Pharmacogenetic interactions of efavirenz or rifampin and isoniazid with levonorgestrel emergency contraception during treatment of HIV or tuberculosis.

OBJECTIVE: In AIDS Clinical Trials Group study A5375, a pharmacokinetic trial of levonorgestrel emergency contraception, double-dose levonorgestrel (3 mg, versus standard dose 1.5 mg) offset the induction effects of efavirenz or rifampin on plasma levonorgestrel exposure over 8 h post-dose (AUC 0-8h ). We characterized the pharmacogenetics of these interactions. METHODS: Cisgender women receiving efavirenz- or dolutegravir-based HIV therapy, or on isoniazid-rifampin for tuberculosis, were followed after a single oral dose of levonorgestrel. Linear regression models, adjusted for BMI and age, characterized associations of CYP2B6 and NAT2 genotypes (which affect plasma efavirenz and isoniazid exposure, respectively) with levonorgestrel pharmacokinetic parameters. RESULTS: Of 118 evaluable participants, 17 received efavirenz/levonorgestrel 1.5 mg, 35 efavirenz/levonorgestrel 3 mg, 34 isoniazid-rifampin/levonorgestrel 3 mg, and 32 (control group) dolutegravir/levonorgestrel 1.5 mg. There were 73 Black and 33 Asian participants. Regardless of genotype, women on efavirenz and isoniazid-rifampin had higher levonorgestrel clearance. In the efavirenz/levonorgestrel 3 mg group, CYP2B6 normal/intermediate metabolizers had levonorgestrel AUC 0-8h values similar to controls, while CYP2B6 poor metabolizers had AUC 0-8h values of 40% lower than controls. In the isoniazid-rifampin group, NAT2 rapid/intermediate acetylators had levonorgestrel AUC 0-8h values similar to controls, while NAT2 slow acetylators had AUC 0-8h values 36% higher than controls. CONCLUSION: CYP2B6 poor metabolizer genotypes exacerbate the efavirenz-levonorgestrel interaction, likely by increased CYP3A induction with higher efavirenz exposure, making the interaction more difficult to overcome. NAT2 slow acetylator genotypes attenuate the rifampin-levonorgestrel interaction, likely by increased CYP3A inhibition with higher isoniazid exposure.

Pharmacogenetics of interaction between depot medroxyprogesterone acetate and efavirenz, rifampicin, and isoniazid during treatment of HIV and tuberculosis.

OBJECTIVE: In AIDS Clinical Trials Group study A5338, concomitant rifampicin, isoniazid, and efavirenz was associated with more rapid plasma medroxyprogesterone acetate (MPA) clearance compared to historical controls without tuberculosis or HIV therapy. We characterized the pharmacogenetics of this interaction. METHODS: In A5338, women receiving efavirenz-based HIV therapy and rifampicin plus isoniazid for tuberculosis underwent pharmacokinetic evaluations over 12 weeks following a 150-mg intramuscular injection of depot MPA. Data were interpreted with nonlinear mixed-effects modelling. Associations between individual pharmacokinetic parameters and polymorphisms relevant to rifampicin, isoniazid, efavirenz, and MPA were assessed. RESULTS: Of 62 A5338 participants in four African countries, 44 were evaluable for pharmacokinetic associations, with 17 CYP2B6 normal, 21 intermediate, and 6 poor metabolizers, and 5 NAT2 rapid, 20 intermediate, and 19 slow acetylators. There were no associations between either CYP2B6 or NAT2 genotype and MPA Cmin at week 12, apparent clearance, Cmax, area under the concentration-time curve (AUC) or half-life, or unexplained interindividual variability in clearance, and uptake rate constant or mean transit time of the slow-release fraction (P > 0.05 for each). In exploratory analyses, none of 28 polymorphisms in 14 genes were consistently associated with MPA pharmacokinetic parameters, and none withstood correction for multiple testing. CONCLUSIONS: Study A5338 suggested that more frequent depot MPA dosing may be appropriate for women receiving rifampicin, isoniazid, and efavirenz. The present results suggest that knowledge of CYP2B6 metabolizer or NAT2 acetylator status does not inform individualized DMPA dosing in this setting.

