Human immunodeficiency virus and acquired immune deficiency syndrome in women

In contrast to the first 2 decades of the human immunodeficiency (HIV) pandemic, women now account for about one-half of all HIV infections globally. Most HIV infection in women is acquired sexually. An estimated 70% of all HIV-infected women live in sub-Saharan Africa, where women have about three-fold higher rates of HIV infection than do men. Women acquire HIV infection about 5–7 years earlier than men, and this age and sex disparity in HIV acquisition is a key driver of the epidemic in sub-Saharan Africa. In South Africa, HIV infection in 15–20-year-old women is three- to six-fold higher than their male peers, despite similar ages of sexual debut. The excess burden of HIV infection in women must result from a complex interplay of biological, social, cultural and political factors.

One outcome of HIV infection in women is a concomitant epidemic of HIV in infants that is acquired during pregnancy, intra-partum or post-partum in breastfed infants. Advances in understanding the natural history of HIV infection in infants in the 1990s informed the development of targeted interventions to reduce transmission to infants through prophylactic use of anti-retroviral drugs, resulting in a substantial decline of HIV transmission to infants. The gains made in almost eliminating HIV infection in infants should be applied to women; however, knowledge of HIV acquisition in women (including pregnant women) remains limited.

Life expectancy and fertility rates in women have reduced substantially owing to advancing HIV disease. Increasing access to anti-retroviral treatment is starting to affect survival of women, but it is young women who continue to bear the brunt of the epidemic in sub-Saharan Africa and continue to contribute disproportionately to reversals in gains made on Millennium Development Goals MDG4, MDG5, MDG6 (infant mortality rates, maternal mortality rates, and tuberculosis cases) as a result of advancing HIV disease.

Preventing sexual transmission of human immunodeficiency disease

Although reducing sexual transmission of HIV has remained elusive for most of the first 25 years of the HIV pandemic, significant advances have been made since February 2010. Thus, prevention options have expanded from abstinence, mutual monogamy, use of male and female condoms, knowledge of HIV status, medical male circumcision, and treatment of sexually transmitted infections to the promise of a vaccine through the RV 144 trial findings, prophylactic use of anti-retroviral drugs, and treatment as prevention. The implications of these advances, particularly in relation to use of anti-retroviral drugs for women, remain uncertain. Although CAPRISA 004, Partners PrEP, and the Botswana TDF2 trials reported a protective effect of prophylactic use of gel or oral formulation of tenofovir or oral truvada in women ranging from 39–72%, the FEMPrEP and VOICE trials reported no effect of oral and gel formulations of tenofovir, respectively.

Despite advances in HIV prevention and the promise of the use of antiretroviral drugs for prevention, many gaps remain. The needs of women should be addressed, particularly in situations where abstinence is not an option and where faithful, mutually monogamous relationships or consistent use of male or female condoms are also not options. Why is it that 3 decades into the pandemic, we still do not have female-initiated HIV prevention methods? What can we learn from the past and how has the past shaped our responses to the HIV epidemic?

Preventing sexual transmission of human immunodeficiency disease

Although reducing sexual transmission of HIV has remained elusive for most of the first 25 years of the HIV pandemic, significant advances have been made since February 2010. Thus, prevention options have expanded from abstinence, mutual monogamy, use of male and female condoms, knowledge of HIV status, medical male circumcision, and treatment of sexually transmitted infections to the promise of a vaccine through the RV 144 trial findings, prophylactic use of anti-retroviral drugs, and treatment as prevention. The implications of these advances, particularly in relation to use of anti-retroviral drugs for women, remain uncertain. Although CAPRISA 004, Partners PrEP, and the Botswana TDF2 trials reported a protective effect of prophylactic use of gel or oral formulation of tenofovir or oral truvada in women ranging from 39–72%, the FEMPrEP and VOICE trials reported no effect of oral and gel formulations of tenofovir, respectively.

Despite advances in HIV prevention and the promise of the use of antiretroviral drugs for prevention, many gaps remain. The needs of women should be addressed, particularly in situations where abstinence is not an option and where faithful, mutually monogamous relationships or consistent use of male or female condoms are also not options. Why is it that 3 decades into the pandemic, we still do not have female-initiated HIV prevention methods? What can we learn from the past and how has the past shaped our responses to the HIV epidemic?

Lessons from sexual and reproductive health in the pre-human immunodeficiency era

Historically, sexually transmitted diseases (also referred to as venereal diseases) were seen as conditions in which women were the vectors and men the victims. Accordingly, prevention of venereal diseases often concentrated on men such as soldiers and sailors. The first controlled trial of the male condom randomly assigned condoms to sailors going on shore leave, and showed a protective effect against gonorrhea for men. In the HIV era, this trial has been cited as evidence for the effectiveness of the male condom with little consideration for women. Indeed a common assumption of HIV prevention efforts, including use of condoms, unfounded on any evidence, is that men will take responsibility and use condoms or adopt other prevention advances and thereby protect women. The current epidemic trajectories indicate otherwise.

In contrast, the evolution of fertility control had women bearing the consequences of unplanned and often inconvenient pregnancies. Although the use of condoms, like withdrawal, was understood to be protective actions that men could take, if protection failed, men in some instances bore some of the blame and the consequences. With the development of hormonal contraceptives, the responsibility shifted almost exclusively to women, and some argue resulted in men not using condoms.

