improvements in this latter setting are in process. In order to improve the results, a better selection of candidates for liver transplantation at an earlier stage of their liver disease will be needed, as well as an accurate scoring of severity of liver disease in HIV-infected patients, and an accessibility to liver transplantation taking into account the severity of liver disease through MELD score or modified MELD score. Better management of HAART after transplantation and a more effective antiviral therapy against HCV are also required.
9. HCV/HIV co-infected liver transplant recipients
Survival at 1-year post-transplantation varies from 58% to 89% [48], [49], [50], [51] (Table 4). The largest series from Spain (N=60) found patient survival rates of 90% at 1 year and 67% at 3 years [51]. Smaller series from Europe and the U.S. report 3-year survival rates of 56% to 88%. Two recently published studies comparing survival in HCV/HIV co-infected and HCV-monoinfected transplant recipients found a significantly lower survival in co-infected patients [27], [30]. In a French study of 35 HCV/HIV-infected and 44 HCV-infected recipients, 2- and 5-year patient survival rates were 73% vs. 91% and 51% vs. 81%, respectively (p=0.004) [27]. MELD was the only significant predictor of mortality, though donor age was of borderline significance (p=0.06). HIV infection per se did not predict survival. In a US study of 27 HCV/HIV-infected and 41 HCV-infected recipients, 3- and 5-year patient survival rates were 56% vs. 72% and 33% vs. 72%, respectively (p=0.07) [30]. Predictors of mortality were evaluated only in co-infected patients and found to be African-American race, pre-transplant MELD score >20, intolerance of HAART post-transplant, and high post-transplant HCV viral load [30].
The reason for the differences in survival among centers has not been systematically evaluated but may be related to differences in severity of disease at the time of transplantation, donor characteristics, or frequency of post-transplant complications including acute rejection and infections. Donor factors are of particular importance as donor age is known to strongly influence HCV disease severity in HCV-monoinfected patients and there may be center-specific differences in the use of extended-criteria donor in HCV/HIV-infected patients. The incidence of acute rejection does not appear to be increased in HCV/HIV co-infected patients [27], but effects of treated acute rejection on HCV disease progression may differ in co-infected patients compared to monoinfected patients. This has not been studied.
Interactions between HAART drugs, specifically protease inhibitors (PIs) and non-nucleotide reverse transcriptase inhibitors such as efavirenz, and calcineurin inhibitors and sirolimus are well-recognized [37], [38]. In addition to drug interactions, monitoring for HAART-associated hepatotoxicity is important. Mitochondrial toxicity related to nucleoside analogues has been described with HAART. One study from France found evidence of mitochondrial dysfunction in 5 patients with severe recurrent HCV, with most cases developing while patients were on DDI or D4T and in cases, with concurrent use of ribavirin [29]. Discerning HAART-related hepatotoxicity on a background of recurrent HCV disease can be difficult, if not impossible, so a high index of suspicion is needed for patients with severe or unexpected deterioration in liver dysfunction.
Recurrent HCV disease is the single greatest challenge in the management of co-infected patients and the leading cause of reduced survival. Recurrence of HCV is nearly universal, though, quite remarkably, there are reports of spontaneous clearance of HCV post-transplantation among co-infected patients [28]. Clinical evidence of recurrence appears earlier than in HIV-uninfected HCV patients (median time 2 months). Rate of fibrosis progression is enhanced. In one controlled study, the proportion with bridging fibrosis or cirrhosis at 2- and 5-year post-transplantation was 28% and 48% for HCV-HIV co-infected patients versus 10% and 18% in HCV-monoinfected patients [27]. The proportion of graft losses specifically attributed to recurrent disease is 27-54% with follow-up periods of up to 5 years (Table 4). Cholestatic hepatitis, the most severe form of recurrent HCV following transplantation, has been reported in most series of HCV/HIV co-infected patients, though accurate incidence data are lacking [27], [40]. Prognosis for patients with this presentation appears poor but stabilization with antiviral therapy has been reported [40].
