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The Journey of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) from Lab to Clinic.

ABSTRACT: Human immunodeficiency virus (HIV) infection is now pandemic. Targeting HIV-1 reverse transcriptase (HIV-1 RT) has been considered as one of the most successful targets for the development of anti-HIV treatment. Among the HIV-1 RT inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a definitive place due to their unique antiviral potency, high specificity, and low toxicity in antiretroviral combination therapies used to treat HIV. Until now, >50 structurally diverse classes of compounds have been reported as NNRTIs. Among them, six NNRTIs were approved for HIV-1 treatment, namely, nevirapine (NVP), delavirdine (DLV), efavirenz (EFV), etravirine (ETR), rilpivirine (RPV), and doravirine (DOR). In this perspective, we focus on the six NNRTIs and lessons learned from their journey through development to clinical studies. It demonstrates the obligatory need of understanding the physicochemical and biological principles (lead optimization), resistance mutations, synthesis, and clinical requirements for drugs.

SUBMITTER: Namasivayam V

PROVIDER: S-EPMC7049092 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Project description:IntroductionThe rise of HIV-1 drug resistance to non-nucleoside reverse-transcriptase inhibitors (NNRTI) threatens antiretroviral therapy's long-term success (ART). NNRTIs will remain an essential drug for the management of HIV-1 due to safety concerns associated with integrase inhibitors. We fitted a dynamic transmission model to historical data from 2000 to 2018 in nine countries of southern Africa to understand the mechanisms that have shaped the HIV-1 epidemic and the rise of pretreatment NNRTI resistance.MethodsWe included data on HIV-1 prevalence, ART coverage, HIV-related mortality, and survey data on pretreatment NNRTI resistance from nine southern Africa countries from a systematic review, UNAIDS and World Bank. Using a Bayesian hierarchical framework, we developed a dynamic transmission model linking data on the HIV-1 epidemic to survey data on NNRTI drug resistance in each country. We estimated the proportion of resistance attributable to unregulated, off-programme use of ART. We examined each national ART programme's vulnerability to NNRTI resistance by defining a fragility index: the ratio of the rate of NNRTI resistance emergence during first-line ART over the rate of switching to second-line ART. We explored associations between fragility and characteristics of the health system of each country.ResultsThe model reliably described the dynamics of the HIV-1 epidemic and NNRTI resistance in each country. Predicted levels of resistance in 2018 ranged between 3.3% (95% credible interval 1.9-7.1) in Mozambique and 25.3% (17.9-33.8) in Eswatini. The proportion of pretreatment NNRTI resistance attributable to unregulated antiretroviral use ranged from 6% (2-14) in Eswatini to 64% (26-85) in Mozambique. The fragility index was low in Botswana (0.01; 0.0-0.11) but high in Namibia (0.48; 0.16-10.17), Eswatini (0.64; 0.23-11.8) and South Africa (1.21; 0.83-9.84). The combination of high fragility of ART programmes and high ART coverage levels was associated with a sharp increase in pretreatment NNRTI resistance.ConclusionsThis comparison of nine countries shows that pretreatment NNRTI resistance can be controlled despite high ART coverage levels. This was the case in Botswana, Mozambique, and Zambia, most likely because of better HIV care delivery, including rapid switching to second-line ART of patients failing first-line ART.

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The Journey of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) from Lab to Clinic.

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