"Why Not Just go on PrEP?": A Study to Inform Implementation of an HIV Prevention Intervention Among Hispanic/Latino Men Who Have Sex With Men in the Northeastern United States.

BACKGROUND: Preexposure prophylaxis (PrEP) is an effective biological option for HIV prevention yet persistent disparities in PrEP uptake and retention exist among Hispanic/Latino men who have sex with men (MSM). We evaluated barriers and facilitators to PrEP care among Hispanic/Latino MSM at risk for and living with HIV. SETTING: A small urban setting in the Northeastern United States. METHODS: This was a mixed-methods, exploratory, sequential, qualitative and quantitative pilot study among Latino MSM at-risk and/or living with HIV across (1) semistructured qualitative interviews (N = 15) and (2) cross-sectional survey (N = 98). RESULTS: Participants reported a diverse range of sexual identities, HIV statuses, and PrEP statuses. Qualitative participants described feelings of isolation in both Hispanic/Latino and queer communities that made it challenging to learn about HIV prevention or PrEP from peers. Participants in the survey indicated that they would be more inclined to uptake PrEP if PrEP were offered in primary care settings (n = 61; 62.2%); there were specific LGBTQ+ affirming medical settings (n = 36; 36.7%); and/or they could meet other people who are currently on PrEP and sharing experiences online (n = 46; 46.9%) or in person (n = 38; 38.8%). Findings were organized to reflect determinants and implementation strategies that could be used to improve PrEP uptake among this population. CONCLUSIONS: This mixed-methods study identified several challenges and opportunities for increasing the reach of PrEP to Hispanic/Latino MSM. These findings should be used to inform tailored implementation strategies to promote PrEP uptake among this at-risk yet currently underserved population.

Factors driving decisions in the use of HIV pre-exposure prophylaxis: a real-world study in the United States.

Background: Uptake of pre-exposure prophylaxis (PrEP) in the United States (US) remains below target, despite reported high efficacy in prevention of HIV infection and being considered as a strategy for ending new HIV transmissions. Here, we sought to investigate drivers for PrEP use and barriers to increased uptake using real-world data. Methods: Data were drawn from the Adelphi PrEP Disease Specific Programme™, a cross-sectional survey of PrEP users and PrEP non-users at risk for HIV and their physicians in the US between August 2021 and March 2022. Physicians reported demographic data, clinical characteristics, and motivations for prescribing PrEP. PrEP users and non-users reported reasons for or against PrEP use, respectively. Bivariate analyses were performed to compare characteris tics of users and non-users. Results: In total, 61 physicians reported data on 480 PrEP users and 121 non-users. Mean ± standard deviation of age of users and non-users was 35.3 ± 10.8 and 32.5 ± 10.8 years, respectively. Majority were male and men who have sex with men. Overall, 90.0% of users were taking PrEP daily and reported fear of contracting HIV (79.0%) and having at-risk behaviors as the main drivers of PrEP usage. About half of non-users (49.0%) were reported by physicians as choosing not to start PrEP due to not wanting long-term medication. PrEP stigma was a concern for both users (50.0%) and non-users (65.0%). More than half felt that remembering to take PrEP (57.0%) and the required level of monitoring (63.0%) were burdensome. Conclusions: Almost half of people at risk for HIV were not taking PrEP due to not wanting long-term daily medication and about half of current PrEP users were not completely adherent. The most common reason for suboptimal adherence was forgetting to take medication. This study highlighted drivers for PrEP uptake from physician, PrEP user, and non-user perspectives as well as the attributes needed in PrEP products to aid increased PrEP uptake.

Landmark trial may herald new era in HIV prevention.

Twice-yearly lenacapavir injections provide 100% protection in study in African women.

Adherence to antiretroviral therapy among people living with HIV attending medication-assisted treatment clinics in Dar es Salaam, Tanzania: a cross-sectional study.

