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COMMENTARY

Future of nonnucleoside reverse

transcriptase inhibitors COMMENTARY

Nicolas Sluis-Cremera,1

The nonnucleoside (RT) inhibi- reduce clinical efficacy. Furthermore, nearly all of the tors (NNRTIs) are small molecules that bind to HIV-1 resistance mutations are located within or adjacent to RT at a site distinct from the DNA polymerase active the NNRTI-binding pocket, and there is little evidence site of the and block retroviral reverse transcrip- to suggest that any one mutation confers resistance to tion via an allosteric mechanism of action (1). Nevira- only a single agent. As such, there is a high level of pine (NVP) was the first NNRTI approved in 1996 by cross-resistance within the NNRTI class (8). Transmitted the US Food and Administration for the treatment NNRTI resistance is also becoming a major issue (9), of HIV-1 , followed by in 1997, particularly in low- and middle-income countries (EFV) in 1998, (ETV) in 2008, and (LMIC), and could significantly impact both treatment (RPV) in 2011. For almost 20 y NNRTIs served and prevention strategies. Furthermore, in 2015, the US as the cornerstone of combination antiretroviral Department of Health and Human Services down- (cART). Indeed, most first-line cART included one graded Atripla (EFV + fumarate and NNRTI (typically NVP, EFV, or RPV) in combination with ), a widely used first-line cART regimen, two / RT inhibitors. Just last month, from “recommended” to “alternative,” and it is likely RPV and the inhibitor were ap- that its use will also be phased out in other countries, proved as the first once-daily, single-pill, two-drug regimen including LMIC, in the next 5–10 y. Where does this for the maintenance treatment of virologically suppressed leave the NNRTI class? Is it possible to develop a new HIV-1 infection. ETV can be included in salvage cART for generation of NNRTIs, with improved antiviral activity the treatment of HIV-1–infected ART-experienced indi- and resistance profile, that rekindles the enthusiasm viduals, including those with prior NNRTI exposure. for their use in treatment and prevention strategies? NNRTIs have also been used to prevent HIV-1 infection. NVP has been used to prevent mother-to-child trans- A New Class of Potent NNRTIs mission (2), the MTN-020/ASPIRE and RING trials dem- In PNAS, Kudalkar et al. (10) describe the activity, onstrated that a vaginal ring containing the NNRTI both in vitro and in a humanized (Hu-PBL) mouse model dapivirine can prevent HIV-1 infection in women (3, of HIV-1 infection, of a new class of very potent catechol 4), and a completed phase II , HPTN 076, diether-based NNRTIs. The lead compound (compound I) recently assessed the safety and acceptability of a long- exhibited robust antiviral activity in HIV-1–infected T cells

acting formulation of RPV for preexposure prophylaxis (EC50 ∼2 nM), demonstrated synergistic antiviral activity (PrEP) (5). In the development pipeline, with antiretrovirals from other drug classes, and was (MK-1439) is in phase III clinical trials for the treatment shown in a prior study to have remarkable in vivo safety of HIV-1 infection (6), while the urea-PETT derivative and pharmacokinetic properties (11). In HIV-1– MIV-150, formulated as microbicidal gel, is in a phase I infected humanized mice compound I potently sup- study to evaluate safety, , pharmacody- pressed plasma viral loads and prevented CD4+ T cell namics, and acceptability (7). loss. Importantly, the authors also demonstrated that compound I was amenable to formulation in poly Limitations of Approved NNRTIs (lactide-coglycolide) nanoparticles which slowly released Despite the success of NNRTIs in both the treatment the inhibitor over a 3-wk time period and provided sus- and prevention of HIV-1, this antiviral has tained antiviral activity in the HIV-1–infected Hu-PBL reached a critical juncture, with an unclear future. All mice. Collectively, these studies highlight that com- NNRTIs bind to the same pocket in HIV-1 RT, and the pound I could be considered a promising late-stage genetic barrier to NNRTI resistance is low. Typically, preclinical candidate and tantalizingly suggest that the EFV, NVP, and RPV require only a single mutation to catechol diethers could be one future of the NNRTI class.

