Associations between antiretroviral regimen and changes in blood pressure: results from the D2EFT study.

In this randomised, controlled study in 14 low- and middle-income countries, individuals taking dolutegravir with darunavir/ritonavir for 48 weeks had a greater increase in systolic and diastolic blood pressure than individuals taking two nucleoside reverse transcriptase with darunavir/ritonavir. The difference remained significant after controlling for confounding factors including weight gain.

Trends in mortality in people with HIV from 1999 to 2020: a multi-cohort collaboration.

BACKGROUND: Mortality among people with HIV declined with the introduction of combination antiretroviral therapy. We investigated trends over time in all-cause and cause-specific mortality in people with HIV from 1999-2020. METHODS: Data were collected from the D:A:D cohort from 1999 through January 2015 and RESPOND from October 2017 through 2020. Age-standardized all-cause and cause-specific mortality rates, classified using Coding Causes of Death in HIV (CoDe), were calculated. Poisson regression models were used to assess mortality trends over time. RESULTS: Among 55716 participants followed for a median of 6 years (IQR 3-11), 5263 participants died (crude mortality rate [MR] 13.7/1000 PYFU; 95%CI 13.4-14.1). Changing patterns of mortality were observed with AIDS as the most common cause of death between 1999- 2009 (n = 952, MR 4.2/1000 PYFU; 95%CI 4.0-4.5) and non-AIDS defining malignancy (NADM) from 2010 -2020 (n = 444, MR 2.8/1000 PYFU; 95%CI 2.5-3.1). In multivariable analysis, all-cause mortality declined over time (adjusted mortality rate ratio [aMRR] 0.97 per year; 95%CI 0.96, 0.98), mostly from 1999 through 2010 (aMRR 0.96 per year; 95%CI 0.95-0.97), and with no decline shown from 2011 through 2020 (aMRR 1·00 per year; 95%CI 0·96-1·05). Mortality due all known causes except NADM also declined over the entire follow-up period. CONCLUSION: Mortality among people with HIV in the D:A:D and/or RESPOND cohorts decreased between 1999 and 2009 and was stable over the period from 2010 through 2020. The decline in mortality rates was not fully explained by improvements in immunologic-virologic status or other risk factors.

Semi-supervised mixture multi-source exchangeability model for leveraging real-world data in clinical trials.

The traditional trial paradigm is often criticized as being slow, inefficient, and costly. Statistical approaches that leverage external trial data have emerged to make trials more efficient by augmenting the sample size. However, these approaches assume that external data are from previously conducted trials, leaving a rich source of untapped real-world data (RWD) that cannot yet be effectively leveraged. We propose a semi-supervised mixture (SS-MIX) multisource exchangeability model (MEM); a flexible, two-step Bayesian approach for incorporating RWD into randomized controlled trial analyses. The first step is a SS-MIX model on a modified propensity score and the second step is a MEM. The first step targets a representative subgroup of individuals from the trial population and the second step avoids borrowing when there are substantial differences in outcomes among the trial sample and the representative observational sample. When comparing the proposed approach to competing borrowing approaches in a simulation study, we find that our approach borrows efficiently when the trial and RWD are consistent, while mitigating bias when the trial and external data differ on either measured or unmeasured covariates. We illustrate the proposed approach with an application to a randomized controlled trial investigating intravenous hyperimmune immunoglobulin in hospitalized patients with influenza, while leveraging data from an external observational study to supplement a subgroup analysis by influenza subtype.

Changes in atherosclerotic cardiovascular disease risk over time among people living with HIV.

OBJECTIVE: To describe changes in atherosclerotic cardiovascular disease (ASCVD) risk over time among people living with HIV (PLHIV). METHODS: We used data from the TREAT Asia HIV Observational Database (TAHOD) and the Australian HIV Observational Database (AHOD). Five-year ASCVD risk was calculated using the D:A:D equation. Individuals were eligible for inclusion if they were aged ≥18 years, had started ART, had no previous history of ASCVD and had complete ASCVD risk factor data available within the first 5 years of ART initiation. RESULTS: A total of 3368 adults contributed data, 3221 were from TAHOD and 147 were from AHOD. The median age at ART initiation was 36 [IQR 31-43] years for TAHOD participants, and 42 [IQR 35-50] years for AHOD participants. Most TAHOD (70.4%) and AHOD (91.8%) participants were male. Overall, ASCVD risk increased from 0.84% (95% CI 0.81%-0.87%) at ART initiation to 1.34% (95% CI 1.29%-1.39%) after 5 years on ART. After adjusting for traditional and HIV-associated ASCVD risk factors, ASCVD risk increased at a similar rate among sub-populations defined by HIV exposure (heterosexuals, men who have sex with men, people who inject drugs), race/ethnicity (Caucasian and Asian) and nadir CD4 at ART initiation (<200 and ≥200 cells/mm3). CONCLUSIONS: These findings emphasize the growing burden of ASCVD risk among PLHIV and the need to develop interventions that are effective across a broad range of HIV sub-populations.

