Concentrating Exclusively on Sexual Transmission of HIV is Misplaced

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Anti-HIV Gels Fail

Clinical trial of a cellulose sulphate vaginal gel as a protective measure against HIV infection has failed. The international trial organised by CONRAD, a reproductive-health research group based in Virgina, USA>, ended when the gel was found not only to be ineffective, but also to increase the risk of HIV infection [1]. This is the third large-scale clinical trial of a microbicidal gel aimed at protecting against HIV infection and AIDS to fail so far.

Activists, particularly in the United States, have been heavily promoting the concept of microbicide gels that might allow women to protect themselves from HIV infection through sexual intercourse.

Dozens of candidate micobicides are being tested in labs around the world. But things have to change, according to the mainstream HIV research community. Hard choices have to be made on which candidate gels should go on to phase III trials because these trials are expensive and time-consuming [2]. They are also risky for trial subjects, as often turns out.

The microbicides tested in phase II trials all belong to first generation products that aim to make the vagina less hospitable to HIV, but don’t target the virus directly. None of these has worked so far. One, Saffy gel, simply failed to protect against infection; the other two, cellulose sulphate and the spermicide nonoxynol-9, led to higher HIV infection rates than controls. Meanwhile three other products are undergoing phase III trials.

Most researchers see more promise in new microbicides under development that contain gel formulations of antiretroviral drugs, and many are in the pipelines. The question now is whether all the products should automatically be pushed into phase III trials.

It is difficult to choose the best candidates without doing large human studies because different research groups use different preclinical testing methods, and there is no agreement on which of these tests best predicts how a microbicide will act in patients.

These problems beset all medical interventions aimed at prevention or therapy, as there is no agreement over the mechanisms whereby HIV is supposed to cause AIDS [3, 4] (On Quitting HIV and Beyond the HIV-Causes-AIDS Model, this series).

Each research group is investing in its own product and so will be reluctant to step aside for others. The field may need a guiding hand from an impartial body, which does not exist now. It has been suggested that a working group on microbicides currently being set up by the US National Institutes of Health’s Office of AIDS Research may serve this role [2].

It is between the devil and the deep blue sea for the drug developers. They may end up jettisoning useful products in avoiding redundancy, or else waste a lot of financial resources and endangering trial subjects in large clinical trials.

The question no one in the microbicide development community is asking is why so much effort is dedicated to preventing sexual transmission, which is disproportionate to the low probability of that happening. The male to female HIV transmission probability varies from 0.0001 – 0.004, increasing with viral load in semen, and further increases when the male partners are acutely infected [5].          

The research community is cheered by two pieces of good news despite the failure of microbicide gels. First, drug treatment against the herpes simplex 2 virus (HSV-2) cuts the levels of HIV RNA in the blood and genitals of women infected with both viruses [6], raising hopes that it may contribute to controlling the disease. Epidemiological evidence has suggested that infection with HSV-2  is associated with increased genital shedding of HIV-1 RNA and HIV-transmission. Second, the US National Institutes of Health has put a premature stop to two large controlled trials on male circumcision in Uganda and Kenya that it funded [7], because the effects of the procedure were already clear. As in a previous study in South Africa, also terminated early, the results showed that circumcision reduced a man’s risk of HIV infection by 50 to 60 percent. Further studies are in progress to see if circumcision could reduce transmission of HIV to women sexual partners.

Circumcision and non-sexual transmission

However, there is considerable doubt over whether sexual transmission of HIV alone could account for the rapid spread of AIDS, given the acknowledged low rate of heterosexual HIV transmission in Africa as elsewhere [3] (On Quitting HIV, this series). Thus, concentrating efforts exclusively on reducing sexual transmission at the expense of  non-sexual transmission can seriously backfire, even if we ignore the inherent racism involved in stigmatising black Africans as sexually promiscuous and irresponsible [3, 8] (“Let Us Live and Let Them Die”, this series).

In fact, remarkable proportions of self-reported virgins and adolescents in eastern and southern Africa are infected with HIV, but non-sexual routes of transmission have yet to be properly investigated in these populations [9].

For example, a survey by blood tests carried out in rural northeast Tanzania in 1995 found 4.5 percent of self-reported virgins ages 15 to 24 were HIV positive. Similar studies over the past 10 years found HIV prevalence in virgins between 0.1 – 6.5 percent in Ethiopia, 6.4 percent in Kenya, 2.2 percent in Malawi, 0.7 –5.5 percent in South Africa, 6.5 percent in Zambia and 0.5 percent in Uganda. In recent prospective cohort studies in Malawi and Zimbabwe, the annual incidence of HIV infection in persons reporting no sexual exposure during study intervals was 1.2 to 2.4 percent. For decades, researchers, journalists and community members (including children) in sub-Saharan Africa have recognized the potential for HIV transmission through circumcision. Most circumcisions are done by traditional practitioners outside formal healthcare settings, and typically in large numbers in rapid succession. If someone circumcised is HIV infected, then transmission may occur to those subsequently circumcised. Transmission can also happen in formal healthcare settings through unhygienic practices and blood-contaminated surgical instruments, or contaminated needles for injection.

The research team led by Interdisciplinary Scientific Research in Seattle, Washington, in the United States decided to conduct a study assessing the relationship between male and female circumcision and prevalence of HIV infection among virgins and adolescents in Kenya, Lesotho and Tanzania [9]. The results confirmed what they had surmised.

Circumcised male and female virgins were substantially more likely to be HIV-infected than uncircumcised virgins in every sample. Circumcision was common among Kenyan (75 percent) and Tanzanian (63 percent) male virgins, but comparatively uncommon among Kenyan females (18 percent) and Lesothoan male virgins (21 percent). For Kenyan females, the prevalence was 3.2 percent among the circumcised versus 1.4 percent among the uncircumcised, an odds ratio (OR) of 2.38; for Kenyan males, 1.8 percent versus 0 percent; For Lesothoan males, 6.1 percent versus 1.9 percent, OR 3.36; Tanzanian males: 2.9 percent versus 1.0 percent, OR 2.99.

Among adolescents, regardless of sexual experience, circumcision was just as strongly associated with prevalent HIV infection. However, this association changes direction dramatically with age: from a moderate to strong positive association in adolescents (age < 18 years) to the lack of circumcision associated with HIV infection in early adulthood, and remains so for older age groups; uncircumcised adults were more likely to be HIV positive than circumcised adults.

Self-reported sexual experience was independently related to HIV infection only among adolescent females in Kenya, but not among all adolescent males in Kenya, Lesotho and Tanzania.

Circumcision does not exhaust the non-sexual modes of HIV transmission, as some uncircumcised virgins and adolescents were infected.

The authors warn [9] that before promoting male circumcision as an HIV preventive intervention, large and sustained investments and improvements in the safety of care in all settings must be made. Otherwise, “such initiatives may well facilitate transmission of HIV and other blood-borne pathogens.”

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