Hepatitis C virus (HCV) protease variability and anti-HCV protease inhibitor resistance in HIV/HCV-coinfected patients

Objectives

Data on the natural selection of isolates harbouring mutations within the NS3 protease, conferring resistance to hepatitis C virus (HCV) protease inhibitors (PIs), are limited for HIV/HCV‐coinfected patients. The aim of this study was to describe the natural prevalence of mutations conferring resistance to HCV PIs in HIV/HCV‐coinfected patients compared with HCV‐monoinfected patients.

Methods

The natural prevalences of HCV PI resistance mutations in 120 sequences from HIV/HCV‐coinfected patients (58 genotype 1a, 18 genotype 1b and 44 genotype 4) and 501 sequences from HCV‐monoinfected patients (476 genotype 1 and 25 genotype 4), retrieved from GenBank as a control group, were compared.

Results

Of 76 sequences from HIV/HCV genotype 1‐coinfected patients, six (7.9%) showed amino acid substitutions associated with HCV PI resistance (V36L, n=1; V36M, n=2; T54S, n=2; R155K, n=1). In 31 of 476 (6.5%) HCV genotype 1 sequences retrieved from the GenBank database, HCV PI resistance mutations were found. The difference was not statistically significant (P=0.6). All of the sequences from HIV/HCV genotype 4‐coinfected patients and those retrieved from the GenBank database had amino acid changes at position 36 (V36L).

Conclusion

Our study suggests that the natural prevalence of strains resistant to HCV PIs does not differ between HCV‐monoinfected and HIV/HCV‐coinfected patients. Further studies on larger cohorts are needed to confirm these findings and to evaluate the impact of these mutations in clinical practice.     

Impact of hyperglycaemia and cholesterol levels on the outcome of hepatitis C virus (HCV) treatment in HIV/HCV-coinfected patients

Objectives

High serum total cholesterol and low‐density lipoprotein (LDL) levels have been demonstrated to increase the probability of a sustained viral response (SVR) in chronic hepatitis C. Conversely, insulin resistance reduces SVR rates. We investigated the influence of baseline glucose and lipid values on the outcome of hepatitis C virus (HCV) treatment in HIV‐1 infected subjects.

Methods

We retrospectively reviewed the charts of HIV/HCV‐coinfected patients treated with an interferon‐based regimen from 2002 to 2008. Fasting glucose levels and total cholesterol, LDL and triglyceride levels were recorded prior to the initiation of treatment.

Results

Of the 96 patients enrolled in the study, 36 (37.5%) had genotype 1, 48 (50%) genotype 2 or 3 and 12 (12.5%) genotype 4. SVR was obtained in 25% (nine of 36) and 70% (42 of 60) of patients with genotype 1 and other genotypes, respectively. In the multivariate analysis, the independent predictors of SVR were: genotype other than genotype 1 [adjusted odds ratio 9.64, confidence interval (CI) 2.7–34.3; P<0.0001], HCV viraemia [adjusted odds ratio 0.36, CI 0.15–0.9; P=0.028], fasting glucose ≥100 mg/dL [adjusted odds ratio 0.13, CI 0.034–0.51; P=0.003], and cholesterol level ≥190 mg/dL [adjusted odds ratio 5.96, CI 1.6–22.3; P=0.008].

Conclusions

Higher baseline serum glucose and cholesterol levels may be significant prognostic indicators for anti‐HCV treatment outcome in HIV/HCV‐coinfected patients.     

