Perspectives on Injectable HIV Pre-Exposure Prophylaxis: A Qualitative Study of Health Care Providers in the United States.

The introduction of injectable HIV pre-exposure prophylaxis (PrEP) has the potential to significantly change the biomedical HIV prevention landscape. However, effective implementation will require health care providers to adopt, prescribe, and administer injectable PrEP within clinical settings. This study qualitatively examined challenges and benefit of injectable PrEP implementation from the perspective of health care providers. From April to August 2022, we conducted 19 in-depth interviews with current PrEP-prescribing health care providers in New York State, including 3 physician assistants, 5 physicians, and 11 nurse practitioners. Interviews were audio-recorded, transcribed verbatim, and thematically analyzed to report semantic-level themes regarding injectable PrEP implementation. More than half of participants (61%) were aware of injectable PrEP; only 21% had experience prescribing it. Qualitative findings highlighted five themes. Three themes represented implementation challenges, including speculative concerns about side effects, appointment compliance, and practical and logistical considerations. The remaining two themes described benefits of injectable PrEP relative to oral PrEP, which included greater convenience and enhanced privacy. Findings from this qualitative study make significant applied contributions to the sparse knowledge on health care provider perspectives of injectable PrEP post-US Food and Drug Administration approval and their concerns and considerations regarding implementation in real-world clinical settings.

Rapid Initiation of Antiretroviral Therapy Under the Treat-All Policy Reduces Loss to Follow-Up and Virological Failure in Routine Human Immunodeficiency Virus Care Settings in China: A Retrospective Cohort Study (2016-2022).

Following the World Health Organization's guidelines for rapid antiretroviral therapy (ART) initiation [≤7 days after human immunodeficiency virus (HIV) diagnosis], China implemented Treat-All in 2016 and has made significant efforts to provide timely ART since 2017. This study included newly diagnosed HIV adults from Tianjin, China, between 2016 and 2022. Our primary outcome was loss to follow-up (LTFU) at 12 months after enrollment. The secondary outcome was 12-month virological failure. The association between rapid ART and LTFU, as well as virological failure, was assessed via Cox regression and logistic regression. A total of 896 (19.1%) of 4688 participants received ART ≤7 days postdiagnosis. The rate of rapid ART has increased from 7.5% in 2016 to 33.3% by 2022. The rapid ART group had an LTFU rate of 3.3%, as opposed to 5.0% in the delayed group. The rapid ART group had a much reduced virological failure rate (0.6% vs. 1.8%). Rapid ART individuals had a reduced likelihood of LTFU [adjusted hazard ratio: 0.65, 95% confidence intervals (CI): 0.44-0.96] and virological failure (adjusted odds ratio: 0.35, 95% CI: 0.12-0.80). The real-world data indicated that rapid ART is practicable and beneficial for Chinese people with HIV, providing evidence for its widespread implementation and scaling up.

Understanding Attitudes of Postpartum Cisgender Women Toward Integration of HIV Prevention Services into Routine Prenatal and Postpartum Sexual Health Discussions.

Oral pre-exposure prophylaxis (PrEP) is an effective, user-controlled method for HIV prevention. However, awareness, uptake, and adherence to PrEP remain low among cisgender women (CGW). The prenatal and postpartum periods present an opportunity for delivery of comprehensive sexual health services that include HIV prevention education and services. However, little is known about postpartum CGW's attitudes toward integration of HIV prevention education and services into obstetric care in the US. We conducted semistructured interviews with 20 postpartum CGW in the Bronx, NY from July to November 2022 to explore their experiences with prenatal and postpartum sexual health care, examine their attitudes toward integration of HIV prevention services into obstetric sexual health care, and identify components of future implementation strategies. Transcripts were analyzed thematically using a framework approach. Among CGW interviewed, fewer than half reported prior knowledge of PrEP. Ten participants preferred long-acting injectable PrEP relative to six who preferred daily oral PrEP. Most participants reported no discussion of sex with their provider during pregnancy, and when discussions occurred, they focused on permission or prohibition of sexual activity. Participants described a reliance on providers to lead prenatal sexual health discussions. Even when not perceived as personally relevant, most respondents valued education on HIV prevention and PrEP services. In the postpartum period, sexual health discussions were similarly limited despite participants describing complex experiential sexual health concerns. This study supports the potential for integration of HIV prevention education and services into routine prenatal and postpartum sexual health discussions in an area of high HIV prevalence in the US.

