Therapeutic effects of antiretroviral therapy (ART) in patients with multidrug resistant tuberculosis (MDR-TB) and HIV infection have not been established.
The objective of this study was to assess therapeutic outcomes of ART integration with MDR-TB treatment.
A subgroup of MDR-TB patients from the SAPiT study, a randomized controlled trial, conducted in an out-patient clinic in Durban, South Africa from 2008–2012
Clinical outcomes at 18 months were compared in patients randomized to receive ART within 12 weeks of standard first-line tuberculosis treatment initiation with those who commenced ART after completing tuberculosis treatment.
Mycobacterium tuberculosis drug susceptibility was available in 489 (76%) of 642 SAPiT patients; 23 had MDR-TB, 14 in the integrated treatment arm and 9 in the sequential treatment arm. At 18 months, the mortality rate was 11.9/100 person-years (95% confidence interval (CI): 1.4–42.8) in the combined integrated treatment arm and 56.0/100 person-years (95%CI: 18.2–130.8) in the sequential treatment arm, (Hazard Ratio adjusted for baseline CD4 count and whether MDR-TB treatment was initiated: 0.14; 95% CI: 0.02–0.94; P=0.04).
Despite the small sample size, the 86% reduction in mortality due to early initiation of ART in MDR-TB patients was statistically significant.
MDR-TB; HIV treatment
Globally, herpes simplex virus type 2 (HSV-2) infection is the most common cause of genital ulcer disease. Effective prevention strategies for HSV-2 infection are needed to achieve the goals of the World Health Organization global strategy for the prevention and control of sexually transmitted infections.
We assessed the effectiveness of pericoital tenofovir gel, an antiviral microbicide, in preventing HSV-2 acquisition in a subgroup of 422 HSV-2–negative women enrolled in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 study, a double-blind, randomized, placebo-controlled trial. Incident HSV-2 cases were identified by evidence of seroconversion on an HSV-2 IgG enzyme-linked immunosorbent assay between study enrollment and exit. A confirmatory analysis was performed by Western blot testing.
The HSV-2 incidence rate was 10.2 cases per 100 person-years (95% confidence interval [CI], 6.8 to 14.7) among 202 women assigned to tenofovir gel, as compared with 21.0 cases per 100 person-years (95% CI, 16.0 to 27.2) among 222 women assigned to placebo gel (incidence rate ratio, 0.49; 95% CI, 0.30 to 0.77; P = 0.003). The HSV-2 incidence rate among the 25 women with vaginal tenofovir concentrations of 10,000 ng per milliliter or more was 5.7 cases per 100 person-years, as compared with 15.5 cases per 100 person-years among the 103 women with no detectable vaginal tenofovir (incidence rate ratio, 0.37; 95% CI, 0.04 to 1.51; P = 0.14). As confirmed by Western blot testing, there were 16 HSV-2 seroconversions among women assigned to tenofovir gel as compared with 36 among those assigned to the placebo gel (incidence rate ratio, 0.45; 95% CI, 0.23 to 0.82; P = 0.005).
In this study in South Africa, pericoital application of tenofovir gel reduced HSV-2 acquisition in women. (Funded by the U.S. Agency for International Development and others; ClinicalTrials.gov number, NCT00441298.)
South Africa has over 6,000,000 HIV infected individuals and the province of KwaZulu-Natal (KZN) is the most severely affected. As public health initiatives to better control the HIV epidemic are implemented, timely, detailed and robust surveillance data are needed to monitor, evaluate and inform the programmatic interventions and policies over time. We describe the rationale and design of the HIV Incidence Provincial Surveillance System (HIPSS) to monitor HIV prevalence and incidence.
The household-based survey will include a sample of men and women from two sub-districts of the uMgungundlovu municipality (Vulindlela and the Greater Edendale) of KZN, South Africa. The study is designed as two sequential cross-sectional surveys of 10,000 randomly selected individuals aged 15–49 years to be conducted one year apart. From the cross sectional surveys, two sequential cohorts of HIV negative individuals aged 15–35 years will be followed-up one year later to measure the primary outcome of HIV incidence. Secondary outcomes include the laboratory measurements for pulmonary tuberculosis, sexually transmitted infections and evaluating tests for estimating population-level HIV incidence.
