Elina Teicher

Survival and recurrence of hepatitis C after liver transplantation in patients coinfected with human immunodeficiency virus and hepatitis C virus

Liver transplantation in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is a recent indication. In a single center, we have compared the survival and severity of recurrent HCV infection after liver transplantation in HIV‐HCV–coinfected and HCV‐monoinfected patients. Seventy‐nine patients receiving a first liver graft for HCV‐related liver disease between 1999 and 2005 were included. Among them, 35 had highly active antiretroviral therapy–controlled HIV infection. All patients were monitored for HCV viral load and liver histology during the posttransplantation course. Coinfected patients were younger (43 ± 6 versus 55 ± 8 years, P < 0.0001) and had a higher Model for End‐Stage Liver Disease (MELD) score (18.8 ± 7.4 versus 14.8 ± 4.7; P = 0.008). The 2‐year and 5‐year survival rates were 73% and 51% and 91% and 81% in coinfected patients and monoinfected patients, respectively (log‐rank P = 0.004). Under multivariate Cox analysis, survival was related only to the MELD score (P = 0.03; risk ratio, 1.08; 95% confidence interval, 1.01, 1.15). Using the Kaplan‐Meier method, the progression to fibrosis ≥ F2 was significantly higher in the coinfected group (P < 0.0001). Conclusion: The results of liver transplantation in HIV‐HCV–coinfected patients were satisfactory in terms of survival benefit. Earlier referral of these patients to a liver transplant unit, the use of new drugs effective against HCV, and an avoidance of drug toxicity are mandatory if we are to improve the results of this challenging indication for liver transplantation. (HEPATOLOGY 2007.)

Coronary heart disease in HIV-infected patients in the highly active antiretroviral treatment era

Objectives: To assess the incidence and the clinical features of coronary heart disease in HIV-infected patients. To assess atherosclerosis risk factors in this population. Methods: A review of our experience consisting of 16 patients with acute myocardial infarction (AMI) was the basis of our retrospective analysis of two cohorts in France. Incidence was compared with the national database on the incidence of AMI in the general population. Results: Incidence appears to be between 5 and 5.5 per 1000 person-years among HIV-infected patients. This accounts for at least a threefold increase in incidence (1.52 per 1000 person-years reported in the Monica database registry in France). Age of onset of AMI in HIV-infected patients (younger than 50 years in most cases) is a point of major concern and is an indirect way to confirm the increased incidence. AMI was typically of sudden onset without prior history of angina pectoris. Treatment and prognosis of AMI in this population has no specificity. Patients with coronary heart disease present several risk factors such as tobacco smoking, hypertension, diabetes mellitus and low high-density lipoprotein level. The links between AMI and protease inhibitor exposure is still a matter of debate, and longer duration of follow-up is needed in order to reach any conclusion. Conclusions: Coronary heart disease is of a higher than expected incidence in HIV-infected patients. The limitation of risk factors (mainly tobacco smoking) is a new challenge. An adaptation of the Framingham score is necessary to state the individual risk. Prospective, controlled studies are necessary to assess new strategies such as the role of statins and switching therapeutic regimens.

HIV-associated vascular diseases: Structural and functional changes, clinical implications

After more than two decades of AIDS epidemic, the spectrum of HIV-associated vascular diseases has mainly evolved from infectious and inflammatory vasculitides to premature atherosclerosis, its related contributing conditions (metabolic syndrome, dyslipidemia, insulin resistance syndrome) and complications (acute coronary and cerebrovascular syndromes). Today, as the AIDS epidemic further progresses worldwide and as the life expectancy of HIV-infected patients treated with effective antiviral regimens has dramatically increased, more than 10% of patients experience cardiovascular manifestations. The complex interplay between viral infection, inflammatory and cytokines pathways, protease inhibitors-induced hyperlipidemia and direct effects on endothelial cells has not, by far, been integrated in a single comprehensive pathogenesis network. However, recognition of its main components has resulted in a broader appreciation of cardiovascular risk and risk factors in HIV-infected/treated patients. Cardiovascular prevention is required in more than one half of HIV-infected/treated patients to achieve a reliable effectiveness of modern antiretroviral therapy. As the prognosis of HIV patients improves continuously, this rate is also likely to increase in the future.

Effect of Highly Active Antiretroviral Therapy on Tacrolimus Pharmacokinetics in Hepatitis C Virus and HIV Co-Infected Liver Transplant Recipients in the ANRS HC-08 Study