Similar recovery of liver function after response to all‐oral HCV therapy in patients with cirrhosis with and without HIV coinfection

Among patients with cirrhosis, recovery of liver function after SVR to all‐oral direct‐acting antivirals (DAA) in HIV/HCV coinfection could be different to that in HCV monoinfection. Because of this, we compared the changes in several markers of liver function between HCV‐monoinfected and HIV/HCV‐coinfected patients with cirrhosis who achieved SVR12 to DAA combinations. In this retrospective cohort study, cirrhotics included in the HEPAVIR‐DAA and GEHEP‐MONO cohorts were selected if they had SVR12 to all‐oral DAAs. Patients treated with atazanavir were excluded. Liver function improvement was defined as Child‐Pugh‐Turcotte (CPT) decrease ≥1 and/or MELD decrease ≥2 between baseline and SVR12. Liver function worsening was defined as a CPT increase ≥1 and/or MELD increase ≥2 and/or decompensations between baseline and SVR12. We included 490 patients, 270 (55%) of them with HIV coinfection. Liver function improved in 50 (56%) HCV‐infected individuals and in 82 (57%) HIV/HCV‐coinfected patients (P = 0.835). Liver function worsened in 33 (15%) HCV‐monoinfected patients and in 33 (13%) HIV/HCV‐coinfected patients (P = 0.370). Factors independently related with liver function improvement were male gender [adjusted OR (AOR) 2.1 (95% confidence interval, 95% CI: 1.03‐4.2), P = 0.040], bilirubin < 1.2 mg/dL (AOR 1.8 [95% CI: 1.004‐3.3], P = 0.49), and INR < 1.3 (AOR 2.4 [95% CI: 1.2‐5.0], P = 0.019) at baseline. After multivariate analysis, albumin < 3.5 g/dL was associated with liver function worsening (AOR 6.1 [95% CI: 3‐12.5], P < 0.001). Liver function worsening and improvement rates after responding to DAA are similar among HCV‐monoinfected and HIV/HCV‐coinfected cirrhotics. Gender, INR, bilirubin, and albumin levels were associated with liver function changes after response to DAAs.     

Sustained virological response according to the type of early virological response in HCV and HCV/HIV

Background. The most important factors to predict the sustained virological response (SVR) are the genotype and the fibrosis grade, although there are other predictive factors to be considered, mainly in HCV/ HIV coinfected patients.Aim. To evaluate different prognostic factors to obtain the SVR in HCV monoin-fected and HCV/HIV coinfected genotype I patients emphasizing the type of early virological response (EVR)-complete or partial.Methods. This is a cohort study, retrospective, where the registers of HCV mo-noinfected or HCV/HIV coinfected patients, genotype I, treated with pegylated interferon + ribavirin were reviewed. The prognostic factors: age greater than 40 years, viral load higher than 600,000UI/mL, and fibrosis grade (score METAVIR) were evaluated pre-treatment, and also the EVR considering the reduction of 100 times of the basal viral load (partial EVR) or negative PCR (complete EVR) in the week 12. In the statistical analysis, multivariate analysis was used. The significance level adopted was 5%.Results. There were 323 HCV monoinfected and 59 HCV/HIV coinfected. The SVR was 35.3% in monoinfected and 23% in coinfec-ted patients. The worst results was observed in those with age greater than 40 years, high viral load, pronounced fibrosis (F4) and partial EVR, with an expected probability of 1.9% for SVR in those coinfected and 3.8% in monoinfected. In conclusion, patients with cirrhosis HCV genotype 1, age greater than 40 years, high viral load, coinfected with HIV or not, will present a low SVR if did not obtain negative PCR in week 12, and should be evaluated for discontinuation.     

Role of rapid virological response in prediction of sustained virological response to Peg-IFN plus ribavirin in HCV / HIV co-infected individuals

