HIV/hepatitis C Virus Research Articles

Atherosclerosis risk in HIV-infected patients: The influence of hepatitis C virus co-infection

BackgroundThe influence of hepatitis C virus (HCV) infection on atherosclerosis risk in HIV-infected patients has not been adequately evaluated in real-life situations. Objectives and methodsWe compared indexes of early atherosclerosis evaluated by echo-Doppler ultrasound (presence of plaque in carotid or femoral arteries) in 18 HCV–HIV co-infected patients versus 22 HIV mono-infected patients. ResultsPrevalence of subclinical carotid plaque was significantly higher in HCV–HIV co-infected patients (p=0.04), despite of the fact LDL-cholesterol and blood pressure (BP) were lower in the co-infected patients (p=0.003). HCV chronic infection (OR=10; IC: 1.5–72; p=0.02) was an independent risk factor. ConclusionThis cross sectional study suggests that HCV infection might be an independent cardiovascular risk factor in HCV–HIV co-infected patients. HCV infection might be considered as not only a liver infection but also as a metabolic disease in HIV patients, justifying regular cardiovascular surveillance.

Role of retroviral restriction factors in the interferon-α-mediated suppression of HIV-1 in vivo.

The antiviral potency of the cytokine IFN-α has been long appreciated but remains poorly understood. A number of studies have suggested that induction of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3 (APOBEC3) and bone marrow stromal cell antigen 2 (BST-2/tetherin/CD317) retroviral restriction factors underlies the IFN-α-mediated suppression of HIV-1 replication in vitro. We sought to characterize the as-yet-undefined relationship between IFN-α treatment, retroviral restriction factors, and HIV-1 in vivo. APOBEC3G, APOBEC3F, and BST-2 expression levels were measured in HIV/hepatitis C virus (HCV)-coinfected, antiretroviral therapy-naïve individuals before, during, and after pegylated IFN-α/ribavirin (IFN-α/riba) combination therapy. IFN-α/riba therapy decreased HIV-1 viral load by -0.921 (±0.858) log(10) copies/mL in HIV/HCV-coinfected patients. APOBEC3G/3F and BST-2 mRNA expression was significantly elevated during IFN-α/riba treatment in patient-derived CD4+ T cells (P < 0.04 and P < 0.008, paired Wilcoxon), and extent of BST-2 induction was correlated with reduction in HIV-1 viral load during treatment (P < 0.05, Pearson's r). APOBEC3 induction during treatment was correlated with degree of viral hypermutation (P < 0.03, Spearman's ρ), and evolution of the HIV-1 accessory protein viral protein U (Vpu) during IFN-α/riba treatment was suggestive of increased BST-2-mediated selection pressure. These data suggest that host restriction factors play a critical role in the antiretroviral capacity of IFN-α in vivo, and warrant investigation into therapeutic strategies that specifically enhance the expression of these intrinsic immune factors in HIV-1-infected individuals.

From nonalcoholic fatty liver to nonalcoholic steatohepatitis and cirrhosis in HIV-infected patients

Steatosis or nonalcoholic fatty liver disease (NAFLD) is commonly associated with abdominal obesity and metabolic disorders. It may evolve to severe liver injuries including nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. HIV-infected patients are aging and face an increased prevalence of abdominal obesity and metabolic disorders. We provide here an overview of NAFLD in HIV-infected patients for a better management of these patients. Steatosis is observed in 30-40% of HIV-infected patients, associated with increased adiposity and metabolic disorders. Whereas steatosis has probably a benign prognosis, clinically silent lesions of NASH are frequent in patients undergoing liver biopsy with often fibrosis and even cirrhosis. Fibrosis severity is related to age, insulin resistance and stavudine/didanosine-based therapy. Noninvasive markers of fibrosis are useful for the management of NAFLD-suspected patients. In addition to lifestyle changes, new treatment options are emerging and need to be evaluated in these patients. Steatosis is also common in HIV-hepatitis C virus (HCV) co-infected patients and worsens fibrosis progression but does not impact on the rate of sustained virological response. HIV-infected patients are at risk of NAFLD, a silent disease that can progress to more severe liver injuries. An accurate screening of these patients should be considered to prevent harmful evolution.

