Treatment-failure to direct antiviral HCV regimens in real world: frequency, patient characteristics and rescue therapy - data from the German hepatitis C registry (DHC-R).

BACKGROUND: Virologic failure to approved combinations of direct antiviral agents (DAA) in patients with chronic hepatitis C virus (HCV) infection is rare. Mostly it involves difficult to treat patients with advanced liver disease and prior interferon-experience. Before approval of VOX/VEL/SOF, a restricted number of patients received rescue treatment, and the choice of DAA combinations for re-treatment were selected on an individual basis. In the present analysis, patient characteristics and rescue-regimens after virologic failure mainly based on first generation DAAs are described. PATIENTS AND METHODS: Data were obtained from the German Hepatitis C-Registry (DHC-R), which is a national multicenter real-world cohort currently including about 16 500 patients recruited by more than 250 centers. The present analysis is based on 6683 patients who initiated a DAA therapy and for whom follow-up data (per-protocol analysis) were available. RESULTS: Among the patients, 188 (2.8 %) experienced a virologic relapse. Compared to SVR-patients, relapse patients were significantly more often male (77.7 % versus 56.9 %, respectively, p < 0.001), showed cirrhosis significantly more (48.4 % versus 28.1 %, respectively, p < 0.001) and a prior interferon-containing therapy (46.3 % versus 39.0 %, respectively, p = 0.049). The majority of patients who relapsed were infected with genotype 1 (47.4 %) followed by genotype 3 (29.8 %), and 95 relapse patients started DAA re-treatment. Characteristics of patients with rescue-treatment are similar to these of patients with relapse after initial DAA treatment. Thirty-one of 39 patients with complete follow-up data achieved SVR (79.5 %), and 8 patients had a relapse again (20.5 %). Patients who received rescue treatment including a new DAA class according to guidelines, except patients who received VOX/VEL/SOF, showed higher SVR rates than the entire group (21/25, 84 %). All patients who received VOX/VEL/SOF achieved SVR (n = 4, 100 %). CONCLUSIONS: Patients with failure with DAA combination therapies are a difficult but urgent to treat population with the frequent presence of cirrhosis and prior treatment failure with interferon-based therapies. Rescue therapy with inclusion of a new DAA class leads to high SVR rates, but multiple targeted therapy with VOX/VEL/SOF seems to be most effective.

Prevalence and persistence of transmitted drug resistance mutations in the German HIV-1 Seroconverter Study Cohort.

The prevalence of transmitted drug resistance (TDR) in antiretroviral therapy (ART)-naïve individuals remains stable in most developed countries despite a decrease in the prevalence of acquired drug resistance. This suggests that persistence and further transmission of HIV-1 that encodes transmitted drug resistance mutations (TDRMs) is occurring in ART-naïve individuals. In this study, we analysed the prevalence and persistence of TDRMs in the protease and reverse transcriptase-sequences of ART-naïve patients within the German HIV-1 Seroconverter Study Cohort who were infected between 1996 and 2017. The prevalence of TDRMs and baseline susceptibility to antiretroviral drugs were assessed using the Stanford HIVdb list and algorithm. Mean survival times of TDRMs were calculated by Kaplan-Meier analysis. The overall prevalence of TDR was 17.2% (95% CI 15.7-18.6, N = 466/2715). Transmitted NNRTI resistance was observed most frequently with 7.8% (95% CI 6.8-8.8), followed by NRTI resistance (5.0%, 95% CI 4.2-5.9) and PI resistance (2.8%, 95% CI 2.2-3.4). Total TDR (OR = 0.89, p = 0.034) and transmitted NRTI resistance (OR = 0.65, p = 0.000) decreased between 1996 and 2017 but has remained stable during the last decade. Viral susceptibility to NNRTIs (6.5%-6.9% for individual drugs) was mainly reduced, while <3% of the recommended NRTIs and PIs were affected. The longest mean survival times were calculated for the NNRTI mutations K103N (5.3 years, 95% CI 4.2-5.6) and E138A/G/K (8.0 years, 95% CI 5.8-10.2 / 7.9 years, 95% CI 5.4-10.3 / 6.7 years, 95% CI 6.7-6.7) and for the NRTI mutation M41L (6.4 years, 95% CI 6.0-6.7).The long persistence of single TDRMs indicates that onward transmission from ART-naïve individuals is the main cause for TDR in Germany. Transmitted NNRTI resistance was the most frequent TDR, showing simultaneously the highest impact on baseline ART susceptibility and on TDRMs with prolonged persistence. These results give cause for concern regarding the use of NNRTI in first-line regimens.

