Lisa A. Mills

Prevention of HIV-1 Infection with Early Antiretroviral Therapy

BACKGROUND Antiretroviral therapy that reduces viral replication could limit the transmission of human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. METHODS In nine countries, we enrolled 1763 couples in which one partner was HIV-1-positive and the other was HIV-1-negative; 54% of the subjects were from Africa, and 50% of infected partners were men. HIV-1-infected subjects with CD4 counts between 350 and 550 cells per cubic millimeter were randomly assigned in a 1:1 ratio to receive antiretroviral therapy either immediately (early therapy) or after a decline in the CD4 count or the onset of HIV-1-related symptoms (delayed therapy). The primary prevention end point was linked HIV-1 transmission in HIV-1-negative partners. The primary clinical end point was the earliest occurrence of pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death. RESULTS As of February 21, 2011, a total of 39 HIV-1 transmissions were observed (incidence rate, 1.2 per 100 person-years; 95% confidence interval [CI], 0.9 to 1.7); of these, 28 were virologically linked to the infected partner (incidence rate, 0.9 per 100 person-years, 95% CI, 0.6 to 1.3). Of the 28 linked transmissions, only 1 occurred in the early-therapy group (hazard ratio, 0.04; 95% CI, 0.01 to 0.27; P<0.001). Subjects receiving early therapy had fewer treatment end points (hazard ratio, 0.59; 95% CI, 0.40 to 0.88; P=0.01). CONCLUSIONS The early initiation of antiretroviral therapy reduced rates of sexual transmission of HIV-1 and clinical events, indicating both personal and public health benefits from such therapy. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 052 ClinicalTrials.gov number, NCT00074581.).

Antiretroviral therapy for the prevention of HIV-1 transmission

BACKGROUND An 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. METHODS We 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. RESULTS Index 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. CONCLUSIONS The 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 .).

Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial

BACKGROUND Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes. METHODS The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00074581. FINDINGS 1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373-522) cells per μL in patients assigned to the early treatment group and 428 (357-522) cells per μL in those allocated delayed antiretroviral treatment. In the delayed group, antiretroviral treatment was initiated at a median CD4 count of 230 (IQR 197-249) cells per μL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment (hazard ratio 0·73, 95% CI 0·52-1·03; p=0·074). New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation (0·64, 0·43-0·96; p=0·031), tuberculosis developed in 17 versus 34 patients, respectively (0·49, 0·28-0·89, p=0·018), and primary non-AIDS events were rare (12 in the early group vs nine with delayed treatment). In total, 498 primary and secondary outcomes occurred in the early treatment group (incidence 24·9 per 100 person-years, 95% CI 22·5-27·5) versus 585 in the delayed treatment group (29·2 per 100 person-years, 26·5-32·1; p=0·025). 26 people died, 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group. INTERPRETATION Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes. The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment. FUNDING US National Institute of Allergy and Infectious Diseases.

Botswana's progress toward achieving the 2020 UNAIDS 90-90-90 antiretroviral therapy and virological suppression goals: a population-based survey

BACKGROUND HIV programmes face challenges achieving high rates of HIV testing and treatment needed to optimise health and to reduce transmission. We used data from the Botswana Combination Prevention Project study survey to assess Botswanas progress toward achieving UNAIDS targets for 2020: 90% of all people living with HIV knowing their status, 90% of these receiving sustained antiretroviral therapy (ART), and 90% of those having virological suppression (90-90-90). METHODS A population-based sample of individuals was recruited and interviewed in 30 rural and periurban communities from Oct 30, 2013, to Nov 24, 2015, as part of a large, ongoing community-randomised trial designed to assess the effect of a combination prevention package on HIV incidence. A random sample of about 20% of households in each community was selected. Consenting household residents aged 16-64 years who were Botswana citizens or spouses of citizens responded to a questionnaire and had blood drawn for HIV testing in the absence of documentation of positive HIV status. Viral load testing was done in all HIV-infected participants, irrespective of treatment status. We used modified Poisson generalised estimating equations to obtain prevalence ratios, corresponding Huber robust SEs, and 95% Wald CIs to examine associations between individual sociodemographic factors and a binary outcome indicating achievement of the three individual and combined overall 90-90-90 targets. The study is registered at ClinicalTrials.gov, number NCT01965470. FINDINGS 81% of enumerated eligible household members took part in the survey (10% refused and 9% were absent). Among 12 610 participants surveyed, 3596 (29%) were infected with HIV, and 2995 (83·3%, 95% CI 81·4-85·2) of these individuals already knew their HIV status. Among those who knew their HIV status, 2617 (87·4%, 95% CI 85·8-89·0) were receiving ART (95% of those eligible by national guidelines, and 73% of all infected people). Of the 2609 individuals receiving ART with a viral load measurement, 2517 (96·5%, 95% CI 96·0-97·0) had viral load of 400 copies per mL or less. Overall, 70·2% (95% CI 67·5-73·0) of HIV-infected people had virological suppression, close to the UNAIDS target of 73%. INTERPRETATION UNAIDS 90-90-90 targets are achievable even in resource-constrained settings with high HIV burden. FUNDING US Presidents Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention.