Antiretroviral therapy (ART) access, HIV-1 RNA viral load, and CD4 cell counts in HIV positive individuals will assess the effectiveness of the HIV treatment cascade. Household and individual-level socio-demographic characteristics, exposure to HIV programmatic interventions and risk behaviours will be assessed as predictors of HIV incidence. The incidence rate ratio of the two cohorts will be calculated to quantify the change in HIV incidence between consecutive samples. In anticipation of better availability of population-level HIV prevention and treatment programmes leading to decreases in HIV incidence, the sample size provides 84 % power to detect a reduction of 30 % in the HIV incidence rate between surveys.
The results from HIPSS will provide critical data regarding HIV prevalence and incidence in this community and will establish whether HIV prevention and treatment efforts in a “real world”, non-trial setting have an impact on HIV incidence at a population level. Importantly, the study design and methods will inform future methods for HIV surveillance.
Young women in sub-Saharan Africa are disproportionately affected by HIV, making the development of women initiated and controlled methods of prevention, including microbicides, a priority. Adherence is pivotal to microbicide efficacy and partner related factors are known to impact adherence. An analysis of disclosure of gel use to sexual partners and adherence in CAPRISA 004 women was conducted to better understand this relationship. Partner disclosure was significantly associated with a modest 4.2 % increased adherence (71.0 vs. 66.8 %, p = 0.03). Most women rated the experience of disclosure as positive, despite 6.7 % of partners expressing a negative reaction. Participants who disclosed were more likely to reside with their regular partner (14.4 vs. 8.4 %; p = 0.01) and reported consistent condom use at baseline (32.9 vs. 20.9 %; p< 0.01). Partner disclosure needs to be better understood as a potential facilitator or barrier to microbicide adherence.
Adherence; Partner disclosure; HIV prevention; Microbicides; Pre-exposure prophylaxis
Rationale and objective
Hypericum perforatum (St John’s Wort) is used to treat depression, but the effectiveness has not been established. Recent guidelines described the analysis of clinical trials with missing data, inspiring the re-analysis of this trial using proper missing data methods. The objective was to determine whether hypericum was superior to placebo in treating major depression.
A placebo-controlled, randomized clinical trial was conducted for 8 weeks to determine the effectiveness of hypericum or sertraline in reducing depression, measured using the Hamilton depression scale. We performed sensitivity analyses under different assumptions about the missing data process.
340 participants were randomized, with 28% lost to follow-up. The missing data mechanism was not missing completely at random. Under missing at random assumptions, some sensitivity analyses found no difference between either treatment arm and placebo, while some sensitivity analyses found a significant difference between sertraline and placebo (95% credible interval [−0.31;−0.01]), but not between hypericum and placebo [−0.08;0.22]. The results were similar when the missing data process was assumed to be missing not at random (95%credible interval for week by sertraline interaction [−0.31;−0.01]; week by hypericum interaction [−0.08;0.22]).
There is no difference between hypericum and placebo, regardless of the assumption about the missing data process. There is a significant difference between sertraline and placebo with some statistical methods used. It is important to conduct an analysis that takes account of missing data using valid statistically principled methods. The assumptions about the missing data process could influence the results.
St John’s Wort; hypericum perforatum; herbal medicine; antidepressant; sertraline; Hamilton depression scale; Bayesian; multiple imputation; missing at random; missing not at random
To determine if urinary lipoarabinomannan (LAM) may serve as a biomarker to monitor antituberculosis (TB) therapy response, and whether LAM results before and after treatment are predictive of patient outcomes.
Outpatient referral clinic and tertiary hospital in South Africa.
Adults (≥18 years) with ≥2 TB-related symptoms (cough, fever, weight loss, night sweats) for ≥2 weeks being initiated on anti-TB therapy.
On enrolment, we obtained urine and nebulised sputum specimens, offered HIV testing and started participants on anti-TB therapy for ≥6 months. We collected urine samples after the 2-month intensive treatment phase and at the completion of anti-TB therapy. Positive LAM results were graded from 1 (low) to 5 (high). Participants were followed for >3 years.
The primary outcome was change in urine LAM results during anti-TB therapy. The secondary outcome was all-cause mortality.