Understanding HIV/AIDS dynamics: insights from CD4+T cells, antiretroviral treatment, and country-specific analysis.

In this article, we present a mathematical model for human immunodeficiency virus (HIV)/Acquired immune deficiency syndrome (AIDS), taking into account the number of CD4+T cells and antiretroviral treatment. This model is developed based on the susceptible, infected, treated, AIDS (SITA) framework, wherein the infected and treated compartments are divided based on the number of CD4+T cells. Additionally, we consider the possibility of treatment failure, which can exacerbate the condition of the treated individual. Initially, we analyze a simplified HIV/AIDS model without differentiation between the infected and treated classes. Our findings reveal that the global stability of the HIV/AIDS-free equilibrium point is contingent upon the basic reproduction number being less than one. Furthermore, a bifurcation analysis demonstrates that our simplified model consistently exhibits a transcritical bifurcation at a reproduction number equal to one. In the complete model, we elucidate how the control reproduction number determines the stability of the HIV/AIDS-free equilibrium point. To align our model with the empirical data, we estimate its parameters using prevalence data from the top four countries affected by HIV/AIDS, namely, Eswatini, Lesotho, Botswana, and South Africa. We employ numerical simulations and conduct elasticity and sensitivity analyses to examine how our model parameters influence the control reproduction number and the dynamics of each model compartment. Our findings reveal that each country displays distinct sensitivities to the model parameters, implying the need for tailored strategies depending on the target country. Autonomous simulations highlight the potential of case detection and condom use in reducing HIV/AIDS prevalence. Furthermore, we identify that the quality of condoms plays a crucial role: with higher quality condoms, a smaller proportion of infected individuals need to use them for the potential eradication of HIV/AIDS from the population. In our optimal control simulations, we assess population behavior when control interventions are treated as time-dependent variables. Our analysis demonstrates that a combination of condom use and case detection, as time-dependent variables, can significantly curtail the spread of HIV while maintaining an optimal cost of intervention. Moreover, our cost-effectiveness analysis indicates that the condom use intervention alone emerges as the most cost-effective strategy, followed by a combination of case detection and condom use, and finally, case detection as a standalone strategy.

Prevalence of overweight and obesity among adolescents living with HIV after dolutegravir - based antiretroviral therapy start in Kampala, Uganda.

BACKGROUND: Dolutegravir (DTG)-based antiretroviral therapy (ART) is currently the preferred first-line treatment for persons living with HIV (PLHIV) including children and adolescents in many low- and middle-income countries including Uganda. However, there are concerns about excessive weight gain associated with DTG especially in adults. There remains paucity of current information on weight-related outcomes among adolescents on DTG. We determined the prevalence of excessive weight gain and associated factors among adolescents living with HIV (ALHIV) receiving DTG-based ART in Kampala, Uganda. METHODS: Cross-sectional study involving ALHIV aged 10-19 years on DTG-based ART for at least one year were recruited from public health facilities in Kampala between February and May 2022. Excessive weight gain was defined as becoming overweight or obese per body mass index (BMI) norms while on DTG-based ART for at least one year. Demographic, clinical and laboratory data were collected using interviewer-administered questionnaires and data extracted from medical records. At enrolment, blood pressure and anthropometry were measured and blood was drawn for blood glucose and lipid profile. Data was summarised using descriptive statistics and logistic regression was performed to determine the associated factors. RESULTS: We enrolled 165 ALHIV with a median age of 14 years (IQR 12-16). Eighty (48.5%) were female. The median duration on ART and DTG was 8 years (IQR 7-11) and 2 years (IQR 1-3) respectively. At DTG initiation, the majority of participants (152/165, 92.1%) were ART-experienced, and had normal BMI (160/165, 97%). Overall, 12/165 (7.3%) adolescents (95% CI: 4.2-12.4) had excessive weight gain. No factors were significantly associated with excessive weight gain after DTG start in ALHIV. However, all ALHIV with excessive weight gain were females. CONCLUSION: Our study found a prevalence of 7.3% of overweight and obesity in ALHIV after initiating DTG. We did not find any factor significantly associated with excessive weight gain in ALHIV on DTG. Nonetheless, we recommend ongoing routine monitoring of anthropometry and metabolic markers in ALHIV as DTG use increases globally, to determine the exact magnitude of excessive weight gain and to identify those at risk of becoming overweight or obese while taking the medication.