Introduction: the prevalence of human immunodeficiency virus (HIV) among people who inject drugs (PWIDs) in Tanzania is estimated at 35%, significantly surpassing the 4.6% HIV prevalence of the general population. People who inject drugs living with HIV have been reported to exhibit lower adherence to antiretroviral therapy (ART), leading to increased rates of mortality, morbidity, and HIV transmission. This study assessed adherence to ART and associated factors among PWIDs in Dar es Salaam. Methods: this cross-sectional study involved 277 PWIDs living with HIV who attended MAT clinics in Dar es Salaam from May to July 2022. Antiretroviral therapy adherence was assessed using a validated one-month self-recall medication adherence scale, and associated factors were obtained through a structured questionnaire. Statistical analyses included chi-square tests, Fisher exact tests, and log-binomial regression. Data were analyzed using STATA version 15, with a p-value of <0.05 considered statistically significant. Results: this study found that 83% of the study participants had a high level of adherence to ART. Additionally, the results revealed that PWIDS who consume alcohol were less likely to have high adherence to ART (aPR 0.820). On the other hand, higher odds of ART adherence were observed among participants who had family support (aPR 1.028) and those who had adequate knowledge of ART benefits (aPR 1.285). Conclusion: the government and development partners should implement novel interventions such as alcohol reduction programs, ART education, and expanded HIV community outreach services. These interventions have the potential to improve ART adherence and reduce HIV transmission among PWIDs.

Potential healthcare resource use and associated costs of every 2 month injectable cabotegravir plus rilpivirine long-acting regimen implementation in the Spanish National Healthcare System compared to daily oral HIV treatments.

INTRODUCTION: HIV treatment currently consists of daily oral antiretroviral therapy (ART). Cabotegravir + rilpivirine long-acting (CAB + RPV LA) is the first ART available in Spain administered every 2 months through intramuscular injection by a healthcare professional (HCP). The objective of this analysis was to assess potential healthcare resource use (HRU) and cost impact of implementing CAB + RPV LA vs. daily oral ART at National Health System (NHS) hospitals. METHODS: Online quantitative interviews and cost analysis were performed. Infectious disease specialists (IDS), hospital pharmacists (HP) and nurses were asked about their perception of potential differences in HRU between CAB + RPV LA vs. daily oral ART, among other concepts of interest. Spanish official tariffs were applied as unit costs to the HRU estimates (€2022). RESULTS: 120 responders (n = 40 IDS, n = 40 HP, n = 40 nurses) estimated an average number of annual visits per patient by speciality (IDS, HP, and nurse, respectively) of 3.3 vs. 3.7; 4.4 vs. 6.2; 6.1 vs. 3.9, for CAB + RPV LA vs. daily oral ART, and 3.0 vs. 3.2; 4.8 vs. 5.8; 6.9 vs. 4.9, respectively when adjusting by corresponding specialist responses. Estimation by the total sample led to an annual total cost per patient of €2,076 vs. €2,473, being €2,032 vs. €2,237 after adjusting by corresponding HCP, for CAB + RPV LA vs. daily oral ART. CONCLUSIONS: These results suggest that the implementation of CAB + RPV LA in NHS hospitals would not incur in increased HRU-related costs compared to current daily oral ARTs, being potentially neutral or even cost-saving.

The Challenge of Adherence to a Complex Antiretroviral Therapy Regimen in an Individual With Multidrug-Resistant HIV.

Limited therapeutic options are available for patients with multidrug-resistant HIV. This report describes a 38-year-old female who was perinatally infected with HIV-1 and treated with 14 different antiretroviral regimens over 27 years, gradually leading to 4-class drug resistance. Despite various attempts to obtain sustained viral suppression, including the off-label administration of intravenous foscarnet and enfuvirtide, and thorough follow-up with 16 viral genotyping/phenotyping from 1999 to 2021, viral control was not maintained. Recently, the introduction of a regimen with fostemsavir and lenacapavir resulted in long-term viral suppression.

