Quarraisha Abdool Karim

Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women

Vaginal Gel Versus HIV HIV prevention technologies for women are urgently needed, especially in sub-Saharan Africa where young women bear the greatest burden of the HIV epidemic. Abdool Karim et al. (p. 1168; published online 19 July) present the results of the CAPRISA 004 randomized control trial. The nearly 3-year-long trial, conducted in urban and rural South African women, tested the efficacy of a vaginal gel containing the antiretroviral drug tenofovir in preventing HIV infection. The dosing strategy required application of the gel both before and after coitus, and with this regime HIV infection was reduced by approximately 39% overall, by 54% in women with high adherence to the protocol, and with no increase in overall adverse event rates. Tenofovir in a vaginal gel formulation shows significant protection against HIV infection in a randomized control trial. The Centre for the AIDS Program of Research in South Africa (CAPRISA) 004 trial assessed the 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 women) with placebo gel (n = 444 women) in sexually active, HIV-uninfected 18- to 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 (person time of study observation) (38 out of 680.6 women-years) compared with 9.1 per 100 women-years (60 out of 660.7 women-years) in the placebo gel arm (incidence rate ratio = 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 to 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 seroconverters. Tenofovir gel could potentially fill an important HIV prevention gap, especially for women unable to successfully negotiate mutual monogamy or condom use.

Evolution of an HIV glycan–dependent broadly neutralizing antibody epitope through immune escape

Neutralizing antibodies are likely to play a crucial part in a preventative HIV-1 vaccine. Although efforts to elicit broadly cross-neutralizing (BCN) antibodies by vaccination have been unsuccessful, a minority of individuals naturally develop these antibodies after many years of infection. How such antibodies arise, and the role of viral evolution in shaping these responses, is unknown. Here we show, in two HIV-1–infected individuals who developed BCN antibodies targeting the glycan at Asn332 on the gp120 envelope, that this glycan was absent on the initial infecting virus. However, this BCN epitope evolved within 6 months, through immune escape from earlier strain-specific antibodies that resulted in a shift of a glycan to position 332. Both viruses that lacked the glycan at amino acid 332 were resistant to the Asn332-dependent BCN monoclonal antibody PGT128 (ref. 8), whereas escaped variants that acquired this glycan were sensitive. Analysis of large sequence and neutralization data sets showed the 332 glycan to be significantly under-represented in transmitted subtype C viruses compared to chronic viruses, with the absence of this glycan corresponding with resistance to PGT128. These findings highlight the dynamic interplay between early antibodies and viral escape in driving the evolution of conserved BCN antibody epitopes.

Preliminary outcomes of a paediatric highly active antiretroviral therapy cohort from KwaZulu-Natal, South Africa

BackgroundFew studies address the use of paediatric highly active antiretroviral therapy (HAART) in Africa.MethodsWe 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.ResultsFrom 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.ConclusionThis report suggests that paediatric HAART can be effective despite the challenges of a resource-limited setting.

Ratio of Monocytes to Lymphocytes in Peripheral Blood Identifies Adults at Risk of Incident Tuberculosis Among HIV-Infected Adults Initiating Antiretroviral Therapy

