Nevirapine resistance

Cheeseman, K. Barringer, D. Pauletti, C. K. Shih, M. Myers, and J. Griffin, Nevirapine resistance mutations of immunodeficiency virus type 1 selected during therapy, J. Virol. 68 1660 (1994). 

Nevirapine is a noncompetitive inhibitor that binds to a site on the HIV-1 reverse transcriptase that is distant from the active site, inducing a conformational change that disrupts catalytic activity. As the target site is HIV-1-specific and is not essential for the enzyme, resistance can develop rapidly. A single mutation at either codon 103 or codon 181 of reverse transcriptase decreases susceptibility more than a hundredfold. Nevirapine resistance is also associated... 

Havlir DV, Eastman S, Gamst A, Richman DD (1996) Nevirapine-resistant human immunodeficiency virus kinetics of replication and estimated prevalence in untreated patients. J Virol... 

Lehman DA, Wamalwa DC, McCoy CO, Matsen FA, Langat A, Chohan BH, et al. Low-frequency nevirapine resistance at multiple sites may predict treatment failure in infants on nevirapine-based treatment. J Acquir Immune Defic Syndr 2012 60(3) 225-33. 

Eshleman SH, Hoover DR, Chen S, Hudelson SE, Guay LA, Mwatha A, Fiscus SA, Mmiro F, Musoke P, Jackson JB et al, (2005a) Nevirapine (NVP) resistance in women with HIV-1 sub-type C, compared with subtypes A and D, after the administration of single-dose NVP. J Infect Dis 192 30-36... 

Lee EJ, Kantor R, Zijenah L, Sheldon W, Emel L, Mateta P, Johnston E, Wells J, Shetty AK, Coovadia H et al. (2005) Breast-mUk shedding of drug-resistant HIV-1 subtype C in women exposed to single-dose nevirapine. J Infect Dis 192 1260-1264... 

Lecossier D, Shulman NS, Morand-Joubert L, Shafer RW, Joly V, Zolopa AR, Clavel F, Hance AJ (2005) Detection of minority populations of HlV-1 expressing the K103N resistance mutation in patients faihng nevirapine. J Acquir Immune Defic Syndr 38 37-42... 

Rifampin Daily for 4 months For persons who are contacts of patients with isoniazid-resistant rifampin susceptible TB. In HIV-infected patients, protease inhibitors or NNRTIs generally should not be administered concurrently with rifampin rifabutin can be used as an alternative for patients treated with indinavir, nelfinavir, amprenivir, ritonavir, orefavirenz, and possibly with nevirapine or soft-gel saquinavir5 B (II) B (III)... 

HIV-1 resistance to NNRTIs rapidly arises following passage of the virus in cell culture in the presence of the compounds. The 181 Tyr — Cys mutation is most commonly seen, and it leads to resistance, or at least to reduced sensitivity, to most of the NNRTIs (i.e., TIBO, HEPT, nevirapine, pyridinone, BHAP, TSAO, a-APA) [78-84], The 188 Tyr —> His mutation is associated with resistance to TIBO [85], but not nevirapine [82], The 103 Lys —> Asn mutation is associated mainly with resistance to TIBO and pyridinone [78,85], The 100 Leu —> lie mutation is associated mainly with resistance to TIBO [85,86]. The 106 Val —> Ala mutation mainly leads to resistance to nevirapine and HEPT [83,84,87]. The 138 Glu — Lys mutation is responsible for resistance to TSAO [88,89]. The 190 Gly — Glu mutation accounts for resistance to quinoxaline [68], while also leading to a dramatic reduction in RT activity [90] and the 236 Pro — Leu mutation is responsible for resistance to BHAP [91]. 