Summary.  The objective of the study was to evaluate the role of rapid virological response (RVR) in predicting sustained virological response (SVR) rates to hepatitis C virus (HCV) therapy. 65 HIV / HCV co-infected patients commenced HCV treatment per protocol. HIV / HCV patients with a mean CD4 count of 502 were treated for 24–48 weeks depending on genotype. Virological response was assessed at weeks 4 (RVR), 12 [early virological response (EVR)], 24, at end of treatment (EOTR) and 24 weeks post-completion of treatment (SVR). Primary end-point was defined as undetectable HCV RNA at 24 weeks post-treatment completion. Fifty-five per cent of co-infected patients were on highly active anti-retroviral therapy. A majority of patient group were male. 60% of HIV / HCV patients achieved SVR (35% genotype 1 / 4; 77% genotype 2 / 3). 24 HIV / HCV patients achieved undetectable HCV levels compared with baseline by week 4. The positive predictive value (PPV) of RVR at week 4 for subsequent SVR in HIV–HCV co-infected patients was 100%; the negative predictive value (NPV) was 57%. Significant variables associated with SVR were: (i) lower median pre-treatment HCV viral load, (ii) genotype 2 / 3 disease and (iii) achievement of RVR. Independent variables associated with RVR were low pre-treatment HCV viral load and genotype 2 / 3 disease. Achievement of RVR, a negative HCV-PCR, at week 4 of treatment is predictive of SVR in this cohort of patients. This may be used to guide optimal treatment duration in patient groups. More significantly, the data serve to highlight the subgroup of patients who, on achieving RVR, should be actively supported to complete HCV treatment with full dose therapy, especially patients co-infected with G2 / 3 disease for whom 6 months' full dose therapy may be sufficient to obtain a SVR.     

Impact of HCV eradication with direct-acting antiviral agents on serum gamma globulin levels in HCV and HCV/HIV coinfected patients

Backgroundchronic viral infections by both HCV and HIV may lead to polyclonal activation of B cells resulting in hypergammaglobulinemia. This study retrospectively analyzed the effect of HCV eradication with interferon-free direct-acting antiviral agents (DAAs) on the gamma globulin levels in HCV-infected patients with or without HIV coinfection to identify factors potentially associated with gamma globulins decrease.MethodsThe charts of patients treated with DAAs for HCV chronic infection between January 2015-June 2019 were retrospectively reviewed. Gamma globulin levels before treatment and 12 weeks after the end of anti-HCV therapy were evaluated along with liver tests, liver fibrosis stage by elastography, SVR achievement, HIV-coinfection. Multivariate analyses were carried out to assess the factors and the potential confounders related to the changes in gamma globulin levels.ResultsA significant decrease of gamma globulin concentration was found in both cirrhotic and non-cirrhotic HCV-infected patients after treatment (from mean ± SD of 1.5 ± 0.44 g/dL to 1.31 ± 0.37 g/dL; p = 0.0001). Adjusted linear regression analyses of serum gamma globulin changes from baseline to SVR12 showed a positive significant association with pre-treatment gamma-globulin levels (β-coefficient −0.23; p = 0.0001), Metavir fibrosis score (β-coefficient -0.74; p = 0.008), ALT values and baseline HCV-RNA levels > 800,000. No difference was found between HIV-infected and HIV-uninfected patients.ConclusionsOur study confirms previous preliminary observation of the decrease of serum gamma globulins after HCV eradication either achieved with interferon-based therapy or with DAAs, suggesting a leading role of the virus on the activation of B cell compartment and gamma globulins production.     

Alcohol Consumption and Hepatitis C Virus (HCV) RNA Levels in HIV/HCV Coinfected Patients

Background: The impact of Hepatitis C virus (HCV) RNA levels on the evolution of chronic HCV infection-related liver damage is controversial. Heavy alcohol use is believed to have a deleterious impact on the course of HCV disease, but current knowledge about the possible effect of alcohol use on HCV RNA levels in HIV/HCV coinfected patients is limited. Methods: We examined 107 HIV/HCV-infected individuals with current or past unhealthy alcohol use to assess the association between alcohol consumption (any drinking vs. abstinent) and HCV RNA levels. Results: Participants were 75% male, with a mean age of 43 years, and 63% were on antiretroviral therapy. Mean (SD) log HIV RNA was 3.1 (1.4) and mean (SD) log HCV RNA was 6.1 (0.8). Past-month alcohol use was present in 38% of participants. In a multivariable linear regression analysis we found no significant differences in mean log HCV RNA levels between those reporting alcohol use and those who were abstinent [β (95%CI): −0.04 (−0.34, 0.26), p = 0.79)]. There was no significant association between any heavy drinking day and HCV RNA level (0.07, 95% CI: (−0.24, 0.38), p = 0.66). Conclusions: We did not detect significant associations between alcohol use and HCV RNA levels among HIV/HCV coinfected patients.     

