Liver transplantation for HIV/hepatitis C virus co-infected patients
- Funding sources: This study was partially supported by the Health and Labor Sciences Research Grant from the Ministry of Health, Labor and Welfare Japan, regarding Research on Indication of Liver Transplantation for HIV/HCV co-infected Patients.
Since the introduction of antiretroviral therapy (ART) in the mid-1990s, AIDS-related death has been dramatically reduced, and hepatitis-C-virus (HCV)-related liver failure or hepatocellular carcinoma has currently become the leading cause of death in HIV/HCV co-infected patients. Liver transplantation may be one of the treatments of choices in such cases, but the indications for transplantation, perioperative management including both HIV and HCV treatments, immunosuppression and the prevention/treatment of infectious complications are all still topics of debate. With the improved understanding of the viral behaviors of both HIV and HCV and the development of novel strategies, especially to avoid drug interactions between ART and immunosuppression, liver transplantation has become a realistic treatment for HIV/HCV co-infected patients.
IN JAPAN, IN the late 1980s, contaminated blood production of coagulation factor for hemophilia caused co-infection of HIV and hepatitis C virus (HCV). Actually, greater than 90% of HIV-infected patients have HCV as well.
After antiretroviral therapy (ART) was introduced in the late 1990s, successful control of HIV was achieved in most cases and death due to AIDS was dramatically reduced, but HCV-related death due to liver failure or hepatocellular carcinoma became a serious problem, not only in Japan, but all over the world.[2-6] In such cases, liver transplantation (LT) is the only treatment option to achieve long-term survival, but several modifications of perioperative management are required. In this review, the outcome and the points of management of LT for HIV/HCV co-infected patients were reviewed.
Reported Outcome of LT for HIV/HCV Patients
THE REPORTED OUTCOMES of LT for HIV and HIV/HCV co-infected patients from Western countries after the introduction of ART are summarized in Table 1.[7-11] In general, most reports concluded that the results were worse than in the cases with HCV mono-infection, with a 3-year survival of approximately 60–70%. In Japan, the Tokyo group reported six cases of living donor liver transplantation (LDLT) between 2001 and 2004, of whom four died. These unfavorable outcomes are likely related to the difficulties of determining the indications for LT and of perioperative management, including HIV/HCV treatment and the prevention and treatment of infectious complications. Terrault et al. reported that older donor age, combined kidney–liver transplantation, an anti-HCV positive donor and a body mass index of less than 21 kg/m2 were independent predictors of graft loss. After transplantation, several studies showed that acute cellular rejection was more frequent and severer in HIV/HCV co-infected patients than that in HCV mono-infected patients, possibly due to the difficulties in achieving optimal immunosuppression because of interactions between antiretroviral agents and immunosuppression.[10, 11]
Table 1. Outcome of liver transplantation for HIV/hepatitis C virus co-infection
|de Vera et al.||2006||USA||27||67||56||33|
|Schreibman et al.||2007||USA||15||73||73||–|
|Duclos-Vallee et al.||2008||France||35||–||73||51|
|Terrault et al.||2012||USA||89||76||60||–|
|Miro et al.||2012||Spain||84||88||62||54|
Special Issues Regarding LT Indications for HIV/HCV Co-Infection
ART-related non-cirrhotic portal hypertension
IN HCV MONO-INFECTED patients, LT should be considered when the patients develop deteriorated liver function as indicated by a Child–Pugh classification of B or C. In HIV/HCV co-infected patients, liver failure due to HCV hepatitis was generally enhanced by ART-related hepatotoxicity, especially non-cirrhotic portal hypertension.[13-15] Accordingly, not only in cases with deteriorated liver function but also in class A cases, the patients can easily develop severe liver dysfunction suddenly,[16, 17] so that all HIV/HCV co-infected patients should be carefully followed up so as not to miss the chance for LT. Also, Murillas et al. reported that Model for End-Stage Liver Disease (MELD) score is the best prognostic factor in HIV-infected patients, so that HIV/HCV co-infected patients may be considered for LT before MELD score increase to achieve comparable results with HCV mono-infected patients. Several studies showed the aggressive fibrosis in HIV/HCV co-infected patients compared with HCV mono-infected patients,[19, 20] but the mechanism of this aggressive fibrosis remains unclear. Recently, transient elastography or acoustic radiation force impulse imaging to check for liver stiffness has been introduced as an effective and non-invasive modality to determine patients' candidacy for LT.[21-23]
Count of CD4+ T lymphocytes
Generally, the count of CD4+ T lymphocytes has been required to be more than 200/μL to perform general elective surgeries in HIV-infected patients, but in HIV/HCV co-infected patients, current studies show that a count of more than 100/μL is acceptable,[25, 26] because patients generally have portal hypertension which can cause pancytopenia. In such patients, the ratio of CD4/CD8 is reported to be a feasible marker to predict postoperative complications including opportunistic infections. When the ratio is less than 0.15, the incidence of infectious complications is significantly higher.