The 181 Tyr — Cys mutation, which is responsible for resistance to most NNRTIs, has been found to suppress the 215 mutation (Thr — Phe/ Tyr), which is responsible for resistance to AZT [94], and, vice versa, the 181 Tyr — Cys mutation can be suppressed by AZT, which thus means that the mutations at positions 181 and 215 counteract each other. Yet other mutations have proved to counteract each other 236 Pro — Leu vs 138 Glu —> Lys, and, as mentioned, 215 Thr > Phe/Tyr vs 184 Met > Val, and 215 Thr — Phe/Tyr vs 74 Leu > Val [47]. Based on the resistance mutations that counteract each other, combinations of different drugs could be envisaged—namely, combinations of AZT with either TIBO, a-APA, HEPT, nevirapine, or pyridinone—and these two drug combinations could be extended to three- or four-drug combinations by the addition of another ddN analogue (such as 3TC) and/or another NNRTI (such as BHAP or TSAO). 

Resistant virus Resistant virus emerges rapidly and uniformly when nevirapine is administered as monotherapy. Therefore, always administer nevirapine in... 

This group includes nevirapine, efavirenz and delavirdine. Nevirapine was the first agent of this new class of drugs. It has convincingly been shown that combinations of AZT and ddl with nevirapine were more effective than AZT and ddl alone. It was also shown that the use of nevirapine alone rapidly induced resistance. The most frequently occurring adverse reaction to nevirapine is rash and it is advised to discontinue nevirapine in patients who develop a severe rash. 

One large randomised controlled trial demonstrates that nevirapine given to mothers as a single dose at the onset of labour and to babies as a single dose within 72 hours of birth is more effective than an intrapartum and post-partum regimen of zidovudine. However this regimen can cause NNRTI resistant virus in mother and child. 

Etravirine has in vitro activity against a wide variety of wild-type and NNRTT-resistant HIV-1, and it was approved in the USA for use in treatment-experienced patients with HIV infection in early 2008. Etravirine may be effective against strains of HIV that have developed resistance to first-generation NNRTTs, depending on the number of mutations present. Although etravirine has a higher genetic barrier to resistance than the other NNRTTs, mutations selected by etravirine usually are associated with resistance to efavirenz, nevirapine, and delavirdine. 

A single dose of nevirapine (200 mg) is effective in the prevention of transmission of HIV from mother to newborn when administered to women at the onset of labor and followed by a 2-mg/kg oral dose to the neonate within 3 days after delivery. There is no evidence of human teratogenicity. However, resistance has been documented after this single dose. 

Nevirapine is a member of the dipyridodiazepinone class of chemicals and is a nonnucleoside reverse transcriptase inhibitor that induces a conformational change in HIV-1 reverse transcriptase. Although the conformational change is at a distance from its active site, it disrupts its catalytic activity. It blocks both RNA-dependent and DNA-dependent DNA polymerase activity but does not affect the activity of the template or nucleoside triphosphate. Nevirapine does not inhibit HIV-2 reverse transcriptase or human DNA polymerases a, (3 or y. The resistance to the drug results from site-directed mutagenesis at codons 103 or 181, and also at 100, 106, 108, 188 and 190 of viral reverse transcriptase. The development of resistance to one nonnucleoside reverse transcriptase implies that HIV will also be resistant to the rest of the drugs in this class. 

After oral administration, nevirapine is rapidly absorbed with a bioavailability of 93%, and peak plasma concentrations are achieved in 4h. Food or antacids do not interfere with its absorption. It is very lipophilic, crosses the placenta and its presence has been reported in breast milk. Nevirapine is mainly metabolized by the cytochrome P-450 system (CYP3A4 and CYP2B6) to hydroxy-lated metabolites, and after metabolism, the primary route of excretion is through urine. It has an elimination half-life of 25-30 h. Nevirapine can induce its own metabolism by stimulating the cytochrome P-450 system, which results in the reduction of the half-life of subsequent doses. In combination with other antiretroviral agents, nevirapine is recommended for the treatment of HIV infection in adults and children. It should not be administered alone since resistance develops rapidly. 

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