Effect of the relationship between anaemia and systemic inflammation on the risk of incident tuberculosis and death in people with advanced HIV: a sub-analysis of the REMEMBER trial.

Background: Tuberculosis (TB) is an infectious morbidity that commonly occurs in people living with HIV (PWH) and increases the progression of HIV disease, as well as the risk of death. Simple markers of progression are much needed to identify those at highest risk for poor outcome. This study aimed to assess how baseline severity of anaemia and associated inflammatory profiles impact death and the incidence of TB in a cohort of PWH who received TB preventive therapy (TPT). Methods: This study is a secondary posthoc analysis of the AIDS Clinical Trials Group A5274 REMEMBER clinical trial (NCT0138008), an open-label randomised clinical trial of antiretroviral-naïve PWH with CD4 <50 cells/µL, performed from October 31, 2011 to June 9, 2014, from 18 outpatient research clinics in 10 low- and middle-income countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda) who initiated antiretroviral therapy and either isoniazid TPT or 4-drug empiric TB therapy. Plasma concentrations of several soluble inflammatory biomarkers were measured prior to the commencement of antiretroviral and anti-TB therapies, and participants were followed up for at least 48 weeks. Incident TB or death during this period were primary outcomes. We performed multidimensional analyses, logistic regression analyses, survival curves, and Bayesian network analyses to delineate associations between anaemia, laboratory parameters, and clinical outcomes. Findings: Of all 269 participants, 76.2% (n = 205) were anaemic, and 31.2% (n = 84) had severe anaemia. PWH with moderate/severe anaemia exhibited a pronounced systemic pro-inflammatory profile compared to those with mild or without anaemia, hallmarked by a substantial increase in IL-6 plasma concentrations. Moderate/severe anaemia was also associated with incident TB incidence (aOR: 3.59, 95% CI: 1.32-9.76, p = 0.012) and death (aOR: 3.63, 95% CI: 1.07-12.33, p = 0.039). Interpretation: Our findings suggest that PWH with moderate/severe anaemia display a distinct pro-inflammatory profile. The presence of moderate/severe anaemia pre-ART was independently associated with the development of TB and death. PWH with anaemia should be monitored closely to minimise the occurrence of unfavourable outcomes. Funding: National Institutes of Health.

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.

Long-Term Benefits from Early Antiretroviral Therapy Initiation in HIV Infection.

BACKGROUND: For people with HIV and CD4+ counts >500 cells/mm3, early initiation of antiretroviral therapy (ART) reduces serious AIDS and serious non-AIDS (SNA) risk compared with deferral of treatment until CD4+ counts are <350 cells/mm3. Whether excess risk of AIDS and SNA persists once ART is initiated for those who defer treatment is uncertain. METHODS: The Strategic Timing of AntiRetroviral Treatment (START) trial, as previously reported, randomly assigned 4684 ART-naive HIV-positive adults with CD4+ counts .500 cells/mm3 to immediate treatment initiation after random assignment (n = 2325) or deferred treatment (n= 2359). In 2015, a 57% lower risk of the primary end point (AIDS, SNA, or death) for the immediate group was reported, and the deferred group was offered ART. This article reports the follow-up that continued to December 31, 2021. Cox proportional-hazards models were used to compare hazard ratios for the primary end point from randomization through December 31, 2015, versus January 1, 2016, through December 31, 2021. RESULTS: Through December 31, 2015, approximately 7 months after the cutoff date from the previous report, the median CD4+ count was 648 and 460 cells/mm3 in the immediate and deferred groups, respectively, at treatment initiation. The percentage of follow-up time spent taking ART was 95% and 36% for the immediate and deferred groups, respectively, and the time-averaged CD4+ difference was 199 cells/mm3. After January 1, 2016, the percentage of follow-up time on treatment was 97.2% and 94.1% for the immediate and deferred groups, respectively, and the CD4+ count difference was 155 cells/mm3. After January 1, 2016, a total of 89 immediate and 113 deferred group participants experienced a primary end point (hazard ratio of 0.79 [95% confidence interval, 0.60 to 1.04] versus hazard ratio of 0.47 [95% confidence interval, 0.34 to 0.65; P<0.001]) before 2016 (P=0.02 for hazard ratio difference). CONCLUSIONS: Among adults with CD4+ counts >500 cells/mm3, excess risk of AIDS and SNA associated with delaying treatment initiation was diminished after ART initiation, but persistent excess risk remained. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Factors associated with prevalent Mycobacterium tuberculosis infection and disease among adolescents and adults exposed to rifampin-resistant tuberculosis in the household.

