In Southern Africa, and especially recently in South Africa, ‘anti-sugar daddy’ campaigns to discourage age-disparate relationships (ADR) between young women and older men, have been common (1). Politicians have been discouraging such relationships and attributing the severe HIV epidemic in South Africa to such relationships (2,3), though evidence for the importance of ADR in the transmission of HIV infection is limited. In 2014, when Harling et al. (4) were unable to find evidence that ADR is important in driving HIV incidence, many organisations and activists stopped advising against ADR (5). For the past few years, the HIV prevention community has been in abeyance about whether ADR-prevention interventions are appropriate, and if so, what should the messages contain.

The results from recent studies my colleagues and I have conducted offer a more nuanced picture about the nature of age differences and HIV transmission. Age differences in heterosexual relationships have the potential to both elevate the individual-level risk of acquiring HIV (e.g. through decreased condom use, longer relationship durations, and higher sex frequencies) (6,7), and help sustain the epidemic within some populations of South Africa and Malawi (8). Although the way in which age differences contribute to transmission may be different than what has been previously described in observational studies. The results suggest that moralising approaches stigmatising all relationships where the male partner is 5 or more years older, may not be appropriate, nor evidence-based. In reality, there cannot be a cut-off for age differences above which risk increases across all populations (7,8). Moreover – though this is common sense – age differences have the ability to affect transmission risk in men, as well as women (8). Complicating all of this, is the observation that high individual variability in partner ages, in addition to relationship age differences, is probably what drives transmission (7,8). Given these complexities, I propose the following public health intervention recommendations:

1. Raising awareness about potential HIV risks associated with larger age differences should be context dependent and evidence-based. For example, it might be appropriate to raise awareness among 18-49-year-old women on Likoma Island about the fact that increasingly large age differences may put them at heightened risk of HIV infection until the age differences approach 12 years (7). However, larger age differences than 12 may potentially protect them from HIV transmission (7). It would not be appropriate to use that same information to raise awareness about age difference related risks in an urban, Johannesburg setting, for example, since this is an entirely new context with different social norms. In other settings the same sexual risk behaviours may not be associated with the same age differences. It should be additionally noted that the results from one study alone should not be used as the basis for an HIV risk awareness campaign.
2. There is a need to strengthen cultural, economic, educational and legal structures to protect and empower women (9). While there is evidence to suggest that women have control over partnership formation, as well as the number and type of partners they have, within these relationships they have less power in condom use negotiations and sex frequencies (10). Young women in Southern Africa have growing aspirations and limited opportunities for financial independence. Programmes incentivising women to stay in school longer, like state-sponsored cash-transfers, or start businesses, like micro-lending programmes, are examples of some avenues that may lead to financial independence, and thus, increased relationship power. However, if these programmes are not sustained over the long-term, so that young women have the opportunity to develop useful skills for a modern economy or acquire productive assets, then they may not be effective.
3. Thus far most of the intervention suggestions and framings of this topic in the literature have focussed on women. However, our studies also point to the need to protect young men from HIV transmission by older or age-similar partners. One of the most efficacious interventions for preventing transmission from women to men is medical male circumcision (13–15). Voluntary medical male circumcision programmes are ongoing, but there are still several barriers to scale-up. Lack of funding, programme inefficiencies, demand creation, low capacity of government to manage programmes, as well as time-consuming and invasive medical procedures are all seen as shortcomings of the current programmes (16).
   These intervention strategies have the potential to curb HIV incidence and potentially eliminate key transmission pathways in certain age groups, but they will require a great deal of political will to accomplish them. The high HIV incidence among young women is a multi-faceted problem, which cannot be addressed wholesale with campaigns to stigmatise sugar daddy relationships. Understanding age-mixing dynamics in high HIV prevalence settings is the key to identifying transmission pathways in those populations. Awareness of the male and female motives for partner age variability and preferences should be the basis for interventions to eliminate those transmission chains.