Impact of IL28B gene polymorphisms on interferon- 3 plasma levels during pegylated interferon- /ribavirin therapy for chronic hepatitis C in patients coinfected with HIV

The mechanism explaining the strong association between IL28B rs12979860 polymorphisms and treatment outcome in chronic hepatitis C remains unclear. We explore whether IL28B protein [interferon (IFN)-λ3] plasma levels may vary according to IL28B genotype and/or following pegylated IFN-α/ribavirin therapy. A total of 112 HIV/hepatitis C virus (HCV)-coinfected patients who completed a course of pegylated IFN-α/ribavirin therapy were examined. Sustained virological response (SVR) was achieved by 56% of patients. IL28B rs12979860 alleles were genotyped using the 5' nuclease assay with specific TaqMan probes. A specific enzyme immunoassay was used to measure IFN-λ3 plasma levels before initiating anti-HCV therapy and at week 4 of treatment. No significant differences between CC and non-CC IL28B carriers were found at baseline, either in the proportion of patients with detectable IFN-λ3 plasma levels or in their median values. In contrast, median IFN-λ3 plasma levels at week 4 of therapy significantly increased with respect to baseline in CC carriers [34.3 (16.7-56.3) versus 15.6 (15.6-30.3) pg/mL, respectively; P < 0.0001], but not in CT/TT carriers. Unexpectedly, increases in IFN-λ3 at week 4 of therapy did not predict SVR. The exogenous administration of IFN-α may induce IFN-λ3 release in IL28B CC carriers, but not in CT/TT carriers. However, this finding does not account for the link between IL28B polymorphisms and treatment outcome.

Incidence of low and high-energy fractures in persons with and without HIV infection

To compare fracture risk in persons with and without HIV infection and to examine the influence of highly active antiretroviral therapy (HAART) initiation on risk of fracture. Population-based nationwide cohort study using Danish registries. Outcome measures were time to first fracture at any site, time to first low-energy and high-energy fracture in HIV-infected patients (n = 5306) compared with a general population control cohort (n = 26 530) matched by sex and age during the study period 1995-2009. Cox regression analyses were used to estimate incidence rate ratios (IRRs). HIV-infected patients had increased risk of fracture [IRR 1.5, 95% confidence interval (CI) 1.4-1.7] compared with population controls. The relative risk was lower in HIV-monoinfected patients (IRR 1.3, 95% CI 1.2-1.4) than in HIV/hepatitis C virus (HCV)-coinfected patients (IRR 2.9, 95% CI 2.5-3.4).Both HIV-monoinfected and HIV/HCV-coinfected patients had increased risk of low-energy fracture, IRR of 1.6 (95% CI 1.4-1.8) and 3.8 (95% CI 3.0-4.9). However, only HIV/HCV-coinfected patients had increased risk of high-energy fracture, IRR of 2.4 (95% CI 2.0-2.9). Among HIV-monoinfected patients the risk of low-energy fracture was only significantly increased after HAART exposure, IRR of 1.8 (95% CI 1.5-2.1). The increased risk in HAART-exposed patients was not associated with CD4 cell count, prior AIDS, tenofovir or efavirenz exposure, but with comorbidity and smoking. HIV-infected patients had increased risk of fracture compared with population controls. Among HIV-monoinfected patients the increased risk was observed for low-energy but not for high-energy fractures, and the increased risk of low-energy fracture was only observed in HAART-exposed patients.

Naturally occurring hepatitis C virus (HCV) NS3/4A protease inhibitor resistance-related mutations in HCV genotype 1-infected subjects in Italy

To assess the prevalence of hepatitis C virus (HCV) NS3/4A protease inhibitor (PI) resistance mutations in HCV genotype 1-infected PI-naive individuals in Italy. One hundred and twelve patients infected with HCV genotype 1a or 1b (based on Versant HCV Genotype 2.0 or 5'UTR/core sequencing) and never treated with any HCV PI were evaluated. The whole NS3 region was analysed by population sequencing and mutations related to resistance to linear and macrocyclic PIs were recorded. Forty-six HCV-monoinfected and 66 HCV/HIV-coinfected subjects were studied. Complete NS3 sequence information was obtained for 109 (97.3%) samples: 67 subtype 1a and 42 subtype 1b. Subtype assignment by NS3 sequencing was concordant in 100.0% and 83.9% of cases with the original 5'UTR sequencing and Versant result, respectively. At least one mutation related to PI resistance was detected in 21 (19.3%) isolates. However, 11 of these had only Q80K, expected to confer resistance to one investigational macrocyclic compound, and were detected only in subtype 1a. Boceprevir and telaprevir resistance-related mutations were detected in 10 (9.2%) isolates and included V36L, T54S and V55A. Only one isolate harboured two mutations (V36L and T54S). There was no association between HCV PI resistance and HIV coinfection or exposure to HIV PIs. A minority of untreated HCV genotype 1 patients in Italy harbour a virus population carrying HCV PI resistance-related mutations. The clinical implications of this finding warrant further analysis.

