Abstract
When microbicides used for HIV prevention contain antiretroviral drugs, there is concern for the potential emergence of drug-resistant HIV following use in infected individuals who are either unaware of their HIV infection status or who are aware but still choose to use the microbicide. Resistant virus could ultimately impact their responsiveness to treatment and/or result in subsequent transmission of drug-resistant virus. We tested whether drug resistance mutations (DRMs) would emerge in macaques infected with simian immunodeficiency virus expressing HIV reverse transcriptase (SHIV-RT) after sustained exposure to the potent non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 delivered via an intravaginal ring (IVR). We first treated 4 SHIV-RT-infected animals with daily intramuscular injections of MIV-150 over two 21 day (d) intervals separated by a 7 d drug hiatus. In all 4 animals, NNRTI DRMs (single and combinations) were detected within 14 d and expanded in proportion and diversity with time. Knowing that we could detect in vivo emergence of NNRTI DRMs in response to MIV-150, we then tested whether a high-dose MIV-150 IVR (loaded with >10 times the amount being used in a combination microbicide IVR in development) would select for resistance in 6 infected animals, modeling use of this prevention method by an HIV-infected woman. We previously demonstrated that this MIV-150 IVR provides significant protection against vaginal SHIV-RT challenge. Wearing the MIV-150 IVR for 56 d led to only 2 single DRMs in 2 of 6 animals (430 RT sequences analyzed total, 0.46%) from plasma and lymph nodes despite MIV-150 persisting in the plasma, vaginal fluids, and genital tissues. Only wild type virus sequences were detected in the genital tissues. These findings indicate a low probability for the emergence of DRMs after topical MIV-150 exposure and support the advancement of MIV-150-containing microbicides.
Highlights
Development of viral resistance to antiretroviral (ARV) therapy for HIV has been a concern since even before the first anti-HIV drugs were approved
MIV-150 is a potent nucleoside reverse transcriptase inhibitor (NNRTI) that we are developing as a combination microbicide containing zinc acetate (ZA) and CG (MZC) [14,15,17] (Kizima, et al, In revision)
The MZC combination microbicide has been shown to be highly effective against vaginal and rectal simian immunodeficiency virus expressing HIV reverse transcriptase (SHIV-RT) infection of macaques [14,15,17] (Kizima et al, In revision) and HSV-2 and HPV vaginal and rectal infections of mice (Kizima et al, In revision). This positions MZC as a promising combination microbicide to test in humans, and the MZC gel is advancing to clinical testing in 2014
Summary
Development of viral resistance to antiretroviral (ARV) therapy for HIV has been a concern since even before the first anti-HIV drugs were approved. In addition to posing a significant clinical challenge, in resourcelimited settings [4,5], transmission of drug-resistant virus could complicate control of the HIV pandemic [2,6,7,8,9]. Prophylactic strategies such as Pre-Exposure Prophylaxis (PrEP) and microbicides, which are targeted toward HIV-uninfected individuals, could potentially be used by infected persons, some of whom are unaware of their HIV status [10], thereby enhancing the selection and transmission of drug-resistant HIV [11]. In conjunction with providing female controlled HIV prevention options, IVRs may afford more consistent use and improved protection over methods requiring pericoital application [18,19]
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