Pharmacokinetics and Pharmacodynamics of Depot Medroxyprogesterone Acetate in African Women Receiving Treatment for Human Immunodeficiency Virus and Tuberculosis: Potential Concern for Standard Dosing Frequency.

BACKGROUND: Effective contraception is critical to young women with HIV-associated tuberculosis (TB), as unintended pregnancy is associated with increased perinatal morbidity and mortality. The effects of co-administration of efavirenz and rifampicin on the pharmacokinetics of depot medroxyprogesterone acetate (DMPA) are unknown. We hypothesized that clearance of medroxyprogesterone acetate (MPA) would increase when given with rifampicin and efavirenz, thus increasing risk of ovulation. METHODS: This pharmacokinetics (PK) study assessed DMPA among HIV/TB coinfected women on an efavirenz-based antiretroviral treatment and rifampicin-based TB treatment. Plasma MPA concentrations and progesterone were measured predose (MPA only) and 2, 4, 6, 8, 10, and 12 weeks after a single DMPA 150 mg intramuscular injection. The primary outcome measure, MPA concentration (<0.1 ng/mL) at week 12, was assessed using exact 95% Clopper-Pearson confidence intervals. MPA PK parameters were calculated using noncompartmental analysis. RESULTS: Among 42 PK-evaluable women from 5 African countries, median age was 32 years and median CD4 was 414 cells/mm3. Five women (11.9%; 95% CI, 4.0-25.6%) had MPA <0.1 ng/mL at week 12; of these, one had MPA <0.1 ng/mL at week 10. The median clearance of MPA was 19 681 L/week compared with 12 118 L/week for historical controls. There were no adverse events related to DMPA, and progesterone concentrations were <1 ng/mL for all women for the study duration. CONCLUSIONS: DMPA, when given with rifampicin and efavirenz, was safe. MPA clearance was higher than in women with HIV not on ART, leading to subtherapeutic concentrations of MPA in 12% of women, suggesting that more frequent dosing might be needed. CLINICAL TRIALS REGISTRATION: NCT02412436.

Pharmacogenetic interactions between antiretroviral drugs and vaginally administered hormonal contraceptives.

OBJECTIVE: In AIDS Clinical Trials Group study A5316, efavirenz lowered plasma concentrations of etonogestrel and ethinyl estradiol, given as a vaginal ring, while atazanavir/ritonavir increased etonogestrel and lowered ethinyl estradiol concentrations. We characterized the pharmacogenetics of these interactions. METHODS: In A5316, women with HIV enrolled into control (no antiretrovirals), efavirenz [600 mg daily with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)], and atazanavir/ritonavir (300/100 mg daily with NRTIs) groups. On day 0, a vaginal ring was inserted, releasing etonogestrel/ethinyl estradiol 120/15 µg/day. Intensive plasma sampling for antiretrovirals was obtained on days 0 and 21, and single samples for etonogestrel and ethinyl estradiol on days 7, 14, and 21. Seventeen genetic polymorphisms were analyzed. RESULTS: The 72 participants in this analysis included 25, 24 and 23 in the control, efavirenz, and atazanavir/ritonavir groups, respectively. At day 21 in the efavirenz group, CYP2B6 genotype was associated with increased plasma efavirenz exposure (P = 3.2 × 10), decreased plasma concentrations of etonogestrel (P = 1.7 × 10), and decreased ethinyl estradiol (P = 6.7 × 10). Compared to controls, efavirenz reduced median etonogestrel concentrations by at least 93% in CYP2B6 slow metabolizers versus approximately 75% in normal and intermediate metabolizers. Efavirenz reduced median ethinyl estradiol concentrations by 75% in CYP2B6 slow metabolizers versus approximately 41% in normal and intermediate metabolizers. CONCLUSION: CYP2B6 slow metabolizer genotype worsens the pharmacokinetic interaction of efavirenz with hormonal contraceptives administered by vaginal ring. Efavirenz dose reduction in CYP2B6 slow metabolizers may reduce, but will likely not eliminate, this interaction.

