HCV-coinfected Patients Research Articles

Changes in Biomarkers of Liver Disease during Successful Combination Antiretroviral Therapy in HIV–HCV-Coinfected Individuals

We investigated changes in biomarkers of liver disease in HIV-HCV-coinfected individuals during successful combination antiretroviral therapy (cART) compared to changes in biomarker levels during untreated HIV infection and to HIV-monoinfected individuals. Non-invasive biomarkers of liver disease (hyaluronic acid [HYA], aspartate aminotransferase-to-platelet ratio index [APRI], Fibrosis-4 [FIB-4] index and cytokeratin-18 [CK-18]) were correlated with liver histology in 49 HIV-HCV-coinfected patients. Changes in biomarkers over time were then assessed longitudinally in HIV-HCV-coinfected patients during successful cART (n=58), during untreated HIV-infection (n=59), and in HIV-monoinfected individuals (n=17). The median follow-up time was 3.4 years on cART. All analyses were conducted before starting HCV treatment. Non-invasive biomarkers of liver disease correlated significantly with the histological METAVIR stage (P<0.002 for all comparisons). The mean ±sd area under the receiver operating characteristic (AUROC) curve values for advanced fibrosis (≥F3 METAVIR) for HYA, APRI, FIB-4 and CK-18 were 0.86 ±0.05, 0.84 ±0.08, 0.80 ±0.09 and 0.81 ±0.07, respectively. HYA, APRI and CK-18 levels were higher in HIV-HCV-coinfected compared to HIV-monoinfected patients (P<0.01). In the first year on cART, APRI and FIB-4 scores decreased (-35% and -33%, respectively; P=0.1), mainly due to the reversion of HIV-induced thrombocytopaenia, whereas HYA and CK-18 levels remained unchanged. During long-term cART, there were only small changes (<5%) in median biomarker levels. Median biomarker levels changed <3% during untreated HIV-infection. Overall, 3 patients died from end-stage liver disease, and 10 from other causes. Biomarkers of liver disease highly correlated with fibrosis in HIV-HCV-coinfected individuals and did not change significantly during successful cART. These findings suggest a slower than expected liver disease progression in many HIV-HCV-coinfected individuals, at least during successful cART.

Impact of HCV Treatment and Depressive Symptoms on Adherence to Haart among HIV–HCV-Coinfected Patients: Results from the Anrs-Co13-Hepavih Cohort

The additional burden of HCV infection in HIV-HCV-coinfected individuals may have some consequences on adherence to HAART. Few studies have explored the pattern of correlates of non-adherence to HAART while simultaneously considering the impact of HCV treatment and depressive symptoms on adherence to HAART. We used longitudinal data to assess factors associated with non-adherence to HAART. The French national prospective cohort ANRS-CO13-HEPAVIH is a multicentrer cohort, which recruited 1,175 HIV-HCV-coinfected patients in 17 hospital outpatient units delivering HIV and HCV care in France between October 2006 and June 2008. For this analysis, we selected participants on HAART with self-reported data for adherence to HAART (n=727 patients, 1,190 visits). Data were collected using self-administered questionnaires and medical records. A mixed logistic regression model based on an exchangeable correlation matrix was used to identify factors associated with non-adherence to HAART. Patients reported non-adherence to HAART in 808 (68%) of the 1,190 visits. Four variables remained associated with non-adherence to HAART after multivariate analysis: hazardous alcohol consumption, cocaine use and depressive symptoms, regardless of whether treatment for depression was being received. Finally, patients being treated for HCV infection were less likely to be non-adherent to HAART. Besides the problem of polydrug use, two other dimensions deserve special attention when considering adherence to HAART in HIV-HCV-coinfected patients. Access to HCV treatment should be encouraged as well adequate treatment for depression in this population to improve adherence and response to HAART.

