HIV This Week

Hunter M. The changing political economy of sex in South Africa: the significance of unemployment and inequalities to the scale of the AIDS pandemic. Soc Sci Med. 2007;64(3):689-700.

Between 1990 and 2005, HIV prevalence rates in South Africa jumped from less than 1% to around 29%. Important scholarship has demonstrated how racialized structures entrenched by colonialism and apartheid set the scene for the rapid unfolding of the AIDS pandemic, like other causes of ill-health before it. Of particular relevance is the legacy of circular male-migration, an institution that for much of the 20th century helped to propel the transmission of sexually transmitted infections among black South Africans denied permanent urban residence. But while the deep-rooted antecedents of AIDS have been noted, less attention has been given to more recent changes in the political economy of sex, including those resulting from the post-apartheid government's adoption of broadly neo-liberal policies. As an unintentional consequence, male migration and apartheid can be seen as almost inevitably resulting in AIDS, a view that can disconnect the pandemic from contemporary social and economic debates. Combining ethnographic, historical, and demographic approaches, and focusing on sexuality in the late apartheid and early post-apartheid periods, this article outlines three interlinked dynamics critical to understanding the scale of the AIDS pandemic: (1) rising unemployment and social inequalities that leave some groups, especially poor women, extremely vulnerable; (2) greatly reduced marital rates and the subsequent increase of one person households; and (3) rising levels of women's migration, especially through circular movements between rural areas and informal settlements/urban areas. As a window into these changes, the article gives primary attention to the country's burgeoning informal settlements--spaces in which HIV rates are reported to be twice the national average--and to connections between poverty and money/sex exchanges.

Editors´note: Political economy analyses help conceptualise HIV as a symptom of ‘structural violence’ with sex as a mode of transmission. Housing, employment, and social equality are clearly linked to HIV, both historically and contemporarily, and help explain the striking scale of the South African epidemic. This article, which suggests ways to reconfigure the response to AIDS around a more politically enabling agenda, makes for thought-provoking reading.

Kang M, Dunbar M, Laver S, Padian N. University of California Programme in Women's Health, University of California-San Francisco, 50 Beale Street, San Francisco, CA 94105, USA. Maternal versus paternal orphans and HIV/STI risk among adolescent girls in Zimbabwe. AIDS Care. 2008;20(2):214-7.

The AIDS epidemic has contributed to a drastic increase in the number of orphans in Zimbabwe. Orphans (whether orphaned by AIDS or other causes) have been shown to have economic and educational disadvantages as well as poor reproductive health outcomes. Kang and colleagues recruited a convenience sample of 200 girls in a peri-urban area of Zimbabwe to examine the impact of orphan status (compared to non-orphans) on household composition, education, risk behaviour, pregnancy and prevalent HIV and HSV-2 infection. In the study population, maternal orphans were more likely to be in households headed by themselves or a sibling, to be sexually active, to have had a sexually transmitted infection, to have been pregnant and to be infected with HIV. Paternal orphans were more likely to have ever been homeless and to be out of school. The findings suggest that maternal care and support is important for HIV prevention. This finding corroborates previous research in Zimbabwe and has implications for intervention strategies among orphan girls.

Editors´note: Because of recruitment methodology, these results are not generalizable, however they do provide food for thought. Although paternal orphanhood had more of an impact on household financial stability and orphaned girls’ educational attainment, the loss of a mother affected behavioural risk and biological outcomes (HIV, HSV-2). Keeping mothers alive helps reduce sexual risk in adolescent girls. How would orphaned adolescent girls in Zimbabwe benefit from support and mentoring by women in their communities?

van Sighem A, Zhang S, Reiss P, Gras L, van der Ende M, Kroon F, Prins J, de Wolf F; on Behalf of the ATHENA National Observational Cohort Study. Immunologic, Virologic, and Clinical Consequences of Episodes of Transient Viraemia During Suppressive Combination Antiretroviral Therapy. J Acquir Immune Defic Syndr. 2008 May 1;48(1):104-8.