Barriers to Oral PrEP: A Qualitative Study of Female Sex Workers, PrEP Prescribers, Policymakers, and Community Advocates in Morocco.

In 2017, Morocco became the first Arab country to incorporate pre-exposure prophylaxis (PrEP) in its HIV-prevention program. Yet no research has been published on PrEP from Morocco. Although female sex workers are one of the target populations of PrEP in Morocco, their enrollment in PrEP is lower than men who have sex with men. In this study, we conducted 38 semi-structured interviews with female sex workers, physicians who prescribe PrEP, policymakers, and community advocates to identify problems associated with access to and use of PrEP. We also investigated preferences for daily oral, vaginal ring, and long-acting injectable PrEP. A reflexive thematic analysis revealed seven themes: PrEP stigma; stigmatization and criminalization of sex work; one size doesn't fit all; knowledge and misconceptions about PrEP; economic burden; inconvenience of PrEP pills; and preferred PrEP modalities. This paper discusses the implications of the findings for increasing access and use of PrEP in Morocco.

Factors that Influence Uptake of Oral PrEP among Female Sex Workers One of the most recent scientific advancements in the history of the HIV pandemic was the introduction of pre-exposure prophylaxis (PrEP). However, the uptake of PrEP in the Arab world is low. In this paper we interviewed female sex workers, physicians who prescribe PrEP, policymakers, and community advocates to identify problems associated with access to and use of PrEP. Several barriers were identified including stigma attached to PrEP, misconceptions about PrEP, and financial burden. Although most female sex workers in our study were interested in using PrEP, the delivery methods of PrEP should be tailored to fit the lifestyle and personal circumstances of potential users.

Harnessing private sector strategies for family planning to deliver the Dual Prevention Pill, the first multipurpose prevention technology with pre-exposure prophylaxis, in an expanding HIV prevention landscape.

INTRODUCTION: The Dual Prevention Pill (DPP) combines oral pre-exposure prophylaxis (PrEP) with oral contraception (OC) to prevent HIV and pregnancy. Noting the significant role played by the private sector in delivering family planning (FP) services in countries with high HIV burden, high level of private sector OC uptake, and the recent growth in self-care and technology-based private sector channels, we undertook qualitative research in Kenya, South Africa and Zimbabwe to prioritize private sector service delivery approaches for the introduction of the DPP. METHODS: Between March 2022 and February 2023, we conducted a literature review and key informant interviews with 34 donors and implementing partners, 19 government representatives, 17 private sector organizations, 13 pharmacy and drug shop representatives, and 12 telehealth agencies to assess the feasibility of DPP introduction in private sector channels. Channels were analysed thematically based on policies, level of coordination with the public sector, data systems, supply chain, need for subsidy, scalability, sustainability and geographic coverage. RESULTS: Wide geographic reach, ongoing pharmacy-administered PrEP pilots in Kenya and South Africa, and over-the-counter OC availability in Zimbabwe make pharmacies a priority for DPP delivery, in addition to private networked clinics, already trusted for FP and HIV services. In Kenya and South Africa, newer, technology-based channels such as e-pharmacies, telehealth and telemedicine are prioritized as they have rapidly grown in popularity due to nationwide accessibility, convenience and privacy. Findings are limited by a lack of standardized data on service uptake in newer channels and gaps in information on commodity pricing and willingness-to-pay for all channels. CONCLUSIONS: The private sector provides a significant proportion of FP services in countries with high HIV burden yet is an untapped delivery source for PrEP. Offering users a range of access options for the DPP in non-traditional channels that minimize stigma, enhance discretion and increase convenience could increase uptake and continuation. Preparing these channels for PrEP provision requires engagement with Ministries of Health and providers and further research on pricing and willingness-to-pay. Aligning FP and PrEP delivery to meet the needs of those who want both HIV and pregnancy prevention will facilitate integrated service delivery and eventual DPP rollout, creating a platform for the private sector introduction of multipurpose prevention technologies.