Among 90 participants, 57 (63%) had culture-confirmed pulmonary TB. Among the 88 participants tested, 82 (93%) were HIV-infected with median CD4 168/mm3 (IQR 89–256/mm3). During anti-TB therapy, the percentage of LAM-positive participants decreased from baseline to 2 months (32% to 16%), and from baseline to 6-months (32% to 10%) (p values <0.005). In multivariate longitudinal analyses, urine LAM positivity and grade decreased among those with culture-confirmed pulmonary TB (p<0.0001), and had no change in sputum culture-negative participants. At the 2-month visit, participants with positive laboratory-based LAM or rapid LAM with ≥2+ grade had a significantly greater risk of mortality. In analyses adjusted for age, sex, baseline Karnofsky score and HIV status, participants with a rapid LAM ≥2+ grade after 2 months of anti-TB therapy had a 5.6-fold (95% CI 1.2 to 25.2) greater risk of mortality.
Rapid urine LAM testing may be a valuable tool to monitor anti-TB therapy response and to assess prognosis of patients being treated for pulmonary TB in HIV-endemic regions.
The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial demonstrated a 39% reduction in HIV infection, with a 54% HIV reduction in women who used tenofovir gel consistently. A confirmatory trial is expected to report results in early 2015. In the interim, we have a unique window of opportunity to prepare for and devise effective strategies for the future policy and programmatic scale-up of tenofovir gel provision. One approach is to integrate tenofovir gel provision into family planning (FP) services. The CAPRISA 008 implementation trial provides an opportunity to provide post-trial access to tenofovir gel while generating empiric evidence to assess whether integrating tenofovir gel provision into routine FP services can achieve similar levels of adherence as the CAPRISA 004 trial.
This is a two-arm, open-label, randomized controlled non-inferiority trial. A maximum of 700 sexually active, HIV-uninfected women aged 18 years and older who previously participated in an antiretroviral prevention study will be enrolled from an urban and rural site in KwaZulu-Natal, South Africa. The anticipated study duration is 30 months, with active accrual requiring approximately 12 months (following which an open cohort will be maintained) and follow-up continuing for approximately 18 months. At each of the two sites, eligible participants will be randomly assigned to receive tenofovir gel through either FP services (intervention arm) or through the CAPRISA research clinics (control arm). As part of the study intervention, a quality improvement approach will be used to assist the FP services to expand their current services to include tenofovir gel provision.
This protocol aims to address an important implementation question on whether FP services are able to effectively incorporate tenofovir gel provision for this at-risk group of women in South Africa. Provision of tenofovir gel to the women from the CAPRISA 004 trial meets the ethical obligation for post-trial access, and helps identify a potential avenue for future scale-up of microbicides within the public health system of South Africa.
This trial was registered with the South Africa Department of Health (reference: DOH-27-0812-4129) and ClinicalTrials.gov (reference: NCT01691768) on 05 July 2012.
South Africa; HIV prevention; Microbicide; Tenofovir gel; Health systems strengthening; Implementation
Anaemia is a common clinical finding in HIV infected women and has been associated with advanced disease. The use of antiretroviral drugs such as Zidovudine (ZDV) either for prevention of mother to child transmission (MTCT) of HIV or used in combination with other antiretrovirals have been implicated in the development or increased severity of anaemia. We report the prevalence, type, severity and incidence of anaemia in a cohort of HIV infected women who initiated antiretroviral prophylaxis or treatment during pregnancy.
Methods and Materials
This is a retrospective cohort data analysis of 408 HIV infected pregnant women who participated in a breastfeeding intervention study (HPTN 046 Study, ClinicalTrials.gov NCT 00074412) in South Africa. Women initiated zidovudine prophylaxis for PMTCT or triple antiretroviral treatment in pregnancy according to the standard of care. Laboratory and clinical data in pregnancy, <72 hours and 2 weeks postdelivery were extracted from the main database and analysed.
The mean Hb concentration was 10.6 g/dL at baseline and 262/408 (64.2%) women were diagnosed with anaemia (Hb<11 g/dL) in pregnancy, 48/146 (32.9%) subsequently developed anaemia intrapartum or postpartum and 89/310 (28.7%) of all cases of anaemia remained unresolved by 2 weeks postdelivery. In a univariate analysis, CD4 count and gravidity were significant risk factors for anaemia in pregnancy, RR 1.41; 1.23–1.61 (p<0.001) and 1.10; 1.01–1.18 (p = 0.02) respectively. After adjusting for antiretroviral regimen, age and gravidity in a multivariable analysis, only the CD4 count remains a significant risk factor for anaemia in pregnancy and postdelivery.