ObjectiveTo characterise the interactions between tacrolimus and antiretroviral drug combinations in hepatitis C virus-HIV co-infected patients who had received a liver transplant.DesignAn observational, open-label, multiple-dose, two-period, one-sequence design clinical trial in which patients received tacrolimus as an immunosuppressive therapy during the postoperative period and then had an antiretroviral drug regimen added. Tacrolimus pharmacokinetics were evaluated at steady state during these two periods.MethodsFourteen patients participated in the study and seven participated in the intensified pharmacokinetic protocol. Patients were included if they had undergone liver transplantation for end-stage chronic hepatitis C, absence of opportunistic infection, a CD4 cell count of >150 cells/μL and an undetectable HIV plasma viral load (<50 copies/mL) under highly active antiretroviral therapy. During the posttransplantation period, the tacrolimus dose was adjusted according to blood concentrations. When liver function and the tacrolimus dose were stable, antiretroviral therapy was reintroduced.ResultsWhen lopinavir/ritonavir were added to the tacrolimus regimen (seven patients), the tacrolimus dose was reduced by 99% to maintain the tacrolimus concentration within the therapeutic range. Only two patients were treated with nelfinavir, which led to a wide variation in inhibition of tacrolimus metabolism. When efavirenz (four patients) or a nucleoside analogue combination (one patient) was added, very little change in tacrolimus dosing was required.ConclusionThe lopinavir/ritonavir combination markedly inhibited tacrolimus metabolism, whereas the effect of efavirenz was small. Tacrolimus dosing must be optimised according to therapeutic drug monitoring and the antiretroviral drug combination.

Prospective evaluation of blood concentration of mitochondrial DNA as a marker of toxicity in 157 consecutively recruited untreated or HAART-treated HIV-positive patients.

Highly active antiretroviral therapy (HAART) can cause mitochondrial toxicity. The concentration of mitochondrial DNA (mtDNA) in peripheral blood cells has been reported to be a marker of this toxicity. However, these observations are controversial and were drawn from small series. Thus, we analysed the value of blood mtDNA as a marker of mitochondrial toxicity in a large cohort of human immunodeficiency virus (HIV)-infected out-patients during routine clinical evaluations. Real-time quantitative PCR was used to determine the mtDNA to nuclear DNA (nDNA) ratio in peripheral blood mononuclear cells from 157 consecutive HIV-1-infected patients (13 naive, 144 receiving HAART) and 30 HIV-1-uninfected patients. The mtDNA to nDNA ratio was significantly lower in both groups of HIV-infected patients than in the control group. No significant difference was observed between treated and naive HIV-infected patients. Lactataemia was significantly lower in controls than in the group of HIV-treated patients. None of the treated patients had lactataemia >5 mmol/l or bicarbonates <20 mmol/l. Triglyceride levels were significantly higher in the HAART-treated patients than in the nontreated patients. Clinical symptoms of lipodystrophy were observed in 62 HAART-treated patients. These symptoms were not associated with an abnormal mtDNA to nDNA ratio or plasma triglyceride concentration. The mtDNA to nDNA ratio was lower in DDI/D4T-treated patients than in AZT/3TC-treated patients. In conclusion, there are no obvious links between the mtDNA to nDNA ratio in peripheral mononuclear cells and any clinical symptoms or lactate level. Thus, the mtDNA to nDNA ratio in leukocytes does not seem to be an accurate marker of mild and/or long-term mitochondrial toxicity.

Long-term follow-up of liver transplanted HIV/hepatitis B virus coinfected patients: perfect control of hepatitis B virus replication and absence of mitochondrial toxicity.

Background:In patients coinfected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV), evolution toward cirrhosis and its complications is more rapid and severe than in patients infected with HBV alone. The outcome of liver transplantation in HBV–HIV-coinfected patients is poorly understood in terms of survival rate, HBV reactivation and mitochondrial toxicity on the liver graft. Patients and methods:Between November 2002 and June 2007, 13 HIV-positive patients underwent liver transplantation because of end-stage liver disease due to HBV with or without coinfection with hepatitis D or C virus. These patients were prospectively followed for an average of 32 ± 5.2 months (range 10–63 months). Results:All patients were alive at the end of the follow-up period and had normal liver function. Their HBV viral load was undetectable, no cccDNA was found in the liver graft and HIV infection was nonprogressive under antiretroviral therapy. Moreover, no mitochondrial toxicity was noted in the liver graft, as assessed by the spectrophotometric analysis of respiratory chain activities and by quantifying the mitochondrial DNA copy number. Conclusion:HBV–HIV-coinfected patients can successfully undergo liver transplantation with excellent results in terms of survival, control of HBV replication after transplantation and mitochondrial toxicity.

A new indication for liver transplantation: Nodular regenerative hyperplasia in human immunodeficiency virus–infected patients

Nodular regenerative hyperplasia is one of the causes of noncirrhotic portal hypertension and has recently been described in human immunodeficiency virus–infected patients, and the potential role of a prothrombotic state and hepatotoxic antiretroviral medication has been suggested. Moreover, it is now established that liver transplantation is feasible in HIV‐infected patients. We describe here our experience concerning 3 HIV‐infected patients with severe complications of nodular regenerative hyperplasia treated with liver transplantation. Liver Transpl 14:1194–1198, 2008.