Dynamic of Mixed HCV Infection in Plasma and PBMC of HIV/HCV Patients Under Treatment With Peg-IFN/Ribavirin

The extent of mixed hepatitis C virus (HCV) genotype in different compartments (plasma and peripheral blood mononuclear cell, PBMC) and possible association with treatment efficacy in HIV/HCV coinfected patients remains to be unknown.The objective of this study was to elucidate the frequency of mixed genotype infection (MG), its profile in different compartments during anti-HCV treatment, and the possible influence of different genotypes on the response rate.The compartmentalization of HCV population was investigated by next-generation sequencing in 19 HIV/HCV coinfected patients under anti-HCV treatment with peginterferon/ribavirin (P–R). Ten individuals were nonresponder (NR) or relapser (RE) to P–R treatment and 9 had a sustained virological response (SVR).Eleven/nineteen (58%) patients had MG in plasma compartment. Ten or 12 patients infected by a difficult to treat genotype (DTG) 1 or 4 as dominant strain, had an MG, whereas only 1/7 individuals infected by easy to treat genotype (ETG) harbored a mixed genotype, P = 0.006. HCV–RNA was more frequently detected in PBMC of NR (10/10) than in those of SVR (5/9), P = 0.032. Mixed genotype infection was detected in 6/15 (40%) PBMC-positive cases and was not associated with P–R treatment response. By multivariate analysis, MG in plasma samples was the most important viral factor affecting the treatment response (P = 0.0237).Detection of MG in plasma of HIV/HCV coinfected patients seems to represent the major determinant of response to P–R treatment. This finding may have important clinical implication in light of the new therapeutic approach in HIV/HCV coinfected individuals suggesting that combination treatment with direct acting antivirals could be less effective in MG.     

Response predictors and clinical benefits of hepatitis C retreatment with pegylated interferon and ribavirin in HIV/HCV coinfection

Background. Hepatitis C is a leading cause of mortality among HIV-infected individuals. Therefore, eradication of HCV in this population is a priority. There are scarce data regarding retreatment efficacy of HIV/ HCV coinfected patients. The aim of our study was to evaluate efficacy, predictors of response, and long term clinical benefits of sustained virological response (SVR) after hepatitis C retreatment in a population of HIV/HCV coinfected patients.Material and methods. We evaluated efficacy, safety, and clinical benefits of peginterferon(alfa-2a or alfa-2b) and ribavirin in a restrospective, observational, multicentric study, including 47 HIV/HCV coinfected patients, non-responders to previous treatment with conventional interferon alfa-2a and ribavirin. The primary endpoint of efficacy was SVR, defined as undetectable viral load 24 weeks after end of treatment. Death, liver disease progression, CD4 counts, and AIDS defining illness were the endpoints to access clinical benefits of treatment response.Results. In our analysis, 31.9% patients reached SVR. Genotypes 2/3 had a significant better SVR (66.7%) compared to genotypes 1/4 (33.3%) (p = 0.022). During follow-up, deaths (6.89%) and hepatic decompensation (28.6%) occurred only in the nonresponder group, while there were no cases of death or hepatic decompensation among the responder group(p = 0.037).Conclusion. Nearly one third of patients (mainly those with genotypes 2/3) reached SVR after hepatitis C retreatment in this group of HIV/HCV coinfected patients. SVR was protective against hepatic decompensation and death in a two-year follow-up period. Retreatment may be an effective and safe way to eradicate HCV until new anti-HCV drugs become available to this group of patients.     