BACKGROUND: Understanding factors associated with prevalent Mycobacterium tuberculosis infection and prevalent TB disease in household contacts of patients with drug-resistant tuberculosis (TB) may be useful for TB program staff conducting contact investigations. METHODS: Using data from a cross-sectional study that enrolled index participants with rifampin-resistant pulmonary TB and their household contacts (HHCs), we evaluated HHCs age ≥15 years for factors associated with two outcomes: Mycobacterium tuberculosis infection and TB disease. Among HHCs who were not already diagnosed with current active TB disease by the TB program, Mycobacterium tuberculosis infection was determined by interferon-gamma release assay (IGRA). TB disease was adjudicated centrally. We fitted logistic regression models using generalized estimating equations. RESULTS: Seven hundred twelve HHCs age ≥15 years enrolled from 279 households in eight high-TB burden countries were a median age of 34 years, 63% female, 22% current smokers and 8% previous smokers, 8% HIV-positive, and 11% previously treated for TB. Of 686 with determinate IGRA results, 471 tested IGRA positive (prevalence 68.8% (95% Confidence Interval: 64.6%, 72.8%)). Multivariable modeling showed IGRA positivity was more common in HHCs aged 25-49 years; reporting prior TB treatment; reporting incarceration, substance use, and/or a period of daily alcohol use in the past 12 months; sharing a sleeping room or more evenings spent with the index participant; living with smokers; or living in a home of materials typical of low socioeconomic status. Forty-six (6.5% (95% Confidence Interval: 4.6%, 9.0%)) HHCs age ≥15 years had prevalent TB disease. Multivariable modeling showed higher prevalence of TB disease among HHCs aged ≥50 years; reporting current or previous smoking; reporting a period of daily alcohol use in the past 12 months; and reporting prior TB treatment. CONCLUSION: We identified overlapping and distinct characteristics associated with Mycobacterium tuberculosis infection and TB disease that may be useful for those conducting household TB investigations.

Higher Dose Oral Fluconazole for the Treatment of AIDS-related Cryptococcal Meningitis (HIFLAC)-report of A5225, a multicentre, phase I/II, two-stage, dose-finding, safety, tolerability and efficacy randomised, amphotericin B-controlled trial of the AIDS Clinical Trials Group.

BACKGROUND: The WHO recommended 1200mg/day of fluconazole (FCZ) in the induction phase of cryptococcal meningitis (CM) in HIV prior to 2018 in regions where amphotericin-B (AMB) was unavailable. A 2-stage AMB-controlled, dose-escalation study to determine the maximum tolerated dose and the safety/efficacy of an induction-consolidation strategy of higher doses FCZ (1200mg-2000mg/day), adjusted for weight and renal function (eGFR)in adults with CM was undertaken. METHODS: In Stage-1, three induction doses of FCZ (1200mg/day, 1600mg/day and 2000mg/day) were tested in sequential cohortsand compared with AMB in a 3:1 ratio. A particular dose was not tested in Stage 2 if there were significant predetermined safety or efficacy concerns. In Stage-2, the 1200mg dose was excluded per protocol because of increased mortality, and participants were randomised to 1600mg, 2000mg FCZ or AMB in a 1:1:1 ratio. FINDINGS: One hundred and sixty eight participants were enrolled with 48, 50, and 48 in the AMB, 1600mg and 2000mg cohorts. The Kaplan Meier proportion for mortality (90% CI) at 10 and 24 weeks for AMB was 17% (10, 29) and 24% (15, 37), compared to 20% (12, 32) and 30% (20, 43) for 1600mg, and 33% (23, 46) and 38% (27, 51) for 2000mg/day FCZ. With the exception of a higher incidence of gastrointestinal side effects in the 2000mg cohort, both induction doses of FCZ were safe and well tolerated. There were no life-threatening changes in electrocardiogram QTc which were similar across all doses of FCZ and AMB. The median (IQR) change in log10 cryptoccal colony forming units (CFU) from week 0 to week 2 was -8(-4.1,-1.9) for AMB; -2.5(-4.0, -1.4) for 1600mg FCZ and -8 (-3.2, -1.0) for 2000mg FCZ. The proportion (90% CI) CSF CM negative at 10 weeks was 81%(71,90) for AMB; 56%(45,69) for 1600mg FCZ and 60%(49,73) for 2000mg FCZ. INTERPRETATION: Induction phase weight and renal-adjusted doses of 1600mg and 2000mg/day FCZ for CM were safe and well tolerated except for increased GI side effects in the 2000mg/day dose, and had similar times to achieve CSF sterilization, but took significantly longer than AMB. The WHO recommended 1200mg FCZ was associated with a high mortality. While not statistically significant, mortality was numerically lower in the AMB compared to 1600mg and 2000mg FCZ These data make a case for a phase 3 study of higher doses of FZC.

