Kennedy Otwombe

Early time-limited antiretroviral therapy versus deferred therapy in South African infants infected with HIV: results from the children with HIV early antiretroviral (CHER) randomised trial

BACKGROUND Interim results from the children with HIV early antiretroviral (CHER) trial showed that early antiretroviral therapy (ART) was life-saving for infants infected with HIV. In view of the few treatment options and the potential toxicity associated with lifelong ART, in the CHER trial we compared early time-limited ART with deferred ART. METHODS CHER was an open-label randomised controlled trial of HIV-infected asymptomatic infants younger than 12 weeks in two South African trial sites with a percentage of CD4-positive T lymphocytes (CD4%) of 25% or higher. 377 infants were randomly allocated to one of three groups: deferred ART (ART-Def), immediate ART for 40 weeks (ART-40W), or immediate ART for 96 weeks (ART-96W), with subsequent treatment interruption. The randomisation schedule was stratified by clinical site with permuted blocks of random sizes to balance the numbers of infants allocated to each group. Criteria for ART initiation in the ART-Def group and re-initiation after interruption in the other groups were CD4% less than 25% in infancy; otherwise, the criteria were CD4% less than 20% or Centers for Disease Control and Prevention severe stage B or stage C disease. Combination therapy of lopinavir-ritonavir, zidovudine, and lamivudine was the first-line treatment regimen at ART initiation and re-initiation. The primary endpoint was time to failure of first-line ART (immunological, clinical, or virological) or death. Comparisons were done by intention-to-treat analysis, with use of time-to-event methods. This trial is registered with ClinicalTrials.gov, number NCT00102960. FINDINGS 377 infants were enrolled, with a median age of 7·4 weeks, CD4% of 35%, and HIV RNA log 5·7 copies per mL. Median follow-up was 4·8 years; 34 infants (9%) were lost to follow-up. Median time to ART initiation in the ART-Def group was 20 weeks (IQR 16-25). Time to restarting of ART after interruption was 33 weeks (26-45) in ART-40W and 70 weeks (35-109) in ART-96W; at the end of the trial, 19% of patients in ART-40W and 32% of patients in ART-96W remained off ART. Proportions of follow-up time spent on ART were 81% in the ART-Def group, 70% in the ART-40W group, and 69% in the ART-96W group. 48 (38%) of 125 children in the ART-Def group, 32 (25%) of 126 in the ART-40W group, and 26 (21%) of 126 in the ART-96W group reached the primary endpoint. The hazard ratio, relative to ART-Def, was 0·59 (95% CI 0·38-0·93, p=0·02) for ART-40W and 0·47 (0·27-0·76, p=0·002) for ART-96W. Three children in ART-Def, three in ART-40W, and one in ART-96W switched to second-line ART. INTERPRETATION Early time-limited ART had better clinical and immunological outcomes than deferred ART, with no evidence of excess disease progression during subsequent treatment interruption and less overall ART exposure than deferred ART. Longer time on primary ART permits longer subsequent interruption, with marginally better outcomes. FUNDING US National Institutes of Health.

Early severe HIV disease precedes early antiretroviral therapy in infants: Are we too late?

To describe the degree of HIV disease progression in infants initiating antiretroviral therapy (ART) by three months of age in a programmatic setting in South Africa.

Morbidity and Mortality among Infants Born to HIV-Infected Women in South Africa: Implications for Child Health in Resource-Limited Settings

BACKGROUND We examined correlates of infant morbidity and mortality within the first 3 months of life among HIV-exposed infants receiving post-exposure antiretroviral prophylaxis in South Africa. METHODS We conducted a prospective cohort study of 848 mother-child dyads. Multivariable Cox proportional hazards models were used. RESULTS The main causes of infant morbidity were gastrointestinal and respiratory infections. Morbidity was higher with infant HIV infection (HR: 2.61; 95% CI: 1.40-4.85; p = 0.002) and maternal plasma viral load (PVL) >100,000 copies ml⁻¹ (HR: 1.87; 95% CI: 1.01-3.48; p = 0.048), and lower with maternal age < 20 years (HR: 0.25; 95% CI: 0.07-0.88; p = 0.031). Mortality was higher with infant HIV infection (HR: 4.10; 95% CI: 1.18-14.31; p = 0.027) and maternal PVL >100,000 copies ml⁻¹ (HR: 6.93; 95% CI: 1.64-29.26; p = 0.008). Infant feeding status did not influence the risk of morbidity nor mortality. CONCLUSIONS Future interventions that minimize pediatric HIV infection and reduce maternal viremia, which are the main predictors of child health soon after birth, will impact positively on infant health outcomes.