Developing a Modified Directly Observed Therapy Intervention for Hepatitis C Treatment in a Methadone Maintenance Program: Implications for Program Replication

Background: Hepatitis C virus (HCV) is a prevalent chronic blood-borne infection among opioid-dependent patients on methadone maintenance treatment (MMT). Despite case reports and case–control studies, a randomized controlled trial (RCT) examining HCV treatment adherence in methadone-maintained patients is lacking and was the impetus for this ongoing RCT examining modified directly administered therapy for HCV treatment integrated within a MMT. Methods: Subjects were randomized 1:1 to receive HCV treatment as modified directly observed therapy (mDOT) into the MMT program or at a liver specialty clinic as self-administered therapy (SAT). Randomization was stratified based on HIV status and HCV genotype. Results: Twenty-one subjects to date have enrolled in this pilot study. The mDOT subjects have had greater success in starting treatment and 10 of the 12 mDOT subjects achieved early virologic response (EVR) at week 12 and 6 of those 10 achieved sustained virologic response (SVR). Of the nine SAT subjects, only three achieved EVR at week 12 and only one achieved SVR despite not completing the treatment. Conclusions: Hepatitis C treatment can be successfully integrated into a methadone maintenance clinic, and mDOT can be implemented with a methadone clinic’s existing nursing and medical staff. Patients struggling with concurrent substance use and mental illness comorbidity may be successfully addressed in such settings and facilitate access to and completion of treatment through the utilization of on-site clinical services for HCV treatment and adherence support with mDOT. The exact importance of site of services and adherence support remains a significant area for future investigation.

Optimizing Hepatitis C Therapy in HIV/hepatitis C Virus (HCV) Coinfected Patients: Analysis of HCV Viral Kinetics on Treatment

Hepatitis C virus (HCV) infection is potentially curable, but the sustained virological response (SVR) has been shown to be lower in patients coinfected HIV. A single-centre experience treating individuals with HCV and HIV coinfection is reported. Twenty-one patients who received standard doses of pegylated interferon with weight-based dosing of ribavirin (mean 14.3 mg/kg) were retrospectively reviewed. Qualitative HCV polymerase chain reaction (PCR) was performed prospectively every four weeks if the patient remained HCV PCR positive. All patients with HCV genotype 1 were treated for 48 weeks. Patients with genotype 2 or 3 were treated for 24 weeks and 32 weeks to 36 weeks if their HCV RNA level was undetectable after four weeks (RVR4) or eight weeks (RVR8) of therapy, respectively. If RVR8 was not achieved, the treatment was continued for 48 weeks. There were no dropouts or dose reductions within the first 12 weeks of treatment. SVR status was available for 20 patients and adequate serum for viral kinetics analyses was available for 17 patients. Eighty per cent of the patients achieved SVR (50% genotype 1; 100% genotypes 2 and 3). The week 8 viral load remained elevated for all genotype 1 nonresponders. High effectiveness rates were seen, particularly in patients with HCV genotype 2 and 3 who were treated for shorter durations. HCV viral loads after eight weeks of therapy helped distinguish patients with HCV genotype 1 who would respond to therapy. Hepatitis C virus (HCV) infection is potentially curable, but the sustained virological response (SVR) has been shown to be lower in patients coinfected HIV. A single-centre experience treating individuals with HCV and HIV coinfection is reported. Twenty-one patients who received standard doses of pegylated interferon with weight-based dosing of ribavirin (mean 14.3 mg/kg) were retrospectively reviewed. Qualitative HCV polymerase chain reaction (PCR) was performed prospectively every four weeks if the patient remained HCV PCR positive. All patients with HCV genotype 1 were treated for 48 weeks. Patients with genotype 2 or 3 were treated for 24 weeks and 32 weeks to 36 weeks if their HCV RNA level was undetectable after four weeks (RVR4) or eight weeks (RVR8) of therapy, respectively. If RVR8 was not achieved, the treatment was continued for 48 weeks. There were no dropouts or dose reductions within the first 12 weeks of treatment. SVR status was available for 20 patients and adequate serum for viral kinetics analyses was available for 17 patients. Eighty per cent of the patients achieved SVR (50% genotype 1; 100% genotypes 2 and 3). The week 8 viral load remained elevated for all genotype 1 nonresponders. High effectiveness rates were seen, particularly in patients with HCV genotype 2 and 3 who were treated for shorter durations. HCV viral loads after eight weeks of therapy helped distinguish patients with HCV genotype 1 who would respond to therapy.

