Hepatitis C virus transmission between eight high-income countries among men who have sex with men: a whole-genome analysis.

BACKGROUND Microelimination of the hepatitis C virus (HCV) among men who have sex with men (MSM) could be complicated by continuous external introductions and the emergence of phylogenetic clusters harbouring clinically significant resistance-associated substitutions (RAS). To investigate international clustering and the prevalence and transmission of RAS, we aimed to analyse whole-genome HCV sequences from MSM with a recently acquired infection who participated in a large, international HCV treatment trial. METHODS For this whole-genome analysis, we obtained HCV sequences from 128 MSM who had acquired HCV within the past 12 months and were participating in the REACT trial. The participants from whom sequences were obtained were recruited at 24 sites in eight countries. We inferred maximum-likelihood phylogenies and identified transmission clusters for HCV genotypes separately. We constructed time-scaled phylogenies to estimate cluster introduction dates and used a Bayesian Skygrid approach to estimate the effective population size over the past 50 years. We calculated the prevalence of RAS and the extent of RAS transmission in the study population. FINDINGS The majority of recent HCV infections were part of international networks that arose in the late 1990s and early 2000s. Sequences obtained in the same country clustered frequently, and in 36% of subclusters since 2015 we found evidence of international transmission. European MSM were more likely than non-European MSM to be in a cluster (odds ratio 11·9 [95% CI 3·6-43·4], p<0·0001). The effective population size decreased rapidly since around 2015 in Europe. RAS associated with substantially diminished cure rates were infrequently detected and transmission of highly resistant viruses was not observed. INTERPRETATION Despite antiviral treatment becoming widely available, international transmission of HCV among MSM has still occurred over the past 8 years, which could complicate microelimination of the virus in this population. RAS-enriched clusters and widespread RAS transmission are currently not a threat to elimination goals. These findings support an international approach for HCV microelimination among MSM. FUNDING National Institutes of Health and Dr. C.J. Vaillant Fonds

Sexual and drug use risk behaviour trajectories among people treated for recent HCV infection: the REACT study.

INTRODUCTION Exploration of sexual and drug use behaviours following treatment for recent hepatitis C virus (HCV) is limited. This analysis modelled behavioural trajectories following treatment for recent HCV and assessed reinfection. METHODS Participants treated for recent HCV in an international trial (enrolled 2017-2019) were followed at 3-monthly intervals for up to 2 years to assess longitudinal behaviours. Population-averaged changes were assessed using generalized estimating equations. Distinct behavioural trajectories were identified using group-based trajectory modelling. HCV reinfection incidence was calculated using person-years (PY) of observation. RESULTS During the follow-up of 212 participants (84% gay and bisexual men [GBM]; 69% HIV; 26% current injecting drug use [IDU]), behavioural trajectories for IDU and stimulant use (past month) did not change. However, population-averaged decreases in the likelihood of daily IDU (adjusted odds ratio [AOR] 0.83; 95% CI 0.72, 0.95) and opioid use (AOR 0.84; 95% CI 0.75, 0.93) were observed. Among GBM, behavioural trajectories for chemsex did not change. Population-averaged decreases in condomless anal intercourse with casual male partners (CAI-CMP) (AOR 0.95; 95% CI 0.90, 0.99) and group-sex (AOR 0.86; 95% CI 0.80, 0.93) were observed, but masked distinct trajectories. While a proportion had a decreased probability of CAI-CMP (23%) and group-sex (59%) post-treatment, a substantial proportion retained a high probability of these behaviours. High HCV reinfection incidence was observed for the sustained high probability IDU (33.0/100 PY; 95% CI 17.7, 61.3) and chemsex (23.3/100 PY; 95% CI 14.5, 37.5) trajectories. CONCLUSIONS Limited sexual and drug use behavioural change was observed following treatment for recent HCV, supporting access to surveillance and (re)treatment

Screening for Hepatitis C Virus Reinfection Using a Behaviour-Based Risk Score among Men Who Have Sex with Men with HIV:Results from a Case–Control Diagnostic Validation Study