Attitudes toward Family Planning among HIV-Positive Pregnant Women Enrolled in a Prevention of Mother-To-Child Transmission Study in Kisumu, Kenya

Background Preventing unintended pregnancies among HIV-positive women through family planning (FP) reduces pregnancy-related morbidity and mortality, decreases the number of pediatric HIV infections, and has also proven to be a cost-effective way to prevent mother-to-child HIV transmission. A key element of a comprehensive HIV prevention agenda, aimed at avoiding unintended pregnancies, is recognizing the attitudes towards FP among HIV-positive women and their spouse or partner. In this study, we analyze FP attitudes among HIV-infected pregnant women enrolled in a PMTCT clinical trial in Western Kenya. Methods and Findings Baseline data were collected on 522 HIV-positive pregnant women using structured questionnaires. Associations between demographic variables and the future intention to use FP were examined using Fishers exact tests and permutation tests. Most participants (87%) indicated that they intended to use FP. However, only 8% indicated condoms as a preferred FP method, and 59% of current pregnancies were unintended. Factors associated with positive intentions to use FP were: marital status (p = 0.04), having talked to their spouse or partner about FP (p<0.001), perceived spouse or partner approval of FP (p<0.001), previous use of a FP method (p = 0.006), attitude toward the current pregnancy (p = 0.02), disclosure of a sexually transmitted infection (STI) diagnosis (p = 0.03) and ethnic group (p = 0.03). Conclusion A significant gap exists between future FP intentions and current FP practices. Support and approval by the spouse or partner are key elements of FP intentions. Counseling services should be offered to both members of a couple to increase FP use, especially given the high number of unplanned pregnancies among HIV-positive women. Condoms should be promoted as part of a dual use method for HIV and STI prevention and for contraception. Integration of individual and couple FP services into routine HIV care, treatment and support services is needed in order to avoid unintended pregnancies and to prevent mother-to-child HIV transmission.

Evaluation of Quantification of HIV-1 RNA Viral Load in Plasma and Dried Blood Spots by Use of the Semiautomated Cobas Amplicor Assay and the Fully Automated Cobas Ampliprep/TaqMan Assay, Version 2.0, in Kisumu, Kenya

ABSTRACT In Kenya, HIV-1 viral load monitoring is commonly performed with the Cobas Amplicor using plasma specimens. Interest is growing in transitioning to real-time PCR (RT-PCR), such as the Cobas Ampliprep/Cobas TaqMan (CAP/CTM), using dried blood spots (DBS). Before implementation, direct evaluation of the two assays using DBS field specimens is required. This study compares the sensitivity, specificity, negative and positive predictive values (NPV and PPV, respectively), concordance, and agreement between HIV-1 viral load measurements using plasma and DBS specimens obtained from 512 HIV-1-infected pregnant females enrolled in the Kisumu Breastfeeding Study and tested with the Cobas Amplicor and CAP/CTM assays. The sensitivity and NPV of viral load detection in DBS specimens were higher with CAP/CTM (sensitivity, 100%; 95% confidence interval [CI], 99.1 to 100.0%; NPV, 100%; 95% CI, 59.0 to 100.0%) than the Cobas Amplicor (sensitivity, 96.6%; 95% CI, 94.3 to 98.1%; NPV, 58.8%; 95% CI, 40.7 to 75.4%). The PPVs were comparable between both assays when using DBS. The specificity of viral load detection in DBS specimens was lower with CAP/CTM (77.8%; 95% CI, 40.0 to 97.2%) than that of the Cobas Amplicor (95.2%; 95% CI, 76.2 to 99.9%). Good concordance and agreement were observed when paired plasma and DBS specimens were tested with both assays. Lower specificity with the CAP/CTM is likely due to proviral HIV-1 DNA amplification and lower detection limits with RT-PCR. However, the CAP/CTM has better sensitivity and higher throughput than the Cobas Amplicor. These findings suggest that DBS may be a suitable alternative to plasma when using RT-PCR, which could increase access to viral load monitoring in resource-limited settings.

Data Resource Profile: Network for Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA Network)

Data Resource Profile : Network for Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA Network)

Shame, guilt, and stress: Community perceptions of barriers to engaging in prevention of mother to child transmission (PMTCT) programs in western Kenya.