Home Birth in the Era of COVID-19: Counseling and Preparation for Pregnant Persons Living with HIV.

With the coronavirus disease 2019 (COVID-19) pandemic in the United States, a majority of states have instituted "shelter-in-place" policies effectively quarantining individuals-including pregnant persons-in their homes. Given the concern for COVID-19 acquisition in health care settings, pregnant persons with high-risk pregnancies-such as persons living with HIV (PLHIV)-are increasingly investigating the option of a home birth. Although we strongly recommend hospital birth for PLHIV, we discuss our experience and recommendations for counseling and preparation of pregnant PLHIV who may be considering home birth or at risk for unintentional home birth due to the pandemic. We also discuss issues associated with implementing a risk mitigation strategy involving high-risk births occurring at home during a pandemic. KEY POINTS: · Coronavirus disease 2019 pandemic has increased interest in home birth.. · Women living with HIV are pursuing home birth.. · Safe planning is paramount for women living with HIV desiring home birth, despite recommending against the practice..

Miscarriage among women in the United States Women's Interagency HIV Study, 1994-2017.

BACKGROUND: Relatively little is known about the frequency and factors associated with miscarriage among women living with HIV. OBJECTIVE: The objective of the study was to evaluate factors associated with miscarriage among women enrolled in the Women's Interagency HIV Study. STUDY DESIGN: We conducted an analysis of longitudinal data collected from Oct. 1, 1994, to Sept. 30, 2017. Women who attended at least 2 Women's Interagency HIV Study visits and reported pregnancy during follow-up were included. Miscarriage was defined as spontaneous loss of pregnancy before 20 weeks of gestation based on self-report assessed at biannual visits. We modeled the association between demographic, behavioral, and clinical covariates and miscarriage (vs live birth) for women overall and stratified by HIV status using mixed-model logistic regression. RESULTS: Similar proportions of women living with and without HIV experienced miscarriage (37% and 39%, respectively, P = .638). In adjusted analyses, smoking tobacco (adjusted odds ratio, 2.0), alcohol use (adjusted odds ratio, 4.0), and marijuana use (adjusted odds ratio, 2.0) were associated with miscarriage. Among women living with HIV, low HIV viral load (<4 log10 copies/mL) (adjusted odds ratio, 0.5) and protease inhibitor (adjusted odds ratio, 0.4) vs the nonuse of combination antiretroviral therapy use were protective against miscarriage. CONCLUSION: We did not find an increased odds of miscarriage among women living with HIV compared with uninfected women; however, poorly controlled HIV infection was associated with increased miscarriage risk. Higher miscarriage risk among women exposed to tobacco, alcohol, and marijuana highlight potentially modifiable behaviors. Given previous concern about antiretroviral therapy and adverse pregnancy outcomes, the novel protective association between protease inhibitors compared with non-combination antiretroviral therapy and miscarriage in this study is reassuring.

Moderating Factors in an Anti-stigma Intervention for African American Women with HIV in the United States: A Secondary Analysis of the UNITY Trial.

African American women experience higher rates of HIV than other women in the United States, and stigma has been identified as an important determinant of engagement in HIV care. Our study examined whether key variables moderated the effect of an anti-stigma intervention on outcomes among African American women receiving treatment for HIV. Twelve potential moderators included: age, years lived with HIV, marital status, employment status, education level, PTSD diagnosis, alcohol use, social support, baseline CD4 count, baseline viral load, and number of children. Outcomes included changes in: HIV-related stigma, social support, depressive symptoms, PTSD symptoms, alcohol use, viral load, and engagement in HIV care. Results suggest that the intervention is associated with greater improvement in engagement in care among participants with PTSD or depression at baseline, and may help maintain engagement in care among participants experiencing certain mental health conditions. This provides opportunities to address discriminatory structural barriers that lead to stigma and drop-offs in HIV care.

