Effects of Hepatitis C Virus (HCV) Eradication on Bone Mineral Density in Human Immunodeficiency Virus/HCV-Coinfected Patients.

BACKGROUND: Little is known about the effects of eradication of hepatitis C virus (HCV) on bone mineral density (BMD) and biomarkers of bone remodeling in human immunodeficiency virus (HIV)/HCV-coinfected patients. METHODS: We prospectively assessed standardized BMD (sBMD) at the lumbar spine and femoral neck, World Health Organization BMD categories at both sites, and plasma concentrations of soluble receptor activator of NF-κß ligand (sRANKL), and osteoprotegerin (OPG) at baseline (the date of initiation of anti-HCV therapy) and at 96 weeks. RESULTS: A total of 238 patients were included. The median age was 49.5 years, 76.5% were males, 48.3% had cirrhosis, 98.3% were on antiretroviral therapy, median CD4+ cell count was 527 cells/µL, and 86.6% had HIV-1 RNA <50 copies/mL. The prevalence of osteoporosis at baseline at the lumbar spine (LS) and femoral neck (FN) was 17.6% and 7.2%, respectively. Anti-HCV therapy comprised pegylated interferon (peg-IFN) and ribavirin (RBV) plus 1 direct-acting antiviral in 53.4%, peg-IFN/RBV in 34.5%, and sofosbuvir/RBV in 12.2%. A total of 145 (60.9%) patients achieved sustained virologic response (SVR). No significant effect of SVR was observed on sBMD for the interaction between time and SVR either in the LS (P = .801) or the FN (P = .911). Likewise, no significant effect of SVR was observed in plasma levels of sRANKL (P = .205), OPG (P = .249), or sRANKL/OPG ratio (P = .123) for the interaction between time and SVR. No significant correlation was found between fibrosis by transient elastography, and LS and FN sBMD, at baseline and week 96. CONCLUSIONS: SVR was not associated with significant changes in BMD nor biomarkers of bone remodeling in HIV/HCV-coinfected persons.

HCV eradication with IFN-based therapy does not completely restore gene expression in PBMCs from HIV/HCV-coinfected patients.

OBJECTIVE: To evaluate the impact of hepatitis C virus (HCV) elimination via interferon (IFN)-based therapy on gene expression profiles related to the immune system in HIV/HCV-coinfected patients. METHODS: We conducted a prospective study in 28 HIV/HCV-coinfected patients receiving IFN-based therapy at baseline (HIV/HCV-b) and week 24 after sustained virological response (HIV/HCV-f). Twenty-seven HIV-monoinfected patients (HIV-mono) were included as a control. RNA-seq analysis was performed on peripheral blood mononuclear cells (PBMCs). Genes with a fold-change (FC) ≥ 1.5 (in either direction) and false discovery rate (FDR) ≤ 0.05 were identified as significantly differentially expressed (SDE). RESULTS: HIV/HCV-b showed six SDE genes compared to HIV-mono group, but no significantly enriched pathways were observed. For HIV/HCV-f vs. HIV/HCV-b, we found 58 SDE genes, 34 upregulated and 24 downregulated in the HIV/HCV-f group. Of these, the most overexpressed were CXCL2, PDCD6IP, ATP5B, IGSF9, RAB26, and CSRNP1, and the most downregulated were IFI44 and IFI44L. These 58 SDE genes revealed two significantly enriched pathways (FDR < 0.05), one linked to Epstein-Barr virus infection and another related to p53 signaling. For HIV/HCV-f vs. HIV-mono group, we found 44 SDE genes that revealed 31 enriched pathways (FDR < 0.05) related to inflammation, cancer/cell cycle alteration, viral and bacterial infection, and comorbidities associated with HIV/HCV-coinfection. Five genes were overrepresented in most pathways (JUN, NFKBIA, PIK3R2, CDC42, and STAT3). CONCLUSION: HIV/HCV-coinfected patients who eradicated hepatitis C with IFN-based therapy showed profound gene expression changes after achieving sustained virological response. The altered pathways were related to inflammation and liver-related complications, such as non-alcoholic fatty liver disease and hepatocellular carcinoma, underscoring the need for active surveillance for these patients.

Eradication of hepatitis C virus and non-liver-related non-acquired immune deficiency syndrome-related events in human immunodeficiency virus/hepatitis C virus coinfection.

