Combination anti-HIV antibodies provide sustained virological suppression.

Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV)1. However, eradication of the virus in individuals with HIV has not been possible to date2. Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication3. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.

Persistence on oral pre-exposure prophylaxis (PrEP) among female sex workers in eThekwini, South Africa, 2016-2020.

BACKGROUND: Despite the established efficacy of PrEP to prevent HIV and the advantages of a user-controlled method, PrEP uptake and persistence by women in both trials and demonstration projects has been suboptimal. We utilized real-world data from an HIV service provider to describe persistence on oral PrEP among female sex workers (FSW) in eThekwini, South Africa. METHODS: We examined time from PrEP initiation to discontinuation among all FSW initiating PrEP at TB HIV Care in eThekwini between 2016-2020. We used a discrete time-to-event data setup and stacked cumulative incidence function plots, displaying the competing risks of 1) not returning for PrEP, 2) client discontinuation, and 3) provider discontinuation. We calculated hazard ratios using complementary log-log regression and sub-hazard ratios using competing risks regression. RESULTS: The number of initiations increased each year from 155 (9.3%, n = 155/1659) in 2016 to 1224 (27.5%, n = 1224/4446) in 2020. Persistence 1-month after initiation was 53% (95% CI: 51%-55%). Younger women were more likely to discontinue PrEP by not returning compared with those 25 years and older. Risk of discontinuation through non-return declined for those initiating in later years. Despite the COVID-19 pandemic, a greater number of initiations and sustained persistence were observed in 2020. CONCLUSIONS: Low levels of PrEP persistence were observed, consistent with data among underserved women elsewhere. Encouragingly, the proportion of women persisting increased over time, even as the number of women newly initiating PrEP and staff workload increased. Further research is needed to understand which implementation strategies the program may have enacted to facilitate these improvements and what further changes may be necessary.

Brief Report: Impact of the COVID-19 Pandemic on Virological Suppression in People Living With HIV Attending a Large Italian HIV Clinic.

BACKGROUND: We assessed the impact of the coronavirus disease 2019 (COVID-19) pandemic on HIV suppression rates in people living with HIV (PLWH) attending a large Italian HIV clinic. SETTING: The HIV outpatient clinic of the Infectious Diseases Department of Luigi Sacco Hospital, Milan, Italy, which serves more than 5000 PLWH per year. METHODS: A before and after quasi-experimental study design was used to make a retrospective assessment of the monthly trend of HIV-RNA determinations of ≥50 among the PLWH attending our clinic, with "before" being the period from January 1, 2016 to February 20, 2020, and "after" being the period from February 21, 2020 to December 31, 2020 (the COVID-19 period). Interrupted time series analysis was used to evaluate any changes in the trend. RESULTS: During the study period, 70,349 HIV-RNA viral load determinations were made, and the percentage of HIV-RNA viral load determinations of <50 copies/mL increased from 88.4% in 2016 to 93.2% in 2020 (P < 0.0001). There was a significant monthly trend toward a decrease in the number of HIV-RNA determinations of ≥50 copies/mL before the pandemic (ß -0.084; standard error 0.015; P < 0.001), and this did not significantly change after it started (ß -0.039, standard error 0.161; P = 0.811). CONCLUSIONS: A high prevalence of viral suppression was maintained among the PLWH referring to our clinic, despite the structural barriers raised by the COVID-19 pandemic. The use of simplified methods of delivering care (such as teleconsultations and multiple antiretroviral treatment prescriptions) may have contributed to preserving this continuum.

Facilitators and barriers of 2-1-1 HIV pre-exposure prophylaxis.

