The US Centers for Disease Control (CDC) has found that oral pre-exposure prophylaxis (PrEP) using a combined tenofovir/FTC (Truvada) pill is still effective against HIV with the M184V resistance mutation, which confers complete resistance to FTC (emtricitabine, Emtriva) and to its sister drug 3TC (lamivudine, Epivir).
In animal studies, five monkeys given oral Truvada PrEP, and then challenged vaginally with a form of HIV that had the M184V mutation and which was adapted to infect monkeys (SHIV), remained uninfected after 14 once-a-week exposures to the virus. In contrast five animals not given PrEP and challenged with SHIV with M184V were infected.
One out of five animals challenged with a non-resistant, wild-type virus was infected after 14 challenges when the same PrEP regimen was used.
The PrEP regimen used was intermittent: a once-a-week dose of Truvada was given three days before the challenge with SHIV, and then another dose two hours afterwards, in line with previous animal data, which found that this was the most effective regimen.
CDC researcher Gerardo Garcia-Lerma said that the potential of PrEP to create resistance, and whether it would fail with resistant virus, were crucial research questions. This particularly applies to the M184V mutation, which is one of the most common HIV resistance mutations and was found to arise in two subjects in the iPrEx PrEP trial who took Truvada while, unbeknownst to them, they had acute HIV infection.
There is thus concern about what would happen if Truvada PrEP gave rise to an increase in the proportion of people with HIV with the M184V resistance mutation.
Garcia-Lerma said that the CDC study showed that “exposure to drug-resistant viruses does not necessarily associate with failure of PrEP.”
Fitness assays showed that the strain of SHIV with M184V used in the study replicated 30 times less efficiently and was four times less infectious than the non-resistant virus used (because of this, the dose of PrEP used against the M184V-mutant virus was lower). Furthermore the virus, while completely resistant to FTC, was two to four times more sensitive to tenofovir than wild-type, non-resistant virus.
In other PrEP trials in animals, Truvada was seen to be more effective than tenofovir alone when used as oral PrEP, and animals with M184V are effectively only taking tenofovir as an active drug. Garcia-Lerma speculated that the hypersensitivity to tenofovir seen was compensating for the missing antiviral effect of FTC, which was why Truvada was just as effective in animals with M184V virus.
He also, when questioned, speculated that keeping up the dose of FTC, even if it had no antiviral effect, could serve to maintain the M184V mutation and this useful tenofovir hypersensitivity. However he agreed that repeating the study using tenofovir alone would be necessary to prove this hypothesis.
Abstract and webcast
You can view the abstracts from this research on the official conference website:
Abstract 31: www.retroconference.org/2011/Abstracts/40022.htm
You can also watch webcasts of presentations made at the conference.
The webcast from the conference session HIV Prevention: HSV2, Topical and Oral PrEP, and Circumcision, includes the speaker Gerardo Garcia-Lema.
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Cong M-E et al. (presenter Garcia-Lerma G) Complete protection against rectal transmission of an emtricitabine-resistant SHIV162p3-M184V mutant by intermittent prophylaxis with Truvada. 18th Conference on Retroviruses and Opportunistic Infections, Boston, abstract 31, 2011.