HIV-Related Stigma and Viral Suppression Among African-American Women: Exploring the Mediating Roles of Depression and ART Nonadherence.

We used baseline data from a sample of African-American women living with HIV who were recruited to participate in a stigma-reduction intervention in Chicago and Birmingham (2013-2015) to (1) evaluate the relationship between HIV-related stigma and viral suppression, and (2) assess the role of depression and nonadherence to antiretroviral therapy (ART) as mediators. Data from women were included in this secondary analysis if they were on ART, had viral load data collected within 8-weeks of study entry and had complete covariate data. We used logistic regression to estimate the total effect of HIV-related stigma (14-item Stigma Scale for Chronic Illness) on viral suppression (< 200 copies/mL), and serial mediation analysis to estimate indirect effects mediated by depressive symptoms (8-item Patient Health Questionnaire) and ART nonadherence (number of days with missed doses). Among 100 women who met study inclusion criteria, 95% reported some level of HIV-related stigma. In adjusted models, higher levels of HIV-related stigma were associated with lower odds of being virally suppressed (AOR = 0.93, 95% CI = 0.89-0.98). In mediation analysis, indirect effects through depression and ART nonadherence were not significant. Findings suggest that HIV-related stigma is common among African-American women living with HIV, and those who experience higher levels of stigma are less likely to be virally suppressed. However, the mechanisms remain unclear.

Risk and protective factors of posttraumatic stress disorder among African American women living with HIV.

We sought to examine risk and protective factors for Posttraumatic Stress Disorder (PTSD) among African American women living with HIV. This is a cross-sectional analysis of baseline data from a randomized trial of an HIV stigma reduction intervention. We examined data from two-hundred and thirty-nine African American women living with HIV. We examined whether age, marital status, level of education, internalized HIV-related stigma, and social support as potential protective and risk factors for PTSD symptoms using logistic regression. We analyzed bi-variate associations between each variable and PTSD symptoms, and constructed a multivariate logistic regression model adjusting for all variables. We found 67% reported clinically significant PTSD symptoms at baseline. Our results suggest that age, education, and internalized stigma were found to be associated with PTSD symptoms (p < 0.001), with older age and more education as protective factors and stigma as a risk factor for PTSD. Therefore, understanding this relationship may help improve assessment and treatment through evidence- based and trauma-informed strategies.

Trends of and factors associated with live-birth and abortion rates among HIV-positive and HIV-negative women.

BACKGROUND: Little is known about fertility choices and pregnancy outcome rates among HIV-infected women in the current combination antiretroviral treatment era. OBJECTIVE: We sought to describe trends and factors associated with live-birth and abortion rates among HIV-positive and high-risk HIV-negative women enrolled in the Women's Interagency HIV Study in the United States. STUDY DESIGN: We analyzed longitudinal data collected from Oct. 1, 1994, through Sept. 30, 2012, through the Women's Interagency HIV Study. Age-adjusted rates per 100 person-years live births and induced abortions were calculated by HIV serostatus over 4 time periods. Poisson mixed effects models containing variables associated with live births and abortions in bivariable analyses (P < .05) generated adjusted incidence rate ratios and 95% confidence intervals. RESULTS: There were 1356 pregnancies among 2414 women. Among HIV-positive women, age-adjusted rates of live birth increased from 1994 through 1997 to 2006 through 2012 (2.85-7.27/100 person-years, P trend < .0001). Age-adjusted rates of abortion in HIV-positive women remained stable over these time periods (4.03-4.29/100 person-years, P trend = .09). Significantly lower live-birth rates occurred among HIV-positive compared to HIV-negative women in 1994 through 1997 and 1997 through 2001, however rates were similar during 2002 through 2005 and 2006 through 2012. Higher CD4+ T cells/mm3 (≥350 adjusted incidence rate ratio, 1.39 [95% CI 1.03-1.89] vs <350) were significantly associated with increased live-birth rates, while combination antiretroviral treatment use (adjusted incidence rate ratio, 1.35 [95% CI 0.99-1.83]) was marginally associated with increased live-birth rates. Younger age, having a prior abortion, condom use, and increased parity were associated with increased abortion rates among both HIV-positive and HIV-negative women. CD4+ T-cell count, combination antiretroviral treatment use, and viral load were not associated with abortion rates. CONCLUSION: Unlike earlier periods (pre-2001) when live-birth rates were lower among HIV-positive women, rates are now similar to HIV-negative women, potentially due to improved health status and combination antiretroviral treatment. Abortion rates remain unchanged, illuminating a need to improve contraceptive services.