Enhanced peer-group strategies to support the prevention of mother-to-child HIV transmission leads to increased retention in care in Uganda: A randomized controlled trial.

INTRODUCTION: Despite the scale-up of Option B+, long-term retention of women in HIV care during pregnancy and the postpartum period remains an important challenge. We compared adherence to clinic appointments and antiretroviral therapy (ART) at 6 weeks, 6, and and 24 months postpartum among pregnant women living with HIV and initiating Option B+. Women were randomized to a peer group support, community-based drug distribution and income-generating intervention called "Friends for Life Circles" (FLCs) versus the standard of care (SOC). Our secondary outcome was infant HIV status and HIV-free survival at 6 weeks and 18 months postpartum. METHODS: Between 16 May 2016 and 12 September 2017, 540 ART-naïve pregnant women living with HIV at urban and rural health facilities in Uganda were enrolled in the study at any gestational age. Participants were randomized 1:1 to the unblinded FLC intervention or SOC at enrolment and assessed for adherence to the prevention of mother-to-child HIV transmission (PMTCT) clinic appointments at 6 weeks, 12, and 24 months postpartum, self-reported adherence to ART at 6 weeks, 6 and 24 months postpartum and supported by plasma HIV-1 RNA viral load (VL) measured at the same time points, retention in care through the end of study, and HIV status and HIV-free survival of infants at 18 months postpartum. The FLC groups were formed during pregnancy within 4 months of enrollment and held monthly meetings in their communites, and were followed up until the last group participant reached 24 months post delivery. We used Log-rank and Chi-Square p-values to test the equality of Kaplan-Meier survival probabilities and hazard rates (HR) for failure to retain in care for any reason by study arm. RESULTS: There was no significant difference in adherence to PMTCT clinic visits or to ART or in median viral loads between FLC and SOC arms at any follow-up time points. Retention in care through the end of study was high in both arms but significantly higher among participants randomized to FLC (86.7%) compared to SOC (79.3%), p = 0.022. The adjusted HR of visit dropout was 2.4 times greater among participants randomized to SOC compared to FLC (aHR = 2.363, 95% CI: 1.199-4.656, p = 0.013). Median VL remained < 400 copies/ml in both arms at 6 weeks, 6, and 24 months postpartum. Eight of the 431 infants tested at 18 months were HIV positive (1.9%), however, this was not statistically different among mothers enrolled in the FLC arm compared to those in the SOC arm. At 18 months, HIV-free survival of children born to mothers in the FLC arm was significantly higher than that of children born to mothers in the SOC arm. CONCLUSIONS: Our findings suggest that programmatic interventions that provide group support, community-based ART distribution, and income-generation activities may contribute to retention in PMTCT care, HIV-free survival of children born to women living with HIV, and ultimately, to the elimination of mother-to-child HIV transmission (EMTCT). TRIAL REGISTRATION: NCT02515370 (04/08/2015) on ClinicalTrials.gov.

Twelve-month effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide in people with HIV from the Canadian cohort of the observational BICSTaR study.