An alternative strategy for men who have sex with men (MSM) experiencing challenges with daily HIV pre-exposure prophylaxis (PrEP) includes 2-1-1 dosing. Understanding 2-1-1 PrEP facilitators and barriers, especially during the SARS-CoV-2 pandemic, may guide researchers and healthcare providers in future studies and clinical preparedness. We conducted a national cross-sectional study of MSM in the US who had taken 2-1-1 PrEP to examine facilitators and barriers of this on-demand PrEP dosing option. With the shelter-in-place orders in March 2020, this study was adapted to include questions on how the SARS-CoV-2 pandemic affected participants' PrEP use. A total of 140 individuals participated in the survey, 106 of which completed questions pertaining to the SARS-CoV-2 pandemic. The most common reasons for switching from once-daily to 2-1-1 PrEP included having sex less frequently (63.6%) and wanting to take fewer pills (46.4%). Participants reported high medication adherence based on each component of 2-1-1 PrEP dosing (>84%). The most common barriers with 2-1-1 PrEP dosing included unplanned sexual encounters resulting in missing the double-dose pre-sex (43.6%) and trouble remembering doses post-sex (29.3%). Facilitators of the 2-1-1 PrEP dosing strategy included reductions in sexual encounters (63.6%), preference to take fewer pills (46.4%), need to reduce cost (22.1%), and desire to reduce side effects (19.3%). Challenges to receiving PrEP services during the pandemic included obtaining laboratory testing (25.5%) and PrEP refills (either receipt of a refill authorization from a healthcare provider or processing of a refill from the pharmacy) (18.9%). 2-1-1 PrEP is an effective HIV prevention method; therefore, understanding facilitators and barriers of this dosing strategy can result in continuous provision of HIV prevention efforts, particularly during a pandemic.

Ethical issues in establishing the efficacy and safety of long-acting injectable pre-exposure prophylaxis for HIV prevention: the HPTN 083 trial.

Two multinational clinical trials have shown safety and efficacy of long-acting injectable cabotegravir for HIV pre-exposure prophylaxis (PrEP). These results will alter the landscape of HIV prevention and related research. Nevertheless, designing and conducting this research involved several ethical issues. This Viewpoint describes how we managed ethical issues over the duration of one of these trials (HPTN 083). Specifically, we discuss the rationale for pursuing a long-acting injectable agent in the presence of effective oral PrEP, trial design choices, site selection and local standards of prevention, data monitoring and early stopping, effects of the COVID-19 pandemic, post-trial access, and assessment of long-term safety.

A mixed-methods evaluation of the uptake of novel differentiated ART delivery models in a national sample of health facilities in Uganda.

INTRODUCTION: Since 2017, Uganda has been implementing five differentiated antiretroviral therapy (ART) delivery models to improve the quality of HIV care and to achieve health-system efficiencies. Community-based models include Community Client-Led ART Delivery and Community Drug Distribution Points. Facility-based models include Fast Track Drug Refill, Facility Based Group and Facility Based Individual Management. We set out to assess the extent of uptake of these ART delivery models and to describe barriers to uptake of either facility-based or community-based models. METHODS: Between December 2019 and February 2020, we conducted a mixed-methods study entailing a cross-sectional health facility survey (n = 116) and in-depth interviews (n = 16) with ART clinic managers in ten case-study facilities as well as six focus group discussions (56 participants) with patients enrolled in differentiated ART models. Facilities were selected based on the 10 geographic sub-regions of Uganda. Statistical analyses were performed in STATA (v13) while qualitative data were analysed by thematic approach. RESULTS: Most facilities 63 (57%) commenced implementation of differentiated ART delivery in 2018. Fast Track Drug Delivery was the most common facility-based model (implemented in 100 or 86% of health facilities). Community Client-Led ART Delivery was the most popular community model (63/116 or 54%). Community Drug Distribution Points had the lowest uptake with only 33 (24.88%) facilities implementing them. By ownership-type, for-profit facilities reported the lowest uptake of differentiated ART models. Barriers to enrolment in community-based models include HIV-related stigma and low enrolment of adult males in community models. CONCLUSION: To the best of our knowledge this is the first study reporting national coverage of differentiated ART delivery models in Uganda. Overall, there has been a higher uptake of facility-based models. Interventions for enhancing the uptake of differentiated ART models in for-profit facilities are recommended.

Design and challenges of a large HIV prevention clinical study on mother-to-child transmission: ANRS 12397 PROMISE-EPI study in Zambia and Burkina Faso.

