Human Immunodeficiency Virus (HIV), the causative agent for acquired immunodeficiency syndrome (AIDS), is a significant contributor to the global burden of disease with undesirable implications for individuals and countries (Want et al., 2016). As of 2016, there were 36.7 million HIV-positive individuals worldwide (WHO, 2017). Half of the HIV-positive individuals are adolescent girls and women aged 15 and older with about 60% of cases among those aged 15-24 (UNAIDS, 2017). Sub-Saharan Africa (SSA) suffers from an unequal burden of HIV infections accounting for 71% of all cases with high proportions in Malawi (4%), Uganda (6%), Zimbabwe (6%) and South Africa (25%) (Kharsany and Karim, 2016).
The HIV epidemic in many countries has had devastating effects on the economic growth of the nation, as HIV predominantly affects individuals in their most productive years. Substantial efforts have been made in behavioral, structural and biomedical strategies for HIV prevention and treatment. As a result of the remarkable development and universal scale-up of antiretroviral therapy (ART), there have been major reductions in HIV associated mortality, morbidity, transmission and overall improvements in the quality of life of those living with HIV (Bain et al., 2017). To illustrate, there was a 48% decrease in AIDS-related deaths from 2005 to 2016 (UNAIDS, 2017). Additionally, the rollout of ART is considered highly effective in reducing sexual transmission of HIV, where HIV-negative individuals living in high ART coverage regions were less at risk of an HIV infection compared to those living in low coverage areas (Tanser et al., 2013).
However, the feasibility of attaining high ART coverage remains a challenge. This is mainly because ART initiation requires an HIV diagnosis and high ART coverage requires high retention of patients on treatment, both of which have yet to be achieved in many countries (Maartens et al., 2014). Despite global efforts to strengthen HIV prevention and reduce transmission, the speed at which HIV incidence is declining is far from reaching its target (Bain et al., 2017). Infection trends continue to be high with about 1.9 million new infections diagnosed in 2016 of which two-thirds were in SSA (UNAIDS, 2017). Unprotected heterosexual sex it the primary manner of transmission in the region (Bain et al., 2017). As a result, females aged 15 and older bear a disproportionate burden of HIV infection, accounting for 56% of new cases (UN Women, 2016). Furthermore, females aged 15-24 years acquire HIV infection 5 to 7 years earlier than males of the same age group (Kharsany and Karim, 2016). While global scale-up of treatment has provided a better quality of life to those living with HIV and enabled reductions in transmission, the sustainability of such progress now depends on reducing new infections, particularly among women.
The Need for the Study: The gender disparity in HIV prevalence and incidence in SSA can be attributed to multiple structural, economic, sociocultural, behavioral and biological factors. Biologically, women are more susceptible than men because during sexual intercourse (1) women have a larger area of mucous membrane exposed to the virus and infectious fluid for longer periods, and (2) greater quantities of possibly infected fluids are transferred from men to women (Gilbert and Selikow, 2011). Placing these biological factors within the broader sociocultural context of gender-inequalities gives a more comprehensive understanding of the situation. A multitude of factors including earlier sexual debut among females, high proportions of transactional sex as a result of economic dependency on men, multiple partners with concurrent sexual partnerships, gender-based violence against females and low condom use contribute to increased vulnerability among adolescent girls and young women (Ramjee and Daniels, 2013).
Currently, there are many proven opportunities for HIV prevention including voluntary medical male circumcision (VMMC), programming for behavior change, promotion of condom use, provision of post-exposure prophylaxis (PEP) and more recently pre-exposure prophylaxis (PrEP) (Sued et al., 2016). The combination of these prevention packages has excellent potential in preventing HIV infection from vaginal and anal sexual intercourse. In particular, uptake of VMMC and consistent condom use are considered two of the main interventions in reducing heterosexually acquired HIV (Kharsany and Karim, 2016). However, VMMC and female and male condom use require male consent, meaning the male partner determines the preventative measures a woman can take against HIV. Among women considered at higher risk of sexually transmitted HIV, the nature of female-male relationships constricts women’s agency over their health and sexual rights (UNAIDS, 2017). Thus, prevention becomes ‘inaccessible’. Realizing the gendered nature of current interventions and the need for more female-controlled options, researchers have started looking into other possibilities. In the Partners PrEP Study, the administration of PrEP – i.e. ART in HIV-negative individuals to prevent HIV infection – showed promising results among serodiscordant heterosexual couples with 75% reduction in HIV transmission among female partners (Baeten et al., 2014). Another study found that PrEP resulted in a 62% reduction in HIV transmission (Thigpen et al., 2012).