High Frequency of Advanced Hepatic Disease among HIV/HCV Co-Infected Patients in Cambodia: The HEPACAM Study

Background: Little is known about HIV/Hepatitis C Virus (HCV) co-infection in resource-limited countries, although chronic HCV infection is one of the most relevant comorbidities in HIV population. The aim of this study was to determine the severity of liver disease in a cohort of HIV/HCV co-infected patients followed in Calmette Hospital, Phnom Penh, Cambodia, and to analyse the impact of HCV infection on antiretroviral therapy efficacy and hepatotoxicity. Methods: HIV patients with positive HCV antibodies were enrolled in this cross-sectional study. HIV monoinfected patients formed the control group. Transverse evaluation of co-infected patients was performed collecting clinical, biological, virological and ultrasonographic data. HIV course, response to antiretroviral therapy and frequency of hepatocytolysis were compared in both groups. Results: Among 50 HIV patients known with HCV antibodies, 31 (62%) had positive plasma HCV RNA and were included (58% men, median age 44 years). HCV genotype 1 was the most prevalent (68%), followed by genotype 6 (25%). Twelve patients (39%) met clinical, biological and/or ultrasonographic criteria for cirrhosis. FibroTest stage was 3-4 in 16 patients (52%). HIV/HCV co-infected patients demonstrated similar immune restoration and virological response to antiretroviral therapy as the 160 HIV mono-infected patients. Co-infected patients were more likely to have alanine aminotransferase elevation at baseline and to develop grade 2 or 3 hepatocytolysis in the two years after antiretroviral therapy initiation, specifically when nevirapine was used during the first six months of treatment. Conclusions: HIV/HCV co-infected patients are at increased risk for acquiring severe hepatic fibrosis. HCV coinfection does not affect response to ART. Efavirenz should be preferred to nevirapine in co-infected patients due to hepatotoxicity. Further research is required to target access to appropriate management of HIV/HCV co-infections in resource-limited countries.

Effects of hepatitis C virus infection on the pharmacokinetics of ritonavir-boosted atazanavir in HIV-1-infected patients

Most antiretrovirals are metabolized in the liver, and overexposure could be more common in human immunodeficiency virus (HIV)-infected patients with hepatic impairment. Careful monitoring of potential drug-related liver injury in clinical practice is necessary. The aim of our study was to analyze the trough concentrations (C (trough)) of atazanavir (ATV) in the plasma of HIV/hepatitis C virus (HCV)-co-infected patients and to compare the values with those of a HIV-infected control population. C (trough) values (22-26 h after last intake) of atazanavir, following the administration of atazanavir/ritonavir 300/100 mg once daily as part of antiretroviral therapy, were assessed by HPLC. We also collected data on dosing of atazanavir, and on demographic (age, gender, and ethnicity), physiological (weight and body mass index), and clinical parameters (CD4+ cell count, HIV-RNA viremia, co-medication, and hepatitis C co-infection). A total of 28 Caucasian HIV-infected adults were studied, of whom 13 were HIV/HCV co-infected. No baseline characteristics differed between the two cohorts, except statistically significant differences regarding ALT, AST, and total bilirubin. The median (range) plasma ATV C (trough) levels were 0.62 (0.05-3.22) μg/ml in HIV patients and 0.32 (0.04-3.37) μg/ml in HIV/HCV patients. Thus, there was no significant difference in plasma trough levels of atazanavir in the two cohorts. In our patients with mild impairment of hepatic function caused by HCV infection, atazanavir C (trough) was comparable in HIV-infected and HIV/HCV-co-infected patients.

