Prevalence, Risk factors, and Shedding of Human Herpes Virus-8 among Men Having Sex With Men Enrolled in a Pre-exposure Prophylaxis Study.

BACKGROUND: Seroprevalence and risk factors for Human Herpesvirus-8 (HHV-8) infection among HIV-negative men who have sex with men (MSM) on pre-exposure prophylaxis (PrEP) have not been well characterized. Our objectives were to assess the prevalence and incidence of HHV-8 infection in MSM enrolled on PrEP and assess viral shedding in seropositive participants. METHODS: The ANRS IPERGAY study enrolled 429 participants in France and Canada to evaluate oral PrEP for HIV-1 prevention. Stored sera samples at day 0 (D0) and last visit were tested for the detection of HHV-8 antibodies using an indirect immunofluorescence assay. Baseline characteristics were analyzed to identify risk factors associated with HHV-8 seropositivity. Among seropositive participants, HHV-8 DNA was quantified on available oral and anal swabs, and ORF-K1 typing performed on HHV-8 positive samples. RESULTS: One hundred participants were seropositive at D0 (prevalence of 24%, 95% Confidence Interval (95%CI): 20·0-28·4) and 18/329 seroconverted during the study (incidence rate of 2·66 per 100 person-years, 95%CI: 1·57-4·20). Risk factors independently associated with baseline HHV-8 seropositivity included older age, high number of sexual partners, chemsex use and HSV-2 seropositivity. Among HHV-8 seropositive participants with available swab(s) for virological analysis, 37/115 (32%) displayed HHV-8 oral shedding, and 5/113 (4.4%) anal shedding at least once. Four patients had positive viral load before seroconversion. CONCLUSION: Prevalence and incidence of HHV-8 infection were high in HIV-negative PrEP users. Among seropositive participants, HHV-8 DNA is mainly detected in saliva, which may play a major role in viral transmission in this population.

In utero exposure to antiretroviral drugs and pregnancy outcomes: Analysis of the French ANRS pharmacovigilance database.

AIMS: In 2018, 1.07 million pregnant women received antiretroviral drugs, raising whether this affects pregnancy outcomes. We assessed the adverse pregnancy outcomes associated with prenatal antiretroviral drug exposure, notified to the French ANRS pharmacovigilance system. METHODS: An exhaustive case report series has been performed using the ANRS pharmacovigilance database. All ANRS-sponsored HIV clinical research studies using antiretroviral drugs either in pregnant women or women of childbearing age were eligible from 2004 to 2019. We analysed the following pregnancy outcomes: abortion, ectopic pregnancy, stillbirth, prematurity (<37 weeks of gestational age), low birth weight (<2500 g) and congenital abnormalities. A logistic regression was performed to assess the odds ratio (OR) for each outcome separately (if occurrence >50) compared to the outcome observed when exposed to non-nucleoside-reverse-transcriptase-inhibitor (NNRTI)-based regimen as the reference. RESULTS: Among the 34 studies selected, 918 deliveries occurred, of whom 88% had pregnancy outcomes documented. Pregnant women were mainly exposed to PI (n = 387, 48.6%), NNRTI (n = 331, 41.5%) and INI-based combinations (n = 40, 5.0%, 18 on dolutegravir). Compared to NNRTI-based combinations, there was no significant association observed with exposure to other antiretroviral combination for spontaneous abortion, prematurity or low birth weight, except an increased risk of low birth weight in new-born exposed to exclusive nucleoside-reverse-transcriptase-inhibitor (NRTI) combinations (n = 4; OR 7.50 [1.49-37.83]). CONCLUSIONS: Our study, mainly based on protease inhibitor (PI) and NNRTI-based regimens, is overall reassuring on the risk of adverse pregnancy outcomes, except for NRTI which should be interpreted cautiously (small number, indication bias). In this study, the number of integrase inhibitor (INI)-based combinations was too low to draw any conclusions.

Hepatitis C virus (HCV) incidence among men who have sex with men (MSM) living with HIV: results from the French Hospital Database on HIV (ANRS CO4-FHDH) cohort study, 2014 to 2017.

