Last week, the World Health Organization (WHO) issued guidelines on what has got to be the most awaited HIV prevention drug in recent years. Lenacapavir, a long-acting type of antiretroviral medication, is now recommended by the WHO for the prevention of HIV infection in highly exposed individuals. What makes lenacapavir stand out compared to other forms of pre-exposure prophylaxis (PrEP) is that it only needs to be given twice a year. In pivotal clinical trials done over three years, lenacapavir prevented HIV infection in 100 percent of women and 96 percent of men. I wrote about this drug last year, and while there was a lot of excitement then, there were also a lot of questions about feasibility, cost, and safety. Since then, many of these questions have been answered, and the cost is projected to be very reasonable for low and lower-middle-income countries.

In the past, HIV prevention has heavily focused on nonpharmacologic interventions due to the lack of effective vaccines and prophylactic medication. The “ABCDEs” of HIV prevention were all that we had: A for abstinence, B for be faithful, C for condoms, D for don’t do (illicit IV) drugs, and E for education. PrEP or the use of antiretrovirals for preventing HIV infection, was conceived as an additional means of prevention since infections continued to occur among highly exposed individuals. PrEP has had a long history of ups and downs, and many countries have struggled to implement it.

Pharmacologic therapy of HIV in the Philippines currently uses three separate antiretroviral drugs, two of which are from a class called nucleoside reverse transcriptase inhibitors (NRTIs), and one from a different class. This second class of drug can be a non-nucleoside reverse transcriptase inhibitor (NNRTI) such as efavirenz, a protease inhibitor (PI) such as lopinavir-ritonavir, or, most recently, an integrase strand transfer inhibitor (INSTI) such as dolutegravir. There are other drug classes, but these are not available locally.

Using fewer than three drugs or fewer than two drug classes to treat HIV has historically resulted in drug-resistant HIV. With PrEP, since recipients are not yet infected with HIV, it was postulated that one or two drugs could be used to prevent HIV from establishing an infection at the time of exposure. Since there is some pre-existing drug resistance among circulating HIV strains globally, it was decided that a two-drug combination, tenofovir plus emtricitabine, was a better choice for PrEP than a single drug.

PrEP using these two drugs was predicated on two important conditions: That the person using PrEP was demonstrated to be HIV negative when it was started; and that he or she was willing to undergo periodic testing. The first condition is because the inadvertent use of PrEP in a person with HIV would result in suboptimal treatment of HIV, with the virus becoming resistant to both agents quickly and compromising future treatment options. The second condition was that if the patient did have a breakthrough infection, then it would be detected early, and the person could be shifted to a three-drug regimen before resistance could develop.

The original clinical trials that showed good efficacy for PrEP in preventing sexually transmitted HIV used a daily regimen. These trials enrolled people without HIV but were highly exposed to people with HIV. These subjects were asked to take PrEP as a pill every day and advised to use protection during their sexual encounters. They were tested for HIV periodically. Over the observation period, there was no significant development of resistance, and there was a significant drop in HIV infections among those taking PrEP compared to those who took a sham pill or placebo. Some people did have a hard time taking the drug combination daily, but when they analyzed the people who had measurable drug levels in their bloodstream, it was clear that PrEP could be more than 90 percent effective in preventing HIV infection. Unfortunately, most people in real life would rather not take daily medication since it is an added expense and risks more side effects. Therefore, a second form of PrEP, on-demand PrEP, was proposed. On-demand PrEP means taking the PrEP pills a day before the exposure, on the day itself, and the day after, rather than daily. This was shown to be about as effective as daily PrEP, and the WHO has endorsed both methods as a way of preventing HIV. However, despite this strong recommendation, the uptake of PrEP has remained suboptimal.

To address suboptimal PrEP uptake, scientists began working on injectable, long-acting formulations. Prior to the availability of lenacapavir, the most promising long-acting PrEP formulation was a drug called cabotegravir. Cabotegravir is an INSTI, just like dolutegravir, and is used as a single agent and can last up to 90 days. The reason cabotegravir could be used as a single agent, unlike oral PrEP, is that the INSTIs as a class are much more durable than NRTIs to the development of resistance. INSTI resistance, however, can still develop with time and suboptimal use. While injectable cabotegravir was seen as a significant step forward in making PrEP convenient and more effective, it still wasn’t ideal due to the potential for resistance. In fact, the latest US Department of Health and Human Services (DHHS) HIV guidelines recommend specific testing for INSTI resistance among people who have breakthrough infections after using cabotegravir PrEP because of this risk. In the Philippines, only our laboratory at the National Institutes of Health is doing routine INSTI testing, and it isn’t cheap.

Enter lenacapavir, which addresses all of the shortcomings of previous PrEP formulations. Unlike daily or on-demand PrEP, adherence to lenacapavir is not an issue since it only needs to be given twice a year, once every 26 weeks. Since lenacapavir is a completely different class of HIV drug, there is no risk of cross-resistance with drugs being used to treat people with HIV, unlike with tenofovir, emtricitabine, or long-acting cabotegravir. The last barrier is access due to cost. New drugs are usually very expensive since the manufacturer has a limited amount of time to recover the cost of research and development until the patent expires.

Thanks to the hard work of activists and advocates who campaigned for the drug companies to drastically lower antiretroviral prices for poorer countries, HIV drugs have been among the most accessible in resource-limited settings. For instance, while the WHO-recommended regimen of dolutegravir, lamivudine, and tenofovir costs over $700 per month in developed countries, it has been licensed to low and lower-middle-income countries for around $50 a year. This also applies to oral PrEP, where the cost of one month of tenofovir plus emtricitabine is around $25 per month, compared to many times that in richer countries.

Gilead, the maker of lenacapavir, has proactively engaged different stakeholders about making lenacapavir available for high-priority, low-resource settings with increasing HIV incidence, like the Philippines. We asked them to price lenacapavir at least at par with the annual cost of daily PrEP. While there has been no official statement on the final price, some reports suggest that lenacapavir could be produced for as little as $80 a year, or about $40 per injection.

If Gilead decides to go with this pricing estimate, it will enable our government to deploy a highly effective new strategy to curb our record-high increase in new HIV cases. This strategy has to go hand in hand with increased access to community-based HIV testing and linkage to care for those who test positive. Putting all people with HIV on treatment will suppress their viral load and prevent transmission. The use of very effective PrEP for highly exposed HIV negative individuals, coupled with finding and putting all people with HIV on treatment, will drastically decrease transmission rates in the community. If we can successfully implement this approach, there is a very real possibility of not only successfully curbing our new infections but also of potentially eliminating HIV in our country within our lifetime.