van Sighem and colleagues aimed to investigate immunologic, virologic, and clinical consequences of episodes of transient viraemia in patients with sustained virologic suppression. From the AIDS Therapy Evaluation Project, Netherlands cohort, 4447 previously therapy-naive patients were selected who were on continuous combination antiretroviral therapy and had initial success (2 consecutive HIV RNA measurements <50 copies/mL). During episodes of viral suppression (RNA <50 copies/mL), low-level viraemia (RNA 50 to 1000 copies/mL), or high-level viraemia (RNA >1000 copies/mL) after initial success, the occurrence of therapy changes, drug resistance, and clinical events was assessed. During 11,187 person-years of follow-up, 1281 (28.8%) patients had at least 1 RNA measurement >50 copies/mL. Among 8069 episodes, there were 5989 (74.2%) episodes of suppression, 1711 (21.2%) episodes of low-level viraemia, and 369 (4.6%) episodes of high-level viraemia. Most episodes of low-level viraemia consisted of </=2 RNA measurements (93.7%), were without clinical events or therapy changes (79.6%), and were without changes in CD4 cell counts. Therapy changes (52.3% of episodes) and resistance (23.3%) were frequently observed during high-level viraemia. In conclusion, episodes of low-level viraemia are frequent and short-lasting, and the low proportion of episodes with clinical events suggests that leaving therapy unchanged is a clinically acceptable strategy. In contrast, high-level viraemia is associated with resistance and is often followed by therapy changes.

Editors´note: Although the focus here is on whether viraemia should be an indication for a change in therapy, viraemia in previously naive patients on treatment has potential relevance for transmission risk. A high proportion of patients were viraemic during winter when influenza and the common cold are more prevalent, suggesting that antigenic stimulation due to other infections may play a role. Thus, although effective antiretroviral treatment reduces viral load, blips can still occur – 28.8% of continuously treated patients in this large-cohort experienced at least one transient episode of viraemia.

Kwara A, Delong A, Rezk N, Hogan J, Burtwell H, Chapman S, Moreira CC, Kurpewski J, Ingersoll J, Caliendo AM, Kashuba A, Cu-Uvin S. Antiretroviral drug concentrations and HIV RNA in the genital tract of HIV-infected women receiving long-term highly active antiretroviral therapy. Clin Infect Dis. 2008;46(5):719-25.

Kwara and colleagues aimed to determine antiretroviral drug concentrations and human immunodeficiency virus (HIV) RNA rebound in cervicovaginal fluid in relation to blood plasma in women receiving suppressive highly active antiretroviral therapy. Thirty-four HIV-infected women who had plasma HIV RNA levels < or =80 copies/mL for at least 6 months were enrolled. Sixty-eight paired cervicovaginal fluid  and blood plasma  drug concentrations and HIV RNA levels were determined before and 3-4 h after drug administration. For each woman and antiretroviral drug, the cervicovaginal fluid:blood plasma  drug concentration ratios before and after drug administration were calculated. The nonparametric Wilcoxon rank sum test was used to determine if these ratios were different from 1.0. Lamivudine (administered to 20 patients) and tenofovir (administered to 16) had significantly higher concentrations in cervicovaginal fluid than in blood plasma  before drug administration, with mean cervicovaginal fluid:blood plasma  concentration ratios of 3.19 (95% confidence interval, 1.2-8.5) and 5.2 (95% confidence interval, 1.2-22.6), respectively. Efavirenz (administered to 13 patients) and lopinavir (administered to 6) had significantly lower concentrations in cervicovaginal fluid, with mean cervicovaginal fluid:blood plasma  concentration ratios of 0.01 (95% confidence interval, 0.00-0.03) and 0.03 (0.01-0.11), respectively. During the study visit (median time after enrolment, 6 months), blood plasma  and cervicovaginal fluid detectable HIV RNA levels were observed 7 patients (20.6%) and 1 patient (2.9%), respectively. Despite lower cervicovaginal fluid concentrations of key antiretroviral therapy components, such as efavirenz and lopinavir, virologic rebound was rare. The high concentrations of tenofovir and lamivudine in cervicovaginal fluid may have implications for the prevention of sexual transmission during antiretroviral therapy and for pre-exposure or post-exposure prophylaxis.

