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ImportanceRecent advances in treatment and prevention of HIV warrant updated recommendations to guide optimal practice.ObjectiveBased on a critical evaluation of new data, to provide clinicians with recommendations on use of antiretroviral drugs for the treatment and prevention of HIV, laboratory monitoring, care of people aging with HIV, substance use disorder and HIV, and new challenges in people with HIV, including COVID-19 and monkeypox virus infection.Evidence ReviewA panel of volunteer expert physician scientists were appointed to update the 2020 consensus recommendations. Relevant evidence in the literature (PubMed and Embase searches, which initially yielded 7891 unique citations, of which 834 were considered relevant) and studies presented at peer-reviewed scientific conferences between January 2020 and October 2022 were considered.FindingsInitiation of antiretroviral therapy (ART) is recommended as soon as possible after diagnosis of HIV. Barriers to care should be addressed, including ensuring access to ART and adherence support. Integrase strand transfer inhibitor–containing regimens remain the mainstay of initial therapy. For people who have achieved viral suppression with a daily oral regimen, long-acting injectable therapy with cabotegravir plus rilpivirine given as infrequently as every 2 months is now an option. Weight gain and metabolic complications have been linked to certain antiretroviral medications; novel strategies to ameliorate these complications are needed. Management of comorbidities throughout the life span is increasingly important, because people with HIV are living longer and confronting the health challenges of aging. In addition, management of substance use disorder in people with HIV requires an evidence-based, integrated approach. Options for preexposure prophylaxis include oral medications (tenofovir disoproxil fumarate or tenofovir alafenamide plus emtricitabine) and, for the first time, a long-acting injectable agent, cabotegravir. Recent global health emergencies, like the SARS-CoV-2 pandemic and monkeypox virus outbreak, continue to have a major effect on people with HIV and the delivery of services. To address these and other challenges, an equity-based approach is essential.Conclusions and RelevanceAdvances in treatment and prevention of HIV continue to improve outcomes, but challenges and opportunities remain.

The use of undetectable viral load (VL) to negotiate condomless anal intercourse (CLAI) in HIV serodiscordant male relationships has become more common as more data regarding the effectiveness of antiretroviral treatments for the prevention of HIV transmission has been described. We examined viral load agreements (VLAs) for condomless sex in the presence of an undetectable VL in 343 HIV serodiscordant male couples in Australia, Brazil and Thailand. Factors associated with having a VLA included having agreements for the HIV-positive partner to report his VL result (p

People with human immunodeficiency virus (HIV) have higher rates of certain comorbidities, particularly cardiovascular disease and cancer, than people without HIV1–5. In view of observations that somatic mutations associated with age-related clonal hematopoiesis (CH) are linked to similar comorbidities in the general population6–10, we hypothesized that CH may be more prevalent in people with HIV. To address this issue, we established a prospective cohort study, the ARCHIVE study (NCT04641013), in which 220 HIV-positive and 226 HIV-negative participants aged 55 years or older were recruited in Australia. Demographic characteristics, clinical data and peripheral blood were collected to assess the presence of CH mutations and to identify potential risk factors for and clinical sequelae of CH. In total, 135 CH mutations were identified in 100 (22.4%) of 446 participants. CH was more prevalent in HIV-positive participants than in HIV-negative participants (28.2% versus 16.8%, P = 0.004), overall and across all age groups; the adjusted odds ratio for having CH in those with HIV was 2.16 (95% confidence interval 1.34–3.48, P = 0.002). The most common genes mutated overall were DNMT3A (47.4%), TET2 (20.0%) and ASXL1 (13.3%). CH and HIV infection were independently associated with increases in blood parameters and biomarkers associated with inflammation. These data suggest a selective advantage for the emergence of CH in the context of chronic infection and inflammation related to HIV infection. In a prospective cohort study, HIV-positive participants have a higher incidence of clonal hematopoiesis than HIV-negative ones, implicating clonal hematopoiesis in the increased risks of individuals with HIV for malignancy and cardiovascular disease.

Background Markers of HIV disease severity are associated with increased liver fibrosis in HIV/Hepatitis C virus (HCV) co-infected individuals. HCV treatment may reverse liver fibrosis, but evidence among HIV/HCV-coinfected populations and the impact of HIV parameters on fibrosis regression is limited. We aimed to assess the influence of surrogate markers of HIV-infection and other determinants of liver stiffness before hepatitis C virus (HCV) treatment and changes after HCV cure in people living with HIV (PLHIV). Methods We used data from an HCV treatment implementation study aiming for HCV micro-elimination among gay and bisexual men with HIV in Melbourne, Australia (co-EC Study). We obtained liver stiffness measurements (LSM) before and after direct-acting antiviral treatment using transient elastography (FibroScan). Linear mixed models were used to evaluate determinants of pre-treatment LSM and changes in LSM following cure with duration in years between pre- and post-LSM assessment as main exposure variable. Results Al least one LSM was available in 173 participants, and 98 participants had two LSMs. Median pre- and post-treatment LSMs were 5.7 and 5.1 kilopascal (kPa), respectively. Median time between transient elastography measurements was 1.3 years (Interquartile range=0.9-2.1). In multivariable analysis, longer duration of known HIV infection, a lower CD4 and CD8 T-cell count and hazardous alcohol consumption were associated with higher LSM values prior to treatment initiation. Successfully treated patients had a 6% (95%CI= -10,-2%) annual decrease (0.34 kPa predicted decrease) in LSM following cure. Changes in LSM values did not depend on any of the pre-treatment HIV markers or other factors. Conclusion Low levels of liver stiffness were observed prior to treatment initiation and a small decrease (6%) in LSM following HCV cure in PLHIV. No clear predictors affecting change in LSM following cure were found in this study, including markers of HIV infection. However, markers of advanced HIV immunodeficiency and hazardous alcohol consumption remained associated with higher LSM values even after HCV cure.

