Principles of Resistance to NNRTIs
The non-nucleoside reverse transcriptase inhibitors (NNRTIs) exert their antiviral effect blocking HIV reverse transcription, the process whereby HIV RNA is converted to HIV DNA (Figure 1). The HIV reverse transcription process is generated by the enzyme reverse transcriptase, a heterodimer consisting of a p66 and a p51 subunit; the polymerase domain is embedded in the p66 subunit (Figure 2). The NNRTIs bind to a hydrophobic pocket in the p66 subunit which is in close proximity to the active polymerase site (Figure 3). Binding of the NNRTI causes hyperextension of the reverse transcriptase thumb region, which cause a conformational change in this polymerase domain (Figure 4), thereby blocking the process of DNA polymerization, a critical step in HIV reverse transcription. The NNRTI hydrophobic binding pocket region is predominantly lined by amino acid codons 98 to 108 and 179 to 190. Resistance to NNRTIs typically occurs as a result of mutation(s) involving amino acids that line the NNRTI binding pocket, which prevents NNRTI binding (Figure 5). Although the five NNRTI drugs—efavirenz (Sustiva), nevirapine (Viramune), delavirdine (Rescriptor), etravirine (Intelence), and rilpivirine (Edurant)—bind to the same general region in the binding pocket, subtle differences exist in the interaction between the specific drug and the hydrophobic pocket, and as a result drug-specific mutations can develop. Unfortunately, the emergence of characteristic NNRTI-associated mutations can occur with rapid virologic rebound and high-level phenotypic resistance. These characteristic mutations presumably exist at low levels in all antiretroviral therapy-naive patients. When an NNRTI is used in a sub-optimal regimen, or when patients do not adequately adhere with therapy, NNRTI-resistant mutants can be selected within 1 to 4 weeks.[,]
NNRTI Resistance Profiles
Among patients who fail an efavirenz-based regimen, the K103N mutation is the most common NNRTI mutation observed; three other mutations can cause primary resistance: Y188L, G190S, and G190A. The patient in this case experienced virologic failure on an efavirenz-based regimen and had the emergence of the K103N mutation, a mutation that confers have high-level phenotypic resistance to efavirenz and nevirapine. Although early virologic failure with efavirenz characteristically involves a single mutation, such as the K103N mutation (or dual mutations), prolonged virologic failure leads to the accumulation of multiple mutations that may include L100I, V108I, Y181C/I, and P225H; the development of these multiple mutations compounds the level of NNRTI resistance.[,] Among patients with early virologic failure when taking a combination antiretroviral therapy regimen that includes nevirapine, approximately 80% develop the K103N or Y188C/L/H mutations.[,] In about 20% of patients who fail a nevirapine-based regimen, the mutations V106A/M or Y181C/I initially emerge. Patients treated with nevirapine monotherapy most commonly develop the Y181C mutation. It appears the Y181C is less likely to emerge in persons taking a thymidine analogue, namely zidovudine (Retrovir) or stavudine (Zerit).[,,] Patients who fail therapy on rilpivirine (Edurant) most often develop a mutation that involves the E138 amino acid (E138A/G/K/Q/R/V); among these, the E138K is the most often seen. A solitary E138 mutation is associated with a moderate decrease in rilpivirine activity, but when it occurs in conjunction with the M184I mutation, major reduction in rilpivirine activity occurs.[,,,,] Some patients who have virologic failure with rilpivirine will develop a K101E mutation. With early delavirdine failure, the K103N or Y181C is generally observed as the initial mutation; failure with delavirdine is really only of historic interest since this NNRTI is no longer used in clinical practice in the United States.
NNRTI Cross Resistance
The K103N mutation that occurs in patients who fail an efavirenz-based regimen confers cross-resistance to nevirapine, but not to etravirine or rilpivirine.[,,,,] Available data regarding cross-resistance and the Y181C mutation, which can occur with nevirapine failure, suggest intermediate resistance with efavirenz, etravirine, and rilpivirine.[,,,,,] For patients who fail a rilpivirine-containing regimen with an E138K mutation, there is potential low-level cross resistance to efavirenz, nevirapine, and etravirine. Thus, typically patients who fail an efavirenz-based regimen have a better chance of responded to etravirine in the future than those who fail a rilpivirine-based regimen. The use of etravirine in patients with prior NNRTI failure is complicated and several scoring systems have been generated to predict the likely efficacy of etravirine in patients with multiple NNRTI-associated mutations.[,,,]
Resistance with NNRTIs and Viral Fitness
All resistance mutations have the potential to impair viral replication. Mutations in the NNRTI class appear to have markedly less impact on viral replication than do protease inhibitor-related mutations.
Taken together, data from multiple studies suggest the K103N mutation has minimal impact on viral fitness and thus virus that contains the K103N mutation can exists as a highly resistant and highly fit virus. Accordingly, experts do not recommend continuing NNRTI medications in the setting of the K103N mutation. In patients who fail rilpivirine and have E138K and M184I mutations, the E138K mutation appears to nullify any fitness benefit that might be achieved by maintaining the M184I mutation.