Axel Baumgarten

Genetic variation in IL28B and treatment-induced clearance of hepatitis C virus in HIV-positive patients with acute and chronic hepatitis C.

Recently, a IL28B (rs 12979860) gene polymorphism was identified as a predictor for response to hepatitis C virus-specific treatment in human immunodeficiency virus (HIV)-uninfected and -infected patients with chronic hepatitis C. In an analysis of HIV-infected patients with acute hepatitis C, we found that the IL28B genotype was associated with serum levels of hepatitis C virus RNA, g-GT, and CD4 cell count. In contrast to HIV-infected patients with chronic hepatitis C, the IL28B genotype was not significantly associated with treatment response rates in patients with acute hepatitis C. Thus, effects of the IL28B single-nucleotide polymorphism may differ in HIV-infected patients with chronic and acute hepatitis C.

Initial Presentation of Acute Hepatitis C Virus (HCV) Infection among HIV-Negative and HIV-Positive Individuals—Experience from 2 Large German Networks on the Study of Acute HCV Infection

To the Editor—We greatly appreciate the analysis by Migliori et al. [1], on behalf of the Tuberculosis Network in Europe Trial Group (TBNET), that compared our data with their results in the treatment of classic extensively drug-resistant tuberculosis (XDR-TB) versus the treatment of multidrug-resistant TB (MDR-TB) resistant to streptomycin (STM) and fluoroquinolones (FQNs). One of the motivating elements in our analysis was to test the validity of the implication that XDR-TB, as currently defined, is associated with a substantially worse prognosis. Although the unfavorable outcomes in the TBNET report did not equal those in our series, the trends were similar. Success rates in the MDRTB resistant to STM and FQNs and XDRTB groups were 50% and 34%, respectively; the rates of treatment failure were 7% and 19%, respectively; and the rates of culture conversion were 71% and 47%, respectively. We believe that both analyses support the singular therapeutic challenge of XDR-TB. All 12 of our patients with MDR-TB resistant to STM and FQNs were treated with second-line injectables. This may be the reason that the outcomes in our patients with MDR-TB resistant to STM and FQNs were more similar to the outcomes in the patients with “simple” MDR-TB than they were to those in patients with XDR-TB. Thus, it would be important to know how many of the 14 patients with MDR-TB resistant to STM and FQNs in the TBNET cohort were treated with a second-line injectables. To date, none of the published series of MDR-TB, MDR-TB resistant to STM and FQNs, or XDR-TB provide sufficient data to meet evidence-based standards for treatment of these cases. Furthermore, because of the extraordinary number of variables involved, ideal data may not be obtained in the near future. However, the information in these 2 reports should be incrementally important in the search for optimal management of drug-resistant TB. Acknowledgments

HCV reinfection incidence and spontaneous clearance rates in HIV-positive men who have sex with men in Western Europe

BACKGROUND & AIMS Moderate cure rates of acute hepatitis C virus (HCV) infections with pegylated interferon and ribavirin have been described in the last decade in men who have sex with men (MSM), who are also coinfected with the human immunodeficiency virus (HIV). However, a subsequent high incidence of HCV reinfections has been reported regionally in men who both clear the infection spontaneously or who respond to treatment. METHODS Retrospective analysis of reinfections in HIV infected MSM in eight centers from Austria, France, Germany, and the UK within the NEAT network between May 2002 and June 2014. RESULTS Of 606 individuals who cleared HCV spontaneously or were successfully treated, 149 (24.6%) presented with a subsequent HCV reinfection. Thirty out of 70 (43%) who cleared again or were successfully treated, presented with a second reinfection, 5 with a third, and one with a fourth reinfection. The reinfection incidence was 7.3/100 person-years (95% CI 6.2-8.6). We found a trend for lower incidence among individuals who had spontaneously cleared their incident infection than among individuals who were treated (Hazard ratio 0.62, 95% CI 0.38-1.02, p=0.06). Spontaneous clearance of reinfection was associated with ALT levels >1000IU/ml and spontaneous clearance of a prior infection. CONCLUSIONS HCV reinfection is an issue of major concern in HIV-positive MSM. Prevention strategies are needed for high risk groups to reduce morbidity and treatment costs. HIV-positive MSM with a prior HCV infection should be tested every 3 to 6months for reinfection. Those who had achieved a reinfection should be tested every 3months. LAY SUMMARY We evaluated the occurrence of HCV reinfection in HIV-positive men who have sex with men. We found an alarming incidence of 7.3/100 person-years. Prevention measures need to address this specific subgroup of patients at high risk for HCV.