Rapid scale-up of preexposure prophylaxis resulted in a redistribution of human immunodeficiency virus and sexually transmitted infection testing across services in Victoria, Australia and did not negatively impact testing among gay and bisexual and other men who have sex with men not using preexposure prophylaxis., Objective Scale-up of human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP) has raised concerns regarding its impact on clinic capacity and access to HIV testing. We describe enrolment in PrEPX, a large PrEP implementation study in Victoria, Australia, and the impact of PrEP uptake and maintenance on existing health services. Methods We describe enrolment between July 26, 2016, and March 31, 2018, and trends in HIV testing among PrEPX participating and nonparticipating gay and bisexual and other men who have sex with men (GBM) at 5 study clinics participating in a sentinel surveillance system (ACCESS). We evaluated HIV and STI testing trends using segmented linear regression across the prestudy (January 2015 to June 2016) and PrEPX study (July 2016 to March 2018) periods. Findings There were 2,049 individuals who registered interest in study participation: 72% enrolled into the study. Study clinics enrolled participants rapidly; of 4265 people enrolled in PrEPX (98% GBM), 1000 enrolled by week 3, 88% (n = 876) of whom enrolled at ACCESS sites. Prestudy period HIV testing rates were increasing at all ACCESS sites. In the month PrEPX commenced, there was an additional 247 HIV tests among PrEPX participants (P < 0.01) and no significant change among non-PrEPX GBM (P = 0.72). Across the study period, HIV testing increased by 7.2 (P < 0.01) and 8.9 (P < 0.01) tests/month among PrEPX participants and non-PrEPX GBM, respectively. The HIV testing increased among non-PrEPX GBM at sexual health clinics (18.8 tests/month, P < 0.01) and primary care clinics (7.9 tests/month, P < 0.01). Similar trends were observed across testing for all measured STIs. Conclusions Rapid PrEP scale-up is possible without a reduction in HIV testing among GBM not using PrEP.

OBJECTIVE People living with HIV have an increased risk of cardiovascular disease (CVD) despite effective antiretroviral therapy (ART). Monocytes play a key role in the early stages of atherosclerosis-driven CVD by forming lipid-laden foam cells within artery walls. HIV infection potentiates foam cell formation ex vivo, but the mechanisms contributing to this are not known. METHODS We investigated the atherosclerosis-promoting potential of monocytes from 39 virologically suppressed men living with HIV (MLHIV) on ART and no evidence of CVD, and 25 HIV-uninfected controls of comparable age, sex, smoking status and CVD risk. RESULTS Despite absence of clinical atherosclerosis in both MLHIV and uninfected cohorts (evidenced by a carotid intima-media thickness of 0.6 mm for both groups; P = 0.254), monocytes from MLHIV showed increased potential to form atherosclerosis-promoting foam cells compared with controls in an ex-vivo assay (36.6% vs. 27.6%, respectively, P = 0.003). Consistent with observations of persistent inflammation and immune/endothelial activation in ART-treated HIV infection, levels of soluble tumour necrosis factor receptor II, CXCL10 and soluble VCAM-1 were elevated in MLHIV (P ≤ 0.005 for all), but were not significantly associated with foam cell formation. Foam cell formation was associated with an impaired ability of monocytes to undergo reverse transmigration, and a reduced ability to efflux cholesterol ex vivo (P

BACKGROUND In Australia, one-third of human immunodeficiency virus (HIV) diagnoses occur late, with an estimated 11% of people with HIV unaware of their diagnosis. Undiagnosed and untreated HIV infection increases morbidity in the HIV positive person and allows onward transmission of HIV. AIM To determine the rate of HIV testing in acute general medicine patients with HIV indicator conditions (IC) and evaluate the effectiveness of an educational intervention in improving testing rates. METHODS Single-centre, tertiary hospital, before-after study of general medicine inpatients with IC for 12 weeks prior and 10 weeks post an educational intervention focusing on recommendations for HIV testing including IC. The REASON Cohort Discovery Tool was used to search for the IC using ICD-10 codes and laboratory data. The presence of IC was estimated, and HIV testing rates before and after the intervention were compared. Regression analysis was utilised to identify characteristics associated with HIV testing. RESULTS Of 1414 admissions in the baseline period and 946 in the post-period, 161 (11.4%) and 132 (14.0%) had at least one IC present respectively. There were 18 (11.2%) HIV tests performed for admissions with IC in the pre-period which increased to 27 (20.5%) (P = 0.028) in the post-period. Younger patients were more likely to be tested and regression analysis identified the educational intervention (adjusted odds ratio) 2.2 (1.1, 4.4) to be significantly associated with testing. CONCLUSIONS Although HIV testing rates for IC doubled following the intervention, they remained unacceptably low. The recently introduced electronic medical record presents opportunities to prompt HIV testing.

Antiretroviral (ARV) side effects are a critical determinant of adherence among people living with HIV (PLWH). Integrase strand transfer inhibitors (INSTIs), a commonly used ARV, have been reported to cause weight gain. We determined the relative importance of weight gain compared with other side effects from the perspective of PLWH.Melbourne Sexual Health Centre and the Alfred Hospital in Victoria, Australia.We conducted a discrete choice experiment survey to explore PLWH's preferences for 8 short-term side effects (eg, weight gain and depression) and 4 long-term side effects (eg, long-term weight gain and risks of heart attack). We sent an anonymous survey link through short message service (SMS) and postcards to PLWH attending both centers between July and August 2021. The choice data were analyzed using random parameter logit (RPL) and latent class (LCM) models.Three hundred thirty-five respondents were included: most were male (88.1%). In the RPL analyses, weight gain was the second most important attribute after depression for short-term side effects and the third most important attribute after risk of heart attack and kidney problem for long-term side effects. In the LCM analyses, 23.9% were most sensitive to short-term weight gain, whereas 16.0% were most sensitive to long-term weight gain.Weight gain was the second most important short-term side effect and the third most important long-term side effect in a cohort of Australian PLWH. However, weight gain was the most important side effect of ARV for a significant minority.