Epidemiology and outcome of infections in human immunodeficiency virus/hepatitis c virus-coinfected liver transplant recipients: A FIPSE/GESIDA Prospective Cohort Study

Information about infections unrelated to acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus (HIV)-infected liver recipients is scarce. The aims of this study were to describe the prevalence, clinical characteristics, time of onset, and outcomes of bacterial, viral, and fungal infections in HIV/hepatitis C virus (HCV)-coinfected orthotopic liver transplant recipients and to identify risk factors for developing severe infections. We studied 84 consecutive HIV/HCV-coinfected patients who underwent liver transplantation at 17 sites in Spain between 2002 and 2006 and were followed until December 2009. The median age was 42 years, and 76% were men. The median follow-up was 2.6 years (interquartile range = 1.25-3.53 years), and 54 recipients (64%) developed at least 1 infection. Thirty-eight (45%) patients had bacterial infections, 21 (25%) had cytomegalovirus (CMV) infections (2 had CMV disease), 13 (15%) had herpes simplex virus infections, and 16 (19%) had fungal infections (7 cases were invasive). Nine patients (11%) developed 10 opportunistic infections with a 44% mortality rate. Forty-three of 119 infectious episodes (36%) occurred in the first month after transplantation, and 53 (45%) occurred after the sixth month. Thirty-six patients (43%) had severe infections. Overall, 36 patients (43%) died, and the deaths were related to severe infections in 7 cases (19%). Severe infections increased the mortality rate almost 3-fold [hazard ratio (HR) = 2.9, 95% confidence interval (CI) = 1.5-5.8]. Independent factors for severe infections included a pretransplant Model for End-Stage Liver Disease (MELD) score >15 (HR = 3.5, 95% CI = 1.70-7.1), a history of AIDS-defining events before transplantation (HR = 4.0, 95% CI = 1.9-8.6), and non-tacrolimus-based immunosuppression (HR = 2.5, 95% CI = 1.3-4.8). In conclusion, the rates of severe and opportunistic infections are high in HIV/HCV-coinfected liver recipients and especially in those with a history of AIDS, a high MELD score, or non-tacrolimus-based immunosuppression.

Prediction of response to pegylated interferon plus ribavirin in HIV/hepatitis C virus (HCV)-coinfected patients using HCV genotype, IL28B variations, and HCV-RNA load

This study aimed at developing a predictive algorithm based on interleukin 28B (IL28B) genotype, hepatitis C virus (HCV) genotype, and plasma HCV-RNA load, which could accurately allow us to define the probability of response to pegylated interferon (Peg-IFN) plus ribavirin (RBV) therapy in HIV/HCV-coinfected patients. Five hundred and twenty-one treatment-naive HIV-infected patients, who initiated HCV therapy with Peg-IFN/RBV, were analysed in an on-treatment basis. Patients were categorized as unlikely responders, uncertain responders, and anticipated responders (<20%, 20-60%, and >60% probability to achieve SVR, respectively). HCV genotype, baseline HCV-RNA load, and IL28B genotype were confirmed as independent predictors of SVR in a logistic regression analysis. A stepwise algorithm based on these three variables was created based on 321 patients and evaluated in the remaining 200 patients. Unlikely responders included patients with genotype 1 or 4, HCV-RNA load ≥600,000IU/ml, and rs12979860 non-CC (rate of SVR: 17.3%). Anticipated responders were those with HCV genotype 2-3, patients harboring HCV genotype 4 and IL28B CC, as well as those who simultaneously bore HCV genotype 1, HCV-RNA load <600,000IU/ml, and IL28B CC (rate of SVR 74.1%, 77.8%, and 64.4%, respectively). The area under the receiver operating characteristic curve of the model was 0.77 (0.733-0.814). The combined use of IL28B genotype, HCV genotype, and HCV-RNA load enables to easily identify patients with a high and very low likelihood of SVR. HCV therapy could be deferred in the latter patients, until more effective options are available, at least if they do not show advanced liver fibrosis.