We assessed non-liver-related non-acquired immunodeficiency syndrome (AIDS)-related (NLR-NAR) events and mortality in a cohort of human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients treated with interferon (IFN) and ribavirin (RBV), between 2000 and 2008. The censoring date was May 31, 2014. Cox regression analysis was performed to assess the adjusted hazard rate (HR) of overall death in responders and nonresponders. Fine and Gray regression analysis was conducted to determine the adjusted subhazard rate (sHR) of NLR deaths and NLR-NAR events considering death as the competing risk. The NLR-NAR events analyzed included diabetes mellitus, chronic renal failure, cardiovascular events, NLR-NAR cancer, bone events, and non-AIDS-related infections. The variables for adjustment were age, sex, past AIDS, HIV transmission category, nadir CD4+ T-cell count, antiretroviral therapy, HIV RNA, liver fibrosis, HCV genotype, and exposure to specific anti-HIV drugs. Of the 1,625 patients included, 592 (36%) had a sustained viral response (SVR). After a median 5-year follow-up, SVR was found to be associated with a significant decrease in the hazard of diabetes mellitus (sHR, 0.57; 95% confidence interval [CI], 0.35-0.93; P = 0.024) and decline in the hazard of chronic renal failure close to the threshold of significance (sHR, 0.43; 95% CI, 0.17-1.09; P = 0.075). CONCLUSION: Our data suggest that eradication of HCV in coinfected patients is associated not only with a reduction in the frequency of death, HIV progression, and liver-related events, but also with a reduced hazard of diabetes mellitus and possibly of chronic renal failure. These findings argue for the prescription of HCV therapy in coinfected patients regardless of fibrosis stage. (Hepatology 2017;66:344-356).

Comparison of the prognostic value of liver biopsy and FIB-4 index in patients coinfected with HIV and hepatitis C virus.

BACKGROUND: We compared the prognostic value of liver biopsy (LB) and FIB-4 index in patients with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection. METHODS: We studied patients from the Grupo de Estudio del SIDA 3603 study cohort, in whom fibrosis was evaluated at baseline using both LB (Metavir score) and FIB-4 index. We assessed overall death (OD) and liver-related events (LREs), defined as decompensation or hepatocellular carcinoma, whichever occurred first. We used receiver operating characteristic (ROC) curves to determine the ability of LB and FIB-4 to predict outcomes. We also assessed the association between advanced fibrosis-LB (F3 or greater) or FIB-4 (≥3.25)-and outcomes using multivariate Cox regression analysis. RESULTS: The study sample comprised 903 patients (328 with sustained virologic response [SVR]). Baseline fibrosis by LB was as follows: F0, n = 71; F1, n = 242; F2, n = 236; F3, n = 236; F4, n = 118. Fibrosis by FIB-4 was as follows: ≤1, n = 148; >1 to <3.25, n = 597; ≥3.25, n = 158. After a median follow-up of 62 months, there were 46 deaths and 71 LREs. The area under the ROC curves for OD/LREs was 0.648 and 0.742 for LB and FIB-4, respectively (P = .006). Similar results were found for patients without SVR and for OD and LREs separately. The adjusted hazard ratios of OD or LRE were 1.740 (95% confidence interval [CI], 1.119-2.7.06; P = .014) for advanced fibrosis assessed by LB and 3.896 (95% CI, 2.463-6.160; P < .001) assessed by FIB-4. CONCLUSIONS: FIB-4 outperformed LB as a predictor of OD and LRE. These findings are of relevance for clinical practice and research and call into question the role of LB as a gold standard for assessing prognosis in HIV/HCV coinfection.

Association of baseline CD4+ cell count and HIV-RNA on sustained virologic response to interferon-ribavirin in HIV/HCV coinfected patients.