Absence of liver steatosis in HIV–HCV co-infected patients receiving regimens containing tenofovir or abacavir

In human immunodeficiency virus-hepatitis C virus (HIV-HCV) co-infected patients, steatosis has been independently associated with a number of antiretroviral drugs, including stavudine, especially in patients with non-3 HCV genotypes. We retrospectively investigated the presence of steatosis among HIV-HCV co-infected and HCV mono-infected patients, and the role of tenofovir disoproxil fumarate (TDF) or abacavir (ABC) in determining hepatic steatosis. Liver steatosis was retrospectively evaluated in all consecutive biopsies performed in the period 2000-2008 in HCV mono-infected and HIV-HCV co-infected patients. A steatosis rate of >5 % was considered to be significant, and a multivariate logistic analysis was performed to evaluate factors associated with steatosis. In total, 393 HCV-infected patients underwent liver biopsy during the study period, of whom 205 (52.2 %) were co-infected with HIV. A steatosis rate of >5 % was diagnosed in 33.0 % of HCV mono-infected and in 47.8 % of HIV-HCV co-infected patients (P = 0.003). The rate of steatosis was higher in patients resuming antiretroviral therapy (54.7 %) than in naïve patients (33.3 %; P = 0.006). When the overall population was considered, steatosis was associated to HCV genotype 3 [odds ratio (OR) 4.53, 95 % confidence interval (CI) 2.71-7.58; P < 0.001]. In terms of the use of nucleos(t)ide drugs in HIV co-infected patients, multivariate analysis showed that only in patients with HCV genotypes other than genotype 3 was steatosis related to the use of stavudine (OR 5.38, 95 % CI 1.18-24.53; P = 0.03). The use of TDF (OR 1.07, 95 % CI 0.39-2.88; P = 0.898) or ABC (OR 0.592, 95 % CI 0.09-4.07; P = 0.594) was not associated with steatosis. In HCV mono-infected and HIV-HCV co-infected patients, steatosis appears to be a virus-mediated effect of HCV genotype 3. In HIV patients infected with HCV genotypes other than genotype 3, the risk of developing steatosis was higher in those patients resuming antiretroviral regimens containing old drugs rather than the new antiretrovirals.

The Effect of Unsuccessful Treatment with Peginterferon and Ribavirin on the Liver Fibrosis Course of HIV/HCV-Coinfected Patients

The course over time of different fibrosis parameters in HIV/HCV-coinfected patients who did not suppress HCV during anti-HCV therapy, and in patients who suppressed HCV but relapsed after treatment discontinuation is unclear. A total of 248 patients were included in the study (81 non-responders, 49 relapsers, and 118 control, untreated patients). Four primary non-invasive fibrosis indices (transient elastometry, APRI, Forns, and FIB4), as well as other fibrosis parameters, were evaluated in each group at baseline, at the end of anti-HCV therapy and at the end of follow-up (median 39.35 months from baseline). Groups were comparable in baseline characteristics, except for lower fibrosis indices in the control group. In this group there was a consistent increase in all fibrosis indices over time. On the contrary, treated patients experienced certain improvements in these indices during the period of treatment and a further worsening when the treatment was stopped, to reach the pretreatment values at the end of follow-up. Relapsers had also more favorable course than non-responders in each fibrosis parameter, but the differences were small and not statistically significant. HIV/HCV-coinfected patients who undergo unsuccessful anti-HCV treatment experience some improvement in liver fibrosis as compared to untreated patients, although the differences are small. Relapsers have also a more favorable fibrosis course than non-responders, but the differences are minimal. These improvements are only limited to the treatment period. Therefore the effect of unsuccessful treatment would only represent a transitory delay in fibrosis progression.

Effect of Hepatitis C Treatment on Cd4+T-C El L Counts And The Risk Of Death In HIV–HCV-Coinfected Patients: The Cohere Collaboration