A Standardized Approach for Collection of Objective Data to Support Outcome Determination for Late-Phase Tuberculosis Clinical Trials.

Rationale: We developed a standardized method, possible poor treatment response (PPTR), to help ascertain efficacy endpoints in Study S31/A5349 (NCT02410772), an open-label trial comparing two 4-month rifapentine-based regimens with a standard 6-month regimen for the treatment of pulmonary tuberculosis (TB). Objectives: We describe the use of the PPTR process and evaluate whether the goals of minimizing bias in efficacy endpoint assessment and attainment of relevant data to determine outcomes for all participants were achieved. Methods: A PPTR event was defined as the occurrence of one or more prespecified triggers. Each PPTR required initiation of a standardized evaluation process that included obtaining multiple sputum samples for microbiology. Measurements and Main Results: Among 2,343 participants with culture-confirmed drug-susceptible TB, 454 individuals (19.4%) had a total of 534 individual PPTR events, of which 76.6% were microbiological (positive smear or culture at or after 17 wk). At least one PPTR event was experienced by 92.4% (133 of 144) of participants with TB-related unfavorable outcome and between 13.8% and 14.7% of participants with favorable and not-assessable outcomes. A total of 75% of participants with TB-related unfavorable outcomes had microbiological confirmation of failure to achieve a disease-free cure. Conclusions: Standardized methodologies, such as our PPTR approach, could facilitate unbiased efficacy outcome determinations, improve discrimination between outcomes that are related and unrelated to regimen efficacy, and enhance the ability to conduct pooled analyses of contemporary trials.

Pharmacokinetics of dose-adjusted levonorgestrel emergency contraception combined with efavirenz-based antiretroviral therapy or rifampicin-containing tuberculosis regimens.

OBJECTIVES: To determine if double-dose levonorgestrel emergency contraception (EC) in combination with efavirenz or rifampicin, 2 drugs known to decrease levonorgestrel exposure, resulted in similar pharmacokinetics compared to standard-dose levonorgestrel EC without drug-drug interactions. STUDY DESIGN: We conducted a phase 2, open-label, multicenter, partially randomized, 4 parallel group trial in pre-menopausal females ≥16 years old without an indication for EC and not on hormonal contraception. Participants on dolutegravir-based antiretroviral therapy (ART) received levonorgestrel 1.5 mg (control group); those on rifampicin-containing tuberculosis therapy received levonorgestrel 3 mg; those on efavirenz-based ART were randomized 1:2 to levonorgestrel 1.5 mg or 3 mg. Plasma was collected through 48 hours post-dose to assess levonorgestrel pharmacokinetics. Area under the concentration-time curve (AUC) over 8 hours was the primary outcome. Levonorgestrel pharmacokinetic parameters were compared between groups using geometric mean ratios (GMR) with 90% confidence intervals. RESULTS: The median (Q1, Q3) age for all participants (n = 118) was 34 (27, 41) years and BMI was 23.2 (20, 26.3) kg/m2. Participants receiving levonorgestrel 1.5mg plus efavirenz (n = 17) had 50% lower AUC0-8h compared to the control group (n = 32) [0.50 (0.40, 0.62)]. Participants receiving levonorgestrel 3 mg had a similar AUC0-8h when receiving either efavirenz (n = 35) [0.99 (0.81, 1.20)] or rifampicin (n = 34) [1.16 (0.99, 1.36)] compared to control. Levonorgestrel 3 mg resulted in similar or higher maximum concentration with either efavirenz [1.17 (0.96, 1.41)] or rifampicin [1.27 (1.09, 1.49)] compared to the control group. CONCLUSIONS: Doubling the dose of levonorgestrel EC successfully increased levonorgestrel exposure over the first 8 hours in participants receiving either efavirenz-based ART or rifampicin-containing tuberculosis therapy. IMPLICATIONS: Adjusting levonorgestrel emergency contraception from 1.5 mg to 3 mg improves levonorgestrel pharmacokinetic exposure in participants receiving either efavirenz-based antiretroviral regimens or rifampicin-containing tuberculosis therapy. These data support guideline recommendations to double the dose of levonorgestrel emergency contraception in persons on medications that decrease levonorgestrel exposure by inducing levonorgestrel metabolism.