BackgroundDespite the availability of highly effective direct-acting antivirals (DAAs) and the expected treatment as prevention (TasP) effect, transmission of hepatitis C virus (HCV) persists in men who have sex with men (MSM) who engage in high-risk sexual behaviours.AimWe aimed to estimate the incidence of primary HCV infection among MSM living with HIV in France when DAA was readily available.MethodsWe used data from a large French hospital cohort of persons living with HIV (ANRS CO4-FHDH) prospectively collected between 2014 and 2017. HCV incidence rates were calculated using person-time methods for HCV-negative MSM at inclusion who had serological follow-up from 1 January 2014 to 31 December 2017. Sensitivity analyses were performed by varying the main assumptions to assess their impact on the results.ResultsOf 14,273 MSM living with HIV who were initially HCV-seronegative, 330 acquired HCV during follow-up over 45,866 person-years (py), resulting in an overall estimated incidence rate of 0.72/100 py (95% CI: 0.65-0.80). HCV incidence significantly decreased from 0.98/100 py (95% CI: 0.81-1.19) in 2014 to 0.45/100 py (95% CI: 0.35-0.59) in 2017 (54% decrease; 95% CI: 36-67). This trend was confirmed by most of the sensitivity analyses.ConclusionThe primary incidence of HCV was halved for MSM living with HIV between 2014 and 2017. This decrease may be related to unrestricted DAA availability in France for individuals living with HIV. Further interventions, including risk reduction, are needed to reach HCV micro-elimination in MSM living with HIV.

Changes in Sexual Behaviors in Men Who Have Sex with Men: A Comparison Between the Double-Blind and Open-Label Extension Phases of the ANRS-IPERGAY Trial.

Pre-Exposure Prophylaxis (PrEP) is changing the landscape of HIV prevention, and may bring changes in sexual behaviors. The double-blind phase (DBP) and open-label extension (OLE) study of the ANRS-IPERGAY trial allowed us to assess changes in sexual behavior of men who have sex with men (MSM) taking sexual activity-based (i.e., on-demand) PrEP. Generalized Estimating Equation (GEE) models found a significant decrease in the number of sexual partners (Coefficient [CI95%], p value; - 0.37[- 0.70 to - 0.04], p = 0.03) between the DBP and OLE as well as in the number of sexual relations (- 0.25 [- 0.49 to 0.00], 0.04). GEE estimates also showed that respondents' most recent sexual relation was less likely to have been with an unknown casual partner during the OLE than during the DBP (Odds Ratio [CI95%], p value: 0.75[0.62-0.92], 0.005). Furthermore, they showed an increase in the proportion of condomless anal sex in the OLE (1.32[1.04-1.67], 0.02), a decrease in the proportion of 'suboptimal PrEP adherence' over time (0.75[0.58-0.97], p = 0.03), a decrease in PrEP only use (0.73[0.55-0.96], 0.03) and in both PrEP and condom use over time (0.70[0.51-0.95], 0.02) and finally, a decrease in alcohol consumption between the DBP and OLE (0.74[0.61-0.90], 0.002). We observed both protective and risky behaviors in terms of HIV and STI risk after on-demand PrEP uptake in the OLE phase. Our findings are consistent with results from previous PrEP trials.

Incidence of Hepatocellular Carcinoma After Direct Antiviral Therapy for HCV in Patients With Cirrhosis Included in Surveillance Programs.