Role of individualization of hepatitis C virus (HCV) therapy duration in HIV/HCV-coinfected individuals

OBJECTIVE: The aim of this study was to assess the efficacy, safety and tolerability of pegylated interferon and ribavirin in HIV/hepatitis C virus (HCV)-coinfected patients, prescribed for the same duration and at the same dosage as that used in HCV monoinfection studies. DESIGN: It was an open-label, single-centre, prospective study. METHODS: Forty-five patients coinfected with HIV and HCV with CD4 counts >200 cells/microL were treated with pegylated interferon-alpha2b 1.5 microg/kg/week and ribavirin 1000-1200 mg/day for 24-48 weeks depending on HCV genotype. Safety and tolerability were assessed weekly for the first month and monthly thereafter. Virological response was assessed at weeks 4, 12 and 24 and at the end of treatment and 12 and 24 weeks post completion of treatment. The primary endpoint was defined as undetectable HCV RNA at 24 weeks post completion of treatment [sustained virological response (SVR)]. RESULTS: The majority of patients were male and had been injecting drug users. Sixty per cent were on antiretroviral therapy. In an intention-to-treat analysis, 53% had an SVR (genotype 1, 19% and genotype 2/3, 75%). All patients who had undetectable HCV RNA at week 4 of HCV treatment [very early virological response (VEVR)] had a SVR. On multivariate analysis only HCV genotype predicted SVR. Adverse events occurred frequently. CONCLUSIONS: These results indicate that 24 weeks of HCV treatment may be adequate for HIV-infected individuals coinfected with HCV genotype 2 or 3. VEVR can predict SVR in this group and may be used to guide the subgroup of genotype 2/3 individuals who will respond to 24 weeks of treatment.     

Very early prediction of response to HCV treatment with PEG‐IFN‐alfa‐2a and ribavirin in HIV/HCV‐coinfected patients

Summary. The objective of this study was to find very early viral kinetic markers to predict nonresponse to hepatitis C virus (HCV) therapy in a group of human immunodeficiency virus (HIV)/HCV‐coinfected patients. Twenty‐six patients (15 HCV genotype‐1 and 11 genotype‐3) were treated with a 48‐week regimen of peginterferon‐alfa‐2a (PEG‐IFN) (180 μg/week) and weight‐based ribavirin (11 mg/kg/day). Samples were collected at baseline; 4, 8, 12, 18, 24, 30, 36 and 42 h; days 2, 3, 4, 7, 8, 15, 22, 29, 43 and 57 then weekly and monthly. Five patients discontinued treatment. Seven patients (27%) achieved a sustained virological response (SVR). Nadir HCV RNA levels were observed 1.6 ± 0.3 days after initiation of therapy, followed by a 0.3‐ to 12.9‐fold viral rebound until the administration of the second dose of PEG‐IFN, which were not associated with SVR or HCV genotype. A viral decline <1.19 log for genotype‐1 and <0.97 log for genotype‐3, 2 days after starting therapy, had a negative predictive value (NPV) of 100% for SVR. The day 2 virological response had a similar positive predictive value for SVR as a rapid virological response at week 4. In addition, a second‐phase viral decline slope (i.e., measured from day 2 to 29) <0.3 log/week had a NPV = 100% for SVR. We conclude that first‐phase viral decline at day 2 and second‐phase viral decline slope (<0.3 log/week) are excellent predictors of nonresponse. Further studies are needed to validate these viral kinetic parameters as early on‐treatment prognosticators of nonresponse in patients with HCV and HIV.     

Hepatitis C virus (HCV) treatment uptake and changes in the prevalence of HCV genotypes in HIV/HCV‐coinfected patients