Editors´note: Both non-nucleoside reverse transcriptase inhibitors and protease inhibitors penetrate poorly into the genital tract achieving concentrations from 3 to 33% of their concentrations in paired blood plasma. Whether this creates the equivalent of local suboptimal therapy which could lead to genital tract viral drug resistance is not known. The good news is that the nucleoside reverse transcriptase inhibitors that form the backbone of combination therapy not only accumulate but actually concentrate in cervicovaginal fluid, which could have implications for prevention of onward HIV transmission.

Belza MJ, de la Fuente L, Suárez M, Vallejo F, García M, López M, Barrio G, Bolea A; Health And Sexual Behaviour Survey Group. Men who pay for sex in Spain and condom use: prevalence and correlates in a representative sample of the general population. Sex Transm Infect. 2008;84:207–211.

Belza and colleagues aimed to estimate the percentage of men who have paid for heterosexual sex in Spain and the percentage who used condoms. They aimed to identify the main factors associated with these behaviours and to describe opinions about condoms. Sexual behaviour probability sample survey in men aged 18–49 years resident in Spain in 2003 (n=5153). Computer-assisted face to face and self interview was used. Bivariate and multivariate logistic regression analyses were performed. 25.4% (n=1306) of the men had paid for heterosexual sex at some time in their lives; 13.3% (n=687) in the last 5 years and 5.7% (n=295) in the last 12 months. In the logistic analysis this behaviour was associated with older age, lower education, being unmarried, foreign birth, being a practicing member of a religious group, unsatisfactory communication with parents about sex, age under 16 years at first sexual intercourse and having been drunk in the last 30 days. Of the men who had paid for sex in the previous 5 years, 95% (n=653) had used a condom in the most recent paid contact. In the multivariate analysis, not using a condom was associated with age over 30 years and first sexual intercourse before age 16 years. Men who did not use condoms in the last commercial intercourse had more negative opinions about condoms. In conclusion, the prevalence of paying for heterosexual sex among Spanish men is the highest ever described in developed countries. The many variables associated with paying for sex and condom use permit the characterisation of male clients of prostitution and should facilitate targeting HIV prevention policies.

Editors´note: There have been many studies of female sex workers but little research on the prevalence of paying for sex in the general male population. This study is intriguing not only because condom use in these encounters is so high but because a quarter of men have paid for sex at some point in their lives. Aside from a number of expected associations, logistical regression found that practicing members of a religious group (94.4% of whom were Catholic) – defined as attending religious services once a week or more - had a higher prevalence of commercial sex relations and were less likely to use condoms in these encounters.

Watts DH, Park JG, Cohn SE, Yu S, Hitti J, Stek A, Clax PA, Muderspach L, Lertora JJ. Safety and tolerability of depot medroxyprogesterone acetate among HIV-infected women on antiretroviral therapy: ACTG A5093. Contraception. 2008;77(2):84-90. Epub 2007 Dec 21.

Concomitant use of antiretroviral drugs and hormonal contraceptives may change the metabolism of each and the resulting safety profiles. We evaluated the safety and tolerability of depot medroxyprogesterone acetate among women on antiretroviral drugs. HIV-infected women on selected antiretroviral drug regimens or no antiretroviral drugs were administered medroxyprogesterone acetate 150 mg intramuscularly and evaluated for 12 weeks for adverse events, changes in CD4+ count and HIV RNA levels, and ovulation. Seventy evaluable subjects were included, 16 on nucleoside only or no antiretroviral drugs, 21 on nelfinavir-containing regimens, 17 on efavirenz-containing regimens and 16 on nevirapine-containing regimens. Nine Grade 3 or 4 adverse events occurred in seven subjects; none were judged related to medroxyprogesterone acetate. The most common findings possibly related to medroxyprogesterone acetate were abnormal vaginal bleeding (nine, 12.7%), headache (three, 4.2%), abdominal pain, mood changes, insomnia, anorexia and fatigue, each occurring in two (2.9%) subjects. No significant changes in CD4+ count or HIV RNA levels occurred with DMPA. No evidence of ovulation was detected, and no pregnancies occurred. In conclusion, the clinical profile associated with medroxyprogesterone acetate administration in HIV-infected women, most on antiretroviral drugs, appears similar to that seen in HIV-uninfected women. medroxyprogesterone acetate prevented ovulation and did not affect CD4+ counts or HIV RNA levels. In concert with previously published medroxyprogesterone acetate/antiretroviral drugs interaction data, these data suggest that medroxyprogesterone acetate can be used safely by HIV-infected women on the antiretroviral drugs studied.