Prescription of HIV Post-Exposure Prophylaxis in emergency care units and return for follow-up appointments in specialized services in Salvador, Brazil, 2018: a cross-sectional study.

OBJECTIVE: To analyze HIV Post-Exposure Prophylaxis (PEP) prescription and return for follow-up appointments. METHODS: This was a descriptive cross-sectional study using data on people who sought PEP in emergency care units (UPAs) and specialized medical services in Salvador, BA, Brazil, between January-December/2018. RESULTS: Of the 1,525 people who sought PEP at UPAs, 1,273 (83.5%) met PEP eligibility criteria, while 252 (16.5%) did not; of the eligible group, 1,166 (91.6%) had antiretrovirals prescribed, while 107 (8.4%) eligible people did not; of the total number of people with PEP prescriptions, only 226 (19.4%) returned for the first follow-up appointment, 115 (9.9%) for the second, and 33 (2.8%) for the third in order to complete the protocol. CONCLUSION: We found a significant proportion of eligible users who did not have PEP prescribed at UPAs and a significant loss of return for specialized service follow-up appointments.

Client experiences with "Dynamic Choice Prevention," a model for flexible patient-centred HIV prevention delivery in rural Eastern Africa.

INTRODUCTION: Identifying the optimal approaches to offering HIV prevention to meet the needs of those at risk is a high priority, particularly given the expanding toolkit of biomedical HIV prevention options. An ongoing study in rural East African communities evaluated the uptake of choices in product, testing mode and location of care delivery through a structured patient-centred HIV prevention delivery model. In this qualitative study, we sought to understand clients' experiences of this "dynamic choice prevention model" (DCP) and highlight pathways of action to inform HIV prevention delivery models. METHODS: In-depth semi-structured interviews were conducted from November 2021 through March 2022 with a purposively selected sample of n = 56 participants in DCP trials (across outpatient departments, antenatal clinics and community settings), and n = 21 healthcare providers (total n = 77). A seven-person multi-regional team translated and inductively coded transcript data. We used a framework analysis approach to identify emergent themes. RESULTS: Individuals taking up HIV pre-exposure prophylaxis (PrEP) reported feelings of relief, liberation from fears of acquiring HIV and satisfaction with being able to take action despite partners' behaviours. Couples used a range of approaches afforded by the study to persuade partners to get tested and opt for PrEP. Post-exposure prophylaxis (PEP) use was less common, although women welcomed it in the event of sexual coercion or assault. Participants discussed switching from PEP to PrEP after familiarizing themselves with usage and ascertaining ongoing risk. Participants felt respected by providers, trusted them and appreciated being able to contact them directly for telephone support. Prevention uptake was hindered by stigma, limited experience with and knowledge of prevention methods, gendered and generational power dynamics within intimate partnerships and families, and negative perceptions of methods due to the products themselves. Participants anticipated long-acting injectable PrEP could solve their challenges regarding pill size, daily pill burden and the likelihood of unwanted disclosure. CONCLUSIONS: Diverse preferences and barriers to uptake of prevention require a choice of HIV prevention options, locations and delivery modalities-but in addition, flexible, competent and friendly care provision is crucial to promote uptake. Helping clients feel valued, and addressing their unique needs and challenges, enables their agency to prioritize their health.

Steady-state pharmacokinetics of lamivudine in end-stage kidney failure persons with detectable and undetectable HIV-1 RNA in peritoneal dialysis effluent.