Pegylated interferon and ribavirin combination therapy is the mainstay for management of recurrent HCV disease. Rates of sustained virologic response (SVR) are predicted to be low in co-infected patients, given the combined effects of HIV infection and post-transplant status on the efficacy of treatment. Since SVR rates are approximately 15% lower in co-infected than monoinfected non-transplant HCV patients, and HCV-infected transplant patients without HIV have SVR rates at least 10% lower than non-transplant HCV- infected persons, an SVR rate of 20-30% is predicted to the maximal achievable in co-infected transplant recipients. Available data, with the exception of one outlier [50], indicate a SVR is achievable in only 11-27% of treated patients [27], [30], [48], [50] (Table 5). Biochemical responses on treatment are obtained in more than half of patients but histological stabilization or improvement is rarely seen in virologic non-responders (Table 5). Like HCV-monoinfected transplant recipients, tolerability of full-dose therapy is limited and likely contributes to the poor SVR rates.
A myriad of unknowns regarding optimizing antiviral therapy exist. Obviously, better tolerated and more efficacious drugs are needed. The optimal timing of treatment needs to be determined. While tolerability of treatment may limit early antiviral therapy, initiation of treatment at the first signs of histological disease may be warranted to minimize risk of progression. Whether a specific immunosuppressive regimen is better suited to concurrent antiviral therapy is unknown. Certainly a stable immunosuppressive regimen is essential prior to starting treatment to minimize risk of acute or chronic rejection during antiviral treatment but beyond this general adage, the optimal regimen is unclear.
1. Introduction (D. Samuel)
This forum aims to review the current situation of liver transplantation in HIV-infected patients. A few years ago, the possibility of transplantation in HIV-infected patients was considered an unrealizable dream. Several major improvements have made this therapeutic intervention possible. First, the advent of highly active antiretroviral therapy (HAART) has dramatically modified the prognosis of HIV-infected patients. Second, the very effective prophylaxis of HBV reinfection using a combination of hyperimmune globulin anti-HBs and nucleos/tide analogues after liver transplantation has dramatically improved the prognosis of liver transplantation in HBV-infected patients. Third, the greater understanding of mechanisms involved in HCV recurrence after liver transplantation and the improvement in antiviral therapy post-transplantation gives a reasonably optimistic view of the future of liver transplantation in HCV-infected patients. Here, it is our aim to explore new indications for this group of patients.
2. How big is the problem? (R. Weber)
Worldwide, an estimated 33.2 million persons are currently living with HIV infection including 15.4 million women and 2.5 million children under 15 years [1]. In 2007, 2.1 million adults and 0.4 million children were newly infected, and 2.1 million died from HIV infection. Globally, HIV infection is mostly transmitted via heterosexual contacts, but intravenous drug use or homosexual contacts contribute to HIV epidemiology in some geographic areas. Regional statistics show enormous differences in prevalence and incidence of HIV infection. Only a minority of infected persons - 0.76 million persons in Western and Central Europe and 1.3 million in North America - are living in resource-rich countries with unrestricted access to therapy. Based on projections of economic and social development and considering the historically observed relationships of those with burden of disease, global HIV/AIDS-related mortality is projected to possibly rise to 6.5 million in 2030. This model assumes coverage with antiretroviral drugs will have reached 80% by 2012. Under optimistic assumptions including increased prevention activities, HIV/AIDS deaths are projected to increase to 3.7 million in 2030 [2]. In higher income countries mortality is expected to stabilize or to decrease during the next decades, therefore, the burden of HIV-related diseases and death will mainly affect low-income countries.
Modern combination of antiretroviral therapy completely suppresses HIV-1 replication which results in restoration of cellular immune function, clinical improvement, and a dramatic decrease of mortality from 20-30 per 100 person-years before introduction of potent drug regimens in 1995 to 1.5-2.5 per 100 person-years in recent years [3]. Nevertheless, the risk of death from AIDS is still substantial due to therapeutic failure, late initiation of treatment, interruption or refusal of treatment, incomplete adherence to therapy, or drug resistance. Unfortunately, the search for a vaccine has failed so far, and there is currently no reasonable evidence that there will ever be one [4].
