Nonnucleoside Reverse Transcriptase Inhibitor Resistance and the Role of the Second-Generation Agents

Abstract

NNRTI resistance is an increasing problem that may impair the chances for therapeutic success in HIV-infected patients. Novel agents such as etravirine and rilpivirine provide new, sensitive options for patients and significantly improve the rate of virologic suppression when appropriately applied.

Prevalence and Outcomes of Recycling NNRTIs Despite Documented NNRTI Resistance in HIV-Infected Children and Youth

“…It appears that providers were not as concerned about the presence of non-K103N mutations or chose to recycle because the absence of K103N would increase the likelihood of success suppressing viral replication with efavirenz or nevirapine. Non-K103N mutations have a greater impact on the newer generation NNRTIs (i.e., etravirine and rilpivirine), 7 and further accumulation of these mutations resulting from reintroduction of efavirenz or nevirapine would likely compromise the future utility of the newer agents in these patients. Even though some individuals recycling NNRTIs achieved virologic suppression, particularly those who had lower levels of viremia on a prior regimen before recycling of the NNRTI-based regimen, they were equally as likely to not achieve virologic suppression.…”

“…Residual viral suppression by NRTIs even in the setting of documented NRTI resistance has been reported; 17 this phenomenon is less likely to occur with NNRTIs in the setting of NNRTI resistance. 7 The presence of NNRTI-R predicts NNRTI failure. 18 Using protease inhibitors in participants with documented NNRTI-R may be superior in terms of achieving virologic suppression and improved CD4 cell count outcomes.…”

“…Cross-resistance among the NNRTIs nevirapine and efavirenz limits the use of other agents in the class with the exception of the newer generation of NNRTIs currently consisting of etravirine and rilpivirine. 7 Both of these agents were specifically designed to be effective despite the presence of the K103N mutation; however, non-K103N mutations such as G190A/S, Y181C/I, V179D/F, L100I, K101E/P, and V106I can still compromise their efficacy.…”

Antiretroviral drug toxicity in relation to pharmacokinetics, metabolic profile and pharmacogenetics

“…ETV is highly bound to plasma proteins (99.9%), principally to albumin and a-1-acid glycoprotein (AAG) [69]. ETV undergoes hepatic metabolism by CYP3A4, CYP2C9 and CYP2C19 and is a CYP3A4 inducer and an inhibitor of CYP2C9 and CYP2C19 and P-gp [71]. Methylhydroxylation of the dimethylbenzonitrile to form mono-or dihydroxy-ETV accounts for the majority of ETV metabolism whereas hydroxylation of the dimethylbenzonitrile without the methyl groups plays only a minor role.…”

Targeting HIV: Past, Present and Future

“…(26), both have a higher genetic barrier to resistance than their first generation counterparts. There is cross-resistance between etravirine and rilpivirine [62,63]. They may be used sequentially in patients with acquired NNRTI resistance mutations such as K103N, but may lead to additional NNRTI mutations and a new RAM, E138R [64].…”