Antiretroviral Initiation at ≥800 CD4+ Cells/mm3 Associated With Lower Human Immunodeficiency Virus Reservoir Size.

BACKGROUND: Identifying factors that determine the frequency of latently infected CD4+ T cells on antiretroviral therapy (ART) may inform strategies for human immunodeficiency virus (HIV) cure. We investigated the role of CD4+ count at ART initiation for HIV persistence on ART. METHODS: Among participants of the Strategic Timing of Antiretroviral Treatment Study, we enrolled people with HIV (PWH) who initiated ART with CD4+ T-cell counts of 500-599, 600-799, or ≥ 800 cells/mm3. After 36-44 months on ART, the levels of total HIV-DNA, cell-associated unspliced HIV-RNA (CA-US HIV-RNA), and two-long terminal repeat HIV-DNA in CD4+ T cells were quantified and plasma HIV-RNA was measured by single-copy assay. We measured T-cell expression of Human Leucocyte Antigen-DR Isotype (HLA-DR), programmed death-1, and phosphorylated signal transducer and activator of transcription-5 (pSTAT5). Virological and immunological measures were compared across CD4+ strata. RESULTS: We enrolled 146 PWH, 36 in the 500-599, 60 in the 600-799, and 50 in the ≥ 800 CD4 strata. After 36-44 months of ART, total HIV-DNA, plasma HIV-RNA, and HLA-DR expression were significantly lower in PWH with CD4+ T-cell count ≥ 800 cells/mm3 at ART initiation compared with 600-799 or 500-599 cells/mm3. The median level of HIV-DNA after 36-44 months of ART was lower by 75% in participants initiating ART with ≥ 800 vs 500-599 cells/mm3 (median [interquartile range]: 16.3 [7.0-117.6] vs 68.4 [13.7-213.1] copies/million cells, respectively). Higher pSTAT5 expression significantly correlated with lower levels of HIV-DNA and CA-US HIV-RNA. Virological measures were significantly lower in females. CONCLUSIONS: Initiating ART with a CD4+ count ≥ 800 cells/mm3 compared with 600-799 or 500-599 cells/mm3 was associated with achieving a substantially smaller HIV reservoir on ART.

High Prevalence of Tuberculosis Infection and Disease in Child Household Contacts of Adults With Rifampin-resistant Tuberculosis.

BACKGROUND: Household contact (HHC) investigation is an important strategy to identify individuals with tuberculosis (TB) exposure, infection and disease, including those who may benefit from tuberculosis preventive therapy (TPT). Data in children exposed to rifampin-resistant TB are limited. METHODS: In preparation for and to inform the feasibility of an interventional trial, HHC of adults with pulmonary rifampin-resistant TB from high TB-burden countries were evaluated in a cross-sectional study. Using interferon-gamma release assay and study-specific and 2015 international consensus definitions of intrathoracic TB in children, we evaluated the prevalence and predictors of TB infection and disease in child (<15 years) HHCs. RESULTS: Of 303 child HHCs, median age (range) 7 years (0-14), 57% [95% confidence interval (CI): 50%-64%] had a positive interferon-gamma release assay result (TB infected). TB infection was associated with the index case smoking (P = 0.034), being the parent or sleeping in the same room (P = 0.002) and the child HHC being age ≥5 years and having attended school (P = 0.013). Four had study-defined confirmed TB and 9 had probable TB, a prevalence of 4.3% (95% CI: 2.6%-7.1%). Using the international consensus definitions, 4 had confirmed TB and 49 had unconfirmed TB, a prevalence of 17.2% (95% CI: 12.9%-22.4%). Twenty (7%) children had received TPT. CONCLUSIONS: The prevalence of TB infection and disease was high in child HHC exposed to rifampin-resistant TB. Few children had routinely received TPT. High-quality evidence is needed to inform strong recommendations for and access to TPT in children exposed to TB resistant to rifampin.

Hepatitis B surface antigen and hepatitis B RNA changes in HIV/hepatitis B virus co-infected participants receiving hepatitis B virus-active antiretroviral therapy.

