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BackgroundHIV-exposed, uninfected (HEU) infants suffer high morbidity and mortality in the first year of life compared to HIV-unexposed, uninfected (HUU) infants, but accurate data on the contribution of malaria are limited.MethodsThe incidence of febrile illnesses and malaria were evaluated in a birth cohort of HEU infants. Infants were prescribed daily trimethoprim-sulfamethoxazole (TS) prophylaxis from 6 weeks of age until exclusion of HIV-infection after cessation of breastfeeding. Infants were followed for all illnesses using passive surveillance and routine blood smears were done monthly. Malaria was diagnosed as a positive blood smear plus fever. Placental malaria was determined by histopathology, placental blood smear and PCR. Risk factors for time to first episode of malaria were assessed using a Cox proportional hazards model. Malaria incidence among HEU infants aged 6-12 months was compared to that in other cohorts of HEU and HUU infants from the same region.ResultsAmong 361 HEU infants enrolled, 248 completed 12 months of follow-up resulting in 1562 episodes of febrile illness and 253 episodes of malaria after 305 person-years of follow-up. The incidence of febrile illness was 5.12 episodes per person-year (PPY), ranging from 4.13 episodes PPY in the first 4 months of life to 5.71 episodes PPY between 5 and 12 months of age. The overall malaria incidence was 0.83 episodes per person-year (PPY), increasing from 0.03 episodes PPY in the first 2 months of life to 2.00 episodes PPY between 11 and 12 months of age. There were no episodes of complicated malaria. The prevalence of asymptomatic parasitaemia was 1.2 % (19 of 1568 routine smears positive). Infants born to mothers with parasites detected from placental blood smears were at higher risk of malaria (hazard ratio = 4.51, P

Background Human immunodeficiency virus (HIV) treatment reduces tuberculosis (TB) disease and mortality; however, the population-level impact of universal HIV-test-and-treat interventions on TB infection and transmission remain unclear. Methods In a sub-study nested in the SEARCH trial, a community cluster-randomized trial (NCT01864603), we assessed whether a universal HIV-test-and-treat intervention reduced population-level incident TB infection in rural Uganda. Intervention communities received annual, population-level HIV testing and patient-centered linkage. Control communities received population-level HIV testing at baseline and endline. We compared estimated incident TB infection by arms, defined by tuberculin skin test conversion in a cohort of persons aged 5 and older, adjusting for participation and predictors of infection, and accounting for clustering. Results Of the 32 trial communities, 9 were included, comprising 90 801 participants (43 127 intervention and 47 674 control). One-year cumulative incidence of TB infection was 16% in the intervention and 22% in the control; SEARCH reduced the population-level risk of incident TB infection by 27% (adjusted risk ratio = 0.73; 95% confidence interval [CI]:.57–.92, P =.005). In pre-specified analyses, the effect was largest among children aged 5–11 years and males. Conclusions A universal HIV-test-and-treat intervention reduced incident TB infection, a marker of population-level TB transmission. Investments in community-level HIV interventions have broader population-level benefits, including TB reductions. [ABSTRACT FROM AUTHOR]

ObjectiveWe sought to measure retention in care and identify predictors of nonretention among patients receiving antiretroviral therapy (ART) with streamlined delivery during the first year of the ongoing Sustainable East Africa Research on Community Health (SEARCH) 'test-and-treat' trial (NCT 01864603) in rural Uganda and Kenya.DesignProspective cohort of patients in the intervention arm of the SEARCH study.MethodsWe measured retention in care at 12 months among HIV-infected adults who linked to care and were offered ART regardless of CD4 cell count, following community-wide HIV-testing. Kaplan-Meier estimates and Cox proportional hazards modeling were used to calculate the probability of retention at 1 year and identify predictors of nonretention.ResultsAmong 5683 adults (age ≥15) who linked to care, 95.5% [95% confidence interval (CI): 92.9-98.1%] were retained in care at 12 months. The overall probability of retention at 1 year was 89.3% (95% CI: 87.6-90.7%) among patients newly linking to care and 96.4% (95% CI: 95.8-97.0%) among patients previously in care. Younger age and pre-ART CD4 cell count below country treatment initiation guidelines were predictors of nonretention among all patients. Among those newly linking, taking more than 30 days to link to care after HIV diagnosis was additionally associated with nonretention at 1 year. HIV viral load suppression at 12 months was observed in 4227 of 4736 (89%) of patients retained with valid viral load results.ConclusionHigh retention in care and viral suppression after 1 year were achieved in a streamlined HIV care delivery system in the context of a universal test-and-treat intervention.

BackgroundIn Africa, up to 30% of HIV-infected patients who are clinically eligible for antiretroviral therapy (ART) do not start timely treatment. We assessed the effects of an intervention targeting prevalent health systems barriers to ART initiation on timing and completeness of treatment initiation.MethodsIn this stepped-wedge, non-blinded, cluster-randomised controlled trial, 20 clinics in southwestern Uganda were randomly assigned in groups of five clinics every 6 months to the intervention by a computerised random number generator. This procedure continued until all clinics had crossed over from control (standard of care) to the intervention, which consisted of opinion-leader-led training and coaching of front-line health workers, a point-of-care CD4 cell count testing platform, a revised counselling approach without mandatory multiple pre-initiation sessions, and feedback to the facilities on their ART initiation rates and how they compared with other facilities. Treatment-naive, HIV-infected adults (aged ≥18 years) who were clinically eligible for ART during the study period were included in the study population. The primary outcome was ART initiation 14 days after first clinical eligibility for ART. This study is registered with ClinicalTrials.gov, number NCT01810289.FindingsBetween April 11, 2013, and Feb 2, 2015, 12 024 eligible patients visited one of the 20 participating clinics. Median CD4 count was 310 cells per μL (IQR 179-424). 3753 of 4747 patients (weighted proportion 80%) in the intervention group had started ART by 2 weeks after eligibility compared with 2585 of 7066 patients (38%) in the control group (risk difference 41·9%, 95% CI 40·1-43·8). Vital status was ascertained in a random sample of 208 patients in the intervention group and 199 patients in the control group. Four deaths (2%) occurred in the intervention group and five (3%) occurred in the control group.InterpretationA multicomponent intervention targeting health-care worker behaviour increased the probability of ART initiation 14 days after eligibility. This intervention consists of widely accessible components and has been tested in a real-world setting, and is therefore well positioned for use at scale.FundingNational Institute of Allergy and Infectious Diseases (NIAID) and the President's Emergency Fund for AIDS Relief (PEPFAR).