Intimate partner violence (IPV) is a worldwide epidemic, not delimited by geographic or socioeconomic boundaries (1, 2). The size, drivers, and dynamics of this epidemic are uncertain, but there is no denying that IPV occurs on a frightening scale in sub-Saharan Africa. In the past, IPV was called domestic violence. The more precise terminology recognises that IPV is different from other forms of violence in the home (for instance, against children or elders). It also recognises that violence occurs in all kinds of intimate partnerships, not only those that are marital or cohabiting.

Physical and sexual violence are the most well-studied forms of IPV from an epidemiological point of view. Both of these have serious implications for other aspects of physical and mental health. In particular, women who have experienced IPV are more likely to be HIV-positive. This has been observed and replicated in enough cross-sectional and cohort studies (3, 4) for us to have a reasonably good idea of the strength of the association (that is, the unadjusted or bivariate association). However, it is one thing to observe that IPV is correlated with HIV, and even that IPV is a predictor of future HIV infection, but quite another thing to understand the underlying reasons.

Looking for an explanation

In a modelling study (5), Leigh Johnson and I investigated some closely related questions about HIV and IPV in South Africa. What are the plausible reasons for the observed association between IPV and HIV? Does IPV cause HIV infection? If we can reduce IPV, is it realistic to expect a reduction in HIV incidence? This project was a branch of a much more extensive programme seeking to model the social and structural drivers of HIV and test out intervention strategies (6).

An agent-based model (ABM), also called an individual-based model, simulates random interactions within a varied population of individuals. ABMs are well-suited to investigating the social drivers of HIV. They are more accurate than some other modelling approaches when assessing the role of high-risk population subgroups, and their risky behaviours, in the spread of sexually transmitted infections (7). While ABMs can be challenging to build and run, they have the advantage of being very intuitive because they mimic the interpersonal networking processes that occur in real life. It is also easy to imitate a cross-sectional or a cohort study, and extract data from the simulations that can be compared to findings from those studies.

We used a pre-existing model (8) that incorporates the natural history of HIV in South Africa and simulates the virus within a representative population of individuals. The individuals in the model age with time and engage in behaviours like forming and dissolving intimate partnerships, marrying, having sex with and without condoms, bearing children, having commercial sex, and taking concurrent partners.

In the first stage of the study, we augmented that list of behaviours by including the perpetration of violence by men against their female intimate partners. This involved setting the rates at which different kinds of relationships become violent and allowing the rates to vary according to the individuals involved. Parameters were adjusted until the model predicted a prevalence of IPV that was consistent with the best available statistical estimates. At this stage, IPV was not allowed to affect the dynamics of the network – it was like a dye added to a water system, which traces the flow but does not interact with the system.

Discovering some confounding factors

At this first stage, it was surprising to find that IPV was a correlate and a predictor of HIV. With a baseline assumption that men’s violent tendencies were distributed independently of their propensity for risky sexual behaviours (namely, frequent and concurrent partnering and engagement in sex work) the IPV-HIV association was visible but not quite as strong as observed in the real world. We then moved away from the assumption that violent tendencies are distributed independently of risky sexual behaviours because we know with some confidence that high-risk men are more likely to be perpetrators of violence (see (5), Table A1). Building this assumption into the model increased the strength of the association between HIV and IPV so that it matched real-world observations.

The insight gained from this result is that the empirical situation might be explained entirely by two sources of confounding. Firstly, some women are more exposed to both IPV and HIV simply as a result of having more partners. Secondly, men who are prone to sexual risk-taking are disproportionately prone to violence. It follows from their risk-taking that those men are more likely to be HIV-positive, and it makes sense that we find elevated HIV incidence and prevalence in survivors of IPV.

The end result is that it is not necessarily true that IPV has any causal relationship with HIV. It is worth emphasising that this result is contrary to what we expected at the outset because it is quite widely-believed that there are causal pathways leading from IPV to HIV infections. The kinds of confounding that we discovered are difficult to detect in observational studies, because it is necessary to collect data on couples, but there is at least one study (9) that did so and reached a similar conclusion.