INTRODUCTION: With advances in hepatitis B virus (HBV) therapies, there is a need to identify serum biomarkers that assess the HBV covalently closed circular DNA (cccDNA) reservoir and predict functional cure in HIV/HBV co-infection. METHODS: In this retrospective study, combining samples from HIV/HBV co-infected participants enrolled in two ACTG interventional trials, proportions achieving HBsAg less than 0.05 log10 IU/ml and HBV RNA less than log10 1.65 U/ml or not detected (LLoQ/NEG) in response to DUAL [tenofovir TDF+emtricitabine (FTC)] vs. MONO [FTC or lamivudine (3TC)] HBV-active ART, were measured. Predictors of qHBsAg less than 0.05 log10 IU/ml were evaluated in logistic regression models. RESULTS: There were 88 participants [58% women, median age 34; 47 on DUAL vs. 41 on MONO HBV-active ART]. Twenty-one percent achieved HBsAg less than 0.05 log10 IU/ml (30% DUAL vs. 10% MONO). Time to HBsAg less than 0.05 log10 IU/ml was lower (P  = 0.02) and the odds of achieving HBsAg less than 0.05 log10 IU/ml were higher (P = 0.07) in DUAL participants. HBV RNA became less than LLoQ/NEG in 47% (DUAL 60% vs. MONO 33%). qHBsAg less than 3 log10 IU/ml was the strongest predictor of HBsAg less than 0.05 log10 IU/ml. CONCLUSION: This study supports current recommendations of TDF-based DUAL-HBV active ART for initial use in HIV/HBV co-infection. HBV RNA could be a useful marker of treatment response in HIV/HBV co-infected patients on HBV-active ART.

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.

Efavirenz Pharmacokinetics and Human Immunodeficiency Virus Type 1 (HIV-1) Viral Suppression Among Patients Receiving Tuberculosis Treatment Containing Daily High-Dose Rifapentine.

BACKGROUND: A 4-month regimen containing rifapentine and moxifloxacin has noninferior efficacy compared to the standard 6-month regimen for drug-sensitive tuberculosis. We evaluated the effect of regimens containing daily, high-dose rifapentine on efavirenz pharmacokinetics and viral suppression in patients with human immunodeficiency virus (HIV)-associated tuberculosis (TB). METHODS: In the context of a Phase 3 randomized controlled trial, HIV-positive individuals already virally suppressed on efavirenz--containing antiretroviral therapy (ART) (EFV1), or newly initiating efavirenz (EFV2) received TB treatment containing rifapentine (1200 mg), isoniazid, pyrazinamide, and either ethambutol or moxifloxacin. Mid-interval efavirenz concentrations were measured (a) during ART and TB cotreatment (Weeks 4, 8, 12, and 17, different by EFV group) and (b) when ART was taken alone (pre- or post-TB treatment, Weeks 0 and 22). Apparent oral clearance (CL/F) was estimated and compared. Target mid-interval efavirenz concentrations were > 1 mg/L. Co-treatment was considered acceptable if > 80% of participants had mid-interval efavirenz concentrations meeting this target. RESULTS: EFV1 and EFV2 included 70 and 41 evaluable participants, respectively. The geometric mean ratio comparing efavirenz CL/F with vs without TB drugs was 0.79 (90% confidence interval [CI] .72-.85) in EFV1 and 0.84 [90% CI .69-.97] in EFV2. The percent of participants with mid-interval efavirenz concentrations > 1mg/L in EFV1 at Weeks 0, 4, 8, and 17 was 96%, 96%, 88%, and 89%, respectively. In EFV2, at approximately 4 and 8 weeks post efavirenz initiation, the value was 98%. CONCLUSIONS: TB treatment containing high-dose daily rifapentine modestly decreased (rather than increased) efavirenz clearance and therapeutic targets were met supporting the use of efavirenz with these regimens, without dose adjustment. CLINICAL TRIALS REGISTRATION: NCT02410772.

Sexually transmitted infections among HIV serodiscordant partners: A secondary analysis of HIV Prevention Trial Network 052.

Sexually transmitted infections (STIs) remain a public health concern because of their interaction(s) with HIV. In the HPTN 052 study, STIs were evaluated in both HIV-positive index cases and their HIV-negative partners at enrollment and at yearly follow-up visits. Our definition for STI was based on any infection with Chlamydia trachomatis, Neisseria gonorrhoeae, syphilis, or Trichomonas vaginalis. We used log-binomial regression models to identify factors associated with prevalent STIs. Generalized estimating equation models with the Poisson distribution were used to compare STI incidence between HIV-positive index cases and HIV-negative partners. 8.1% of the participants had STIs at enrollment. The prevalence of STIs (8.9 vs. 7.2) was higher in HIV-positive index cases than HIV-negative partners. Being female (prevalence ratio (PR) = 1.61; 95% CI: 1.20-2.16) or unmarried (PR = 1.92; 95% CI: 1.17-3.14) was associated with prevalent STIs. Compared to HIV-negative male partners, HIV-positive female index cases had a higher risk of STI acquisition (incidence rate ratio (IRR) = 2.25; 95% CI: 1.70-2.97). While we are implementing HIV prevention interventions for HIV-negative people, we should also intensify targeted STI prevention interventions, especially among HIV-positive women.