BACKGROUND & AIMS: Retrospective studies have found an unexpectedly high incidence of hepatocellular carcinoma (HCC) among patients with hepatitis C virus (HCV)-associated cirrhosis who received direct-acting antiviral (DAA) agents. We analyzed data from the ANRS CO12 CirVir cohort to compare the incidence of HCC in patients with cirrhosis who received DAA therapy vs patients treated with interferon (IFN). METHODS: Data were collected from 1270 patients with compensated biopsy-proven HCV-associated cirrhosis recruited from 2006 through 2012 at 35 centers in France. For descriptive purpose, patients were classified as follows: patients who received DAA treatment (DAA group, n = 336), patients who achieved a sustained virologic response (SVR) following an IFN-based regimen (SVR-IFN group, n = 495), or patients who never received DAA treatment and never had an SVR following IFN therapy (non-SVR group, n = 439). The patients were included in HCC surveillance programs based on ultrasound examination every 6 months, and clinical and biological data were recorded. To account for confounding by indication due to differences in patient characteristics at treatment initiation, we constructed a time-dependent Cox regression model weighted by the inverse probability of treatment and censoring (IPTCW) to assess the treatment effects of DAA on time until HCC. RESULTS: Compared with patients in the SVR-IFN group, patients in the DAA group were older, higher proportions had diabetes or portal hypertension, and liver function was more severely impaired. The crude 3-year cumulative incidences of HCC were 5.9% in the DAA group, 3.1% in the SVR-IFN group, and 12.7% in the non-SVR group (overall P < .001; unadjusted hazard ratio [HR] for HCC 2.03; 95% confidence interval [CI] 1.07-3.84; P = .030 for the DAA group vs the SVR-IFN group). HCC characteristics were similar among groups. Among patients with HCC, the DAA group received less-frequent HCC screening than the other 2 groups (P = .002). After Cox analyses weighted by the IPTCW, we found no statistically significant increase in risk of HCC associated with DAA use (HR 0.89; 95% CI 0.46-1.73; P = .73). CONCLUSIONS: Analysis of data from the ANRS CO12 CirVir cohort reveals that the apparent increase in HCC incidence observed in patients with cirrhosis treated with DAAs compared with patients who achieved SVR following an IFN therapy can be explained by patient characteristics (age, diabetes, reduced liver function) and lower screening intensity.

Non-virological factors are drivers of hepatocellular carcinoma in virosuppressed hepatitis B cirrhosis: Results of ANRS CO12 CirVir cohort.

Worldwide, hepatocellular carcinoma (HCC) occurs mainly in Asian patients with hepatitis B virus (HBV) infection. This study aimed to decipher the environmental and virological factors associated with HCC occurrence and validate risk scoring systems in a French multicentre prospective cohort of HBV cirrhotic patients. Patients with biopsy-proven Child-Pugh A viral cirrhosis included in the ANRS CO12 CirVir cohort who were HBsAg(+) without hepatitis C coinfection were selected for: (a) interview through a standardized questionnaire reporting coffee consumption and HCC familial history; (b) HBsAg quantification using baseline and sequential 2-year frozen sera; (c) baseline HBV genotype determination; and (d) assessment of risk factors and applicability of HCC risk scores (Kaplan-Meier analysis, Cox models). Among 317 patients studied (261 men, median age 53 years, past or ongoing antiviral treatment 93.3% and baseline detectable HBV DNA in 88 patients), the baseline and 2-year median HBsAg levels were 810 and 463 IU/mL, respectively. After a median follow-up of 65.2 months, 27 HCC cases were diagnosed (annual incidence: 1.6%). Three factors were independently associated with HCC occurrence: age > 50 years, platelets ≤ 150 × 103 /mm3 and body mass index ≥ 30 kg/m2 . Two out of five risk scores were validated, and the most accurate was PAGE-B at 1 year. Moreover, HCC in patients without maintained virological suppression seems more aggressive and less accessible to curative treatment. In conclusion, in French patients with HBV cirrhosis mostly virally suppressed, independent HCC risk factors were host-related (age, obesity) or linked to the severity of cirrhosis (thrombopenia), and the European PAGE-B score was the most accurate risk score.

Eradication of Hepatitis C Virus Infection in Patients With Cirrhosis Reduces Risk of Liver and Non-Liver Complications.