The BICSTaR (BICtegravir Single Tablet Regimen) study is investigating the effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in people with human immunodeficiency virus (HIV) treated in routine clinical practice. BICSTaR is an ongoing, prospective, observational cohort study across 14 countries. Treatment-naïve (TN) and treatment-experienced (TE) people with HIV (≥18 years of age) are being followed for 24 months. We present an analysis of the primary endpoint (HIV-1 RNA < 50 copies/mL; missing-equals-excluded [M = E]) at month 12 in the BICSTaR Canada cohort, including secondary (CD4 count, CD4/CD8 ratio, safety/tolerability) and exploratory (persistence, treatment satisfaction) endpoints. In total, 201 participants were enrolled in the BICSTaR Canada cohort. The analysis population included 170 participants (TN, n = 10; TE, n = 160), with data collected between November 2018 and September 2020. Of the participants, 88% were male, 72% were White, and 90% had ≥ 1 comorbid condition(s). Median (quartile [Q]1-Q3) age was 50 (39-58) years and baseline CD4 count was 391.5 (109.0-581.0) cells/µL in TN participants and 586.0 (400.0-747.0) cells/µL in TE participants. After 12 months of B/F/TAF treatment, HIV-1 RNA was < 50 copies/mL in 100% (9/9) of TN-active participants and 97% (140/145) of TE-active participants (M = E analysis). Median (Q1-Q3) CD4 cell count increased by +195 (125-307) cells/µL in TN participants and by + 30 (-50 to 123) cells/µL in TE participants. Persistence on B/F/TAF was high through month 12 with 10% (1/10) of TN and 7 % (11/160) of TE participants discontinuing B/F/TAF within 12 months of initiation of treatment. No resistance to B/F/TAF emerged. Study drug-related adverse events occurred in 7% (12/169) of participants, leading to B/F/TAF discontinuation in 4 of 169 participants. Improvements in treatment satisfaction were observed in TE participants. B/F/TAF demonstrated high levels of effectiveness, persistence, and treatment satisfaction, and was well tolerated through month 12 in people with HIV treated in routine clinical practice in Canada.

Key informant views on potential acceptability and feasibility of long-acting antiretroviral treatment for HIV in Kenya.

BACKGROUND: In 2020, 14% of diagnosed persons living with HIV (PLWH) in Kenya were not taking antiretroviral therapy (ART), and 19% of those on ART had unsuppressed viral loads. Long-acting antiretroviral therapy (LA-ART) may increase viral suppression by promoting ART uptake and adherence. We conducted key informant (KI) interviews with HIV experts in Kenya to identify product and delivery attributes related to the acceptability and feasibility of providing LA-ART to PLWH in Kenya. METHODS: Interviews were conducted via Zoom on potential LA-ART options including intra-muscular (IM) injections, subcutaneous (SC) injections, implants, and LA oral pills. KI were asked to discuss the products they were most and least excited about, as well as barriers and facilitators to LA-ART roll-out. In addition, they were asked about potential delivery locations for LA-ART products such as homes, pharmacies, and clinics. Interviews were recorded and transcribed, and data were analyzed using a combination of inductive and deductive coding. RESULTS: Twelve KI (5 women, 7 men) participated between December 2021 and February 2022. Overall, participants reported that LA-ART would be acceptable and preferable to PLWH because of fatigue with daily oral pills. They viewed IM injections and LA oral pills as the most exciting options to ease pill burden and improve adherence. KI felt that populations who could benefit most were adolescents in boarding schools and stigmatized populations such as sex workers. SC injections and implants were less favored, as they would require new training initiatives for patients or healthcare workers on administration. In addition, SC injections would require refrigeration and needle disposal after use. Some KI thought patients, especially men, might worry that IM injections and implants would impact fertility, given their role in family planning. Pharmacies were perceived by most KI as suboptimal delivery locations; however, given ongoing work in Kenya to include pharmacies in antiretroviral delivery, they recommended asking patients their views. CONCLUSION: There is interest and support for LA-ART in Kenya, especially IM injections and LA oral pills. Identifying patient preferences for modes and delivery locations and addressing misconceptions about specific products as they become available will be important before wide-scale implementation.

Effects of statins beyond lipid-lowering agents in ART-treated HIV infection.