Hepatic opportunistic infections and malignancies were found among 30-75% of patients with AIDS at autopsy prior to the availability of antiretroviral therapy, but liver disease rarely was the primary cause of morbidity and rarely contributed to mortality. Such a finding is still true in resource-poor countries without treatment programs. HIV itself appears not to affect liver function and no findings specific or pathognomonic for AIDS were identified in liver tissue. In contrast, in patients with access to potent antiretroviral therapy, deaths due to immunodeficiency-related complications have decreased and an increasing proportion of deaths are due to complications of liver diseases. Among 1246 deaths observed in the prospective D:A:D cohort study between 1999 and 2004, liver-related death was even the most frequent cause of non-AIDS-related deaths: 31.1% of the patients died from AIDS, 14.5% due to liver-related diseases, 11.0% from cardiovascular diseases, 9.4% from non-AIDS malignancies, and 33.8% from other causes [3]. In this study, liver-related deaths were a consequence of chronic hepatitis B (HBV) or hepatitis C virus (HCV) co-infection in 76% of the patients. Interestingly, there was a strong association between severity of cellular immunodeficiency and risk of liver-related death [3]. A total of 2.7% of deaths were reported to be directly associated with antiretroviral medication.
Liver-related diseases among HIV-infected persons are caused by HBV and HCV co-infections, hepatotoxic medication, alcohol, illegal drugs, malignancies, metabolic and immunologic mechanisms, and non-HIV-related diseases (Table 1). Globally, an estimated 370 million persons are affected by chronic HBV and 130 million by HCV infection [5]. Because HIV, HBV and HCV share common routes of transmission, an estimated 2-4 million HIV-infected persons are co-infected with HBV and 4-5 million with HCV. The prevalence of co-infections differ by geographic region and by patients' demographic and behavioral characteristics. The prevalence of chronic HBV infection is between 6-17% among HIV-infected persons living in HBV endemic areas, and 4-17% among persons living in Europe or the USA depending on sexual or injection drug use behavior. The prevalence of HCV co-infection ranges from 1-5% in persons who acquired HIV infection by heterosexual or homosexual contacts to 70-95% in current or former injection drug users and transfused hemophiliac patients. Thus, co-infections due to HBV and HCV are the most frequent causes of liver disease in HIV infection and substantially contribute to morbidity and mortality [5], [6].
3. Criteria for selection of liver transplantation (P. Stock)
The acceptance criteria for liver transplantation in HIV positive recipients continue to evolve with more experience in the co-infected population. During the initial phases of liver transplantation in people with HIV, selection criteria were justifiably conservative secondary to logical concerns that providing further immunosuppression to the HIV-positive recipient could result in progression of HIV to AIDS. There were also ethical concerns regarding the use of a scarce resource in a group of recipients with unknown survival. However, with good early results in many of the pilot trials, these acceptance criteria have been gradually liberalized [21], [22], [23].
During many of the initial clinical trials, solid organ transplantation was limited to patients with an absolute CD4+ T-cell count >200 cells/mL and controllable HIV viremia on HAART therapy. These T-cell counts were chosen as they were consistent with values that reflected an intact immune system. However, many of the co-infected patients with end-stage liver disease have portal hypertension and massive splenomegaly, and an absolute T-cell count <200/mL despite having well-controlled HIV infection. The splenomegaly in these patients could potentially result in splenic sequestration of the T-lymphocytes, and contribute to the relatively lower CD4+ counts noted in many of the co-infected patients. For this reason, the T-cell requirement was dropped to >100 cells/mL. Of note, absolute CD4+ T-cell counts of >200 cells/mL are still required at the time of kidney transplantation in the HIV-positive recipient.