In 2013-14, we achieved 89% adult HIV testing coverage using a hybrid testing approach in 32 communities in Uganda and Kenya (SEARCH: NCT01864603). To inform scalability, we sought to determine: 1) overall cost and efficiency of this approach; and 2) costs associated with point-of-care (POC) CD4 testing, multi-disease services, and community mobilization.We applied micro-costing methods to estimate costs of population-wide HIV testing in 12 SEARCH Trial communities. Main intervention components of the hybrid approach are census, multi-disease community health campaigns (CHC), and home-based testing (HBT) for CHC non-attendees. POC CD4 tests were provided for all HIV-infected participants. Data were extracted from expenditure records, activity registers, staff interviews, and time and motion logs.The mean cost per adult tested for HIV was $20.5 (range: $17.1 - $32.1) [2014 US$], including a POC CD4 test at $16 per HIV+ person identified. Cost per adult tested for HIV was $13.8 at CHC vs. $31.7 via HBT. The cost per HIV+ adult identified was $231 ($87 - $1,245), with variability due mainly to HIV prevalence among persons tested (i.e., HIV positivity rate). The marginal costs of multi-disease testing at CHCs were $1.16/person for hypertension and diabetes, and $0.90 for malaria. Community mobilization constituted 15.3% of total costs.The hybrid testing approach achieved very high HIV testing coverage, with POC CD4, at costs similar to previously reported mobile, home-based, or venue-based HIV testing approaches in sub-Saharan Africa. By leveraging HIV infrastructure, multi-disease services were offered at low marginal costs.

Active TB screening outside of clinics and in communities may reduce undiagnosed TB disease.To determine yield of TB screening during community-based HIV testing campaigns (CHC) in seven rural Ugandan communities within an ongoing cluster randomized trial of universal HIV testing and treatment (SEARCH, NCT:01864603), we offered sputum microscopy to participants with prolonged cough (>2 weeks). We determined the number of persons needed to screen to identify one TB case, and the number of cases identified that linked to clinic and completed TB treatment.Of 36,785 adults enumerated in seven communities, 27,214 (74%) attended CHCs, and HIV testing uptake was >99%, with 941 (3.5%) HIV-infected adults identified. 5,786 (21%) adults reported cough, and 2,876 (11%) reported cough >2 weeks. Staff obtained sputum in 1,099/2,876 (38%) participants with prolonged cough, and identified 10 adults with AFB-positive sputum; 9 new diagnoses, and one known case already on treatment. The number needed to screen to identify one new TB case was 3,024 adults overall: 320 adults with prolonged cough, and 80 HIV-infected adults with prolonged cough.All nine newly diagnosed AFB+ participants linked to TB care within 2 weeks and initiated TB treatment.In a rural Ugandan setting, TB screening as an adjunct to large-scale, mobile HIV testing campaigns provides an opportunity to increase TB case detection.

ObjectiveWe sought to increase adolescent HIV testing across rural communities in east Africa and identify predictors of undiagnosed HIV.DesignHybrid mobile testing.MethodsWe enumerated 116 326 adolescents (10-24 years) in 32 communities of Uganda and Kenya (SearchNCT01864603): 98 694 (85%) reported stable (≥6 months of prior year) residence. In each community we performed hybrid testing: 2-week multidisease community health campaign that included HIV testing, followed by home-based testing of community health campaign nonparticipants. We measured adolescent HIV testing coverage and prevalence, and determined predictors of newly diagnosed HIV among HIV-infected adolescents using multivariable logistic regression.ResultsA total of 86 421 (88%) stable adolescents tested for HIV; coverage was 86, 90, and 88% in early (10-14), mid (15-17), and late (18-24) adolescents, respectively. Self-reported prior testing was 9, 26, and 55% in early, mid, and late adolescents tested, respectively. HIV prevalence among adolescents tested was 1.6 and 0.6% in Ugandan women and men, and 7.1 and 1.5% in Kenyan women and men, respectively. Prevalence increased in mid-adolescence for women and late adolescence for men. Among HIV-infected adolescents, 58% reported newly diagnosed HIV. In multivariate analysis of HIV-infected adolescents, predictors of newly diagnosed HIV included male sex [odds ratio (OR) = 1.97 (95% confidence interval (CI): 1.42-2.73)], Ugandan residence [OR = 2.63 (95% CI: 2.08-3.31)], and single status [OR = 1.62 (95% CI: 1.23-2.14) vs. married)].ConclusionsThe SEARCH hybrid strategy tested 88% of stable adolescents for HIV, a substantial increase over the 28% reporting prior testing. The majority (57%) of HIV-infected adolescents were new diagnoses. Mobile HIV testing for adults should be leveraged to reach adolescents for HIV treatment and prevention.

BackgroundAn interim analysis of data from the HIV Prevention Trials Network (HPTN) 052 trial showed that antiretroviral therapy (ART) prevented more than 96% of genetically linked infections caused by human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. ART was then offered to all patients with HIV-1 infection (index participants). The study included more than 5 years of follow-up to assess the durability of such therapy for the prevention of HIV-1 transmission.MethodsWe randomly assigned 1763 index participants to receive either early or delayed ART. In the early-ART group, 886 participants started therapy at enrollment (CD4+ count, 350 to 550 cells per cubic millimeter). In the delayed-ART group, 877 participants started therapy after two consecutive CD4+ counts fell below 250 cells per cubic millimeter or if an illness indicative of the acquired immunodeficiency syndrome (i.e., an AIDS-defining illness) developed. The primary study end point was the diagnosis of genetically linked HIV-1 infection in the previously HIV-1-negative partner in an intention-to-treat analysis.ResultsIndex participants were followed for 10,031 person-years; partners were followed for 8509 person-years. Among partners, 78 HIV-1 infections were observed during the trial (annual incidence, 0.9%; 95% confidence interval [CI], 0.7 to 1.1). Viral-linkage status was determined for 72 (92%) of the partner infections. Of these infections, 46 were linked (3 in the early-ART group and 43 in the delayed-ART group; incidence, 0.5%; 95% CI, 0.4 to 0.7) and 26 were unlinked (14 in the early-ART group and 12 in the delayed-ART group; incidence, 0.3%; 95% CI, 0.2 to 0.4). Early ART was associated with a 93% lower risk of linked partner infection than was delayed ART (hazard ratio, 0.07; 95% CI, 0.02 to 0.22). No linked infections were observed when HIV-1 infection was stably suppressed by ART in the index participant.ConclusionsThe early initiation of ART led to a sustained decrease in genetically linked HIV-1 infections in sexual partners. (Funded by the National Institute of Allergy and Infectious Diseases; HPTN 052 ClinicalTrials.gov number, NCT00074581 .).