Post-natal HIV infection through breastfeeding remains a challenge in many low and middle-income countries, particularly due to non-availability of alternative infant feeding options and the suboptimal Prevention of Mother to Child Transmission of HIV-1 (PMTCT) cascade implementation and monitoring. The PROMISE-EPI study aims to address the latter by identifying HIV infected mothers during an almost never-missed visit for their infant, the second extended program on immunization visit at 6-8 weeks of age (EPI-2). The study is divided into 3 components inclusive of an open-label randomized controlled trial aiming to assess the efficacy of a responsive preventive intervention compared to routine intervention based on the national PMTCT guidelines for HIV-1 uninfected exposed breastfeeding infants. The preventive intervention includes: a) Point of care testing for early infant HIV diagnosis and maternal viral load; b) infant, single-drug Pre-Exposure Prophylaxis (PrEP) (lamivudine) if mothers are virally unsuppressed. The primary outcome is HIV-transmission rate from EPI-2 to 12 months. The study targets to screen 37,000 mother/infant pairs in Zambia and Burkina Faso to identify 2000 mother/infant pairs for the clinical trial. The study design and challenges faced during study implementation are described, including the COVID-19 pandemic and the amended HIV guidelines in Zambia in 2020 (triple-drug PrEP in HIV exposed infants guided by quarterly maternal viral load). The changes in the Zambian guidelines raised several questions including the equipoise of PrEP options, the standard of care-triple-drug (control arm in Zambia) versus the study-single-drug (intervention arm). Trial registration number (www.clinicaltrials.gov): NCT03869944. Submission category: Study Design, Statistical Design, Study Protocols.

The Impact of COVID-19 on Access to HIV Prevention Services Among Opioid-Dependent Individuals.

The COVID-19 pandemic has necessitated restrictive orders and programmatic changes that may be associated with disruptions in services, including those for opioid-dependent people who inject drugs (PWID). This study aims to assess the impact of COVID-19 pandemic on access to and utilization of various HIV prevention services among PWID with opioid use disorder (OUD). We interviewed 110 PWID enrolled in medication for opioid use disorder (MOUD) treatment (e.g., methadone) between May and October, 2020 to identify if this sample experienced changed in access to the following services due to the COVID-19 pandemic: (a) HIV or sexually transmitted infection (STI) testing, (b) pre-exposure prophylaxis (PrEP) services, (c) HIV counselor or doctor appointments, and (d) clean injection equipment. A majority of the sample reported that COVID-19 had not changed their access to HIV testing or access to STI testing. Almost half of the sample reported that getting an appointment with a doctor decreased due to COVID-19. Participants reported that access to a lab or blood testing, access to injection equipment, and sessions with a case manager or counselor decreased. One-fourth of the 32 participants who were taking PrEP before the onset of COVID-19 reported that they had trouble getting their PrEP prescription due to COVID-19, and some reported that they had difficulty getting the PrEP prescription filled at their pharmacy. Our results indicate that PWID did not experience reduced access to HIV or STI testing, but difficulties in obtaining appointments with HIV counselors or doctors and limited access to PrEP were presented. Innovative strategies are needed to reduce the adverse effects of COVID-19 on HIV prevention among PWID.

Virtual HIV pre-exposure prophylaxis outpatient service in the era of COVID-19.

In the midst of the COVID-19 pandemic, health care providers have had to rapidly change how they deliver care to patients. We discuss how we are delivering a virtual HIV pre-exposure prophylaxis (PrEP) service during this time; challenges faced; challenges expected and goals for the coming months.

Consequences of the COVID-19 pandemic on the continuum of care in a cohort of people living with HIV followed in a single center of Northern Italy.

INTRODUCTION: During the COVID-19 pandemic, hospitals faced increasing pressure, where people living with HIV risked to either acquire SARS-CoV-2 and to interrupt the HIV continuum of care. METHODS: This is a retrospective, observational study. We compared the numbers of medical visits performed, antiretroviral drugs dispensed and the number of new HIV diagnosis and of hospitalizations in a cohort of people living with HIV (PLWH) followed by the Spedali Civili of Brescia between the bimester of the COVID-19 pandemic peak and the bimester of October-November 2019. Data were retrieved from administrative files and from paper and electronic clinical charts. Categorical variables were described using frequencies and percentages, while continuous variables were described using mean, median, and interquartile range (IQR) values. Means for continuous variables were compared using Student's t-tests and the Mann-Whitney test. Proportions for categorical variables were compared using the χ2 test. RESULTS: As of December 31st, 2019, a total of 3875 PLWH were followed in our clinic. Mean age was 51.4 ± 13 years old, where 28% were females and 18.8% non-Italian. Overall, 98.9% were on ART (n = 3834), 93% were viro-suppressed. A total of 1217 and 1162 patients had their visit scheduled at our out-patient HIV clinic during the two bimesters of 2019 and 2020, respectively. Comparing the two periods, we observed a raise of missed visits from 5 to 8% (p < 0.01), a reduction in the number of new HIV diagnosis from 6.4 in 2019 to 2.5 per month in 2020 (p = 0.01), a drop in ART dispensation and an increase of hospitalized HIV patients due to COVID-19. ART regimens including protease inhibitors (PIs) had a smaller average drop than ART not including PIs (16.6 vs 21.6%, p < 0.05). Whether this may be due to the perception of a possible efficacy of PIs on COVID19 is not known. CONCLUSIONS: Our experience highlights the importance of a resilient healthcare system and the need to implement new strategies in order to guarantee the continuum of HIV care even in the context of emergency.