There are some further caveats to the CD4+ T-cell requirements for HIV-positive liver transplant recipients. In the US system for allocation of deceased donor livers, allocation is based on the Model for End-Stage Liver Disease (MELD) score. In addition, there can be a significant decrease in the absolute CD4+ T-cell count in patients with decompensation of liver function and increase of the MELD score. For this reason, the NIH sponsored a US trial studying the safety and efficacy of solid organ transplantation in patients with an absolute CD4+ T-cell count of >100 cells/mL within 3 months of transplantation. Another potential conflict regarding the absolute requirement for a CD4+ count >100 cells/mL relates to the use of interferon therapy to treat HCV pre-transplant. The use of interferon can cause a transient decrease in CD4+ T-cell counts, and for this reason, the absolute CD4+ counts prior to the initiation of interferon therapy should be taken into account in the decision for liver transplantation. The absolute CD4+ T-cell count is not relevant for children, but rather the percentage of CD4+ T-lymphocytes that matters. The percentage of CD4+ T-lymphocytes should be greater than 30 for children between the ages of 1-2 years, and greater than 20 for children between the ages of 2-10.
An undetectable HIV viral load at the time of liver transplantation is clearly a desirable goal for the surgical team in the event of a needle stick. Unfortunately, many liver transplant recipients are unable to tolerate HAART therapy as a result of the significant hepatotoxicity. In the event that an undetectable HIV viral load is not achievable as a result of drug-induced hepatotoxicity requiring termination of HAART therapy, an experienced HIV clinician should predict the ability to control the HIV virus post-transplant. This prediction is based on a complete review of the antiretroviral history, HIV RNA history, as well as resistance testing. Patients with CD4+ counts <100/mL and multi-drug resistant HIV should be excluded from transplantation. This issue is more controversial for patients with CD4+ counts >100/mL but detectable HIV that is multidrug-resistant. Most centers would still consider this as an exclusion criteria, although with more data demonstrating the safety of immunosuppression in the HIV-positive patient as well as an increasing number of antiretroviral agents, this exclusion criteria may be liberalized on a case-by-case basis.
Another selection criterion for liver transplantation that has been liberalized as a result of good early outcomes was the initial exclusion of HIV-positive recipients that have had a history of an opportunistic infection. However, following reconstitution of the immune system with antiretroviral therapy, HIV positive liver transplant recipients are capable of mounting an adequate immune response against most pathogens. As a result, most centers are including patients following reconstitution of the immune system with antiretroviral therapy and appropriate antibiotic treatment. Nonetheless, opportunistic infections for which there is no reliable therapy should they recur post-transplant remain an exclusion criteria. These infections include progressive multifocal leukoencephalopathy (PML), chronic cryptosporidiosis, and multi-drug resistant systemic fungal infections. Patients with a history of AIDS-associated lymphoma are also excluded. Most clinical trials include individuals with a history of resolved cutaneous Kaposi's sarcoma (KS). Recipients with this history require a recent high-resolution CT scan without evidence of pulmonary KS. Recent evidence that the immunosuppressive agent sirolimus is effective in the treatment of KS may further expand the acceptance criteria to include patients with a prior history of visceral KS [24]. In fact, some transplants have been performed in HIV-positive patients with a prior history of visceral KS that has resolved following HAART-mediated reconstitution of the immune system [25]. KS following transplantation and immunosuppression has not been problematic in the early clinical trials of solid organ transplantation in people with HIV.