The persistence of latent HIV proviruses in long-lived CD4(+) T cells despite antiretroviral therapy (ART) is a major obstacle to viral eradication. Because current candidate latency-reversing agents (LRAs) induce HIV transcription, but fail to clear these cellular reservoirs, new approaches for killing these reactivated latent HIV reservoir cells are urgently needed. HIV latency depends upon the transcriptional quiescence of the integrated provirus and the circumvention of immune defense mechanisms. These defenses include cell-intrinsic innate responses that use pattern-recognition receptors (PRRs) to detect viral pathogens, and that subsequently induce apoptosis of the infected cell. Retinoic acid (RA)-inducible gene I (RIG-I, encoded by DDX58) forms one class of PRRs that mediates apoptosis and the elimination of infected cells after recognition of viral RNA. Here we show that acitretin, an RA derivative approved by the US Food and Drug Administration (FDA), enhances RIG-I signaling ex vivo, increases HIV transcription, and induces preferential apoptosis of HIV-infected cells. These effects are abrogated by DDX58 knockdown. Acitretin also decreases proviral DNA levels in CD4(+) T cells from HIV-positive subjects on suppressive ART, an effect that is amplified when combined with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor. Pharmacological enhancement of an innate cellular-defense network could provide a means by which to eliminate reactivated cells in the latent HIV reservoir.

BackgroundMalaria control strategies depend on identifying individuals with parasitemia, who may be asymptomatic but retain the ability to transmit disease. Population-level survey data on parasitemia are limited and traditionally exclude adults and human immunodeficiency virus (HIV)-infected individuals.MethodsWe performed a cross-sectional survey of residents aged 18 months to 94 years in Nankoma, Uganda. Blood specimens were collected using the dried blood spot technique from 9629 residents (87.6%), and samples from a subset of 4131 were tested for malaria parasites, using loop-mediated isothermal amplification. Population-level prevalence was estimated using a weighted proportion, and predictors of parasitemia were identified using a multivariate Poisson regression model.ResultsThe community prevalence of parasitemia was 83.8% (95% confidence interval [CI], 82.9%-84.6%). Parasite prevalence was highest among children aged 5-14 years (94.7%) and lowest among adults (61.9%). In analysis that controlled for age, HIV-infected individuals with an undetectable viral load had a lower risk of parasitemia, compared with HIV-uninfected individuals (adjusted relative risk, 0.16; 95% CI, .10-.27; P < .001).ConclusionsIn a rural Ugandan community, 2 years after distribution of long-lasting insecticide-treated bed nets, the prevalence of malaria parasitemia was high across all ages, peaking in school-aged children. Persons with well-controlled HIV infection had a lower risk of parasitemia, presumably reflecting access to HIV care.

People living with HIV/AIDS anticipate HIV-related stigma and fear disclosure to intimate partners. Yet, disclosure is critical to reducing HIV transmission and improving care engagement. This qualitative study characterized HIV disclosure experiences and normative beliefs among couples in communities participating in an HIV test-and-treat trial in Kenya and Uganda (Sustainable East Africa Research in Community Health, NCT#01864603). In-depth interviews were conducted with care providers (n = 50), leaders (n = 32) and members (n = 112) of eight communities. Data were analyzed using grounded theoretical approaches and Atlas.ti software. Findings confirmed gender differences in barriers to disclosure: while both men and women feared blame and accusation, women also feared violence and abandonment ("I did not tell my husband because [what if] I tell him and he abandons me at the last moment when I am in labor?"). Positive consequences included partner support for increased care-seeking and adherence ("My husband keeps on reminding me 'have you taken those drugs?'") Yet negative consequences included partnership dissolution, blame, and reports of violence ("some men beat their wives just because of that [bringing HIV medications home]"). Among HIV-infected individuals in discordant relationships, men more often reported supportive spouses ("we normally share [HIV-risk-reduction strategies] since I have been infected and she is HIV negative"), than did women ("my husband refused to use condoms and even threatened to marry another wife"). Care providers lent support for HIV-positive women who wanted to engage partners in testing but feared negative consequences: "They engaged the two of us in a session and asked him if we could all test." Findings demonstrate differing experiences and support needs of women and men living with HIV in eastern Africa, with HIV-positive women in discordant couples particularly vulnerable to negative consequences of disclosure. Efforts to strengthen capacity in health systems for gender-sensitive clinician- or counselor-assisted disclosure should be accelerated within test-and-treat efforts.

Expectations about future health and longevity are important determinants of individuals' decisions to invest in physical and human capital. Few population-level studies have measured subjective expectations and examined how they are affected by scale-up of antiretroviral therapy (ART). We assessed these expectations in communities receiving annual HIV testing and universal ART. Longitudinal data on expectations were collected at baseline and one year later in 16 intervention communities participating in the Sustainable East Africa Research in Community Health (SEARCH) trial of the test and treat strategy in Kenya and Uganda (NCT01864603). A random sample of households with and without an HIV-positive adult was selected after baseline HIV testing. Individuals' expectations about survival to 50, 60, 70, and 80 years of age, as well as future health status and economic well-being, were measured using a Likert scale. Primary outcomes were binary variables indicating participants who reported being very likely or almost certain to survive to advanced ages. Logistic regression analyses were used to examine trends in expectations as well as associations with HIV status and viral load for HIV-positive individuals. Data were obtained from 3126 adults at baseline and 3977 adults in year 1, with 2926 adults participating in both waves. HIV-negative adults were more likely to have favorable expectations about survival to 60 years than HIV-positive adults with detectable viral load (adjusted odds ratio [AOR] 1.87, 95% CI 1.53-2.30), as were HIV-positive adults with undetectable viral load (AOR 1.41, 95% CI 1.13-1.77). Favorable expectations about survival to 60 years were more likely for all groups in year 1 compared to baseline (AOR 1.53, 95% CI 1.31-1.77). These findings are consistent with the hypothesis that universal ART leads to improved population-level expectations about future health and well-being. Future research from the SEARCH trial will help determine whether these changes are causally driven by the provision of universal ART.

