RESUMO
The nucleos(t)ide analogs require phosphorylation to the pharmacologically active anabolites in cells. We investigated the hypothesis that single-nucleotide polymorphisms (SNPs) in genes that encode transporters and phosphodiesterase (PDE) enzymes involved in tenofovir (TFV), disoproxil fumarate (TDF), and lamivudine (3TC) disposition will be associated with concentrations of their phosphate anabolites and virologic response. Individuals with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) coinfection receiving TDF/3TC-containing antiretroviral therapy were enrolled. Steady-state TFV diphosphate (TFV-DP) and 3TC triphosphate (3TC-TP) concentrations in peripheral blood mononuclear cells (PBMCs) and dried blood spot samples were quantified. The relationship between genetic variants and TFV-DP and 3TC-TP concentrations as well as with virologic response were examined using multivariable linear regression. Of the 136 participants (median age 43 years; 63% females), 6.6% had HBV non-suppression, and 7.4% had HIV non-suppression. The multidrug resistance protein 2 (encoded by ABCC2 rs2273697) SNP was associated with 3TC-TP concentrations in PBMCs. The human organic anion transporter-1 (encoded by SLC28A2) rs11854484 SNP was associated with HIV non-suppression, and when evaluated together with SNPs with marginal associations (ABCC2 rs717620 and PDE1C rs30561), participants with two or three variants compared to those with none of these variants had an adjusted odds ratio of 48.3 (confidence interval, 4.3-547.8) for HIV non-suppression. None of the SNPs were associated with HBV non-suppression. Our study identified ABCC2 SNP to be associated with 3TC-TP concentrations in PBMCs. Also, a combination of genetic variants of drug transporters and PDE was associated with HIV non-suppression.
RESUMO
Background: Oral pre-exposure prophylaxis (PrEP) using co-formulated emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) is a potent HIV prevention method for men and women, with its efficacy highly dependent on adherence. A pivotal HIV efficacy study combined with a directly observed pharmacological study defined the thresholds for HIV protection in men who have sex with men (MSM), which are the keys to PrEP promotion and development of new PrEP agents. For African women at risk for HIV and belonging to a priority group considered due to disproportionately high incident HIV infections, the variable adherence in PrEP clinical trials and the limited pharmacologic data have resulted in a lack of clarity about the PrEP adherence required for HIV protection. We propose a study to quantify the adherence-concentration-efficacy thresholds of TDF/FTC PrEP among African cisgender women to inform decisions about optimal PrEP dosing and adherence for HIV protection. Methods: We randomized 45 low-risk HIV-uninfected African women, aged 18-30 years old, to directly observe the TDF/FTC PrEP of two, four, or seven doses per week for 8 weeks. A complementary age-matched pregnant women cohort at high risk of HIV, who will receive seven doses per week, was recruited (N = 15) with the primary aim of establishing benchmark concentrations in dried blood spots and peripheral blood mononuclear cells. Plasma, whole blood (WB), urine, hair, vaginal fluid, and vaginal tissue (non-pregnant women only) were archived for future testing. Drug concentrations were measured using methods validated for each biological matrix. Pharmacokinetic models were fitted to drug concentrations to quantify concentration-adherence thresholds. To define the drug concentrations associated with HIV protection, we applied the newly defined thresholds from the primary pharmacologic trial to the subset of women randomized to TDF/FTC or TDF in the Partners PrEP Study with the drug concentration assessed in plasma and WB samples. Multiple imputation was used to construct a data set with drug concentrations at each visit when an HIV test was performed for the entire cohort, replicating the work for MSM. Discussion: The proposed study generated the first African women-specific TDF-PrEP adherence-concentration-efficacy thresholds essential for guiding the accurate interpretation of TDF/FTC PrEP programs and clinical trials of novel HIV prevention products using TDF/FTC as an active control. Clinical Trial Registration: ClinicalTrials.gov, identifier (NCT05057858).