ObjectiveGonorrhoea transmission between men is currently thought to occur primarily to and from the urethra. Transmission without urethral involvement, from throat-to-throat and throat-to-anus, is considered to be uncommon. Using gonorrhoea results from male couples, we aimed to investigate the transmission dynamics of gonorrhoea. If current medical consensus is correct, then most throat and anal infections should be explained by the partner’s urethral infection.MethodsThis is a cross-sectional analysis of gonorrhoea diagnosed by nucleic acid amplification tests in both partners in male couples who attended Melbourne Sexual Health Centre together between March 2015 and June 2017. Isolates obtained from culture-positive infections underwent whole genome sequencing to assess phylogenetic relatedness between partners.ResultsIn all 60 couples (120 men) at least one partner had gonorrhoea, and isolates had very high phylogenetic relatedness between partners. After excluding men with urethral gonorrhoea, among 32 men with anal gonorrhoea, 34% (95% CI 19% to 53 %) had a partner with throat gonorrhoea. After excluding couples where either man had urethral gonorrhoea, among 48 couples in which at least one man had throat gonorrhoea, in 23% (95% CI 12% to 37 %) of couples both men had throat gonorrhoea.ConclusionsThe observed gonorrhoea positivity when urethral infection is absent supports a new paradigm of gonorrhoea transmission, where the throat is a major source of gonorrhoea transmission between men, through tongue kissing, oroanal sex and saliva use as anal lubricant. Public health messages may need to address the risk of saliva exposure during sex.

Background The incidence of end-stage organ disease in people living with HIV (PLWH) is increasing, as people live longer due to potent, tolerable antiretroviral therapy. Consequently, the number of PLWH who would benefit from solid organ transplant (SOT) is rising. Solid organ transplantation experience in PLWH in Australia remains limited. The aim of this study was to retrospectively review the outcomes for SOT in PLWH in Victoria, Australia. Methods A retrospective cohort study of PLWH undergoing SOT over a 15-year period was performed. Adult PLWH over 18 years of age were eligible and identified from the Victorian HIV Service database. Descriptive statistics were used to summarise baseline demographics and clinical data, and outcomes following SOT. Results Nine virologically-suppressed PLWH underwent SOT from HIV-negative donors; 5 kidneys, 2 livers, and 2 bilateral sequential lung transplants. All patients were male, with a median age of 57.3 years (IQR 54.3-60.1), CD4 count of 485 (IQR 342-835) at transplantation, and comorbidities were common at baseline. After a median follow up of 3.9 years (IQR 2.7-7.6), 8 (89%) patents were alive, 7 (78%) had functioning grafts, though 5 (56%) experienced organ rejection. Infections were common. Two patients required modification to their antiretroviral therapy due to significant drug-drug interactions, prior to transplant, while 5 (56%) had modifications post-SOT. No patients experienced HIV virologic failure. Conclusion PLWH with end-stage organ disease experience good clinical and functional outcomes, and should be considered for SOT where indicated. However, multidisciplinary planning and care is essential to optomise care in this patient group. This article is protected by copyright. All rights reserved.

As of January 12, 2021, Australia has reported 28,634 COVID-19 cases. Most (20,411) cases are from the state of Victoria. In response to rising infections and community transmission in July 2020, on August 2nd, several restrictions were imposed for the following 111 days, including an 8pm curfew, a travel restriction to 5 km from home, and closure of nonessential services. It is unknown how this affected people living with HIV (PLHIV), who already experience disproportionate levels of mental health issues, comorbidity, and stigma. An online survey was designed with HIV community-based organizations to investigate the impact of the pandemic on Victorian PLHIV. Participants were recruited voluntarily both through social media and Infectious Diseases clinics at participating hospitals. There were 153 respondents. Most were male (77%), aged between 30 and 60 years (77%), and Australian-born (63%). Forty-three percent, 31%, and 25% reported negative impacts upon personal relationships, employment, and income, respectively. HIV care continued with 95% and 98% being able to access their HIV provider and antiretroviral therapy (ART), respectively. Telehealth was used by 92% and was largely well received. PLHIV reported worry about physical health (68%), mental health (66%), finances (50%),z and accommodation (25%). Fifty percent of participants reported weight gain and 27% increased alcohol intake. This study demonstrated the widespread negative effects of the COVID-19 pandemic on PLHIV in Victoria, although provision of HIV care and ART continued uninterrupted. This highlighted the importance of mental health support and social welfare programs during times of health care and societal strain.

People living with HIV-1 (PLHIV) are at increased risk for cardiovascular disease. OBJECTIVE This study aimed to determine if PLHIV would benefit from starting statins at a lower threshold than currently recommended in the general population. DESIGN A double-blind multicentre, randomised, placebo-controlled trial was performed. METHODS Participants (n = 88) with well controlled HIV, at moderate cardiovascular risk (Framingham score of 10-15%), and not recommended for statins were recruited from Australia and Switzerland. They were randomised 1:1 to rosuvastatin (n = 44) 20 mg daily, 10 mg if co-administered with ritonavir/cobicistat-boosted antiretroviral therapy, or placebo (n = 40) for 96 weeks. Assessments including fasting blood collection and carotid intima media thickness (CIMT) were performed at baseline, and weeks 48 and 96. The primary outcome was the change from baseline to week 96 in CIMT. (clinicaltrials.gov:NCT01813357) RESULTS:: Participants were predominantly male (82 (97·6%)); mean age 54 years (SD 6·0). At 96 weeks there was no difference in the progression of CIMT between the rosuvastatin (mean 0·004 mm, SE 0·0036) and placebo (0·0062 mm, SE 0·0039) arms (p value = 0·684), leading to no difference in CIMT levels between groups at week 96 (rosuvastatin arm, 0·7232 mm (SE 0·030); placebo arm 0·7785 mm (SE 0·032), p = 0·075).Adverse events were common (n = 146) and predominantly in the rosuvastatin arm (108 [73·9%]). Participants on rosuvastatin were more likely to cease study medication due to an adverse event (7 [15.9%] vs 2 [5·0%], p = 0.011). CONCLUSIONS In PLHIV statins prescribed at a lower threshold than guidelines did not lead to improvements in CIMT but was associated with significant adverse events.