Summary. The efficacy of current hepatitis C therapy in HIV/HCV‐coinfected patients is largely dependent on HCV genotype. The annual prevalence of HCV genotypes/subtypes and their influence on HCV clearance with antiviral treatment were examined in a dynamic cohort of HIV/HCV‐coinfected patients followed up in Madrid since 2000. Patients entered the cohort at first visit and left the cohort when HCV clearance was achieved with HCV therapy or when follow‐up was interrupted for any reason, including death. A total of 672 HIV/HCV‐coinfected patients constituted the cohort. The mean follow‐up time was 5.5 years, corresponding to 4108 patient‐years. Mean age at entry was 37 years, and 73% were men and 86% were intravenous drug users. Overall distribution of HCV genotypes was as follows: 57.1% HCV‐1 (1a: 29.2%, 1b: 20.4%, unknown: 7.6%), 1.3% HCV‐2, 25.4% HCV‐3 and 15.9% HCV‐4. A total of 274 (40.8%) patients were treated with peginterferon–ribavirin, of whom 116 (42.3%) achieved HCV clearance following 1–3 courses of therapy. The proportion of HCV‐1/4 rose from 71.7% in 2000 to 76.8% in 2008, whereas the proportion of HCV‐2/3 fell from 28.1% in 2000 to 23.2% in 2008. The yearly prevalence increased for HCV‐1 (R²: 0.92, b: 0.59, P < 0.001) and HCV‐4 (R²: 0.77, b: 0.33, P < 0.005) and conversely diminished for HCV‐3 (R²: 0.94, b: ?0.82, P < 0.001). In summary, the prevalence of HCV‐1 and HCV‐4 has increased over the last decade in HIV/HCV‐coinfected patients, whereas conversely it has declined for HCV‐3, in association with the wider use of HCV therapy (41%) in this population.     

Prevalence and correlates of emotional distress in HIV/HCV coinfection

The mental health needs of patients who are coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are increasingly addressed in medical settings. This study aimed at examining the prevalence and severity of emotional distress in a sample of HIV/HCV coinfected and HIV mono-infected patients and to examine their sociodemographic, clinical, and psychosocial correlates. The Brief Symptom Inventory and the quality of life instrument WHOQOL-HIV-Bref were administered to a sample of 248 HIV/HCV coinfected patients and 482 HIV mono-infected patients. Thirty-nine (15.9%) HIV/HCV coinfected patients and 55 (11.6%) HIV mono-infected patients reported a T-score ≥ 63 for global severity index (GSI), indicative of a need for further psychological evaluation. Coinfected patients reported significantly higher scores on eight of nine dimensions of psychopathology. The larger differences were found on somatization, hostility, paranoid ideation, anxiety, and the GSI. Among HIV/HCV patients, non-highly active antiretroviral therapy (β = ?0.19, p < 0.01) and lower scores for independence (β = ?0.24, p < 0.01) and spiritual (β = ?0.31, p < 0.001) dimensions were significantly associated with higher emotional distress and accounted for 47.2% of the total variance. Among HIV mono-infected patients, being diagnosed for a longer time (β = 0.12, p < 0.05) and having lower scores on physical (β = ?0.23, p < 0.001), social relationships (β = ?0.11, p < 0.05), environmental (β = ?0.17, p < 0.01), and spiritual (β = ?0.21, p < 0.001) dimensions explained 39.4% of the variance of emotional distress. The findings suggest that coinfection with HCV may have an adverse effect on mental health and underscore the interplay of sociodemographic, clinical, and psychosocial variables on emotional distress. Additionally, these data reinforce the need for tailored interventions to improve the overall well-being of both HIV and HIV/HCV patients.     

Optimizing hepatitis C therapy in HIV/hepatitis C virus (HCV) coinfected patients: Analysis of HCV viral kinetics on treatment

INTRODUCTION:

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.

METHODS:

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.

RESULTS:

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.

DISCUSSION:

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.     

Distribution and effects of polymorphic RANTES gene alleles in HIV/HCV coinfection -- a prospective cross-sectional study

AIM: Chemokines and their receptors are crucial for immune responses in HCV and HIV infection. RANTES gene polymorphisms lead to altered gene expression and influence the natural course of HIV infection. Therefore, these mutations may also affect the course of HIV/HCV coinfection. METHODS: We determined allele frequencies of RANTES-403 (G→A), RANTES-28 (C→G) and RANTES-IN1.1 (T→C) polymorphisms using real-time PCR and hybridization probes in patients with HIV (n = 85), HCV (n = 112), HIV/HCV coinfection (n = 121), and 109 healthy controls. Furthermore, HIV and HCV loads as well as CD4+ and CD8+ cell counts were compared between different RANTES genotypes. RESULTS: Frequencies of RANTES-403 A, RANTES-28 G and RANTES-IN1.1 C alleles were higher in HIV infected patients than in healthy controls (-403: 28.2% vs 15.1%, P = 0.002; -28: 5.4% vs 2.8%, not significant; IN1.1: 19.0% vs 11.0%, P = 0.038). In HIV/HCV coinfected patients, these RANTES alleles were less frequent than in patients with HIV infection alone (15.4% P = 0.002; 1.7%; P = 0.048; 12.0%; not significant). Frequencies of these alleles were not significantly different between HIV/HCV positive patients, HCV positive patients and healthy controls. CONCLUSION: All three RANTES polymorphisms showed increased frequencies of the variant allele exclusively in patients with HIV monoinfection. The finding that the frequencies of these alleles remained unaltered in HIV/HCV coinfected patients suggests that HCV coinfection interferes with selection processes associated with these alleles in HIV infection.     