Antiretroviral therapies (ART) have reduced human immunodeficiency virus (HIV) infection-associated morbidity and mortality improving the life of people with HIV (PWH). However, ART lead to residual HIV production, which in conjunction with microbial translocation and immune dysfunction contributes to chronic inflammation and immune activation. PWH on ART remain at an increased risk for cardiovascular diseases (CVDs) including myocardial infarction and stroke; which in part is explained by chronic inflammation and immune activation. Lifestyle factors and certain ART are associated with dyslipidemia characterized by an increase of low-density lipoprotein (LDL), which further contributes in the increased risk for CVDs. Lipid-lowering agents like statins are emerging as immune modulators in decreasing inflammation in a variety of conditions including HIV. The international randomized clinical trial REPRIEVE has shed light on the reduction of CVDs with statin therapy among PWH. Such reports indicate a more than expected benefit of statins beyond their lipid-lowering effects. Bempedoic acid, a first-in-class non-statin LDL-lowering drug with immune modulatory effects, may further aid PWH in combination with statins. Herein, we critically reviewed studies aimed at lipid-lowering and immune-modulating roles of statins that may benefit aging PWH.

Willingness and preferences for long-acting injectable PrEP among US men who have sex with men: a discrete choice experiment.

INTRODUCTION: Cabotegravir long-acting injectable HIV pre-exposure prophylaxis (LA-PrEP) was shown to be safe and effective in multiple clinical trials. Increasing uptake and persistence among populations with elevated risk for HIV acquisition, especially among men who have sex with men (MSM), is critical to HIV prevention. OBJECTIVE: This analysis aims to understand potential users' preferences for LA-PrEP, with audience segmentation. DESIGN: Willingness to use and preferences for LA-PrEP were measured in HIV-negative, sexually active MSM in the 2020 American Men's Internet Survey. Respondents answered a discrete choice experiment with paired profiles of hypothetical LA-PrEP characteristics with an opt-out option (no LA-PrEP). Conditional and mixed logit models were run; the final model was a dummy-coded mixed logit that interacted with the opt-out. SETTING: US national online sample. RESULTS: Among 2506 MSM respondents, most (75%) indicated a willingness to use LA-PrEP versus daily oral PrEP versus no PrEP. Respondents were averse to side effects and increasing costs and preferred increasing levels of protection. Respondents preferred a 2-hour time to obtain LA-PrEP vs 1 hour, with a strong aversion to 3 hours. Overall, there was an aversion to opting out of LA-PrEP, with variations: those with only one partner, no/other insurance or who were Black, Indigenous or People of Colour were significantly less likely to prefer LA-PrEP, while those who were Hispanic/Latino, college educated and <40 years significantly preferred LA-PrEP. CONCLUSIONS: A large proportion of MSM expressed a preference for LA-PrEP over daily oral pills. Most respondents chose LA-PrEP regardless of cost, clinic time, side effects or protection level; however, preferences varied by sociodemographics. These varied groups likely require tailored intervention strategies to achieve maximum LA-PrEP uptake and persistence.

HIV Infection, Antiretroviral Drugs, and the Vascular Endothelium.

Endothelial cell activation, injury, and dysfunction underlies the pathophysiology of vascular diseases and infections associated with vascular dysfunction, including human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome. Despite viral suppression with combination antiretroviral therapy (ART), people living with HIV (PLWH) are prone to many comorbidities, including neurological and neuropsychiatric complications, cardiovascular and metabolic diseases, premature aging, and malignancies. HIV and viral proteins can directly contribute to the development of these comorbidities. However, with the continued high prevalence of these comorbidities despite viral suppression, it is likely that ART or some antiretroviral (ARVs) drugs contribute to the development and persistence of comorbid diseases in PLWH. These comorbid diseases often involve vascular activation, injury, and dysfunction. The purpose of this manuscript is to review the current literature on ARVs and the vascular endothelium in PLWH, animal models, and in vitro studies. I also summarize evidence of an association or lack thereof between ARV drugs or drug classes and the protection or injury/dysfunction of the vascular endothelium and vascular diseases.