Liver Fibrosis Progression After Acute Hepatitis C Virus Infection in HIV-Positive Individuals

Fibrosis progression after acute hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected patients with follow-up >9 months became similar to reported rates from studies in chronic HIV/HCV coinfection, as measured with transient elastometry. The duration of follow-up and serum alanine transaminase correlated with liver stiffness, and short follow-up resulted in high fibrosis progression rates.

Variation in IFNL4 genotype and response to interferon-based therapy of hepatitis C in HIV-positive patients with acute and chronic hepatitis C.

The IFNL4 ss469415590 polymorphism has recently be shown to better predict treatment response in chronic hepatitis than the IL28B rs12979860 variant. However, no data exist in patients with HIV/hepatitis C virus (HCV) coinfection. Analysing 206 HCV(+)/HIV(+) and 162 HCV(+)/HIV(−) patients, we found that compared with IL28B rs12979860, IFNL4 ss469415590 was strongly associated with response to interferon/ribavirin therapy in HCV(+)/HIV(−) individuals but not in HIV(+)/HCV(+) patients. Thus, effects of the IFNL4 variant may differ in HIV(+) and HIV(−) patients.

The impact of interleukin 28B rs12979860 single nucleotide polymorphism and liver fibrosis stage on response-guided therapy in HIV/HCV-coinfected patients.

Objective:According to the European AIDS Clinical Society (EACS) guidelines for response-guided therapy (RGT) of chronic hepatitis C virus (HCV) infection in HIV-positive patients, HCV-genotype (GT) and rapid virologic response (RVR) exclusively determine the duration of antiviral therapy with pegylated interferon and ribavirin (PEGIFN+RBV). The aim of this study was to investigate the impact of interleukin 28B rs12979860 single nucleotide polymorphism (IL28B) and liver fibrosis stage on RGT in HIV/HCV-coinfected patients. Design:Four hundred and thirty HIV/HCV-coinfected patients treated with PEGIFN+RBV were included in this multinational, retrospective analysis. Methods:Advanced liver fibrosis was defined as either METAVIR F3/F4 or liver stiffness more than 9.5 kPa. Results:In patients with GT1/4 without RVR (GT1/4-noRVR), higher sustained virologic response (SVR) rates were observed in patients with extended treatment duration (48 weeks: 35% vs. 72 weeks: 60%; P = 0.008). In GT1/4-noRVR patients without advanced liver fibrosis (48 weeks: 45% vs. 72 weeks: 61%; P = 0.176), or with IL28B C/C (48 weeks: 48% vs. 72 weeks: 69%; P = 0.207), SVR rates did not vary significantly throughout the treatment duration subgroups. In contrast, in patients with advanced liver fibrosis (48 weeks: 11% vs. 72 weeks: 45%; P = 0.031), or IL28B non-C/C (48 weeks: 28% vs. 72 weeks: 56%; P = 0.011), extended treatment duration was associated with substantially higher SVR rates. GT2/3 patients with RVR (GT2/3-RVR) with shortened treatment duration (24 weeks) displayed SVR rates ranging from 83 to 100%, regardless of IL28B and liver fibrosis stage. Conclusion:Our study confirms the concept of RGT in HIV/HCV coinfection and supports the extension of therapy duration to 72 weeks for patients with GT1/4-noRVR, especially in patients with IL28B non-C/C or advanced liver fibrosis. The results of our study strongly support the shortening of therapy duration to 24 weeks in GT2/3-RVR patients, regardless of IL28B and advanced liver fibrosis.

The cytotoxic lymphocyte antigen 4 polymorphisms affect response to hepatitis C virus-specific therapy in HIV(+) patients with acute and chronic hepatitis C virus co-infection.

