18 research outputs found
Phase 2 Study of the Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Men Who Have Sex With Men (HPTN 069/ACTG A5305)
Maraviroc (MVC) is a candidate for human immunodeficiency virus (HIV) pre-exposure prophylaxis
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Genetic Variation of the Kinases That Phosphorylate Tenofovir and Emtricitabine in Peripheral Blood Mononuclear Cells.
Tenofovir (TFV) disoproxil fumarate and emtricitabine (FTC) are used in combination for HIV treatment and pre-exposure prophylaxis (PrEP). TFV disoproxil fumarate is a prodrug that undergoes diester hydrolysis to TFV. FTC and TFV are nucleoside/nucleotide reverse transcriptase inhibitors that upon phosphorylation to nucleotide triphosphate analogs competitively inhibit HIV reverse transcriptase. We previously demonstrated that adenylate kinase 2, pyruvate kinase, muscle and pyruvate kinase, liver and red blood cell phosphorylate TFV in peripheral blood mononuclear cells (PBMC). To identify the kinases that phosphorylate FTC in PBMC, siRNAs targeted toward kinases that phosphorylate compounds structurally similar to FTC were delivered to PBMC, followed by incubation with FTC and the application of a matrix-assisted laser desorption ionization-mass spectrometry method and ultra high performance liquid chromatography-UV to detect the formation of FTC phosphates. Knockdown of deoxycytidine kinase decreased the formation of FTC-monophosphate, while siRNA targeted toward thymidine kinase 1 decreased the abundance of FTC-diphosphate. Knockdown of either cytidine monophosphate kinase 1 or phosphoglycerate kinase 1 decreased the abundance of FTC-triphosphate. Next-generation sequencing of genomic DNA isolated from 498 HIV-uninfected participants in the HIV Prevention Trials Network 069/AIDS Clinical Trials Group A5305 clinical study, revealed 17 previously unreported genetic variants of TFV or FTC phosphorylating kinases. Of note, four individuals were identified as simultaneous carriers of variants of both TFV and FTC activating kinases. These results identify the specific kinases that activate FTC in PBMC, while also providing further insight into the potential for genetic variation to impact TFV and FTC activation
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Genetic Variation of the Kinases That Phosphorylate Tenofovir and Emtricitabine in Peripheral Blood Mononuclear Cells.
Tenofovir (TFV) disoproxil fumarate and emtricitabine (FTC) are used in combination for HIV treatment and pre-exposure prophylaxis (PrEP). TFV disoproxil fumarate is a prodrug that undergoes diester hydrolysis to TFV. FTC and TFV are nucleoside/nucleotide reverse transcriptase inhibitors that upon phosphorylation to nucleotide triphosphate analogs competitively inhibit HIV reverse transcriptase. We previously demonstrated that adenylate kinase 2, pyruvate kinase, muscle and pyruvate kinase, liver and red blood cell phosphorylate TFV in peripheral blood mononuclear cells (PBMC). To identify the kinases that phosphorylate FTC in PBMC, siRNAs targeted toward kinases that phosphorylate compounds structurally similar to FTC were delivered to PBMC, followed by incubation with FTC and the application of a matrix-assisted laser desorption ionization-mass spectrometry method and ultra high performance liquid chromatography-UV to detect the formation of FTC phosphates. Knockdown of deoxycytidine kinase decreased the formation of FTC-monophosphate, while siRNA targeted toward thymidine kinase 1 decreased the abundance of FTC-diphosphate. Knockdown of either cytidine monophosphate kinase 1 or phosphoglycerate kinase 1 decreased the abundance of FTC-triphosphate. Next-generation sequencing of genomic DNA isolated from 498 HIV-uninfected participants in the HIV Prevention Trials Network 069/AIDS Clinical Trials Group A5305 clinical study, revealed 17 previously unreported genetic variants of TFV or FTC phosphorylating kinases. Of note, four individuals were identified as simultaneous carriers of variants of both TFV and FTC activating kinases. These results identify the specific kinases that activate FTC in PBMC, while also providing further insight into the potential for genetic variation to impact TFV and FTC activation
Sexual behavior and medication adherence in men who have sex with men participating in a pre-exposure prophylaxis study of combinations of Maraviroc, Tenofovir Disoproxil Fumarate and/or Emtricitabine (HPTN 069/ACTG 5305)
HPTN 069/ACTG 5305 was designed to evaluate potential new PrEP regimens that included maraviroc, tenofovir disoproxil fumarate, and/or emtricitabine. The current analyses assessed antiretroviral (ARV) plasma concentrations in relation to sexual behavior in 224 cisgender men who have sex with men and 2 transgender women at risk for HIV. Poisson generalized estimating equations (GEE) regression were used to test for associations between self-reported sexual behavior, sociodemographic, behavioral variables, and study drug levels The median (IQR) age was 30 [25, 37] years old; 48.2% had completed college; 27.4% were Black and 21.7% Latino. At weeks 24 and 48, one third of participants reported condomless anal sex (CAS) in the prior month with more than one partner. CAS was associated with daily ARV drug use (χ = 12.64, p = 0.002). Older individuals and those with greater education were more likely to ingest ARV drugs daily (χ = 9.36, p = 0.009 and χ = 8.63, p = 0.013, respectively), while neither race nor ethnicity was associated with daily ARV drug use. Participants who reported recent condomless anal sex and/or advanced education had higher rates of daily ARV drug use. These data support the need for ongoing adherence counseling in clinical trials of new PrEP modalities
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Phase 2 Study of the Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Men Who Have Sex With Men (HPTN 069/ACTG A5305).
