Nonnucleoside Reverse Transcriptase Inhibitors

NNRTIs differ chemically from NRTIs, but have in common a high degree of antiretroviral activity. NNRTIs bind directly to HIV reverse tran-scriptase and prevent replication of HIV in infected cells.

2.2.1. Neuiripine (Diplyidodiazepinone)

Neviripine is quite potent and has significant impact on p24, CD4 counts, and quantitative viral RNA loads. Its use as a monotherapy is contra-indicated due to the rapid development of resistance. Resistance to nev-iripine is characterized by a substitution of cystine for tyrosine at position 181. Neviripine was studied simultaneously in children and adults and is safe, well tolerated, and now approved.27 The major side effect is the development of a rash which can be associated with fever and hepatocellular injury, which, in some circumstances, requires discontinuance of the medication.

Efavirenz is a NNRTI available as capsule (50, 100, 200 mg) for oral administration. Its activity against HIV is mediated predominantly by non-competitive inhibition of HIV-1 reverse transcriptase. Efavirenz has a halflife of52-76h after a single dose; therefore it can be given once daily. Thus, it is an attractive medication for adolescent use. One or more reverse transcriptase (RT) mutations at amino acid positions 100,101,103,108,190 and 225, especially the 103 lysine-to-asparagine mutations, results in a loss to susceptibility to efavirenz. Rapid emergence of HIV-1 strains that are cross-resistant to NNRTIs has been observed. The only available data regarding safety, dosing, and virologic and immunological efficacy of efavirenz in children are from an open label study (PACTG 382) of efavirenz combined with nelfinavir and NRTIs in 57 pediatric patients, some as young as 3 years of age. In a preliminary intent-to-treat analysis, after 20 weeks of therapy, 65% of children had plasma HIV RNA levels <400 copies/ml, and 52% had HIV RNA levels <50 copies/ml.2829 However, there are currently no pharmacokinetic data available on the appropriate dosage of efavirenz in children under age 3 years, and although a liquid preparation is currently under study, only a capsular formulation is currently available. A skin rash can develop with efavirenz similar to that seen with neviripine. Prophylaxis with appropriate antihistamine prior to initiation of therapy should be considered. Changing trimethoprim-sulfamethoxazole to dapsone when possible for Pneumocystis carinii pneumonia (PCP) prophylaxis may be considered. Other toxicities include hepatocellular enzyme elevation and increases in serum cholesterol.


One other NNRTI, delavirdine, is approved for adults, but there is little experience in children.

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