Antiretroviral hair levels, self-reported adherence, and virologic failure in second-line regimen patients in resource-limited settings.

OBJECTIVE: To evaluate associations between hair antiretroviral hair concentrations as an objective, cumulative adherence metric, with self-reported adherence and virologic outcomes. DESIGN: Analysis of cohort A of the ACTG-A5288 study. These patients in resource-limited settings were failing second-line protease inhibitor-based antiretroviral therapy (ART) but were susceptible to at least one nucleoside reverse transcriptase inhibitor (NRTI) and their protease inhibitor, and continued taking their protease inhibitor-based regimen. METHODS: Antiretroviral hair concentrations in participants taking two NRTIs with boosted atazanavir (n = 69) or lopinavir (n = 112) were analyzed at weeks 12, 24, 36 and 48 using liquid-chromatography--tandem-mass-spectrometry assays. Participants' self-reported percentage of doses taken in the previous month; virologic failure was confirmed HIV-1 RNA at least 1000 copies/ml at week 24 or 48. RESULTS: From 181 participants with hair samples (61% women, median age: 39 years; CD4+ cell count: 167 cells/µl; HIV-1 RNA: 18 648 copies/ml), 91 (50%) experienced virologic failure at either visit. At 24 weeks, median hair concentrations were 2.95 [interquartile range (IQR) 0.49-4.60] ng/mg for atazanavir, 2.64 (IQR 0.73--7.16) for lopinavir, and 0.44 (IQR 0.11--0.76) for ritonavir. Plasma HIV-1 RNA demonstrated inverse correlations with hair levels (rs -0.46 to -0.74) at weeks 24 and 48. Weaker associations were seen with self-reported adherence (rs -0.03 to -0.24). Decreasing hair concentrations were significantly associated with virologic failure, the hazard ratio (95% CI) for ATV, LPV, and RTV were 0.69 (0.56-0.86), 0.77 (0.68-0.87), and 0.12 (0.06-0.27), respectively. CONCLUSION: Protease inhibitor hair concentrations showed stronger associations with subsequent virologic outcomes than self-reported adherence in this cohort. Hair adherence measures could identify individuals at risk of second-line treatment failure in need of interventions.

Resistance to Mycobacterium tuberculosis Infection Among Household Contacts: A Multinational Study.

BACKGROUND: Some contacts of patients with tuberculosis remain negative on tests for tuberculosis infection, despite prolonged exposure, suggesting they might be resistant to Mycobacterium tuberculosis infection. The objective of this multinational study was to estimate the proportion of household contacts resistant to M. tuberculosis (resisters). METHODS: We conducted a longitudinal study enrolling index patients enrolled in treatment for pulmonary multidrug- or rifampin-resistant tuberculosis and their household contacts. Contacts were tested for tuberculosis infection with a tuberculin skin test (TST) and interferon-gamma release assay (IGRA) at baseline and after 1 year. Exposure was quantified based on index patients' infectiousness, index patient and household contact interaction, and age. We explored multiple definitions of resistance to tuberculosis infection by varying TST negativity cutoffs (0 vs <5 mm), classification of missing test results, and exposure level. RESULTS: In total, 1016 contacts were evaluated from 284 households; 572 contacts aged ≥5 years had TST and longitudinal IGRA results available. And 77 (13%) or 71 (12%) contacts were classified as resisters with a <5 mm or 0 mm TST threshold, respectively. Among 263 highly exposed contacts, 29 (11%) or 26 (10%) were classified as resisters using TST cutoffs of <5 mm and 0 mm, respectively. The prevalence of resisters did not differ substantially by sex, age, human immunodeficiency virus (HIV) coinfection, or comorbid conditions. CONCLUSIONS: At least 10% of household contacts can be classified as resistant to tuberculosis infection, depending on the definition used, including those with high exposure. Further studies to understand genetic or immunologic mechanisms underlying the resister phenotype may inform novel strategies for therapeutics and vaccines.