Improving national data collection systems from voluntary counselling and testing centres in Kenya

PROBLEM Voluntary counselling and testing (VCT) data from the registered sites in Kenya have been fraught with challenges, leading to insufficient statistics in the national office for planning purposes. An exercise was carried out to determine the barriers to the flow of data in VCT sites in Kenya. APPROACH A record-based survey was conducted at 332 VCT sites in Kenya. Data from on-site records were compared with those in the national office. The exercise was conducted in 2004 between 5 September and 15 October. LOCAL SETTING All registered VCT sites in Kenya. RELEVANT CHANGES After the exercise, various measures to enhance VCT data collection and reporting were implemented. They include the provision of a uniform data collection and reporting tool to all the districts in the country, the strengthening of a feedback mechanism to update provinces and districts on their reporting status and increased support to the data component of the national quality assurance for VCT. LESSONS LEARNED Periodical field visits by the national officials to offer on-the-job training about data management to data collectors and to address data quality issues can dramatically improve the quality and completeness of VCT reports. The perceived relevance of the data and the data collection process to those working at the sites is the critical factor for data quality and timeliness of reporting.

Reactivity of routine HIV antibody tests in children who initiated antiretroviral therapy in early infancy as part of the Children with HIV Early Antiretroviral Therapy (CHER) trial: a retrospective analysis

BACKGROUND Early antiretroviral therapy (ART) and virological suppression can affect evolving antibody responses to HIV infection. We aimed to assess frequency and predictors of seronegativity in infants starting early ART. METHODS We compared HIV antibody results between two of three treatment groups of the Children with HIV Early Antiretroviral Therapy (CHER) trial, done from July, 2005, until July, 2011, in which infants with HIV infection aged 5·7-12·0 weeks with a percentage of CD4-positive T lymphocytes of at least 25% were randomly assigned to immediate ART for 96 weeks (ART-96W) or deferred ART until clinical or immunological progression (ART-Def). We measured antibody from all available stored samples for ART-96W and ART-Def at trial week 84 using three assays: fourth-generation enzyme immunoassay HIV antigen-antibody combination, HIV-1 and HIV-2 rapid antibody test, and quantitative anti-gp120 IgG ELISA. We also assessed odds of seropositivity with respect to age of ART initiation and cumulative viral load. The CHER trial was registered with ClinicalTrials.gov, number NCT00102960. FINDINGS The median age of the infants from when samples were taken (184 samples from 268 infants) was 92 weeks (IQR 90·6-93·4). More specimens from the ART-96W group were seronegative than from the ART-Def group by enzyme immunoassay (ART-96W 49 [46%] of 107 vs ART-Def eight [11%] of 75; p<0·0001) and rapid antibody test (54 [53%] of 101 vs eight [11%] of 74; p<0·0001). Median anti-gp120 IgG concentration was lower in the ART-96W group (230 μg/μL [IQR 133-13 129]) than in the ART-Def group (6870 μg/μL [1706-53 645]; p<0·0001). If ART was started between 12 and 24 weeks of age, odds of seropositivity were increased 13·7 times (95% CI 3·1-60·2; p=0·001) compared with starting it between 0 and 12 weeks. All children starting ART aged older than 24 weeks were seropositive. Cumulative viral load to week 84 correlated with anti-gp120 IgG concentrations (coefficient 0·54; p<0·0001) and increased odds of seropositivity (odds ratio 1·59 [95% CI 1·1-2·3]) adjusted for ART initiation age. INTERPRETATION About half of children starting ART before 12 weeks of age were HIV seronegative by almost 2 years of age. HIV antibody tests cannot be used to reconfirm HIV diagnosis in children starting early ART. Long-term effects of seronegativity need further study. Clear guidelines are needed for retesting alongside improved diagnostic tests. FUNDING Wellcome Trust, Medical Research Council, and National Institutes of Health.