Men's uptake of HIV testing is critical to the success of "test and treat" strategies in generalized epidemics. This study sought to identify cultural factors and community processes that influence men's HIV testing uptake in the baseline year of an ongoing test-and-treat trial among 334,479 persons in eastern Africa (SEARCH, NCT#01864603). Data were collected using participant observation at mobile community health campaigns (CHCs) (n = 28); focus group discussions (n = 8 groups) with CHC participants; and in-depth interviews with care providers (n = 50), leaders (n = 32), and members (n = 112) of eight communities in Kenya and Uganda. An 8-person research team defined analytical codes and iteratively refined them during data collection using grounded theoretical approaches, and textual data were coded using Atlas.ti software. Structural and cultural barriers, including men's mobility and gender norms valorizing risk-taking and discouraging health-seeking behavior, were observed, and contributed to men's lower participation in HIV testing relative to women. Men's labor opportunities often require extended absences from households: during planting season, men guarded fields from monkeys from dawn until nightfall; lake fishermen traveled long distances and circulated between beaches. Men often tested "by proxy", believing their wives' HIV test results to be their status. Debates about HIV risks were vigorous, with many men questioning "traditional" masculine gender norms that enhanced risks. The promise of antiretroviral therapy (ART) to prolong health was a motivating factor for many men to participate in testing. Flexibility in operating hours of HIV testing including late evening and weekend times along with multiple convenient locations that moved were cited as facilitating factors enhancing male participating in HIV testing. Mobile testing reduced but did not eliminate barriers to men's participation in a large-scale "test & treat" effort. However, transformations in gender norms related to HIV testing and care-seeking are underway in eastern Africa and should be supported.

Noncommunicable conditions such as cardiovascular disease, hypertension, renal and bone diseases, and malignancies as well as infectious complications are an ongoing concern during the course of treated HIV disease. Research in this area continues to focus on the epidemiology and risk factors for these conditions, on identifying the contributions of HIV-related immunopathology to specific and collective end-organ diseases, and on evaluating interventions to prevent or reduce the morbidity associated with these conditions. Data presented at the 2016 Conference on Retroviruses and Opportunistic Infections provided new insights into all of these areas.

BackgroundThe Xpert MTB/RIF (Xpert) assay is a rapid nucleic acid amplification test widely used in settings of high tuberculosis prevalence to detect tuberculosis as well asrpoBmutations associated with rifampin resistance. Data are needed on the diagnostic performance of Xpert in lower-prevalence settings to inform appropriate use for both tuberculosis detection and the need for respiratory isolation.MethodsXpert was compared to 2 sputum samples, each evaluated with acid-fast bacilli (AFB) smear and mycobacterial culture using liquid and solid culture media, from participants with suspected pulmonary tuberculosis from the United States, Brazil, and South Africa.ResultsOf 992 participants enrolled with evaluable results, 22% had culture-confirmed tuberculosis. In 638 (64%) US participants, 1 Xpert result demonstrated sensitivity of 85.2% (96.7% in participants with AFB smear-positive [AFB(+)] sputum, 59.3% with AFB smear-negative [AFB(-)] sputum), specificity of 99.2%, negative predictive value (NPV) of 97.6%, and positive predictive value of 94.9%. Results did not differ between higher- and low-prevalence settings. A second Xpert assay increased overall sensitivity to 91.1% (100% if AFB(+), 71.4% if AFB(-)), with specificity of 98.9%. In US participants, a single negative Xpert result predicted the absence of AFB(+)/culture-positive tuberculosis with an NPV of 99.7%; NPV of 2 Xpert assays was 100%, suggesting a role in removing patients from airborne infection isolation. Xpert detected tuberculosis DNA and mutations associated with rifampin resistance in 5 of 7 participants with rifampin-resistant, culture-positive tuberculosis. Specificity for rifampin resistance was 99.5% and NPV was 98.9%.ConclusionsIn the United States, Xpert testing performed comparably to 2 higher-tuberculosis-prevalence settings. These data support the use of Xpert in the initial evaluation of tuberculosis suspects and in algorithms assessing need for respiratory isolation.

BackgroundIn high tuberculosis (TB) burden countries, a significant proportion of the latent TB reservoir is established by the age 5 years. There are critical knowledge gaps in our understanding of the age-specific prevalence of TB infection and the influence of HIV exposure on TB infection in the first 5 years of life among HIV-uninfected children in sub-Saharan Africa.MethodsWe measured TB infection with the Quantiferon Gold-in-Tube (QFT) and tuberculin skin tests (TST) in 447 children ≤60 months and their 284 HIV-infected and IV-uninfected mothers in rural Uganda.ResultsThe overall prevalence of TB infection in children ≤60 months by TST was 24% (95% confidence intervals [CI]: 19.9-27.9). The prevalence of TST positivity was highest among children in their first year of life (36%; 95% CI: 26.0-45.9) and declined with age to 19% at 36-60 months of age, χ test for trend P = 0.014. In contrast, 4% (95% CI: 1.9-5.87%) of children had a positive QFT, and there was no trend detected with age, P = 0.576. QFT positivity was detected as early as 5 months. HIV-exposed uninfected children had significantly higher odds of TB infection by QFT (odds ratio [OR]: 21.2; P = 0.008; 95% CI: 2.2-204.7) or positive TST or QFT (OR, 2.4; P = 0.020; 95% CI: 1.2-5.1) compared with HIV-unexposed uninfected children, adjusting for age, BCG vaccination and a positive maternal TST or QFT.ConclusionsAn appreciable prevalence of TB infection was detected in early childhood. HIV-exposed uninfected children have a higher risk for TB infection compared with children born to HIV-uninfected mothers.