Summary Background Most studies assessing the HIV care cascade have typically been cross-sectional analyses, which do not capture the transition time to subsequent stages. We aimed to assess the longitudinal HIV cascade of care in Australia, and changes over time in transition times and associated factors. Methods In this longitudinal cohort study, we included linked data for gay and bisexual men (GBM) with a new HIV diagnosis who attended clinics participating in the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance in New South Wales and Victoria between Jan 1, 2012, and Dec 31, 2019. We assessed three cascade transition periods: diagnosis to linkage to care (stage 1 transition); linkage to care to antiretroviral therapy (ART) initiation (stage 2 transition); and ART initiation to virological suppression (viral load ≤200 copies per mL; stage 3 transition). We also calculated the probability of remaining virologically suppressed after the first recorded viral load of less than 200 copies per mL. We used the Kaplan-Meier method to estimate transition times and cumulative probability of stage transition. Findings We included 2196 GBM newly diagnosed with HIV between 2012 and 2019 contributing 6747 person-years of follow-up in our analysis. Median time from HIV diagnosis to linkage to care (stage 1 transition) was 2 days (IQR 1–3). Median time from linkage to care to ART initiation (stage 2 transition) was 33 days (30–35). Median time from ART initiation to first recorded virological suppression (stage 3 transition) was 49 days (47–52). The cumulative probability of ART initiation within 90 days of linkage to care increased from 36·9% (95% CI 32·9–40·6) in the 2012–13 calendar period to 94·1% (91·2–96·0) in the 2018–19 calendar period and cumulative probability of virological suppression within 90 days of ART initiation increased from 54·3% (48·8–59·3) in the 2012–13 calendar period to 82·9% (78·4–86·4) in the 2018–19 calendar period. 91·6% (90·1–93·1) of GBM remained virologically supressed up to 2 years after their first recorded virological suppression event. Interpretation In countries with high cross-sectional cascade estimates such as Australia, the impact of treatment as prevention is better estimated using longitudinal cascade analyses. Funding National Health and Medical Research Council Australia.

Background Weight gain effects of individual antiretroviral drugs are not fully understood. We investigated associations between a prespecified clinically significant increase (>7%) in body-mass index (BMI) and contemporary antiretroviral use. Methods The International Cohort Consortium of Infectious Diseases (RESPOND) is a prospective, multicohort collaboration, including data from 17 well established cohorts and over 29 000 people living with HIV. People with HIV under prospective follow-up from Jan 1, 2012, and older than 18 years were eligible for inclusion. Each cohort contributed a predefined minimum number of participants related to the size of the specific cohort (with a minimum of 1000 participants). Participants were required to have CD4 cell counts and HIV viral load measurement in the 12 months before or within 3 months after baseline. For all antiretroviral drugs received at or after RESPOND entry, changes from pre-antiretroviral BMI levels (baseline) were considered at each BMI measurement during antiretroviral treatment. We used logistic regression to identify individual antiretrovirals that were associated with first occurrence of a more than 7% increase in BMI from pre-antiretroviral BMI. We adjusted analyses for time on antiretrovirals, pre-antiretroviral BMI, demographics, geographical region, CD4 cell count, viral load, smoking status, and AIDS at baseline. Findings 14 703 people were included in this study, of whom 7863 (53middot5%) had a more than 7% increase in BMI. Compared with lamivudine, use of dolutegravir (odds ratio [OR] 1middot27, 95% CI 1middot17-1middot38), raltegravir (1middot37, 1middot20-1middot56), and tenofovir alafenamide (1middot38, 1middot22-1middot35) was significantly associated with a more than 7% BMI increase, as was low pre-antiretroviral BMI (2middot10, 1middot91-2middot31 for underweight vs healthy weight) and Black ethnicity (1middot61, 1middot47-1middot76 vs White ethnicity). Higher CD4 count was associated with a reduced risk of BMI increase (0middot97, 0middot96-0middot98 per 100 cells per mu L increase). Relative to lamivudine, dolutegravir without tenofovir alafenamide (OR 1middot21, 95% CI 1middot19-1middot32) and tenofovir alafenamide without dolutegravir (1middot33, 1middot15-1middot53) remained independently associated with a more than 7% increase in BMI; the associations were higher when dolutegravir and tenofovir alafenamide were used concomitantly (1middot79, 1middot52-2middot11, and 1middot70, 1middot44-2middot01, respectively). Interpretation Clinicians and people with HIV should be aware of associations between weight gain and use of dolutegravir, tenofovir alafenamide, and raltegravir, particularly given the potential consequences of weight gain, such as insulin resistance, dyslipidaemia, and hypertension. Funding The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands national observational HIV cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The ICONA Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort and The University of Cologne HIV Cohorts, ViiV Healthcare, and Gilead Sciences. Copyright (c) 2021 Elsevier Ltd. All rights reserved.