Background. Eight decades ago, the ratio of monocytes to lymphocytes (hereafter, the “ML ratio”) was noted to affect outcomes of mycobacterial infection in rabbits. Recent transcriptomic studies support a role for relative proportions of myeloid and lymphoid transcripts in tuberculosis outcomes. The ML ratio in peripheral blood is known to be governed by hematopoietic stem cells with distinct biases. Methods. The predictive value of the baseline ML ratio was modeled in 2 prospective cohorts of HIV-infected adults starting cART in South Africa (primary cohort, 1862 participants; replication cohort, 345 participants). Incident tuberculosis was diagnosed with clinical, radiographic, and microbiologic methods per contemporary guidelines. Kaplan-Meier survival analyses and Cox proportional hazards modeling were conducted. Results. The incidence rate of tuberculosis differed significantly by baseline ML ratio: 32.61 (95% confidence interval [CI], 15.38–61.54), 16.36 (95% CI, 12.39–21.23), and 51.80 (95% CI, 23.10–101.71) per 1000 patient-years for ML ratios of less than the 5th percentile, between the 5th and 95th percentiles, and greater than the 95th percentile, respectively (P = .007). Neither monocyte counts nor lymphocyte counts alone were associated with tuberculosis. After adjustment for sex, World Health Organization human immunodeficiency virus disease stage, CD4+ T-cell counts, and previous history of tuberculosis, hazards of disease were significantly higher for patients with ML ratios of less than the 5th percentile or greater than the 95th percentile (adjusted hazard ratio, 2.47; 95% CI, 1.39–4.40; P = .002). Conclusions. The ML ratio may be a useful, readily available tool to stratify the risk of tuberculosis and suggests involvement of hematopoietic stem cell bias in tuberculosis pathogenesis.

Utility of Tuberculosis directly observed therapy programs as sites for access to and provision of antiretroviral therapy in resource-limited countries.

The overwhelming share of the global human immunodeficiency virus (HIV) infection and disease burden is borne by resource-limited countries. The explosive spread of HIV infection and growing burden of disease in these countries has intensified the need to find solutions to improved access to treatment for HIV infection. The epidemic of HIV infection and acquired immune deficiency syndrome (AIDS) has been accompanied by a severe epidemic of tuberculosis. Tuberculosis has become the major cause of morbidity and mortality in patients with HIV disease worldwide. Among the various models of provision of HIV/AIDS care, one logical but unexplored strategy is to integrate HIV/AIDS and tuberculosis care and treatment, including highly active antiretroviral therapy, through existing tuberculosis directly observed therapy programs. This strategy could address the related issues of inadequate access and infrastructure and need for enhanced adherence to medication and thereby potentially improve the outcome for both diseases.

Limited HIV-1 Superinfection in Seroconverters from the CAPRISA 004 Microbicide Trial

ABSTRACT HIV-1 superinfection (SI) occurs when an infected individual acquires a distinct new viral strain. The rate of superinfection may be reflective of the underlying HIV risk in a population. The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 clinical trial demonstrated that women who used a tenofovir-containing microbicide gel had lower rates of HIV infection than women using a placebo gel. Women who contracted HIV-1 during the trial were screened for the occurrence of superinfection by next-generation sequencing of the viral gag and env genes. There were two cases (one in each trial arm) of subtype C superinfection identified from the 76 women with primary infection screened at two time points (rate of superinfection, 1.5/100 person-years). Both women experienced a >0.5-log increase in viral load during the window when superinfection occurred. The rate of superinfection was significantly lower than the overall primary HIV incidence in the microbicide trial (incidence rate ratio [IRR], 0.20; P = 0.003). The women who seroconverted during the trial reported a significant increase in sexual contact with their stable partner 4 months after seroconversion (P < 0.001), which may have lowered the risk of superinfection in this population. The lower frequency of SI compared to the primary incidence is in contrast to a report from a general heterosexual African population but agrees with a study of high-risk women in Kenya. A better understanding of the rate of HIV superinfection could have important implications for ongoing HIV vaccine research.

HIV treatment in South Africa: overcoming impediments to get started

In South Africa the euphoria of the peaceful transition from apartheid to democracy has been dulled by the devastation of HIV/AIDS. The epidemic has had a disproportionate effect on poor previously disenfranchised groups in which the apartheid migrant labour system had destroyed family life and created conjugal instability. South Africa is now in the midst of a maturing epidemic and AIDS dominates almost all aspects of medical care. HIV-1 prevalence reached 24·5% in pregnant women attending public health services in 2002. Highly active antiretroviral therapy (HAART) symbolises hope for many communities. But access to these lifesaving drugs was severely restricted until the 2000 International AIDS Conference in Durban South Africa. This defining moment in global solidarity and advocacy for treatment access changed the discourse on AIDS treatment in poor countries from “if” to “when”. The change was largely due to rapid price reductions and funding made available by among others the Global Fund to fight AIDS Tuberculosis and Malaria. (excerpt)