In conclusion, anaemia was most common among women in the advanced stage of HIV infection (CD4<200 cells/mm3). There was no evidence of an association between ZDV or triple ARVs and anaemia.
Background. Diagnosis and treatment of sexually transmitted infections (STIs) is a public health priority, particularly in regions where the incidence of human immunodeficiency virus (HIV) infection is high. In most developing countries, STIs are managed syndromically. We assessed the adequacy of syndromic diagnosis of STIs, compared with laboratory diagnosis of STIs, and evaluated the association between STI diagnosis and the risk of HIV acquisition in a cohort of high-risk women.
Methods. HIV-uninfected high-risk women (n = 242) were followed for 24 months. Symptoms of STIs were recorded, and laboratory diagnosis of common STI pathogens was conducted every 6 months. Forty-two cytokines were measured by Luminex in cervicovaginal lavage specimens at enrollment. Human immunodeficiency virus type 1 (HIV-1) infection was evaluated monthly.
Results. Only 12.3% of women (25 of 204) who had a laboratory-diagnosed, discharge-causing STI had clinically evident discharge. Vaginal discharge was thus a poor predictor of laboratory-diagnosed STIs (sensitivity, 12.3%; specificity, 93.8%). Cervicovaginal cytokine concentrations did not differ between women with asymptomatic STIs and those with symptomatic STIs and were elevated in women with asymptomatic STIs, compared with women with no STIs or bacterial vaginosis. Although laboratory-diagnosed STIs were associated with increased risk of HIV infection (hazard ratio, 3.3 [95% confidence interval, 1.5–7.2)], clinical symptoms were not.
Conclusions. Syndromic STI diagnosis dependent on vaginal discharge was poorly predictive of laboratory-diagnosed STI. Laboratory-diagnosed STIs were associated with increased susceptibility to HIV acquisition, while vaginal discharge was not.
Although recent WHO guidelines recommend withdrawing stavudine (d4T) from first-line ART therapy, it remains commonly used in resource-constrained settings. In 2006, WHO recommended decreasing the dose of d4T from 40mg to 30mg to mitigate toxicities. We compared the incidence and severity of peripheral neuropathy (PN) by d4T dose in a retrospective cohort study.
Patients’ charts from an ART-naïve population at a rural clinic in KZN, South Africa were retrospectively reviewed for signs and symptoms of incident PN and were graded for severity using the DAIDs scale. Patients enrolled prior to the WHO guideline change were enrolled if they were on d4T 40mg for at least 6 months. After the guideline change all patients were initiated on d4T 30mg.
A total of 475 patients were analyzed; 235 in the 40mg cohort (152.7 person-years [py]) and 240 in the 30mg cohort (244.7py). Incidence of peripheral neuropathy was 90.4/100 py (95% CI:75.9–106.8) in the 40mg cohort versus 40.5/100py (95% CI:32.9–49.3) in the 30mg group (incidence rate ratio [IRR]=0.45, p <0.0001). There was no difference in proportion of severe peripheral neuropathy cases (grade 3/4) between the cohorts; 8.3% in the 40mg group and 8.9% in the 30mg group (p=1.0). In a multivariate analysis risk of peripheral neuropathy was associated with increasing age (HR=1.65 95% CI:1.24–2.19), 40 mg dose (HR=2.1, 95% CI:1.61–2.74) and concurrent tuberculosis therapy (HR= 1.41 95% CI:1.06–1.87).
Incidence of peripheral neuropathy in the 40mg cohort was extremely high and though lower in the 30mg cohort, the rate was nonetheless unacceptably high.
HIV-1 drug resistance monitoring in resource-poor settings is crucial due to limited drug alternatives. Recent reports of the increased prevalence of CXCR4 usage in subtype C infections may have implications for CCR5 antagonists in therapy. We investigated the prevalence of drug resistance mutations and CXCR4 coreceptor utilization of viruses from HIV-1 subtype C-infected children. Fifty-one children with virological failure during highly active antiretroviral therapy (HAART) and 43 HAART-naive children were recruited. Drug resistance genotyping and coreceptor utilization assessment by phenotypic and genotypic methods were performed. At least one significant drug resistance mutation was present in 85.4% of HAART-failing children. Thymidine analogue mutations (TAMs) were detected in 58.5% of HAART-failing children and 39.0% had ≥3 TAMs. CXCR4 (X4) or dual (R5X4)/mixed (R5, X4) (D/M)-tropic viruses were found in 54.3% of HAART-failing and 9.4% of HAART-naive children (p<0.0001); however, the HAART-failing children were significantly older (p<0.0001). In multivariate logistic regression, significant predictors of CXCR4 usage included antiretroviral treatment, older age, and lower percent CD4+ T cell counts. The majority of genotypic prediction tools had low sensitivity (≤65.0%) and high specificity (≥87.5%) for predicting CXCR4 usage. Extensive drug resistance, including the high percentage of TAMs found, may compromise future drug choices for children, highlighting the need for improved treatment monitoring and adherence counseling. Additionally, the increased prevalence of X4/D/M viruses in HAART-failing children suggests limited use of CCR5 antagonists in salvage therapy. Enhanced genotypic prediction tools are needed as current tools are not sensitive enough for predicting CXCR4 usage.