Background Limited data exist that compare clinical outcomes of 2-drug regimens (2DRs) and 3-drug regimens (3DRs) in people living with human immunodeficiency virus. Methods Antiretroviral treatment–experienced individuals in the International Cohort Consortium of Infectious Diseases (RESPOND) who switched to a new 2DR or 3DR from 1 January 2012–1 October 2018 were included. The incidence of clinical events (AIDS, non-AIDS cancer, cardiovascular disease, end-stage liver and renal disease, death) was compared between regimens using Poisson regression. Results Of 9791 individuals included, 1088 (11.1%) started 2DRs and 8703 (88.9%) started 3DRs. The most common 2DRs were dolutegravir plus lamivudine (22.8%) and raltegravir plus boosted darunavir (19.8%); the most common 3DR was dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (46.9%). Individuals on 2DRs were older (median, 52.6 years [interquartile range, 46.7–59.0] vs 47.7 [39.7–54.3]), and a higher proportion had ≥1 comorbidity (81.6% vs 73.9%). There were 619 events during 27 159 person-years of follow-up (PYFU): 540 (incidence rate [IR] 22.5/1000 PYFU; 95% confidence interval [CI]: 20.7–24.5) on 3DRs and 79 (30.9/1000 PYFU; 95% CI: 24.8–38.5) on 2DRs. The most common events were death (7.5/1000 PYFU; 95% CI: 6.5–8.6) and non-AIDS cancer (5.8/1000 PYFU; 95% CI: 4.9–6.8). After adjustment for baseline demographic and clinical characteristics, there was a similar incidence of events on both regimen types (2DRs vs 3DRs IR ratio, 0.92; 95% CI: .72–1.19; P = .53). Conclusions This is the first large, international cohort to assess clinical outcomes on 2DRs. After accounting for baseline characteristics, there was a similar incidence of events on 2DRs and 3DRs. 2DRs appear to be a viable treatment option with regard to clinical outcomes. Further research on resistance barriers and long-term durability of 2DRs is needed.

People with human immunodeficiency virus (HIV) have higher rates of certain comorbidities, particularly cardiovascular disease and cancer, than people without HIV

Objectives Primary objective: To determine the efficacy of a candidate antiviral on time to virological cure compared to standard of care within 14 days of randomisation Secondary objectives: • To determine the safety of the antiviral • To determine the clinical benefit of the antiviral over placebo according to the WHO 7-point ordinal scale • To determine the clinical benefit of the antiviral over placebo on time to resolution of clinical symptoms • To determine the effect of the antiviral over placebo on biomarkers of inflammation and immune activation Trial design This is a multi-centre, triple-blind, randomised placebo controlled phase II, 2-arm trial with parallel-group design with allocation ratio 1:1. Participants Inclusion Criteria: • Provision of informed consent by the participant • Age ≥18 years • Confirmed SARS-CoV-2 by nucleic acid testing in the past 5 days • COVID-19 related symptom initiation within 5 days • Female patients of childbearing potential must have a negative pregnancy test at Screening. Female patients of childbearing potential and fertile male patients who are sexually active with a female of childbearing potential must use highly effective methods of contraception throughout the study and for 1 week following the last dose of study treatment. Exclusion criteria: • Known allergy to the study medication • Is on another clinical trial investigating an antiviral treatment for COVID-19 • Pregnancy • Patients with severe hepatic dysfunction equivalent to Grade C in the Child-Pugh classification • Patients with renal impairment requiring dialysis • Is deemed by the Investigator to be ineligible for any reason Participants will be recruited from, and the study visits will take place at Alfred Hospital, Monash Health, Austin Health in Victoria, Australia for hospitalised participants as well as recruitment in the community in participants homes for eligible people not requiring hospitalisation. Intervention and comparator The first candidate antiviral is favipiravir Arm 1: Favipiravir 1800 mg favipiravir BD on Day 1 followed by 800 mg BD favipiravir for the next 13 days. Arm 2: Placebo Main outcomes Primary outcome: Time to virological cure as defined by 2 successive throat (or combined nose/throat) swabs negative for SARS-CoV-2 by nucleic acid testing during the 14 days after enrolment. Randomisation Randomisation performed at the Alfred Hospital Clinical Trials Pharmacy using computer generated block-randomisation lists with 6 participants per block. Within each block half of the participants will be randomised to the candidate antiviral and the other half to placebo. Randomisation is stratified by study site, with participants enrolled in the community considered as a study site. Blinding (masking) Study participants, study investigators and the study statistician will be blinded to treatment allocation. Numbers to be randomised (sample size) The study aims to recruit 190 people (95/arm) with the first candidate antiviral favipiravir Trial Status Protocol version 2.0 Dated 31-Jul-2020. Recruitment will take place between July 2020 and December 2020. Trial registration clinicaltrials.gov NCT04445467 First posted 24-Jun-2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Statins may help prevent cardiovascular disease (CVD) in people with HIV (PWH) with chronic inflammation due to their pleotropic lipid lowering and anti-inflammatory properties.The impact of 48 weeks of rosuvastatin therapy on inflammation and immune activation in a double-blind, placebo-controlled trial in PWH at moderate CVD risk was assessed.Rosuvastatin not alter plasma levels of IL-6, soluble (s)TNF-RII, CXCL10, sCD14 or sVCAM-1 (p≥0.1 for all). Proportions of CD16 + monocyte subsets were increased in PWH receiving rosuvastatin.The potential benefits of statin use in PWH with normal lipid levels requires further clinical outcome research.