Unintended Pregnancies Observed With Combined Use of the Levonorgestrel Contraceptive Implant and Efavirenz-based Antiretroviral Therapy: A Three-Arm Pharmacokinetic Evaluation Over 48 Weeks.

BACKGROUND: Levonorgestrel subdermal implants are preferred contraceptives with an expected failure rate of <1% over 5 years. We assessed the effect of efavirenz- or nevirapine-based antiretroviral therapy (ART) coadministration on levonorgestrel pharmacokinetics. METHODS: This nonrandomized, parallel group, pharmacokinetic evaluation was conducted in three groups of human immunodeficiency virus-infected Ugandan women: ART-naive (n = 17), efavirenz-based ART (n = 20), and nevirapine-based ART (n = 20). Levonorgestrel implants were inserted at baseline in all women. Blood was collected at 1, 4, 12, 24, 36, and 48 weeks. The primary endpoint was week 24 levonorgestrel concentrations, compared between the ART-naive group and each ART group by geometric mean ratio (GMR) with 90% confidence interval (CI). Secondary endpoints included week 48 levonorgestrel concentrations and unintended pregnancies. RESULTS: Week 24 geometric mean levonorgestrel concentrations were 528, 280, and 710 pg/mL in the ART-naive, efavirenz, and nevirapine groups, respectively (efavirenz: ART-naive GMR, 0.53; 90% CI, .50, .55 and nevirapine: ART-naive GMR, 1.35; 90% CI, 1.29, 1.43). Week 48 levonorgestrel concentrations were 580, 247, and 664 pg/mL in the ART-naive, efavirenz, and nevirapine groups, respectively (efavirenz: ART-naive GMR, 0.43; 90% CI, .42, .44 and nevirapine: ART-naive GMR, 1.14; 90% CI, 1.14, 1.16). Three pregnancies (3/20, 15%) occurred in the efavirenz group between weeks 36 and 48. No pregnancies occurred in the ART-naive or nevirapine groups. CONCLUSIONS: Within 1 year of combined use, levonorgestrel exposure was markedly reduced in participants who received efavirenz-based ART, accompanied by contraceptive failures. In contrast, nevirapine-based ART did not adversely affect levonorgestrel exposure or efficacy. CLINICAL TRIALS REGISTRATION: NCT01789879.

HIV Transmission Risk Behavior in a Cohort of HIV-Infected Treatment-Naïve Men and Women in the United States.

Antiretroviral therapy (ART) can minimize HIV transmission. Prevention benefits may be compromised by barriers to virologic suppression, and by increased condomless sex among those initiating ART. We evaluated condomless sex in a cohort of HIVinfected US individuals poised to initiate ART in a clinical trial. We assessed partner and sex act type, condom use, and perception of infectiousness. Six percent of participants reported as not infectious; men who have sex with men were more likely to perceive high infectivity. Prevalence of condomless sex was 44 %; 74 % of those also reported homosexual acquisition of HIV. Predictors of increased risk of condomless sex included greater numbers of lifetime partners, recent stimulant drug use and an HIV-positive or unknown serostatus partner. In the context of serodifferent partners, lower perception of infectiousness was also associated with a higher risk of condomless sex. Results highlight opportunities for prevention education for HIV infected individuals at ART initiation.

Neighborhood community characteristics associated with HIV disease outcomes in a cohort of urban women living with HIV.