BackgroundIntermittent treatment with sulfadoxine-pyrimethamine is widely recommended for the prevention of malaria in pregnant women in Africa. However, with the spread of resistance to sulfadoxine-pyrimethamine, new interventions are needed.MethodsWe conducted a double-blind, randomized, controlled trial involving 300 human immunodeficiency virus (HIV)-uninfected pregnant adolescents or women in Uganda, where sulfadoxine-pyrimethamine resistance is widespread. We randomly assigned participants to a sulfadoxine-pyrimethamine regimen (106 participants), a three-dose dihydroartemisinin-piperaquine regimen (94 participants), or a monthly dihydroartemisinin-piperaquine regimen (100 participants). The primary outcome was the prevalence of histopathologically confirmed placental malaria.ResultsThe prevalence of histopathologically confirmed placental malaria was significantly higher in the sulfadoxine-pyrimethamine group (50.0%) than in the three-dose dihydroartemisinin-piperaquine group (34.1%, P=0.03) or the monthly dihydroartemisinin-piperaquine group (27.1%, P=0.001). The prevalence of a composite adverse birth outcome was lower in the monthly dihydroartemisinin-piperaquine group (9.2%) than in the sulfadoxine-pyrimethamine group (18.6%, P=0.05) or the three-dose dihydroartemisinin-piperaquine group (21.3%, P=0.02). During pregnancy, the incidence of symptomatic malaria was significantly higher in the sulfadoxine-pyrimethamine group (41 episodes over 43.0 person-years at risk) than in the three-dose dihydroartemisinin-piperaquine group (12 episodes over 38.2 person-years at risk, P=0.001) or the monthly dihydroartemisinin-piperaquine group (0 episodes over 42.3 person-years at risk, P

BackgroundDespite large investments in HIV testing, only an estimated 45% of HIV-infected people in sub-Saharan Africa know their HIV status. Optimum methods for maximising population-level testing remain unknown. We sought to show the effectiveness of a hybrid mobile HIV testing approach at achieving population-wide testing coverage.MethodsWe enumerated adult (≥15 years) residents of 32 communities in Uganda (n=20) and Kenya (n=12) using a door-to-door census. Stable residence was defined as living in the community for at least 6 months in the past year. In each community, we did 2 week multiple-disease community health campaigns (CHCs) that included HIV testing, counselling, and referral to care if HIV infected; people who did not participate in the CHCs were approached for home-based testing (HBT) for 1-2 months within the 1-6 months after the CHC. We measured population HIV testing coverage and predictors of testing via HBT rather than CHC and non-testing.FindingsFrom April 2, 2013, to June 8, 2014, 168,772 adult residents were enumerated in the door-to-door census. HIV testing was achieved in 131,307 (89%) of 146,906 adults with stable residence. 13,043 of 136,033 (9·6%, 95% CI 9·4-9·8) adults with and without stable residence had HIV; median CD4 count was 514 cells per μL (IQR 355-703). Among 131,307 adults with stable residence tested, 56,106 (43%) reported no previous testing. Among 13,043 HIV-infected adults, 4932 (38%) were unaware of their status. Among 105,170 CHC attendees with stable residence 104,635 (99%) accepted HIV testing. Of 131,307 adults with stable residence tested, 104,635 (80%; range 60-93% across communities) tested via CHCs. In multivariable analyses of adults with stable residence, predictors of non-testing included being male (risk ratio [RR] 1·52, 95% CI 1·48-1·56), single marital status (1·70, 1·66-1·75), age 30-39 years (1·58, 1·52-1·65 vs 15-19 years), residence in Kenya (1·46, 1·41-1·50), and migration out of the community for at least 1 month in the past year (1·60, 1·53-1·68). Compared with unemployed people, testing for HIV was more common among farmers (RR 0·73, 95% CI 0·67-0·79) and students (0·73, 0·69-0·77); and compared with people with no education, testing was more common in those with primary education (0·84, 0·80-0·89).InterpretationA hybrid, mobile approach of multiple-disease CHCs followed by HBT allowed for flexibility at the community and individual level to help reach testing coverage goals. Men and mobile populations remain challenges for universal testing.FundingNational Institutes of Health and President's Emergency Plan for AIDS Relief.

Food insecurity is associated with poor virologic outcomes, but this has not been studied during pregnancy and breastfeeding. We assessed sustained viral suppression from 8 weeks on antiretroviral therapy to 48 weeks postpartum among 171 pregnant and breastfeeding Ugandan women; 74.9% experienced food insufficiency. In multivariable analysis, food insufficiency [adjusted odds ratio (aOR) 0.38, 95% confidence interval (CI): 0.16 to 0.91], higher pretreatment HIV-1 RNA (aOR 0.55 per 10-fold increase, 95% CI: 0.37 to 0.82), and lopinavir/ritonavir versus efavirenz (aOR 0.49, 95% CI: 0.24 to 0.96) were associated with lower odds of sustained viral suppression. Interventions to address food security may improve virologic outcomes among HIV-infected women.

Food insecurity is associated with poor virologic outcomes, but this has not been studied during pregnancy and breastfeeding. We assessed sustained viral suppression from 8 weeks on antiretroviral therapy to 48 weeks postpartum among 171 pregnant and breastfeeding Ugandan women; 74.9% experienced food insufficiency. In multivariable analysis, food insufficiency [adjusted odds ratio (aOR) 0.38, 95% confidence interval (CI): 0.16 to 0.91], higher pretreatment HIV-1 RNA (aOR 0.55 per 10-fold increase, 95% CI: 0.37 to 0.82), and lopinavir/ritonavir versus efavirenz (aOR 0.49, 95% CI: 0.24 to 0.96) were associated with lower odds of sustained viral suppression. Interventions to address food security may improve virologic outcomes among HIV-infected women.

BackgroundLittle is known about the expression of inhibitory molecules cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed-death-1 (PD-1) on Mycobacterium tuberculosis (Mtb)-specific CD4 T-cells and how their expression is impacted by TB treatment.MethodsCryopreserved PBMCs from HIV-TB co-infected and TB mono-infected patients with untreated and treated tuberculosis (TB) disease were stimulated for six hours with PPD and stained. Using polychromatic flow cytometry, we characterized the differentiation state, cytokine profile, and inhibitory molecule expression on PPD-specific CD4 T-cells.ResultsIn our HIV-TB co-infected cohort, TB treatment increased the proportion of PPD-specific CD4 T-cells co-producing IFN-γ+IL-2+TNF-α+ and IFN-γ+IL-2+ (p = 0.0004 and p = 0.0002, respectively) while decreasing the proportion of PPD-specific CD4 T-cells co-producing IFN-γ+MIP1-β+TNF-α+ and IFN-γ+MIP1-β+. The proportion of PPD-specific CD4 T-cells expressing an effector memory phenotype decreased (63.6% vs 51.6%, p = 0.0015) while the proportion expressing a central memory phenotype increased (7.8% vs. 21.7%, p = 0.001) following TB treatment. TB treatment reduced the proportion of PPD-specific CD4 T-cells expressing CTLA-4 (72.4% vs. 44.3%, p = 0.0005) and PD-1 (34.5% vs. 29.2%, p = 0.03). Similar trends were noted in our TB mono-infected cohort.ConclusionTB treatment alters the functional profile of Mtb-specific CD4 T-cells reflecting shifts towards a less differentiated maturational profile and decreases PD-1 and CTLA-4 expression. These could serve as markers of reduced mycobacterial burden. Further study is warranted.