RESUMO
This randomized controlled study assessed the feasibility, acceptability, and preliminary impact of the PrEP iT! mHealth intervention designed to improve PrEP adherence among young men who have sex with men (YMSM). A national sample of 80 YMSM in the U.S. (Mage = 25 years; 54% racial/ethnic minority), recruited through social media ads, were randomized to either the PrEP iT! or usual PrEP care conditions. Participants completed online surveys and submitted self-collected dried blood sample (DBS) data as measures of PrEP adherence. Differences in PrEP adherence across treatment arms and between participants with high versus low engagement in PrEP iT! were assessed. Retention was high at the three (94%) and six (93%) month assessment, and participants in PrEP iT! reported satisfactory acceptability of the intervention. There were no significant differences in self-reported or DBS-derived PrEP adherence between randomized groups. However, YMSM in the PrEP iT! group with high PrEP adherence (the equivalent of four or more doses/week through self-report and DBS-derived measures) demonstrated significantly higher engagement in the intervention than those with low PrEP adherence (the equivalent of 3 or fewer doses/week). Overall, the PrEP iT! intervention demonstrated strong feasibility and acceptability. The finding that high PrEP iT! intervention engagement was associated with protective levels of PrEP adherence suggests it is a viable adherence support tool that should be further evaluated in definitive trial among YMSM who need basic support, or as part of a more comprehensive adherence support package for those who need greater assistance.Trial registration Clinical Trials # NCT04509076 (registered August 10, 2020).
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Homossexualidade Masculina , Adesão à Medicação , Profilaxia Pré-Exposição , Minorias Sexuais e de Gênero , Telemedicina , Humanos , Masculino , Infecções por HIV/prevenção & controle , Adesão à Medicação/estatística & dados numéricos , Minorias Sexuais e de Gênero/psicologia , Projetos Piloto , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Profilaxia Pré-Exposição/métodos , Homossexualidade Masculina/psicologia , Homossexualidade Masculina/estatística & dados numéricos , Estados Unidos , Adulto Jovem , Estudos de Viabilidade , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Aceitação pelo Paciente de Cuidados de Saúde/psicologiaRESUMO
BACKGROUND: An increasing number of countries are currently implementing or scaling-up HIV pre-exposure prophylaxis (PrEP) care. With the introduction of PrEP, there was apprehension that condom use would decline and sexually transmitted infections (STIs) would increase. To inform sexual health counselling and STI screening programmes, we aimed to study sexual behaviour and STI incidence among men who have sex with men (MSM) and transgender women who use long-term daily or event-driven PrEP. METHODS AND FINDINGS: The Amsterdam PrEP demonstration project (AMPrEP) was a prospective, closed cohort study, providing oral daily PrEP and event-driven PrEP to MSM and transgender women from 2015 to 2020. Participants could choose their PrEP regimen and could switch at each three-monthly visit. STI testing occurred at and, upon request, in-between 3-monthly study visits. We assessed changes in numbers of sex partners and condomless anal sex (CAS) acts with casual partners over time using negative binomial regression, adjusted for age. We assessed HIV incidence and changes in incidence rates (IRs) of any STI (i.e., chlamydia, gonorrhoea, or infectious syphilis) and individual STIs over time using Poisson regression, adjusted for age and testing frequency. A total of 367 participants (365 MSM) commenced PrEP and were followed for a median 3.9 years (interquartile range [IQR] = 3.4-4.0). Median age was 40 years (IQR = 32-48), 315 participants (85.8%) self-declared ethnicity as white and 280 (76.3%) had a university or university of applied sciences degree. Overall median number of sex partners (past 3 months) was 13 (IQR = 6-26) and decreased per additional year on PrEP (adjusted rate ratio [aRR] = 0.86/year, 95% confidence interval [CI] = 0.83-0.88). Overall median number of CAS acts with casual partners (past 3 months) was 10 (IQR = 3-20.5) and also decreased (aRR = 0.92/year, 95% CI = 0.88-0.97). We diagnosed any STI in 1,092 consultations during 1,258 person years, resulting in an IR of 87/100 person years (95% CI = 82-92). IRs of any STI did not increase over time for daily PrEP or event-driven PrEP users. Two daily PrEP users, and no event-driven PrEP users, were diagnosed with HIV during their first year on PrEP. Study limitations include censoring follow-up due to COVID-19 measures and an underrepresentation of younger, non-white, practically educated, and transgender individuals. CONCLUSIONS: In this prospective cohort with a comparatively long follow-up period of 4 years, we observed very low HIV incidence and decreases in the numbers of casual sex partners and CAS acts over time. Although the STI incidence was high, it did not increase over time. TRIAL REGISTRATION: The study was registered at the Netherlands Trial Register (NL5413) https://www.onderzoekmetmensen.nl/en/trial/22706.