BACKGROUND: Renally adjusted lamivudine dosages are effective. However, some of the kidney failure patients managed with lamivudine-containing regimens are failing to suppress HIV in peritoneal dialysis (CAPD) effluent. The steady-state lamivudine pharmacokinetics among these patients was evaluated. METHODS: This overnight open-label pharmacokinetic study enrolled participants living with HIV and managed with CAPD. Lamivudine levels in blood serum and CAPD effluent samples were quantified using liquid chromatography coupled with a mass spectrometer. Pharmacokinetic measures were obtained through non-compartmental analysis. RESULTS: Twenty-eight participants were recruited with a median antiretroviral (ARV) drug duration of 8 (IQR,4.5-10.5) years and a CAPD duration of 13.3 (IQR,3.3-31.9) months. 14.3% (4/28) had detectable unsuppressed HIV-1 viral load in CAPD effluents. The majority (78,6%,22/28) of participants received a 50 mg dose, while 10.7% (3/28), and another 10.7% (3/28) received 75 mg and 300 mg dosages, respectively. Among those treated with 75 and 300 mg, 66.7% (2/3) and 33.3% (1/3) had detectable HIV-VL in CAPD, respectively. The peritoneal membrane characteristics and CAPD system strengths were variable across the entire study population. Lamivudine exposure was increased in blood serum (50 mg-AUC0-24 h, 651.3 ng/mL; 75 mg-AUC0-24 h, 677.84 ng/mL; 300 mg-AUC0-24 h, 3135.89 ng/mL) compared to CAPD effluents (50 mg-AUC0-24 h, 384.91 ng/mL; 75 mg-AUC0-24 h, 383.24 ng/mL; 300 mg-AUC0-24 h, 2001.60 ng/mL) among the entire study population. The Cmax (50 mg, 41.5 ng/mL; 75 mg, 53.2 ng/mL; 300 mg, 199.1 ng/mL) and Cmin (50 mg, 17.8 ng/mL; 75 mg, 16.4 ng/mL; 300 mg, 76.4 ng/mL) measured in serum were within the therapeutic levels. CONCLUSIONS: Steady-state lamivudine pharmacokinetic measures were variable among the entire study population. However, the total lamivudine exposure was within the therapeutic levels.

Consensus recommendations for use of long-acting antiretroviral medications in the treatment and prevention of HIV-1: Endorsed by the American Academy of HIV Medicine, American College of Clinical Pharmacy, Canadian HIV and Viral Hepatitis Pharmacists Network, European AIDS Clinical Society, and Society of Infectious Diseases Pharmacists: An executive summary.

Five long-acting (LA) antiretrovirals (ARVs) are currently available in a limited number of countries worldwide for HIV-1 prevention or treatment - cabotegravir, rilpivirine, lenacapavir, ibalizumab, and dapivirine. Implementing use of LA ARVs in routine clinical practice requires significant changes to the current framework of HIV-1 prevention, treatment, and service provision. Given the novelty, complexity, and interdisciplinary requirements of safe and optimal use of LA ARVs, consensus recommendations on the use of LA ARVs will assist clinicians in optimizing use of these agents. The purpose of these recommendations is to provide guidance for the clinical use of LA ARVs for HIV-1 treatment and prevention. In addition, future areas of research are identified and discussed.

Consensus recommendations for use of long-acting antiretroviral medications in the treatment and prevention of HIV-1: Endorsed by the American Academy of HIV Medicine, American College of Clinical Pharmacy, Canadian HIV and Viral Hepatitis Pharmacists Network, European AIDS Clinical Society, and Society of Infectious Diseases Pharmacists.

Five long-acting (LA) antiretrovirals (ARVs) are currently available in a limited number of countries worldwide for HIV-1 prevention or treatment-cabotegravir, rilpivirine, lenacapavir, ibalizumab, and dapivirine. Implementing use of LA ARVs into routine clinical practice requires significant changes to the current framework of HIV-1 prevention, treatment, and service provision. Given the novelty, complexity, and interdisciplinary requirements needed to safely and optimally utilize LA ARVs, consensus recommendations on the use of LA ARVs will assist clinicians in optimizing use of these agents. The purpose of these recommendations is to provide guidance for the clinical use of LA ARVs for HIV-1 treatment and prevention. In addition, future areas of research are also identified and discussed.

[Long-acting injection therapies: New opportunities and challenges]. / Lang wirksame Injektionstherapien: Chance und Herausforderung.