BackgroundAntiretroviral therapy scale-up in Sub-Saharan Africa has created a growing, aging HIV-positive population at risk for non-communicable diseases such as hypertension. However, the prevalence and risk factors for hypertension in this population remain incompletely understood.MethodsWe measured blood pressure and collected demographic data on over 65,000 adults attending multi-disease community health campaigns in 20 rural Ugandan communities (SEARCH Study: NCT01864603). Our objectives were to determine (i) whether HIV is an independent risk factor for hypertension, and (ii) awareness and control of hypertension in HIV-positive adults and the overall population.ResultsHypertension prevalence was 14% overall, and 11% among HIV-positive individuals. 79% of patients were previously undiagnosed, 85% were not taking medication, and 50% of patients on medication had uncontrolled blood pressure. Multivariate predictors of hypertension included older age, male gender, higher BMI, lack of education, alcohol use, and residence in Eastern Uganda. HIV-negative status was independently associated with higher odds of hypertension (OR 1.2, 95% CI: 1.1-1.4). Viral suppression of HIV did not significantly predict hypertension among HIV-positives.SignificanceThe burden of hypertension is substantial and inadequately controlled, both in HIV-positive persons and overall. Universal HIV screening programs could provide counseling, testing, and treatment for hypertension in Sub-Saharan Africa.

In 2021, there were more than 150,000 new HIV infections among children; however, only 52% of children living with HIV were on antiretroviral treatment (ART) [1]. Untreated infants and young [...]

Introduction: Achieving HIV epidemic control globally will require new strategies to accelerate reductions in HIV incidence and mortality. Universal test and treat (UTT) was evaluated in four randomized population-based trials (BCPP/Ya Tsie, HPTN 071/PopART, SEARCH, ANRS 12249/TasP) conducted in sub-Saharan Africa (SSA) during expanded antiretroviral treatment (ART) eligibility by World Health Organization guidelines and the UNAIDS 90-90-90 campaign. Discussion: These three-year studies were conducted in Botswana, Zambia, Uganda, Kenya and South Africa in settings with baseline HIV prevalence from 4% to 30%. Key observations across studies were: (1) Universal testing (implemented via a variety of home and community-based testing approaches) achieved >90% coverage in all studies. (2) When coupled with robust inkage to HIV care, rapid ART start and patient-centred care, UTT achieved among the highest reported population levels of viral suppression in SSA. Significant gains in population-level viral suppression were made in regions with both low and high baseline population viral load; however, viral suppression gains were not uniform across all sub-populations and were lower among youth. (3) UTT resulted in marked reductions in community HIV incidence when universal testing and robust linkage were present. However, HIV elimination targets were not reached. In BCPP and HPTN 071, annualized HIV incidence was approximately 20% to 30% lower in the intervention (which included universal testing) compared to control arms (no universa testing). In SEARCH (where both arms had universal testing), incidence declined 32% over three years. (4) UTT reduced HIV associated mortality by 23% in the intervention versus control communities in SEARCH, a study in which mortality was comprehensively measured. Conclusions: These trials provide strong evidence that UTT inclusive of universal testing increases population-level viral suppression and decreases HIV incidence and mortality faster than the status quo in SSA and should be adapted at a sub-country eve as a public health strategy. However, more is needed, including integration of new prevention interventions into UTT, in order to reach UNAIDS HIV elimination targets. Keywords: HIV testing; antiretroviral therapy; HIV elimination; HIV care continuum; HIV prevention; HIV care continuum; public health; universal access, (1) | INTRODUCTION HIV 'treatment as prevention' captivated the HIV field over a decade ago. When antiretroviral therapy (ART) was shown to be associated with the secondary benefit of HIV [...]

We evaluated the acceptability and use of macronutrient supplementation among HIV-infected pregnant Ugandan women receiving antiretroviral therapy in a clinical study (NCT 00993031). We first conducted formative research among 56 pregnant and lactating women to select a supplement regimen. Acceptability and use of the supplementation regimen (35 sachets of lipid-based nutrient supplements (LNS) and 4 or 6 kg of instant soy porridge for the household provided monthly) were evaluated among 87 pregnant women. Organoleptic assessments of LNS were favorable. Participants reported consuming LNS a mean of 6.1 days per week, and adherence to recommended consumption behaviors (e.g. frequency, quantity, not sharing) was >80 %. Few women reported negative social consequences of supplementation. The majority of participants also consumed most of the porridge intended for the household. In sum, LNS was acceptable and used regularly. Larger studies to evaluate physical and psychosocial consequences of LNS during pregnancy among HIV-infected women are warranted.

Purpose of reviewLong-acting injectable antiretroviral therapy (ART) formulations hold great promise in helping to close the significant gap between efficacy and effectiveness in HIV treatment by eliminating the requirement for lifelong daily pills. However, significant systems-level and individual challenges to implementation of long-acting ART in HIV treatment are anticipated.Recent findingsStudies of long-acting ART formulations are burgeoning, but the drugs are still in early phases of investigation and key knowledge gaps in pharmacokinetics and pharmacodynamics, as well as their effectiveness in settings with the largest burden of HIV disease and in key populations, remain. Extrapolating from the literature on implementation barriers to using long-acting contraception on a global scale, we explore the implementation barriers to rolling-out long-acting ART, including country approval and endorsements; prioritization of patient populations for preferred use, clinic infrastructure requirements, steady supply chains, decentralization of care, provider and patient training programs, and laboratory monitoring; and the need to examine patient preferences and conduct rigorous implementation science research to effectively scale-up this intervention.SummaryLong-acting ART for HIV treatment harbors exciting potential to shift treatment paradigms. Current knowledge gaps in the use of these agents remain, leading to multiple anticipated systems-level and individual-level barriers to implementation. Addressing these gaps and barriers will help fulfill the promise of these agents against the pandemic.

