Lenacapavir PrEP ‘special cases’: young people, missed doses and drug interactions

An entire session at the 13th International AIDS Society Conference on HIV Science (IAS 2025) in Kigali, Rwanda was devoted to the PURPOSE 1 and PURPOSE 2 studies of the six-monthly injectable PrEP drug lenacapavir, which reflects its importance as a step forward in HIV prevention.

Lenacapavir for PrEP has recently received positive decisions by drug regulators in the US and Europe. Its brand name will be slightly different in those two markets – Yeztugo and Yeytuo, respectively (and when used as part of HIV treatment, it’s Sunlenca). During the conference, the World Health Organization issued guidelines recommending it. The dose is two 1.5ml vials of lenacapavir, given as subcutaneous injections, every six months (plus an oral ‘loading dose’ when starting – more on this below).

Two presentations in the PURPOSE session covered young people, the oral ‘loading dose’, interactions with other drugs and situations such as being late for an injection. Another covered pregnancy and breastfeeding, and has already been reported by aidsmap.

Lenacapavir PrEP in young people

Dr Katherine Gill of the Desmond Tutu HIV Centre in Cape Town told the conference that young people aged 15-24 acquired 28% of the world’s 1.8 million new HIV infections every year, making them a key target population for injectable PrEP.

She added that “PURPOSE 1 and 2 were the most racially, ethnically, age-, gender-, and geographically diverse PrEP pivotal trials” ever conducted. Both studies enrolled people from the age of 16 up: PURPOSE 1, the study of cisgender women in Africa, had an upper age limit of 25, while PURPOSE 2, the global study of sexual and gender minorities, had no upper age limit, but did not recruit many 16-17 year olds. So for the purposes of studying lenacapavir in young people, Gill and her team compared 16 and 17 year olds in PURPOSE 1 with the rest of that study’s population, and 16-25 year olds with the rest of the study population in PURPOSE 2.

In PURPOSE 1, 2140 women received lenacapavir injections (rather than placebos), of whom just 56 (2.6%) were aged 16-17. In PURPOSE 2, 2183 people received lenacapavir, including 752 (34%) who were aged 25 or under.

There was very little difference in the efficacy of PrEP related to age. As already reported, lenacapavir was 100% efficacious in PURPOSE 1. In PURPOSE 2, there were two HIV infections in people taking lenacapavir.

However, to underline Gill’s words about the vulnerability of youth, in PURPOSE 1, 49 of the 55 new HIV infections in women taking PrEP tablets (emtricitabine plus either tenofovir alafenamide or tenofovir disoproxil) were under 25 years of age. In PURPOSE 2, there were two infections on lenacapavir and nine on oral PrEP; both of the infections on lenacapavir and three of those on oral PrEP were in people aged 25 or under.

Both the people in PURPOSE 2 who acquired HIV despite receiving lenacapavir acquired a drug resistance mutation to lenacapavir. While lenacapavir is rarely used for treatment, resistance does appear to develop quite frequently – another four people in each study were retrospectively found to have had acute HIV infection when they enrolled (so were excluded from the efficacy figures), and of these eight, five also acquired lenacapavir resistance.

There was little difference between younger and older people in drug levels or in adverse events in either study. Most (95%) of the youth cohort in both studies chose to continue lenacapavir, as opposed to switching to oral PrEP, for the open-label phase of the trials.

The loading dose and missed injections

Professor Linda-Gail Bekker, the Director of the Desmond Tutu HIV Foundation, presented some important information about the dosing of lenacapavir.

The first was regarding the ‘loading dose’. When people start lenacapavir, as well as their two injections, it is important that they also take four 300mg lenacapavir pills – two on the day of their injections and two the following day. This is because without them, lenacapavir reaches protective levels slowly, only reaching the level known as ‘IQ4’ an average of 28 days after the first injection. But adding in oral lenacapavir ensures this level is reached within two days and stays there for that first month.