Use of Darunavir-Cobicistat as a Treatment Option for Critically Ill Patients with SARS-CoV-2 Infection.

We retrospectively reviewed patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections who were admitted to an intensive care unit in Daegu, South Korea. The outcomes of patients who did (cases) or did not (controls) receive darunavir-cobicistat (800-150 mg) therapy were compared. Fourteen patients received darunavir-cobicistat treatment, and 96 received other antiviral therapy (controls). Overall, the darunavir-cobicistat group comprised patients with milder illness, and the crude mortality rate of all patients in the darunavir-cobicistat group was lower than that in the controls [odds ratio (OR) 0.20, 95% confidence interval (CI) 0.04-0.89, p=0.035]. After 1:2 propensity-score matching, there were 14 patients in the darunavir-cobicistat group, and 28 patients in the controls. In propensity score-matched analysis, the darunavir-cobicistat group had lower mortality than the controls (OR 0.07, 95% CI 0.01-0.52, p=0.009). In conclusion, darunavir-cobicistat therapy was found to be associated with a significant survival benefit in critically ill patients with SARS-CoV-2 infection.

Universal test and treat in relation to HIV disease progression: results from a stepped-wedge trial in Eswatini.

OBJECTIVES: Universal test and treat (UTT) is recommended for people living with HIV (PLHIV) to reduce morbidity/mortality and minimize transmission. However, concerns exist that this strategy may lead to more crowded hospitals, longer wait times and poorer service, adversely impacting health outcomes for clients with severe disease. We assessed how UTT was related to markers of disease progression in PLHIV overall and specifically among clients with low CD4 count/high World Health Organization (WHO) stage. METHODS: The analysis was conducted using data from a stepped-wedge trial of UTT in 14 government-managed health facilities in Eswatini from 2014 to 2017. Disease progression was defined as CD4 count falling below 200 cells/µL or baseline value, > 10% weight loss, body mass index (BMI) dropping below 18.5, incident tuberculosis (TB) or HIV-related death; these outcomes also were assessed individually. We assessed multivariate Cox proportional hazard models overall and specifically among clients with CD4 count < 350 cells/µL or WHO stage 3-4 at enrolment. RESULTS: Eight hundred and seven of 3176 clients demonstrated at least one marker of disease progression over 2339 person-years of follow-up. Overall, 62.4% of clients were female; 57.2% were < 35 years old. Compared to clients not exposed to UTT, those exposed to UTT had a lower rate of disease progression overall [adjusted hazard ratio (aHR) 0.60; 95% confidence interval (CI) 0.46-0.78] and a lower rate of CD4 decline (aHR 0.40; 95% CI 0.27-0.58). When the analysis was limited to clients with CD4 count < 350 cells/µL or WHO stage 3-4, UTT was not associated with disease progression (aHR 0.92; 95% CI 0.66-1.29). CONCLUSIONS: UTT reduced HIV disease progression overall and was not detrimental for clients with more severe disease.

Coronavirus disease 2019 in an orthotopic liver transplant recipient living with human immunodeficiency virus.

Coronavirus disease 2019 (COVID-19), mediated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can manifest with flu-like illness and severe pneumonia with acute respiratory distress syndrome (ARDS). Immunocompromised patients merit particular attention as altered host immunity may influence both disease severity and duration of viral shedding as is described with several other ribonucleic acid respiratory viruses. Yet immunocompromised status alone, in the absence of other comorbidities, may not necessarily predict severe illness presentations and poorer clinical outcomes as indicated by recent reports of COVID-19-infected solid organ transplant recipients and people living with human immunodeficiency virus (HIV). Such patients may even be spared the robust inflammatory response that precipitates ARDS associated with COVID-19, complicating the management of iatrogenic immunosuppression in this setting. We present a case of an orthotopic liver transplant recipient with well-controlled HIV who successfully recovered from a mild, flu-like illness attributed to SARS-CoV-2.