Effect of in-utero HIV exposure and antiretroviral treatment strategies on measles susceptibility and immunogenicity of measles vaccine.

Introduction:The high burden of maternal HIV-infection in sub-Saharan Africa may affect measles control. We evaluated the effect of in-utero HIV-exposure and antiretroviral treatment (ART) strategies on measles antibody kinetics prior and following measles vaccination. Methods:Infants aged 6–12 weeks were enrolled. This included HIV-uninfected infants born to HIV-uninfected (HUU) and HIV-infected mothers (HEU). Additionally, we enrolled perinatal HIV-infected infants with CD4% equal or greater than 25% randomized to deferred-ART until clinically or immunologically indicated (Group-3) or immediate-ART initiation (Group-4). Group-4 was further randomized to interrupt ART at 1 year (Group-4a) or 2 years of age (Group-4b). Additionally, a convenience sample of HIV-infected infants with CD4+ less than 25% initiated on immediate-ART was enrolled (Group-5). Measles immunoglobulin-G antibodies were quantified by an indirect enzyme immunoassay with titers 330 mIU/ml or more considered ‘sero-protective’. The referent group was HUU-children. Results:The proportion with sero-protective titers at 7.3 weeks of age was higher in HUU (65.2%) compared with any HIV-infected group (range: 16.7–41.8%), but dropped to less than 17% in all groups at age 19.6 weeks. Twenty-eight weeks following the first measles vaccine, Group-4a was less likely to have sero-protective titers (79.3%) as compared to HUU (91.1%; P < 0.0001), Group-3 (95.7%; P = 0.003) or Group-4b (92.1%; P = 0.018). Although the proportion with sero-protective levels were similar between groups immediately postbooster dose, this was lower in HEU (79.6%; P = 0.002) and Group-4a (80.3%; P = 0.010) compared with HUU (94.3%) 41-weeks later. Conclusion:Greater waning of immunity among HIV-infected children in whom ART was interrupted and in HEU following a booster-dose, indicate the possible need for further measles-booster doses after 2 years of age in these children.

Factors associated with not testing for HIV and consistent condom use among men in Soweto, South Africa.

Background Besides access to medical male circumcision, HIV testing, access to condoms and consistent condom use are additional strategies men can use to prevent HIV acquisition. We examine male behavior toward testing and condom use. Objective To determine factors associated with never testing for HIV and consistent condom use among men who never test in Soweto. Methods A cross-sectional survey in Soweto was conducted in 1539 men aged 18–32 years in 2007. Data were collected on socio-demographic and behavioral characteristics to determine factors associated with not testing and consistent condom use. Results Over two thirds (71%) of men had not had an HIV test and the majority (55%, n = 602) were young (18–23). Of those not testing, condom use was poor (44%, n = 304). Men who were 18–23 years (aOR: 2.261, CI: 1.534–3.331), with primary (aOR: 2.096, CI: 1.058–4.153) or high school (aOR: 1.622, CI: 1.078–2.439) education, had sex in the last 6 months (aOR: 1.703, CI: 1.055–2.751), and had ≥1 sexual partner (aOR: 1.749, CI: 1.196–2.557) were more likely not to test. Of those reporting condom use (n = 1036, 67%), consistent condom use was 43% (n = 451). HIV testing did not correlate with condom use. Conclusion Low rates of both condom use and HIV testing among men in a high HIV prevalence setting are worrisome and indicate an urgent need to develop innovative behavioral strategies to address this shortfall. Condom use is poor in this population whether tested or not tested for HIV, indicating no association between condom use and HIV testing.