A final area regarding selection of the HIV-positive liver transplant recipient relates to the type of viral co-infection (HBV versus HCV) affecting the potential recipient. To date, most centers performing transplants in people with HIV have not altered selection criteria based on the type of co-infection. However, initial trials are consistently reporting significantly better outcomes in the HBV/HIV co-infected patients as compared to the HCV/HIV co-infected patients. Despite the presence of lamivudine-resistant HBV in the majority of patients who have been on lamivudine therapy for HIV management, the development of further resistance to HBV has not been seen following transplantation and the administration of immunosuppression. In fact, reports from the early clinical trials demonstrate excellent patient and graft survival rates comparable to the HIV-negative HBV-positive transplant recipients [26]. Unfortunately, hepatitis C recurrence remains a significant problem in the HIV/HCV co-infected patient following transplantation. Although HCV reinfection following liver transplantation is problematic in all patients regardless of HIV status, it appears that reinfection may be significantly exacerbated in the co-infected patient, resulting in poorer patient survival. A recent report has identified high MELD scores at the time of transplant to predict poor outcome in this group of patients [27]. In this report, the five-year survival rates of the co-infected patients versus monoinfected patients was 51% and 81%, respectively. Although the HIV/HCV co-infected cohorts have significantly poorer outcomes, there are also a number of these recipients who have done well. Interestingly, a few HIV/HCV co-infected patients have spontaneously cleared the HCV virus in the absence of interferon therapy [28]. With more experience with liver transplantation in the HIV/HCV co-infected group, it may be possible to identify a cohort of patients that will do better following transplantation. It may turn out that transplantation in HIV/HCV co-infected patients may have to be limited to patients with lower MELD scores, higher body/mass indices, and absence of renal insufficiency. Isolating the factors which have resulted in poorer outcomes will lead to further refinement in the selection criteria for HIV/HCV co-infected patients. Clearly, this refinement will be dependent on the efficacy of newer therapies for the management of hepatitis C recurrence following liver transplantation.
4. Immunosuppression in HIV-infected patients: are any special precautions necessary? (J.-C. Duclos-Vallee)
In the current era of highly active antiretroviral therapy (HAART), several reports have clearly demonstrated that liver transplantation (LT) is feasible in HIV-infected patients. Results have been excellent in HIV/HBV co-infected patients, while in HIV/HCV co-infected patients, outcomes have been satisfactory in terms of survival benefit because most patients had a high MELD score [26], [27], [29], [30]. We focus here on managing the degree of immunosuppression before and after liver transplantation in HIV-infected patients, with goals of (1) not compromising survival after LT and (2) improving the results of LT in the subgroup of HIV/HCV co-infected patients.
4.1. What degree of immunosuppression is acceptable or should be considered prior to liver transplantation?
Patients with uncontrolled HIV viral load secondary to resistance to HAART should be excluded from LT, not only because of the risk of transmission by needle stick, but also because of the potential risk for septic complications after liver transplantation.
With respect to the CD4+ cell count, it is currently difficult to define a CD4+ threshold that should exclude patients from LT. In the first 35 HIV/HCV co-infected patients transplanted at Paul Brousse Hospital, all had a CD4+ cell count >100 cells/mL which did not constitute a factor likely to affect post-LT survival. However, although Ragni et al. noted that cumulative survival among HIV-positive recipients was similar to that of age- and race-comparable HIV-negative recipients, they did observe poorer survival among patients with a CD4+ cell count <200 cells/mL [21]. This factor should be taken into account because the CD4+ cell count will remain stable after LT but may decrease when pegylated interferon therapy is administered for treatment of HCV recurrence. Interestingly, in a recent series at Paul Brousse Hospital, CD4+ cell counts <150 cells/mL were observed in 7 patients, and 6 of these seven patients developed severe chronic hepatitis C [27]. Clearly, the impact of a low CD4+ cell count on the degree of severity of HCV recurrence needs to be demonstrated in a larger patient series [27].
Another important point to consider is how the CD4+ cell count influences the survival of HIV/HCV co-infected patients under HAART therapy; in fact, a CD4+ cell gain of less than 100 cells/mL after starting HAART was one of the most consistent factors associated with the emergence of severe hepatic events in a recent study by Pineda et al. [31]. This low CD4+ level was due in part to splanchnic sequestration secondary to portal hypertension [32] and thus caused by advanced fibrosis, as has been shown in previous studies [33]. A low CD4+ count could thus constitute a new marker for liver disease severity in HIV/HCV co-infected patients and be integrated in a specific MELD score for HIV-infected patients prior to transplantation, thus improving the prediction of survival of this subgroup.