In regard to latent opportunistic infections that occur before LT, they are not absolute contraindications when they can be expected to be controlled. Infections regarded as contraindications for LT included uncontrollable multidrug resistance HIV infection, chronic Cryptosporidium enteritis, progressive multifocal leukoencephalopathy and lymphoma.
Management of HIV/HCV in LT
Management of HIV
THE NUMBER OF HIV RNA copies before LT is suggested as an independent risk factor of postoperative mortality, so that HIV should be controlled sufficiently before LT. Accordingly, in the patients who are under consideration to receive LT, ART can be safely stopped before LT because HIV is generally well-controlled for a long period by ART. After LT, ART should be restarted as soon as possible because HIV RNA appears at 3–30 days after ART is stopped, but the timing of restart of ART depends on the patient's condition, including liver function. As long as the liver function has not fully recovered, or partial liver graft such as in LDLT has not sufficiently regenerated yet, ART cannot be started. Castells et al. reported in their case–control study that ART was started at a median of 8 days after LT (range, 4–28 days). In principle, the ART administrated after LT should be the same as the pretransplant regimen, but the majority of ART drugs including protease inhibitor (PI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) have interactions with calcineurin inhibitors (CNI) or mammalian target of rapamycin (mTOR), so that the monitoring of blood levels of immunosuppression is extremely important to avoid infectious complications or rejection. Currently, a novel HIV-1 integrase inhibitor, raltegravir (RAL), is expected to be a feasible drug because it has no interactions with CNI, unlike other drugs.[35, 36]
Management of HCV
The treatment strategy for HCV in HIV/HCV co-infected patients is the same as in HCV mono-infected patients. Combination therapy of pegylated interferon (PEG IFN) and ribavirin is the standard treatment both before and after LT. The timing of the induction therapy after LT is controversial. A Tokyo group proposed early induction as a preemptive therapy before patients develop hepatitis, while several other reports showed favorable results when the treatment was administrated only after the development of hepatitis was confirmed by liver biopsy.[38, 39] Theoretically, the treatment should be started as soon as possible, because in HIV/HCV co-infected patients, HCV recurrence may be accelerated in an immunocompromised state.[30, 40] The novel protease inhibitor, telaprevir, is currently introduced as an effective drug to achieve sustained viral response of 70%, even in genotype 1b, with PEG IFN/ribavirin in a non-transplant setting, but this drug is metabolized via cytochrome P450 as a substrate, as are CNI and various protease inhibitors of ART for HIV. Close monitoring of the CNI trough level should be performed, and although triple therapy with telaprevir/PEG IFN/ribavirin is currently reported to be effective to prevent HCV recurrence after LT in HCV mono-infected cases, special attention should be paid when this regimen is adapted in HIV/HCV co-infected patients.
AS PREVIOUSLY MENTIONED, many factors including ART, anti-HCV treatment and an HIV-related immunocompromised state make post-LT immunosuppressive treatment difficult. Many ART drugs, both PI and NNRTI, cause instability in the blood concentration of CNI through the cytochrome P3A4 (CYP3A4)-related metabolism. Most PI cause the overconcentration of CNI by inhibiting CYP3A4, while most NNRTI cause decreased levels of CNI by stimulating CYP3A4.[29, 42] As mentioned earlier, RAL is introduced as a key drug in LT in HIV positive patients, because the metabolism of this drug is not related to CYP450, so it does not affect the blood concentration of CNI. Several reports have demonstrated both the in vitro and in vivo effectiveness of rapamycin in reducing HIV replication,[43-45] and Di Benedetto et al. found that rapamycin monotherapy was significantly beneficial in long-term immunosuppression maintenance and HIV control after LT. Mycophenolate mofetil is expected to be an effective immunosuppressive drug because of its efficacy in reducing HIV infection by both virological and immunological mechanisms.[47-49] Using these drugs, a more effective regimen of immunosuppression with ART may be established.
In regard to the steroid, several studies proposed that a steroid-free regimen can be safely applied and effective in LT for HCV cirrhosis. Also, in HIV/HCV co-infected patients, steroid-free protocol may be beneficial to prevent both HIV and HCV recurrence after LT.[50, 51]
LIVER TRANSPLANTATION FOR HIV/HCV co-infected patients remains challenging, but with recent developments in perioperative management and novel drugs for both HIV and HCV, the results are likely to be improved.