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.     

Cognitive function, mood and health-related quality of life in hepatitis C virus (HCV)-monoinfected and HIV/HCV-coinfected individuals commencing HCV treatment

OBJECTIVES: The aim of the study was to examine cognitive function, mood and health-related quality of life (HRQOL), and their interrelationships, among hepatitis C virus (HCV)-monoinfected and HIV/HCV-coinfected individuals. METHODS: Baseline neuropsychological and HRQOL measures of HCV-monoinfected and HIV/HCV-coinfected individuals commencing HCV treatment were examined from a prospective cohort study conducted between April 2003 and August 2005 in Sydney, Australia. Participants' neuropsychological performance and HRQOL were measured using computer-based battery, Trail Making Tests (TMT), Depression Anxiety Stress Scales (DASS), the Hepatitis Quality of Life Questionnaire (HQLQ), and the Visual Analogue Scale (VAS). Neuropsychological measures of HCV-infected patient groups were compared with those of two control groups consisting of HIV-monoinfected and uninfected individuals. RESULTS: Similar cognitive function, mood and HRQOL were found in HCV-monoinfected (n=19) and HIV/HCV-coinfected (n=15) individuals. When compared with the HIV-monoinfected (n=30) and uninfected control (n=30) groups, subtle cognitive impairment in attention was found in the HIV/HCV-coinfected group (P<0.05). Twenty-one percent of the HCV-monoinfected group were classified as having cognitive impairment compared with 10% or less in the other groups. Sociodemographic characteristics, mood, HRQOL and HCV indices did not correlate with cognitive function. CONCLUSIONS: Our findings indicate no statistically significant difference in neuropsychological and HRQOL impairments between HIV/HCV-coinfected individuals with nonadvanced HIV disease and HCV-monoinfected individuals. This lack of significant difference may relate to the relatively small study population.     

Hepatitis C virus resistance to protease inhibitors

Recent advances in molecular biology have led to the development of novel small molecules that target specific viral proteins of the hepatitis C virus (HCV) life cycle. These drugs, collectively termed directly acting antivirals (DAA) against HCV, include a range of non-structural (NS) 3/NS4A protease, NS5B polymerase, and NS5A inhibitors at various stages of clinical development. The rapid replication rate of HCV, along with the low fidelity of its polymerase, gives rise to generations of mutations throughout the viral genome resulting in remarkable sequence variation in the HCV population, known as a quasispecies. The efficacy of DAAs is limited by the presence of those mutations that give rise to amino-acid substitutions within the targeted protein, and that affect the viral sensitivity to these compounds. Thus, due to the high genetic variability of HCV, variants with reduced susceptibility to DAA can occur naturally even before treatment begins, but usually at low levels. Not surprisingly then, these changes are selected in patients either breaking through or not responding to potent DAA treatment. In vitro or in vivo, six major position mutations in the NS3 HCV protease (36, 54, 155, 156, 168, and 170) have now been reported associated with different levels of resistance. The amino acid composition at several of the drug resistance sites can vary between the HCV genotypes/subtypes, resulting in different consensus amino acids leading to a reduction in replicative fitness as well as reduced DAA sensitivity. Different amino acid diversity profiles for HCV genotypes/subtypes suggest differences in the position/type of immune escape and drug resistance mutations. Also, different pathways of resistance profiles based on the chemical scaffold (linear or macrocyclic) of the protease inhibitors have been described. This review first describes how resistance to a protease inhibitor can develop and then provides an overview of the mechanism of how particular mutations confer varying levels of resistance to protease inhibitor, which have been identified and characterized using both genotypic and phenotypic tools. Future potential therapeutic strategies to assist patients who do develop resistance to protease inhibitors are also outlined. The challenge developing new HCV protease inhibitors should take into consideration not only the antiviral potency of the drugs, the occurrence and importance of side effects, the frequency of oral administration, but also the resistance profiles of these agents.     