Recent successes of antiretroviral pre-exposure prophylaxis (PrEP) in preventing HIV infection have raised questions whether further placebo controlled trials of new HIV-prevention technologies are ethically justifiable. A trial with active agent(s) in the comparator group can be designed either as a superiority or non-inferiority trial. In a non-inferiority trial the hypothesis tested is that the intervention is not inferior to, by a predefined clinically relevant amount, or at least as effective as, the comparator. Non-inferiority trials pose challenges in data interpretation.
Firstly it is possible to show equivalence of two non-effective interventions. If the active comparator intervention is ineffective, the new intervention would be shown to be non-inferior to this inactive intervention, while neither intervention is superior to placebo or no intervention. The second challenge is that any effect that dilutes the true efficacy of an intervention in a trial, such as non-adherence, loss to follow-up or protocol violations, makes it easier for the two interventions to be declared equivalent. Non-differential low adherence is unlikely to lead to the conclusion that an inferior intervention is non-inferior. However, differential adherence between study arms, which is more likely in non-blinded trials, is likely to bias the results and lead to incorrect conclusions.
Investigators conducting non-inferiority trials will have to pay special attention to supporting, measuring and maintaining high adherence. The goal in future non-inferiority trials should be to maintain similar levels of high adherence in all study arms, but at a minimum to reduce the likelihood of differential adherence across study arms.
We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, optimal time to initiate ART during tuberculosis treatment remains contentious.
To address this, we conducted a 3-arm, open-label randomized controlled trial in South Africa in acid-fast bacilli smear positive patients (n=642) with HIV and CD4+ counts <500 cells/mm3. Findings on the early therapy group (ART initiated within 4 weeks of tuberculosis treatment initiation, n=214) and late therapy group (ART initiated within the first 4 weeks of the continuation phase of tuberculosis treatment, n=215) are presented here.
Median CD4+ count and viral load at baseline was 150 cells/mm3 and 161000 copies/ml, being similar in both groups. Incidence rate of AIDS or death was 6.9 (18/259.4) and 7.8 (19/244.2) per 100 person-years in the early and late therapy groups respectively (Incidence Rate Ratio (IRR)=0.89; 95%Confidence Interval (95%CI): 0.44,1.79; P=0.73). However, in patients with CD4+ counts <50 cells/mm3, the incidence rates of AIDS or death were 8.5 (early) and 26.3 (late) per 100 person-years (IRR=0.32; 95%CI: 0.07,1.13; P=0.06). Immune reconstitution inflammatory syndrome (IRIS) incidence rates were 20.2 (early) and 7.7 (late) per 100 person-years (IRR=2.62; 95%CI: 1.48,4.82; P<0.001). Adverse events requiring antiretroviral drug switches occurred in 10 (early) and 1 (late) patients (P=0.006).
The benefits of AIDS-free survival balanced against the risks of IRIS and ART-related adverse events, support early ART initiation in patients with CD4+ counts <50 cells/mm3 and deferred ART initiation to the continuation phase of tuberculosis treatment when CD4+ counts are higher.