Optimized threshold for serum HCV RNA to predict treatment outcomes in hepatitis C patients receiving peginterferon alfa‐2a/ribavirin

Summary. It is unclear whether the current threshold for ‘high’ hepatitis C virus (HCV) RNA level (800 000 IU/mL) is optimal for predicting sustained virological response (SVR). We retrospectively analysed pretreatment HCV RNA levels and SVR rates in 1529 mono‐infected and 176 HIV–HCV co‐infected patients treated with peginterferon alfa‐2a (40 kD) plus ribavirin. We improved the threshold for differentiating low and high viral load by fitting semiparametric generalized additive logistic regression models to the data and constructing receiver operating characteristics curves. Among HCV genotype 1 mono‐infected patients, the difference in SVR rates between those with low and high baseline HCV RNA levels was 27% (70%vs 43%) when 400 000 IU/mL was used and 16% (59%vs 43%) when 800 000 IU/mL was used. In HIV–HCV genotype 1 co‐infected patients, the difference was 51% (71%vs 20%) when 400 000 IU/mL was used and 43% (61%vs 18%) when 800 000 IU/mL was used. A lower threshold (200 000 IU/mL) was identified for genotype 1 mono‐infected patients with ‘normal’ alanine aminotransferase (ALT) levels. No threshold could be identified in HCV genotype 2 or 3 patients. A threshold HCV RNA level of 400 000 IU/mL is optimal for differentiating high and low probability of SVR in genotype 1‐infected individuals with elevated ALT.     

Treatment Response and Drug Resistance Profiling of Genotype 6 of Hepatitis C Virus in HCV/HIV Co-Infected Patients: A Pilot Study from INDIA

Hepatitis C Virus (HCV) genotype (GT) 6 demonstrates maximum genomic diversity out of all the known genotypes of HCV, attributable to its inherent intra-genotype and inter-genotype recombination property. This is the most common genotype seen in HCV/HIV co-infected cases. HIV/HCV co-infection is linked with increased genetic diversity in HCV structural genes. The detailed information on the distribution of HCV GT6, its subtypes, and resistance to currently available antiviral drugs is limited in the Indian subcontinent. Therefore, in this single-center retrospective cross-sectional study, we aimed to map the occurrence of HCV GT6, its subtypes and resistance-associated substitution (RAS), and its correlation with antiviral treatment response in HCV-infected patients. From a cohort of 2052 HCV-infected patients, the overall prevalence of GT6 was 2.5% (n = 53), with a maximum of 81.1% (n = 43) seen in HCV/HIV co-infected patients. Nine different subtypes, 6a, 6b, 6f, 6i, 6n, 6u, 6v, 6w, and 6xa, were detected in the Indian population for the first time, with a predominance of 6xa (41.5%), a rare subtype, followed by 6n (39.6%). The phylogenetic analysis by the neighbor-joining method revealed three prominent viral clades, 6v, 6n, and 6xa–6u. The baseline (before treatment initiation) plasma samples of all GT6-infected patients were retrieved from −80 °C and a part of the NS5a and NS5b region of the viral genome was analyzed for the presence of RAS. No RASs were seen in the NS5b region, while in two patients (3.7%) RASs were seen at baseline in the NS5a region of the virus. Sustained viral response (SVR) was attained in 81% (n = 43) of patients. No difference in GT6 subtype distribution or occurrence of RAS was seen between mono-infected HCV and HIV/HCV co-infected cases. Our study revealed that RAS at baseline did not influence the attainment of SVR and the currently available antiviral therapy is effective against GT6 mono-infected and HIV/HCV co-infected patients.     

