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1.  When to start antiretroviral therapy during tuberculosis treatment 
Purpose of review
Effective treatment exists for TB and for HIV but treating both diseases simultaneously presents several challenges. This review assessed the evidence for timing of antiretroviral therapy (ART) initiation in patents co-infected with TB.
Recent findings
Published evidence clearly demonstrates that TB HIV integration is essential for improved survival, but the question of when to start ART during TB treatment is more complex. Five randomised controlled trials assessed this question; four trials showed no difference in incidence rates of AIDS or death between TB patients initiating ART within 2 months compared to later during TB therapy, while one trial showed a significant survival gain with ART initiation within 2 weeks of TB therapy start. All five studies found improved AIDS-free survival with earlier ART initiation in TB patients with low CD4+ T-cell counts, except among patients with TB meningitis. The survival benefit was however, accompanied by increased immune reconstitution inflammatory syndrome events.
Summary
The trial data support the World Health Organisation recommendations on when to start ART in TB-HIV co-infected patients including earlier ART initiation in severely immune-compromised patients. However, several challenges remain in integrating TB and HIV treatment in public health care services. Additional research on timing of ART is needed for patients with drug-resistant and extra-pulmonary TB, notably TB meningitis.
doi:10.1097/QCO.0b013e32835ba8f9
PMCID: PMC3616247  PMID: 23188213
HIV; tuberculosis; antiretroviral therapy; immune reconstitution inflammatory syndrome (IRIS)
2.  Overview of Microbicides for the prevention of human immunodeficiency virus 
Human immunodeficiency virus (HIV) prevention tools that women can use and control are urgently needed. Microbicides are chemical products applied to the vagina or rectum to prevent the sexual transmission of HIV. Four classes of candidate microbicides have been tested to date: those that (1) enhance the natural defences in the vagina to inactivate HIV; (2) inactivate HIV in the vagina; (3) prevent HIV from attaching to, and fusing with, the host cells; and (4) prevent HIV from replicating in genital tract host cells. Despite numerous disappointing efficacy trial results over the past 20 years, substantial progress is now being made in microbicide development after the release of the CAPRISA 004 trial, which provided proof-of-concept that topical antiretroviral microbicides can prevent sexual transmission of HIV and herpes simplex type-2 infection. Microbicides, which fill an important gap for women-controlled prevention methods, have the potential to alter the course of the HIV pandemic.
doi:10.1016/j.bpobgyn.2012.01.010
PMCID: PMC3383397  PMID: 22386823
HIV; women; microbicide prevention
3.  Symptomatic Vaginal Discharge Is a Poor Predictor of Sexually Transmitted Infections and Genital Tract Inflammation in High-Risk Women in South Africa 
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.
doi:10.1093/infdis/jis298
PMCID: PMC3490689  PMID: 22517910
4.  A drug evaluation of 1% tenofovir gel and tenofovir disoproxil fumarate tablets for the prevention of HIV infection 
Introduction
More than a million people acquire HIV infection annually. Pre-exposure prophylaxis (PrEP) using antiretrovirals is currently being investigated for HIV prevention. Oral and topical formulations of tenofovir have undergone pre-clinical and clinical testing to assess acceptability, safety and effectiveness in preventing HIV infection.
Areas covered
The tenofovir drug development pathway from compound discovery; pre-clinical animal model testing and human testing were reviewed for safety, tolerability, and efficacy. Tenofovir is well tolerated and safe when used both systemically or applied topically for HIV prevention. High drug concentrations at the site of HIV transmission and concomitant low systemic drug concentrations are achieved with vaginal application. Coitally applied gel may be the favoured prevention option for women compared to the tablets which may be more suitable for prevention in men and sero-discordant couples. However, recent contradictory effectiveness outcomes in women need to be better understood.
Expert opinion
Emerging evidence has brought new hope that antiretrovirals can potentially change the course of the HIV epidemic when used as early treatment for prevention, as topical or oral PrEP. Although some trial results appear conflicting, behavioral factors, adherence to dosing, and pharmacokinetic properties of the different tenofovir formulations and dosing approaches offer plausible explanations for most of the variations in effectiveness observed in different trials.
doi:10.1517/13543784.2012.667072
PMCID: PMC3460694  PMID: 22394224
ART; NtRTI; tenofovir; tenofovir disoproxil fumarate; HIV prevention; microbicide; PMPA – [9-R-(2-Phosphonomethoxypropyl) adenine]
5.  Integration of Antiretroviral Therapy with Tuberculosis Treatment 
The New England journal of medicine  2011;365(16):1492-1501.
Background
We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, optimal time to initiate ART during tuberculosis treatment remains contentious.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1056/NEJMoa1014181
PMCID: PMC3233684  PMID: 22010915
6.  Contraceptive Choices, Pregnancy Rates, and Outcomes in a Microbicide Trial 
Obstetrics and gynecology  2011;118(4):895-904.
Objective
Women who become pregnant during the conduct of biomedical HIV prevention trials are taken off the study product for safety reasons. High pregnancy rates can compromise statistical integrity in these trials. The comprehensive contraceptive curriculum developed for the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial was evaluated for its ability to enhance contraceptive uptake, reduce pregnancy rates, and preserve statistical integrity.
Methods
Contraceptive- and pregnancy-related eligibility criteria were specified in the protocol. We enrolled women who opted for a non-barrier method of contraceptive and provided hormonal contraceptives on-site at no cost. At each monthly study visit, we provided pregnancy prevention counselling and performed pregnancy testing. Study product was withheld on pregnancy diagnosis, but women continued with monthly follow-up.
Results
Contraceptive usage was high throughout the study with 100% uptake at baseline and 94.71% use after a mean of 18 months follow-up at exit. Injectable progestins, particularly medroxyprogesterone acetate, remained the preferred choice of contraceptive. After 30 months of follow-up, 54 pregnancies were reported out of 889 participants, giving a pregnancy incidence rate of 3.95 per 100 woman-years (95% CI: 2.96 to 5.17). Of all pregnancies, 2/3 (64.81%) resulted in a full-term live birth, while 18.52% and 11.11% pregnancies culminated as miscarriage and terminated pregnancies, respectively. There were no congenital anomalies in the early neonatal period. Pregnancies resulted in 1.56% of woman-years of study follow-up lost due to temporary product withdrawal.
Conclusion
The CAPRISA 004 contraceptive curriculum was an effective strategy for maintaining low pregnancy rates, thereby minimizing product withdrawal and loss of follow-up time.
doi:10.1097/AOG.0b013e31822be512
PMCID: PMC3178043  PMID: 21934454
7.  Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women 
Science (New York, N.Y.)  2010;329(5996):1168-1174.
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.
doi:10.1126/science.1193748
PMCID: PMC3001187  PMID: 20643915
8.  Timing of Initiation of Antiretroviral Drugs during Tuberculosis Therapy 
The New England journal of medicine  2010;362(8):697-706.
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1056/NEJMoa0905848
PMCID: PMC3076221  PMID: 20181971
9.  Recruitment of high risk women for HIV prevention trials: baseline HIV prevalence and sexual behavior in the CAPRISA 004 tenofovir gel trial 
Trials  2011;12:67.
Background
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.
Purpose
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.
Methods
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.
Results
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).
Conclusion
The populations selected provide suitable diverse target groups for HIV prevention intervention studies.
Trial registration
ClinicalTrials.gov: NCT 00441298
doi:10.1186/1745-6215-12-67
PMCID: PMC3063209  PMID: 21385354

Results 1-10 (10)