Since the development of an effective antiretroviral therapy (ART) in 1996, substantial progress has been made in terms of efficacy, safety and ease of use. While at the beginning of the ART era the foremost goal necessarily was patient survival, over time it has become increasingly possible to shift the focus towards aspects of patient's quality of life. The latest developments are the long-acting injection therapies (LAI), foregoing for the first time the necessity to take pills. The only available injection therapy so far comprises 2 intramuscular injections every 2 months, with 3 ml of Cabotegravir 600 mg and 3 ml of Rilpivirine 900 mg being injected, respectively. Through this, patient's needs that were hitherto precluded from consideration could be addressed. These needs are inextricably linked to the stigmata people living with HIV (PLWH) are still confronted with on a daily basis. LAI have the potential to relieve PLWH of some of the heavy psychological burdens associated with the continued stigmatization. However, as a new therapy, new challenges need to be considered the use of LAI.

Navigating Pre-exposure Prophylaxis Access: Qualitative Insights From Black Women at a Northeastern Historically Black College and University.

ABSTRACT: Black women are essential to ending the HIV epidemic in the United States; yet prevention, access, testing, and structural racism affect how HIV disproportionately affects them. Limited public health research focuses on Black women attending Historically Black Colleges and Universities (HBCUs) and the ability to address HIV prevention, such as pre-exposure prophylaxis (PrEP) uptake. PrEP is a once-daily oral pill used to prevent HIV transmission and has suboptimal uptake within the Black community. This generic qualitative descriptive analysis identifies the barriers and facilitators of PrEP uptake among Black women attending an HBCU using the health belief model. Overall, 22 Black college women participated in a 60-minute focus group. Emergent categories were as follows: (a) Barriers-stigma, cost, and side effects; (b) Facilitators-PrEP's effectiveness, exposure to HIV, and unprotected sex. Our findings can inform future efforts to increase PrEP uptake among Black women attending an HBCU.

Effectiveness and safety of dolutegravir plus lamivudine in treating HIV in China, including outcomes of patients coinfected with tuberculosis.

Antiretroviral regimens for human immunodeficiency virus (HIV) infection have continuously evolved; however, antiretrovirals can cause severe adverse reactions. Two-drug regimen therapy can decrease lifetime cumulative drug exposure and long-term toxicities associated with multiple antiretrovirals. The preferred 2-drug regimen constitutes dolutegravir (DTG) and lamivudine (3TC). This study determined the rate of virological suppression and incidence of adverse events at week 48 in treatment-naïve people living with HIV initiated on DTG + 3TC. This was a single-center, retrospective, observational study. Treatment-naïve people aged ≥18 years who received at least 1 DTG + 3TC dose between May 2020 and May 2022 were included. Eighty-nine people living with HIV were enrolled. Twenty-five (28.1%) patients with a DTG + 3TC regimen at baseline were analyzed because of comorbidities, and 48% because of concomitant tuberculosis (TB). Viral suppression at 48 weeks was achieved in 91.67% of patients, and TB was well controlled. At week 48, 84 (94.38%) patients had viral loads < 50 copies/mL, and 21 (91.31%) of the 23 participants with a baseline HIV-1-RNA level ≥ 1 × 105 copies/mL achieved virological success. Fifteen (88.23%) of the 17 participants with a baseline CD4 + cell count of <200 cells/µL achieved virological suppression. The median CD4 + cell count change from baseline was 539.5 cells/µL. No significant changes in triglycerides, low-density lipoprotein cholesterol, weight, or creatinine were observed from baseline to 48 weeks. One patient had severe insomnia at 4 weeks. Our findings support the real-world effectiveness and low metabolic impact of DTG + 3TC. Using DTG + 3TC in patients coinfected with TB and HIV has favorable therapeutic outcomes.

Impact of a point-of-care urine tenofovir assay on adherence to HIV pre-exposure prophylaxis among women in Kenya: a randomised pilot trial.