BackgroundThe short- and long-term effects of anti-hepatitis C treatment on mortality in the HIV–HCV-coinfected population have not been evaluated in observational cohorts. Such evaluations must use methods that allow for time-varying prognostic factors that both predict treatment and are affected by prior treatment. We aimed to study immunological changes in HIV–HCV-coinfected individuals during HCV treatment and to estimate the effect of HCV-treatment on mortality.MethodsPatients were included if they were aged ≥16 years, were HIV–HCV-coinfected and were enrolled in the COHERE cohort. Data were pooled within COHERE in December 2009 in EuroCoord. Random-effects models were used to model immunological changes during HCV treatment. Marginal structural models were used to estimate the effect of HCV treatment on mortality, allowing for time-dependent confounders affected by prior treatment.ResultsIn total, 780/6,433 (12%) HIV–HCV-coinfected patients initiated HCV treatment (interferon [IFN] and ribavirin n=692, IFN alone n=88). CD4+T-cell counts decreased during the first 12 weeks of treatment ( P&lt;0.0001) and stabilized from week 24 onwards. The estimated mortality hazard ratio for comparing HCV-treated with -untreated individuals was 0.72 (95% CI 0.43, 1.21). The estimated hazard ratio for liver-related death was 0.57 (95% CI 0.21, 1.55).ConclusionsDespite its effect in reducing CD4+T-cell counts, the effect of HCV treatment on mortality was in the direction of benefit and our results excluded a substantial increase in mortality. Such benefit may be related to a lower risk of liver-related death. New HCV treatment strategies might contribute to a further reduction in mortality.

Antiretroviral Therapy and Sustained Virological Response to HCV Therapy are Associated with Slower Liver Fibrosis Progression in HIV–HCV-Coinfected Patients: Study from the Anrs Co 13 Hepavih Cohort

The aim of this study was to describe changes in repeated liver stiffness (LS) measurements and to assess the determinants of increase in LS in HIV-HCV-coinfected patients. HIV-HCV-coinfected adults enrolled in the ANRS CO 13 HEPAVIH cohort, for whom two results of LS, evaluated over ≥24 months, were available. Patients with unreliable LS results were not included. LS was measured at baseline and every year thereafter. Determinants of LS increase were assessed using linear (primary outcome: last LS minus first LS value) and logistic (secondary outcome: ≥30% increase in the initial LS value) regression analyses. A total of 313 patients (mean age 45 years, 67.4% male) were included. Overall, 93.9% were receiving antiretroviral treatment (ART). The mean baseline CD4(+) T-cell count was 471 cells/mm(3) and 72.2% of patients had undetectable plasma HIV RNA. The mean interval between the first and last LS measurements was 33.5 months. No significant difference was found between baseline and follow-up mean LS values (P=0.39). However, a decrease of ≥30% in LS was observed in 48 (15.3%) patients and an increase of ≥30% in 64 (20.5%) patients. In multivariate linear and logistic analyses, excessive alcohol intake (β coefficient 6.8; P=0.0006) and high HCV viral load (OR 1.7, 95% CI 1.1, 2.5; P=0.01) were independently associated with an increase in LS, whereas time on ART>114.5 months (OR 0.5, 95% CI 0.3, 0.9; P=0.03) and achievement of sustained virological response (OR 0.1, 95% CI 0.01, 0.9; P=0.04) were independently associated with no increase in LS. Our findings show that long-term ART and achieving sustained virological response in HIV-HCV-coinfected patients are both significantly associated with lack of increase in LS over a 33-month period.

A Prospective Evaluation of Pulmonary, Systemic and Hepatic Haemodynamics in HIV–HCV-Coinfected Patients before and after Antiviral Therapy with Pegylated Interferon and Ribavirin

Patients coinfected with HIV and HCV are at risk for developing portal hypertension (PHT), hyperdynamic circulation and pulmonary arterial hypertension (PAH). Data on the influence of antiviral therapy with pegylated interferon-α (PEG-IFN-α) and ribavirin (RBV) are limited. Haemodynamic parameters, including hepatic venous pressure gradient (HVPG), pulmonary arterial pressure (PAP(mean)), cardiac output (CO) and systemic vascular resistance (SysVR), were prospectively evaluated before and after PEG-IFN-α+RBV therapy in 80 HIV-HCV-coinfected patients. Baseline evaluation showed a mean HVPG of 4.7 mmHg, CO of 6.15 l/min and PAP(mean) of 14.8 mmHg. PHT was present in 26% of patients, hyperdynamic circulation in 5% and PAH in 4%. Patients with advanced fibrosis (METAVIR stage F3/F4; n=32) had significantly higher CO (P=0.008), lower SysVR (P=0.035), higher PAP(mean) (P=0.018) and higher pulmonary vascular resistance (P=0.022) than patients with stage F0-F2 fibrosis (n=48). Both hyperdynamic circulation and PAH were significantly associated with liver stiffness, fibrosis stage and portal pressure; a non-significant trend was found for CD4(+) T-cell counts and HIV RNA levels. No significant changes in PAP(mean), CO and SysVR were observed after PEG-IFN-α+RBV treatment, although a significant decrease in HVPG was noted in patients with HCV eradication (P=0.013). The overall prevalence of hyperdynamic circulation and PAH in HIV-HCV coinfection is low. Advanced fibrosis, increased liver stiffness, elevated portal pressure and probably CD4(+) T-cell count and HIV viraemia represent risk factors for hyperdynamic circulation and PAH. PHT is present in 26% of HIV-HCV-coinfected patients evaluated for antiviral therapy. Successful HCV eradication significantly decreases HVPG.

