Liver transplantation for patients with human immunodeficiency virus and hepatitis C virus co-infection: update in 2013
Because of the progress of anti-retroviral therapy (ART) for human immunodeficiency virus (HIV), mortality due to opportunistic infection resulting in AIDS has been remarkably reduced. However, meanwhile, half of those patients have died of end-stage liver cirrhosis due to hepatitis C virus (HCV) with liver cirrhosis and early occurrence of hepatocellular carcinoma. Recently, in 2013, non-cirrhotic portal hypertension due to ART drugs or still unknown mechanisms have become problematic with early progression of the disease in this patient population. Liver transplantation (LT) could be one treatment of choice in such cases, but the indications for LT perioperative management, including both HIV and HCV treatments and immunosuppression, are still challenging. In this review, we update the literature on HIV/HCV co-infection and LT as well as recent effort for modifying allocation system for those patients.
The causes of death of human immunodeficiency virus (HIV) infected patients have dramatically changed since 1995. A major background factor behind these trends is the improved HIV control achieved with anti-retroviral therapy (ART) . Despite dramatic reduction of death due to acquired immunodeficiency syndrome (AIDS), co-infected hepatitis C virus (HCV)-related death due to liver failure or hepatocellular carcinoma (HCC) became a serious problem, not only in Japan but all over the world, including England . In Japan, in the late 1980s, contaminated blood products for hemophilia caused co-infection by HIV and HCV. In such cases, liver transplantation (LT) is the only possible treatment option to achieve long-term survival, but several modifications of perioperative management are required recently for better outcome.
In this review, the outcome and the points of management of LT for HIV/HCV co-infected patients were reviewed to save relatively young patients with HIV/HCV co-infection bearing HCC [3, 4], non-cirrhotic portal hypertension (NCPH) [5-7], and decompensated liver cirrhosis [8, 9]. An updated critical review of the literature in 2013 was performed, and new information on problems and results for LT for HIV/HCV co-infection were included.
Upcoming topics regarding LT indications for HIV/HCV co-infection in 2013
Non-cirrhotic portal hypertension
In HIV/HCV coinfected patients, liver failure due to HCV hepatitis was enhanced by ART-related hepatotoxicity, especially manifesting as non-cirrhotic portal hypertension [5-7]. One of the ART drugs, Didanosin (DDI), has been suspected for serious morbidity. Thus, not only in cases with deteriorated liver function, such as in Child–Pugh B or C cases, but also even in Class A cases, patients' liver function can easily deteriorate abruptly [10, 11]. The actual natural course of pure NCPH is unknown, because it can be modulated with HCV or other causes and reported as only case series. However, an important study regarding “Non-cirrhotic portal hypertension in HIV mono-infected patients without HCV” was published in 2012 . All five patients had portal hypertensive symptoms such as ascites or variceal bleeding after ART medication. We need to await their prognostic information, since it can be extrapolated into HIV/HCV co-infected patients after successful HCV eradication.
Therefore, all HIV/HCV co-infected patients should be carefully followed up so as not to miss the opportunity for LT. Recently, in Japan, a scoring system was created for listing a deceased donor LT for those patients with HIV/HCV co-infection due to previous contaminated blood products.
Recently it became evident that HCC in HIV/HCV co-infected patients develop HCC at a very early stage of life, such as in the 30s and 40s [3, 4]. The molecular mechanism of its development still remains unclear, but surveillance in those patients should be considered for HCC strictly. In Japan, HIV/HCV co-infected hemophilic patients have been undergoing periodic examination for liver-related disease on a research basis. Early detection could contribute to treatment choices such as liver resection or liver transplantation. Regardless of the infectious status of HIV, treatment strategy for HCC in HIV/HCV infected patients should be the same in HCV mono-infected patients. Namely, whether liver resection could be performed or not should be based on the liver functional reserve. Also radio frequency ablation and transarterial chemoembolization can be selected according to the location, size and number of HCC.