BACKGROUND: Adherence challenges with oral tenofovir-based pre-exposure prophylaxis (PrEP) are common. We developed a point-of-care assay to objectively assess tenofovir in urine and conducted a pilot trial examining the impact of counselling informed by use of this urine assay on long-term PrEP adherence. METHODS: This randomised trial enrolled women not in serodiscordant partnerships 3 months after PrEP initiation at the Kenya Medical Research Institute to compare standard-of-care adherence counselling versus counselling informed by the urine assay (urine-test counselling group) every 3 months for 12 months. In the standard of care group, urine samples were stored and tested at study end without participant feedback. Here we report the adherence primary outcome of hair concentrations of tenofovir at 12 months as a long-term metric (undetectable levels defined long-term non-adherence), as well as urine concentrations of tenofovir at each visit as a short-term adherence metric and acceptability of the assay assessed by quantitative surveys. Data were analysed by randomisation group. This completed trial was registered with ClinicalTrials.gov (NCT03935464). FINDINGS: From March 17, 2021 to Jan 18, 2022 we enrolled 49 women in the urine-test counselling group and 51 in the standard of care group; retention was 86 (86%) of 100. Nine (21%) of 42 in the urine-test counselling group had hair samples at 12 months with tenofovir concentrations below the limit of quantification compared with 15 (37%) of 41 in the standard of care group. The relative odds of long-term non-adherence in the standard of care group compared with urine-test counselling were 3·53 (95% CI 1·03-12·03; p=0·044). Pre-intervention, urine tenofovir was detectable in 65% in the urine-test counselling group and 71% in the standard of care group (p=0·68). At 12 months, 31 (72%) of 43 in the intervention group had detectable urine tenofovir compared with 19 (45%) of 42 in the standard of care group (p=0·0015). 40 (93%) of 43 participants liked the test very much and only one disliked the test. One participant in the standard of care group was withdrawn at the 6-month visit due to HIV seroconversion. INTERPRETATION: A low-cost urine tenofovir assay to inform PrEP counselling resulted in improvement in both short-term and long-term metrics of adherence. This urine tenofovir assay could help to improve long-term PrEP adherence. FUNDING: National Institute of Allergy and Infectious Diseases and National Institutes of Health.

No dose adjustment of metformin or substrates of organic cation transporters (OCT)1 and OCT2 and multidrug and toxin extrusion protein (MATE)1/2K with fostemsavir coadministration based on modeling approaches.

Fostemsavir is an approved gp120-directed attachment inhibitor and prodrug for the treatment of human immunodeficiency virus type 1 infection in combination with other antiretrovirals (ARVs) in heavily treatment-experienced adults with multi-drug resistance, intolerance, or safety concerns with their current ARV regimen. Initial in vitro studies indicated that temsavir, the active moiety of fostemsavir, and its metabolites, inhibited organic cation transporter (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs) at tested concentration of 100 uM, although risk assessment based on the current Food and Drug Administration in vitro drug-drug interaction (DDI) guidance using the mechanistic static model did not reveal any clinically relevant inhibition on OCTs and MATEs. However, a DDI risk was flagged with EMA static model predictions. Hence, a physiologically based pharmacokinetic (PBPK) model of fostemsavir/temsavir was developed to further assess the DDI risk potential of OCT and MATEs inhibition by temsavir and predict changes in metformin (a sensitive OCT and MATEs substrate) exposure. No clinically relevant impact on metformin concentrations across a wide range of temsavir concentrations was predicted; therefore, no dose adjustment is recommended for metformin when co-administered with fostemsavir.

HIV-1 infection kinetics, drug resistance, and long-term safety of pre-exposure prophylaxis with emtricitabine plus tenofovir alafenamide (DISCOVER): week 144 open-label extension of a randomised, controlled, phase 3 trial.