4.2. Should immunosuppression be managed specifically following liver transplantation?
Apart from the study conducted by Schreibman et al. [34], where HIV-infected patients experienced significantly higher mortality from infectious complications (4 out of 15 transplanted patients), all the other reports have reported a good control of HIV infection and CD4+ cell counts with HAART after liver transplantation [21], [26], [27], [29], [30].
The principal problem after liver transplantation in HIV/HCV infected patients is the severity of HCV infection recurrence on the liver graft [27], [29], [30]. In the monoinfected population, viral factors such as a high viral load prior to LT, and host factors such as donor age >50 years have been associated with a more severe recurrence of HCV infection [35]. Moreover, an immunosuppressed status is one of the most powerful determinants of post-transplant disease progression as it induces an increase in viral load [35]. Corticosteroid boluses have been associated with a more severe course of HCV recurrence and therefore should be avoided in co-infected transplant patients. It is of course essential to ensure a tailor-made immunosuppression in order to control HCV recurrence and prevent acute rejection in the subgroup of HIV/HCV co-infected patients. Rapid corticosteroid withdrawal after LT should also be avoided in co-infected patients, since it has been associated with a more rapid fibrosis progression in HCV-monoinfected transplant recipients [36]. The data currently available have failed to reveal any consistent differences in the incidence or severity of recurrent hepatitis C between the two types of calcineurin inhibitor (CNI) (tacrolimus or cyclosporine) in monoinfected patients, thus it is too early to recommend either of these immunosuppressant agents in HIV/HCV co-infected patients [36]. It should also be noted that findings concerning the effects of other immunosuppressant agents (such as MMF, anti-IL2 receptor antibodies, sirolimus and azathioprine) on the severity of HCV recurrence have so far been controversial in the HCV-monoinfected population [35].
Because cyclosporine and tacrolimus are substrates of cytochrome P-450 3A (CYP3A) and P-glycoprotein, their elimination is influenced by the use of other drugs that interact with these two enzymes, such as non-nucleoside reverse-transcriptase inhibitors (NNRTI) (which are often CYP3A inducers) and protease inhibitors (which are inhibitors of P-glycoprotein) [37]. To illustrate this type of interaction, recent studies have shown that subjects receiving protease inhibitors (PI) and cyclosporine had a 3-fold increase in AUC cyclosporine levels, necessitating an 85% reduction in the cyclosporine dosage over a two-year period (Table 2) [37]. As for tacrolimus, when efavirenz or a nuclesoide analogue combination was added, very little change in dosing was required. By contrast, nelfinavir and particularly lopinavir/ritonavir have been shown to markedly inhibit the first pass metabolism of tacrolimus, resulting in an increase in its elimination half-life and a reduction in its oral clearance [38]. Overall, these results clearly demonstrate that drug-drug interactions can be managed through the careful monitoring of tacrolimus and cyclosporine blood concentrations during the post-transplant period, particularly when PIs are being administered concomitantly [37].
A satisfactory assessment of immunosuppression status prior to LT, and individualized management of immunosuppressant therapy following LT are of crucial importance in HIV-infected patients, and particularly when trying to minimize the severity of HCV recurrence in HIV/HCV co-infected patients. There is no doubt that implementation of these recommendations will improve the survival of HIV-infected patients following LT in the very near future.
5. Management before and after liver transplantation: What do we know? (N. Terrault)
The published results show that liver transplantation in HCV/HIV and HBV/HIV co-infected patients can be successfully performed with overall short-term survival rates [39] comparable to non-HIV- infected patients [40]. Center-specific outcomes among liver transplant recipients with HCV/HIV co-infection are variable with some centers reporting lower survival in HCV/HIV compared to HCV-monoinfected patients [27], [30].