Neurocognitive Effects of HIV, Hepatitis C, and Substance Use History

HIV-associated neurocognitive dysfunction persists in the highly active antiretroviral therapy (HAART) era and may be exacerbated by comorbidities, including substance use and hepatitis C virus (HCV) infection. However, the neurocognitive impact of HIV, HCV, and substance use in the HAART era is still not well understood. In the current study, 115 HIV-infected and 72 HIV-seronegative individuals with significant rates of lifetime substance dependence and HCV infection received comprehensive neuropsychological assessment. We examined the effects of HIV serostatus, HCV infection, and substance use history on neurocognitive functioning. We also examined relationships between HIV disease measures (current and nadir CD4, HIV RNA, duration of infection) and cognitive functioning. Approximately half of HIV-infected participants exhibited neurocognitive impairment. Detectable HIV RNA but not HIV serostatus was significantly associated with cognitive functioning. HCV was among the factors most consistently associated with poorer neurocognitive performance across domains, while substance use was less strongly associated with cognitive performance. The results suggest that neurocognitive impairment continues to occur in HIV-infected individuals in association with poor virologic control and comorbid conditions, particularly HCV coinfection.

Challenges and opportunities for hepatitis C drug development in HIV–hepatitis C virus-co-infected patients

The approval of the first direct-acting antivirals (DAAs) against the hepatitis C virus (HCV) has been eagerly expected for treating chronic hepatitis C in HIV individuals given that progression to cirrhosis and end-stage liver disease occurs faster in the co-infected population. The appropriate and judicious use of DAAs may provide cure to a large number of HIV-HCV patients. On the contrary, the widespread use of DAAs will occasionally be off-label or under unsatisfactory medical conditions, which may result in undesirable toxicities, drug interactions or selection of drug resistance in HCV. As a result of using first-generation DAAs in HIV-HCV-co-infected patients, a growing proportion of the remaining hepatitis C individuals will be those harboring non-HCV 1 genotypes or drug-resistant HCV variants. Over time, the largest reservoir of HCV genotype 1 patients will accumulate in resource-poor nations where access to hepatitis C therapy has been elusive and HIV treatment remains the primary health issue for the co-infected population.

HIV and hepatitis C co-infection

Highly active antiretroviral therapy (HAART)-related hepatotoxicity, a relevant side effect in HIV/hepatitis C virus (HCV) co-infected patients, has evolved over time. Antiretroviral therapy might have a positive effect on the liver of HIV/HCV co-infected patients, but data are conflicting. HIV treatments have evolved and we have currently a drug armamentarium with a good liver safety profile. Most of the current first-line HAART regimens recommended by guidelines fit well to HIV/HCV co-infected patients. There are now multiple retrospective studies that suggest a possible benefit of HIV control and protection of CD4 cell counts to the liver of HIV/HCV co-infected patients. However, data are conflicting at times. This factor along with the methodological limitations of these studies prevent us from drawing definitive conclusions. Even assuming a positive effect, HAART does not appear to fully correct the adverse effect of HIV infection on HCV-related outcomes. In the era of HCV direct antiviral agents, the timing of HIV and HCV therapies has to be individualized in HIV/HCV co-infected patients given the variety of scenarios. With current HIV drug armamentarium it is possible to construct HAART regimens with optimal liver safety profile for HCV co-infected patients. The possible positive effect of HAART on the HCV-infected liver should not distract from the main intervention, which is HCV eradication with specific treatment.

Current treatment for chronic hepatitis C virus/HIV-infected individuals

Liver disease is an important cause of morbidity and mortality in the era of combination antiretroviral therapy in HIV/hepatitis C virus (HCV) co-infected patients. This review highlights the role of pegylated interferon-alpha (peg-IFN) and ribavirin (RBV) therapy and examines factors associated with response and strategies to maximize responses. HCV viral clearance is lower in HIV co-infected patients than in HCV mono-infected patients. However, in patients who attain sustained response there is clinical benefit in terms of liver disease associated morbidity and mortality and treatment is costeffective. Predictors of response appear similar, although there are a number of modifiable patient-associated and HIV-associated factors that could be addressed. Moreover, the use of weight-based RBV and treatment length guided by early viral responses improve response rate. Avoidance of drug-drug interactions and use of haematopoietic growth factors reduce adverse events and dose reductions and ultimately increase response rates. Very early prediction of treatment futility is promising. Induction dosing strategies have not yielded positive results, though twice weekly peg-IFN-alpha-2a induction therapy merits further investigation. Peg-IFN/RBV therapy plays an important role in the management of HCV in HIV-infected patients. Efforts to maximize response to current therapy need to continue while we await new therapies.