Investigating rates and predictors of viral blips, low-level viraemia and virological failure in the Australian HIV observational database.

OBJECTIVES: Australia has made significant progress towards achieving the UNAIDS's 95-95-95 cascade targets including HIV viral suppression. To investigate the burden of HIV viraemia, we assessed viral blips, low-level viraemia (LLV) and virologic failure (VF) in an Australian cohort. METHODS: We studied the proportion of people with viral suppression, viral blips, LLV and VF in the Australian HIV observational database (AHOD) between 2010 and 2021. The association between blips or LLV, and VF was investigated using Cox regression, and predictors of viral blips and LLV were assessed using repeated-measured logistic regression. RESULTS: Among 2544 AHOD participants who were in follow-up and on antiretroviral therapy (ART) from 1 January 2010 (88.7% male), 444 had experienced VF (incidence rate: 2.45 [95% CI: 2.23-2.69] per 100 person-years [PY]) during 18,125 PY of follow-up (a median of 7.6 years). The proportion of people with VF decreased over time, whereas rates of blips and LLV remained stable. Participants with blips (hazard ratio, 2.89; 95% CI: 2.31-3.61) and LLV (4.46; 95% CI: 3.38-5.89) were at increased risk of VF. Hepatitis B co-infection, longer documented treatment interruption duration, younger age and lower CD4 at ART initiation, and protease inhibitors-based initial regimen were associated with an increased risk of VF. Common predictors of blips and LLV such as higher HIV-1 RNA and lower CD4 at ART initiation, longer treatment interruption, more VL testing and types of care settings (hospitals vs. sexual health services) were identified. CONCLUSIONS: Blips and LLV predict subsequent VF development. We identified important predictors of HIV viraemia including VF among individuals on INSTI-based regimens to help direct HIV management plans.

The association between single-nucleotide polymorphisms within type 1 interferon pathway genes and human immunodeficiency virus type 1 viral load in antiretroviral-naïve participants.

BACKGROUND: Human genetic contribution to HIV progression remains inadequately explained. The type 1 interferon (IFN) pathway is important for host control of HIV and variation in type 1 IFN genes may contribute to disease progression. This study assessed the impact of variations at the gene and pathway level of type 1 IFN on HIV-1 viral load (VL). METHODS: Two cohorts of antiretroviral (ART) naïve participants living with HIV (PLWH) with either early (START) or advanced infection (FIRST) were analysed separately. Type 1 IFN genes (n = 17) and receptor subunits (IFNAR1, IFNAR2) were examined for both cumulated type 1 IFN pathway analysis and individual gene analysis. SKAT-O was applied to detect associations between the genotype and HIV-1 study entry viral load (log10 transformed) as a proxy for set point VL; P-values were corrected using Bonferroni (P < 0.0025). RESULTS: The analyses among those with early infection included 2429 individuals from five continents. The median study entry HIV VL was 14,623 (IQR 3460-45100) copies/mL. Across 673 SNPs within 19 type 1 IFN genes, no significant association with study entry VL was detected. Conversely, examining individual genes in START showed a borderline significant association between IFNW1, and study entry VL (P = 0.0025). This significance remained after separate adjustments for age, CD4+ T-cell count, CD4+/CD8+ T-cell ratio and recent infection. When controlling for population structure using linear mixed effects models (LME), in addition to principal components used in the main model, this was no longer significant (p = 0.0244). In subgroup analyses stratified by geographical region, the association between IFNW1 and study entry VL was only observed among African participants, although, the association was not significant when controlling for population structure using LME. Of the 17 SNPs within the IFNW1 region, only rs79876898 (A > G) was associated with study entry VL (p = 0.0020, beta = 0.32; G associated with higher study entry VL than A) in single SNP association analyses. The findings were not reproduced in FIRST participants. CONCLUSION: Across 19 type 1 IFN genes, only IFNW1 was associated with HIV-1 study entry VL in a cohort of ART-naïve individuals in early stages of their infection, however, this was no longer significant in sensitivity analyses that controlled for population structures using LME.