Assuntos
Homossexualidade Masculina , Profilaxia Pré-Exposição , Comportamento Sexual , Infecções Sexualmente Transmissíveis , Humanos , Masculino , Profilaxia Pré-Exposição/métodos , Incidência , Adulto , Infecções Sexualmente Transmissíveis/prevenção & controle , Infecções Sexualmente Transmissíveis/epidemiologia , Estudos Prospectivos , Seguimentos , Infecções por HIV/prevenção & controle , Infecções por HIV/epidemiologia , Países Baixos/epidemiologia , Feminino , Adulto Jovem , Pessoa de Meia-Idade , Fármacos Anti-HIV/uso terapêutico , Pessoas Transgênero , Parceiros SexuaisRESUMO
This case-control study explored cumulative tenofovir exposure among patients with HIV/HBV co-infection with HIV viral suppression. Among patients taking tenofovir disoproxil fumarate, median TFV-DP levels in dried blood spots were â¼3-fold lower among patients with incomplete HBV viral suppression (n=4) compared to those with complete suppression (n=5) (516 vs.1456 fmol/punch).
RESUMO
We evaluated hair tenofovir (TFV) concentrations as an adherence metric for HIV pre-exposure prophylaxis (PrEP) during pregnancy and postpartum and compared hair levels with tenofovir-diphosphate (TFV-DP) levels in dried blood spots (DBS). Overall, 152 hair samples from 102 women and 36 hair-DBS paired samples from 29 women were collected from a subset of women in a cluster randomized trial. Having a partner known to be living with HIV was associated with higher hair TFV levels (p<0.001). Hair TFV concentrations were strongly correlated with DBS TFV-DP levels (r=0.76, p<0.001), indicating hair as promising cumulative adherence metric for perinatal PrEP assessment.
RESUMO
BACKGROUND: QUANTI-TAF aimed to establish tenofovir-diphosphate/emtricitabine-triphosphate (TFV-DP/FTC-TP) adherence benchmarks in dried blood spots (DBS) for persons with HIV (PWH) receiving tenofovir alafenamide/emtricitabine (TAF/FTC)-based antiretroviral therapy (ART). METHODS: During a 16-week pharmacokinetic study, PWH received TAF/FTC-based ART co-encapsulated with an ingestible sensor to directly measure cumulative (enrollment to final visit) and 10-day adherence. At monthly visits, intraerythrocytic concentrations of TAF/FTC anabolites (TFV-DP/FTC-TP) in DBS were quantified by LC-MS/MS and summarized at steady-state (week 12 or 16) as median (IQR). Linear mixed-effects models evaluated factors associated with TFV-DP/FTC-TP. RESULTS: 84 participants (86% male, 11% female, and 4% transgender), predominantly receiving bictegravir/TAF/FTC (73%) enrolled. 92% completed week 12 or 16 (94% receiving unboosted ART). TFV-DP for <85% (7/72), ≥85%-<95% (9/72), and ≥95% (56/72) cumulative adherence was 2696 (2039-4108), 3117 (2332-3339), and 3344 (2605-4293) fmol/punches. All participants with ≥85% cumulative adherence had TFV-DP ≥1800 fmol/punches. Adjusting for cumulative adherence, TFV-DP was higher with boosted ART, lower BMI, and in non-Blacks. FTC-TP for <85% (14/77), ≥85%-<95% (6/77), and ≥95% (57/77) 10-day adherence was 3.52 (2.64-4.48), 4.58 (4.39-5.06), and 4.96 (4.21-6.26) pmol/punches. All participants with ≥85% 10-day adherence had FTC-TP ≥2.5 pmol/punches. Low-level viremia (HIV-1 RNA ≥20-<200 copies/mL) occurred at 60/335 (18%) visits in 33/84 (39%) participants (range: 20-149 copies/mL), with similar TFV-DP (3177 [2494-4149] fmol/punches) compared with HIV-1 RNA <20 copies/mL visits (3279 [2580-4407] fmol/punches). CONCLUSIONS: We propose PK-based TFV-DP (≥1800 fmol/punches)/FTC-TP (≥2.5 pmol/punches) benchmarks in DBS for PWH receiving unboosted TAF/FTC-based ART with ≥85% adherence. In the setting of high adherence, low-level viremia was common.