CD81 expression in peripheral blood lymphocytes before and after treatment with interferon and ribavirin in HIV/HCV coinfected patients

Background

CD81 is expressed on lymphocytes and confers HCV viral infectivity support. The aim of our study was to quantify CD81 expression in peripheral blood B‐ and T‐cells of HCV/HIV‐coinfected patients and healthy subjects to examine its association with several HCV virological characteristics and the therapeutic responsiveness to HCV antiviral treatment.

Methods

We carried out a cross‐sectional study on 122 naïve patients. For a duration of 48 weeks, 24 out of 122 patients underwent HCV antiviral therapy with interferon (IFN)‐α and ribavirin. T‐ and B‐cell subsets were analysed by flow cytometry.

Results

We found that HIV/HCV coinfected patients with HCV‐RNA ≥850 000 IU/mL had lower values of %CD19+CD81‐CD62L+ and %CD19+CD62L+; and higher values of CD19+CD81+CD62L− and CD19+CD81+ percentages and absolute counts than patients with HCV‐RNA <850 000 IU/mL. Similarly, HIV/HCV coinfected patients with the genotype 1 had lower values of %CD19+CD81−CD62L+ and higher values of CD3+CD81+CD62L− and CD3+CD81+ percentages and absolute counts than patients without genotype 1. Moreover, we found that HIV/HCV coinfected patients had higher values of %CD19+HLA‐DR+CD25+, %CD19+CD40+CD25+ and %CD19+CD25+ than healthy control patients. When we studied the B‐ and T‐cell subset kinetics of 24 HIV/HCV coinfected patients on HCV antiviral therapy, we found a significant decrease in CD3+CD81+and CD3+CD81+CD62L− subsets and a significant increase in CD3+CD62L+ and CD3+CD81+CD62L+ percentages and absolute counts, but the variation in these markers disappeared several months after stopping the treatment.

Conclusions

We observed a different pattern of CD81 T‐cell and B‐cell levels in naïve HIV/HCV coinfected patients according to HCV virological status and their subsequent variations during HCV antiviral treatment. CD81 expression might influence HCV pathogenesis and response to HCV antiviral treatment.

     

Early decline of the HCV core antigen can predict SVR in patients with HCV treated by Pegylated interferon plus ribavirin combination therapy

OBJECTIVE: Pegylated interferon (PEG‐IFN) plus ribavirin (RBV) combination therapy is now a popular treatment for patients with chronic hepatitis C; however, the reported sustained virologic response (SVR) rate remains at nearly 50% in genotype 1b infected patients. Therefore, it is of clinical benefit to be able to predict the effect of combination therapy on individual patients earlier in the treatment. We estimated the predictive serum HCV core antigen levels for SVR in the early therapeutic stage of combination therapy. METHODS: The HCV core antigen in patients with high‐level HCV viremia, in whom standard PEG‐IFNα2b plus RBV combination therapy had been completed, was measured at baseline and at 3, 7, 14, 28 and 84 days of treatment, and their SVR was determined at 24 weeks after treatment. Sixty genotype 1b‐ and 30 genotype 2‐infected patients were included. RESULTS: Thirty (50%) genotype 1b and 27 (90%) genotype 2 patients achieved a SVR. In genotype 1b patients the decline of HCV core antigen levels was statistically different between the SVR and non‐SVR groups. When we defined a separation level at 500 fmol/L, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for SVR at day 7 was 79.4%, 88.5%, 90%, 76.7%, and 83.3%, respectively. In genotype 2 patients, there was no significant difference in the HCV core antigen values between the SVR and non‐SVR groups. CONCLUSION: In genotype 1b patients, 500 fmol/L of HCV core antigen level at day 7 was the best predictor for therapeutic response in the early stage of treatment.