144-week outcomes of lopinavir/ritonavir (LPV/r)-based first-line ART in 1,409 HIV-infected patients: data from the German STAR/STELLA cohort.

INTRODUCTION: STAR/STELLA is a prospective[TS1] cohort of HIV patients initiated on LPV/r-based ART in routine clinical practice. Here, virologic/immunologic outcomes and safety data of LPV/r-based first-line ART over a period of 144 weeks are presented. METHODS: Analysis included ART-naïve patients who started on LPV/r before July 2011 (i.e. patients with ≥144 weeks since ART initiation). Safety evaluation included adverse events (AEs), discontinuations (disc.) due to AEs, and symptoms assessed with the self-report ACTG Symptom Distress Module (ASDM; high score=high distress). RESULTS: 1409 patients were included (84% men; 76% on TDF+FTC), with a large proportion in advanced stages of HIV disease at ART initiation: 48% had a CD4 count <200/µL, 55% had HIV RNA levels >100,000 c/mL. 53% of patients (n=746) remained on LPV/r for at least 144 weeks. Time on drug was longer for patients initiated before 2008 than in subsequent years (HRadj, 1.2; 95% CI, 1.0-1.4; p=0.04; hazard ratio adjusted for CD4 <200/µL and HIV RNA >100,000 c/mL). Main reasons for d/c were: AEs (19.3%), patient wish (9.2%), virologic/immunologic failure (4.1%), and noncompliance (2.8%); 1.6% of patients died. By week 144, 33% of patients had >750 CD4/µL (Kaplan-Meier estimate): time to CD4 count >750 c/ µL, stratified by BL CD4 count, is shown in Figure 1. CONCLUSION: In the STAR/STELLA observational cohort, LPV/r-based ART demonstrated good virologic outcomes and immune recovery in ART-naïve patients over 144 weeks, with significant improvements in symptom distress. Over three years, <5% of patients discontinued LPV/r due to virologic/immunologic failure, and 19% of patients discontinued for tolerability reasons.

Consensus interferon and ribavirin for patients with chronic hepatitis C and failure of previous interferon-alpha therapy.

BACKGROUND: The efficacy of consensus interferon (CIFN), a synthetic IFN with optimised in vitro activity, was assessed in chronic hepatitis C virus (HCV) patients who had failed the pretreatment with interferon-alpha (IFNalpha) and ribavirin. METHODS: One hundred and three patients after non-response (n=69) or relapse (n=34) to IFNalpha+/-ribavirin were randomly assigned to high-dose induction (CIFN 27-->9 microg daily for 24 weeks, 9 microg t.i.w. for 24 weeks) or low-dose treatment (CIFN 18 microg t.i.w. for 12 weeks, 9 microg t.i.w. for 36 weeks); each with ribavirin 800 mg/day. Follow-up was 24 weeks. RESULTS: Non-responder patients treated with high-dose induction had higher early virological response rates (63% vs. 39%, P<0.05). This initial positive effect was lost during the last 24 weeks of treatment yielding sustained virological response (SVR) rates of 26% in both groups. Relapse patients revealed SVR in 70% and 38% in groups A and B (NS). Treatment was well tolerated with side effect-related preterm discontinuations in 8% and 5%. CONCLUSIONS: CIFN and ribavirin treatment induced considerable SVR rates in patients with non-response or relapse to IFNalpha+/-ribavirin. Viral elimination rates might be further increased by continuous daily administration of CIFN and weight-adjusted ribavirin dosing.