BACKGROUND: Data characterising the long-term use and safety of emtricitabine plus tenofovir disoproxil fumarate as daily oral pre-exposure prophylaxis (PrEP) are scarce and there are uncertainties regarding the value of routine HIV-1 RNA testing during oral PrEP follow-up. METHODS: The DISCOVER trial was a randomised, controlled, phase 3 trial in which cisgender men and transgender women aged 18 years and older with a high likelihood of acquiring HIV were recruited from 94 clinics in Europe and North America and randomly assigned to receive either emtricitabine plus tenofovir disoproxil fumarate (200/25 mg) tablets daily, with matched placebo tablets, or emtricitabine plus tenofovir alafenamide (200/300 mg) tablets daily, with matched placebo tablets, for at least 96 weeks. After completion of the trial, participants were offered enrolment in this 48-week open-label extension study of emtricitabine plus tenofovir alafenamide. In participants diagnosed with HIV during the randomised and open-label phases of the study, we characterised HIV-1 test results and measured HIV-1 RNA viral load retrospectively when available. Adherence based on tenofovir diphosphate concentrations in dried blood spots and genotypic resistance were assessed in participants diagnosed with HIV. Safety assessments included adverse events, laboratory parameters, and, in a subset of participants, bone mineral density. HIV-1 incidence in participants initially randomly assigned to receive emtricitabine plus tenofovir alafenamide was estimated using a Poisson distribution. Changes from baseline in safety endpoints were described in participants assigned to received emtricitabine plus tenofovir alafenamide and in those who switched from emtricitabine plus tenofovir disoproxil fumarate during the open-label phase. This trial is registered with ClinicalTrials.gov, NCT02842086, and is ongoing. FINDINGS: Between Sept 13, 2016, and June 30, 2017, 5399 participants were enrolled and randomly assigned in DISCOVER. 2699 were assigned to receive emtricitabine plus tenofovir disoproxil fumarate and 2700 were assigned to receive emtricitabine plus tenofovir alafenamide, of whom 2693 and 2694, respectively, received at least one dose of study drug. 2115 (79%) assigned to emtricitabine plus tenofovir disoproxil fumarate switched to emtricitabine plus tenofovir alafenamide in the open-label phase, and 2070 (77%) continued with emtricitabine plus tenofovir alafenamide in the open-label phase. As of data cutoff (Dec 10, 2020), after 15 817 person-years of follow-up, 27 new HIV-1 diagnoses were observed across the total study period, with three occurring during the open-label phase. In participants who were initially assigned to emtricitabine plus tenofovir alafenamide, the incidence was 0·13 per 100 person-years (95% CI 0·061-0·23; ten of 2670). Stored plasma samples were available for 23 of 27 participants, including 22 with incident infection. In four (17%) of 23 participants, retrospective testing detected HIV-1 RNA before serological HIV-1 test positivity; one was a suspected baseline infection. Of the three incident cases, all three were non-adherent to PrEP and none developed drug resistance. Among participants taking emtricitabine plus tenofovir alafenamide for up to 144 weeks, markers of glomerular filtration and proximal renal tubule dysfunction (ß2-microglobulin to creatinine ratio and retinol-binding protein to creatinine ratio) improved or remained stable at 144 weeks compared with baseline, bone mineral density in hip and lumbar spine increased or remained stable from baseline to week 144 (n=191), cholesterol and glucose concentrations remained stable, and median bodyweight increased by less than 1 kg per year. In participants who switched from emtricitabine plus tenofovir disoproxil fumarate during the open-label phase (2115 [79%] of 2693), markers of glomerular filtration and proximal renal tubule dysfunction improved or remained stable, bone mineral density increased, cholesterol concentrations increased, glucose concentrations were similar, and median bodyweight increased more compared with those who remained on emtricitabine and tenofovir alafenamide. INTERPRETATION: Routine HIV-1 RNA testing for follow-up of individuals on daily oral PrEP provides modest additional clinical benefit. Long-term use of emtricitabine and tenofovir alafenamide as daily oral PrEP is safe and well tolerated and can be an especially appropriate choice for people with bone or renal morbidities. FUNDING: Gilead Sciences.