6. Management of HBV and HCV before transplantation
There are several challenges in the management of HIV-infected patients with HBV or HCV co-infection requiring transplantation. The first is to minimize deaths on the waiting list. Late referral is one factor likely contributing to deaths without transplantation [41], [26]. However, a more rapid progression from first decompensation to death is frequent, particularly in HCV/HIV-infected patients. In controlled studies, survival in co-infected patients with decompensated cirrhosis was significantly shorter than in HIV-uninfected patients [42]. The time from first manifestation of liver decompensation to death was 16 versus 48 months in co-infected versus HCV-monoinfected patients [42] and predictors of mortality after first decompensation are age, severity of liver disease (MELD and CPT scores) and the nature of the decompensation event [42]. For HBV/HIV co-infected patients, survival to the time of transplantation is related to severity of disease at presentation and whether uncontrolled drug-resistant HBV infection is present [26], [43]. Given the higher wait-list mortality in HIV-infected patients, strategies to shorten waiting times, such as use of living donors or extended criteria donors, are an important consideration. Additionally, there may be a future need to consider MELD exemption points to insure HIV-infected patients have comparable wait-list mortality risk to HIV-uninfected patients.
7. Management of HBV and HCV after transplantation
The other major challenge relates to the long-term management of recurrent viral diseases, especially HCV. Like HIV-uninfected transplant recipients, graft and patient survival require prevention of reinfection or control of progressive HBV and HCV diseases. For HBV-infected patients, prophylactic therapies including hepatitis B immunoglobulin and nucleos/tide analogues are the cornerstone of management. For HCV-infected patients, no prophylactic therapies are currently available and the focus is on management of progressive disease post-transplantation using pegylated interferon and ribavirin. The safety and efficacy of the therapies available to manage these viral diseases are largely responsible for the very different outcomes in HBV/HIV co-infected patients versus HCV/HIV co-infected patients.
8. HBV/HIV co-infected liver transplant recipients
The goal of pre-transplant management in any HBV patient is to have a low level of HBV DNA at the time of transplantation to reduce the risk of HBV recurrence post-transplantation. Additionally, sustained suppression of HBV DNA is associated with clinical improvement and can obviate the need for liver transplantation. Lamivudine resistance is common among referred patients due to the frequent use of lamivudine as part of HAART [26]. To prevent selection of drug-resistant HBV in co-infected patients, experts recommend using combination therapy of tenofovir plus emtricitabine or tenofovir plus lamivudine, as these drugs are effective against lamivudine-resistant and wild-type HBV and also have anti-HIV activity [43]. These same drug combinations represent an excellent antiviral strategy for liver transplant recipients with and without lamivudine-resistant HBV.
The total number of transplant patients studied is relatively small (N=25) but results are uniform among reports to date (Table 3). The median survival at 1 year is 100% (range 75-100%), with no reported deaths from recurrent HBV disease [34], [39], [44], [45], [46] (Table 3). Longer-term survival data are lacking. All centers have reported use of combination prophylaxis using HBIG plus antivirals and HBV recurrence has been prevented in the majority. Of note, among centers using indefinite HBIG plus antivirals, there have been no reports of HBV recurrence, whereas in the one center using limited duration HBIG (1-12 months post-transplantation only), recurrence at 1 year was 11% [44]. Since tenofovir, lamivudine and emtricitabine are part of HAART, interruptions in HAART due to intolerance or lack of efficacy requires consideration of the effects of drug interruption on HBV infection. In these situations, we have used HBIG alone as prophylaxis when the duration of ART interruption is short-term. Alternatively HBIG with an alternative HBV drug that does not have HIV activity, such as adefovir or telbivudine, could be used.
Prophylactic therapy should be continued life-long. The detection of low level of HBV DNA in 53% of HBV/HIV liver transplant recipients who were HBsAg negative on combination prophylaxis [47] urges caution in minimizing prophylactic therapies in these patients. Indeed, provision of prophylaxis using therapies with different mechanisms of action such as combination HBIG and nucleos/tide analogues would be predicted to minimize risk of HBV recurrence long-term.
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