Factors Associated With Recent Decline in Anal Health Among Older Gay and Bisexual Men: A Cross-sectional Analysis.

ABSTRACT: We investigated factors associated with "worse than usual" anal health among gay and bisexual men aged ≥35 years recruited to a longitudinal study of anal human papillomavirus infection/lesions from September 2010 to August 2015.Among 616 participants (median age 49 years; 36% HIV-positive), 42 (6.8%) reported worse than usual anal health in the last 4 weeks. Associated factors included spending less time with gay friends (odds ratio [OR] = 2.25, 95% CI = 1.06-4.77), most time "feeling down"(OR = 9.17, 95% CI = 2.94-28.59), reduced libido (OR = 2.90, 95% CI = 1.52-5.52), current anal symptoms (OR = 6.55, 95% CI = 2.54-16.90), recent anal wart diagnosis (OR = 4.33, 95% CI = 1.98-9.49), and fear of developing anal cancer (OR = 9.34, 95% CI = 4.52-19.28).Concerns regarding anal health should be routinely discussed by clinicians, and potentially associated psychosocial, physical, and sexual issues further explored.

Plasma Human Immunodeficiency Virus 1 RNA and CD4+ T-Cell Counts Are Determinants of Virological Nonsuppression Outcomes With Initial Integrase Inhibitor-Based Regimens: A Prospective RESPOND Cohort Study.

BACKGROUND: There are conflicting data regarding baseline determinants of virological nonsuppression outcomes in persons with human immunodeficiency virus (HIV) starting antiretroviral treatment (ART). We evaluated the impact of different baseline variables in the RESPOND cohort. METHODS: We included treatment-naive participants aged ≥18 who initiated 3-drug ART, in 2014-2020. We assessed the odds of virological suppression (VS) at weeks 48 and 96 using logistic regression. Viral blips, low-level viremia (LLV), residual viremia (RV), and virological failure (VF) rates were assessed using Cox regression. RESULTS: Of 4310 eligible participants, 72% started integrase strand transfer inhibitor (INSTI)-based regimens. At 48 and 96 weeks, 91.0% and 93.3% achieved VS, respectively. At 48 weeks, Kaplan-Meier estimates of rates were 9.6% for viral blips, 2.1% for LLV, 22.2% for RV, and 2.1% for VF. Baseline HIV-1 RNA levels >100 000 copies/mL and CD4+ T-cell counts ≤200/µL were negatively associated with VS at weeks 48 (adjusted odds ratio, 0.51 [95% confidence interval, .39-.68] and .40 [.27-.58], respectively) and 96 and with significantly higher rates of blips, LLV, and RV. CD4+ T-cell counts ≤200/µL were associated with higher risk of VF (adjusted hazard ratio, 3.12 [95% confidence interval, 2.02-4.83]). Results were consistent in those starting INSTIs versus other regimens and those starting dolutegravir versus other INSTIs. CONCLUSIONS: Initial high HIV-1 RNA and low CD4+ T-cell counts are associated with lower rates of VS at 48 and 96 weeks and higher rates of viral blips, LLV, and RV. Low baseline CD4+ T-cell counts are associated with higher VF rates. These associations remain with INSTI-based and specifically with dolutegravir-based regimens. These findings suggest that the impact of these baseline determinants is independent of the ART regimen initiated.

What are the predictors of change in multimorbidity among people with HIV? A longitudinal observational cohort study.

INTRODUCTION: Multimorbidity is common among people living with HIV (PLWH), with numerous cross-sectional studies demonstrating associations with older age and past immunosuppression. Little is known about the progression of multimorbidity, particularly in the setting of long-term access to antiretrovirals. This study aims to determine factors predictive of change in multimorbidity in PLWH. METHODS: People living with HIV who attended a regional HIV service were recruited to a consented observational cohort between September 2016 and March 2020. Demographic data, laboratory results and a Cumulative Illness Rating Scale (CIRS) were collected at enrolment and first clinical review of every subsequent year. Change in CIRS score was calculated from enrolment to February 2021. Associations with change were determined through univariate and multivariate linear regression. RESULTS: Of 253 people, median age was 58.9 [interquartile range (IQR): 51.9-64.4] years, 91.3% were male, and HIV was diagnosed a median of 22.16 years (IQR: 12.1-30.9) beforehand. Length of time in the study was a median of 134 weeks (IQR: 89.0-179.0), in which a mean CIRS score change of 1.21 (SD 2.60) was observed. Being older (p < 0.001) and having a higher body mass index (p = 0.008) and diabetes (p = 0.014) were associated with an increased likelihood of worsening multimorbidity. PLWH with a higher level of multimorbidity at baseline were less likely to worsen over time (p < 0.001). CONCLUSION: As diabetes and weight predict worsening multimorbidity, routine diabetes screening, body mass index measurement, and multimorbidity status awareness are recommended.