Current results of LT for HIV/HCV co-infected patients in 2013
Indications for LT
As HCV mono-infected patients, LT should be considered when patients develop deteriorated liver function as indicated by a Child–Pugh score of class B or C in co-infected patients. Recently, Murillas et al. reported that the Model for End-stage Liver Disease (MELD) score is the best prognostic factor in HIV-infected patients . HIV/HCV co-infected patients might be considered for LT before their MELD score increases to achieve comparable results with HCV mono-infected patients. Several studies showed that aggressive fibrosis in HIV/HCV co-infected patients compared with HCV mono-infected patients [14, 15], but the mechanism of this aggressive fibrosis remains unclear. Recently, transient elastography or acoustic radiation force impulse (ARFI) imaging to check for liver stiffness has been introduced as an effective and noninvasive modality to determine patients' candidacy for LT [16, 17].
Regardless of the presence of hemophilia, the indications and methods for performing liver transplantation remains unchanged for patients with HIV/HCV co-infection. In fact, after a successful liver transplantation, hemophilia can normally be cured. Usually, the conditions for liver transplantation are as follows: (1) AIDS symptoms have not surfaced; (2) CD4+ T lymphocyte count is 150–200/μl or above; and (3) as a result of ART, the amount of HIV RNA in the blood by PCR method is below the level of sensitivity of the assay.
In HIV/HCV co-infected patients, current studies show that a count of more than 100/μl CD4+ T lymphocytes is acceptable [18, 19], because patients generally have portal hypertension, which can cause leukocytopenia. In such patients, the ratio of CD4/CD8 is reported to be a realistic 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 2013, based on the evidence of rapid progression of the liver cirrhosis and portal hypertension in patients with HIV/HCV co-infection, a ranking system for waiting list of deceased donor LT has been set up in Japan. Even HIV/HCV co-infected liver cirrhotic patients with Child–Pugh class A can be listed for LT as “point 3” because of NCPH nature. Also co-infected patients with Child–Pugh class B and C can be listed as “point 6” and “point 8” based on the data from our HIV/AIDS project team of the Ministry of Health, Labor, and Welfare of Japan, and world literatures [21-23]. It is basically considered for previous victims of contaminated blood products for hemophilia.
Results of LT for patients with HIV/HCV co-infection
In the United States and Europe, liver transplantation from deceased donors has been performed in HIV patients since the 1980s. At that time, the outcomes of LT were very poor . Recent series of reports are listed in Table 1 [24-31]. The reality is that, in addition to those listed therein, there have been many sporadic reports, such as reviews, expectations for liver transplantation, and assessment of indications.
Table 1. Updated outcome of liver transplantation for HIV positive recipients
|Duclos-Vallee et al. ||2008||France||35||–||73||51|| |
|Tsukada et al. ||2011||Japan||6||66||66||50||Only LDLT, only hemophilia|
|Terrault et al. ||2012||US||89||76||60||–|| |
|Miro et al. ||2012||Spain||84||88||62||54|| |
|Anadol et al. ||2012||Germany||32||90||65||60|| |
|Harbell et al. ||2012||USA||125||91||67||–|| |
|Baccarani et al. ||2012||Italy||32||–||79||69|| |
|Di Benedetto et al. ||2012||Italy||30||75||65||50||with HCC|
|Ragni et al. ||2013||USA||15||71||38||–||only hemophilia|
In general, most reports concluded that the results were 10% worse than in the cases with HCV mono-infection, with a 3-year survival of around 60–70%. Recently, a 5-year patient survival of around 50% was reported, and there is debate whether these results can be accepted for patients of a younger age and were co-infected through previous use of a contaminated blood product. In Japan, the Tokyo group reported six cases of living donor liver transplantation (LDLT) between 2001 and 2004 . Terrault et al. reported that older donor age, combined kidney-liver transplantation, an anti-HCV positive donor, and a body mass index <21 kg/m2 were independent predictors of graft loss . After LT, several studies showed that acute cellular rejection was more frequent and more severe in HIV/HCV co-infected patients than in HCV mono-infected patients, possibly due to difficulties in achieving optimal immunosuppression because of interactions between antiretroviral agents and immunosuppression.