In the early days of the HIV epidemic, notwithstanding the infections reported in heterosexual men and women acquired through blood transfusions and or injecting drug use patterns, the fact that the first descriptions of the epidemic involved men having sex with men in the USA and in Europe made HIV appear to be a man’s disease. For the first 2 decades of the HIV pandemic, HIV infection of women through heterosexual encounters was reported as either rare or not occurring in industrialised countries. This perception of the epidemic in the USA was critical in shaping research priorities and the provision of funding by the National Institutes for Health, the largest research funding body. The establishment in the USA of a large-scale, prospective study of ‘at risk’ men early in the epidemic is one example of this. In contrast, a comparable study among women in the USA had to wait more than a decade. Even now, it remains a problem that men do not encourage emphasis on the disease in women in more industrialised countries.

In contrast, in Sub-Saharan Africa and the Caribbean, although HIV infection in women was a recognised priority, the focus of research efforts was on reducing infant transmission of HIV. Studies on reducing mother-to-child transmission of HIV started to flourish in the late 1980s and early1990s in the USA and Africa, but research groups remained uninterested in pursuing research on HIV in women. Uninfected pregnant women were largely ignored, and the HIV-positive mothers a focus only in so far as they were pregnant and a vehicle to address the needs of the infants. A few sporadic reports were published of the stigma, fear, experience of violence and loss of security experienced by mothers who disclosed their HIV status learnt during HIV testing at a pre-natal visit. Only more recently has attention started to focus on the health of the infected mother based on growing evidence that efforts to reduce HIV infection in infants or improve health outcomes in the infant is strongly influenced by the health of the mother. Male responsibility for pregnancy and HIV risk in these settings is only slowly starting to emerge.

Indeed, the separation between fertility control and venereal diseases ensured that service providers were also unprepared for their role in responding to the HIV epidemic. A good example of this is where family planning staff had been trained for years in providing contraceptive counselling to discourage use of condoms as an unreliable method of contraception. In the early days of the epidemic, clients requesting use of condoms in addition to more reliable forms of contraceptives were discouraged, as family-planning service providers had not made the connection with HIV until dual counselling for HIV prevention and fertility control became mainstream in the late 1990s.

The history of microbicides

Before the HIV pandemic, women had not used male condoms themselves. Consequently, it became clear that, when they initiated condom use, it was met with suspicion and blame, and issues of love and trust were raised. In this context, advising women to initiate male condom use in their relationships was absurd.

This impasse was first reported independently by several groups in the USA in the late 1980s, and led to numerous discussions convened by scientists, feminists, artists and political groups in the USA and from developing countries. The idea of creating a virucide was borne from these deliberations, and was later more fully developed by Lori Heise and Chris Elias, at the Population Council and became known as a microbicide. The presence of women from Africa in these deliberations was a sharp reminder of the urgent need and magnitude of the challenge for African women, and was an important impetus for the work initiated by the Global Campaign for Microbicides. The search for a microbicide became recognised as a movement for women and, at first, to a large extent by women. The Global Campaign for Microbicides played a critical role in identifying potential obstacles to clinical testing of microbicides and developing consensus statements to address clinical trial ethics, scientific, investment and logistical challenges. At the same time, in Belgium, Marie Laga and Peter Piot were experimenting with a microbicide in the Congo. In the UK, an early advocate was Alan Stone, at the Medical Research Council.

By the mid-1990s, the quest for a microbicide was taken up by Family Health International, CONRAD, The International Center for Research on Women, The National Institute for Allergy and Infectious Disease (Pro 2000 ^® , Buffer gel ^® ), and The National Institute of Child Health and Human Development. The International Center for Research on Women under the leadership of Geeta Rao Gupta, with funding from The United States Agency for International Development, commissioned critical studies in several African countries to enhance understanding of vulnerability of women to HIV. These studies remain seminal contributions to understanding the social, political and economic factors that shape HIV risk in women in sub-Saharan Africa.

Zena Stein’s commentary in the American Journal of Public Health in the mid-1990s is uniformly regarded as the pivotal catalyst to multiple parallel efforts for the quest for a microbicide, primarily funded by small biotechnology companies and the public sector. The increase in the number of clinical trials in the field with a vast array of products led to the establishment of Alliance for Microbicide Development in 1998 by Polly Harrison. The Alliance gathered together a wide range of players to co-ordinate and synergise efforts for the development of a microbicide.

The XIIITH International AIDS Society conference hosted in Durban in 2000 was a historic moment in the development of microbicides, as it was the first international AIDS conference to have a plenary talk on microbicides. In this meeting, the disappointing findings of the Col-1492 trial results were reported ; however, the positive news was the Gates Foundation announcement of $20 million to CONRAD for microbicide development, marking the first substantial investment in microbicide development and acknowledgement of the urgent need for preventative options for women. Shortly thereafter, the Rockefeller Foundation commissioned a report on the development of a microbicide by the Boston Consulting group, which culminated in the establishment of the International Partnership on Microbicides and, independently, the National Institutes for Health funded Microbicides Trial Network (MTN) in the mid-2000s. The creation of IPM and MTN, together with the experience garnered in the previous decade through the conduct of the pre-clinical and clinical studies, resulted in generating a momentum and scientific focus initiated almost 2 decades earlier by persistent endeavours by scientists, non-governmental organisations, donors, advocates and tens of thousands of volunteers participating in the research.

At the Microbicides 2006 meeting hosted in Cape Town, the potential role of microbicides among men who have sex with men was highlighted. It is anticipated that this convergence of needs for a rectal and vaginal microbicide will benefit men and women, and increase efforts in finding an effective microbicide.

The release of the positive results of 1% tenofovir gel at the International AIDS Society conference in Vienna signalled the first light at the end of the tunnel, but much remains to be done before we have a safe and efficacious product that can be used by men and women.