Objective:Cytotoxic lymphocyte antigen 4 (CTLA4), a co-receptor expressed on T lymphocytes, is involved in the regulation of T-cell functions. Here, we analyzed the potential impact of the CTLA4 polymorphisms on response to hepatitis C virus (HCV)-specific treatment in HIV(+) patients co-infected with HCV. Patients and methods:A total of 184 HIV/HCV co-infected Caucasian patients were enrolled into this study, including 109 patients with chronic and 75 patients with acute hepatitis C. CTLA4 genotypes were determined by LightCycler PCR. Results:We found the CTLA4 −318 C/C genotype to be associated with sustained virological response in HCV/HIV co-infection (P = 0.035). Moreover, response rates were significantly higher in patients with a +49G/G genotype [23/29 (79.3%)] than in carriers of other +49 genotypes [59/155 (38.1%); OR 6.2; P = 0.00005]. Of note, the CTLA4 +49G/G genotype was confirmed as an independent predictor for treatment response in both patients with acute and chronic hepatitis C. Conclusion:CTLA4 polymorphisms are associated with treatment-induced resolution of HCV infection in HIV co-infected patients. These findings underline the impact of genetic host factors for successful treatment.

High efficacy of sofosbuvir/velpatasvir and impact of baseline resistance-associated substitutions in hepatitis C genotype 3 infection

Twelve weeks of the pangenotypic direct‐acting antiviral (DAA) combination sofosbuvir/velpatasvir (SOF/VEL) was highly efficient in patients with hepatitis C virus (HCV) genotype 3 (GT3) infection in the ASTRAL‐3 approval study. However, presence of resistance‐associated substitutions (RASs) in the HCV nonstructural protein 5A (NS5A) was associated with lower treatment response.

New dolutegravir resistance pattern identified in a patient failing antiretroviral therapy

The most recently approved antiretroviral, the integrase inhibitor dolutegravir (DTG), is described to be a very potent drug with a unique resistance profile, but a certain degree of cross‐resistance to RAL or EVG induced drug resistance, which is mediated mainly by integrase mutations at positions 140 and 148. The impact of a single N155H mutation to DTG resistance is described to be minor. However, there is only rare data available about the impact of N155H in the context of secondary site integrase mutations. Here, we present a case of virological failure in a DTG treated patient based on N155H mutation background.

Real-world effectiveness of sofosbuvir-based treatment regimens for chronic hepatitis C genotype 3 infection: Results from the multicenter German hepatitis C cohort (GECCO-03)

There are limited data regarding the real world effectiveness of direct acting antivirals (DAA) for the therapy of chronic genotype 3 hepatitis C virus (HCV) infection. All HCV genotype 3 infected patients from the German hepatitis C cohort (GECCO), which is a prospective database of nine German hepatitis C treatment centers, were included in the study. Three hundred forty‐two chronically infected HCV genotype 3 patients were analyzed (253 males [74.0%], mean age 47.3 years, 127 cirrhotic patients [37.1%] mostly with Child A cirrhosis, 113 treatment experienced patients [37.1%], 38 HCV/HIV co‐infected patients [11.1%]). SVR12 rates in the “intention‐to‐treat” analysis were as follows: sofosbuvir/ribavirin 69.4% (75/108), sofosbuvir/peginterferon/ribavirin 80.6% (58/72), sofosbuvir/daclatasvir ± ribavirin for 12 weeks 88.3% (53/63), sofosbuvir/daclatasvir ± ribavirin for 24 weeks 79.3% (23/29), sofosbuvir/ledipasvir ± ribavirin for 12 weeks 71.4% (10/14), and sofosbuvir/ledipasvir ± ribavirin for 24 weeks 86.7% (26/30). Forty patients were lost to follow‐up, 23 patients had a relapse, 4 patients stopped treatment prematurely and 1 patient died. Female sex (P = 0.038) and treatment with two different DAAs (P = 0.05) were predictors for SVR12 in the multivariate analysis. In conclusion, sofosbuvir/daclatasvir ± ribavirin for 12 weeks and sofosbuvir/ledipasvir ± ribavirin for 24 weeks are effective for the treatment of HCV genotype 3 infected patients including cirrhotic, treatment‐experienced or HIV/HCV co‐infected patients.