UNLABELLED: BACKGROUND AND RATIONALE FOR THE STUDY: We assessed the association of CD4+ T-cell counts and HIV-RNA on sustained viral response (SVR) after therapy with pegylated interferon and ribavirin (PR) in HIV/HCV coinfected patients. We examined two large cohorts of coinfected patients treated with PR in Spain between 2000 and 2008. SVR was defined as undetectable HCV-RNA at 24 weeks after the end of PR. RESULTS: We studied 1682 patients, of whom 38% achieved SVR. Baseline factors independently associated with reduced odds of SVR included genotype 1 or 4, HCV-RNA > 500,000 IU/mL, advanced liver fibrosis, CDC clinical category C, and detectable HIV-RNA. By multivariate logistic regression analysis, we found that, in comparison with patients with combination antiretroviral therapy (cART) and undetectable HIV-RNA, the odds ratio [95% confidence interval (CI)] of SVR was 0.56 (0.41-0.78) for cART and detectable HIV-RNA, 0.86 (0.56-2.57) for no-cART and detectable HIV-RNA, and 1.38 (0.74-2.57) for no-cART and undetectable HIV-RNA. CONCLUSIONS: Detectable HIV-RNA, but not CD4+ T-cell count, was associated with reduced odds of SVR. However, this finding was only confirmed for cART and detectable HIV-RNA, raising the question as whether this represents a true association of HIV-RNA on response to PR or a spurious association due to poor adherence to treatment.

Clinical effects of viral relapse after interferon plus ribavirin in patients co-infected with human immunodeficiency virus and hepatitis C virus.

BACKGROUND & AIMS: Sustained viral response (SVR) after therapy with interferon-ribavirin (IF-RB) reduces liver-related (LR) complications and mortality in HIV/HCV-co-infected patients. Here, we assess the impact of end-of-treatment response with subsequent relapse (REL) on LR events (LR death, liver decompensation, hepatocellular carcinoma, or liver transplantation), and liver stiffness (LS) by transient elastography. METHODS: We analyzed the GESIDA 3603 Cohort (HIV/HCV-co-infected patients treated with IF-RB in 19 centers in Spain). Response to IF-RB was categorized as SVR, REL, and no response (NR). The study started when IF-RB was stopped and ended at death or the last follow-up visit. Multivariate regression analyses were adjusted for age, sex, HIV category of transmission, CDC clinical category, nadir CD4+ cell count, HCV genotype, HCV-RNA viral load, and liver fibrosis. RESULTS: Of 1599 patients included, response was categorized as NR in 765, REL in 250 and SVR in 584. Median follow-up was more than 4 years in each group. Taking the group of patients with NR as reference, we found that the adjusted hazard ratios (95% confidence interval) of liver-related events (liver-related death, liver decompensation, hepatocellular carcinoma, liver transplantation) for patients with REL and for patients with SVR were 0.17 (0.05; 0.50) and 0.03 (0; 0.20), respectively. We also found that SVR was followed by less liver stiffness than both REL and NR. However, REL was associated with less liver stiffness than NR. CONCLUSIONS: Best outcomes were achieved with an SVR. However, REL was associated with less LR mortality, decompensation, and liver stiffness than NR.

Sustained virological response to interferon plus ribavirin reduces non-liver-related mortality in patients coinfected with HIV and Hepatitis C virus.

BACKGROUND: Sustained virological response (SVR) after therapy with interferon plus ribavirin reduces liver-related complications and mortality in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). We assessed the effect of SVR on HIV progression and mortality not related to liver disease. METHODS: An observational cohort study including consecutive HIV/HCV-coinfected patients treated with interferon plus ribavirin between 2000 and 2008 in 19 centers in Spain. RESULTS: Of 1599 patients, 626 (39%) had an SVR. After a median follow-up of approximately 5 years, we confirmed that failure to achieve an SVR was associated with an increased risk of liver-related events and liver-related death. We also observed higher rates of the following events in nonresponders than in responders: AIDS-defining conditions (rate per 100 person years, 0.84 [95% confidence interval (CI), .59-1.10] vs 0.29 [.10-.48]; P= .003), non-liver-related deaths (0.65 [.42-.87] vs 0.16 [.02-.30]; P = .002), and non-liver-related, non-AIDS-related deaths (0.55 [.34-.75] vs 0.16 [.02-.30]; P = .002). Cox regression analysis showed that the adjusted hazard ratios of new AIDS-defining conditions, non-liver-related deaths, and non-liver-related, non-AIDS-related deaths for nonresponders compared with responders were 1.90 (95% CI, .89-4.10; P = .095), 3.19 (1.21-8.40; P = .019), and 2.85 (1.07-7.60; P = .036), respectively. CONCLUSIONS: Our findings suggest that eradication of HCV after therapy with interferon plus ribavirin in HIV/HCV-coinfected patients is associated not only with a reduction in liver-related events but also with a reduction in HIV progression and mortality not related to liver disease.

