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.     

Treatment of hepatitis C virus (HCV) infection in patients coinfected with HIV in the HIV Outpatient Study (HOPS), 1999–2007

Summary. Liver disease due to hepatitis C virus (HCV) infection is a leading cause of non‐AIDS‐related morbidity and mortality in patients infected with HIV. We assessed the frequency of and predictors for initiation of treatment for HCV infection among patients coinfected with HCV/HIV enrolled in the HIV Outpatient Study (HOPS) during 1999–2007. We included patients with confirmed HCV infection, at least 1 year of subsequent follow‐up, and no evidence of prior HCV treatment. We assessed predictors of HCV treatment initiation using Cox proportional hazards analyses. During 1999–2007, 103 (20%) HOPS patients coinfected with HCV/HIV initiated HCV treatment during a median of 4.3 years of follow‐up (interquartile range: 2.7, 6.7). In multivariable analysis, non‐Hispanic black race/ethnicity (hazard ratio HR] 0.3; 95% confidence interval [CI] = 0.2, 0.6) was independently associated with a lower likelihood of HCV treatment. Elevated alanine aminotransferase (ALT; HR 3.5; 95% CI = 2.2, 5.6) and CD4+ cell count ≥500 cells/mm³ (HR 1.8; 95% CI = 1.2, 2.8) at the start of observation were independently associated with higher likelihood of HCV treatment. For patients starting observation in 1999–2001, 2002–2004 and 2005–2007, 5%, 11% and 21% of patients initiated treatment during the first year of follow‐up, respectively. Between 1999 and 2007, despite a stable low fraction of patients coinfected with HCV/HIV initiating treatment for HCV infection, an increasing proportion initiated treatment within the first year after the infection was confirmed. Treatment of HCV infection in patients coinfected with HCV/HIV should be considered a priority, given the increased risk of accelerated end‐stage liver disease.     

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.     

The prevalence of hepatitis C virus (HCV) infection in HIV‐positive individuals in the UK – trends in HCV testing and the impact of HCV on HIV treatment outcomes

Summary. We examined the prevalence of hepatitis C virus (HCV) infection among HIV‐positive individuals in the UK, trends in HCV testing and the impact of HCV on HIV treatment outcomes. Trends over time in HCV prevalence were calculated using each patient’s most recent HCV status at the end of each calendar year. Logistic regression was used to identify factors associated with having a HCV antibody test, and Cox regression was used to determine whether HCV status was associated with the time to experiencing an immunological response to highly active antiretroviral treatment (HAART), time to virological response and viral rebound. Of the 31 765 HIV‐positive individuals seen for care between January 1996 and September 2007, 20 365 (64.1%) individuals were tested for HCV, and 1807 (8.9%) had detectable HCV antibody. The proportion of patients in follow‐up ever tested for HCV increased over time, from 782/8505 (9.2%) in 1996 to 14 280/17 872 (79.9%) in 2007. Nine thousand six hundred and sixty‐nine individuals started HAART for the first time in or after January 2000, of whom, 396 (4.1%) were HCV positive. Presence of HCV infection did not affect initial virological response, virological rebound or immunological response. The cumulative prevalence of HCV in the UK CHIC Study is 8.9%. Despite UK guidelines, over 20% of HIV‐positive individuals have not had their HCV status determined by 2007. HCV infection had no impact on HIV virological outcomes or immunological response to HIV treatment. The long‐term impact on morbidity and mortality remain to be determined.     