Drug susceptibility patterns of Mycobacterium tuberculosis from adults with multidrug-resistant tuberculosis and implications for a household contact preventive therapy trial.

BACKGROUND: Drug susceptibility testing (DST) patterns of Mycobacterium tuberculosis (MTB) from patients with rifampicin-resistant tuberculosis (RR-TB) or multidrug-resistant TB (MDR-TB; or resistant to rifampicin and isoniazid (INH)), are important to guide preventive therapy for their household contacts (HHCs). METHODS: As part of a feasibility study done in preparation for an MDR-TB preventive therapy trial in HHCs, smear, Xpert MTB/RIF, Hain MTBDRplus, culture and DST results of index MDR-TB patients were obtained from routine TB programs. A sputum sample was collected at study entry and evaluated by the same tests. Not all tests were performed on all specimens due to variations in test availability. RESULTS: Three hundred eight adults with reported RR/MDR-TB were enrolled from 16 participating sites in 8 countries. Their median age was 36 years, and 36% were HIV-infected. Routine testing on all 308 were confirmed as having RR-TB, but only 75% were documented as having MDR-TB. The majority of those not classified as having MDR-TB were because only rifampicin resistance was tested. At study entry (median 59 days after MDR-TB treatment initiation), 280 participants (91%) were able to produce sputum for the study, of whom 147 (53%) still had detectable MTB. All but 2 of these 147 had rifampicin DST done, with resistance detected in 89%. Almost half (47%) of the 147 specimens had INH DST done, with 83% resistance. Therefore, 20% of the 280 study specimens had MDR-TB confirmed. Overall, DST for second-line drugs were available in only 35% of the 308 routine specimens and 15% of 280 study specimens. CONCLUSIONS: RR-TB was detected in all routine specimens but only 75% had documented MDR-TB, illustrating the need for expanded DST beyond Xpert MTB/RIF to target preventive therapy for HHC.

Correlates and Timing of Reproductive Aging Transitions in a Global Cohort of Midlife Women With Human Immunodeficiency Virus: Insights From the REPRIEVE Trial.

BACKGROUND: Reproductive aging may contribute to cardiometabolic comorbid conditions. We integrated data on gynecologic history with levels of an ovarian reserve marker (anti-müllerian hormone [AMH)] to interrogate reproductive aging patterns and associated factors among a subset of cisgender women with human immunodeficiency virus (WWH) enrolled in the REPRIEVE trial. METHODS: A total of 1449 WWH were classified as premenopausal (n = 482) (menses within 12 months; AMH level ≥20 pg/mL; group 1), premenopausal with reduced ovarian reserve (n = 224) (menses within 12 months; AMH <20 pg/mL; group 2), or postmenopausal (n = 743) (no menses within12 months; AMH <20 pg/mL; group 3). Proportional odds models, adjusted for chronologic age, were used to investigate associations of cardiometabolic and demographic parameters with reproductive aging milestones (AMH <20 pg/mL or >12 months of amenorrhea). Excluding WWH with surgical menopause, age at final menstrual period was summarized for postmenopausal WWH (group 3) and estimated among all WWH (groups 1-3) using an accelerated failure-time model. RESULTS: Cardiometabolic and demographic parameters associated with advanced reproductive age (controlling for chronologic age) included waist circumference (>88 vs ≤88 cm) (odds ratio [OR], 1.38; 95% confidence interval, 1.06-1.80; P = .02), hemoglobin (≥12 vs <12 g/dL) (2.32; 1.71-3.14; P < .01), and region of residence (sub-Saharan Africa [1.50; 1.07-2.11; P = .02] and Latin America and the Caribbean [1.59; 1.08-2.33; P = .02], as compared with World Health Organization Global Burden of Disease high-income regions). The median age (Q1, Q3) at the final menstrual period was 48 (45, 51) years when described among postmenopausal WWH, and either 49 (46, 52) or 50 (47, 53) years when estimated among all WWH, depending on censoring strategy. CONCLUSIONS: Among WWH in the REPRIEVE trial, more advanced reproductive age is associated with metabolic dysregulation and region of residence. Additional research on age at menopause among WWH is needed. CLINICAL TRIALS REGISTRATION: NCT0234429.

Successful recruitment of a multi-site international randomized placebo-controlled trial in people with HIV with attention to diversity of race and ethnicity: critical role of central coordination.