CD4+ T-Cell Count at Antiretroviral Therapy Initiation in the "Treat-All" Era in Rural South Africa: An Interrupted Time Series Analysis.

BACKGROUND: South Africa implemented universal test and treat (UTT) in September 2016 in an effort to encourage earlier initiation of antiretroviral therapy (ART). METHODS: We therefore conducted an interrupted time series (ITS) analysis to assess the impact of UTT on mean CD4 count at ART initiation among adults aged ≥16 years attending 17 public sector primary care clinics in rural South Africa, between July 2014 and March 2019. RESULTS: Among 20 599 individuals (69% women), CD4 counts were available for 74%. Mean CD4 at ART initiation increased from 317.1 cells/µL (95% confidence interval [CI], 308.6 to 325.6) 1 to 8 months prior to UTT to 421.0 cells/µL (95% CI, 413.0 to 429.0) 1 to 12 months after UTT, including an immediate increase of 124.2 cells/µL (95% CI, 102.2 to 146.1). However, mean CD4 count subsequently fell to 389.5 cells/µL (95% CI, 381.8 to 397.1) 13 to 30 months after UTT but remained above pre-UTT levels. Men initiated ART at lower CD4 counts than women (-118.2 cells/µL, 95% CI, -125.5 to -111.0) throughout the study. CONCLUSIONS: Although UTT led to an immediate increase in CD4 count at ART initiation in this rural community, the long-term effects were modest. More efforts are needed to increase initiation of ART early in those living with human immunodeficiency virus, particularly men.

Antiretroviral Initiation at ≥800 CD4+ Cells/mm3 Associated With Lower Human Immunodeficiency Virus Reservoir Size.

BACKGROUND: Identifying factors that determine the frequency of latently infected CD4+ T cells on antiretroviral therapy (ART) may inform strategies for human immunodeficiency virus (HIV) cure. We investigated the role of CD4+ count at ART initiation for HIV persistence on ART. METHODS: Among participants of the Strategic Timing of Antiretroviral Treatment Study, we enrolled people with HIV (PWH) who initiated ART with CD4+ T-cell counts of 500-599, 600-799, or ≥ 800 cells/mm3. After 36-44 months on ART, the levels of total HIV-DNA, cell-associated unspliced HIV-RNA (CA-US HIV-RNA), and two-long terminal repeat HIV-DNA in CD4+ T cells were quantified and plasma HIV-RNA was measured by single-copy assay. We measured T-cell expression of Human Leucocyte Antigen-DR Isotype (HLA-DR), programmed death-1, and phosphorylated signal transducer and activator of transcription-5 (pSTAT5). Virological and immunological measures were compared across CD4+ strata. RESULTS: We enrolled 146 PWH, 36 in the 500-599, 60 in the 600-799, and 50 in the ≥ 800 CD4 strata. After 36-44 months of ART, total HIV-DNA, plasma HIV-RNA, and HLA-DR expression were significantly lower in PWH with CD4+ T-cell count ≥ 800 cells/mm3 at ART initiation compared with 600-799 or 500-599 cells/mm3. The median level of HIV-DNA after 36-44 months of ART was lower by 75% in participants initiating ART with ≥ 800 vs 500-599 cells/mm3 (median [interquartile range]: 16.3 [7.0-117.6] vs 68.4 [13.7-213.1] copies/million cells, respectively). Higher pSTAT5 expression significantly correlated with lower levels of HIV-DNA and CA-US HIV-RNA. Virological measures were significantly lower in females. CONCLUSIONS: Initiating ART with a CD4+ count ≥ 800 cells/mm3 compared with 600-799 or 500-599 cells/mm3 was associated with achieving a substantially smaller HIV reservoir on ART.

Incidence of hypertension in people with HIV who are treated with integrase inhibitors versus other antiretroviral regimens in the RESPOND cohort consortium.