Importance Data on the use of antiretroviral drugs, including new drugs and formulations, for the treatment and prevention of HIV infection continue to guide optimal practices. Objective To evaluate new data and incorporate them into current recommendations for initiating HIV therapy, monitoring individuals starting on therapy, changing regimens, preventing HIV infection for those at risk, and special considerations for older people with HIV. Evidence Review New evidence was collected since the previous International Antiviral (formerly AIDS) Society–USA recommendations in 2018, including data published or presented at peer-reviewed scientific conferences through August 22, 2020. A volunteer panel of 15 experts in HIV research and patient care considered these data and updated previous recommendations. Findings From 5316 citations about antiretroviral drugs identified, 549 were included to form the evidence basis for these recommendations. Antiretroviral therapy is recommended as soon as possible for all individuals with HIV who have detectable viremia. Most patients can start with a 3-drug regimen or now a 2-drug regimen, which includes an integrase strand transfer inhibitor. Effective options are available for patients who may be pregnant, those who have specific clinical conditions, such as kidney, liver, or cardiovascular disease, those who have opportunistic diseases, or those who have health care access issues. Recommended for the first time, a long-acting antiretroviral regimen injected once every 4 weeks for treatment or every 8 weeks pending approval by regulatory bodies and availability. For individuals at risk for HIV, preexposure prophylaxis with an oral regimen is recommended or, pending approval by regulatory bodies and availability, with a long-acting injection given every 8 weeks. Monitoring before and during therapy for effectiveness and safety is recommended. Switching therapy for virological failure is relatively rare at this time, and the recommendations for switching therapies for convenience and for other reasons are included. With the survival benefits provided by therapy, recommendations are made for older individuals with HIV. The current coronavirus disease 2019 pandemic poses particular challenges for HIV research, care, and efforts to end the HIV epidemic. Conclusion and Relevance Advances in HIV prevention and management with antiretroviral drugs continue to improve clinical care and outcomes among individuals at risk for and with HIV.

The accelerated agenda of COVID-19 research will benefit the future of HIV testing, treatment, and prevention There will be a continued expansion of the research infrastructure needed to work with both viruses, specifically high containment laboratories and animal facilities Diagnostic, antiviral, and vaccine companies are involved in COVID-19 research, including companies that have not previously engaged in viral infectious disease Given the scale of testing needed in the COVID-19 pandemic, the introduction of testing capabilities in LMICs could also be used for HIV and tuberculosis These overlapping epidemics represent an opportunity to extend cross-disciplinary research into the integrated service delivery for HIV, tuberculosis, and COVID-19, and aim to achieve sustained benefits of prevention and treatment Finally, the accelerated pathways to develop COVID-19 vaccines resulting in clinical trials of multiple candidates within months of discovery of SARS-CoV-2 should be applied to challenges such as developing an HIV vaccine Arguably, the most important lesson of the HIV response is that no country could go it alone in bringing this deadly virus to its current state of a chronic treatable condition We need to heed this lesson to avoid nationalistic responses that jeopardise global access to solutions and cannot succeed against a global pandemic

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.

Background Frailty is associated with mortality and morbidity in the general geriatric population, but less is known about its impact among the aging but generally younger population with human immunodeficiency virus (HIV). Methods The impact of frailty on all-cause mortality during 6 years of follow-up and incident comorbidity during 4 years of follow-up was assessed among 598 HIV-positive and 550 comparable HIV-negative participants aged ≥ 45 years of the AGEhIV Cohort Study. Frailty encompasses 5 domains; weight loss, low physical activity, exhaustion, decreased grip strength, and slow gait speed. Presence of ≥ 3 denotes frailty, 1–2 prefrailty, and 0 robust. Multivariable Cox and logistic regression models were used to assess the independent relationships of frailty with both outcomes, adjusting for HIV infection and traditional risk factors. Results At baseline, 7.5% (n = 86) of participants were frail. During follow-up, 38 participants died. Mortality rate was significantly higher among frail participants: 25.7/1000 person-years of follow-up (PYFU) (95% confidence interval [CI], 14.2–46.4) compared with prefrail (7.2/1000 PYFU [95% CI, 4.7–11.2]) and robust (2.3/1000 PYFU [95% CI, 1.1–4.9]). In fully adjusted analyses, frailty remained strongly associated with death (hazard ratio, 4.6 [95% CI, 1.7–12.5]) and incident comorbidity (odds ratio, 1.9 [95% CI, 1.1–3.1]). No interactions were observed between frailty and HIV status in all analyses. Conclusions Frailty is a strong predictor of both mortality and incident comorbidity independent from other risk factors. Clinical Trials Registration NCT01466582., Frailty was a strong predictor of mortality and incident comorbidity in our HIV-positive and HIV-negative participants who, although aging, were not yet considered of geriatric age. Moreover, frailty impacted the risk of these outcomes independently from other recognized risk factors.

Integrase strand transfer inhibitor-based antiretroviral therapy can cause weight gain. It is unknown if this is a class effect, with limited data regarding raltegravir. In 37 virologically suppressed adults (36 men, mean age 49 years) who switched from tenofovir disoproxil fumarate to raltegravir 400 mg twice daily, mean weight changes from baseline at weeks 24, 48 and 96 were not significant (maximum 0.8 kg at week 24; all P ≥ 0.16). Weight gain may not occur with all integrase strand transfer inhibitors.

OBJECTIVE To compare the effects of switching tenofovir disoproxil fumarate (TDF) or treatment with an intravenous bisphosphonate on bone mineral density (BMD) in HIV-positive adults with low bone mass. DESIGN Two-year, randomized, open-label study at 10 sites in Australia and Spain. PARTICIPANTS Of 112 adults on TDF-based antiretroviral therapy (ART) screened, 87 with low BMD (T-score