ART history prior to conception: trends and association with postpartum disengagement from HIV care in Khayelitsha, South Africa (2013-2019): a retrospective cohort study.

INTRODUCTION: In recent years, the expansion of HIV treatment eligibility has resulted in an increase in people with antiretroviral therapy (ART) experience prior to pregnancy but little is known about postpartum engagement in care in this population. We examined differences in disengagement from HIV care after delivery by maternal ART history before conception. METHODS: We analysed data from people living with HIV (aged 15-49) in Khayelitsha, South Africa, with ≥1 live birth between April 2013 and March 2019. We described trends over time in ART history prior to estimated conception, classifying ART history groups as: (A) on ART with no disengagement (>270 days with no evidence of HIV care); (B) returned before pregnancy following disengagement; (C) restarted ART in pregnancy after disengagement; and (D) ART new start in pregnancy. We used Kaplan-Meier curves and proportional-hazards models (adjusted for maternal age, number of pregnancy records and year of delivery) to examine the time to disengagement from delivery to 2 years postpartum. RESULTS: Among 7309 pregnancies (in 6680 individuals), the proportion on ART (A) increased from 19% in 2013 to 41% in 2019. The proportions of those who returned (B) and restarted (C) increased from 2% to 13% and from 2% to 10%, respectively. There was a corresponding decline in the proportion of new starts (D) from 77% in 2013 to 36% in 2019. In the first recorded pregnancy per person in the study period, 26% (95% CI 25-27%) had disengaged from care by 1 year and 34% (95% CI 33-36%) by 2 years postpartum. Individuals who returned (B: aHR 2.10, 95% CI 1.70-2.60), restarted (C: aHR 3.32, 95% CI 2.70-4.09) and newly started ART (D: aHR 2.41, 95% CI 2.12-2.74) had increased hazards of postpartum disengagement compared to those on ART (A). CONCLUSIONS: There is a growing population of people with ART experience prior to conception and postpartum disengagement varies substantially by ART history. Antenatal care presents an important opportunity to understand prior ART experiences and an entry into interventions for strengthened engagement in HIV care.

How Would You Manage HIV Pre-exposure Prophylaxis in This Patient With Medical Comorbidities? : Grand Rounds Discussion From Beth Israel Deaconess Medical Center.

Despite advances in treatment, HIV infection remains an important cause of morbidity and mortality, with more than 30 000 new cases diagnosed in the United States each year. There are several interventions traditionally used to prevent HIV transmission, but these vary in effectiveness and there are challenges to their implementation. In 2014, the Centers for Disease Control and Prevention published initial guidance on the use of antiretroviral pre-exposure prophylaxis (PrEP) to prevent transmission of HIV infection in persons at risk based on multiple studies that showed it to be highly efficacious in various populations. It was updated in 2021 to reflect new drug options. The U.S. Preventive Services Task Force also recently updated its recommendations for PrEP, which strongly support its use in persons at risk. Despite its well-established effectiveness, the implementation of PrEP in clinical practice has been variable, especially among populations underserved by the medical system and marginalized by society. Fewer than one third of persons in the United States who are eligible for PrEP currently receive it. Here, 2 physicians experienced in HIV PrEP debate how best to identify patients who might benefit from PrEP, how to decide what regimen to use, and how to monitor therapy.

Salvage Therapy Including Foscarnet and Ibalizumab for Multidrug-Resistant Human Immunodeficiency Virus Type 2 Infection.

We evaluated Ibalizumab (IBA)-containing standardized optimized salvage regimen (with or without a 4-week foscarnet induction) in individuals harboring multidrug-resistant human immunodeficiency virus type 2 (HIV-2). Nine were included; 2 achieved virological suppression after foscarnet induction with a sustained suppression at Week 24 after IBA initiation, and an additional individual at Week 24 after Ibalizumab initiation.

Effects of the COVID-19 pandemic on HIV service delivery and viral suppression: Findings from the SHARP program in Northern Nigeria.