OBJECTIVE: To compare the incidence of hypertension in people living with HIV receiving integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) versus non-nucleoside reverse transcriptase inhibitors (NNRTIs) or boosted protease inhibitors (PIs) in the RESPOND consortium of HIV cohorts. METHODS: Eligible people with HIV were aged ≥18 years who initiated a new three-drug ART regimen for the first time (baseline), did not have hypertension, and had at least two follow-up blood pressure (BP) measurements. Hypertension was defined as two consecutive systolic BP measurements ≥140 mmHg and/or diastolic BP ≥90 mmHg or initiation of antihypertensives. Multivariable Poisson regression was used to determine adjusted incidence rate ratios (aIRRs) of hypertension, overall and in those who were ART naïve or experienced at baseline. RESULTS: Overall, 4606 people living with HIV were eligible (INSTIs 3164, NNRTIs 807, PIs 635). The median baseline systolic BP, diastolic BP, and age were 120 (interquartile range [IQR] 113-130) mmHg, 78 (70-82) mmHg, and 43 (34-50) years, respectively. Over 8380.4 person-years (median follow-up 1.5 [IQR 1.0-2.7] years), 1058 (23.0%) participants developed hypertension (incidence rate 126.2/1000 person-years, 95% confidence interval [CI] 118.9-134.1). Participants receiving INSTIs had a higher incidence of hypertension than those receiving NNRTIs (aIRR 1.76; 95% CI 1.47-2.11), whereas the incidence was no different in those receiving PIs (aIRR 1.07; 95% CI 0.89-1.29). The results were similar when the analysis was stratified by ART status at baseline. CONCLUSION: Although unmeasured confounding and channelling bias cannot be excluded, INSTIs were associated with a higher incidence of hypertension than were NNRTIs, but rates were similar to those of PIs overall, in ART-naïve and ART-experienced participants within RESPOND.

Physical function limitation among gay and bisexual men aged ≥55years with and without HIV: findings from the Australian Positive and Peers Longevity Evaluation Study (APPLES).

BACKGROUND: As people living with HIV now have a life expectancy approaching that of the general population, clinical care focuses increasingly on the management and prevention of comorbidities and conditions associated with aging. We aimed to assess the prevalence of physical function (PF) limitation among gay and bisexual men (GBM) and determine whether HIV is associated with severe PF limitation in this population. METHODS: We analysed cross-sectional data from GBM aged ≥55years in the Australian Positive and Peers Longevity Evaluation Study who completed a self-administered survey on health and lifestyle factors. PF was measured using the Medical Outcomes Study-Physical Functioning scale. Factors associated with severe PF limitation were assessed using logistic regression. RESULTS: The survey was completed by 381 men: 186 without HIV and 195 with HIV. Median age was 64.3years for GBM without HIV and 62.1years for GBM with HIV. Compared with men without HIV, those with HIV had higher proportions of severe (13.3% vs 8.1%) and moderate-to-severe (26.7% vs 24.2%) PF limitation. Severe PF limitation commonly involved difficulty with vigorous activity (95% with severe PF limitation described being limited a lot), climbing several flights of stairs (68.4% limited a lot), bending, kneeling or stooping (60.5% limited a lot), and walking 1km (55.0% limited a lot). In a model adjusted for age, body mass index, typical duration of physical activity, psychological distress, and number of comorbidities, we found a significant association between HIV and severe PF limitation (adjusted odds ratio 3.3 vs not having HIV, 95% confidence interval 1.3-8.7). CONCLUSIONS: The biological mechanisms underlying this association require further investigation, particularly given the growing age of the HIV population and inevitable increase in the burden of PF limitation.

A New Method for Estimating the Incidence of Infectious Diseases.

Ambitious World Health Organization targets for disease elimination require monitoring of epidemics using routine health data in settings of decreasing and low incidence. We evaluated 2 methods commonly applied to routine testing results to estimate incidence rates that assume a uniform probability of infection between consecutive negative and positive tests based on 1) the midpoint of this interval and 2) a randomly selected point in this interval. We compared these with an approximation of the Poisson binomial distribution, which assigns partial incidence to time periods based on the uniform probability of occurrence in these intervals. We assessed bias, variance, and convergence of estimates using simulations of Weibull-distributed failure times with systematically varied baseline incidence and varying trend. We considered results for quarterly, half-yearly, and yearly incidence estimation frequencies. We applied the methods to assess human immunodeficiency virus (HIV) incidence in HIV-negative patients from the Treatment With Antiretrovirals and Their Impact on Positive and Negative Men (TAIPAN) Study, an Australian study of HIV incidence in men who have sex with men, between 2012 and 2018. The Poisson binomial method had reduced bias and variance at low levels of incidence and for increased estimation frequency, with increased consistency of estimation. Application of methods to real-world assessment of HIV incidence found decreased variance in Poisson binomial model estimates, with observed incidence declining to levels where simulation results had indicated bias in midpoint and random-point methods.