We assessed the predictive capacity of the HCV-MOSAIC risk score, originally developed for primary early HCV infection, as a screening tool for HCV reinfection in 103 men who have sex with men (MSM) with HIV using data from the MOSAIC cohort, including MSM with HIV/HCV-coinfection who became reinfected (cases, n = 27) or not (controls, n = 76) during follow-up. The overall predictive capacity of the score was assessed using the area under the receiver operating characteristic (AUROC) curve. The effects of covariates on the receiver operating characteristic (ROC) curve were assessed using parametric ROC regression. The score cut-off validated for primary early infection (≥2.0) was used, from which the sensitivity and specificity were calculated. The AUROC was 0.74 (95% confidence interval (CI) = 0.63–0.84). Group sex significantly increased the predictive capacity. Using the validated cut-off, sensitivity was 70.4% (95%CI = 49.8–86.2%) and specificity was 59.2% (95%CI: 47.3–70.4%). External validation from a cohort of 25 cases and 111 controls, all MSM with HIV, resulted in a sensitivity of 44.0% (95%CI = 24.4–65.1) and specificity of 71.2% (95%CI = 61.8–79.4). The HCV-MOSAIC risk score may be useful for identifying individuals at risk of HCV reinfection. In sexual health or HIV-care settings, this score could help guide HCV-RNA testing in MSM with a prior HCV infection.</p

Reasons for not commencing direct-acting antiviral treatment despite unrestricted access for individuals with HIV and hepatitis C virus: a multinational, prospective cohort study.

BACKGROUND Individuals with HIV and hepatitis C virus (HCV) who remain untreated with direct-acting antivirals can contribute to HCV transmission and HCV-related mortality. We aimed to compare rates of uptake of direct-acting antivirals following unrestricted access to this treatment in high-income countries and examine factors associated with remaining untreated. METHODS This multinational, prospective cohort study used data from the International Collaboration on Hepatitis C Elimination in HIV Cohorts (InCHEHC). We analysed data from nine observational cohorts participating in the InCHEHC, including data from six high-income countries (Australia, Canada, France, the Netherlands, Spain, and Switzerland). We included individuals aged 18 years and older, with HIV and HCV (ie, HCV-RNA positive without evidence of spontaneous clearance) during unrestricted access to interferon-free direct-acting antiviral treatment in each country. We calculated the cumulative proportion of participants who remained untreated with direct-acting antivirals, with follow-up starting after the date of unrestricted access or cohort inclusion, whichever occurred most recently. Factors associated with the commencement rate of direct-acting antiviral treatment were assessed using competing-risks regression with the Fine-Gray method. FINDINGS The date of unrestricted access to direct-acting antiviral treatment for people with HIV ranged from Nov 1, 2014, in France to Nov 1, 2017, in Switzerland. We included 4552 individuals with HIV-HCV, mainly men who have sex with men (MSM; n=2156 [47%]) and people who inject or have injected drugs (n=1453 [32%]). 1365 (30%) of 4552 participants remained untreated with direct-acting antivirals. For individuals treated with direct-acting antivirals, median time from start of follow-up to treatment was 5 months (IQR 2-12). For individuals who were not treated with direct-acting antivirals, median follow-up was 22 months (8-30). Being linked to care in Australia, France, or the Netherlands, on antiretroviral therapy, having undetectable HIV RNA, and shorter duration since first positive HCV test were independently associated with higher commencement rate of direct-acting antiviral treatment. Compared with MSM, male heterosexuals and females with unknown or other routes of HIV transmission (ie, neither injection drug use nor heterosexual transmission) had lower rates of commencement. INTERPRETATION Despite unrestricted access, almost a third of individuals with HIV-HCV remained untreated with direct-acting antivirals during follow-up, with variation in commencement rate of HCV treatment between countries and key populations. Increased efforts are required to reach the remaining individuals with HIV who are HCV-viraemic to achieve HIV-HCV micro-elimination. FUNDING None