aDepartment of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 Author contributions: N.S.-C. wrote the paper. The author declares no conflict of interest. Published under the PNAS license. See companion article 10.1073/pnas.1717932115. 1Email: [email protected].

www.pnas.org/cgi/doi/10.1073/pnas.1720975115 PNAS Early Edition | 1of2 Downloaded by guest on September 30, 2021 In PNAS, Kudalkar et al. (10) rightly propose that compound I levels of RPV are needed in female genital tract tissue compared may be a promising NNRTI to evaluate for PrEP. However, what with tissue to prevent HIV-1 infection in vitro. additional developments and/or research are needed to fully as- Finally, and perhaps most importantly, we need to comprehensively sess its potential for use as a PrEP agent? As described above, the understand the resistance and NNRTI cross-resistance profiles of long-acting formulation of compound I was effective over a 3-wk compound I, particularly against transmitted drug-resistance vari- period. There is clearly room for improvement here, considering ants such as K101E, K103N, Y181C, and G190A, which are preva- that pharmacokinetic data from a phase I study suggest that long- lent in all geographic regions and HIV-1 subtypes (9). acting RPV administered every 8 wk could sustain plasma and tissue drug levels necessary for preventing HIV-1 infection (12). Acknowledgments The author’s research is supported by the National Institute of and We also need to understand the pharmacokinetic and pharma- Infectious Diseases and the National Institute of General Medical Sci- I codynamic activities of compound in both ectocervical and co- ences of the National Institutes of Health, Grants R01 AI081571 and R01 lonic tissues. For example, Dezzutti et al. (13) reported that higher GM068406.

1 Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA (1992) Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 256:1783–1790. 2 Guay LA, et al. (1999) Intrapartum and neonatal single-dose compared with for prevention of mother-to-child of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 354:795–802. 3 Nel A, et al.; Ring Study Team (2016) Safety and efficacy of a dapivirine vaginal ring for HIV prevention in women. N Engl J Med 375:2133–2143. 4 Baeten JM, et al.; MTN-020–ASPIRE Study Team (2016) Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. N Engl J Med 375:2121–2132. 5 Jackson A, McGowan I (2015) Long-acting rilpivirine for HIV prevention. Curr Opin HIV AIDS 10:253–257. 6 Schürmann D, et al. (2016) A randomized, double-blind, placebo-controlled, short-term monotherapy study of doravirine in treatment-naive HIV-infected individuals. AIDS 30:57–63. 7 Friedland BA, et al. (2016) First-in-human trial of MIV-150 and zinc acetate coformulated in a carrageenan gel: Safety, pharmacokinetics, acceptability, adherence, and pharmacodynamics. J Acquir Immune Defic Syndr 73:489–496. 8 Sluis-Cremer N (2014) The emerging profile of cross-resistance among the nonnucleoside HIV-1 reverse transcriptase inhibitors. 6:2960–2973. 9 Rhee SY, et al. (2015) Geographic and temporal trends in the molecular epidemiology and genetic mechanisms of transmitted HIV-1 drug resistance: An individual-patient- and sequence-level meta-analysis. PLoS Med 12:e1001810. 10 Kudalkar SN, et al. (2018) From in silico hit to long-acting late-stage preclinical candidate to combat HIV-1 infection. Proc Natl Acad Sci USA, 10.1073/ pnas.1717932115. 11 Kudalkar SN, et al. (2017) Structural and preclinical studies of computationally designed non-nucleoside reverse transcriptase inhibitors for treating HIV infection. Mol Pharmacol 91:383–391. 12 McGowan I, et al. (2016) Long-acting rilpivirine as potential pre-exposure prophylaxis for HIV-1 prevention (the MWRI-01 study): An open-label, phase 1, compartmental, pharmacokinetic and pharmacodynamic assessment. Lancet HIV 3:e569–e578. 13 Dezzutti CS, et al. (2016) Distinct pharmacodynamic activity of rilpivirine in ectocervical and colonic explant tissue. Antimicrob Agents Chemother 60:2765–2770.

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