Scientific research and development has thankfully increased the number of prevention options we have today to stop the spread of several infections including HIV and TB. But are they actual choices for the people-at-risk of getting infected?

The deadly gap and unacceptable delay in converting scientific breakthroughs into public health gains must be eliminated if we are to end AIDS and TB.

“We have to fill the product introduction gap - accelerate time to regulatory approvals of product introduction to impact; demand creation and programme platforms for prevention; and differentiated and integrated service delivery for people. We must also fill the product development gap - long acting and event driven; user-friendly and developed with users; dual purpose and multi-purpose methods must be our top priority,” said Mitchell Warren, Executive Director of AVAC. Mitchell was speaking at AIDS 2024 Affiliated Independent Event on TB and HIV organised recently in lead up to 25th International AIDS Conference (AIDS 2024).

“We have to work simultaneously to fill the gaps in both areas. If we neglect one of them, we are not going to create the sustainable and durable end to either TB or AIDS. That is what combination treatment and prevention has to look like. Also, it takes a global community of advocates, researchers, policymakers, funders to move forward,” emphasised Mitchell.

Mitchell wears many hats (and with great aplomb). He is also a member of the Scientific Advisory Board of the President’s Emergency Plan for AIDS Relief (PEPFAR), the International AIDS Society (IAS) Governing Council, IAS Towards an HIV Cure Initiative, President of the TB Alliance Stakeholder Association, and Past President of the Global HIV Vaccine Enterprise.

Biggest challenge: The people we leave behind

Thankfully the targets such as ending TB, AIDS and malaria by 2030 are ambitious but sadly these are not met. “They hopefully drive policies, programmes and investments, but they rarely actually achieve the success that we seek. Targets that were established in 2014 - 10 years ago - for where the world needed to be by 2020 to have fewer than 500,000 new HIV infections per year, have been missed. The gap between the targets set up to end the AIDS epidemic by 2030 and what was actually achieved, is huge. The gap got larger over the last 5 years, particularly because of the COVID-19,” said Mitchell.

“And yet UNAIDS rightly put out more ambitious targets in 2020 for where we needed to be in 2025. The good news is that these new targets recognise a much greater centrality around policies and behaviour change and put the individual at the centre of the epidemic (that was not the case in 2020). But we still have a long way to go before we come even close to what we call the 95-95-95 targets. But more important is the recognition that the people we are leaving behind are our biggest worry. We sought to develop a method mix in HIV prevention- like what had happened in contraception. Until 2006 there was not much else for contraception, other than male and female condoms and behaviour change. But now we see a very robust set of methods in the mix,” said Mitchell.

“However, an important point to remember is that even though contraception R&D has brought dozens of methods over many years of hard work and investment, yet most people are given only one or two of those options. They do not get that full method mix,” he added.

95-95-95 refers to global targets of achieving at least 95% of people living with HIV know their status, 95% of those who know their status are receiving lifesaving antiretroviral therapy, and 95% of those on therapy are virally suppressed. According to the WHO, there is “zero risk” of HIV transmission from those who remain virally suppressed. In other words, Undetectable equals untransmittable or #UequalsU should have been a reality for all with HIV.

Develop new prevention options and deliver them at scale equitably

“Our task is not only to develop additional HIV prevention options but also to deliver them at scale with speed and with equity, to actually have an impact on the epidemic. We now have a range of methods available- oral Pre-Exposure Prophylaxis (PrEP), the vaginal ring, injectable cabotegravir now moving into implementation studies, and next generation products,” said Mitchell Warren. PrEP is one of the new HIV prevention options for HIV-negative people who can reduce the risk of HIV acquisition by taking an antiretroviral medication.

Biomedical options are critically important as they are the fruits of science developed through research and development (R&D) processes. “But translating them into choices for people is what our job is, as public health practitioners - not just to develop but to deliver and to make sure that those products reach people as viable choices. This requires policy makers, donors, governments, implementers to make the mix available, accessible and affordable,” said Mitchell.

“That is the main challenge ahead of us as we get more and more of these methods in the mix. We have more HIV prevention options now but are they actual choices? In contraception, we know choice matters because when we increased contraceptive availability in clinics, in community-based programmes (and not just in R&D pipeline) contraceptive use actually went up. What about HIV? Studies have proved that expanding testing and treating and then introducing PrEP has lowered the incidence of HIV in communities that had access to it (studies done in rural Kenya and Uganda). This was 3 years ago” shared Mitchell.