Evaluating causal mechanisms

In the second stage of the study, we modelled some hypothesised causal pathways separately and in combination, to see if they might yield another explanation for the association between IPV and HIV. At this stage, IPV was allowed to interact with the network.

Based on our literature review, there is some evidence that IPV disempowers women to the extent that they cannot negotiate about condoms with their partners. It is also likely that IPV disrupts and breaks up relationships, discourages marriage, and (possibly) encourages concurrent partnering. There is also evidence that HIV-positive women in violent relationships are less adherent to antiretroviral therapy, which could affect perpetrators and cause some feedback effects.

The behavioural changes (in condom use, break-up rates and treatment adherence) that were assumed to follow from IPV had a negligible effect on HIV outcomes in the model. This was consistent when we imitated cohort and cross-sectional studies, set up counterfactuals (what would have happened if there were never any IPV), and simulated interventions (what would happen if IPV were suddenly halved).

The result is that while it may be true that IPV has a causal relationship with HIV, the effect size is probably tiny. It is therefore unlikely that IPV prevention strategies would reduce HIV incidence, even if they succeeded in reducing IPV. There are some putative causal mechanisms that we did not simulate; we mention this limitation in the article (5), together with some caveats that are typical of agent-based modelling.

Considering the implications

There are some noteworthy trends in HIV control: testing and diagnosis, treatment as prevention, pre-exposure prophylaxis, and behaviour change for primary prevention. On the other hand, the science behind primary prevention of IPV still has a long way to go, despite some promising developments in both theory and practice (10).

Some of the largest randomised controlled trials on IPV prevention have derived momentum from the belief that therein lies a way to prevent HIV. The message that we hope to convey is that IPV is an epidemic and a human rights issue worthy of more attention, independently of its perceived role as an antecedent risk factor for HIV.

The HIVR4P conference is a global scientific conference that exclusively focuses on biomedical HIV prevention research. HIVR4P supports research on HIV vaccines, microbicides, PrEP, treatment as prevention, and other biomedical prevention approaches (1). The HIVR4P 2018 conference which was organised by Global HIV Vaccine Enterprise was held from 21 – 25 October 2018 in Madrid, Spain. The conference brought together about 1500 HIV researchers, policymakers and advocates from around the world. The four-day conference program comprised of plenary sessions,  oral presentation sessions and poster sessions, meet-the-expert lunches, symposia and roundtables. Various pre-conference satellite sessions sponsored by research and community-based organisations from around the world were also held.

HIV prevention choices

“Whose choice is it anyway?” was the theme question verbalised by many of the world’s leading scientists, researchers and advocates. The discussion about choice arose in response to National Institutes of Health’s (NIH) new funding priorities which were concluded after NIH’s 2017 survey “Refining the Research Enterprise” Request for Input on Research Priorities (2). Every seven years, the NIH reviews its HIV prevention and treatment research priorities as well as its funding of HIV clinical trials networks working in the United States and globally. The new funding proposal for streamlining the HIV clinical research networks was presented in early 2018. The NIH resolved to modify HIV prevention research priorities giving preference to long-acting, systemic formulations such as vaccines, implants and injectables while declining the need for user-controlled, short-acting, non-systemic options such as the vaginal and rectal microbicides. The NIH reassured support for multi-purpose prevention products that were shown to be highly efficacious. Several presenters at the HIVR4P felt that if the level of efficacy for locally acting investigational products was competitively contrasted against systemic products, then the bar could be too high to be reached. Several advocacy groups and researchers objected to the microbicides being under threat.