Highly active antiretroviral therapy (HAART) requires strict adherence to achieve optimal clinical and survival benefits. A study was done to explore the factors affecting HAART adherence among HIV positive adults by reviewing routinely collected patient information in the Centre for the AIDS Programme of Research in South Africa’s (CAPRISA) AIDS Treatment Programme. Records of 688 patients enrolled between 2004 and 2006 were analysed. Patients were considered adherent if they had taken at least 95% of their prescribed drugs. Generalized estimating equations were used to analyse the data. The results showed that HAART adherence increased over time, however, the rate of increase differed by some of the socio-demographic and behavioural characteristics of the patients. For instance, HAART adherence increased in both urban and rural treatment sites over time, but the rate of increase was higher in the rural site. This helped identify sub-populations, such as the urban population, that required ongoing adherence counseling.
adherence; HAART; generalized estimating equations (GEE); longitudinal study; pill count approach
Young women are at disproportionate risk of HIV infection in South Africa. Understanding risk behaviors and factors associated with ability to negotiate safe sex and condom use is likely to be key in curbing the spread of HIV. Traditionally prevention efforts have focused on creating behavioral changes by increasing knowledge about HIV/AIDS.
This was a cross-sectional analysis from a prospective observational cohort study of 245 women at a high-risk of HIV infection in KwaZulu-Natal, South Africa.
Participants demonstrated a high level of HIV/AIDS knowledge. Overall, 60.3% of participants reported condom use. Reported condom use at last sexual encounter varied slightly by partner type (57.0% with steady versus 64.4% with casual partners), and self-perceived ability to choose to use a condom was significantly lower with steady partners compared to casual partners (p<0.01). In multivariate analysis, women who had high school education were more likely to use condoms at their last sex encounter compared to those with only primary school education (RR of 1.36 (95% Confidence Interval (CI) 1.06–1.75) and 1.46 (95% CI 1.13–1.88) for grades 8–10 and 11–12, respectively). Those who used condoms as a contraceptive method were twice as likely to use condoms compared to women who did not report using them as a contraceptive method. Greater perceived ability to choose to use condoms was associated with higher self-reported condom use at last encounter, irrespective of partner type (RR = 2.65 (95% CI 2.15–32.5).
Self-perceived ability to use condoms, level of formal education and condom use as a contraceptive were all significantly associated with self-reported condom use at last sexual encounter. These findings suggest that that gender inequality and access to formal education, as opposed to lack of HIV/AIDS knowledge, prevent safer sexual practices in South Africa.
This study explores the influence of baseline factors on first-month adherence to highly active antiretroviral therapy (HAART) among adults. The study design involved a review of routinely collected patient information in the CAPRISA AIDS Treatment (CAT) programme, at a rural and an urban clinic in KwaZulu-Natal Province, South Africa. The records of 688 patients enrolled in the CAT programme between June 2004 and September 2006 were analysed. Adherence was calculated from pharmacy records (pill counts) and patients were considered adherent if they had taken at least 95% of their prescribed drugs. Logistic regression was used to analyse the data and account for confounding factors. During the first month of therapy, 79% of the patients were adherent to HAART. HAART adherence was negatively associated with a higher baseline CD4 count. Women had better adherence if they attended voluntarily testing and counselling or if they had taken an HIV test because they were unwell, while men had higher adherence if they were tested due to perceived risk of HIV infection. HAART adherence was positively associated with higher age among patients who possessed cell phones and among patients who provided a source of income in the urban setting, but not in the rural setting. Though long-term data from this cohort is required to fully evaluate the impact of non-adherence in the first month of treatment, this study identifies specific groups of patients at higher risk for whom adherence counselling should be targeted and tailored. For example, first-month HAART adherence can be improved by targeting patients initiated on treatment with a high CD4 count.
baseline survey; compliance; CD4 count; HAART; health information; pill counts; statistical analysis
The CAPRISA 004 trial assessed effectiveness and safety of a 1% vaginal gel formulation of tenofovir, a nucleotide reverse transcriptase inhibitor, for the prevention of HIV acquisition in women. A double-blind, randomized controlled trial was conducted comparing tenofovir gel (n=445) with placebo gel (n=444) in sexually active, HIV-uninfected 18-40 year-old women in urban and rural KwaZulu-Natal, South Africa HIV serostatus, safety, sexual behavior and gel and condom use were assessed at monthly follow-up visits for 30 months. HIV incidence in the tenofovir gel arm was 5.6 per 100 women-years (wy), i.e. person time of study observation, (38/680.6wy) compared to 9.1 per 100 wy (60/660.7wy) in the placebo gel arm (Incidence Rate Ratio (IRR)=0.61; p=0.017).In high adherers (gel adherence >80%), HIV incidence was 54% lower (p=0.025) in the tenofovir gel arm. In intermediate adherers (gel adherence 50-80%) and low adherers (gel adherence < 50%) the HIV incidence reduction was 38% and 28% respectively. Tenofovir gel reduced HIV acquisition by an estimated 39% overall, and by 54% in women with high gel adherence. No increase in the overall adverse event rates was observed. There were no changes in viral load and no tenofovir resistance in HIV seroconvertors. Tenofovir gel could potentially fill an important HIV prevention gap, especially for women unable to successfully negotiate mutual monogamy or condom use.