Unique and differential protein signatures within the mononuclear cells of HIV-1 and HCV mono-infected and co-infected patients

BackgroundPathogenesis of liver damage in patients with HIV and HCV co-infection is complex and multifactorial. Although global awareness regarding HIV-1/HCV co-infection is increasing little is known about the pathophysiology that mediates the rapid progression to hepatic disease in the co-infected individuals.ResultsIn this study, we investigated the proteome profiles of peripheral blood mononuclear cells from HIV-1 mono-, HCV mono-, and HIV-1/HCV co-infected patients. The results of high-resolution 2D gel electrophoresis and PD quest software quantitative analysis revealed that several proteins were differentially expressed in HIV-1, HCV, and HIV-1/HCV co-infection. Liquid chromatography-mass spectrometry and Mascot database matching (LC-MS/MS analysis) successfully identified 29 unique and differentially expressed proteins. These included cytoskeletal proteins (tropomyosin, gelsolin, DYPLSL3, DYPLSL4 and profilin-1), chaperones and co-chaperones (HSP90-beta and stress-induced phosphoprotein), metabolic and pre-apoptotic proteins (guanosine triphosphate [GTP]-binding nuclear protein Ran, the detoxifying enzyme glutathione S-transferase (GST) and Rho GDP-dissociation inhibitor (Rho-GDI), proteins involved in cell prosurvival mechanism, and those involved in matrix synthesis (collagen binding protein 2 [CBP2]). The six most significant and relevant proteins were further validated in a group of mono- and co-infected patients (n = 20) at the transcriptional levels.ConclusionsThe specific pro- and anti- apoptotic protein signatures revealed in this study could facilitate the understanding of apoptotic and protective immune-mediated mechanisms underlying HIV-1 and HCV co-infection and their implications on liver disease progression in co-infected patients.

Prevalence of Natural Polymorphisms at the HCV Ns5A Gene Associated with Resistance to Daclatasvir, An Ns5A Inhibitor

Daclatasvir (BMS-790052) is an investigational molecule that inhibits the HCV NS5A protein and shows potent antiviral activity apparently across all HCV genotypes. Selection of drug resistance mutations has been reported only for HCV genotype 1, and no information exists for other HCV variants and/or in HIV-HCV-coinfected individuals. All interferon-α-naive, HIV-HCV-coinfected patients newly attended at Hospital Carlos III (Madrid, Spain) in 2011 were identified. Changes reported to be associated with daclatasvir resistance in the in vitro replication system for HCV genotype/subtypes 1a/1b (M28T, Q30H/R, L31F/M/V, P32L and Y93C/H/N) were examined. A total of 78 HIV-HCV-coinfected individuals as well as 635 NS5A sequences deposited at Los Alamos HCV database were analysed. None of the NS5A sequences from HCV-1a or HCV-3 showed changes associated with daclatasvir resistance. By contrast, all NS5A sequences from HCV-4 harboured L31M. The double mutant L31M+Y93H was found in 7% of HCV-1b and 13% of HCV-4. Finally, all NS5A sequences from HCV-1b and HCV-4 harboured changes at codon 28 (M28L) and 30 (L30R), which are of unknown significance. The rate of all these NS5A polymorphisms did not differ significantly when comparing HIV-HCV-coinfected patients and sequences from HCV-monoinfected subjects deposited at Los Alamos HCV database. Primary resistance mutations to daclatasvir, an investigational HCV NS5A inhibitor, are not seen in HCV-1a or in HCV-3 as natural polymorphisms. By contrast, they can be recognized in most HCV-1b and HCV-4 strains, regardless HIV coinfection.