While global scale-up of prevention of mother-to-child transmission of HIV (PMTCT) services has been expansive, only half of HIV-infected pregnant women receive antiretroviral regimens for PMTCT in sub-Saharan Africa. To evaluate social factors influencing uptake of PMTCT in rural Kenya, we conducted a community-based, cross-sectional survey of mothers residing in the KEMRI/CDC Health and Demographic Surveillance System (HDSS) area. Factors included referrals and acceptability, HIV-related stigma, observed discrimination, and knowledge of violence. Chi-squared tests and multivariate regression analyses were used to detect stigma domains associated with uptake of PMTCT services. Most HIV-positive women (89%) reported blame or judgment of people with HIV, and 46% reported they would feel shame if they were associated with someone with HIV. In multivariate analyses, shame was significantly associated with decreased likelihood of maternal HIV testing (Prevalence Ratio 0.91, 95% Confidence Interval 0.84-0.99), a complete course of maternal antiretrovirals (ARVs) (PR 0.73, 95% CI 0.55-0.97), and infant HIV testing (PR 0.86, 95% CI 0.75-0.99). Community perceptions of why women may be unwilling to take ARVs included stigma, guilt, lack of knowledge, denial, stress, and despair or futility. Interventions that seek to decrease maternal depression and internalization of stigma may facilitate uptake of PMTCT.

Menstrual Needs and Associations with Sexual and Reproductive Risks in Rural Kenyan Females: A Cross-Sectional Behavioral Survey Linked with HIV Prevalence

Abstract Background: Females in low and middle income countries (LMICs) have difficulty coping with menstrual needs, but few studies have examined the social or health implications of these needs. Methods: Responses from 3418 menstruating females aged 13–29 years were extracted from an HIV and behavioral risks cross-sectional survey conducted in rural western Kenya. We examined sanitary products used, provision of products from sexual partners or from transactional sex, and demographic and sexual exposures. Results: Overall, 75% of females reported using commercial pads and 25% used traditional materials such as cloth or items like paper or tissue, with 10% of girls <15 years old depending on makeshift items. Two-thirds of females with no education relied on traditional items. Having attended secondary school increased the odds of using commercial pads among married (adjusted odds ratios [AOR] 4.8, 95% confidence interval [CI] 3.25–7.12) and single females (AOR 2.17, 95% CI 1.04–4.55). Married females had lower odds of pad use if they reported early (<12 years of age) compared with later (≥18 years) sexual debut (64% vs. 78%, AOR 0.45, 95% CI 0.21–0.97). Two-thirds of pad users received them from sexual partners. Receipt was lower among married females if partners were violent (AOR 0.67, 95% CI 0.53–0.85). Receipt among single females was higher if they had two or more sexual partners in the past year (AOR 2.11, 95% CI 1.04–4.29). Prevalence of engaging in sex for money to buy pads was low (1.3%); however, 10% of 15-year-olds reported this, with girls ≤15 having significantly higher odds compared with females over 15 (AOR 2.84, 95% CI 0.89–9.11). The odds of having transactional sex for pads was higher among females having two or more partners in the past 12 months (AOR 4.86, 95% CI 2.06–11.43). Conclusions: Menstrual needs of impoverished females in rural LMICs settings likely leads to increased physical and sexual harms. Studies are required to strengthen knowledge and to evaluate interventions to reduce these harms.

Community-based evaluation of PMTCT uptake in Nyanza Province, Kenya.

Introduction Facility-based assessments of prevention of mother-to-child HIV transmission (PMTCT) programs may overestimate population coverage. There are few community-based studies that evaluate PMTCT coverage and uptake. Methods During 2011, a cross-sectional community survey among women who gave birth in the prior year was performed using the KEMRI-CDC Health and Demographic Surveillance System in Western Kenya. A random sample (n = 405) and a sample of women known to be HIV-positive through previous home-based testing (n = 247) were enrolled. Rates and correlates of uptake of antenatal care (ANC), HIV-testing, and antiretrovirals (ARVs) were determined. Results Among 405 women in the random sample, 379 (94%) reported accessing ANC, most of whom (87%) were HIV tested. Uptake of HIV testing was associated with employment, higher socioeconomic status, and partner HIV testing. Among 247 known HIV-positive women, 173 (70%) self-disclosed their HIV status. Among 216 self-reported HIV-positive women (including 43 from the random sample), 82% took PMTCT ARVs, with 54% completing the full antenatal, peripartum, and postpartum course. Maternal ARV use was associated with more ANC visits and having an HIV tested partner. ARV use during delivery was lowest (62%) and associated with facility delivery. Eighty percent of HIV infected women reported having their infant HIV tested, 11% of whom reported their child was HIV infected, 76% uninfected, 6% declined to say, 7% did not recall; 79% of infected children were reportedly receiving HIV care and treatment. Conclusions Community-based assessments provide data that complements clinic-based PMTCT evaluations. In this survey, antenatal HIV test uptake was high; most HIV infected women received ARVs, though many women did not self-disclose HIV status to field team. Community-driven strategies that encourage early ANC, partner involvement, and skilled delivery, and provide PMTCT education, may facilitate further reductions in vertical transmission.