Association of ITPA gene polymorphisms and the risk of ribavirin-induced anemia in HIV/hepatitis C virus (HCV)-coinfected patients receiving HCV combination therapy.

Polymorphisms of the ITPA gene have been associated with anemia during combination therapy in hepatitis C virus (HCV)-monoinfected patients. Our aim was to confirm this association in HIV/HCV-coinfected patients. In this prospective, observational study, 73 HIV/HCV-coinfected patients treated with pegylated interferon plus ribavirin (RBV) were enrolled. Two single nucleotide polymorphisms within or adjacent to the ITPA gene (rs1127354 and rs7270101) were genotyped. The associations between the ITPA genotype and anemia or treatment outcome were examined. Fifty-nine patients (80.8%) had CC at rs1127354, whereas 14 (19.2%) had a CA/AA ITPA genotype. Percent decreases from baseline hemoglobin level were significantly greater in patients with the CC genotype than in those with the CA/AA genotype at week 4 (P = 0.0003), week 12 (P < 0.0001), and week 36 (P = 0.0102) but not at the end of treatment. RBV dose reduction was more often needed in patients with the CC genotype than in those with the CA/AA genotype (odds ratio [OR] = 11.81; 95% confidence interval [CI] = 1.45 to 256.17; P = 0.0039), as was erythropoietin therapy (OR = 8.28; 95% CI = 1.04 to 371.12; P = 0.0057). Risk factors independently associated with percent hemoglobin nadir decrease were RBV dose reduction (OR = 11.72; 95% CI = 6.82 to 16.63; P < 0.001), baseline hemoglobin (OR = 1.69; 95% CI = 0.23 to 3.15; P = 0.024), and body mass index (OR = -0.7; 95% CI = -1.43 to 0.03; P = 0.061). ITPA polymorphism was not an independent predictor of sustained virological response. Polymorphisms at rs1127354 in the ITPA gene influence hemoglobin levels during combination HCV therapy and the need for RBV dose reduction and erythropoietin use in HIV/HCV-coinfected patients.

Effect of accompanying antiretroviral drugs on virological response to pegylated interferon and ribavirin in patients co-infected with HIV and hepatitis C virus.

OBJECTIVES: The effects of antiretroviral drugs on the response to pegylated interferon plus ribavirin remain uncertain. We evaluated whether antiretroviral drugs affected the response to pegylated interferon plus ribavirin in patients co-infected with HIV and hepatitis C virus (HCV). METHODS: We conducted a retrospective analysis of two cohorts of HIV/HCV-co-infected patients treated with pegylated interferon plus ribavirin between 2001 and 2007 in Spain. The outcome measure was sustained virological response (SVR). Logistic regression models were used to test possible associations between non-response and pre-treatment characteristics, including accompanying antiretroviral drugs. RESULTS: The study sample comprised 1701 patients: 63% were infected with HCV genotype (G) 1 or 4 and 88% were taking highly active antiretroviral therapy (HAART). Factors independently associated with increased odds of SVR were G2 or 3, HVC RNA <500,000 IU/mL and CDC clinical category A or B. When we adjusted for these prognostic factors and dose of ribavirin/kg, the adjusted odds ratio (AOR) of SVR for patients without HAART was 1.31 [95% confidence interval (CI) 0.91-1.88; P = 0.144]. Taking the backbone of tenofovir and lamivudine/emtricitabine as a reference, we found that, with the exception of regimens including zidovudine, the effect of other nucleoside reverse transcriptase inhibitor backbones had little effect on SVR. The AOR of SVR for zidovudine and lamivudine was 0.65 (95% CI 0.46-0.93, P = 0.017). We carried out several sensitivity analyses, the results of which were consistent with the findings of the primary analysis. CONCLUSIONS: Our results suggest that, with the exception of regimens including zidovudine, accompanying antiretroviral drugs have little effect on the virological response to pegylated interferon plus ribavirin in HIV/HCV-co-infected patients.

Prevalence of hepatitis E infection in HIV/HCV-coinfected patients in Spain (2012-2014).