Pretreatment assessment and predictors of hepatitis C virus treatment in US veterans coinfected with HIV and hepatitis C virus

The US Department of Veterans Affairs (VA) cares for many human immunodeficiency virus/hepatitis C virus (HIV/HCV)-coinfected patients. VA treatment recommendations indicate that all HIV/HCV-coinfected patients undergo evaluation for HCV treatment and list pretreatment assessment tests. We compared clinical practice with these recommendations. We identified 377 HIV/HCV-coinfected veterans who began HCV therapy with pegylated interferon and ribavirin and 4135 HIV/HCV-coinfected veterans who did not but were in VA care at the same facilities during the same period. We compared laboratory and clinical characteristics of the two groups and estimated multivariate logistic regression models of receipt of HCV treatment. Overall, patients had high rates of receipt of tests necessary for HCV pretreatment assessment. Patients starting HCV treatment had higher alanine aminotransferase (ALT), lower creatinine, higher CD4 counts and lower HIV viral loads than patients not starting HCV treatment. In the multivariate model, positive predictors of starting HCV treatment included being non-Hispanic whites, having higher ALTs, lower creatinines, higher HCV viral loads, higher CD4 counts, undetectable HIV viral loads and receiving HIV antiretrovirals. A history of chronic mental illness and a history of hard drug use were negative predictors. Most HIV/HCV-coinfected patients received the necessary HCV pretreatment assessments, although rates of screening for hepatitis A and B immunity can be improved. Having well-controlled HIV disease is by far the most important modifiable factor affecting the receipt of HCV treatment. More research is needed to determine if the observed racial differences in starting HCV treatment reflect biological differences, provider behaviour or patient preference.     

Changes in liver fibrosis in HIV/HCV‐coinfected patients following different outcomes with peginterferon plus ribavirin therapy

There is scarce information about the impact of antiviral treatment on subsequent progression of liver fibrosis in HIV‐infected patients with chronic hepatitis C who experience different outcomes following peginterferon‐ribavirin therapy. We conducted a retrospective study of a cohort of HIV/HCV‐coinfected patients with longitudinal assessment of liver fibrosis using elastometry. Patients were split out into four groups according to the prior peginterferon‐ribavirin response: sustained virological response (SVR), relapse (R), partial response (PR) and null response (NR). A group of untreated, coinfected patients was taken as control. Significant liver fibrosis progression (sLFP) was defined as a shift from baseline Metavir estimates ≤F2 to F3‐F4, or by >30% increase in liver stiffness in patients with baseline F3‐F4. Conversely, significant liver fibrosis regression (sLFR) was defined as a shift from baseline Metavir estimates F3‐F4 to ≤F2, or by >30% reduction in liver stiffness in patients that kept on F3‐F4. A total of 498 HIV/HCV‐coinfected patients were examined. They were classified as follows: 138 (27.7%) SVR, 40 (8%) R, 61 (12.2%) PR, 71 (14.3%) NR and 188 (37.8%) naive. After a mean follow‐up of 53.3 months, sLFP occurred less frequently in patients with SVR (7.2%) compared with R (25%; P = 0.002), PR (23%; P = 0.002), NR (29.6%; P < 0.001) and naïve (19.7%; P = 0.002). Conversely, sLFR was 26.1% in SVR compared with 10% in R (P = 0.03), 14.8% in PR (P = 0.06), 16.9% in NR (P = 0.07) and 10.6% in naïve (P < 0.001). Sustained clearance of serum HCV‐RNA following a course of antiviral treatment is the major determinant of liver fibrosis regression in HIV/HCV‐coinfected patients.     

Autoantibodies and hepatitis C virus genotypes in chronic hepatitis C patients in Estonia