RESUMO
BACKGROUND: On-demand topical products could be an important tool for HIV prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG; 16 mg/20 mg) insert administered rectally. METHODS: MTN-039 was a Phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid (RF), and rectal tissue (RT) were collected over 72 hours (hr) following rectal administration of one and two TAF/EVG inserts for each participant. ClinicalTrials.gov Identifier: NCT04047420. RESULTS: TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. RT EVG peaked at 2-hr (median 2 inserts= 9 ng/mg) but declined to BLQ in the majority of samples at 24-hr, whereas TFV-DP remained high >2,000 fmol/million cells for 72-hr with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each timepoint for both 1 and 2 inserts (p<0.065 and p<0.039, respectively). DISCUSSION: Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours.
RESUMO
OBJECTIVE: We assessed the association and concordance between self-reported oral pre-exposure prophylaxis (PrEP) intake in a diary app and intraerythrocytic drug metabolite concentrations. DESIGN: AMPrEP was a prospective demonstration study providing daily and event-driven PrEP to MSM in Amsterdam, the Netherlands (2015-2020). METHODS: Participants could record their PrEP intake in a diary app. Dried blood spots (DBS) were taken at 6, 12, 24, and 48âmonths and analysed for tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations. We included TFV-DP measurements preceded by diary completion on at least 90% of days in the 6âweeks prior. We examined the association between self-reported PrEP intake (i.e. number of pills) and TFV-DP concentrations using tobit regression with a random intercept per participant. We also calculated concordance between categorized PrEP intake (i.e. <2, 2-3, 4-6 or 7 pills per week) and categorized TFV-DP concentrations (i.e. <350, 350-699,700-1249 or ≥1250âfmol/punch) using weighted Cohen's kappa. Last, we calculated concordance between self-reported recent PrEP intake (yes/no, in past 2 days) and quantifiability of FTC-TP (yes/no) using Cohen's kappa. RESULTS: Seven hundred and fifty-nine DBS measurements from 282 MSM were included. Self-reported PrEP intake was strongly and positively associated with TFV-DP concentration ( ß â=â0.77, 95% CIâ=â0.70-0.84, P â<â0.0001). Concordance between categorized PrEP intake and TFV-DP concentration was moderate ( κ â=â0.44, 95% CIâ=â0.39-0.50). Concordance between self-reported recent PrEP intake and FTC-TP quantifiability was perfect ( κ â=â0.83, 95% CI 0.76-0.90). CONCLUSION: Self-reported PrEP intake in a diary app is strongly correlated with actual use, and therefore reliable for comparing PrEP adherence between groups. Still, suboptimal criterion validity according to clinically relevant categories warrants caution when assessing 6-week reported adherence for individuals.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Profilaxia Pré-Exposição , Humanos , Profilaxia Pré-Exposição/métodos , Masculino , Países Baixos , Infecções por HIV/prevenção & controle , Estudos Prospectivos , Adulto , Fármacos Anti-HIV/administração & dosagem , Organofosfatos/administração & dosagem , Adenina/análogos & derivados , Adenina/administração & dosagem , Adenina/farmacocinética , Homossexualidade Masculina , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Autorrelato , Tenofovir/administração & dosagem , Teste em Amostras de Sangue SecoRESUMO
OBJECTIVE: Concentrations of tenofovir diphosphate (TFV-DP) and lamivudine triphosphate (3TC-TP) in cells are correlates of medication adherence and antiviral activity. However, studies have yet to characterize the simultaneous relationship between TFV-DP and 3TC-TP concentrations with HIV and hepatitis B virus (HBV) suppression. METHODS: Individuals with HIV/HBV coinfection on tenofovir disoproxil fumarate (TDF)-containing antiretroviral therapy (ART) were enrolled. Peripheral blood mononuclear cells (PBMCs) and dried blood spots (DBS) samples were collected and steady-state TFV-DP and 3TC-TP concentrations quantified using validated methods. The relationship between patient factors, TFV-DP, and 3TC-TP concentrations in PBMCs and DBS with HBV and HIV viral suppression were examined. RESULTS: Of 138 participants on TDF-containing ART for a median duration (range) of 6 (0.75-15) years, the median age was 43âyears and 64% were women. Overall, 128 (92.8%) and 129 (93.5%) had suppressed HIV and HBV viral loads, respectively. Of the 128 participants with suppressed HIV, 122 (95.3%) had suppressed HBV. Self-reported ART adherence, recent change to dolutegravir-based ART, TFV-DP, and 3TC-TP concentrations in PBMCs and DBS were associated with HIV RNA suppression, while HBe antigen positivity, HIV suppression, and TFV-DP concentrations in DBS were associated with HBV DNA suppression (including six persons with HBV nonsuppression and HIV suppression). CONCLUSION: Long-term TDF/3TC-conatining ART was highly efficacious in individuals with HIV/HBV coinfection. Higher TFV-DP concentrations were predictive of suppression for both viruses. Persistent HBV viremia on TDF/3TC-containg ART requires additional research, but may represent poor adherence and the need for adherence interventions or novel antivirals.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV , Coinfecção , Citidina Trifosfato/análogos & derivados , Didesoxinucleotídeos , Infecções por HIV , Organofosfatos , Humanos , Feminino , Adulto , Masculino , Vírus da Hepatite B , Fármacos Anti-HIV/uso terapêutico , Leucócitos Mononucleares , Coinfecção/tratamento farmacológico , Lamivudina/uso terapêutico , Tenofovir/uso terapêutico , Viremia/tratamento farmacológicoRESUMO
Treatment nonadherence is a pressing issue in people living with HIV (PLWH), as they require lifelong therapy to maintain viral suppression. Poor adherence leads to antiretroviral (ARV) resistance, transmission to others, AIDS progression, and increased morbidity and mortality. Long-acting (LA) ARV therapy is a promising strategy to combat the clinical drawback of user-dependent dosing. Islatravir (ISL) is a promising candidate for HIV treatment given its long half-life and high potency. Here we show constant ISL release from a subdermal LA nanofluidic implant achieves viral load reduction in SHIV-infected macaques. Specifically, a mean delivery dosage of 0.21 ± 0.07 mg/kg/day yielded a mean viral load reduction of -2.30 ± 0.53 log10 copies/mL at week 2, compared to baseline. The antiviral potency of the ISL delivered from the nanofluidic implant was higher than oral ISL dosed either daily or weekly. At week 3, viral resistance to ISL emerged in 2 out of 8 macaques, attributable to M184V mutation, supporting the need of combining ISL with other ARV for HIV treatment. The ISL implant produced moderate reactivity in the surrounding tissue, indicating tolerability. Overall, we present the ISL subdermal implant as a promising approach for LA ARV treatment in PLWH.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Animais , Humanos , Fármacos Anti-HIV/uso terapêutico , Macaca , Infecções por HIV/tratamento farmacológico , Desoxiadenosinas/uso terapêutico , AntirretroviraisRESUMO
Non-suppressible HIV-1 viremia (NSV) is defined as persistent low-level viremia on antiretroviral therapy (ART) without evidence of ART non-adherence or significant drug resistance. Unraveling the mechanisms behind NSV would broaden our understanding of HIV-1 persistence. Here we analyzed plasma virus sequences in eight ART-treated individuals with NSV (88% male) and show that they are composed of large clones without evidence of viral evolution over time in those with longitudinal samples. We defined proviruses that match plasma HIV-1 RNA sequences as 'producer proviruses', and those that did not as 'non-producer proviruses'. Non-suppressible viremia arose from expanded clones of producer proviruses that were significantly larger than the genome-intact proviral reservoir of ART-suppressed individuals. Integration sites of producer proviruses were enriched in proximity to the activating H3K36me3 epigenetic mark. CD4+ T cells from participants with NSV demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, participants with NSV showed significantly lower HIV-specific CD8+ T cell responses compared with untreated viremic controllers with similar viral loads. We identified potential critical host and viral mediators of NSV that may represent targets to disrupt HIV-1 persistence.