Despite high mortality rates in tuberculosis patients with HIV co-infection, there is continued controversy on when to initiate antiretroviral therapy (ART) in these patients.
We conducted an open-label randomized controlled trial in Durban, South Africa to determine optimal timing of ART initiation in relation to TB treatment. Acid-fast bacilli (AFB) smear positive tuberculosis patients with HIV infection and CD4+ counts <500 cells/mm3 (n=642) were randomized to one of two integrated treatment arms (ART initiation during tuberculosis treatment) or to a sequential treatment arm (ART initiation upon tuberculosis treatment completion). Participants received standard tuberculosis therapy, cotrimoxazole prophylaxis and once daily didanosine, lamivudine and efavirenz ART regimen. The primary endpoint was all-cause mortality.
This analysis compares data from the sequential treatment arm and the combined integrated treatment arms up to 1 September 2008, when the Safety Monitoring Committee recommended halting the sequential treatment arm. Demographic, clinical and laboratory characteristics at baseline and adverse event rates during follow-up were similar in the study arms. Mortality was 56% lower (hazard ratio: 0.44; 95% Confidence Interval: 21% to 75%; p = 0.003) in the integrated arm (5.4 per 100 person-years (25 deaths; n=429)) compared to sequential arm (12.1 per 100 person-years (27 deaths; n=213)). Mortality rates were lower regardless of CD4+ count level.
Initiating ART during tuberculosis treatment in AFB positive patients with HIV co-infection and CD4+ counts <500 cells/mm3 significantly improves survival and provides further impetus for the integration of tuberculosis and AIDS services.
Young women in sub-Saharan Africa bear a disproportionate burden of HIV infection compared to men but have limited options to reduce their HIV risk. Microbicides could fill an important HIV prevention gap for sexually active women who are unable to successfully negotiate mutual monogamy or condom use.
This paper describes the baseline sample characteristics in the CAPRISA 004 trial which assessed the safety and effectiveness of the vaginal microbicide, 1% tenofovir gel for HIV prevention in South Africa.
This analysis assessed the baseline demographic, clinical and sexual behavior data of women screened and enrolled into the trial. The characteristics were summarized using descriptive summary measures; expressed as means and percent for categorical variables.
HIV prevalence at screening was 25.8% [95% Confidence Interval (CI):23.9-27.7). Of the 889 eligibly enrolled women who contributed follow-up data, rural participants recruited from a family planning (FP) clinic were younger, more likely to be living apart from their regular partner, reported lower coital frequency, had lower condom use (p < 0.001). In contrast, urban participants recruited from a sexually transmitted disease (STD) clinic reported higher numbers of lifetime sexual partners, new partners in the last 30 days and receiving money in exchange for sex (p < 0.001).
The populations selected provide suitable diverse target groups for HIV prevention intervention studies.
ClinicalTrials.gov: NCT 00441298
To describe the baseline demographic data, clinical characteristics and HIV-incidence rates of a cohort at high risk for HIV infection in South Africa as well as the challenges experienced in establishing and maintaining the cohort.
Between August 2004 and May 2005 a cohort of HIV-uninfected women was established for the CAPRISA 002 Acute Infection Study, a natural history study of HIV-1 subtype C infection. Volunteers were identified through peer-outreach. The cohort was followed monthly to determine HIV infection rates and clinical presentation of early HIV infection. Risk reduction counselling and male and female condoms were provided. After screening 775 individuals, a cohort of 245 uninfected high-risk women was established. HIV-prevalence at screening was 59.6% (95% CI: 55.9% to 62.8%) posing a challenge in accruing HIV-uninfected women. The majority of women (78.8%) were self-identified as sex-workers with a median of 2 clients per day. Most women (95%) reported more than one casual sexual partner in the previous 3 months (excluding clients) and 58.8% reported condom use in their last sexual encounter. Based on laboratory testing, 62.0% had a sexually transmitted infection at baseline. During 390 person-years of follow-up, 28 infections occurred yielding seroincidence rate of 7.2 (95% CI: 4.5 to 9.8) per 100 person-years. Despite the high mobility of this sex worker cohort retention rate after 2 years was 86.1%. High co-morbidity created challenges for ancillary care provision, both in terms of human and financial resources.