Sofosbuvir/velpatasvir for 12 vs. 6 weeks for the treatment of recently acquired hepatitis C infection.

BACKGROUND & AIMS: Shortened duration therapy for acute and recent HCV infection has been shown to be highly effective in several small non-randomised studies with direct-acting antiviral regimens; however, large randomised studies are lacking. METHODS: REACT was an NIH-funded multicentre international, open-label, randomised, phase IV non-inferiority trial examining the efficacy of short course (6-week) vs. standard course (12-week) therapy with sofosbuvir-velpatasvir for recent HCV infection (estimated duration of infection ≤12 months). Randomisation occurred at week 6. The primary endpoint was sustained virological response 12 weeks after treatment end (SVR12) in the intention-to treat (ITT) population. A total of 250 participants were due to be enrolled, but on advice of the data safety and monitoring board the study was halted early. RESULTS: The primary analysis population consisted of 188 randomised participants at termination of study enrolment; short arm (n = 93), standard arm (n = 95). Ninety-seven percent were male and 69% HIV positive. ITT SVR12 was 76/93, 81.7% (95% CI 72.4-89.0) in the short arm and 86/95, 90.5% (95% CI 82.7-95.6) in the standard arm. The difference between the arms was -8.8 (95% CI -18.6 to 1.0). In modified ITT analysis, wherein non-virological reasons for failure were excluded (death, reinfection, loss to follow-up), SVR12 was 76/85, 89.4% (95% CI 80.8-95.0) in the short arm and 86/88, 97.7% in the standard arm (95% CI 92.0-99.7; difference -8.3%, p = 0.025). CONCLUSIONS: In this randomised study in recent HCV infection, a 6-week course of sofosbuvir-velpatasvir did not meet the criteria for non-inferiority to standard 12-week therapy. LAY SUMMARY: In this randomised trial, 188 people with recently acquired hepatitis C infection were randomly assigned to treatment using either a short 6-week course (93 people) or standard 12-week course (95 people) of the hepatitis C treatment sofosbuvir/velpatasvir. There were 9 cases of relapse after treatment with the short course and 2 following the standard course. A shortened course of 6-week therapy for hepatitis C infection appeared to be less effective than a standard 12-week course in people with recently acquired hepatitis C infection. CLINICALTRIALS. GOV IDENTIFIER: NCT02625909.

Short-Duration Pan-Genotypic Therapy With Glecaprevir/Pibrentasvir for 6 Weeks Among People With Recent Hepatitis C Viral Infection.

BACKGROUND AND AIMS: Among treatment-naive individuals with chronic hepatitis C viral (HCV) infection and without cirrhosis, glecaprevir/pibrentasvir for 8 weeks is recommended. The aim of this analysis was to evaluate the efficacy of glecaprevir/pibrentasvir for 6 weeks in people with acute and recent HCV infection. APPROACH AND RESULTS: In this open-label, single-arm, multicenter, international pilot study, adults with recent HCV (duration of infection < 12 months) received glecaprevir/pibrentasvir 300/120 mg daily for 6 weeks. Primary infection was defined by first positive anti-HCV antibody and/or HCV RNA within 6 months of enrollment and either acute clinical hepatitis within the past 12 months (symptomatic seroconversion illness or alanine aminotransferase > 10 × upper limit of normal) or anti-HCV antibody seroconversion within 18 months. Reinfection was defined as new positive HCV RNA within 6 months of enrollment and evidence of prior spontaneous or treatment-induced clearance. The primary endpoint was sustained virologic response at 12 weeks posttreatment (SVR12). Thirty men (median age 43 years, 90% men who have sex with men) received treatment, of whom 77% (n = 23) were human immunodeficiency virus-positive, 47% (n = 14) had ever injected drugs, and 13% (n = 4) had HCV reinfection. The majority had HCV genotype 1 (83%, n = 25), followed by genotype 4 (10%, n = 3) and genotype 3 (7%, n = 2). At baseline, median estimated duration of infection was 29 weeks (range 13, 52) and median HCV RNA was 6.2 log10 IU/mL (range 0.9, 7.7). SVR12 in the intention-to-treat and per-protocol populations was achieved in 90% (27/30) and 96% (27/28), respectively. There was one case of relapse, and there were two cases of nonvirological failure (death, n = 1; loss to follow-up, n = 1). No treatment-related serious adverse events were seen. CONCLUSIONS: Glecaprevir/pibrentasvir for 6 weeks was highly effective among people with acute and recent HCV infection, supporting further evaluation of shortened-duration pan-genotypic therapy in this setting.