Transmission of hepatitis C virus in HIV‐positive and PrEP‐using MSM in England

We sought to characterize risk factors and patterns of HCV transmission amongst men who have sex with men (MSM). MSM with recently acquired HCV (AHCV) were prospectively recruited ('clinic cohort') between January and September 2017. Clinical data and risk behaviours were identified and blood obtained for HCV whole genome sequencing. Phylogenetic analyses were performed, using sequences from this cohort and two other AHCV cohorts, to identify transmission clusters. Sixteen (40.0%) men in the clinic cohort were HIV‐negative MSM. HIV‐negative MSM were younger than HIV‐positive MSM; most (81.3%) had taken HIV PrEP in the preceding year. Eighteen men (45.0%) reported injection drug use; most (34, 85.0%) reported noninjection drug use in the last year. Most in both groups reported condomless anal sex, fisting and sex in a group environment. Few (7, 17.5%) men thought partners may have had HCV. There were 52 sequences in the HCV genotype 1a phylogeny, 18 from the clinic cohort and 34 from other AHCV cohorts; 47 (90.4%) clustered with ≥1 other sequence. There were 7 clusters of 2‐27 sequences; 6 clusters contained HIV‐negative and HIV‐positive MSM and 1 cluster only HIV‐positive MSM. Four of these clusters were part of larger clusters first described in 2007. PrEP‐using MSM are at risk of HCV, sharing similar risk factors to HIV‐positive MSM. Phylogenetics highlights that PrEP‐using and HIV‐positive MSM are involved in the same HCV transmission networks. Few men demonstrated HCV awareness and risk reduction strategies should be expanded

Retreatment for hepatitis C virus direct-acting antiviral therapy virological failure in primary and tertiary settings: The REACH-C cohort

Virological failure occurs in a small proportion of people treated for hepatitis C virus (HCV) with direct-acting antiviral (DAA) therapies. This study assessed retreatment for virological failure in a large real-world cohort. REACH-C is an Australian observational study (n = 10,843) evaluating treatment outcomes of sequential DAA initiations across 33 health services between March 2016 to June 2019. Virological failure retreatment data were collected until October 2020. Of 408 people with virological failure (81% male; median age 53; 38% cirrhosis; 56% genotype 3), 213 (54%) were retreated once; 15 were retreated twice. A range of genotype specific and pangenotypic DAAs were used to retreat virological failure in primary (n = 56) and tertiary (n = 157) settings. Following sofosbuvir/velpatasvir/voxilaprevir availability in 2019, the proportion retreated in primary care increased from 21% to 40% and median time to retreatment initiation declined from 294 to 152 days. Per protocol (PP) sustained virological response (SVR12) was similar for people retreated in primary and tertiary settings (80% vs 81%; p = 1.000). In regression analysis, sofosbuvir/velpatasvir/voxilaprevir (vs. other regimens) significantly decreased likelihood of second virological failure (PP SVR12 88% vs. 77%; adjusted odds ratio [AOR] 0.29; 95%CI 0.11–0.81); cirrhosis increased likelihood (PP SVR12 69% vs. 91%; AOR 4.26; 95%CI 1.64–11.09). Indigenous Australians had lower likelihood of retreatment initiation (AOR 0.36; 95%CI 0.15–0.81). Treatment setting and prescriber type were not associated with retreatment initiation or outcome. Virological failure can be effectively retreated in primary care. Expanded access to simplified retreatment regimens through decentralized models may increase retreatment uptake and reduce HCV-related mortality

Therapeutic strategies for recent hepatitis C virus infection in the era of direct-acting antiviral therapy

