Reimagining HIV Prevention Trials in the Era of 95-95-95

Globally, the HIV response has seen significant progress. In Botswana, for instance, over 95 per cent of people living with HIV (PLHIV) are aware of their status, receive treatment, and achieve viral suppression. These results reflect sustained investment in public health and strong community engagement. As a result, the country has seen a notable decline in HIV incidence.

While this is an encouraging development, it introduces new complexity for HIV prevention researchers.

With fewer new infections, widespread access to antiretroviral therapy (ART), and the availability of proven prevention tools like pre-exposure prophylaxis (PrEP), we are faced with a pressing question:
How do we design HIV prevention trials in settings where the number of new infections is becoming increasingly low?

The Paradox of Success

Traditionally, HIV prevention trials have measured the rate of new HIV infections between those who receive an intervention and those who do not. In high-coverage settings, however, declining incidence makes this approach more challenging. Researchers may need to follow participants for longer periods or recruit larger sample sizes, both of which come with increased costs and logistical complexity.

There is also an important ethical dimension. With effective tools already available, researchers can no longer justify withholding prevention options from control groups.

So, what does this mean for the future of HIV prevention research?

Adapting HIV Prevention Trials for the Future

Researchers are now exploring innovative approaches to ensure that trials remain relevant, efficient and ethical in high-performing contexts like Botswana. Here are six promising directions:

Active Comparator Trials

Placebo-controlled trials are no longer ethical when proven prevention methods like oral PrEP already exist. Future trials are more likely to compare new methods, such as long-acting injectable cabotegravir or vaginal rings, with current standards. The focus will shift from asking “Does it work?” to “Which works better, and for whom?”

Focusing on Key Populations

While overall HIV incidence is declining, specific populations still face disproportionately high risks. These include adolescent girls and young women (AGYW), men who have sex with men (MSM), sex workers and people living in underserved rural or peri-urban areas. Targeting these populations can help ensure trials remain relevant and yield meaningful data.

Implementation Science and Real-World Studies

Not all trials need to test a product's efficacy in a controlled setting. Increasingly, the focus is on understanding how an intervention performs in the real world. Implementation science can help assess how well new methods are adopted, used and integrated into existing health systems, particularly in low-resource or high-risk settings.

Adaptive and Step-Wedge Trial Designs

Adaptive trials are flexible, allowing researchers to make changes during the study based on interim findings. This might involve adjusting sample size or focusing on sub-groups showing early benefit. Step-wedge trials, on the other hand, roll out an intervention across different populations or areas in stages, ensuring that everyone eventually benefits while still enabling a rigorous evaluation.

Using Surveillance and Recency Testing

When traditional trials are not feasible, enhanced HIV surveillance can provide valuable insights. This includes using recent infection testing, phylogenetics and mathematical modelling to identify areas of high transmission and evaluate the impact of prevention strategies at the population level.

External Control Groups

In some cases, a contemporaneous control group within the same trial may not be possible or ethical. Instead, researchers can use external or historical control groups drawn from existing cohort studies, routine surveillance data or previous trials. This method allows for the evaluation of new interventions without depriving anyone of standard prevention options. However, careful attention must be paid to ensuring comparability between the intervention group and the external control group, particularly in terms of HIV risk profiles and background incidence.

Why This Matters for Botswana and Beyond

Botswana’s remarkable progress should not mark the end of innovation, but rather the beginning of a new chapter in HIV prevention, one that is smarter, more focused, and grounded in equity and community engagement.

Future HIV prevention trials will need to reflect:

• The changing dynamics of the epidemic
• The ethical obligation to provide the best available prevention
• The urgency of reaching the groups who are still at risk

Botswana is well positioned to lead this next generation of HIV research, demonstrating not only how to control HIV, but how to take bold steps toward ending the epidemic.

Interested in the Future of HIV Prevention?

If you are a researcher, policymaker, or advocate thinking about trial design in high-coverage settings like Botswana, now is the time to engage. The future of HIV prevention depends on innovation, collaboration and a continued commitment to those most affected.