Throughout the conference, the call for end-user choice for HIV prevention tools was highlighted by various advocacy groups and researchers (3). The importance of meaningful community engagement in the research process was emphasised. The need for a variety of effective HIV prevention tools particularly for females was highlighted strongly. Many expressed support for HIV prevention choices, continuing microbicides research and multi-purpose technologies. During the conference, various speakers pointed to the need for options that can protect vulnerable women without the need for their partner’s knowledge or permission. Many highlighted the importance of developing a multifaceted HIV prevention toolbox because different people have different needs at different times – “one size does not fit all”. Delegates reiterated that putting “all eggs in one basket” would prevent the expansion of HIV prevention method mix by neglecting various research directions. Many comparisons were made to lessons learned from the contraception field.

HIV vaccine research

Numerous presentations highlighted the growing knowledge of immune responses including mucosal immunity, microbiome responses and bNAb generation, among others (4). Updates from the three vaccine efficacy studies underway were presented; and discussions of vaccine approaches such as bNAb and CD8+ T cell pathways, DNA, RNA and mosaic strategies took place. Various global leaders emphasised the need to continue developing the emerging immunogens. Calls were made to begin making plans for a successful vaccine.

PrEP as prevention

The potential impact of PrEP as an HIV prevention intervention was emphasised. Numerous discussions about PrEP highlighted the impact of PrEP in HIV prevention. PrEP acceptability in communities, long-term adherence, targeting of high-risk groups, costs and benefits were emphasised. A recurring theme on PrEP was the varying patterns of distribution and access of PrEP around the globe. Although PrEP was licensed in several countries, it was generally not readily available in most countries. Other researchers highlighted the different responses elicited by PrEP use which raised the possibility that PrEP could work differently for diverse individuals. Several new PrEP drugs and diverse potential delivery options were presented. These aimed to increase PrEP impact and included products such as rings, implants, gels and inserts. Scale-up options, opportunities and challenges to make PrEP available for those who could benefit most were discussed. Limited data was presented on long-acting PrEP including the injectable cabotegravir which was tested in females.

Microbicides

Concern was raised regarding the funding of microbicide research including the dapivirine ring, as well as the development of other new rings, microbicides and female-controlled products (5). Updates were provided on the status of the dapivirine vaginal ring and rectal microbicides. Specific highlighted features of value with microbicides included:

Capacity for multi-purpose products such as HIV prevention combined with contraception and sexually transmitted infection (STI) prevention,

• Vulnerable users such as women, girls, and other receptive partners could discreetly use microbicides ensuring privacy and control,
• Microbicides acceptance and uptake could build on existing practices such as douching or use of lubricants during sex,
• A reduction in the long-term burden on the user and healthcare system was anticipated because microbicides are generally short-acting and could be used on-demand at the time of sex or during the period when the user is sexually active and at risk of contracting HIV infection.

Future of biomedical HIV prevention

Generally, the conference delegates seemed optimistic for the future of HIV prevention research and implementation projects. A sense of expectancy and hope saturated the HIVR4P 2018 meeting with many attendees articulating their anticipation about the range of pipeline approaches and products in development. The high turnout to meetings discussing new HIV prevention products which were still under development showed a high level of interest by the delegates. Topical discussions included the new HIV prevention drugs and delivery systems such as fast-dissolving inserts, implants, gels, films, enemas, biodegradable polymers, refillable reservoirs, osmotic pumps and other products. The increasing number of HIV prevention options available and in development raised various opportunities and challenges which were also discussed extensively.

In line with the demand for a greater choice of HIV prevention products, delegates called for a range of HIV prevention options. Delegates highlighted the importance of long-lasting HIV prevention approaches while also continuing to prioritise the development of safe, effective, acceptable and accessible vaginal and rectal microbicides. The need for evolving HIV clinical trial designs, understanding product end-user preference, evaluation of health system capacity and the managing of the introduction of new HIV prevention products was discussed. A collective call was made for funders and global leaders to maintain financial and political support for future-focused biomedical HIV prevention.