AIM: To determine the prevalence of several autoantibodies in chronic hepatitis C patients, and to find out whether the pattern of autoantibodies was associated with hepatitis C virus (HCV) genotypes. METHODS: Sera from 90 consecutive patients with chronic hepatitis C were investigated on the presence of anti-nuclear (ANA), anti-mitochondrial (AMA), anti-smooth muscle (SMA), anti-liver-kidney microsomal type 1 (LKMA1), anti-parietal cell (PCA), anti-thyroid microsomal (TMA), and anti-reticulin (ARA) autoantibodies. The autoantibodies were identified by indirect immunofluorescence. HCV genotypes were determined by a restriction fragment length polymorphism analysis of the amplified 5' noncoding genome region. RESULTS: Forty-six (51.1%) patients were positive for at least one autoantibody. Various antibodies were presented as follows: ANA in 13 (14.4%) patients, SMA in 39 (43.3%), TMA in 2 (2.2%), and ARA in 1 (1.1%) patients. In 9 cases, sera were positive for two autoantibodies (ANA and SMA). AMA, PCA and LKMAI were not detected in the observed sera. HCV genotypes were distributed as follows: 1b in 66 (73.3%) patients, 3a in 18 (20.0%), and 2a in 6 (6.7%) patients. CONCLUSION: A high prevalence of ANA and SMA can be found in chronic hepatitis C patients. Autoantibodies are present at low titre (1:10) in most of the cases. Distribution of the autoantibodies show no differences in the sex groups and between patients infected with different HCV genotypes.     

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.     

Peginterferon‐alfa mono‐therapy in the treatment of acute hepatitis C in HIV‐infection

The ongoing epidemic of acute hepatitis C (AHC) infection among MSM highlights the need to identify factors allowing for optimal treatment outcome in HIV co‐infected individuals. Cohort study of 105 HIV‐infected patients with AHC infection from five centres in two European countries was carried out. Choice of treatment with pegIFN‐alfa alone (group 1; n = 36) or pegIFN‐alfa and ribavirin (RBV) (group 2; n = 69) was at the discretion of the investigator. Outcome was evaluated as RVR and SVR. Fisher's exact and Mann Whitney U tests were used for statistical analysis. All patients were male, median age was 39 years, main route of transmission MSM (91%). In 69% of patients, clinical signs of acute hepatic infection were missing, dominant HCV genotypes were 1 (64%) and 4 (16%) and mean baseline HCV‐RNA was 3.559.085 IU/mL. 60% received HAART and CD4 cell count was 469/mm³. Overall SVR rate was 64.8% (68/105). SVR was reached in 69% of treated patients in group 1 and in 63% of treated patients in group 2 (P = 0.67) while RVR was seen in 61% and 49%, respectively (P = 0.35). Interestingly, by univariate analysis, SVR rates in group 1 were significantly higher in patients initiating therapy within 4 weeks of AHC diagnosis compared to patients initiating therapy within 5–36 weeks after diagnosis (P = 0.03). PegIFN‐alfa alone or in combination with ribavirin results in similar response rates in HIV‐infected patients with AHC. In particular, when treatment is initiated within 4 weeks of diagnosis, pegIFN mono‐therapy might be sufficient to allow for an optimal treatment response.     

Hepatitis C virus (HCV) genotypes in Spanish patients with HCV infection: relationship between HCV genotype 1b, cirrhosis and hepatocellular carcinoma

Background/Aims: The influence of the infecting virus genotype on the progression of the underlying liver disease in patients with chronic hepatitis C virus (HCV) infection remains controversial. The aim of this study was to investigate the prevalence of HCV genotypes in Spanish patients with chronic HCV infection and to elucidate the relationship between the infecting genotype and severity of the disease.Methods: A cross-sectional, retrospective analysis of frequency distribution of HCV genotypes was carried out in 414 Spanish patients with chronic HCV infection, including 243 patients with asymptomatic or minimally symptomatic chronic hepatitis, 112 patients with cirrhosis and hepatocellular carcinoma and 59 patients with decompensated cirrhosis. HCV genotype was determined by restriction fragment length polymorphisms of the 5′ non-coding region.Results: Infection with HCV genotype 1b was found in 72% of patients with chronic hepatitis and in more than 90% of patients with cirrhosis, with or without hepatocellular carcinoma. Older age, infection with genotype 1b and absence of overt parenteral exposure as a possible source of infection were associated with cirrhosis and hepatocellular carcinoma by univariate analysis and this association was confirmed by regression analysis.Conclusions: HCV genotype 1b is associated with advanced liver disease in our geographical area. However, this may be related to a cohort-effect caused by over-representation of genotype 1b in older patients with more advanced disease, because, in our country, this HCV genotype appeared earlier in time and is therefore associated with more prolonged periods of infection.     

