Nonnucleoside Reverse Transcriptase Inhibitors

NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

The NNRTIs bind directly to HIV-1 reverse transcriptase (Figure 49–4), resulting in allosteric inhibition of RNA- and DNA-dependent DNA polymerase activity. The binding site of NNRTIs is near to but distinct from that of NRTIs. Unlike the NRTI agents, NNRTIs neither compete with nucleoside triphosphates nor require phosphorylation to be active.

Baseline genotypic testing is recommended prior to initiating NNRTI treatment because primary resistance rates range from approximately 2% to 8%. NNRTI resistance occurs rapidly with monotherapy and can result from a single mutation. The K103N and Y181C mutations confer resistance across the entire class of NNRTIs, with the exception of the newest agent, etravirine. Other mutations (eg, L100I, Y188C, G190A) may confer cross-resistance among the NNRTI class. However, there is no cross-resistance between the NNRTIs and the NRTIs; in fact, some nucleoside-resistant viruses display hypersusceptibility to NNRTIs.

As a class, NNRTI agents tend to be associated with varying levels of gastrointestinal intolerance and skin rash, the latter of which may infrequently be serious (eg, Stevens-Johnson syndrome). A further limitation to use of NNRTI agents as a component of antiretroviral therapy is their metabolism by the CYP450 system, leading to innumerable potential drug-drug interactions (Tables 49–3 and 49–4). All NNRTI agents are substrates for CYP3A4 and can act as inducers (nevirapine), inhibitors (delavirdine), or mixed inducers and inhibitors (efavirenz, etravirine). Given the large number of non-HIV medications that are also metabolized by this pathway , drug-drug interactions must be expected and looked for; dosage adjustments are frequently required and some combinations are contraindicated.

DELAVIRDINE

Delavirdine has an oral bioavailability of about 85%, but this is reduced by antacids or H ₂-blockers. It is extensively bound (∼ 98%) to plasma proteins and has correspondingly low cerebrospi-nal fluid levels. Serum half-life is approximately 6 hours.

Skin rash occurs in up to 38% of patients receiving delavirdine; it typically occurs during the first 1–3 weeks of therapy and does not preclude rechallenge. However, severe rash such as erythema multiforme and Stevens-Johnson syndrome have rarely been reported. Other possible adverse effects are headache, fatigue, nausea, diarrhea, and increased serum aminotransferase levels.

Delavirdine has been shown to be teratogenic in rats, causing ventricular septal defects and other malformations at dosages not unlike those achieved in humans. Thus, pregnancy should be avoided when taking delavirdine.

Delavirdine is extensively metabolized by the CYP3A and CYP2D6 enzymes and also inhibits CYP3A4 and 2C9. Therefore, there are numerous potential drug-drug interactions to consider (Tables 49–3 and 49–4). The concurrent use of delavirdine with fosamprenavir and rifabutin is not recom-mended because of decreased delavirdine levels. Other medica-tions likely to alter delavirdine levels include didanosine, lopinavir, nelfinavir, and ritonavir. Co-administration of dela-virdine with indinavir or saquinavir prolongs the elimination half-life of these protease inhibitors, thus allowing them to be dosed twice rather than thrice daily.

EFAVIRENZ

Efavirenz can be given once daily because of its long half-life (40–55 hours). It is moderately well absorbed following oral administration (45%). Since toxicity may increase owing to increased bioavailability after a high-fat meal, efavirenz should be taken on an empty stomach. Efavirenz is principally metabolized by CYP3A4 and CYP2B6 to inactive hydroxylated metabolites; the remainder is eliminated in the feces as unchanged drug. It is highly bound to albumin (∼ 99%), and cerebrospinal fluid levels range from 0.3% to 1.2% of plasma levels.