Malawi has developed an excellent, nation-wide system for monitoring HIV patients and keeping track of key epidemic markers. The success of the Malawi system lies in two things: the focus on simplicity and the use of the data collection process not only to track the epidemic and identify problems to be dealt with but also to give regular feedback and support to every clinic in the country. This achievement is the more remarkable given that Malawi is one of the poorest countries in the world (1), but has one of the most severe epidemics of HIV in the world ranking 9th out of 168 countries by HIV prevalence (2). We in South Africa have much to learn from them.

The epidemic of HIV in Malawi started early (3, 4). In 1987 thirty thousand men working on Anglo-American’s gold-mines were tested for HIV; the men in the study came from South Africa, Malawi, Lesotho, Mozambique, Swaziland and Botswana but not from Rhodesia, now Zimbabwe (5). The prevalence among mine-workers from Malawi was 4%, among those from all other countries, including South Africa, it was 0.03%. In response to this finding, the South African Chamber of Mines stopped recruiting novices from Malawi (6), and the number of Malawians employed on the South African gold-mines fell from 13,090 in 1988 to 2,212 in 1989 (7).

These data are important for two reasons. First, they show that Malawi experienced the effects of HIV before most other countries in southern Africa. Second, while the exclusion of Malawian nationals from working on the gold-mines affected the economy of Malawi in the short term, it almost certainly mitigated the spread of HIV in the long term. The spread of both HIV and TB in southern Africa is largely attributable to the system of oscillating migrant labour, introduced in the early 20th century to ensure a steady supply of cheap labour to the expanding gold mines while avoiding responsibility for the long–term health of their workers (8, 9).

Successful expansion of treatment

In a series of papers Harries and co-workers (10-20) discuss the development of the programme to control HIV and treat and support those infected with HIV in Malawi, drawing heavily on their experience in managing TB (14, 21). The lessons learned from the scale–up of ART and the system of patient monitoring treatment and support are summarised in a recent paper (20). The scale–up of ART in the public sector in Malawi began in earnest in 2004 when 13,000 people were started on ART; by the end of September 2016, 663,000 people, or 68% of the estimated 979,000 HIV positive adults, were on ART. Several factors contributed to this successful expansion of treatment in a low-income country with a substantial epidemic of HIV and may be summarised as follows (20):

1. From the beginning, the emphasis was on simplicity and standardisation.
2. The Malawi Ministry of Health, through the director and staff officers of the HIV Department, took clear leadership and assumed responsibility for national scale up.
3. Financial support for ART scale-up was from one source only: The Global Fund for AIDS, TB and malaria.
4. As clinics were brought on board, staff received an intensive course of training.
5. Every quarter, the HIV Department and its partners conducted supportive supervisory and monitoring visits to all ART sites in the country (referred to as ‘The Quarterly Reports’). The data, results and lessons from these reports are published on a regular basis.
6. Maintaining uninterrupted drug supplies was a top priority.
7. Initially, a dedicated clerk was employed at each clinic to enter patient information retrospectively from patient treatment cards to a single desktop computer.
8. When they began to roll-out an electronic recording and reporting system, designed by the Baobab Health Trust, a local non-governmental organisation, computers were provided in every clinic room and connected to a central server that stored the data. Healthcare workers used simple, robust, touch-screen computers to enter patient information during clinical encounters at the point of care.
9. Key challenges that needed to be overcome included:
   1. Low computer literacy among users;
   2. The need for unique patient identifiers;
   3. Maintaining a clean and reliable electrical power;
   4. Managing the transition from paper to electronic-based records;
   5. Accurately back-entering large numbers of paper-based treatment cards and registers;
   6. Building analytical capacity in the country.

But perhaps the most important lesson from Malawi is that good patient monitoring made it possible to provide support to clinical staff, leading in turn to high treatment coverage and high rates of compliance and a rapid decline in transmission. Good epidemic control starts from good patient monitoring, treatment and support and we in South Africa have much to learn in this regard.