Impact of HCV Eradication on Lipid Metabolism in HIV/HCV Coinfected Patients: Data from ICONA and HepaICONA Foundation Cohort Study

Objectives: HCV shows complex interactions with lipid metabolism. Our aim was to examine total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) changes in HIV/HCV coinfected patients, after achieving sustained virological response (SVR), according to different HCV genotypes and specific antiretroviral use. Methods: HIV/HCV coinfected patients, enrolled in the ICONA and HepaICONA cohorts, who achieved DAA-driven SVR were included. Paired t-tests were used to examine whether the pre- and post-SVR laboratory value variations were significantly different from zero. ANCOVA regression models were employed to estimate the causal effect of SVR and of PI/r use on lipid changes. The interaction between the effect of eradication and HCV genotype was formally tested. Results: six hundred and ninety-nine HIV/HCV coinfected patients were enrolled. After HCV eradication, a significant improvement in liver function occurred, with a significant decrease in AST, ALT, GGT, and total plasmatic bilirubin. TC and LDL-C significantly increased by 21.4 mg/dL and 22.4 mg/dL, respectively (p < 0.001), after SVR, whereas there was no evidence for a change in HDL-C (p = 0.45) and triglycerides (p = 0.49). Notably, the TC and LDL-C increase was higher for participants who were receiving darunavir/ritonavir, and the TC showed a more pronounced increase among HCV genotype 3 patients (interaction-p value = 0.002). Conclusions: complex and rapid changes in TC and LDL-C levels, modulated by HCV genotype and PI/r-based ART combinations, occurred in HIV/HCV coinfected patients after SVR. Further studies are needed to evaluate the clinical impact of these changes on the long-term risk of cardiovascular disease.     

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.     

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.     

Severe transaminitis after interferon-ribavirin therapy in HIV/HCV-coinfected patients: influence of a sustained HCV response

Chronic hepatitis C is an independent risk factor for severe drug hepatotoxicity. Successful treatment of chronic hepatitis C may modulate drug hepatotoxicity, as it is associated with a decline in hepatic enzyme release and halts fibrosis progression in HIV/HCV-coinfected patients. The aim of this study was to determine biological and/or clinical determinants of alanine aminotransferase and/or aspartate aminotransferase elevation (>five-fold above the upper limit of normal in patients with normal baseline levels or >3.5-fold increase from baseline in those with increased baseline levels) in a large prospective cohort of HIV/HCV-coinfected patients on HAART who had previously been treated for HCV infection. Median follow-up exceeded five years. Cox proportional hazards models were used. At baseline, 248 patients had been receiving antiretroviral therapy for a mean of 6.3 (± 3.2) years. Seventy-one patients (29%) had a sustained HCV viral response (SVR). During follow-up, 66 patients (26.6%) received a second course of HCV therapy and 29 (44%) of them had an SVR. Severe transaminitis occurred in 64 patients (26%). In multivariate analysis, no SVR (HR 33.33, 95% CI 4.54-222, P = 0.001) and stavudine-based therapy (HR 2.11, 95% CI 1.12-3.99, P = 0.018) remained significantly associated with severe transaminitis. A SVR to anti-HCV therapy is thus associated with a markedly reduced risk of severe transaminitis during antiretroviral therapy. Treatment of HCV infection should therefore be a priority in HIV-coinfected patients. Stavudine is associated with an increased risk of severe transaminitis.     

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.     

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.     

Impact of liver steatosis on the correlation between liver stiffness and fibrosis measured by transient elastography in patients coinfected with human immunodeficiency virus and hepatitis C virus

Summary. We assessed the effect of different hepatic conditions such as fibrosis, steatosis and necroinflammatory activity on liver stiffness as measured by transient elastography in HIV/HCV‐coinfected patients. We studied all consecutive HIV/HCV‐coinfected patients who underwent liver biopsy and elastography between January 2007 and December 2008. Liver fibrosis was staged following METAVIR Cooperative Study Group criteria. Steatosis was categorized according to the percentage of affected hepatocytes as low (≤10%), moderate (<25%) and severe (≥25%). A total of 110 patients were included. Fibrosis was distributed by stage as follows: F0, n = 13; F1, n = 47; F2, n = 29; F3, n = 18; and F4, n = 3. Liver biopsy revealed the presence of hepatic steatosis in 68 patients (low to moderate, n = 53; and severe n = 15). By univariate regression analysis, fibrosis, necroinflammatory activity, and the degree of steatosis were correlated with liver stiffness. However, in a multiple regression analysis, steatosis and fibrosis were the only independent variables significantly associated with liver stiffness. With a cut‐off of 9.5 kPa to distinguish patients with F ≤ 2 from F ≥ 3, elastography led to a significantly higher number of misclassification errors (25%vs 5%; P = 0.014), most of which were false positives for F ≥ 3. Our study suggests that the correlation between liver stiffness and fibrosis as estimated by transient elastography may be affected by the presence of hepatic steatosis in HIV/HCV‐coinfected patients.     