Outcome and management of HCV/HIV coinfection pre- and post-liver transplantation. A 2015 update

Liver transplantation is increasingly performed in selected HIV-infected patients in most developed countries, with excellent results reported in patients with liver diseases unrelated to HCV. In contrast, survival in HCV/HIV-coinfected liver recipients is poorer than in HCV-monoinfected patients, due to more aggressive recurrence of HCV and consequent graft loss and death. Results from American, French, and Spanish cohort studies showed a 5-year survival rate of only 50-55%. Therefore, it is debated whether liver transplantation should be offered to HCV/HIV-coinfected patients. Studies have shown that the variables more consistently associated with poor outcome are: (1) the use of old or HCV-positive donors, (2) dual liver-kidney transplantation, (3) recipients with very low body mass index and (4) less site experience. However, the most effective factor influencing transplantation outcome is the successful treatment of HCV recurrence with anti-HCV. Survival is 80% in patients whose HCV infection resolves. Unfortunately, the rates of sustained virological response with pegylated-interferon plus ribavirin in coinfected recipients are low, particularly for genotype 1 (only 10%). Here we present a non-systematic review of the literature based on our own experience in different liver transplant scenarios. This review covers selection criteria in HIV-infected patients, pre- and post-LT management, donor selection, anti-HCV treatment, drug interactions with antiretrovirals and anti-HCV direct antiviral agents, hepatocellular carcinoma, and liver retransplantation. Recommendations are rated. Finally, we explain how the introduction of new effective and more tolerable direct antiviral agents may improve significantly the outcome of HCV/HIV-coinfected liver recipients.

Relationship between polymerase gamma (POLG) polymorphisms and antiretroviral therapy-induced lipodystrophy in HIV-1 infected patients: a case-control study.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) used for the treatment of HIV-1 inhibit the replication of mitochondrial DNA (mtDNA), which may contribute to severe mitochondrial toxicity including lipodystrophy, through the inhibition of polymerase gamma (POLG). Polymorphisms of POLG could explain the variation in mitochondrial toxicity in HIV-1-infected patients. We explored the relationship between selected polymorphisms of POLG and lipodystrophy related to NRTIs. We studied single nucleotide polymorphisms (SNP) at three amino acid residues (R1142, E1143 and R1146) and the CAG repeats of POLG in a case-control study including HIV-1 treated patients with lipodystrophy (n=69) and 2 controls (without lipodystrophy) per case matched by age, race and sex (n=138). Compared with matched controls, the polymorphisms in E1143 were significantly more frequent in case patients with lipodystrophy (aOR=4.7; p=0.048), and this was associated with a significant decrease of mtDNA in PBMC. In addition, among the parameters tested, the conditional logistic regression showed that the lipodystrophy has a strong link with E1143 polymorphisms, associated with D4T treatment (aOR=9.29, p=0.002). In conclusion, patients harbouring the changes of E1143 in the catalytic site of POLG exhibit a 4-fold increased risk to develop lipodystrophy than HIV-1 treated patients who do not have changes in E1143 and this risk can increase if the patient presenting the SNP received D4T. These could be due to decreased content of mtDNA in PBMC in these patients. Therefore, the toxicity of NRTIs leading to lipodystrophy in some HIV-1 infected patients could be explained in part by the occurrence of POLG polymorphisms.

Therapy with boceprevir or telaprevir in HIV/hepatitis C virus co-infected patients to treat recurrence of hepatitis C virus infection after liver transplantation.

Objective:Severe hepatitis C virus (HCV) recurrence affects post-transplant survival in HIV/HCV co-infected patients. This article describes the results of triple anti-HCV therapy with boceprevir or telaprevir in seven HIV/HCV co-infected patients following liver transplantation. Methods:All patients had severe HCV recurrence [fibrosis stage ≥F2 or acute hepatitis ≥A2 (n = 5) or fibrosing cholestatic hepatitis (n = 2)] associated with genotype 1a (n = 4) or 1b (n = 3). Patients were treated with Peg-interferon/ribavirin and boceprevir (n = 2) or telaprevir (n = 5) immediately (n = 3) or after a 4-week lead-in phase (n = 4). Immunosuppression included either cyclosporine (n = 5) or tacrolimus (n = 2). Prior to introducing telaprevir, combined antiretroviral therapy was switched in one patient to prevent drug–drug interactions. Results:At 24 weeks after the end of treatment, sustained virological response was observed in 60% (3/5) of the patients treated with telaprevir; no responders were observed in the boceprevir group. Triple anti-HCV therapy was prematurely discontinued in six patients [treatment failure (n = 2), infection (n = 2), acute rejection (n = 1) and myocardial infarction (n = 1)]. Anaemia occurred in all patients, requiring erythropoietin, ribavirin dose reduction and red blood cell transfusions in five patients.Average cyclosporine doses were reduced by 50–84% after telaprevir initiation and by 33% after boceprevir initiation. Tacrolimus doses were reduced by 95% with telaprevir. Conclusion:Our data suggest that in HIV/HCV co-infected patients, triple anti-HCV therapy with telaprevir greatly improved efficacy despite poor tolerability. Significant decreases in cyclosporine or tacrolimus doses are necessary prior to introduction of boceprevir or telaprevir. Close monitoring is essential to prevent drug–drug interactions among antiretroviral therapy, immunosuppressive agents and anti-HCV therapy.