HIV and hepatitis C virus coinfection in Canada: challenges and opportunities for reducing preventable morbidity and mortality

Hepatitis C virus (HCV) has emerged as an important health problem in the era of effective HIV treatment. However, very few data exist on the health status and disease burden of HIV/HCV-coinfected Canadians. HIV/HCV-coinfected patients were enrolled prospectively in a multicentre cohort from 16 centres across Canada between 2003 and 2010 and followed every 6 months. We determined rates of a first liver fibrosis or endstage liver disease (ESLD) event and all-cause mortality since cohort enrolment and calculated standardized mortality ratios compared with the general Canadian population. A total of 955 participants were enrolled in the study and followed for a median of 1.4 (interquartile range 0.5-2.3) years. Most were male (73%) with a median age of 44.5 years; 13% self-identified as aboriginal. There were high levels of current injecting drug and alcohol use and poverty. Observed event rates [per 100 person-years; 95% confidence interval (CI)] were: significant fibrosis (10.21; 8.49, 12.19), ESLD (3.16; 2.32, 4.20) and death (3.72; 2.86, 4.77). The overall standardized mortality ratio was 17.08 (95% CI 12.83, 21.34); 12.80 (95% CI 9.10, 16.50) for male patients and 28.74 (95% CI 14.66, 42.83) for female patients. The primary causes of death were ESLD (29%) and overdose (24%). We observed excessive morbidity and mortality in this HIV/HCV-coinfected population in care. Over 50% of observed deaths may have been preventable. Interventions aimed at improving social circumstances, reducing harm from drug and alcohol use and increasing the delivery of HCV treatment in particular will be necessary to reduce adverse health outcomes among HIV/HCV-coinfected persons.

High plasma CXCL10 levels are associated with HCV-genotype 1, and higher insulin resistance, fibrosis, and HIV viral load in HIV/HCV coinfected patients

BackgroundCXCL10 may contribute to the host immune response against the hepatitis C virus (HCV), liver disease progression, and response to HCV antiviral therapy. The aim of our study was to analyze the relationship among virological, immunological, and clinical characteristics with plasma CXCL10 levels in human immunodeficiency virus (HIV)/HCV-coinfected patients. MethodsWe carried out a cross-sectional study on 144 patients. CXCL10 and insulin were measured using an immunoassay kit. The degree of insulin resistance was estimated for each patient using the homeostatic model assessment (HOMA) method. Insulin resistance was defined as a HOMA index higher than or equal to 3.8. Aspartate aminotransferase (AST) to platelet ratio (APRI), FIB-4, Forns index, HGM1, and HGM2 were calculated. ResultsThe variables associated with log10 CXCL10 levels by univariate analysis were age (b=0.013; p=0.023), prior AIDS-defining condition (b=0.127; p=0.045), detectable plasma HIV viral load (b=0.092; p=0.006), log10 HOMA (b=0.216; p=0.002), HCV-genotype 1 (b=0.114; p=0.071), and liver fibrosis assessed by all non-invasive indexes (log10 APRI (b=0.296; p=0.001), log10 FIB-4 (b=0.436; p<0.001), log10 Forns index (b=0.591; p<0.001), log10 HGM1 (b=0.351; p=0.021), and log10 HGM2 (b=0.215; p=0.018)). However, in multivariate analysis, CXCL10 levels were only associated with HOMA, detectable plasma HIV viral load, HCV-genotype 1 and FIB-4 (R-square=0.235; p<0.001). ConclusionPlasma CXCL10 levels were influenced by several characteristics of patients related to HIV and HCV infections, insulin resistance, and liver fibrosis, indicating that CXCL10 may play an important role in the pathogenesis of both HCV and HIV infections.