Background: The management of recent hepatitis C virus (HCV) infection is uncertain, as the therapeutic landscape evolves with the advent of direct-acting antiviral (DAA) therapy.Aims: The broad aim of this research was to examine novel therapeutic strategies in recent HCV following the availability of DAA therapy. Specific aims included assessing the feasibility, efficacy and safety of response-guided interferon (IFN)-containing and ultra-short IFN-free therapy; calculating reinfection incidence following treatment; and determining the clinical significance of drug-drug interactions in HIV/HCV co-infection.Methods: In Chapters Two and Three, the efficacy and safety of short and/or response-guided treatment among individuals with recent HCV was examined in three open-label trials: ATAHC II (n=52; pegylated-IFN +/- ribavirin), DARE-C I (n=14; pegylated-IFN, ribavirin + telaprevir) and DARE-C II (n=19; sofosbuvir + ribavirin). In Chapter Four, reinfection incidence following treatment for recent HCV was calculated among those who achieved an end-of-treatment response in ATAHC I and II, DARE-C I and II (n=120). In Chapter Five, a simulation of potential drug-drug interactions between combination antiretroviral therapy and DAAs was performed in those with HIV/HCV enrolled in CEASE-D (n=257).Key Findings: A total of 85 individuals (73% HIV) with recent HCV commenced short and/or response-guided treatment between 2010 and 2015; none of the strategies trialled was optimal. Given toxicity, the applicability of an IFN-containing strategy is limited. Conversely, six weeks of sofosbuvir and ribavirin was safe and well tolerated, but efficacy was poor. High reinfection incidence, particularly in individuals reporting injection drug use following treatment, was seen. These trials confirmed the feasibility of short duration therapy in recent HCV and informed contemporary trial design. Optimal DAA regimen choice for future research will be crucial; the combination of a nucleotide analogue and an NS5A inhibitor appears appropriate given potency and little potential for drug-drug interactions in HIV/HCV co-infection.Conclusion: The role and efficacy of ultra-short duration therapy in recent HCV requires further evaluation with potent DAA regimens. The significant risk for HCV reinfection following treatment in individuals with ongoing behaviour facilitating transmission emphasises the need for post-treatment surveillance, harm reduction strategies and education

Association between HTLV-1 infection and adverse health outcomes: a systematic review and meta-analysis of epidemiological studies

International audienceBackgroundHuman T-cell lymphotropic virus type 1 (HTLV-1) is a human retrovirus that causes a lifelong infection. Several diseases, including an aggressive form of leukaemia, have been designated as associated with HTLV-1, whereby having HTLV-1 is a necessary condition for diagnosis. Beyond these diseases, there is uncertainty about other health effects of HTLV-1. We aimed to synthesise evidence from epidemiological studies on associations between health outcomes and HTLV-1.MethodsFor this systematic review and meta-analysis, we searched Embase, MEDLINE, MEDLINE In-Process, and Global Health for publications from their inception to July, 2018. We included cohort, case-control, and controlled cross-sectional studies that compared mortality or morbidity between people with and without HTLV-1. We excluded studies of psychiatric conditions, of symptoms or clinical findings only, of people who had undergone blood transfusion or organ transplant, and of population groups defined by a behavioural characteristic putting them at increased risk of co-infection with another virus. We extracted the risk estimates (relative risks [RRs] or odds ratios [ORs]) that reflected the greatest degree of control for potential confounders. We did a random-effects meta-analysis for groups of effect estimates where case ascertainment methods, age groups, and confounders were similar, presenting pooled estimates with 95% CIs and prediction intervals.FindingsOf the 3318 identified studies, 39 met the inclusion criteria, examining 42 clinical conditions between them. The adjusted risk of death due to any cause was higher in people with HTLV-1 when compared with HTLV-1-negative counterparts (RR 1·57, 95% CI 1·37–1·80). From meta-analysis, HTLV-1 was associated with increased odds of seborrheic dermatitis (OR 3·95, 95% CI 1·99–7·81), Sjogren's syndrome (3·25, 1·85–5·70), and, inversely, with lower relative risk of gastric cancer (RR 0·45, 0·28–0·71). There were a further 14 diseases with significant associations or substantially elevated risk with HTLV-1 from single studies (eczema [children]; bronchiectasis, bronchitis and bronchiolitis [analysed together]; asthma [males]; fibromyalgia; rheumatoid arthritis; arthritis; tuberculosis; kidney and bladder infections; dermatophytosis; community acquired pneumonia; strongyloides hyperinfection syndrome; liver cancer; lymphoma other than adult T-cell leukaemia-lymphoma; and cervical cancer).InterpretationThere is a broad range of diseases studied in association with HTLV-1. However, the elevated risk for death among people with HTLV-1 is not explained by available studies of morbidity. Many of the diseases shown to be associated with HTLV-1 are not fatal, and those that are (eg, leukaemia) occur too rarely to account for the observed mortality effect. There are substantial research gaps in relation to HTLV-1 and cardiovascular, cerebrovascular, and metabolic disease. The burden of disease associated with the virus might be broader than generally recognised