Assessment of liver disease (noninvasive methods)

The purpose of this review is to highlight new findings published in 2010-2011 related to noninvasive fibrosis assessment in HIV/hepatitis C virus (HCV) co-infected patients. Overall, in 2010-2011, 15 studies were published, of which two were excluded because they were published in languages other than English. Eleven studies focused on serum marker panels. Studies sought to validate established panels in HIV/HCV co-infected patients often by comparing multiple serum marker panels in the same population; establish new marker panels using combinations of markers used in previously validated panels; and develop new marker panels using novel methodology. Overall, all panels performed within similar ranges of diagnostic accuracy as measured by the area under the receiver operating characteristic curve (AUROC) but the FibroMeter panel and its derivations achieved the highest performance. Four studies focused on transient elastography. Two studies confirmed its accuracy for identifying fibrosis and cirrhosis and two studies confirmed that misclassification rates are higher in the presence of elevated triglycerides and steatosis. Overall, performance of transient elastography appeared superior to the majority of serum marker panels for the detection of significant fibrosis and cirrhosis in HIV/HCV co-infected patients. Challenges of widespread application of transient elastography remain high misclassification in some subgroups, lack of standardized cut-points and lack of widespread availability. Panels that were newly developed in 2010-2011 specifically for HIV/HCV appeared to perform better than existing panels such as APRI and FIB-4; however, additional external validation will be needed to confirm their accuracy.

Liver toxicity associated with antiretroviral therapy including efavirenz or ritonavir-boosted protease inhibitors in a cohort of HIV/hepatitis C virus co-infected patients

To compare the frequency of grade 3 or 4 transaminase elevations (TEs) in HIV/hepatitis C virus (HCV) co-infected patients who started a three-antiretroviral drug regimen including efavirenz or a ritonavir-boosted protease inhibitor (PI/r) and the influence of pre-existing significant hepatic fibrosis or cirrhosis. All pre-treated or treatment-naive HIV/HCV co-infected patients who started an antiretroviral regimen including two nucleos(t)ide reverse transcriptase inhibitors along with efavirenz or a PI/r in seven Spanish centres from January 2007 to December 2009 were included in this prospective study. Of 262 patients included in this study, 76 (29%) individuals began antiretroviral therapy (ART) including efavirenz and 186 (71%) a PI/r-based combination. The median (interquartile) follow-up was 14.0 (6.2-23.7) months. A total of 20 (7.6%) patients presented grade 3-4 TEs. Four (1.5%) subjects discontinued ART due to this adverse event. Grade 3-4 TEs were observed in 5 (6.6%) subjects receiving efavirenz and 15 (8.1%) treated with PI/r (P = 0.681). Three (6.5%) patients in the efavirenz group with significant fibrosis developed grade 3-4 TEs versus 2 (8.7%) without pre-existing significant fibrosis (P = 0.743). In the PI/r group, the corresponding figures were 10 (8.8%) and 5 (9.3%), respectively (P = 0.931). The frequency of grade 3-4 TEs associated with efavirenz-based ART combinations under clinical practice conditions is low and similar to that found in patients receiving PI/r currently used in HIV/HCV co-infected patients. The baseline fibrosis stage does not have an impact on the development of TEs caused by these antiretroviral drugs in this population.