During the COVID-19 pandemic, HIV programs scaled up differentiated service delivery (DSD) models for people living with HIV (PLHIV). We evaluated the effects of COVID-19 on HIV service delivery and viral suppression in facilities in Northern Nigeria, and determined factors associated with viral suppression among adolescents and adults. We analysed a cross-sectional survey data from facility heads, and retrospective, routinely collected patient data from 63 facilities for PLHIV ≥10 years old in care between April 2019-March 2021, defining study periods as "pre-COVID-19" (before April 2020) and "during COVID-19" (after April 2020). For the pre-COVID and the COVID-19 periods we compared uptake of antiretroviral therapy (ART) refills of ≥3 months (MMD3), and ≥6 months (MM6), missed appointments, viral load (VL) testing, VL testing turnaround time (TAT) and viral suppression among those on ART for ≥6 months using two proportions Z-test and t-tests. We fit a multivariable logistic regression model to determine factors associated with maintaining or achieving viral suppression. Of 84,776 patients, 58% were <40 years, 67% were female, 55% on ART for >5 years, 93% from facilities with community-based ART refill, a higher proportion were on MMD3 (95% versus 74%, p<0.001) and MMD6 (56% versus 22%, p<0.001) during COVID-19 than pre-COVID-19, and a higher proportion had VL testing during COVID-19 (55,271/69,630, [84%]) than pre-COVID-19 (47,747/68,934, [73%], p<0.001). Viral suppression was higher during COVID-19 pandemic compared to the pre-COVID era (93% [51,196/55,216] versus 91% [43,336/47,728], p<0.001), and there was a higher proportion of missed visits (40% [28,923/72,359] versus 39% [26,304/67,365], p<0.001) and increased VL TAT (mean number of days: 38 versus 36, p<0.001) during COVID-19 pandemic and pre-COVID period respectively. Factors associated with maintaining or achieving suppression during COVID-19 were receiving MMD3 and MMD6 refills (OR: 2.8 [95% CI: 2.30-3.47] and OR: 6.3 [95% CI: 5.11-7.69], respectively) and attending clinics with community-based ART refill (OR: 1.6 [95% CI: 1.39-1.87]). The program in Northern Nigeria demonstrated resilience during the COVID-19 pandemic and adoption of MMD had a positive impact on HIV care. Though VL TAT and missed clinic visits slightly increased during the pandemic, VL testing improved and viral suppression moved closer to 95%. Adoption of MMD and community-based models of care at scale are recommended for future pandemic preparedness.

How men influence young women taking PrEP: perspectives from young women, male partners, and male peers in Siaya county, Western Kenya.

BACKGROUND: Daily oral pre-exposure prophylaxis (PrEP) is an effective HIV prevention option for those who are most vulnerable to HIV infection, especially young women (YW). Objection by or lack of support from male sexual partners has been shown to impact YW's ability to take PrEP consistently. We explored the views of YW, and male partners and male peers of YW in Siaya County, Western Kenya, to illustrate how men influence, and can support, YW in using PrEP. METHODS: We used Photovoice to capture the views of YW ages 18-24 who were currently or previously enrolled in the DREAMS program and with current or previous experience taking PrEP. We also captured the views of YW's sexual partners and male peers. The YW completed eight photo assignments that focused on identifying factors influencing their PrEP use, and male participants completed four photo assignments focused on identifying ways men support or hinder YW's PrEP use. Photographs were presented and discussed in same- and mixed-gender groups using the SHOWeD method. YW also participated in in-depth interviews. The analysis focused on identifying themes that described men's influence on YW's PrEP adherence and persistence. RESULTS: Among YW, a restricting male influence on PrEP use emerged in the majority of photo assignments such that YW's photographs and discussions revealed that men were more often viewed as barriers than supporters. YW perceived that they had little autonomy over their sexual lives and choice to use PrEP. YW's PrEP use was perceived to be hindered by stigmatizing community narratives that influenced men's support of PrEP use among women. Male participants suggested that men would support YW's PrEP use if PrEP was better promoted in the community and if men were more knowledgeable about its benefits. CONCLUSIONS: A lack of support from male partners and peers and stigmatizing community narratives influence YW's PrEP use. Community-based programs should include education about PrEP specifically for male partners and peers of YW to positively influence PrEP use among YW.