First clinical study using HCV protease inhibitor danoprevir to treat COVID-19 patients

Introduction:As coronavirus disease 2019 (COVID-19) outbreak globally, repurposing approved drugs is emerging as important therapeutic options. Danoprevir boosted by ritonavir (Ganovo) is a potent hepatitis C virus (HCV) protease (NS3/4A) inhibitor, which was approved and marketed in China since 2018 to treat chronic hepatitis C patients.Methods:This is an open-label, single arm study evaluating the effects of danoprevir boosted by ritonavir on treatment naïve and experienced COVID-19 patients for the first time. Patients received danoprevir boosted by ritonavir (100 mg/100 mg, twice per day). The primary endpoint was the rate of composite adverse outcomes and efficacy was also evaluated.Results:The data showed that danoprevir boosted by ritonavir is safe and well tolerated in all patients. No patient had composite adverse outcomes during this study. After initiation of danoprevir/ritonavir treatment, the first negative reverse real-time PCR (RT-PCR) test occurred at a median of 2 days, ranging from 1 to 8 days, and the obvious absorption in CT scans occurred at a median 3 days, ranging from 2 to 4 days. After 4 to 12-day treatment of danoprevir boosted by ritonavir, all enrolled 11 patients were discharged from the hospital.Conclusion:Our findings suggest that repurposing danoprevir for COVID-19 is a promising therapeutic option.     

Hepatitis C virus (HCV) specific immune responses in anti-HCV positive patients without hepatitis C viraemia

BACKGROUND/AIMS: Most patients infected with hepatitis C virus (HCV) develop chronic infection and persistent viraemia. The immune mechanisms responsible for resolution of viraemia remain poorly understood. HCV specific humoral and cellular immune responses in patients with and without viraemia were investigated. METHODS: In vitro T helper (TH) lymphocyte responses to structural and non-structural HCV proteins were determined by means of proliferative response and cytokine production in 35 anti-HCV positive/HCV RNA negative patients and in 31 patients with chronic HCV infection and persistent viraemia. Humoral responses were determined by measuring HCV specific antibody quantity and specificity. RESULTS: A TH response to two or more HCV proteins was present in 18 of 35 patients with serological viral clearance compared with just one of 31 viraemic patients (p = 0.00001). HCV specific interferon-gamma production was increased only in the former group. In contrast, the antibody levels were significantly lower and directed at fewer HCV antigens in patients with undetectable HCV RNA. CONCLUSIONS: Patients without viraemia after HCV infection frequently have strong TH lymphocyte responses of the TH1 type to multiple HCV antigens many years after the onset of infection, whereas antibody responses are less marked. These results suggest that control of HCV replication may depend on effective TH lymphocyte activation.     

HIV/AIDS病人合并HCV感染对HAART不良反应的影响

目的研究合并丙型肝炎病毒(HCV)感染,对艾滋病病毒(HIV)/艾滋病(AIDS)病人接受高效抗反转录病毒治疗(HAART)后,不良反应发生的影响,为HIV/AIDS合并HCV感染的综合治疗提供依据。方法前瞻性观察167例合并HCV感染的HIV/AIDS患者(HIV/HCV组),接受HAART治疗2-5年出现不良反应的类型、频率、严重程度,以同期264例HIV/AIDS患者(HIV组)作为对照组。结果 167例合并HCV感染的HIV/AIDS患者中,163例(97.6%)出现疲乏症状,163例(97.6%)发生胃肠道反应,107例(64.1%)出现肝功能异常,98例(58.7%)出现血脂升高,83例(49.7%)出现药物性皮疹,56例(33.5%)出现腹泻,52例(31.1%)出现贫血。与HIV组相比,HIV/HCV组出现肝功能损害的频率较高(P<0.05),但严重程度无明显差异(P>0.05),其余不良反应发生的类型、频率及严重程度无显著性差异(P>0.05)。结论 HIV/AIDS病人在HAART过程中可发生多种不良反应,合并HCV感染时更容易发生肝功能损害,选择HAART方案时应尽量选择肝毒性少的药物。