Background: The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) is a multicenter, randomized, placebo-controlled trial, designed to test whether a statin medication can prevent cardiovascular disease in people with HIV. REPRIEVE recently completed enrollment of 7557 participants at over 100 clinical sites globally. Participant groups of focus were women, and racial and ethnic minorities.Objective: To describe recruitment methods and strategies developed by the REPRIEVE Clinical Coordinating Center (CCC) and share best practices learned from the recruitment process.Methods: Enrollment targets were agreed upon with the primary funder, the National Heart, Lung, and Blood Institute (NHLBI) and were milestone driven. Milestones included number of sites activated, number of participants enrolled within specific time frames, and proportion of women and minorities enrolled. Strategies to achieve these milestones included structured interviews with site-designated REPRIEVE Recruitment Champions to develop best practices, development of a multimedia campaign, and site level recruitment support.Results: Recruitment initiated March, 2015 and completed March, 2019. The final accrual target was 7500 participants over 48 months. The trial met this target within the time specified. Overall, 10,613 screens were completed, 48% of participants enrolled from sites outside of North America, 32% were female, 44% were Black or African American, and 25% were Hispanic or Latino.Conclusions: REPRIEVE met its overall projected recruitment goal by using multiple, simultaneous strategies to specifically target a diverse population including minority subgroups. REPRIEVE benefited from the development of recruitment strategies with clear targets and communication of accrual targets to study teams.

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.

Two-way mobile phone intervention compared with standard-of-care adherence support after second-line antiretroviral therapy failure: a multinational, randomised controlled trial.

Background: Antiretroviral therapy (ART) non-adherence causes HIV treatment failure. Past behaviour might predict future behaviour; failing second-line ART could indicate ongoing risk for subsequent non-adherence. We aimed to find out whether a two-way mobile phone-based communication intervention would increase HIV treatment success by improving medication adherence. Methods: We did a multinational, randomised controlled trial of patients at 17 sites in nine lower-income and middle-income countries in Africa, Asia, and the Americas. Patients aged 18 years and older, with HIV infection, and on second-line protease-inhibitor-based antiretroviral regimens, were randomly assigned (1:1) to either two-way mobile phone intervention plus standard of care (MPI + SOC) adherence support or standard-of-care alone (SOC). Our study was nested within a strategy study of ART after second-line ART failure (the main study, A5288). The main study had four cohorts, which were assigned regimens according to ART history and real-time genotype. Randomisation was stratified by the main study cohort with dynamic institutional balancing. Only the clinical management committee was masked, not the participants or site personnel. Text messages were sent over 48 weeks starting once a day and tapering down to once per week; participants were to respond once to each message if taking ART without issues. Repeated non-response to three messages over a 2-week period for the first 8 weeks, and then two messages over a 2-week period for the remainder of the study, triggered problem-solving counselling by staff. For this study, the primary endpoint was plasma HIV-1 RNA 200 copies per mL or less at 48 weeks and the secondary endpoint was virological failure (two consecutive HIV-1 RNA ≥1000 copies per mL) at 24 or more weeks. Prespecified intention-to- treat analyses were adjusted for cohort. Follow-up continued until the last participant had reached 48 weeks, with a median follow-up time of 72 weeks. The trial is registered with ClinicalTrials.gov, number . Findings: Enrolment began on Feb 22, 2013, and ended on Dec 21, 2015, with the last participant completing follow-up on Feb 13, 2017. Of 545 participants in the main study, 521 (96%) were enrolled and randomly assigned to MPI + SOC (n=257) or SOC alone (n=264). 52% of patients were men and the median HIV-1 RNA 4-4 log10 copies per mL (IQR 3.5 to 5-2). At week 48, HIV-1 RNA 200 copies per mL or less was reached in 169 (66%) of 257 patients in the MPI + SOC group and 164 (62%) of 264 patients in the SOC group (estimated difference 3-6% [95% CI -4-6% to 11-9%]; p=0-39). The adjusted odds ratio comparing MPI + SOC and SOC was 1-23 (0-82 to 1-84; p=0-32). Virological failure occurred in 66 (26%) patients in the MPI + SOC group and 89 (34%) patients in the SOC group during the median 72 weeks follow-up (adjusted p=0-027). Observed difference in virological failure favoured MPI + SOC in all cohorts. 23 (4%) participants died, 11 (4%) in the MPI + SOC group and 12 (5%) in the SOC group (p=0-89), with none of the deaths ascribed to ART, the MPI, or study procedures. Interpretation: Two-way MPI did not significantly improve week 48 suppression, but it did modestly affect virological failure. People failing second-line ART might not achieve benefits from phone-based triggers or enhanced adherence support (or both). More effective strategies are needed.