BackgroundMaraviroc (MVC) is a candidate for human immunodeficiency virus (HIV) pre-exposure prophylaxis.MethodsPhase 2 48-week safety/tolerability study was conducted, comparing 4 regimens: MVC alone, MVC plus emtricitabine (FTC), MVC plus tenofovir disoproxil fumarate (TDF), and TDF plus FTC. Eligible participants were HIV-uninfected men and transgender women reporting condomless anal intercourse with ≥1 HIV-infected or unknown-serostatus man within 90 days. At each visit, assessments, laboratory testing, and counseling were done. Analyses were intention to treat.ResultsAmong 406 participants, 84% completed follow-up, 7% stopped early, and 9% were lost to follow-up; 9% discontinued their regimen early. The number discontinuing and the time to discontinuation did not differ among study regimens (P = .60). Rates of grade 3-4 adverse events did not differ among regimens (P = .37). In a randomly selected subset, 77% demonstrated detectable drug concentrations at week 48. Five participants acquired HIV infection (4 MVC alone, 1 MVC + TDF; overall annualized incidence, 1.4% [95% confidence interval, .5%-3.3%], without differences by regimen; P = .32); 2 had undetectable drug concentrations at every visit, 2 had low concentrations at the seroconversion visit, and 1 had variable concentrations.ConclusionsMVC-containing regimens were safe and well tolerated compared with TDF + FTC; this study was not powered for efficacy. Among those acquiring HIV infection, drug concentrations were absent, low, or variable. MVC-containing regimens may warrant further study for pre-exposure prophylaxis.Clinical trials registrationNCT01505114
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Phase 2 Study of the Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Men Who Have Sex With Men (HPTN 069/ACTG A5305).
BackgroundMaraviroc (MVC) is a candidate for human immunodeficiency virus (HIV) pre-exposure prophylaxis.MethodsPhase 2 48-week safety/tolerability study was conducted, comparing 4 regimens: MVC alone, MVC plus emtricitabine (FTC), MVC plus tenofovir disoproxil fumarate (TDF), and TDF plus FTC. Eligible participants were HIV-uninfected men and transgender women reporting condomless anal intercourse with ≥1 HIV-infected or unknown-serostatus man within 90 days. At each visit, assessments, laboratory testing, and counseling were done. Analyses were intention to treat.ResultsAmong 406 participants, 84% completed follow-up, 7% stopped early, and 9% were lost to follow-up; 9% discontinued their regimen early. The number discontinuing and the time to discontinuation did not differ among study regimens (P = .60). Rates of grade 3-4 adverse events did not differ among regimens (P = .37). In a randomly selected subset, 77% demonstrated detectable drug concentrations at week 48. Five participants acquired HIV infection (4 MVC alone, 1 MVC + TDF; overall annualized incidence, 1.4% [95% confidence interval, .5%-3.3%], without differences by regimen; P = .32); 2 had undetectable drug concentrations at every visit, 2 had low concentrations at the seroconversion visit, and 1 had variable concentrations.ConclusionsMVC-containing regimens were safe and well tolerated compared with TDF + FTC; this study was not powered for efficacy. Among those acquiring HIV infection, drug concentrations were absent, low, or variable. MVC-containing regimens may warrant further study for pre-exposure prophylaxis.Clinical trials registrationNCT01505114
Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Women: A Phase 2 Randomized Trial