In STRIDE, slow metabolizer CYP2B6 and NAT2 genotypes were each associated with increased plasma efavirenz concentrations during antituberculosis therapy. Concentrations were greater on therapy than off therapy in 58% with CYP2B6 and 93% with NAT2 slow metabolizer genotypes. Individuals with slow metabolizer genotypes in both genes had markedly elevated concentrations.

Changing treatment practices may be selecting for changes in the drug sensitivity of malaria parasites. We characterized ex vivo drug sensitivity and parasite polymorphisms associated with sensitivity in 459 Plasmodium falciparum samples obtained from subjects enrolled in two clinical trials in Tororo, Uganda, from 2010 to 2013. Sensitivities to chloroquine and monodesethylamodiaquine varied widely; sensitivities to quinine, dihydroartemisinin, lumefantrine, and piperaquine were generally good. Associations between ex vivo drug sensitivity and parasite polymorphisms included decreased chloroquine and monodesethylamodiaquine sensitivity and increased lumefantrine and piperaquine sensitivity with pfcrt 76T, as well as increased lumefantrine sensitivity with pfmdr1 86Y, Y184, and 1246Y. Over time, ex vivo sensitivity decreased for lumefantrine and piperaquine and increased for chloroquine, the prevalences of pfcrt K76 and pfmdr1 N86 and D1246 increased, and the prevalences of pfdhfr and pfdhps polymorphisms associated with antifolate resistance were unchanged. In recurrent infections, recent prior treatment with artemether-lumefantrine was associated with decreased ex vivo lumefantrine sensitivity and increased prevalence of pfcrt K76 and pfmdr1 N86, 184F, and D1246. In children assigned chemoprevention with monthly dihydroartemisinin-piperaquine with documented circulating piperaquine, breakthrough infections had increased the prevalence of pfmdr1 86Y and 1246Y compared to untreated controls. The noted impacts of therapy and chemoprevention on parasite polymorphisms remained significant in multivariate analysis correcting for calendar time. Overall, changes in parasite sensitivity were consistent with altered selective pressures due to changing treatment practices in Uganda. These changes may threaten the antimalarial treatment and preventive efficacies of artemether-lumefantrine and dihydroartemisinin-piperaquine, respectively.

ObjectiveHair concentrations are a noninvasive measure of cumulative antiretroviral exposure and the strongest predictor of viral suppression in large cohorts of nonpregnant patients. We examined hair concentrations of antiretrovirals in relation to virologic outcomes in pregnant and breastfeeding women for the first time.Design and methodsThe Prevention of Malaria and HIV Disease in Tororo trial (NCT00993031) enrolled HIV-infected pregnant Ugandan women at 12-28 weeks gestation who were randomized to lopinavir or efavirenz-based antiretroviral therapy (ART). Small hair samples were collected at 30-34 weeks gestation and 10-25 weeks postpartum. Efavirenz and lopinavir hair concentrations were measured via liquid chromatography/tandem mass spectrometry. Multivariate logistic regression models examined predictors of viral suppression (HIV-1 RNA ≤400 copies/ml) at delivery and 24 weeks postpartum.ResultsAmong 325 women, median CD4 cell count was 366 cells/μl (interquartile range 270-488) at ART initiation. Mean self-reported 3-day adherence was greater than 97% in each arm. Viral suppression was achieved by 98.0% (efavirenz) and 87.4% (lopinavir) at delivery. At 24 weeks postpartum, 92.5% (efavirenz) and 90.6% (lopinavir) achieved viral suppression; 88% of women were breastfeeding. In multivariate models including self-reported adherence and pretreatment HIV-1 RNA, antiretroviral hair concentrations were the strongest predictor of viral suppression at delivery [efavirenz: adjusted odds ratio (aOR) 1.86 per doubling in concentration, 95% confidence interval (CI) 1.14-3.1, P = 0.013; lopinavir: aOR 1.90, 95% CI 1.33-2.7, P = 0.0004] and 24 weeks postpartum (efavirenz: aOR 1.81, 95% CI 1.22-2.7, P = 0.003; lopinavir: aOR 1.53, 95% CI 1.05-2.2, P = 0.026).ConclusionAntiretroviral hair concentrations represent an innovative tool that strongly predicts viral suppression among HIV-infected childbearing women during the critical periods of delivery and breastfeeding.

ObjectivesTargeting high Tuberculosis (TB) transmission sites may offer a novel approach to TB prevention in sub-Saharan Africa. We sought to characterise TB transmission sites in a rural Ugandan township.MethodsWe recruited adults starting TB treatment in Tororo, Uganda, over 1 year. Fifty four TB cases provided names of frequent contacts, sites of residence, health care, work and social activities, and two sputum samples. Mycobacterium tuberculosis (MTB) culture-positive specimens underwent spoligotyping to identify strains with shared genotypes. We visualised TB case social networks, and obtained, mapped and geo-coded global positioning system measures for every location that cases reported frequenting 1 month before treatment. Locations of spatial overlap among genotype-clustered cases were considered potential transmission sites.ResultsSix distinct genotypic clusters were identified involving 21 of 33 (64%) MTB culture-positive, genotyped cases; none shared a home. Although 18 of 54 (33%) TB cases shared social network ties, none of the genotype-clustered cases shared social ties. Using spatial analysis, we identified potential sites of within-cluster TB transmission for five of six genotypic clusters. All sites but one were healthcare and social venues, including sites of drinking, worship and marketplaces. Cases reported spending the largest proportion of pre-treatment person-time (22.4%) at drinking venues.ConclusionsUsing molecular epidemiology, geospatial and social network data from adult TB cases identified at clinics, we quantified person-time spent at high-risk locations across a rural Ugandan community and determined the most likely sites of recent TB transmission to be healthcare and social venues. These sites may not have been identified using contact investigation alone.