Hepatitis E virus (HEV) has emerged as a relevant pathogen for HIV-infected patients. However, there is scarce data on HEV infection in HIV/HCV-coinfected individuals with advanced fibrosis, which seems to increase the risk of HEV infection and worsen the prognosis of liver disease. We aimed to determine the prevalence of anti-HEV antibodies, acute hepatitis E, resolved hepatitis E, and exposure to HEV in HIV/HCV-coinfected patients and to evaluate associations with clinical and epidemiological characteristics. We performed a cross-sectional study on 198 HIV/HCV-coinfected patients, 30 healthy controls and 36 HIV-monoinfected patients. We found a low concordance between techniques used for detection of anti-HEV antibodies (ELISA versus Immunoblot), particularly in HIV/HCV-coinfected patients. HIV/HCV-coinfected patients showed the highest prevalence of IgG against HEV, resolved hepatitis E, and exposure to HEV (19.2%, 17.2%, and 22.2% respectively). However, we did not find any samples positive for HEV-RNA nor significant differences between groups. Moreover, HIV/HCV-coinfected patients with CD4 T-cells <350 cells/mm3 had higher prevalence for anti-HEV IgG antibodies, resolved hepatitis E, and exposure to HEV than healthy controls or those with CD4 T-cells ≥ 350 cells/mm3 (p = 0.034, p = 0.035, and p = 0.053; respectively). In conclusion, HIV/HCV-coinfected patients in Spain have a high prevalence for IgG anti-HEV antibodies, resolved hepatitis E, and exposure to HEV; particularly patients with CD4+T-cells <350 cells/mm3.

Rapid decrease in titer and breadth of neutralizing anti-HCV antibodies in HIV/HCV-coinfected patients who achieved SVR.

The main targets for neutralizing anti-hepatitis C virus (HCV) antibodies (HCV-nAbs) are the E1 and E2 envelope glycoproteins. We have studied the characteristics of HCV-nAbs through a retrospective study involving 29 HIV/HCV-coinfected patients who achieved sustained virological response (SVR) with peg-IFNα + ribavirin anti-HCV therapy. Plasma samples at baseline and week 24 after SVR were used to perform neutralization assays against five JFH1-based HCV recombinant viruses coding for E1 and E2 from genotypes 1a (H77), 1b (J4), 2a (JFH1), 3a (S52) and 4a (ED43). At baseline, the majority of plasma samples neutralized 1a, 1b, 2a, and 4a, but not 3a, genotypes. Twenty-four weeks following SVR, most neutralizing titers declined substantially. Furthermore, titers against 3a and 2a were not detected in many patients. Plasma samples with high HCV-nAb titers neutralized all genotypes, and the highest titers at the starting point correlated with the highest titers at week 24 after SVR. In conclusion, high titers of broad-spectrum HCV-nAbs were detected in HIV/HCV-coinfected individuals, however, those titers declined soon after SVR.

Dysregulation of the Immune System in HIV/HCV-Coinfected Patients According to Liver Stiffness Status.

BACKGROUND: Advanced cirrhosis is related to alterations in immunity. We aimed to evaluate the levels of peripheral CD4⁺ T cells (Tregs) and plasma cytokine in patients coinfected with human immunodeficiency virus and hepatitis C virus (HIV/HCV) according to liver fibrosis stages [evaluated as liver stiffness measure (LSM)] and their linear relationship. METHODS: We performed a cross-sectional study on 238 HIV/HCV-coinfected patients (119 had <12.5 kPa, 73 had 12.5⁻25 kPa, and 46 had >25 kPa). Peripheral T-cell subsets were phenotyped by flow cytometry, plasma biomarkers were assessed by multiplex immunoassays, and LSM was assessed by transient elastography. Results: We found HIV/HCV-coinfected patients had higher values of CD4⁺ Tregs (p < 0.001), memory Tregs (p ≤ 0.001), and plasma cytokine levels [IFN-γ (p ≤ 0.05) and IL-10 (p ≤ 0.01)] compared with healthy donors and HIV-monoinfected patients. In the multivariate analysis, higher LSM values were associated with reduced levels of IL-10 (adjusted arithmetic mean ratio (aAMR) = 0.83; p = 0.019), IL-2 (aAMR = 0.78; p = 0.017), TNF-α (aAMR = 0.67; p < 0.001), and IL-17A (aAMR = 0.75; p = 0.006). When we focus on HIV/HCV-coinfected patients analyzed by LSM strata, patients with ≥25 kPa had lower values of IL-2 (aAMR = 0.66; p = 0.021), TNF-α (aAMR = 0.565; p = 0.003), and IL-17A (aAMR = 0.58; p = 0.003) than patients with <12.5 kPa. CONCLUSION: HIV/HCV-coinfected patients showed an immunosuppressive profile compared to healthy controls and HIV-monoinfected patients. Additionally, HIV/HCV-coinfected patients with advanced cirrhosis (LSM ≥ 25 kPa) had the lowest plasma values of cytokines related to Th1 (IL-2 and TNF-α) and Th17 (IL-17A) response.