Challenges experienced were high baseline HIV-prevalence, lower than anticipated HIV-incidence and difficulties retaining participants. Despite challenges, we have successfully accrued this cohort of HIV-uninfected women with favourable retention, enabling us to study the natural history of HIV-1 during acute HIV-infection. Our experiences provide lessons for others establishing similar cohorts, which will be key for advancing the vaccine and prevention research agenda in resource-constrained settings.
The high prevalence of anaemia and the increased morbidity and mortality associated with anaemia during AIDS has been well described yet there has been little information about anaemia and changes in haemoglobin levels during acute and early HIV-1 infection.
HIV-negative women (n = 245) were enrolled into an observational cohort as part of the Centre for the AIDS Programme of Research in South Africa (CAPRISA) Acute Infection Study. Acute infection was diagnosed following a positive HIV RNA PCR in the absence of antibodies, or detection of HIV-1 antibodies within 3 months of a previously negative antibody test. Haemotologic parameters were assessed before infection and at regular intervals in the first twelve months of HIV infection.
Fifty-seven participants with acute HIV infection were identified at a median of 14.5 days post-infection (range 10–81) and were enrolled in the CAPRISA Acute Infection cohort at a median of 41 days post-infection (range 15–104). Mean haemoglobin prior to HIV-1 infection was 12.7 g/dL, with a mean decline of 0.46 g/dL following infection. The prevalence of anaemia increased from 25.0% prior to HIV-1 infection to 52.6% at 3 months post-infection, 61.1% at 6 months post-infection, and 51.4% at 12 months post-infection.
Haematologic derangements and anaemia with a trend towards iron deficiency are common with acute HIV-1 subtype C infection in this small cohort. The negative impact of anaemia concurrent with established HIV infection upon morbidity and mortality has been well documented but the prognostic potential and long-term effects of anaemia during acute HIV-1 infection remain unknown.
Few studies address the use of paediatric highly active antiretroviral therapy (HAART) in Africa.
We performed a retrospective cohort study to investigate preliminary outcomes of all children eligible for HAART at Sinikithemba HIV/AIDS clinic in KwaZulu-Natal, South Africa. Immunologic, virologic, clinical, mortality, primary caregiver, and psychosocial variables were collected and analyzed.
From August 31, 2003 until October 31, 2005, 151 children initiated HAART. The median age at HAART initiation was 5.7 years (range 0.3–15.4). Median follow-up time of the cohort after HAART initiation was 8 months (IQR 3.5–13.5). The median change in CD4% from baseline (p < 0.001) was 10.2 (IQR 5.0–13.8) at 6 months (n = 90), and 16.2 (IQR 9.6–20.3) at 12 months (n = 59). Viral loads (VLs) were available for 100 children at 6 months of which 84% had HIV-1 RNA levels ≤ 50 copies/mL. At 12 months, 80.3% (n = 61) had undetectable VLs. Sixty-five out of 88 children (73.8%) reported a significant increase (p < 0.001) in weight after the first month. Eighty-nine percent of the cohort (n = 132) reported ≤ 2 missed doses during any given treatment month (> 95%adherence). Seventeen patients (11.3%) had a regimen change; two (1.3%) were due to antiretroviral toxicity. The Kaplan-Meier one year survival estimate was 90.9% (95%confidence interval (CI) 84.8–94.6). Thirteen children died during follow-up (8.6%), one changed service provider, and no children were lost to follow-up. All 13 deaths occurred in children with advanced HIV disease within 5 months of treatment initiation. In multivariate analysis of baseline variables against mortality using Cox proportional-hazards model, chronic gastroenteritis was associated with death [hazard ratio (HR), 12.34; 95%CI, 1.27–119.71) and an HIV-positive primary caregiver was found to be protective against mortality [HR, 0.12; 95%CI, 0.02–0.88). Age, orphanhood, baseline CD4%, and hemoglobin were not predicators of mortality in our cohort. Fifty-two percent of the cohort had at least one HIV-positive primary caregiver, and 38.4% had at least one primary caregiver also on HAART at Sinikithemba clinic.
This report suggests that paediatric HAART can be effective despite the challenges of a resource-limited setting.