Editors´note: These results are reassuring, particularly for women on efavirenz, a drug with potential teratogenic effects. However, the number of study participants was small and this was a 12-week study. Long-term DMPA use is associated with increases in weight and fat distribution, which may be exacerbated by some antiretroviral drugs.

Phillips EJ, Mallal SA. Pharmacogenetics and the potential for the individualization of antiretroviral therapy. Curr Opin Infect Dis. 2008;21(1):16-24.

Genetic associations highlighting differences in the response to HIV infection and treatment have significantly furthered our understanding of the pathogenesis, pharmacokinetics and pharmacodynamics of antiretroviral drug action and toxicities and HIV disease itself. This review focuses on the current knowledge of associations between polymorphisms and treatment outcomes in HIV with particular emphasis on clinically relevant relationships likely to lead to the individualization of antiretroviral therapy. Our understanding of the immunogenetic basis of drug toxicity has been furthered by human leukocyte antigen associations with hypersensitivities for the antiretroviral drugs abacavir and nevirapine. For abacavir in particular, the use of HLA-B*5701 as a screening test appears to be generalizable across racially diverse populations and has been supported by both observational, and blinded randomized controlled trials. Differences in HIV acquisition and progression as well as antiretroviral efficacy and toxicity will continue to provide the basis for research to define the genetic basis of such diversity. Despite the plethora of research in this area, numerous barriers exist to the successful operationalization of genetic testing to the clinic. HLA-B*5701 screening to prevent abacavir hypersensitivity is currently the most relevant to clinical practice and highlights that the promise of cost-effective testing can be facilitated by robust laboratory methodology and quality assurance programs that can be applied to diverse treatment settings.

Editors´note: Drug hypersensitivity syndromes are not directly related to the dose of a drug but are thought to be related to a combination of factors and associated with specific human leukocyte antigen (HLA) alleles within the major histocompatibility complex. In the case of patients starting nevirapine, 16% develop rash, 5% have hypersensitivity reactions with fever and hepatitis, and 0.3% can have severe skin syndromes. Knowledge of HIV pharmacogenetics is growing but unfortunately it will be some time before antiretroviral treatment in the real world can be tailored to patient genetics to avoid hypersensitivity reactions.

During the evolution, the immune system has developed several strategies to fight viral infections. Apoptosis, autophagy and necrosis are different types of cell death that play a main role in the interactions between infective agents and the host, since they are often important defence mechanisms that have to avoid the spreading of the infection. In turn, viruses have evolved numerous ways to evade the host immune system by influencing the behaviour and functionality of several components. HIV infects and kills CD4+ T helper lymphocytes, preferentially those that are antigen-specific, but also encodes proteins with apoptotic capacities, including gp120, gp160, Tat, Nef, Vpr, Vpu, Vif and, last but not least, the viral protease. This latter protein can kill infected and uninfected lymphocytes through the action of several host molecules, mainly members of the tumour necrosis factor family, or via the mitochondrial apoptotic pathway. The proinflammatory state that is characteristic of both the acute and chronic phase of HIV infection facilitates cell death, and is an additional cause of immune damage. Potent antiretroviral drugs that are largely used in therapy can reduce apoptosis by different mechanisms, that not only include the diminished production of the virus by infected cells and the subsequent reduction of inflammation, but also a direct action on the viral protease. The role of the host genetic background is finally crucial in understanding the process of cell death in HIV infection.

Editors´note: Programmed cell death or apoptosis is one of our most ancestral and potent cell defence mechanisms. HIV manipulates the apoptotic machinery to its advantage. For example, some viral proteins cause down- regulation of CD4 preventing gp120-CD4-mediated cell death. If HIV caused massive cell death, it couldn’t survive itself. On our side, we trigger activation of non-infected cells to help cope with the virus but then these innocent bystanders are induced to die by the virus. Research on immunogenetics can provide insights into why some people control HIV better, which may help with the design of antiretroviral therapy for immune reconstitution.