BACKGROUND & AIMS: We performed a prospective study to investigate the effects of a sustained viral response (SVR) on outcomes of patients with hepatitis C virus (HCV) infection and compensated cirrhosis. METHODS: We collected data from 1323 patients included in the prospective Agence Nationale pour la Recherche sur le SIDA et les hépatites virales (ANRS) viral cirrhosis (CirVir) cohort, recruited from 35 clinical centers in France from 2006 through 2012. All patients had HCV infection and biopsy-proven cirrhosis, were Child-Pugh class A, and had no prior liver complications. All patients received anti-HCV treatment before or after inclusion (with interferon then with direct antiviral agents) and underwent an ultrasound examination every 6 months, as well as endoscopic evaluations. SVR was considered as a time-dependent covariate; its effect on outcome was assessed by the Cox proportional hazard regression method. We used a propensity score to minimize confounding by indication of treatment and capacity to achieve SVR. RESULTS: After a median follow-up period of 58.2 months, 668 patients (50.5%) achieved SVR. SVR was associated with a decreased incidence of hepatocellular carcinoma (hazard ratio [HR] compared with patients without an SVR, 0.29; 95% confidence interval [CI], 0.19-0.43; P < .001) and hepatic decompensation (HR, 0.26; 95% CI, 0.17-0.39; P < .001). Patients with SVRs also had a lower risk of cardiovascular events (HR, 0.42; 95% CI, 0.25-0.69; P = .001) and bacterial infections (HR, 0.44; 95% CI, 0.29-0.68; P < .001). Metabolic features were associated with a higher risk of hepatocellular carcinoma in patients with SVRs, but not in patients with viremia. SVR affected overall mortality (HR, 0.27 compared with patients without SVR; 95% CI, 0.18-0.42; P < .001) and death from liver-related and non-liver-related causes. Similar results were obtained in a propensity score-matched population. CONCLUSIONS: We confirmed a reduction in critical events, liver-related or not, in a prospective study of patients with HCV infection and compensated cirrhosis included in the CirVir cohort who achieved an SVR. We found an SVR to reduce overall mortality and risk of death from liver-related and non-liver-related causes. A longer follow-up evaluation is required to accurately describe and assess specific risk factors for complications in this population.

The ANRS-Ipergay trial, an opportunity to use qualitative research to understand the perception of the "participant"-physician relationship.

The ANRS-IPERGAY trial consisted in providing sexual activity-based antiretroviral prophylaxis for HIV prevention (PrEP) with a package of prevention tools (counselling, condoms, HIV and sexually transmitted infections' screening) to highly exposed HIV-negative men who have sex with men (MSM). Few data exist concerning the patient-physician relationship in the particular context of PrEP, where physicians discuss sexual behaviours with MSM who are not classic patients, in that consultation is for prevention purposes, not for illness. This study took place during the open-label extension of ANRS-IPERGAY trial when all participants received PrEP. In this qualitative study, we examined how physicians perceived their relationship with participants in the ANRS-IPERGAY trial. Of all 30 physicians involved in the trial who were contacted by email to participate in an interview about their opinions and perceptions of ANRS-IPERGAY 18 volunteered to participate in the current sub-study. We performed a vertical analysis for each interview to identify the extract in each physician's discourse concerning their relationship with MSM participants, and conducted a horizontal analysis to construct the thematic tree and subsequently investigate differences and similitudes between themes. An analysis of all physicians' discourses showed that the participant-physician relationship during the trial could be described through 4 themes: (i) personal experience of the relationship, (ii) trust and non-judgement, (iii) positive relational climate and (iv) influence of physician's characteristics (age, gender, etc.) on relationship. We found that the particular context of PrEP led some physicians to adopt a patient-as-partner approach during consultations rather than a paternalist or hierarchical approach. Indeed, the close follow-up provided by the trial and the active role of patients in their own prevention care trajectory, are more compatible with the patient-as-partner approach. The prescription of PrEP may lead to an evolution in patient-physician relationships and may even modify the professional identity of physicians.

Association between elevated coffee consumption and daily chocolate intake with normal liver enzymes in HIV-HCV infected individuals: results from the ANRS CO13 HEPAVIH cohort study.