Restoration of CD4+ Responses to Copathogens in HIV-Infected Individuals on Antiretroviral Therapy Is Dependent on T Cell Memory Phenotype

Antiretroviral therapy (ART) induces rapid suppression of viral replication and a progressive replenishment of CD4+ T cells in HIV-infected individuals. However, the effect of ART on restoring pre-existing memory CD4+ T cells specific for common copathogens is still unclear. To better understand the dynamics of Ag-specific CD4+ T cells during ART, we assessed the frequency, functional capacity, and memory profile of CD4+ T cells specific for Mycobacterium tuberculosis and CMV in 15 HIV-infected individuals before and 1 y after ART initiation. After ART initiation, the frequency of M. tuberculosis–specific CD4+ T cells showed little change, whereas CMV-specific CD4+ T cells were significantly lower (p = 0.003). There was no difference in the polyfunctional or memory profile of Ag-specific CD4+ T cells before and after ART. The replenishment of Ag-specific CD4+ T cells correlated with the memory differentiation profile of these cells prior to ART. Pathogen-specific CD4+ T cells exhibiting a late differentiated profile (CD45RO+CD27−) had a lower capacity to replenish (p = 0.019; r = −0.5) compared with cells with an early differentiated profile (CD45RO+CD27+; p = 0.04; r = 0.45). In conclusion, restoration of copathogen-specific memory CD4+ T cells during treated HIV infection is related to their memory phenotype, in which early differentiated cells (such as most M. tuberculosis–specific cells) have a higher replenishment capacity compared with late differentiated cells (such as most CMV-specific cells). These data identify an important, hitherto unrecognized, factor that may limit restoration of copathogen immunity in HIV-infected individuals on ART.

Prevention of HIV by male circumcision

Is effective, but integration with existing sexual health services remains the biggest challenge

Diverse approaches useful for microbicide trials

SIR — The “true culprit” in the Darfur crisis is the National Islamic Front, according to two recent News stories (‘Darfur’s climate roots challenged’ Nature 447, 1038; 2007, and ‘Darfur lake is a “mirage”’ Nature 448, 394–395; 2007). Political scientists understandably point to specific parties, leaders and military factions to account for a specific crisis such as Darfur. It is also understandable that they do not want to make excuses for perpetrators of violence. Still, as quoted, they have gone too far in the opposite direction. They seem to overlook the point that Darfur’s extreme poverty, rising population, growing water stress and desertification are all important contributors to the Darfur crisis. The most authoritative recent study of the subject — the United Nations Environment Programme’s report Sudan: Post-Conflict Environmental Assessment (www.unep.org/ sudan) — rightly notes that desertification, land degradation and climate change are major factors in the crisis, and appropriately comments that they are “generally contributing factors only, not the sole cause for tension”. The report also states that long-term peace in the region will become possible only if environmental and livelihood issues are resolved. These findings are in line with a growing number of studies that find extreme poverty, falling incomes and failing rains are strong predictors of outbreaks of violence in Africa. An excellent new book Too Poor for Peace? (eds L. Brainard and D. Chollet, Brookings Institution Press, 2007) notes that recent research strongly favours the claim that these are the crucial drivers of conflict in less developed countries; much less solid evidence implicates political repression. It is important that considerations of ecology, climate and extreme poverty are integrated with political analyses of conflict. This is especially the case as demographic pressures hit against resource limitations and climate change in the Horn of Africa and elsewhere. Jeffrey D. Sachs The Earth Institute at Columbia University, 535 West 116th St, New York, New York 10027, USA