Mathematical modeling of the HIV transmission risk during the first 24 weeks after initiation of antiretroviral therapy in naïve HIV-infected MSM

Proposal
1403

Title of Proposed Research

Lead Researcher

Juan Berenguer

Affiliation

Hospital General Universitario Gregorio Marañón

Funding Source

An Investigator Sponsored Study (ISS) has been sent to ViiV Heath Care for conducting this study

Potential Conflicts of Interest

Has received research grants from: GILEAD, MSD, BMS, VIIV Healthcare
Has received honoraria for advisory boards and talks from ABBVIE, BMS, GILEAD, MSD, JANSSEN, VIIV Healthcare,

Data Sharing Agreement Date

10 Aug 2016

Lay Summary

Scientific Rationale for Study / Scientific Study Objectives

The HIV epidemic among men who have sex with men (MSM) continues to expand in low, middle, and high-income countries. The disproportionate HIV disease burden in MSM is explained largely by the high per act and per-partner transmission probability of HIV transmission in receptive anal sex [1, 2]. Current strategies are inadequate to control HIV spread among MSM; much more vigorous prevention efforts are required, including the early initiation of antiretroviral therapy (ART) that has been shown to reduce the rates of sexual transmission of HIV-1 [3] and the adaptation and expanded use of pre-exposure prophylaxis (PrEP) to prevent the acquisition of HIV-1 infection [4].
Initiation of ART with regimens based on integrase strand transfer inhibitors (INSTI) is associated with a faster decline in HIV-RNA load than what is observed with regimens based on non-nucleoside transcriptase inhibitors (nnRTI), and protease inhibitors (PI). The clinical impact of this finding is unknown although clinical anecdotes suggest that it may it may cause a rapid decline in HIV RNA in women presenting with HIV in late pregnancy [5].
The objective of this study is to explore the impact of initiation of ART with different regimens in naïve MSM (in the setting of acute and chronic HIV-infection) on the probability of transmission of HIV by mathematical modeling.

Study Data Provided

[{ "PostingID": 1387, "Title": "VIIV-ING113086", "Description": "A randomized, double blind study of the safety and efficacy of GSK1349572 50mg once daily to raltegravir 400mg twice daily both administered with fixed-dose dual nucleoside reverse transcriptase inhibitor therapy over 96 weeks in HIV-1 infected antiretroviral therapy naive adult subjects" },{ "PostingID": 1388, "Title": "VIIV-ING114467", "Description": "A Randomized, Double-Blind Study of the Safety and Efficacy of GSK1349572 Plus Abacavir/Lamivudine Fixed-Dose Combination Therapy Administered Once Daily Compared to Atripla over 96 Weeks in HIV-1 Infected Antiretroviral Therapy Naive Adult Subjects" },{ "PostingID": 2000, "Title": "VIIV-ING114915", "Description": "A Phase IIIb, randomized, open-label study of the safety and efficacy of GSK1349572 (dolutegravir, DTG) 50 mg once daily compared to darunavir/ritonavir (DRV/r) 800 mg/100 mg once daily each administered with fixed-dose dual nucleoside reverse transcriptase inhibitor therapy over 96 weeks in HIV-1 infected antiretroviral naïve adult subjects" }]

Statistical Analysis Plan

Statistical Analysis PlanWe will develop a discrete event simulation (DES) model to estimate the probability of transmitted HIV infection during the first 24 weeks after initiation of cART in naïve HIV-infected MSM in a similar way as has been done in other clinical scenarios of HIV transmission; e.g. discordant couples (male infected - female uninfected) attempting conception [6]. The probability HIV transmission in the scenario we have defined depends on biological parameters that define HIV infectivity, sex behavior parameters, and antiretroviral therapy parameters.Biological parameters that define HIV infectivity• Estimation of per-act probability of transmission of HIV: receptive anal intercourse, insertive anal intercourse according to findings in a systematic review [7].• Estimation of HIV transmission in relation of HIV viral load [8-10]• Estimation of sexually transmitted infections (STI): number of patients with a STI per week (gonorrhea, chlamydia, syphilis); this has been well recorded for example in the Proud and Hipergay trials.• Estimation of HIV transmission in the presence of a STISex behavior parameters• Estimation of number of condomless sexual intercourse (receptive and insertive anal intercourse) during the first 24 weeks after initiation of cART in HIV-infected MSM; according to data reported in recent clinical trials and real life studies of pre-exposure prophylaxis (PrEP) to prevent the acquisition of HIV [11]. Antiretroviral therapy parameters• Regimens to be studied: EFV/FTC/TDF, RAL/FTC/TDF, DTG/ABC/3TC, DTG/FTC/TDF, DRVr/FTC/TDF, and DRVr/ABC/3TC• HIV-RNA dynamics during the first 24 weeks after treatment initiation with the aforementioned regimens will be assessed in the phase III clinical trials SINGLE [12], SPRING-2 [13], and FLAMINGO [14].Uncertainty Analysis• As the model will be based on random assignment of parameters value from their distributions, sensitivity analysis of parameters will not be necessary. To assess the uncertainty inherent to the time-to-event distributions a sensitivity analysis will be done using different time-to-event distributions. An expert on mathematical modeling with experience in the field of HIV will be included in the research team.External consultation with two experts in the field of sexual behavior in MSMReferences1. Beyrer, C., et al., Global epidemiology of HIV infection in men who have sex with men. Lancet, 2012. 380(9839): p. 367-77.2. Beyrer, C., et al., The increase in global HIV epidemics in MSM. AIDS, 2013. 27(17): p. 2665-78.3. Cohen, M.S., et al., Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med, 2011. 365(6): p. 493-505.4. Beyrer, C., Strategies to manage the HIV epidemic in gay, bisexual, and other men who have sex with men. Curr Opin Infect Dis, 2014. 27(1): p. 1-8.5. Westling, K., et al., Rapid decline in HIV viral load when introducing raltegravir-containing antiretroviral treatment late in pregnancy. AIDS Patient Care STDS, 2012. 26(12): p. 714-7.6. Hoffman, R.M., et al., Benefits of PrEP as an Adjunctive Method of HIV Prevention During Attempted Conception Between HIV-uninfected Women and HIV-infected Male Partners. J Infect Dis, 2015.7. Patel, P., et al., Estimating per-act HIV transmission risk: a systematic review. AIDS, 2014. 28(10): p. 1509-19.8. Hollingsworth, T.D., R.M. Anderson, and C. Fraser, HIV-1 transmission, by stage of infection. J Infect Dis, 2008. 198(5): p. 687-93.9. Fraser, C., et al., Variation in HIV-1 set-point viral load: epidemiological analysis and an evolutionary hypothesis. Proc Natl Acad Sci U S A, 2007. 104(44): p. 17441-6.10. Wilson, D.P., et al., Relation between HIV viral load and infectiousness: a model-based analysis. The Lancet, 2008. 372(9635): p. 314-320.11. McCormack, S., et al., Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. Lancet, 2015.12. Walmsley, S.L., et al., Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med, 2013. 369(19): p. 1807-18.13. Raffi, F., et al., Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. The Lancet, 2013. 381(9868): p. 735-743.14. Clotet, B., et al., Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet, 2014. 383(9936): p. 2222-31.

Publication Citation

Abstract can be found here, presented at 9th IAS Conference on HIV Science, July 2017, Paris, France:

http://www.ias2017.org/LinkClick.aspx?fileticket=m3LSDs1z4QY%3d&;tabid=577&portalid=1

see page 502, abstract # WEPEC0967:
"HIV transmission from condomless anal intercourse differs by initial ART regimen in HIV-infected MSM"