Rearranging retroviral regimens for HIV

Rearranging retroviral regimens for HIV-intermittent prophylaxis with oral Truvada protects macaques from rectal SHIV Infection

García-Lerma G, Cong M, Mitchell J, Youngpairoj A, Zheng Q, Masciotra S, Martin A, Kuklenyik Z, Holder A, Lipscomb J, Pau C, Barr J, Hanson D, Otten R, Paxton L, Folks T and Heneine W. Sci Transl Med. 2010. 2: 14ra4.

Antiretroviral drugs have transformed the lives of HIV-infected people by preventing progression to full-blown AIDS. These drugs also dramatically reduce HIV transmission from mothers to infants during pregnancy and breastfeeding, and work in monkeys suggests that daily doses can also reduce transmission from unprotected sex. But prophylactic treatment with antiretroviral drugs is costly and impractical—even if confined to a high-risk population. García-Lerma et al. now show that in monkeys a more realistic medication schedule may work just as well as daily doses. To simulate how people are likely to be infected with HIV, the authors exposed macaque monkeys rectally to 14 weekly doses of simian-human immunodeficiency virus (SHIV) engineered to resemble the human virus. Control macaques treated in this way became infected within the first five exposures to SHIV. Researchers then assessed whether oral, human-equivalent doses of antiretroviral agents could prevent infection in monkeys. The best protection—equivalent to that provided by daily antivirals—occurred when the drug Truvada was given 1, 3, or 7 days before virus exposure followed by a second dose 2 hours after exposure. Less effective, but still better than no treatment at all, was a schedule in which the drug was given 2 hours before or after exposure and then again 24 hours later. Drugs given only 24 or 48 hours after exposure did not safeguard against infection. The results of this study are preliminary, largely because each of the groups had only six macaques, but they are nevertheless promising. If ongoing clinical trials in healthy people show that daily antiretroviral therapy can diminish the chances of acquiring HIV after exposure, a reasonable next step would be to evaluate more practical, less costly drug schedules in humans. For example, a weekly dose followed by a second dose after a possible exposure could prove both effective and tractable. It will also be important to evaluate treatments based solely on exposure, as these would not require ongoing prophylactic drug treatment and would minimize any drug toxicity. If one or more of these therapeutic regimens is successful, antiretroviral drugs may expand the transformation they have already engendered by preventing many more new infections as well as controlling existing ones.

: Despite several limitations of these non-human primate trials, they nonetheless provide food for thought and for human trial design. All the current oral Pre-Exposure Prophylaxis (PrEP) phase IIb and III trials in humans are studying daily administration of either tenofovir (TDF) or a combination of TDF and emtricitabine (FTC). Good complements to each other, FTC appears to have more rapid absorption and tissue distribution while TDF has a long intracellular persistence. Based on these findings of good protection from rectal challenge in macaques given intermittent oral TDF/FTC treatment (varying times before but topping up 2 hours after exposure in active arms), the results of human trials of intermittent PrEP are needed. Intermittent PrEP regimens would likely be easier to adhere to, while decreasing drug costs and probably reducing drug toxicities. Those animals that did become infected appeared to have lower peak levels of virus in the blood. If lower viral set points are confirmed, this may reduce CD4+ cell count depletion and slow disease progression but may also mean less onward transmission. There are many questions to be answered about PrEP before it can be considered as a candidate to join the biomedical component of combination prevention (biomedical, behavioural, structural) strategies. The first question is whether daily administration will prove effective in the current trials of men who have sex with men, people who inject drugs, and heterosexuals at increased risk. If it does, there will be heightened interest in rapidly testing the safety and efficacy of intermittent PrEP in humans to inform policy and programme design decision-making.