Elevated liver stiffness is linked to increased biomarkers of inflammation and immune activation in HIV/hepatitis C virus-coinfected patients.

OBJECTIVES: Immune dysregulation is a hallmark of HIV and hepatitis C virus (HCV) infections. We aimed to evaluate the relationship between liver stiffness measurement (LSM) and biomarkers of T-cell activation, bacterial translocation, inflammation, endothelial dysfunction, and coagulopathy in HIV/HCV-coinfected patients. DESIGN: Cross-sectional study. METHODS: We studied 238 HIV/HCV-coinfected patients, 32 healthy controls, and 39 HIV-monoinfected patients. Patients were stratified according to LSM into four groups: less than 12.5, 12.5-25, 25-40, and more than 40 kPa. T-cell subsets were measured using flow cytometry and plasma biomarkers using immunoassays. RESULTS: HIV/HCV-coinfected patients had higher biomarker levels of immune activation in peripheral blood [T-cell activation (CD4CD38 and CD8CD38), bacterial translocation (soluble CD14), inflammation [IL-1b, IL-6, IL-8, IL-18, IFN-γ-inducible protein 10 (IP-10)] endothelial dysfunction [soluble vascular cell adhesion molecule 1 (sVCAM1), soluble intercellular cell adhesion molecule 1 (sICAM1), and soluble tumor necrosis factor receptor 1 (sTNFR1)], and coagulopathy (plasminogen activator inhibitor-1)] than healthy controls and HIV-monoinfected patients. Moreover, in HIV/HCV-coinfected patients, a direct relationship between LSM and immune activation [T-cell activation (CD8CD38 bacterial translocation (lipopolysaccharide), inflammation (IL-8, IP-10), endothelial dysfunction (sVCAM1, sICAM1, and sTNFR1), and coagulopathy (D-dimer)] was found. Subsequently, patients were stratified into different fibrosis stages, finding that patients with cirrhosis who had LSM at least 40 kPa showed higher biomarker values of immune activation [T-cell activation (CD4CD38 and CD8CD38), bacterial translocation (lipopolysaccharide), inflammation (IL-8, IL-6, IP-10), endothelial dysfunction (sVCAM1, sICAM1, and sTNFR1), and coagulopathy (D-dimer)] than patients from the other three groups (<12.5, 12.5-25, and 25-40 kPa). CONCLUSION: T-cell activation, bacterial translocation, inflammation, endothelial dysfunction, and coagulopathy increased with the severity of liver fibrosis in HIV/HCV-coinfected patients, particularly in patients who had LSM at least 40 kPa.

Human Immunodeficiency Virus/Hepatits C Virus Coinfection in Spain: Elimination Is Feasible, but the Burden of Residual Cirrhosis Will Be Significant.

BACKGROUND: We assessed the prevalence of antibodies against hepatitis C virus (HCV-Abs) and active HCV infection in patients infected with human immunodeficiency virus (HIV) in Spain in 2016 and compared the results with those of similar studies performed in 2002, 2009, and 2015. METHODS: The study was performed in 43 centers during October-November 2016. The sample was estimated for an accuracy of 2% and selected by proportional allocation and simple random sampling. During 2016, criteria for therapy based on direct-acting antiviral agents (DAA) were at least significant liver fibrosis, severe extrahepatic manifestations of HCV, and high risk of HCV transmissibility. RESULTS: The reference population and the sample size were 38904 and 1588 patients, respectively. The prevalence of HCV-Abs in 2002, 2009, 2015, and 2016 was 60.8%, 50.2%, 37.7%, and 34.6%, respectively (P trend <.001, from 2002 to 2015). The prevalence of active HCV in 2002, 2009, 2015, and 2016 was 54.0%, 34.0%, 22.1%, and 11.7%, respectively (P trend <.001). The anti-HCV treatment uptake in 2002, 2009, 2015, and 2016 was 23.0%, 48.0%, 59.3%, and 74.7%, respectively (P trend <.001). In 2016, HCV-related cirrhosis was present in 7.6% of all HIV-infected individuals, 15.0% of patients with active HCV, and 31.5% of patients who cleared HCV after anti-HCV therapy. CONCLUSIONS: Our findings suggest that with universal access to DAA-based therapy and continued efforts in prevention and screening, it will be possible to eliminate active HCV among HIV-infected individuals in Spain in the short term. However, the burden of HCV-related cirrhosis will continue to be significant among HIV-infected individuals.