Chronic immune activation persists despite antiretroviral therapy (ART) in HIV+ individuals and underpins an increased risk of age-related co-morbidities. We assessed the Frailty Index in older HIV+ Australian men on ART. Immunometabolic markers on monocytes and T cells were analyzed using flow cytometry, plasma innate immune activation markers by ELISA, and lipidomic profiling by mass spectrometry. The study population consisted of 80 HIV + men with a median age of 59 (IQR, 56–65), and most had an undetectable viral load (92%). 24% were frail, and 76% were non-frail. Frailty was associated with elevated Glucose transporter-1 (Glut1) expression on the total monocytes (p = 0.04), increased plasma levels of innate immune activation marker sCD163 (OR, 4.8; CI 1.4–15.9, p = 0.01), phosphatidylethanolamine PE(36:3) (OR, 5.1; CI 1.7–15.5, p = 0.004) and triacylglycerol TG(16:1_18:1_18:1) (OR, 3.4; CI 1.3–9.2, p = 0.02), but decreased expression of GM3 ganglioside, GM3(d18:1/18:0) (OR, 0.1; CI 0.0–0.6, p = 0.01) and monohexosylceramide HexCerd(d18:1/22:0) (OR, 0.1; CI 0.0–0.5, p = 0.004). There is a strong inverse correlation between quality of life and the concentration of PE(36:3) (ρ = − 0.33, p = 0.004) and PE(36:4) (ρ = − 0.37, p = 0.001). These data suggest that frailty is associated with increased innate immune activation and abnormal lipidomic profile. These markers should be investigated in larger, longitudinal studies to determine their potential as biomarkers for frailty., Highlights • Frailty in older HIV + men is associated with heightened monocyte glycolytic metabolism and innate immune activation. • Lipid classes including phosphatidylethanolamine, GM3 ganglioside and monohexosylceramide are dysregulated in frailty. • Reduced quality of life in aging HIV + men is associated with monocyte glycolytic metabolism and plasma lipid dysregulation. Despite the achievement of long-term survival, people living with HIV have higher rates of age-related comorbidities and frailty (low physiological reserve) compared to their HIV-negative counterparts, for reasons that are currently unknown. We found that immune cells (monocytes) from frail individuals may be incapable of using glucose efficiently, leading to immune dysfunction. Furthermore, we identified a group of lipids in the blood that is associated with frailty. These previously unrecognized factors might underpin age-related comorbidities including frailty in the aging HIV + population. This knowledge may improve our understanding, and management of the health conditions in people aging with HIV.

Both HIV infection and antiretroviral therapy (ART) are associated with lower bone mineral density (BMD) and increased fracture risk. Because the relative contributions of ART and untreated HIV to BMD loss are unclear, it is important to quantify the effect of ART on bone. We compared the effect of early ART initiation (CD4 >500 cells/μL) with deferred ART on change in BMD in the START Bone Mineral Density substudy, a randomized trial evaluating the effect of immediate ART initiation versus deferring ART (to CD4

OBJECTIVE: To determine the long-term effects of vorinostat on safety and virological parameters in HIV-infected individuals on suppressive antiretroviral therapy (ART). DESIGN: Prospective longitudinal observational extended follow-up of 20 HIV-infected individuals on ART previously enrolled in a clinical trial of daily vorinostat 400 mg for 14 days. Extended follow-up included visits at 6, 12, 18 and 24 months postenrolment in the initial clinical trial. METHODS: Cell-associated unspliced HIV RNA, total HIV DNA and plasma HIV RNA were quantified by PCR, and CD4 and CD8 T cells quantified by flow cytometry. Changes over time in each parameter were assessed using the Wilcoxon matched pair signed-rank test and generalized estimating equations for trend modelling. RESULTS: We recorded a total of 31 adverse events (26 grade 1 and five grade 2) in all study participants (n = 20). There were no significant changes in the number of CD4 or CD8 T cells or plasma HIV RNA over time. In 12 participants for whom baseline samples were available, there were no significant changes in total HIV DNA, cell-associated unspliced HIV RNA, plasma RNA or CD4 and CD8 T cells at 6, 12, 18 or 24 months. CONCLUSION: Extended follow-up for 24 months did not reveal any long-term toxicity or changes in markers of HIV persistence or transcription in participants on ART who had received 14 days of vorinostat.

Summary Background Lipoatrophy is one of the most feared complications associated with the use of nucleoside or nucleotide reverse transcriptase inhibitors (N[t]RTIs). We aimed to assess soft-tissue changes in participants with HIV who had virological failure of a first-line antiretroviral (ART) regimen containing a non-nucleoside reverse transcriptase inhibitor plus two N(t)RTIs and were randomly assigned to receive a second-line regimen containing a boosted protease inhibitor given with either N(t)RTIs or raltegravir. Methods Of the 37 sites that participated in the randomised, open-label, non-inferiority SECOND-LINE study, eight sites from five countries (Argentina, India, Malaysia, South Africa, and Thailand) participated in the body composition substudy. All sites had a dual energy x-ray absorptiometry (DXA) scanner and all participants enrolled in SECOND-LINE were eligible for inclusion in the substudy. Participants were randomly assigned (1:1), via a computer-generated allocation schedule, to receive either ritonavir-boosted lopinavir plus raltegravir (raltegravir group) or ritonavir-boosted lopinavir plus two or three N(t)RTIs (N[t]RTI group). Randomisation was stratified by site and screening HIV-1 RNA. Participants and investigators were not masked to group assignment, but allocation was concealed until after interventions were assigned. DXA scans were done at weeks 0, 48, and 96. The primary endpoint was mean percentage and absolute change in peripheral limb fat from baseline to week 96. We did intention-to-treat analyses of available data. This substudy is registered with ClinicalTrials.gov, number NCT01513122. Findings Between Aug 1, 2010, and July 10, 2011, we recruited 211 participants into the substudy. The intention-to-treat population comprised 102 participants in the N(t)RTI group and 108 participants in the raltegravir group, of whom 91 and 105 participants, respectively, reached 96 weeks. Mean percentage change in limb fat from baseline to week 96 was 16·8% (SD 32·6) in the N(t)RTI group and 28·0% (37·6) in the raltegravir group (mean difference 10·2%, 95% CI 0·1–20·4; p=0·048). Mean absolute change was 1·04 kg (SD 2·29) in the N(t)RTI group and 1·81 kg (2·50) in the raltegravir group (mean difference 0·6, 95% CI −0·1 to 1·3; p=0·10). Interpretation Our findings suggest that for people with virological failure of a first-line regimen containing efavirenz plus tenofovir and lamivudine or emtricitabine, the WHO-recommended switch to a ritonavir-boosted protease inhibitor plus zidovudine (a thymidine analogue nucleoside reverse transcriptase inhibitor) and lamivudine might come at the cost of peripheral lipoatrophy. Further study could help to define specific groups of people who might benefit from a switch to an N(t)RTI-sparing second-line ART regimen. Funding The Kirby Institute and the Australian National Health and Medical Research Council.