Recent studies have found geographic variations in immune and viral human immunodeficiency virus (HIV) disease outcomes associated with census measures of neighborhood poverty and segregation. Although readily available, such aggregate census measures are not based on health behavior models and provide limited information regarding neighborhood effect pathways. In contrast, survey-based measures can capture specific aspects of neighborhood disadvantage that may better inform community-based interventions. Therefore, the aim of this study is to assess the measurement validity of multi-dimensional survey measures of neighborhood disorder compared with census measures as predictors of HIV outcomes in a cohort of 197 low-income women in a major metropolitan area. The multi-dimensional survey measures were related to each other and to census measures of concentrated poverty and racial segregation, but not so highly correlated as to be uniform. We found notable variation between community areas in women's CD4 levels but there was no corresponding geographic variance in viral load, and relationships between community area measures and viral load disappeared after adjustment for individual characteristics, including HIV treatment adherence. In multilevel models adjusting for individual characteristics including substance use, depression, and HIV treatment adherence, one survey measure of neighborhood disadvantage (poor-quality built environment) and one census measure (racial segregation) were significantly associated with greater likelihood of CD4 < 500 (p < .05).

Comparison of the metabolic effects of ritonavir-boosted darunavir or atazanavir versus raltegravir, and the impact of ritonavir plasma exposure: ACTG 5257.

BACKGROUND: Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C24). METHODS: Treatment-naive adult subjects were randomized to ritonavir-boosted atazanavir or darunavir, or raltegravir-based cART. Changes in lipids and other metabolic outcomes over time were estimated. Differences between arms were estimated with 97.5% confidence intervals and compared using pairwise Student t tests. Associations between ritonavir C24 and lipid changes at week 48 were evaluated via linear regression. RESULTS: Analyses included 1797 subjects with baseline fasting data. Baseline lipid profiles and metabolic syndrome rates (approximately 21%) were similar across arms. Comparable increases occurred in total cholesterol, triglycerides, and low-density lipoprotein cholesterol with the boosted protease inhibitors (PIs); each PI had greater increases relative to raltegravir (all P ≤ .001 at week 96). Metabolic syndrome incident rates by week 96 (approximately 22%) were not different across arms. Ritonavir C24 was not different by arm (P = .89) (median, 69 ng/mL and 74 ng/mL in the atazanavir and darunavir arms, respectively) and were not associated with changes in lipid measures (all P > .1). CONCLUSIONS: Raltegravir produced the most favorable lipid profile. Metabolic syndrome rates were high at baseline and increased to the same degree in all arms. Ritonavir C24 was not different in the PI arms and had no relationship with the modest but comparable increases in lipids observed with either atazanavir or darunavir. The long-term clinical significance of the lipid changes noted with the PIs relative to raltegravir deserves further evaluation. CLINICAL TRIALS REGISTRATION: NCT 00811954.

Depot medroxyprogesterone acetate in combination with a twice-daily lopinavir-ritonavir-based regimen in HIV-infected women showed effective contraception and a lack of clinically significant interactions, with good safety and tolerability: results of the ACTG 5283 study.

We conducted an open-label, steady-state pharmacokinetic (PK) study of drug-drug interactions between depot medroxyprogesterone acetate (DMPA) and twice-daily lopinavir (LPV) plus low-dose ritonavir (RTV) (LPV/r) among 24 HIV-infected women and compared the results to those for HIV-infected women receiving DMPA while on no antiretroviral therapy or on nucleosides only (n = 14 subjects from the control arm of AIDS Clinical Trials Group [ACTG] study 5093). The objectives of the study were to address the effect of LPV/r on DMPA and to address the effect of DMPA on LPV/r therapy. PK parameters were estimated using noncompartmental analysis with between-group comparisons of medroxyprogesterone acetate (MPA) PKs and within-subject comparisons of LPV and RTV PKs before and 4 weeks after DMPA dosing. Plasma progesterone concentrations were measured every 2 weeks after DMPA dosing through week 12. Although the MPA area under the concentration-time curve and maximum concentration of drug in plasma were statistically significantly increased in the study women on LPV/r compared to those in the historical controls, these increases were not considered clinically significant. There were no changes in LPV or RTV exposure after DMPA. DMPA was well tolerated, and suppression of ovulation was maintained. (This study has been registered at ClinicalTrials.gov under registration no. NCT01296152.).

Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial.

BACKGROUND: Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons. OBJECTIVE: To evaluate 3 nonnucleoside reverse transcriptase inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability. DESIGN: A phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks. (ClinicalTrials.gov: NCT00811954). SETTING: 57 sites in the United States and Puerto Rico. PATIENTS: Treatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase inhibitors or protease inhibitors. INTERVENTION: Atazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d, plus combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d. MEASUREMENTS: Virologic failure, defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks, and tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir for toxicity. A secondary end point was a combination of virologic efficacy and tolerability. RESULTS: Among 1809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as -10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir. LIMITATION: The trial was open-label, and ritonavir was not provided. CONCLUSION: Over 2 years, all 3 regimens attained high and equivalent rates of virologic control. Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases.

Regional variation in HIV clinical trials participation in the United States.

OBJECTIVES: To ensure generalizability of clinical research results, it is important to enroll a heterogeneous population that is representative of the target clinical population. Earlier studies have found regional variation in participation in human immunodeficiency virus (HIV) clinical trials, with the lowest rates seen in the southern United States. Rates of new HIV diagnoses are highest in the South, highlighting the need for in-depth understanding of disparities in clinical trial participation. We evaluated whether regional variation in study participation remains, and describe factors that facilitate or prevent HIV clinical trial participation by region. METHODS: A one-time, anonymous, bilingual, self-administered survey was conducted among HIV-infected adults receiving HIV care at all 47 domestic AIDS Clinical Trials Group clinical research sites, with a goal of completing 50 surveys per site. χ(2) tests were used to evaluate differences in knowledge of and participation in HIV clinical trials by region, including Northeast, Midwest, South, and West regions. Multivariable logistic regression was used to estimate odds ratios and 95% confidence intervals (CIs) for the effect of region on knowledge of and participation in HIV clinical trials. RESULTS: Of 2263 completed surveys, 2125 were included in this analysis. The proportion of respondents in the South who reported knowledge of studies (66%) was significantly lower than in the Northeast (76%), Midwest (77%), and West (73%) (P = 0.001). Respondents in the South also were the least likely group to report ever having tried to or having participated in a research study (51%) compared with respondents in the Northeast (60%), Midwest (57%), and West (69%; P < 0.001). After adjusting for age, sex, education, race/ethnicity, tobacco use, and alcohol use, the odds ratio for knowledge of and participation in clinical trials for the Northeast (1.36; 95% CI 1.07-1.72) and West (1.85; 95% CI 1.39-2.45) remained significant compared with the South. African American respondents in the South were the most likely population group to report not understanding research studies (15%) as a reason for not participating, compared with the Northeast (9%), Midwest (8%), and West (6%; P < 0.001). CONCLUSIONS: Significant regional variations in knowledge of and participation in HIV clinical trials exist. Our results suggest that increasing awareness and understanding of research studies, particularly among African Americans in the South, may facilitate HIV clinical trial participation that is more representative of the HIV-infected population across the United States.

Minorities remain underrepresented in HIV/AIDS research despite access to clinical trials.