IFNL4 rs368234815 polymorphism is associated with innate resistance to HIV-1 infection.

The interferon (IFN)L4 polymorphism rs368234815 is associated with hepatitis C virus (HCV) spontaneous clearance and response to IFN-based treatments. The role of this polymorphism in HIV-1 infection is controversial. We investigated whether genetic variation at IFNL4 is associated to HIV-1 acquisition. The HCV protective allele TT was associated with decreased likelihood of HIV-1 infection in male intravenous drug users [odds ratio (OR): 0.3; P = 0.006], and this association was not modified by the genotype of CCR5. These results suggest that genetic susceptibility to HCV and HIV-1 infection shares common molecular pathways.

Faldaprevir and pegylated interferon α-2a/ribavirin in individuals co-infected with hepatitis C virus genotype-1 and HIV.

OBJECTIVE: Faldaprevir is a potent, once-daily hepatitis C virus (HCV) NS3/4A protease inhibitor. STARTVerso4 assessed the efficacy and safety of faldaprevir and response-guided pegylated interferon α-2a/ribavirin (PegIFN/RBV) in individuals with HCV/HIV co-infection. DESIGN: A phase 3 open-label study (NCT01399619). METHODS: Individuals (N = 308) co-infected with HCV genotype 1 (treatment-naive or prior interferon relapsers) and HIV [96% on antiretroviral therapy (ART)] received faldaprevir 120 mg (N = 123) or 240 mg (N = 185) and PegIFN/RBV. Those receiving a protease inhibitor or efavirenz ART were assigned to faldaprevir 120 or 240 mg, respectively. Individuals achieving early treatment success (ETS; HCV RNA <25 IU/ml at week 4 and undetectable at week 8) were randomized to 24 or 48 weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). RESULTS: SVR12 was achieved in 221 (72%) individuals, and the rates were comparable across faldaprevir doses. ETS was achieved in 80%, and of these 86% achieved SVR12, with comparable rates with 24 and 48 weeks of PegIFN/RBV (87 and 94%, respectively). In multivariate analysis, age below 40 years, IL28B CC genotype, and baseline HCV RNA below 800 000 IU/ml were associated with SVR12 (P = 0.027, P < 0.0001, and P = 0.0002, respectively), whereas treatment (ART regimen and faldaprevir dose), liver cirrhosis, and genotype 1 subtype were not. The safety profile was comparable to that of faldaprevir in HCV-monoinfected individuals. CONCLUSIONS: High SVR12 rates were achieved with faldaprevir and PegIFN/RBV in HIV/HCV co-infected individuals, regardless of faldaprevir dose and background ART, HCV genotype 1 subtype, or cirrhosis status. SVR rates mirrored those obtained with similar regimens in HCV monoinfected individuals.

IFNL4 ss469415590 variant shows similar performance to rs12979860 as predictor of response to treatment against Hepatitis C Virus genotype 1 or 4 in Caucasians.

OBJECTIVES: The rs12979860 variant, linked to IL28B gene, predicts sustained viral response (SVR) to pegylated-interferon/ribavirin (pegIFN/RBV) therapy in Hepatitis C Virus genotype 1 or 4 (HCV-1/4)-infected patients. Recently, a functional variant, ss469415590, in linkage disequilibrium (LD) with rs12979860, has been discovered. Our objective was to assess the value of ss469415590 to predict SVR to pegIFN/RBV in Caucasian HCV-1/4-infected individuals and to compare its performance with that of rs12979860. METHODS: 272 Caucasian HCV-1/4-infected patients who completed a course of pegIFN/RBV were genotyped for both rs12979860 and ss469415590 markers. Logistic regression models including factors with univariate association with SVR and each genetic marker were elaborated. The area under the receiver operating-characteristic curve (AUROC) was calculated for each model and both were compared. RESULTS: Both markers were in LD (r2 = 0.82). For rs12979860, 66 (64.0%) CC versus 56 (33.1%) T allele carriers achieved SVR (Adjusted OR = 4.156, 95%CI = 2.388-7.232, p = 4.647×10-7). For ss469415590, 66 (66.0%) TT/TT versus 56 (32.5%) -G allele carriers (Adjusted OR = 4.783, 95%CI = 2.714-8.428, p = 6.153×10-8) achieved SVR. The AUROC of the model including rs12979860 was 0.742 (95%CI = 0.672-0.813) and of that based on ss469415590 was 0.756 (95%CI = 0.687-0.826) (p = 0.780). CONCLUSIONS: The ss469415590 variant shows an equivalent performance to predict SVR to pegIFN/RBV than the rs2979860 in Caucasian HCV-1/4-infected patients.