Importance Emerging evidence suggests that risk of bacterial sexually transmitted infections (STIs) increases among gay and bisexual men following initiation of HIV preexposure prophylaxis (PrEP). Objective To describe STI incidence and behavioral risk factors among a cohort of predominantly gay and bisexual men who use PrEP, and to explore changes in STI incidence following PrEP commencement. Design, Setting, and Participants The Pre-exposure Prophylaxis Expanded (PrEPX) Study, a multisite, open-label intervention study, was nested within the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance (ACCESS) clinic network. A total of 4275 participants were enrolled (July 26, 2016–April 1, 2018) in Victoria, Australia. Of these, 2981 enrolled at 5 ACCESS clinics (3 primary care, 1 sexual health, and 1 community-based HIV rapid testing service), had at least 1 follow-up visit, and were monitored until April 30, 2018. Exposures Upon enrollment, participants received daily oral tenofovir disoproxil fumurate and emtricitabine for HIV PrEP, quarterly HIV and STI testing, and clinical monitoring. Main Outcomes and Measures The primary outcome was incidence of chlamydia, gonorrhea, or syphilis. Incidence rates and hazard ratios describing behavioral risk factors of STI diagnosis were calculated. Incidence rate ratios (IRRs), adjusted for change in testing frequency, described changes in STI incidence from 1-year preenrollment to study follow-up among participants with preenrollment testing data (n = 1378). Results Among the 2981 individuals (median age, 34 years [interquartile range, 28-42]), 98.5% identified as gay or bisexual males, 29% used PrEP prior to enrollment, 89 (3%) withdrew and were censored at date of withdrawal, leaving 2892 (97.0%) enrolled at final follow-up. During a mean follow-up of 1.1 years (3185.0 person-years), 2928 STIs were diagnosed among 1427 (48%) participants (1434 chlamydia, 1242 gonorrhea, 252 syphilis). STI incidence was 91.9 per 100 person-years, with 736 participants (25%) accounting for 2237 (76%) of all STIs. Among 2058 participants with complete data for multivariable analysis, younger age, greater partner number, and group sex were associated with greater STI risk, but condom use was not. Among 1378 participants with preenrollment testing data, STI incidence increased from 69.5 per 100 person-years prior to enrollment to 98.4 per 100 person-years during follow-up (IRR, 1.41 [95% CI, 1.29-1.56]). After adjusting for testing frequency, the increase in incidence from 1 year preenrollment to follow-up was significant for any STI (adjusted IRR, 1.12 [95% CI, 1.02-1.23]) and for chlamydia (adjusted IRR, 1.17 [95% CI, 1.04-1.33]). Conclusions and Relevance Among gay and bisexual men using PrEP, STIs were highly concentrated among a subset, and receipt of PrEP after study enrollment was associated with an increased incidence of STIs compared with preenrollment. These findings highlight the importance of frequent STI testing among gay and bisexual men using PrEP.

Introduction There are few data about the range of strategies used to prevent sexual HIV transmission within gay male serodiscordant couples. We examined HIV prevention strategies used by such couples and compared differences between countries. Methods Opposites Attract was a cohort study of male serodiscordant couples in Australia, Brazil and Thailand, from May 2014 (Australia) or May 2016 (Brazil/Thailand) to December 2016. At visits, HIV‐positive partners had viral load (VL) tested; HIV‐negative partners reported sexual behaviour and perceptions of their HIV‐positive partner's VL results. Within‐couple acts of condomless anal intercourse (CLAI) were categorized by strategy: condom‐protected, biomedically protected (undetectable VL and/or pre‐exposure prophylaxis [PrEP]), or not protected by either (HIV‐negative partners engaging in insertive CLAI, receptive CLAI with withdrawal, or receptive CLAI with ejaculation). Results A total of 343 couples were included in this analysis (153 in Australia, 93 in Brazil and 97 in Thailand). Three‐quarters of HIV‐positive partners were consistently virally suppressed (

Men who have sex with men living with human immunodeficiency virus have a high risk of anal cancer. We estimate the likely benefit of human papillomavirus (HPV) vaccination among participants of the Anal Cancer Examination study.Anal swabs were collected for the detection and genotyping of anal HPV DNA by linear array (Roche Diagnostics) in this 2-year multicenter prospective cohort. We calculated the proportion of men, stratified by age, without detectable vaccine type-specific DNA.Overall, 255 men, with a median age of 50 years (interquartile range, 44-56 years) contributed 488.9 person-years of follow-up. After 2 years of follow-up, 149 (58%; 95% confidence interval [CI], 52-65) had at least 1 high-risk HPV (HRHPV), and 71 (28%, 95% CI, 22-34) had HPV types 16/18 detected. Assuming that DNA-negative men would receive vaccine protection, vaccination at baseline could potentially prevent HRHPV infection in 10.2% of men (95% CI, 6.8-14.6, 26 of 255) 2 years later from incident HRHPV covered by the bivalent and quadrivalent vaccine, and 29.4% of men (95% CI, 23.9-35.4, 75/255) from incident HRHPV covered by the nonavalent vaccine.Though there is high prevalence of anal HPV in men who have sex with men living with human immunodeficiency virus, there was also a high incidence of HRHPV vaccine types in the 2-year follow-up, indicating potential for prevention if these men were not previously infected with HPV vaccine types and were vaccinated at their baseline visit.