Assuntos
Infecções por HIV , Soropositividade para HIV , HIV-1 , Humanos , Masculino , Feminino , HIV-1/genética , Viremia , Provírus/genética , Provírus/metabolismo , Infecções por HIV/tratamento farmacológico , Linfócitos T CD4-Positivos , RNA Viral , Carga ViralRESUMO
BACKGROUND: Injectable cabotegravir was superior to daily oral tenofovir disoproxil fumarate plus emtricitabine for HIV prevention in two clinical trials. Both trials had the primary aim of establishing the HIV prevention efficacy of long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) compared with tenofovir disoproxil fumarate plus emtricitabine daily oral PrEP. Long-acting PrEP was associated with diagnostic delays and integrase strand-transfer inhibitor (INSTI) resistance. This report presents findings from the first unblinded year of the HIV Prevention Trials Network (HPTN) 083 study. METHODS: The HPTN 083 randomised controlled trial enrolled HIV-uninfected cisgender men and transgender women at elevated HIV risk who have sex with men, from 43 clinical research sites in Africa, Asia, Latin America, and the USA. Inclusion criteria included: a negative HIV serological test at the screening and study entry, undetectable HIV RNA levels within 14 days of study entry, age 18 years or older, overall good health as determined by clinical and laboratory evaluations, and a creatinine clearance of 60 mL/min or higher. Participants were randomly allocated to receive long-acting injectable cabotegravir or daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP. After study unblinding, participants remained on their original regimen awaiting an extension study. HIV infections were characterised retrospectively at a central laboratory. Here we report the secondary analysis of efficacy and safety for the first unblinded year. The primary outcome was incident HIV infection. Efficacy analyses were done on the modified intention-to-treat population using a Cox regression model. Adverse events were compared across treatment groups and time periods (blinded vs unblinded). This trial is registered with ClinicalTrials.gov, NCT02720094. FINDINGS: Of the 4488 participants who contributed person-time to the blinded analysis, 3290 contributed person-time to the first unblinded year analysis between May 15, 2020, and May 14, 2021. Updated HIV incidence in the blinded phase was 0·41 per 100 person-years for long-acting injectable cabotegravir PrEP and 1·29 per 100 person-years for daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP (hazard ratio [HR] 0·31 [95% CI 0·17-0·58], p=0·0003). HIV incidence in the first unblinded year was 0·82 per 100 person-years for long-acting PrEP and 2·27 per 100 person-years for daily oral PrEP (HR 0·35 [0·18-0·69], p=0·002). Adherence to both study products decreased after study unblinding. Additional infections in the long-acting PrEP group included two with on-time injections; three with one or more delayed injections; two detected with long-acting PrEP reinitiation; and 11 more than 6 months after their last injection. Infection within 6 months of cabotegravir exposure was associated with diagnostic delays and INSTI resistance. Adverse events were generally consistent with previous reports; incident hypertension in the long-acting PrEP group requires further investigation. INTERPRETATION: Long-acting injectable cabotegravir PrEP retained high efficacy for HIV prevention in men and transgender women who have sex with men during the first year of open-label follow-up, with a near-identical HR for HIV risk reduction between long-acting injectable cabotegravir and daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP during the first year after unblinding compared with the blinded period. Extended follow-up further defined the risk period for diagnostic delays and emergence of INSTI resistance. FUNDING: Division of AIDS at the National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and Gilead Sciences.