Bekker emphasised that it was important not to take four pills all at once on the first day. This would overload the body’s ability to metabolise the drug and some would be excreted.

As an audience member commented, achieving protective drug levels within two days of starting lenacapavir is a great advantage over tenofovir-based oral PrEP – guidelines state that women need seven days of pills to reach protective levels in the female genital tract.

The same audience member also asked if the second-day oral dose was directly observed. Bekker said no, but hoped that the previous day’s injection and clinic visit would serve to remind people to take it. Several implementation studies are planned – if adherence to the second oral dose is low, something like a simple text-message reminder could be used.

Oral pills can also be used to cover periods where people are late for an injection appointment. If a lenacapavir injection is missed, then it is possible to maintain levels by taking just one lenacapavir pill per week until injections can be resumed. If, however, the pills are not taken, then it will be necessary to take the full loading dose of four pills along with the next injection. This led to a discussion of whether it might be possible to supply lenacapavir pills to people who thought they might have problems attending for their next injection, such as seasonal workers or travellers.

Drug interactions

Lenacapavir does have interactions with some drugs. The most significant is with rifampicin, a drug used to both treat and prevent TB. This is a strong inducer of the CYP3A enzyme, meaning that it hastens the excretion of other drugs, resulting in lower levels – so low, in the case of lenacapavir, that at first Gilead Sciences said that using the two drugs together was contraindicated.

It is possible, however, to combine lenacapavir and rifampicin in the following way. This regimen is somewhat complex, so complex that Professor Bekker had to go through it again after her presentation. The important thing to remember is that rifampicin must not be started until people have already started lenacapavir.

If somebody needs to start both drugs together:

• Day one: first lenacapavir injections (two 1.5ml vials) plus two 300mg lenacapavir pills.
• Day two: two more 300mg lenacapavir pills.
• Day three: start rifampicin. Inject two more 1.5ml vials of lenacapavir, and take two more 300mg pills.
• Day four: second dose of rifampicin. Add two more 300mg lenacapavir pills.

Rifampicin can be taken as usual after that, without further lenacapavir boosting. A course usually lasts two to four months, depending on the other drugs in the anti-TB regimen.

If starting rifampicin when someone is already on lenacapavir – for example a few weeks or months in between their planned injections – then extra doses of lenacapavir (two injections and four pills in total) should also be given before starting rifampicin. The oral loading dose does not need to be added to subsequent six-monthly lenacapavir injections.

Two other TB drugs, rifabutin and rifapentine, are sometimes used instead. These are moderate inducers of CYP3A: in this case, just one extra 1.5ml vial of lenacapavir should be injected, and can be given alongside the first rifabutin or rifapentine dose.

Lenacapavir is also a substrate of CYP3A which means it moderately inhibits the enzyme’s action. This leads to somewhat higher levels of certain drugs – an effect similar, though not as pronounced, as that caused by the boosting agents ritonavir and cobicistat. The ones most likely to be affected are the PDE5 inhibitors – the erectile dysfunction drugs sildenafil, tadalafil and vardenafil, better known by their brand names Viagra, Cialis and Levitra.

It is recommended that people start at half the normal dose of these drugs, and work up to higher doses until they achieve their desired effect. Although doses may vary, this would usually mean 25mg instead of 50mg of Viagra, 2.5mg instead of 5mg of Cialis, and 5mg instead of 10mg of Levitra.

While Bekker didn’t mention it, the recreational drug ketamine is affected in the same way: when taken by someone using lenacapavir, ketamine levels may be increased, so it’s advisable to take less than usual.

Two statins, lovastatin and simvastatin, are also affected by lenacapavir: as people take varying doses of these, the advice is to start on a low dose. The other statins have no or only theoretical interactions with lenacapavir.

Lenacapavir is now included on the Liverpool HIV Drug Interactions database and it is recommended that people taking it or their doctors consult this if worried about interactions.