He added: “In a recent study presented at International Conference on Retroviruses and Opportunistic Infections (CROI 2024), after expanding treatment and PrEP, they randomized people to a dynamic choice of any prevention product- in the arm that was given a choice between oral PrEP, injectable PrEP and oral PEP compared to the group that just had standard of care- which was basically PrEP in the clinic. More people chose something and in the dynamic choice arm there were no infections whereas there was an incidence rate of about 2% in the standard of care arm. So, clearly choice matters. But perhaps the most important thing from that study was that not everybody chose Cabetogravir (once every two months injectable PrEP). While injectable PrEP was chosen by over 50% of study participants, many more people also began to choose oral PrEP. Only 20% of people used PrEP in standard of care.”

Choice matters

“One way to recognize that choice matters is to understand that no biomedical option is only biomedical- whether for prevention or for treatment; whether for HIV or for TB. These products exist in behavioural and structural contexts. And if we do not address that context, then the best biomedical product goes unused. We have seen in COVID-19, if vaccines do not get used, they do not have any impact. A safe and efficacious vaccine that sits on the shelf is neither safe nor efficacious. So, biomedical products that sit on the shelf do not have any impact unless we address behavioural and structural issues. None of these methods- whether HIV PrEP, TB drugs, advances in a future TB vaccine- can help if we do not address access and equity,” said Mitchell Warren.

Choices matters on multiple levels

“There are at least two elements of choice- choices in products, and also choices in terms of where I want it and from whom I want it. Choice matters on multiple levels. While we develop biomedical products around the pathogen-around the HIV virus or TB bacteria - we need to design the programmes around the people. That is what matters and that is how you get to impact,” rightly said Mitchell Warren.

PrEP rollout

“Over the last 12 years we have learnt a lot about HIV prevention because of PrEP. And yet there is very limited uptake of PrEP. Even though PrEP has grown in the last 3 years, only 7 million people in the world have ever even initiated PrEp at some point. It does not mean that they continue to be PrEP users. Global target for PrEP is about the number of users of safe and effective products and not how many people initiated it once and maybe did not continue. And while we do need to scale up oral PrEP, we also have to think about the pipeline of new products. Just two weeks ago we had the results of the study of Lenacapavir. After results of PURPOSE-2 study come, it will still take more than one year for data to be analysed, reviewed, and go through regulatory guidance. Nonetheless, we may soon have another very potent product called MK8527- a monthly oral tablet being developed by Merck which is in phase-2 study. We also have a dual prevention pill- oral PrEP combined with oral contraception. Many women want a product that meets both of their sexual reproductive health needs- HIV prevention and contraception. This pill could be in the market sometime next year,” shared Mitchell Warren.

Rollout of new tools: Too little and too slow

“We have typically moved far too slowly in moving science into impact - moving a product to the real world. For PrEP we got the evidence in 2010, but it was more than 10 years later that we really began to see the scale of the programme. Same with the dapivirine ring. We knew in 2016 that it was safe and effective. But it has taken years post-efficacy to move into recommendations and to product introduction. The world has moved faster with cabotegravir for which approvals have come much faster. The first was African approval. There are three companies in India that now have licenses to produce generic cabotegravir. But these would get in the market only around 2027. So, things are happening faster than we had with other products. But it is not fast enough to keep pace with an epidemic that continues despite global targets, despite our desire to be done with AIDS,” said Mitchell Warren.

No one of the products will be able to solve all the challenges. We have to think about these products across a number of considerations. In the case of lenacapavir, we have to think about how we are going to deliver an every 6-month injection. Do people want it? Is it discreet enough? What are the side effects? Will we have to train providers? How do we create demand? What will be its cost? A lot of unknowns are still there,” Mitchell rightly pointed out.

Those who choose, use, and pay the dues

“And it is not just the user at the centre (although that is most important). It is often about those who choose, those who use and those who pay the dues. Very often the people who use, do not get to choose. It is the health programmes, or the healthcare providers, the physicians, the Ministries of Health who decide what choice(s) to give to the people. And very often, especially in countries that rely on donor assistance, they can only do this work if the funders invest. If funders do not want to invest in lenacapavir or the dapivirine ring then a user does not get those options. We have to balance across all of these issues.”

And it is the same story with TB. For example, rapid molecular diagnostics that were approved in 2010 (Gene Xpert) and 2017 (Truenat - point-of-care, laboratory independent and decentralised molecular test) are yet to become the upfront TB test for 100% people with presumptive TB. Rollout of new TB treatments such as BPaL and BPALM (six months oral therapy for drug-resistant TB) is way too slow. New TB preventive therapies (shorter one-month 1HP or three months 3HP) are yet to see a rollout in so many high burden countries.

The deadly delays between developing pathbreaking health technologies, and benefitting those for whom these were developed (the most at risk and marginalised and least likely to access care) must end. We have to ensure vaccines convert into vaccinations of the 'last person in queue' first - without any delay. Same holds true for the full range of disease prevention, diagnostics, treatments we have today.