BACKGROUND AND OBJECTIVE: The reasons for minority underrepresentation in HIV/AIDS clinical trials remain unclear. We aimed to evaluate the knowledge, experience, and factors that influence minority participation in HIV/AIDS studies in the United States. METHODS: An anonymous, bilingual, self-administered survey on study participation was given to HIV-infected adults attending AIDS Clinical Trials Group-affiliated clinics in the United States and Puerto Rico. Chi-square tests were used to evaluate differences by race, first language, and level of education. Logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) for factors associated with being talked to about participation in a study. RESULTS: We analyzed 2,175 complete surveys (221 in Spanish). Among respondents, 31% were White, 40% were Black/African American (AA), and 21% were Hispanic. The overall rate of previous participation in any HIV/AIDS study was 48%. Hispanics were less likely to know about studies compared to Whites and AAs (67% vs 74% and 76%, respectively; P < .001). Compared to Whites, AAs and Hispanics were less likely to have been talked to about participating in a study (76% vs 67% and 67%, respectively; P < .001). The OR for being talked to about participating in a study was 0.65 (95% CI, 0.52-0.81) for AAs and 0.65 (95% CI, 0.49-0.85) for Hispanics, compared to Whites. AAs and Hispanics were more likely to state that studies were not friendly to their race (17% and 10% vs 4%; P < .001). CONCLUSIONS: Minorities continue to face barriers for HIV/AIDS trial participation, even when clinical research is available. Enrollment strategies should better target minorities to improve recruitment in HIV/AIDS research.

Human immunodeficiency viruses appear compartmentalized to the female genital tract in cross-sectional analyses but genital lineages do not persist over time.

BACKGROUND: Whether unique human immunodeficiency type 1 (HIV) genotypes occur in the genital tract is important for vaccine development and management of drug resistant viruses. Multiple cross-sectional studies suggest HIV is compartmentalized within the female genital tract. We hypothesize that bursts of HIV replication and/or proliferation of infected cells captured in cross-sectional analyses drive compartmentalization but over time genital-specific viral lineages do not form; rather viruses mix between genital tract and blood. METHODS: Eight women with ongoing HIV replication were studied during a period of 1.5 to 4.5 years. Multiple viral sequences were derived by single-genome amplification of the HIV C2-V5 region of env from genital secretions and blood plasma. Maximum likelihood phylogenies were evaluated for compartmentalization using 4 statistical tests. RESULTS: In cross-sectional analyses compartmentalization of genital from blood viruses was detected in three of eight women by all tests; this was associated with tissue specific clades containing multiple monotypic sequences. In longitudinal analysis, the tissues-specific clades did not persist to form viral lineages. Rather, across women, HIV lineages were comprised of both genital tract and blood sequences. CONCLUSIONS: The observation of genital-specific HIV clades only in cross-sectional analysis and an absence of genital-specific lineages in longitudinal analyses suggest a dynamic interchange of HIV variants between the female genital tract and blood.

Impact of antiretroviral therapy during acute or early HIV infection on virologic and immunologic outcomes: results from a multinational clinical trial.

OBJECTIVE: To assess how antiretroviral therapy (ART) initiation during acute or early HIV infection (AEHI) affects the viral reservoir and host immune responses. DESIGN: Single-arm trial of ART initiation during AEHI at 30 sites in the Americas, Africa, and Asia. METHODS: HIV DNA was measured at week 48 of ART in 5 million CD4 + T cells by sensitive qPCR assays targeting HIV gag and pol . Peripheral blood mononuclear cells were stimulated with potential HIV T cell epitope peptide pools consisting of env , gag , nef, and pol peptides and stained for expression of CD3, CD4, CD8, and intracellular cytokines/chemokines. RESULTS: From 2017 to 2019, 188 participants initiated ART during Fiebig stages I ( n  = 6), II ( n  = 43), III ( n  = 56), IV ( n  = 23), and V ( n  = 60). Median age was 27 years (interquartile range 23-38), 27 (14%) participants were female, and 180 (97%) cisgender. Among 154 virally suppressed participants at week 48, 100% had detectable HIV gag or pol DNA. Participants treated during Fiebig I had the lowest HIV DNA levels ( P  < 0.001). Week 48 HIV DNA mostly did not correlate with concurrent CD4 + or CD8 + T cell HIV-specific immune responses (rho range -0.11 to +0.19, all P  > 0.025). At week 48, the magnitude, but not polyfunctionality, of HIV-specific T cell responses was moderately reduced among participants who initiated ART earliest. CONCLUSION: Earlier ART initiation during AEHI reduced but did not eliminate the persistence of HIV-infected cells in blood. These findings explain the rapid viral rebound observed after ART cessation in early-treated individuals with undetectable HIV DNA by less sensitive methods.