Self-reported anal symptoms and their association with anal pathology among gay and bisexual men: a cross-sectional observational analysis.

Background Anal symptoms may indicate serious pathology. Receptive anal intercourse (RAI) and sexually transmissible infections (STIs) may contribute to a higher prevalence of symptoms among gay and bisexual men (GBM). This study investigated associations with anal symptoms among GBM. METHODS: The Study of the Prevention of Anal Cancer was a longitudinal study of anal human papillomavirus and related lesions in Sydney, Australia. GBM aged ≥35 years were recruited from community settings between September 2010 and August 2015. Information about anal symptoms (discharge, itch, pain defecating, lump, bleeding, 'sores', tearing, tenesmus), STIs and sexual behaviours was collected. High-resolution anoscopy (HRA) and STI testing were performed. Logistic regression analyses on baseline data were performed to assess associations with each symptom. RESULTS: Among 616 participants (median age 49 years, 35.9% HIV positive), 35.3% reported at least one anal symptom within the past week and 65.3% were diagnosed with fistula, fissure, ulcer, warts, haemorrhoids and/or perianal dermatoses at HRA. Anal symptoms were not associated with anal chlamydia, gonorrhoea, warts or syphilis. Self-reported 'sores' were associated with previous anal herpes simplex virus (HSV; P < 0.001). 'Sores' (P < 0.001), itch (P = 0.019), discharge (P = 0.032) and lump (P = 0.028) were independently associated with ulceration. Among participants diagnosed with fissure, fistulae, haemorrhoids and perianal dermatoses, 61.9%, 100%, 62.0% and 63.9% respectively were asymptomatic. Only self-reported anal tear was independently associated with recent RAI. CONCLUSIONS: Previous anal HSV was the only STI associated with any symptom. Anal pathology was highly prevalent, but often asymptomatic. Anal symptoms do not appear to be useful markers of most anal pathology in GBM.

Moving Towards Hepatitis C Microelimination Among People Living With Human Immunodeficiency Virus in Australia: The CEASE Study.

BACKGROUND: Microelimination of hepatitis C virus (HCV) among people living with human immunodeficiency virus (HIV) may be feasible in Australia, given unrestricted access to direct-acting antiviral (DAA) therapy from 2016. Our aim was to evaluate progress towards elimination goals within HIV/HCV-coinfected adults in Australia following universal DAA access. METHODS: The CEASE prospective cohort study enrolled adults with HIV/HCV, irrespective of viremic status, from 14 primary and tertiary clinics in Australia. Annual and cumulative HCV treatment uptake, outcome, and HCV RNA prevalence were evaluated, with follow-up through May 2018 (median follow-up, 2.63 years). Factors associated with DAA uptake were analyzed. RESULTS: Between July 2014 and March 2017, 402 participants who were HIV/HCV antibody positive were enrolled (95% male [80% gay and bisexual men,], 13% cirrhosis, 80% history of injecting drug use [39% currently injecting]). Following universal DAA access, annual HCV treatment uptake in those eligible increased from 7% and 11% per year in 2014 and 2015, respectively, to 80% in 2016. By 2018, cumulative HCV treatment uptake in those ever eligible for treatment was 91% (336/371). HCV viremic prevalence declined from 82% (95% CI, 78-86%) in 2014 to 8% (95% CI, 6-12%) in 2018. Reinfection was reported in only 5 participants for a reinfection incidence of 0.81 per 100 person-years (95% CI, 0.34-1.94). CONCLUSIONS: High uptake and effectiveness of unrestricted DAA therapy in Australia have permitted rapid treatment scale-up, with a dramatic reduction in HCV infection burden and low reinfection rate among people living with HIV, suggesting that microelimination is feasible. CLINICAL TRIALS REGISTRATION: NCT02102451.

Simplified monitoring for hepatitis C virus treatment with glecaprevir plus pibrentasvir, a randomised non-inferiority trial.