The principal adverse effects of efavirenz involve the central nervous system. Dizziness, drowsiness, insomnia, nightmares, and headache tend to diminish with continued therapy; dosing at bedtime may also be helpful. Psychiatric symptoms such as depres-sion, mania, and psychosis have been observed and may necessi-tate discontinuation. Skin rash has also been reported early in therapy in up to 28% of patients; the rash is usually mild to moderate in severity and typically resolves despite continuation. Rarely, rash has been severe or life-threatening. Other potential adverse reactions are nausea, vomiting, diarrhea, crystalluria, ele-vated liver enzymes, and an increase in total serum cholesterol by 10–20%. High rates of fetal abnormalities occurred in pregnant monkeys exposed to efavirenz in doses roughly equivalent to the human dosage; several cases of congenital anomalies have been reported in humans. Therefore, efavirenz should be avoided in pregnant women, particularly in the first trimester.

As both an inducer and an inhibitor of CYP3A4, efavirenz induces its own metabolism and interacts with the metabolism of many other drugs (Tables 49–3 and 49–4). Since efavirenz may lower methadone levels, patients receiving these two agents con-currently should be monitored for signs of opioid withdrawal and may require an increased dose of methadone.

ETRAVIRINE

In 2008, etravirine was approved in the United States for use in treatment-experienced patients with HIV infection. Etravirinemay be effective against strains of HIV that have developed resis-tance to first-generation NNRTIs, depending on the number of mutations present. Although etravirine has a higher genetic barrier to resistance than the other NNRTIs, mutations selected by etravirine usually are associated with resistance to efavirenz, nevirapine, and delavirdine.

The most common adverse effects of etravirine are rash, nausea, and diarrhea. The rash is typically mild and usually resolves after 1–2 weeks without discontinuation of therapy. Rarely, rash has been severe or life-threatening. Laboratory abnormalities include elevations in serum cholesterol, triglyceride, glucose, and hepatic transaminase levels. Transaminase elevations are more common in patients with HBV or HCV co-infection.

Etravirine is a substrate as well as an inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19; it has many therapeuti-cally significant drug-drug interactions (Tables 49–3 and 49–4). Some of the interactions are difficult to predict. For example, etravirine may decrease itraconazole and ketoconazole concentra-tions but increase voriconazole concentrations.

NEVIRAPINE

The oral bioavailability of nevirapine is excellent (> 90%) and is not food-dependent. The drug is highly lipophilic and achieves cerebrospinal fluid levels that are 45% of those in plasma. Serum half-life is 25–30 hours. It is extensively metabolized by the CYP3A isoform to hydroxylated metabolites and then excreted, primarily in the urine.

A single dose of nevirapine (200 mg) is effective in the preven-tion 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.

Rash, usually a maculopapular eruption that spares the palms and soles, occurs in up to 20% of patients, usually in the first 4–6 weeks of therapy. Although typically mild and self-limited, rash is dose-limiting in about 7% of patients. Women appear to have an increased incidence of rash. When initiating therapy, gradual dose escalation over 14 days is recommended to decrease the incidence of rash. Severe and life-threatening skin rashes have been rarely reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Nevirapine therapy should be immedi-ately discontinued in patients with severe rash and in those with accompanying constitutional symptoms; since rash may accom-pany hepatotoxicity, liver function tests should be assessed. Symptomatic liver toxicity may occur in up to 4% of patients and is more frequent in those with higher pretherapy CD4 cell counts (ie, > 250 cells/mm³ in women and > 400 cells/mm³ in men), in women, and in those with HBV or HCV co-infection. Fulminant, life-threatening hepatitis has been reported, typically within the first 18 weeks of therapy. Other adverse effects include fever, nau-sea, headache, and somnolence.

Nevirapine is a moderate inducer of CYP3A metabolism, resulting in decreased levels of amprenavir, indinavir, lopinavir,saquinavir, efavirenz, and methadone. Drugs that induce the CYP3A system, such as rifampin, rifabutin, and St. John’s wort, can decrease levels of nevirapine, whereas those that inhibit CYP3A activity, such as fluconazole, ketoconazole, and clarithro-mycin, can increase nevirapine levels. Since nevirapine may lower methadone levels, patients receiving these two agents concurrently should be monitored for signs of opioid withdrawal and may require an increased dose of methadone.