BACKGROUND & AIMS: We used longitudinal data from the ANRS CO13 HEPAVIH cohort study of HIV-HCV co-infected individuals to investigate whether polyphenol rich food intake through coffee and/or daily chocolate consumption could play a role in reducing liver enzymes levels. METHODS: Longitudinal data collection included self-administered questionnaires and medical data (aspartate aminotransferase (AST) and alanine aminotransferase (ALT) liver enzymes). Two analyses were performed to assess the association between coffee (≥3 cups a day) and daily chocolate intake and abnormal values of AST and ALT (AST or ALT >2.5 × upper normal limit (UNL)) (N=990) over time, after adjustment for known correlates. Logistic regression models based on generalized estimating equations were used to take into account the correlations between repeated measures and estimate adjusted odds ratio. RESULTS: After adjustment, patients reporting elevated coffee consumption and daily chocolate intake were less likely to present abnormal ALT (OR=0.65; p=0.04 and OR=0.57; p=0.04, for coffee and chocolate respectively), while only patients reporting elevated coffee consumption were less likely to have abnormal AST values (p=0.05). Nevertheless, the combined indicator of coffee and chocolate intake was most significantly associated with approximately 40% reduced risk of abnormal liver enzymes (p=0.003 for AST; p=0.002 for ALT). CONCLUSIONS: Elevated coffee consumption and daily chocolate intake appear to be associated with reduced levels of liver enzymes in HIV-HCV co-infected patients. Further experimental and observational research is needed to better understand the role that polyphenol intake or supplementation can play on liver disease and liver injury.

Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890.

BACKGROUND & AIMS: In phase III trials, the safety profile of triple therapy (pegylated interferon/ribavirin with boceprevir or telaprevir) seems to be similar in HCV treatment-experienced cirrhotic and non-cirrhotic patients, but few cirrhotics were included. We report the week 16 safety and efficacy analysis in a cohort of compensated cirrhotics treated in the French Early Access Programme. METHODS: 674 genotype 1 patients, prospectively included, received 48 weeks of triple therapy. The analysis is restricted to 497 patients reaching week 16. RESULTS: A high incidence of serious adverse events (40.0%), and of death and severe complications (severe infection or hepatic decompensation) (6.4%), and a difficult management of anaemia (erythropoietin and transfusion use in 50.7% and 12.1%) were observed. Independent predictors of anaemia < 8 g/dl or blood transfusion were: female gender (OR 2.19, 95% CI 1.11-4.33, p=0.024), no lead-in phase (OR 2.25, 95% CI 1.15-4.39, p=0.018), age ≥ 65 years (OR 3.04, 95% CI 1.54-6.02, p=0.0014), haemoglobin level (≤ 12 g/dl for females, ≤ 13 g/dl for males) (OR 5.30, 95% CI 2.49-11.5, p=0.0001). Death or severe complications were related to platelets count ≤ 100,000/mm(3) (OR 3.11, 95% CI 1.30-7.41, p=0.0105) and albumin <35 g/dl (OR 6.33, 95% CI 2.66-15.07, p=0.0001), with a risk of 44.1% in patients with both. However, the on-treatment virological response was high. CONCLUSIONS: The safety profile was poor and patients with platelet count ≤ 100,000/mm(3) and serum albumin <35 g/L should not be treated with the triple therapy.

Assessment of a psychiatric intervention at community level for people who inject drugs in a low-middle income country: the DRIVE-Mind cohort study in Hai Phong, Viet Nam.