© 2015, Public Library of Science. All rights reserved.Gastrointestinal T lymphocytes are critical for mucosal immunity and HIV pathogenesis, yet little is known about normal T cell numbers and phenotypes in different regions of the gut, or the degree to w

BackgroundMalnutrition may impact the pharmacokinetics (PKs) of antiretroviral medications and virologic responses in HIV-infected children. The authors therefore evaluated the PK of nevirapine (NVP), efavirenz (EFV) and lopinavir (LPV) in associations with nutritional status in a cohort of HIV-infected Ugandan children.MethodsSparse dried blood spot samples from Ugandan children were used to estimate plasma concentrations. Historical PK data from children from 3 resource-rich countries (RRC) were utilized to develop the PK models.ResultsConcentrations in 330 dried blood spot from 163 Ugandan children aged 0.7-7 years were analyzed in reference to plasma PK data (1189 samples) from 204 children from RRC aged 0.5-12 years. Among Ugandan children, 48% was malnourished (underweight, thin or stunted). Compared to RRC, Ugandan children exhibited reduced bioavailability of EFV and LPV; 11% (P=0.045) and 18% (P=0.008), respectively. In contrast, NVP bioavailability was 46% higher in Ugandan children (P

Noncommunicable diseases, such as cardiovascular disease, hypertension, renal and bone disease, and malignancies are an ongoing concern during the course of treated HIV disease. Research in this area continues to focus on the epidemiology and risk factors associated with these conditions, identifying the contributions of HIV-related immunopathology to specific and collective end-organ diseases, and evaluating interventions to prevent or reduce the morbidity associated with these conditions. Infectious complications of HIV, such as tuberculosis and cryptococcal disease, also continue to cause substantial morbidity and mortality; diagnosis, prevention, and treatment of these is an area of focus. The 2015 Conference on Retroviruses and Opportunistic Infections provided new insights into all of these areas.

ObjectiveCombination antiretroviral therapy (ART) is now the global standard for HIV-infected pregnant and breastfeeding women at all CD4⁺ cell counts. We compared the efficacy and safety of an efavirenz versus lopinavir/ritonavir regimen for HIV-infected pregnant women initiating ART in rural Uganda.DesignRandomized clinical trial.MethodsWe performed a planned secondary analysis comparing viral load suppression (HIV-1 RNA ≤400 copies/ml), safety, and HIV transmission to infants in a trial designed to test the hypothesis that lopinavir/ritonavir versus efavirenz-based ART would reduce placental malaria (PROMOTE, ClinicalTrials.gov, NCT00993031). HIV-infected, ART-naive pregnant women at 12-28 weeks gestation and any CD4⁺ cell count were randomized. ART was provided and participants were counseled to breastfeed for 1 year postpartum.ResultsThe median age of the 389 study participants was 29 years; median CD4⁺ cell count was 370 cells/μl. At delivery, virologic suppression was 97.6% in the efavirenz arm and 86.0% in the lopinavir/ritonavir arm (P

© 2014 Bigira et al.Chemoprevention offers a promising strategy for prevention of malaria in African children. However, the optimal chemoprevention drug and dosing strategy is unclear in areas of year-round transmission and resistance to many antimalarial

BackgroundEvidence favoring earlier HIV ART initiation at high CD4+ T-cell counts (CD4>350/uL) has grown, and guidelines now recommend earlier HIV treatment. However, the cost of providing ART to individuals with CD4>350 in Sub-Saharan Africa has not been well estimated. This remains a major barrier to optimal global cost projections for accelerating the scale-up of ART. Our objective was to compute costs of ART delivery to high CD4+count individuals in a typical rural Ugandan health center-based HIV clinic, and use these data to construct scenarios of efficient ART scale-up.MethodsWithin a clinical study evaluating streamlined ART delivery to 197 individuals with CD4+ cell counts >350 cells/uL (EARLI Study: NCT01479634) in Mbarara, Uganda, we performed a micro-costing analysis of administrative records, ART prices, and time-and-motion analysis of staff work patterns. We computed observed per-person-per-year (ppy) costs, and constructed models estimating costs under several increasingly efficient ART scale-up scenarios using local salaries, lowest drug prices, optimized patient loads, and inclusion of viral load (VL) testing.FindingsAmong 197 individuals enrolled in the EARLI Study, median pre-ART CD4+ cell count was 569/uL (IQR 451-716). Observed ART delivery cost was $628 ppy at steady state. Models using local salaries and only core laboratory tests estimated costs of $529/$445 ppy (+/-VL testing, respectively). Models with lower salaries, lowest ART prices, and optimized healthcare worker schedules reduced costs by $100-200 ppy. Costs in a maximally efficient scale-up model were $320/$236 ppy (+/- VL testing). This included $39 for personnel, $106 for ART, $130/$46 for laboratory tests, and $46 for administrative/other costs. A key limitation of this study is its derivation and extrapolation of costs from one large rural treatment program of high CD4+ count individuals.ConclusionsIn a Ugandan HIV clinic, ART delivery costs--including VL testing--for individuals with CD4>350 were similar to estimates from high-efficiency programs. In higher efficiency scale-up models, costs were substantially lower. These favorable costs may be achieved because high CD4+ count patients are often asymptomatic, facilitating more efficient streamlined ART delivery. Our work provides a framework for calculating costs of efficient ART scale-up models using accessible data from specific programs and regions.

BackgroundHuman immunodeficiency virus (HIV)-infected pregnant women are at increased risk of malaria and its complications. In vitro and in vivo data suggest that the HIV protease inhibitors lopinavir/ritonavir may have potent antimalarial activity. We sought to evaluate whether lopinavir/ritonavir-based antiretroviral therapy (ART) reduced the risk of placental malaria.MethodsHIV-infected, ART-naive pregnant women were enrolled between gestational weeks 12 and 28 and randomly assigned to receive lopinavir/ritonavir-based or efavirenz-based ART. Women received daily trimethoprim-sulfamethoxazole prophylaxis and insecticide-treated bed nets at enrollment and were followed up to 1 year after delivery. The primary outcome was placental malaria, defined by the detection of malaria parasites, using microscopy or polymerase chain reaction (PCR) analysis of placental blood specimens. Secondary outcomes included placental malaria, defined by histopathologic results; adverse birth outcomes; incidence of malaria; and prevalence of asymptomatic parasitemia. Analyses were done using an intention-to-treat approach.ResultsOf 389 subjects randomly assigned to a treatment group, 377 were followed through to delivery. There was no significant difference in the risk of placental malaria, as defined by thick smear or PCR findings, between the lopinavir/ritonavir-based and efavirenz-based ART arms (7.4% vs 9.8%; P = .45). Similarly, there were no differences in secondary outcomes between the 2 treatment arms.ConclusionsLopinavir/ritonavir-based ART did not reduce the risk of placental or maternal malaria or improve birth outcomes, compared with efavirenz-based ART.Clinical trials registrationNCT00993031.