Assuntos
Síndrome da Imunodeficiência Adquirida , Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Profilaxia Pré-Exposição , Pessoas Transgênero , Masculino , Feminino , Humanos , Adolescente , Infecções por HIV/tratamento farmacológico , Tenofovir/efeitos adversos , Emtricitabina/efeitos adversos , Fármacos Anti-HIV/efeitos adversos , Estudos Retrospectivos , Síndrome da Imunodeficiência Adquirida/tratamento farmacológicoRESUMO
Broadly neutralizing monoclonal antibodies (mAbs) are being developed for HIV-1 prevention. Hence, these mAbs and licensed oral pre-exposure prophylaxis (PrEP) (tenofovir-emtricitabine) can be concomitantly administered in clinical trials. In 48 US participants (men and transgender persons who have sex with men) who received the HIV-1 mAb VRC01 and remained HIV-free in an antibody-mediated-prevention trial (ClinicalTrials.gov #NCT02716675), we conduct a post-hoc analysis and find that VRC01 clearance is 0.08 L/day faster (p = 0.005), and dose-normalized area-under-the-curve of VRC01 serum concentration over-time is 0.29 day/mL lower (p < 0.001) in PrEP users (n = 24) vs. non-PrEP users (n = 24). Consequently, PrEP users are predicted to have 14% lower VRC01 neutralization-mediated prevention efficacy against circulating HIV-1 strains. VRC01 clearance is positively associated (r = 0.33, p = 0.03) with levels of serum intestinal Fatty Acid Binding protein (I-FABP), a marker of epithelial intestinal permeability, which is elevated upon starting PrEP (p = 0.04) and after months of self-reported use (p = 0.001). These findings have implications for the evaluation of future HIV-1 mAbs and postulate a potential mechanism for mAb clearance in the context of PrEP.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Profilaxia Pré-Exposição , Masculino , Adulto , Humanos , Tenofovir/uso terapêutico , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Anticorpos Monoclonais/uso terapêuticoRESUMO
Pre-exposure prophylaxis (PrEP) with tenofovir (TFV) disoproxil fumarate and emtricitabine administered orally daily is effective in preventing human immunodeficiency virus (HIV) acquisition in both men and women with sufficient adherence; however, the adherence-efficacy relationship in cisgender women has not been well established. We calculated the adherence-efficacy curve for cisgender women by using HIV incidence and plasma TFV concentration data from three trials (FEM-PrEP, VOICE and Partners PrEP). We imputed TFV diphosphate (TFV-DP) concentrations, a measure of long-term adherence, from TFV quantification by using data from the HIV Prevention Trials Network 082 study, which measured both TFV-DP and TFV concentrations. Two, four and seven pills per week reduced HIV incidence by 59.3% (95% credible interval (CrI) 29.9-95.8%), 83.8% (95% CI 51.7-99.8%) and 95.9% (95% CI 72.6-100%), respectively. Our adherence-efficacy curve can be validated and updated by HIV prevention studies that directly measure TFV-DP concentrations. The curve suggests that high adherence confers high protection in cisgender women. However, the lower efficacy with partial adherence highlights the need for new PrEP products and interventions to increase adherence.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Profilaxia Pré-Exposição , Masculino , Humanos , Feminino , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Infecções por HIV/tratamento farmacológico , HIV , Emtricitabina/uso terapêutico , Tenofovir/uso terapêutico , Adesão à MedicaçãoRESUMO
To develop effective PrEP adherence interventions, it is important to understand the interplay between disclosure of pre-exposure prophalxis (PrEP) use, social support, and PrEP adherence. We leveraged the HPTN 082 study conducted among 451 adolescent girls and young women (AGYW) (ages 16 to 25 years, 2016 to 2019) in South Africa and Zimbabwe. Among the 349 who had month three disclosure and PrEP adherence data, 60% (n = 206) felt supported by adults, and 89% (n = 309) disclosed PrEP use to at least one person. PrEP disclosure was not associated with increased adherence, measured by intracellular tenofovir-diphosphate concentrations in dried blood spots. Women who reported having supportive adults, and disclosed to their parents, had higher adherence at 6 months with an increase of 177 fmol/punch (95% CI 12 to 343, t = 2.11, p = 0.04). PrEP interventions that help AGYW identify supportive relationships and effectively communicate the benefits of PrEP may improve PrEP adherence.Clinicaltrials.gov ID number: NCT02732730.
RESUMO
Background: Food insecurity has been linked to suboptimal antiretroviral therapy (ART) adherence in persons with HIV (PWH). This association has not been evaluated using tenofovir diphosphate (TFV-DP) in dried blood spots (DBSs), a biomarker of cumulative ART adherence and exposure. Methods: Within a prospective South African cohort of treatment-naive PWH initiating ART, a subset of participants with measured TFV-DP in DBS values was assessed for food insecurity status. Bivariate and multivariate median-based regression analysis compared the association between food insecurity and TFV-DP concentrations in DBSs adjusting for age, sex, ethnicity, medication possession ratio (MPR), and estimated glomerular filtration rate. Results: Drug concentrations were available for 285 study participants. Overall, 62 (22%) PWH reported worrying about food insecurity and 44 (15%) reported not having enough food to eat in the last month. The crude median concentrations of TFV-DP in DBSs differed significantly between those who expressed food insecurity worry versus those who did not (599 [interquartile range {IQR}, 417-783] fmol/punch vs 716 [IQR, 453-957] fmol/punch; P = .032). In adjusted median-based regression, those with food insecurity worry had concentrations of TFV-DP that were 155 (95% confidence interval, -275 to -35; P = .012) fmol/punch lower than those who did not report food insecurity worry. Age and MPR remained significantly associated with TFV-DP. Conclusions: In this study, food insecurity worry is associated with lower TFV-DP concentrations in South African PWH. This highlights the role of food insecurity as a social determinant of HIV outcomes including ART failure and resistance.