However, further investigation into the potential of prevention using PrEP among younger single women in SSA proved that it was ineffective (Van Damme et al., 2012). This was due to poor adherence stemming from concerns around stigma associated with the use of drugs intended for the treatment of HIV and fear of adverse side effects (ibid.). To address some of these issues, vaginal microbicides – formulated as gels, creams, suppositories or films – were developed (Cottrell et al., 2014). Despite the efficacy of microbicides, the unpredictable pharmacokinetics of microbicides in different individuals was concerning (ibid.). More importantly, the same issue present in other female-centered interventions remained: adherence was low.
Study Summary: Taking into consideration the acute need for new and more convenient HIV prevention interventions, Baeten and colleagues (2016) set out to test the efficacy and safety of a dapivirine containing the intravaginal ring, which is the first long-acting HIV prevention product explicitly designed for women. The study –A Study to Prevent Infection with a Ring for Extended Use (ASPIRE)– was a phase III randomized, double-blind, placebo-controlled, multicentre and parallel arm trial. ASPIRE was conducted with the primary objective of determining whether a sustained-release form of an antiretroviral drug named dapivirine is effective and safe in protecting women at high risk of sexually transmitted HIV. The vaginal ring is designed to be worn constantly for four weeks and then exchanged at the end of the month for a new ring. From August 2012 until June 2015, the study recruited and followed 2629 HIV-negative 18-to-45-year-old women at 15 different sites in South Africa, Uganda, Malawi, and Zimbabwe. The median age of the study participants was 26 years with the majority having at least a secondary school education or higher. The reported number of vaginal intercourse in the three months prior to the study was about 26.5 in both control and treatment groups with about 60% in both groups reporting the use of a condom during last vaginal sex (see p.2126 for more details). The median follow-up time was 1.6 years with 1024 women followed for over two years. Retention during the follow-up period – up to month 33 – was high at 85%. The participants were randomly allocated to placebo or intervention. The study was designed to detect a 60% lower risk of HIV-1 infection among the dapivirine group compared to those on placebo. The trial was also powered to exclude a 25% reduction in the lower boundary of the 95% confidence interval (CI). This is done to confirm that new prevention has a clinically significant benefit. The primary endpoint for safety was assessed by clinicians and was defined as “a composite of any serious adverse event, any grade 2 or 4 adverse event” attributed to dapivirine. The researchers also investigated adherence as a secondary objective of the study. Measurement of adherence was done through drug level testing as well as testing remainder drug levels on the ring itself.
Overall, Baeten et al. (2016) found that the vaginal ring resulted in a modest decrease in HIV incidence. More specifically, women who wore the ring had 27% (95% CI, 1 to 46; P=0.045) lower risk of HIV infection compared to the placebo group. After excluding two sites from the primary analysis due to “lower-than-expected protocol and product adherence” (p.2125), the relative reduction in HIV incidence from wearing the dapivirine vaginal ring compared to placebo was 37% (95% CI, 12 to 56; P=0.007). Post hoc analysis of the results demonstrated that increased efficacy and protection against HIV was associated with an increased level of adherence, which was associated with age. A 61% (95% CI, 32 to 77; P<0.001) reduction in HIV incidence was seen among women aged 25 years and older, while the efficacy was much lower among women younger than 25 with an overall reduction by 10% (95% CI, -41 to 43, P=0.64). In terms of safety, the researchers found that the dapivirine ring was safe as none of the reported adverse events were attributed to the dapivirine ring. In their primary analysis, the authors used intention-to-treat (ITT) analysis. ITT analysis includes every subject who is randomized as per original treatment assignment, ignoring issues such as withdrawal, noncompliance and any deviations from the protocol that occur after randomization (Gupta, 2011).
As a result, ITT analysis generally gives a more conservative treatment effect because of dilution due to deviations from the protocol (ibid.). For their secondary analysis, the researchers used per-protocol analysis to provide a more sensitive analysis of conclusions obtained from the ITT analysis. The per-protocol analysis only includes participants who adhered and completed the treatment as allocated. The per-protocol analysis provides a better estimate of treatment effect, ITT analysis provides a better reflection of practical clinical/real-life setting. Throughout the commentary, HIV refers to HIV-1 and does not include HIV-2. Dapivirine is a highly potent antiretroviral drug originally developed as an oral treatment for HIV. It acts as a non-nucleoside HIV-1 reverse-transcriptase inhibitor. It works by preventing HIV from replicating its genetic material after the virus has entered a healthy cell; thus, halting the development of an HIV infection (IPM, 2018).