BACKGROUND: Access to psychiatric care for people who inject drugs (PWID) is limited/absent and stigmatized in most low-middle-income countries (LMICs). Innovative interventions are needed. We aimed to describe and assess the impact of a community-based psychiatric intervention among PWID in Hai Phong, Vietnam. METHODS: In a cohort study with one year psychiatric follow-up, PWID diagnosed with a psychotic disorder, a major depressive episode, or suicide risk, were recruited from the wider Drug-Related Infections in ViEtnam (DRIVE) project in the city of Hai Phong. The community-based psychiatric intervention included specialized follow-up (free consultations with psychiatrists, free medication, referral to mental health department for hospitalization when necessary) and support from community-based organisations (case management, harm reduction, administrative support, linkage to HIV care, methadone maintenance treatment and mental health support). The main outcome was reduction/remission of symptoms. Access to and retention in psychiatric care, quality-of-life and stigmatization were also measured pre and post-intervention. FINDINGS: Among the 1212 participants screened from March to May 2019, 271 met the inclusion criteria, 233 (86.3%) accepted the intervention and 170 completed the follow-up (72.9%). At inclusion, 80.6% were diagnosed with current depression, 44.7% with psychotic disorder and 42.4% with suicide risk. After a one-year follow-up, these proportions dropped to 15.9%, 21.8%, and 22.9% respectively. Quality-of-life and perceived stigma related to mental health were also significantly improved, while drug use decreased only marginally. INTERPRETATION: Community-based psychiatric interventions are both feasible and efficient in the Vietnamese context. Similar interventions should be implemented and evaluated in other, different LMICs. FUNDING: : This work was supported by grants from NIDA (US) (#DA041978) and ANRS (France) (#13353). The funding agencies had no role in designing the research, data analyses, or preparation of the report.

Community-Based Care in the ANRS-IPERGAY Trial: The Challenges of Combination Prevention.

ANRS-IPERGAY was a community-based randomized trial investigating the efficacy of sexual activity-based HIV pre-exposure prophylaxis (PrEP) in a population of males and transgender females who had sex with men and were at high risk of HIV infection. We qualitatively analyzed the support provided to participants by community-based health workers (CBHW) throughout the trial's double-blind and open-label extension phases. In particular, we showed that the relationship between participants and CBHW strongly influenced self-managed pill intake. The delicate construction of this relationship, balanced between trust and dependence, played an important role in PrEP adherence. CBHW had to deal with various issues surrounding participants' feelings of empowerment regarding their role in the trial, as well as related tensions between various logics and rationalities. They were essential to participants' continued involvement.

Financial sustainability in municipal solid waste management--costs and revenues in Bahir Dar, Ethiopia.

Providing good solid waste management (SWM) services while also ensuring financial sustainability of the system continues to be a major challenge in cities of developing countries. Bahir Dar in northwestern Ethiopia outsourced municipal waste services to a private waste company in 2008. While this institutional change has led to substantial improvement in the cleanliness of the city, its financial sustainability remains unclear. Is the private company able to generate sufficient revenues from their activities to offset the costs and generate some profit? This paper presents a cost-revenue analysis, based on data from July 2009 to June 2011. The analysis reveals that overall costs in Bahir Dar's SWM system increased significantly during this period, mainly due to rising costs related to waste transportation. On the other hand, there is only one major revenue stream in place: the waste collection fee from households, commercial enterprises and institutions. As the efficiency of fee collection from households is only around 50%, the total amount of revenues are not sufficient to cover the running costs. This results in a substantial yearly deficit. The results of the research therefore show that a more detailed cost structure and cost-revenue analysis of this waste management service is important with appropriate measures, either by the privates sector itself or with the support of the local authorities, in order to enhance cost efficiency and balance the cost-revenues towards cost recovery. Delays in mitigating the evident financial deficit could else endanger the public-private partnership (PPP) and lead to failure of this setup in the medium to long term, thus also endangering the now existing improved and currently reliable service. We present four options on how financial sustainability of the SWM system in Bahir Dar might be enhanced: (i) improved fee collection efficiency by linking the fees of solid waste collection to water supply; (ii) increasing the value chain by sales of organic waste recycling products; (iii) diversifying revenue streams and financing mechanisms (polluter-pays-, cross-subsidy- and business-principles); and (iv) cost reduction and improved cost-effectiveness. We argue that in a PPP setup such as in Bahir Dar, a strong alliance between the municipality and private enterprise is important so that appropriate solutions for improved financial sustainability of a SWM system can be sought and implemented.