Lenacapavir-associated drug resistance: implications for scaling up long-acting HIV pre-exposure prophylaxis

Although drug resistance could emerge if lenacapavir is initiated during undiagnosed acute infection or if infection occurs during the drug's pharmacokinetic tail, these cases will not compromise the effectiveness of WHO-recommended therapies, as there is no cross-resistance between lenacapavir and other licensed antiretroviral drugs. Lenacapavir pre-exposure prophylaxis (PrEP) is also unlikely to drive population-level lenacapavir resistance given the rarity of breakthrough infections and the reduced replication capacity of most lenacapavir-resistant variants, which most likely reduces their transmission potential. Conversely, the risk of acquiring lenacapavir-resistant HIV-1 while receiving lenacapavir PrEP is likely to remain extremely low, as lenacapavir-associated drug-resistance mutations are rare among individuals without previous lenacapavir exposure, and widespread use of lenacapavir-based regimens remains years away. Nonetheless, as the number of lenacapavir PrEP programmes increase, surveillance for emerging lenacapavir resistance should also be implemented.