Ribavirin and Interferon Alter Mmp-9 Abundance In Vitro and in HIV–HCV-Coinfected Patients

Matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) are central to tissue remodelling during HIV-HCV infection. Here, we assess the potential for antiviral therapy to modulate MMP abundance in THP-1 monocyte/macrophages and LX-2 hepatic stellate cells, and in a coinfected patient cohort. THP-1 and LX-2 cells were treated with ribavirin (RBV)/interferon-α (IFN-α) and select HIV antivirals. Venous blood was reserved from HIV-HCV-coinfected patients, HIV- and HCV-monoinfected patients, and healthy controls, with the HIV-HCV cohort being sampled again at day 3 and 14 subsequent to the start of combination therapy with RBV/pegylated IFN-α. Samples were subjected to gelatin zymography, real-time RT-PCR and/or ELISA, where appropriate. RBV/IFN-α decreased MMP-9 activity, and increased MMP-9 mRNA and protein expression in THP-1 cells, but not in LX-2 cells. Decreases in MMP-9 activity were mediated by IFN-α, which also attenuated RBV induction of MMP-9 activity and protein expression in THP-1 cells. Saquinavir and lopinavir, HIV protease inhibitors, reduced MMP-9 activity in THP-1 and LX-2 cells, respectively. Plasma MMP-9 activity and expression was higher in HIV-HCV and HIV patients compared with HCV patients and healthy controls. MMP-2 and TIMP-2 levels were similar in all groups. RBV/pegylated IFN-α decreased plasma MMP-9 abundance in HIV-HCV patients. These data demonstrate that RBV/pegylated IFN-α reduce plasma MMP-9 abundance in vivo and may reduce its activity in vitro through immune cells, such as monocyte/macrophages, rather than hepatic stellate cells. The results of this study indicate that such therapy may mediate tissue remodelling associated with HIV-HCV coinfection through effects on MMP-9.

Dyslipidaemia in HIV-infected women on antiretroviral therapy. Analysis of 922 patients from the Spanish VACH cohort

BackgroundInformation concerning lipid disturbances in HIV-infected women on antiretroviral therapy (ART) is scarce. The objective of the study is to describe the lipid profile in a large cohort of HIV-infected women on contemporary ART and analyse differences between regimes and patient's characteristics.MethodsObservational, multicentre, cross-sectional study from the Spanish VACH Cohort. 922 women on stable ART without lipid-lowering treatment were included.ResultsMedian age was 42 years, median CD4 lymphocyte count was 544 cells/mm3, and 85.6% presented undetectable HIV-1 viral load. Median total cholesterol (TC) was 189 mg/dL (interquartile range, IQR, 165-221), HDL cholesterol 53 mg/dL (IQR, 44-64), LDL cholesterol 108 mg/dL (IQR, 86-134), and triglycerides 116 mg/dL (IQR, 85-163). Mean accumulated time on ART was 116 months; 47.4% were on NNRTI-based regimes, 44.7% on PI, and 6.7% on only-NRTI therapy. 43.8% were also hepatitis C (HCV) coinfected. Patients on PI treatment presented higher TC/HDL ratio than those on NNRTI (p < 0.001). Significantly higher HDL values were observed in NNRTI-treated patients. HCV-coinfected patients presented lower TC/HDL ratio than the non HCV-coinfected. In multivariate analysis, factors independently associated with TC/HDL ratio were age, triglyceride levels and HCV co-infection. PI treatment presented a non-significant association with higher TC/HDL ratio.ConclusionsIn HIV-infected women, the NNRTI-based ART is associated with a better lipid profile than the PI-based. Factors unrelated to ART selection may also exert an independent, significant influence on lipids; in particular, age, and triglyceride levels are associated with an increased TC/HDL ratio while HCV co-infection is associated with a reduced TC/HDL ratio.