Kganya Motsha Adolescent Centre: a model for adolescent friendly HIV management and reproductive health for adolescents in Soweto, South Africa

This paper reports on Kganya Motsha Adolescent Centre, an adolescent program specifically established to provide voluntary counseling and testing as well as management of HIV-positive young people in Soweto, South Africa. A retrospective cross-sectional analysis, using clinic records of young people accessing services from 2008 to 2012, was conducted. Of the 11,522 who tested, 7689 (67%) were females. The total number of HIV infections was 410, with an HIV prevalence of 3.6% (95% CI 3.2–3.9%). More females (332, 4% vs. 72, 2%; p < 0.0001) were HIV-infected than males. Of those testing HIV positive, 109 (26.5%) had a median CD4 cell count of 491 (IQR 345–686) cells/mm3. Only 12/410 individuals (2.9%) were eligible for antiretroviral treatment and 10 (2.4%) of those successfully received treatment. The program observed that young people testing HIV positive would not return for follow up blood specimens or confirmatory results. Future programs should consider innovative ways of retaining adolescents in care to reduce potential HIV transmissions that could lead to deteriorating health.

Exposure to and experiences of violence among adolescents in lower socio-economic groups in Johannesburg, South Africa

BackgroundWe explored exposure to and experiences of violence and their risk factors amongst ethnically diverse adolescents from lower socio economic groups in Johannesburg.MethodsThis cross-sectional study recruited a stratified sample of 16–18 year old adolescents from four low socio-economic suburbs in Johannesburg to reflect ethnic group clustering. We collected socio-demographic, sexual behaviour, alcohol and drug use and trauma events data. Proportions and risk factors were assessed by chi-square and logistic regression.ResultsOf 822 adolescents, 57% (n = 469) were female. Approximately 62% (n = 506) were Black, 13% (n = 107) Coloured, 13% (n = 106) Indian and 13% (n = 103) White. Approximately 67% (n = 552) witnessed violence to a non-family member, 28% (n = 228) experienced violence by a non-family member, and 10% (n = 83) reported sexual abuse. Multivariate analysis determined that witnessing violence in the community was associated with being Black (OR: 4.6, 95%CI: 2.7-7.9), Coloured (OR: 3.9, 95%CI: 2.0-7.4) or White (OR: 8.0, 95%CI:4.0-16.2), repeating a grade (OR: 1.5, 95%CI: 1.01-2.1), having more than one sexual partner (OR: 1.7, 95%CI: 1.1-2.5) and ever taking alcohol (OR: 2.1, 95%CI: 1.5-2.9). Witnessing violence in the family was associated with being female (OR: 1.8, 95%CI: 1.3-2.6), being Black (OR: 2.2, 95%CI: 1.1-4.1), or White (OR: 3.0, 95%CI: 1.4-6.4), repeating a grade (OR: 1.6, 95%CI: 1.1-2.2) and ever taking alcohol (OR: 2.9, 95%CI: 2.0-4.3).ConclusionsIn low socio-economic areas in Johannesburg, Black, White and Coloured adolescents experience a high burden of violence. Interventions to mitigate the effects of violence are urgently required.

Multiple Levels of Influence in Predicting Sexual Activity and Condom Use Among Adolescents in Soweto, Johannesburg, South Africa

HIV prevalence amongst 15–19 year olds in South Africa is 6.7% and 2.5% in females and males respectively. Using an interviewer-administered cross-sectional survey, we examined individual, interpersonal, family and community factors associated with sexual activity and condom use among 506 adolescents 16–18 years from Soweto, Johannesburg. The sample was mainly female (59%, n = 298). Using multivariate logistic regression, males (OR:2.6, CI: 1.4–4.8), older partners (OR:4.5, CI: 1.5–13.8), hazardous alcohol use (OR:2.4, CI: 1.1–5.2) and permissive attitudes about sex (OR:1.6, CI: 1.3–2.1) predicted sexual activity. A first partner at a younger age (OR:1.2, CI: 1.1–1.4) and having older partners (OR:0.29, CI: 0.13–0.68) predicted lack of condom use. For females, increasing age (OR:2.7 CI:1.4–5.5), older partners (OR: 3.3 CI:1.4–7.6), and permissive attitudes about sex (OR: 1.6 CI:1.2–2.1) predicted sexual activity. Multiple levels have to be addressed in developing HIV prevention programs for adolescents in Soweto.