Effects of sustained viral response in patients with HIV and chronic hepatitis C and nonadvanced liver fibrosis.

OBJECTIVE: We assessed the effects of sustained viral response (SVR), after treating with interferon-ribavirin (IF-RB), on mortality, liver-related (LR) events (decompensation, hepatocellular carcinoma), HIV progression, and liver stiffness in HIV/hepatitis C virus (HCV)-coinfected patients with nonadvanced liver fibrosis. METHODS: From a cohort of HIV/HCV-coinfected patients treated with IF-RB, we selected those with baseline liver fibrosis stages F0, F1, or F2 according to METAVIR. The study started when IF-RB was stopped and ended at death or at the last follow-up visit. RESULTS: A total of 695 patients were included (HCV genotype 1 or 4, 431; F0, 77; F1, 290; and F2, 328), and 274 patients achieved SVR. After a median follow-up of 4.9 years, the adjusted hazard ratio (aHR) [95% confidence interval (CI)] of LR events or overall death, for patients with SVR taking the group of patients with no SVR as a reference was 0.217 (0.079 to 0.599) (P = 0.003) for the whole cohort with F0 to F2. For patients with F0, the aHR (95% CI) was 0.514 (0.040 to 6.593) (P = 0.609), for patients with F1, the aHR (95% CI) was 0.305 (0.053 to 1.762) (P = 0.185), and for patients with F2, it was 0.075 (0.009 to 0.662) (P = 0.020). We also found that, in comparison with no SVR, SVR was followed by less frequent HIV progression for the entire population (F0 to F2) and less frequent liver stiffness across all categories of fibrosis. CONCLUSIONS: SVR in HIV/HCV-coinfected patients with moderate stages of liver fibrosis is associated with a reduction of mortality and LR events, and with a reduction of progression of HIV and liver fibrosis.

Preemptive erythropoietin plus high ribavirin doses to increase rapid virological responses in HIV patients treated for chronic hepatitis C.

Chronic hepatitis C affects one-third of HIV(+) patients worldwide. High ribavirin (RBV) exposure is crucial to maximize the response to hepatitis C therapy in this population, although it may increase the risk for hemolytic anemia. PERICO is a prospective multicenter trial in which HIV/HCV-coinfected patients are randomized to receive peginterferon (pegIFN) alfa-2a 180 microg/week plus either weight-based RBV (1000-1200 mg/day) or RBV 2000 mg/day, the latest along with erythropoietin alfa (EPO) 30,000 IU/week from the first day until week 4. A total of 149 patients were assessed in a planned interim analysis at week 4. In both arms, 22% of patients achieved negative HCV-RNA (rapid virological response, RVR). Multivariate analysis [OR (IC 95%), p] showed that factors associated with RVR were HCV genotypes 2/3 vs. 1/4 [20 (5-100), <0.01] and baseline HCV-RNA [0.16 (0.07-0.37) per log IU/ml, <0.01]. The occurrence of severe anemia (hemoglobin <10 g/dl) did not differ when comparing RBV vs. high RBV + EPO (7% vs. 3%; p = 0.4). Moreover, RBV plasma trough levels were comparable at week 4 (1.9 vs. 2.4 microg/ml; p = 0.2). Use of high RBV doses with preemptive EPO during the first 4 weeks of hepatitis C therapy is safe, but fails to enhance significantly RBV plasma exposure and RVR rates. Extensive intraerythrocyte accumulation of RBV following boosted production of red blood cells by EPO could explain these findings.