Effect of An Induction Period of Pegylated Interferon-α2A and Ribavirin on Early Virological Response in HIV–HCV-Coinfected Patients: Results from the Coral-2 Study

It is uncertain whether a 4-week induction period of pegylated interferon and ribavirin increases early virological response (EVR) in HIV-HCV-coinfected patients. HIV and HCV genotype 1- and 4-coinfected subjects were randomized to receive pegylated interferon-α2a 270 μg/week plus ribavirin 1,600 mg daily and epoetin-β for 4 weeks, followed by pegylated interferon-α2a at standard dosages plus weight-based ribavirin (WBR) dosage for 8 weeks (induction arm [IA]), or pegylated interferon-α2a plus WBR for 12 weeks (standard therapy arm [SA]). HCV RNA was determined at weeks 0, 1, 2, 3, 4, 8 and 12. Ribavirin plasma trough concentrations were determined at weeks 4 (RBV-C(4)) and 12 (RBV-C(12)). A total of 67 patients were included; 33 in the SA and 34 in the IA. Overall, 25% received nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimens. More patients achieved an HCV RNA decrease ≥1 log(10) at week 4 in the IA than in the SA (62% versus 38%; P=0.017), but EVR rates were similar in the two groups (74% versus 59% in the IA and SA, respectively; P=0.15). Independent predictors of faster HCV RNA decrease at 12 weeks were higher RBV-C(4) and younger age. RBV-C(4) were higher in patients allocated in the IA and in those receiving NRTIs (P=0.039). A 4-week induction with pegylated interferon-α2a plus ribavirin was associated with a greater decrease in HCV RNA at week 4; however, this did not translate into higher EVR rates. Higher RBV doses and avoidance of NRTI-sparing antiretroviral regimens might improve HCV treatment efficacy.

Distributive sharing among HIV–HCV co-infected injecting drug users: the preventive role of trust in one's physician

This study, based on data from the MANIF 2000 cohort study, investigates the relationship between the lending of injecting equipment, drug use, and experience with HIV care. The sample comprised 224 HIV–HCV co-infected patients who reported having injected drugs in the previous six months and their 538 visits to clinical services. Longitudinal data were collected for medical status, and self-reported risk behaviors. A logistic regression GEE model was used to identify correlates of distributive sharing. After multiple adjustment, patients who reported trust in physicians were significantly less likely to report lending injection equipment while cocaine users were at increased risk. Promoting dialog between physicians and injecting drug users (IDUs) may play an important role in HIV–HCV positive prevention.

The impact of HTLV-1 infection on clinical and immunological outcomes in patients coinfected with HIV and hepatitis C virus

We enrolled 102 (72.3%) with HIV/HCV co-infection (Group 1) and 39 (27.7%) triply infected with HIV, HCV, and HTLV-1 (Group 2). We reviewed medical records of two groups of patients followed in two outpatients services in Salvador, Brazil. We collected and compared demographic, behavioral-related information, immunological, virological and histological parameters for HIV-1 and HCV infection. Results Demographics, virological and immunological characteristics were similar in the two groups; a higher proportion of triply infected patients (Group 2) reported any history of injection drug use (IDU) compared to dually infected (Group 1) patients (75% vs. 45.8%; p =0.003). No differences were seen between groups in HIV clinical outcomes (CD4 count and viral load). Alanine aminotransferase levels were significantly higher in HIV/ HCV co-infected patients (p =0.045). Liver fibrosis damage based on Metavir scores were similar between groups (0.97) but were worse with lower CD4 cell count (under 200cells/mm3) (p = 0.01). Conclusions HIV/HTLV-1 and HIV/HCV coinfections may worsen clinical related outcomes, but virological and immunological outcomes were similar in both groups. Hepatic measures were worse in patients with more severe immunosuppression.

The natural history of liver cirrhosis in HIV–hepatitis C virus-coinfected patients

