HIV-1 Drug Resistance in the iPrEx Preexposure Prophylaxis Trial
| Autor: | Susan Buchbinder, Timothy T. Schmidt, Mohamed Abdel-Mohsen, Joseph K. Wong, Peilin Li, Robert M. Grant, L. Gordon Bentley, Juan V. Guanira, Jacqueline Javier, Peter L. Anderson, Megha Mehrotra, Robert Atchison, Vanessa McMahan, Christopher Eden, David V. Glidden, Teri Liegler |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Male
medicine.medical_specialty Nevirapine Genotype AS-PCR Anti-HIV Agents preexposure prophylaxis Population Organophosphonates HIV Infections Context (language use) Emtricitabine Deoxycytidine Transgender Persons minor variant Major Articles and Brief Reports Pre-exposure prophylaxis Internal medicine Drug Resistance Viral medicine Humans Immunology and Allergy Homosexuality Male Tenofovir education education.field_of_study drug resistance business.industry Adenine 454 deep sequencing Viral Load Resistance mutation Virology PrEP 3. Good health Infectious Diseases Mutation HIV-1 FTC/TDF HIV/AIDS RNA Viral Female business Viral load HIV drug resistance medicine.drug |
| Zdroj: | The Journal of Infectious Diseases |
| ISSN: | 1537-6613 0022-1899 |
| DOI: | 10.1093/infdis/jiu233 |
| Popis: | Antiretroviral drugs have demonstrated efficacy when used as preexposure prophylaxis (PrEP) for preventing human immunodeficiency virus (HIV) acquisition through sexual or intravenous exposure in uninfected men, women, and transgendered women [1–5]. A consistent finding among reported randomized, placebo-controlled trials testing oral and topical PrEP strategies is that efficacy is associated with drug exposure [6, 7]. In the iPrEx study, where the safety and efficacy of daily oral dosing of combination nucleoside/nucleotide reverse-transcriptase inhibitors (nRTI) emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) was tested in men and transgender women who have sex with men, a 44% reduction in infection incidence was seen in participants randomized to FTC/TDF compared with placebo [3], and a 99% reduction among those with blood FTC/TDF levels commensurate with daily dosing [8]. In contrast, in the Fem-PrEP and VOICE trials where product adherence was low, the use of oral TDF, TDF/FTC, or tenofovir (TFV) 1% vaginal gel did not significantly reduce HIV infections [9]. Decades of experience with therapeutic use of antiretroviral drugs have accumulated an extensive understanding of the causes and consequences of HIV drug resistance (DR), which emerges with suboptimal antiretroviral therapy (ART), including the dual nRTI regimens such as that recommended for PrEP [10–12]. If HIV infection occurred during suboptimal PrEP use, DR could be selected early in infection [13, 14]. In rhesus macaque studies investigating oral FTC/TDF PrEP, breakthrough infections following rectal exposure showed FTC-selected DR mutations M184V/I [15]. In people with unrecognized infection, antiretroviral use intended as PrEP is functionally postexposure prophylaxis (PEP), where DR can occur in breakthrough systemic infection [2–4, 16, 17]. Additionally, initial efforts administering single-dose nevirapine to mothers at birth for prevention of mother-to-child-transmission (MTCT) resulted in rapid emergence of drug-selected mutations in infected infants measured by population sequencing [18–22]. Ultrasensitive diagnostic assays revealed a substantially higher frequency of mothers and infants with minor variant DR [23–26]. These findings demonstrate that the use of antiretrovirals to prevent infection can select for DR when breakthrough infections occur, and warrant thorough and sensitive monitoring in PrEP studies. We report the results from comprehensive viral DR testing and drug exposure measurements in iPrEx seroconverters in a clinical trial setting. Clinical genotype and phenotype assays were performed to detect resistance in viral populations. We quantified minor variant FTC/TDF-selected mutations by deep sequencing and a novel allele-specific polymerase chain reaction (AS-PCR)–based assay that controls for target sequence polymorphisms and yields improved performance when testing isolates from diverse geographic locations [27–29]. The nature and frequency of DR mutations are presented in the context of concurrent systemic FTC/TDF exposure. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|