RESUMO
Understanding PrEP adherence is key in the formulation of HIV prevention strategies; however, measurement of adherence can be challenging. We compared multiple adherence measures in a two-year study of young Kenyan women at high risk of HIV acquisition. Among 289 participants, concordance between electronic adherence monitoring (EAM) and tenofovir diphosphate (TFV-DP) in dried blood spots ranged from 57 to 72% depending on selected thresholds. Using area under the receiver operating curve, discrimination of quantifiable TFV-DP was high at 0.85 with EAM and low at 0.49-0.54 for multiple self-reported measures. Correlation between EAM and self-reported measures was low (r < 0.11) although correlation within self-reported measures was moderate (r > 0.69). These findings indicate that both TFV-DP and EAM are useful PrEP adherence tools. Adherence would benefit from better availability of less expensive versions of both measurement tools. Additionally, further research on TFV-DP thresholds is needed to inform interpretation and use in understanding PrEP adherence in this population.
RESUMEN: Comprender la adherencia a la PrEP es importante en la formulación de estrategias de prevención del VIH; sin embargo, la medición de la adherencia puede ser difícil. Comparamos múltiples medidas de adherencia en un estudio de dos años de mujeres jóvenes kenianas con alto riesgo de contraer el VIH. Entre 289 participantes, la concordancia entre la monitorización electrónica de la adherencia (EAM) y el tenofovir difosfato (TFV-DP) en las manchas de sangre seca varió del 57% al 72% dependiendo de los umbrales seleccionados. Utilizando el área bajo la curva operativa del receptor, la discriminación de TFV-DP cuantificable fue alta en 0.85 con EAM y baja en 0.490.54 para múltiples medidas autoinformadas. La correlación entre la EAM y las medidas autoinformadas fue baja (r < 0,11), aunque la correlación entre de las medidas autoinformadas fue moderada (r > 0,69). Estos resultados indican que tanto TFV-DP como EAM son herramientas útiles de adherencia a la PrEP. La adherencia se beneficiaría de una mejor disponibilidad de versiones menos costosas de ambas herramientas de medición. Además, se necesita más investigación sobre los umbrales TFV-DP para informar la interpretación y el uso en la comprensión de la adherencia a la PrEP en esta población.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Profilaxia Pré-Exposição , Humanos , Feminino , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Quênia/epidemiologia , Adesão à MedicaçãoRESUMO
The impact of pre-exposure prophylaxis (PrEP) on slowing the global HIV epidemic hinges on effective drugs and delivery platforms. Oral drug regimens are the pillar of HIV PrEP, but variable adherence has spurred development of long-acting delivery systems with the aim of increasing PrEP access, uptake, and persistence. We have developed a long-acting subcutaneous nanofluidic implant that can be refilled transcutaneously for sustained release of the HIV drug islatravir, a nucleoside reverse transcriptase translocation inhibitor that is used for HIV PrEP. In rhesus macaques, the islatravir-eluting implants achieved constant concentrations of islatravir in plasma (median 3.14 nM) and islatravir triphosphate in peripheral blood mononuclear cells (median 0.16 picomole per 106 cells) for more than 20 months. These drug concentrations were above the established PrEP protection threshold. In two unblinded, placebo-controlled studies, islatravir-eluting implants conferred 100% protection against infection with SHIVSF162P3 after repeated low-dose rectal or vaginal challenge in male or female rhesus macaques, respectively, compared to placebo control groups. The islatravir-eluting implants were well tolerated with mild local tissue inflammation and no signs of systemic toxicity over the 20-month study period. This refillable islatravir-eluting implant has potential as a long-acting drug delivery system for HIV PrEP.