To provide detailed information about the natural history of HIV-hepatitis C virus (HCV)-coinfected patients with cirrhosis. Prospective cohort including 340 HIV-HCV-coinfected patients with compensated (n = 248) or decompensated (n = 92) cirrhosis. We evaluated predictors of survival and of first hepatic decompensation. The mortality rate for patients with decompensated and compensated cirrhosis was 27.14 deaths per 100 person-years [95% confidence interval (CI) 18.93-35.35] and 3.98 deaths per 100 person-years (95% CI 2.42-5.54), respectively. Rate of first hepatic decompensation in patients with compensated cirrhosis was 4.62 per 100 persons-years (95% CI 2.91-6.33). In the complete cohort, permanent HAART interruption during follow-up, CD4 cell count nadir and baseline Child-Pugh score (CPS) B or C were significantly associated with shorter survival. In patients with compensated cirrhosis factors significantly associated with decreased survival were having the first hepatic decompensation during follow-up, permanent HAART discontinuation, and CPS B and C at baseline. For patients with compensated cirrhosis, time since diagnosis of HCV infection, CPS B and C and permanent HAART discontinuation were significantly associated with the risk of first hepatic decompensation. Sustained viral response to anti-HCV therapy was not independently associated with better survival in patients with compensated cirrhosis. HIV-HCV-coinfected patients with cirrhosis have a relatively good 3-year survival (87%). In contrast, 2-year survival of patients with decompensated liver cirrhosis is only 50%. Three-year survival was mostly impacted by liver-related factors and HAART maintenance.

Predicted Effect of Direct Acting Antivirals in the Current HIV–HCV-Coinfected Population in Spain

Direct acting antivirals (DAAs) against HCV are eagerly awaited for HIV-HCV-coinfected individuals. However, the activity of first generation drugs is limited to HCV genotype 1 and is lower in cirrhotics, subtype 1a infections, prior interferon (IFN)-α exposure or unfavourable IL28B alleles. Herein, we report the current profile of HIV-HCV-coinfected patients at our institution in an attempt to predict the effect of DAAs. All HIV-HCV-coinfected patients seen at our HIV outpatient clinic in 2011 were identified. Information on serum HCV RNA, HCV genotype/subtype, plasma HIV RNA, prior IFN-α experience, liver fibrosis staging and IL28B alleles was recorded. A total of 424 HIV-HCV-coinfected patients were identified, of whom 174 (41%) were IFN-α-experienced. Mean serum HCV RNA was 6 log IU/ml. HCV genotype/subtype distribution was 166 (39.1%) G1a, 93 (22%) G1b, 85 (20%) G4, 49 (11.5%) G3 and 1 (<1%) G2, and 30 (7%) were unclassified. Of note, 56% of G1a were prior IFN-α-experienced patients. Overall, 37% had advanced liver fibrosis (Metavir score estimates F3-F4). Finally, 70% harboured unfavourable IL28B alleles. The current profile of HIV-HCV-coinfected patients in Spain is dominated by particularly difficult-to-treat individuals, such as those infected with G1a or G4 (59%), advanced liver fibrosis (37%) and unfavourable IL28B alleles (70%). A wide use of prior anti-HCV therapy in our region most likely has resulted in hepatitis C cure of more IFN-α susceptible individuals, with accumulation of a more refractory treatment population. Thus, the use of DAAs in HIV-HCV-coinfected patients will require particular expertise and their benefit might be lower than expected.

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

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.

Drug Resistance and HCV Coinfection in Former Blood Donors Infected with HIV Type 1 in China

Unhygienic blood collection caused an outbreak of HIV-1 and HCV infections among blood donors in rural areas in Henan province, China. Partial HIV-1 pol and HCV NS5b gene sequences were obtained from 97 persons infected with HIV-1 to determine the efficacy of treatment, the prevalence of drug-resistant mutations, and the impact of HCV infection on disease progression of infection with HIV-1. After antiretroviral therapy, 60 out of 97 HIV-1-infected blood donors had their HIV-1 RNA levels reduced to an undetectable level. Drug-resistant mutations to reverse transcriptase inhibitors were detected in one-third of treatment failure patients, with K103N as the most frequent mutation. Drug-resistant mutations were not detected in the other two-thirds of treatment-failure patients, suggesting a poor adherence to the treatment. The majority of HIV-1-infected patients (91.8%) were also infected with HCV. Sequence analysis showed that they were infected with HCV subtype 1b (47.5%) or 2a (52.5%). HCV viral loads were significantly higher in patients infected with subtype 2a than in patients infected with HCV subtype 1b, although no differences in HIV-1 viral loads and CD4(+)T cell counts was observed between the two subtypes. These results suggest that improved adherence and treatment regimens will be critical to effectively treat HIV-1 and HCV-coinfected patients in resource-limited areas.