Lowered outcome can be presumed from previous reports. Final mortality (graft loss) after LT was usually due to infection and multiorgan failure. As in Miro's report the causes due to the higher proportion of organs from donation after cardiac death (DCD) donors, higher rate of combined liver-kidney transplantation, increased rate of acute cellular rejection, HBV co-infection and infection. However, it was of note that there was no death due to infections related to HIV.
Preoperative management of HIV/HCV in liver transplantation
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 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. Also ART can be toxic for the virgin graft, which underwent ischemia/reperfusion injury and liver resection in a donor. Once it is settled down after liver transplant, especially in LDLT cases, ART can be resumed with meticulous adjustment with calcineurin inhibitors.
Actually, after LT, ART should be restarted as soon as possible, because HIV-RNA appears at 3 to 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 yet sufficiently regenerated, 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) . ART administered after LT should be the same as the preLT regimen, but the majority of ART drugs, including protease inhibitors and non-nucleoside reverse transcriptase inhibitors, 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. It can easily overshoot beyond the therapeutic level. Currently, a novel HIV-1 integrase inhibitor, raltegravir, is expected to be a feasible drug because it has no interactions with CNI, unlike other drugs [38, 39]. Therefore, the current recommended strategy in the light of LT could be to try raltegravir as ART before LT and see if HIV can be controlled with raltegravir. If it is the case, CNI could be used as usual after LT. However, if raltegravir cannot control HIV or cannot be applied due to other reasons, meticulous management of CNI (e.g. once a week administration with frequent trough monitoring) or Mycophenolate mofetil protocol should be considered. In fact, the novel protease inhibitor anti-HCV drug, telapreir, has the same character as ART drugs for HIV, and transplants team learn to overcome such drug interactions when post-LT HCV mono-infected patients are treated with telaprevir.
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 in 2013. 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 [40, 41]. As mentioned above, the novel protease inhibitor telaprevir is currently being introduced as an effective drug to achieve sustained viral response (SVR) of 70%, even in genotype 1b, with Peg-IFN/ribavirin in a non-transplant setting , but this drug is metabolized via cytochrome P450, 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 or even without Peg-IFN 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 for HIV/HCV co-infected patients. Additionally, mutational status of the IL28 B genotype should be investigated before interferon therapy for both donor and recipient.
Several reports have demonstrated both the in vitro and in vivo effectiveness of rapamycin in reducing HIV replication [43-45]. 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. Mycophenolic acid, a selective inhibitor of the de novo synthesis of guanosine nucleotides in T and B lymphocytes, has been proposed to inhibit HIV replication in vitro by depleting the substrate (guanosine nucleotides) for reverse transcriptase. Using these drugs, a more effective regimen of immunosuppression with ART may be established. However, more information needs to be obtained to establish concrete immunosuppressive protocol.
As to steroids, several studies proposed that a steroid-free regimen can be safely applied and effective in LT for HCV cirrhosis. In HIV/HCV co-infected patients, a steroid-free protocol may play a beneficial role in preventing both HIV and HCV recurrence after LT [47, 48].
Liver transplantation has been performed also for indication of HCC. The most updated study indicated that the existence of HCC did not change the outcome of LT provided that HCC was downstaged preoperatively for UCSF criteria . Also for these cases sirolimus tended to be used as primary immunosuppressive agents. This encouraging result awaits further reports .
The above is an overview of liver transplantation performed to date in HIV/HCV- co-infected patients. Although, the results are 10% lower in patient survival after LT than those for HCV mono-infected patients, LT could be feasible in selected cases with HIV/HCV co-infection after careful evaluation within suitable stages of the disease. In light of the fact that most HIV/HCV co-infected patients in Japan are the victims of contaminated blood products, it is believed that the importance of liver transplantation will increase in the future in the context of medical relief as well. Our investigating team under the Ministry of Health, Labor, and Welfare of Japan has made all possible efforts to clarify the appropriate timing to put HIV/HCV co-infected patients on a waiting list for LT.
This study was partially supported by a Health and Labor Sciences Research Grant from the Ministry of Health, Labor, and Welfare of Japan, regarding research on indications for liver transplantation in HIV/HCV co-infected patients (Eguchi Project).