Liver transplant outcomes in HIV-infected patients

We read with interest the article entitled ‘Liver transplant outcomes in HIV-infected patients: a systematic review and meta-analysis with a synthetic cohort’ by Cooper et al.[1]. This article is very interesting because it describes systematically 15 cohort studies and 49 case series with individual patient data. It is now generally accepted that liver transplantation in HIV-infected patients is feasible; in HIV/hepatitis C virus (HCV) co-infected patients, we and others have demonstrated that survival at 1 year after liver transplantation ranges from 58% to 89% [2,3]; when we compared these rates with a series of mono-infected patients, survival was lower in the co-infected group, the 2-year and 5-year patient survival rates being 73% vs. 91% and 51% vs. 81%, respectively, (P = 0.004). Moreover, concerning HIV/hepatitis B virus (HBV) co-infected patients, survival was excellent, the rate reaching 100% survival at 5 years [4]. In the study by Cooper et al. [1], some points need to be detailed or explained and discussed. The constitution of a synthetic cohort from grouped case data is an original and interesting method. However, the character of ‘grouped cases’ with a lack of details concerning the indications of liver transplantation (hepatocellular carcinoma or end-stage liver cirrhosis) and virologcial characteristics (HCV viral load at the time of liver transplantation, HCV genotype) is a concern. More generally, provision of such information is particularly important for overcoming the problem of patient heterogeneity. Concerning HIV/HCV co-infected patients, the authors considered that HCV was a negative predictor of patient survival in the unadjusted model [0.23, 95% confidence interval (CI) 0.07–0.79],l but not when it was adjusted by other key predictors of patient survival (0.54, 95% CI 0.17–1.80). This result is surprising; the authors need to provide details on which other predictor factors they used. The authors found that a Model End-Stage Liver Disease (MELD) score of at least 14 is a prognostic factor for survival in nonadjusted analyses. Interpretation of this cut-off point is difficult because it pools different subgroups of patients, such as those with hepatocellular carcinoma and a low MELD score and those with complicated cirrhosis with a high MELD score. In our cohort of HIV/HCV co-infected patients, we demonstrated that the MELD score as a continuous variable was an independent factor for survival under multivariate analysis [2]. The authors found a significant difference in survival as a function of the year of publication (</>2001). This point is interesting; we agree that modifications to antiretroviral regimens may influence postliver transplantation survival [5]; other important factors such as registration on the waiting list of patients with less severe liver disease, or a more systematic introduction of anti-HCV therapy after liver transplantation, also need to be mentioned. The authors found a percentage of fibrosing cholestatic hepatitis of 12% at 5 years after liver transplantation. This very severe complication has been reported in 5% HBV or HCV mono-infected patients. We recently demonstrated that this type of complication occurred in 11 (19%) of 59 HIV/HCV co-infected patients transplanted for end-stage liver disease. Clearly, it is necessary to prevent this high recurrence rate through the early detection of predictive factors and the early initiation of anti-HCV therapy [6]. In conclusion, this study is important because it demonstrates that survival after liver transplantation in HIV-infected patients is similar to that of HIV-negative patients. However, other large studies are needed to individualize prognosis factors after liver transplantation in a well characterized subgroup of HIV-infected patients. Acknowledgements Conflicts of interest None declared.

Liver Toxicity of Antiretroviral Combinations Including Fosamprenavir Plus Ritonavir 1400/100 mg Once Daily in HIV/Hepatitis C Virus-Coinfected Patients

Abstract Our objective was to evaluate the liver toxicity of antiretroviral regimens including fosamprenavir plus ritonavir (FPV/r) 1400/100 mg once daily (QD) in HIV/hepatitis C virus (HCV)-coinfected patients. This was a prospective cohort study that included 117 HIV/HCV-coinfected patients who started FPV/r 1400/100 mg QD-based antiretroviral therapy (ART) and who neither had received a previous antiretroviral regimen containing FPV nor had a past history of virologic failure while receiving protease inhibitors (PI). The primary end point of the study was the occurrence of grade 3-4 liver enzymes elevations (LEE) within 1 year after starting FPV/r QD. Factors potentially associated with grade 3-4 LEE, including baseline liver fibrosis, were analyzed. Eleven (9%) patients had a grade 3-4 LEE during the follow-up, resulting in an incidence of severe liver toxicity of 9% (95% confidence interval 4.1-14.6%). None of these cases led to FPV/r discontinuation. Baseline liver fibrosis could be assessed in 97 (83%) patients. Six of 71 patients (8%) with significant fibrosis had a grade 3-4 LEE versus 2 of 26 (8%) without significant fibrosis (p=1.0). Twenty (21%) patients had cirrhosis at baseline. There were no cases of LEE among cirrhotics. In conclusion, the incidence of severe liver toxicity after 1 year of therapy with FPV/r QD-based ART in HIV/HCV-coinfected patients is similar to what has been reported with other boosted PIs. In addition, the presence of significant fibrosis or cirrhosis was not associated with the emergence of liver toxicity. Thus, ART regimens containing FPV/r QD may be considered safe in HIV/HCV-coinfected patients, including those with cirrhosis.