Differences in liver fibrosis and response to pegylated interferon plus ribavirin in HIV/HCV‐coinfected patients with normal vs elevated liver enzymes

Summary. Severity of liver fibrosis and response to pegylated interferon plus ribavirin (pegIFN–RBV) are not well known in HIV/HCV‐coinfected patients with persistently normal alanine aminotransferase (PNALT). All HIV/HCV‐coinfected patients who had been assessed for liver fibrosis using elastometry during 2005 at our clinic were evaluated. Those with at least 1 year with three prior consecutive ALT measurements below the upper limit of normality were compared with patients with elevated ALT. Response to pegIFN–RBV was assessed in a subset of these patients. We analysed 87 patients with PNALT and 122 with elevated ALT. Compared to patients with elevated ALT, those with PNALT were significantly more often women (42%vs 26%), had greater mean CD4 counts (565 vs 420 cells/mm³), had lower mean serum HCV‐RNA (5.8 vs 6.2 log IU/ml) and were infected by HCV genotype 4 (33%vs 6%). Liver fibrosis was considered as severe (Metavir F3) in 10% of patients with PNALT, and another 4% had cirrhosis based on stiffness values. These numbers were 16% and 35% in patients with elevated ALT. Treatment with pegIFN–RBV was given to 22 and 45 patients with PNALT and elevated ALT, respectively. Sustained virological response was achieved in 50% and 29% of them. In the multivariate analysis, PNALT was independently associated with response (OR: 7.9; 95% CI: 1.4–45.2; P = 0.02). Nearly 15% of HIV/HCV‐coinfected patients with PNALT showed advanced liver fibrosis (Metavir F3‐F4 estimates by elastometry). In summary, response to pegIFN–RBV is higher in patients with PNALT than in those with elevated ALT. Therefore, treatment should not be denied in HIV/HCV‐coinfected patients with PNALT.     

IL28RA polymorphism is associated with early hepatitis C virus (HCV) treatment failure in human immunodeficiency virus‐/HCV‐coinfected patients

Due to the poor rate of response to hepatitis C virus (HCV) with pegylated interferon and ribavirin treatment in HCV/HIV coinfected patients, key factors for predicting failure would be useful. We performed a retrospective study on 291 patients on HCV treatment, who had early virological response (EVR) data. IL28B and IL28RA polymorphisms were performed using the GoldenGate^® assay. Unfavourable genotypes at IL28B (rs12980275 AG/GG and rs8099917 GT/GG) and an unfavourable allele at IL28RA (rs10903035 G) were associated with early treatment failure. However, only the rs12980275 AG/GG genotype and rs10903035 G allele remained independently associated with early failure in the overall population (OR = 4.15 (95% CI = 1.64–10.54) and OR = 2.00 (95% CI = 1.19–3.36), respectively) as well as in GT1/4 patients (OR = 5.07 (95% CI = 1.81–14.22) and OR = 2.03 (95% CI = 1.13–3.66), respectively). Next, a decision tree showed early treatment failure increased from 37.1% to 65.5% when the unfavourable rs12980275 AG/GG and rs10903035 AG/GG genotypes and HCV‐RNA≥ 500.000 IU/mL were taken into account in GT1/4 patients. In contrast, the failure rate decreased from 37.1% to 11.9% when the favourable rs12980275 AA and rs10903035 AA genotypes were detected. The percentage of patients correctly classified was 78.4%, and AUROC was 0.802 ± 0.028. Regarding GT3 patients, the presence of the GCGCA haplotype (all unfavourable alleles) was associated with early treatment failure, while no association was observed for the IL28B polymorphisms. In conclusion, the IL28RA polymorphism was associated with early treatment failure independently of the IL28B SNPs. The combination of IL28B and IL28RA polymorphisms might be a valuable tool for predicting early treatment failure before starting HCV treatment.