Seco-cyclic phorbol derivatives and their anti-HIV-1 activities.

Phorbol esters are recognized for their dual role as anti-HIV-1 agents and as activators of protein kinase C (PKC). The efficacy of phorbol esters in binding with PKC is attributed to the presence of oxygen groups at positions C20, C3/C4, and C9 of phorbol. Concurrently, the lipids located at positions C12/C13 are essential for both the anti-HIV-1 activity and the formation of the PKC-ligand complex. The influence of the cyclopropane ring at positions C13 and C14 in phorbol derivatives on their anti-HIV-1 activity requires further exploration. This research entailed the hydrolysis of phorbol, producing seco-cyclic phorbol derivatives. The anti-HIV-1 efficacy of these derivatives was assessed, and the affinity constant (Kd) for PKC-δ protein of selected seco-cyclic phorbol derivatives was determined through isothermal titration calorimetry. The findings suggest that the chemical modification of cyclopropanols could affect both the anti-HIV-1 activity and the PKC binding affinity. Remarkably, compound S11, with an EC50 of 0.27 µmol·L-1 and a CC50 of 153.92 µmol·L-1, demonstrated a potent inhibitory effect on the intermediate products of HIV-1 reverse transcription (ssDNA and 2LTR), likely acting at the viral entry stage, yet showed no affinity for the PKC-δ protein. These results position compound S11 as a potential candidate for further preclinical investigation and for studies aimed at elucidating the pharmacological mechanism underlying its anti-HIV-1 activity.

Kinetic coevolutionary models predict the temporal emergence of HIV-1 resistance mutations under drug selection pressure.

Drug resistance in HIV type 1 (HIV-1) is a pervasive problem that affects the lives of millions of people worldwide. Although records of drug-resistant mutations (DRMs) have been extensively tabulated within public repositories, our understanding of the evolutionary kinetics of DRMs and how they evolve together remains limited. Epistasis, the interaction between a DRM and other residues in HIV-1 protein sequences, is key to the temporal evolution of drug resistance. We use a Potts sequence-covariation statistical-energy model of HIV-1 protein fitness under drug selection pressure, which captures epistatic interactions between all positions, combined with kinetic Monte-Carlo simulations of sequence evolutionary trajectories, to explore the acquisition of DRMs as they arise in an ensemble of drug-naive patient protein sequences. We follow the time course of 52 DRMs in the enzymes protease, RT, and integrase, the primary targets of antiretroviral therapy. The rates at which DRMs emerge are highly correlated with their observed acquisition rates reported in the literature when drug pressure is applied. This result highlights the central role of epistasis in determining the kinetics governing DRM emergence. Whereas rapidly acquired DRMs begin to accumulate as soon as drug pressure is applied, slowly acquired DRMs are contingent on accessory mutations that appear only after prolonged drug pressure. We provide a foundation for using computational methods to determine the temporal evolution of drug resistance using Potts statistical potentials, which can be used to gain mechanistic insights into drug resistance pathways in HIV-1 and other infectious agents.

Design and Synthesis of New GS-6207 Subtypes for Targeting HIV-1 Capsid Protein.

HIV-1 capsid protein (CA) is the molecular target of the recently FDA-approved long acting injectable (LAI) drug lenacapavir (GS-6207). The quick emergence of CA mutations resistant to GS-6207 necessitates the design and synthesis of novel sub-chemotypes. We have conducted the structure-based design of two new sub-chemotypes combining the scaffold of GS-6207 and the N-terminal cap of PF74 analogs, the other important CA-targeting chemotype. The design was validated via induced-fit molecular docking. More importantly, we have worked out a general synthetic route to allow the modular synthesis of novel GS-6207 subtypes. Significantly, the desired stereochemistry of the skeleton C2 was confirmed via an X-ray crystal structure of the key synthetic intermediate 22a. Although the newly synthesized analogs did not show significant potency, our efforts herein will facilitate the future design and synthesis of novel subtypes with improved potency.