Practical Experience with Analysis and Design of Repeat Low-Dose SHIVSF162P3 Exposure Studies in Female Pigtail Macaques with Varying Susceptibility during Menstrual Cycling
Published Date:Aug 6 2015
Source:AIDS Res Hum Retroviruses. 31(11):1166-1169.
Anti-Infective Agents, Local
Disease Transmission, Infectious
Repeat Low Dose Model
Simian Acquired Immunodeficiency Syndrome
Simian Immunodeficiency Virus
Pubmed Central ID:PMC4636932
Funding:CC999999/Intramural CDC HHS/United States
Y1-A1-068102/PHS HHS/United States
Vaginal SHIVSF162P3 acquisition in pigtail macaques (Macaca nemestrina) is dependent on time point during the menstrual cycle. Susceptibility is higher around menstruation and lower at ovulation in mid cycle. This complicates design of repeat low-dose (RLD) SHIV exposure studies because virus challenges given during low susceptibility periods have lower chances to infect. To account for fluctuating susceptibility, we analyzed menstrual cycles rather than exposures until infection following virus challenges.
We first re-analyzed infection data of 41 macaques receiving placebo or no treatment during once (n=18) or twice (n=23) weekly virus exposures. The same number of cycles was required for infection with either challenge frequency, while it took a median 4 or 6 challenges for once or twice weekly exposures, respectively. More virus challenges to infection likely reflect frequent unsuccessful exposures in frequently exposed animals. When re-analyzing two previously reported biomedical HIV intervention studies, we found 1% Tenofovir gel was 74 or 86 % efficacious based on cycles or exposures (p = 0.019 or = 0.003, respectively, Fisher’s exact test), while 1% Raltegravir gel was 84 or 89 % efficacious, respectively (p = 0.047 or = 0.031).
Evaluating number of menstrual cycles rather than exposures until infection can account for varying susceptibility during the menstrual cycle. Our observations have implications for future study designs such as planning frequency of virus exposures. Menstrual cycle analysis may also avoid potential over-estimation of efficacy against vaginal challenges during low susceptibility periods in the cycle that are unlikely to cause infection.
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