BACKGROUND—Maraviroc (MVC) is a candidate drug for HIV PrEP. OBJECTIVE—To assess the safety/tolerability of MVC-containing PrEP in U.S. women at-risk for HIV over 48 weeks. DESIGN—Phase 2 randomized, controlled, double-blinded study of four PrEP regimens (#NCT01505114). SETTING—Twelve clinical research sites of the HIV Prevention Trials Network and AIDS Clinical Trials Group. PARTICIPANTS—HIV-uninfected women reporting condomless vaginal or anal intercourse with ≥1 HIV-infected or unknown-serostatus man within 90 days. INTERVENTIONS—MVC alone, MVC+emtricitabine (FTC), MVC+tenofovir disoproxil fumarate (TDF), and TDF+FTC (control). MEASUREMENTS—At each visit, clinical and laboratory (including HIV) assessments were conducted. Primary outcomes were grade 3–4 adverse events and time to permanent regimen discontinuation. Analyses were conducted on all randomized participants, according to original regimen assignment. RESULTS—Among 188 participants, 85% completed follow-up, 11% withdrew early, and 4% were lost-to-follow-up; 19% discontinued their regimen prematurely. Number discontinuing and time-to-discontinuation did not differ among regimens. Grade 3/4 adverse events occurred in 5 (MVC), 13 (MVC+FTC), 9 (MVC+TDF) and 8 (TDF+FTC) participants; rates did not differ among regimens. One death occurred (suicide; MVC+FTC), judged not regimen-related. Of available samples at week 48 (n=126), 60% demonstrated detectable drug concentrations. No new HIV infections occurred. LIMITATIONS—Participants were not necessarily high-risk for HIV. Regimen was 3 pills daily. Study was not powered for efficacy. CONCLUSIONS—MVC-containing PrEP regimens were safe and well-tolerated compared to the control regimen of TDF+FTC in U.S. women. No new HIV infections occurred, although whether this was due to low risk of the population or to protection from the study regimens is not certain. MVC-containing PrEP for women may warrant further study. FUNDING SOURCE—U.S. National Institutes of Healt
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Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Women: A Phase 2 Randomized Trial.
BACKGROUND—Maraviroc (MVC) is a candidate drug for HIV PrEP. OBJECTIVE—To assess the safety/tolerability of MVC-containing PrEP in U.S. women at-risk for HIV over 48 weeks. DESIGN—Phase 2 randomized, controlled, double-blinded study of four PrEP regimens (#NCT01505114). SETTING—Twelve clinical research sites of the HIV Prevention Trials Network and AIDS Clinical Trials Group. PARTICIPANTS—HIV-uninfected women reporting condomless vaginal or anal intercourse with ≥1 HIV-infected or unknown-serostatus man within 90 days. INTERVENTIONS—MVC alone, MVC+emtricitabine (FTC), MVC+tenofovir disoproxil fumarate (TDF), and TDF+FTC (control). MEASUREMENTS—At each visit, clinical and laboratory (including HIV) assessments were conducted. Primary outcomes were grade 3–4 adverse events and time to permanent regimen discontinuation. Analyses were conducted on all randomized participants, according to original regimen assignment. RESULTS—Among 188 participants, 85% completed follow-up, 11% withdrew early, and 4% were lost-to-follow-up; 19% discontinued their regimen prematurely. Number discontinuing and time-to-discontinuation did not differ among regimens. Grade 3/4 adverse events occurred in 5 (MVC), 13 (MVC+FTC), 9 (MVC+TDF) and 8 (TDF+FTC) participants; rates did not differ among regimens. One death occurred (suicide; MVC+FTC), judged not regimen-related. Of available samples at week 48 (n=126), 60% demonstrated detectable drug concentrations. No new HIV infections occurred. LIMITATIONS—Participants were not necessarily high-risk for HIV. Regimen was 3 pills daily. Study was not powered for efficacy. CONCLUSIONS—MVC-containing PrEP regimens were safe and well-tolerated compared to the control regimen of TDF+FTC in U.S. women. No new HIV infections occurred, although whether this was due to low risk of the population or to protection from the study regimens is not certain. MVC-containing PrEP for women may warrant further study. FUNDING SOURCE—U.S. National Institutes of Healt