BACKGROUND & AIMS: Direct-acting antiviral (DAA) therapy for HCV has high efficacy and limited toxicity. We hypothesised that the efficacy of glecaprevir-pibrentasvir for chronic HCV with a simplified treatment monitoring schedule would be non-inferior to a standard treatment monitoring schedule. METHODS: In this open-label multicentre phase IIIb trial, treatment-naïve adults with chronic HCV without cirrhosis were randomly assigned (2:1) to receive glecaprevir-pibrentasvir 300 mg-120 mg daily for 8 weeks administered with a simplified or standard monitoring strategy. Clinic visits occurred at baseline and post-treatment week 12 in the simplified arm, and at baseline, week 4, week 8, and post-treatment week 12 in the standard arm. Study nurse phone contact occurred at week 4 and week 8 in both arms. Participants requiring adherence support were not eligible, including those reporting recent injecting drug use. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12), with a non-inferiority margin of 6%. RESULTS: Overall, 380 participants (60% male, 47% genotype 1, 32% genotype 3) with chronic HCV were randomised and treated with glecaprevir-pibrentasvir in the simplified (n = 253) and standard (n = 127) arms. In the intention-to-treat population, SVR12 was 92% (95% CI 89%-95%) in the simplified and 95% (95% CI 92%-99%) in the standard arm (difference between arms -3.2%; 95% CI -8.2% to 1.8%) and did not reach non-inferiority. In the per-protocol population, SVR12 was 97% (95% CI 96%-99%) in the simplified and 98% (95% CI 96%-100%) in the standard arm. No treatment-related serious adverse events were reported. CONCLUSIONS: In patients with chronic HCV infection without cirrhosis, treatment with glecaprevir-pibrentasvir was safe and effective. In comparison to standard monitoring, a simplified monitoring schedule did not achieve non-inferiority. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT03117569. LAY SUMMARY: Direct-acting antiviral (DAA) therapy for hepatitis C is highly effective and well tolerated. The SMART-C randomised trial evaluated an 8-week regimen of glecaprevir-pibrentasvir for hepatitis C treatment, using a simplified monitoring schedule that included no pathology tests or clinic visits during treatment. This simplified strategy produced a high cure rate (92%), but this was not equivalent to the standard monitoring schedule cure rate (95%).

Treating male partners of women with bacterial vaginosis (StepUp): a protocol for a randomised controlled trial to assess the clinical effectiveness of male partner treatment for reducing the risk of BV recurrence.

BACKGROUND: Bacterial vaginosis (BV) is estimated to affect 1 in 3 women globally and is associated with obstetric and gynaecological sequelae. Current recommended therapies have good short-term efficacy but 1 in 2 women experience BV recurrence within 6 months of treatment. Evidence of male carriage of BV-organisms suggests that male partners may be reinfecting women with BV-associated bacteria (henceforth referred to as BV-organisms) and impacting on the efficacy of treatment approaches solely directed to women. This trial aims to determine the effect of concurrent male partner treatment for preventing BV recurrence compared to current standard of care. METHODS: StepUp is an open-label, multicentre, parallel group randomised controlled trial for women diagnosed with BV and their male partner. Women with clinical-BV defined using current gold standard diagnosis methods (≥3 Amsel criteria and Nugent score (NS) = 4-10) and with a regular male partner will be assessed for eligibility, and couples will then be consented. All women will be prescribed oral metronidazole 400 mg twice daily (BID) for 7 days, or if contraindicated, a 7-day regimen of topical vaginal 2% clindamycin. Couples will be randomised 1:1 to either current standard of care (female treatment only), or female treatment and concurrent male partner treatment (7 days of combined antibiotics - oral metronidazole tablets 400 mg BID and 2% clindamycin cream applied topically to the glans penis and upper shaft [under the foreskin if uncircumcised] BID). Couples will be followed for up to 12 weeks to assess BV status in women, and assess the adherence, tolerability and acceptability of male partner treatment. The primary outcome is BV recurrence defined as ≥3 Amsel criteria and NS = 4-10 within 12 weeks of enrolment. The estimated sample size is 342 couples, to detect a 40% reduction in BV recurrence rates from 40% in the control group to 24% in the intervention group within 12 weeks. DISCUSSION: Current treatments directed solely to women result in unacceptably high rates of BV recurrence. If proven to be effective the findings from this trial will directly inform the development of new treatment strategies to impact on BV recurrence. TRIAL REGISTRATION: The trial was prospectively registered on 12 February 2019 on the Australian and New Zealand Clinical Trial Registry (ACTRN12619000196145, Universal Trial Number: U1111-1228-0106, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376883&isReview=true ).