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Nonnucleoside Reverse Transcriptase Inhibitors

The nonnucleoside reverse transcriptase inhibitors (NNRTIs) are a structurally and chemically dissimilar group of antiretrovirals that are potent and highly selective inhibitors of HIV-1 reverse transcriptase. Other retroviral reverse transcriptase enzymes, such as HIV-2, hepatitis viruses, herpes viruses, and mammalian enzyme systems, are unaffected by these compounds. Unlike the nucleoside analogs, the NNRTIs interfere with HIV-1 reverse transcriptase by noncompetitively binding directly to the enzyme downstream from the active catalytic site. The compounds are active in their native state, requiring no phosphorylation or other activity-dependent alteration. They are extensively metabolized in the liver; very little drug is excreted unchanged.¹ See Table 1 for selected pharmacologic characteristics of the five NNRTIs discussed in this article.

The NNRTIs are potent antiretroviral agents that can successfully be used in appropriate triple-therapy regimens. The two main advantages of initiating therapy with an NNRTI-containing regimen are the ability to delay use of protease inhibitors and the favorable adherence properties of NNRTIs, such as once-daily dosing. NNRTI performance in patients with advanced HIV disease has not been as impressive as that achieved with the protease inhibitors, but this may be due to suboptimal study design. See Table 2 for a summary of the advantages and disadvantages of the agents in this group.

Unfortunately, resistance to the NNRTIs can develop rapidly, often following a single mutation. This is particularly true if they are used as monotherapy or are added to a failing or suboptimal regimen of nucleoside analogs. Although structurally dissimilar to each other, all NNRTIs bind the reverse transcriptase enzyme in the same binding pocket. Specifically, substitutions of reverse transcriptase amino acid residues at positions 103, 106, 108, 181, 190, and 236 engender resistance to at least one NNRTI. The mutation at 236 appears to be unique for delavirdine and, when present, may increase susceptibility to other NNRTIs, in contrast to the 103 mutation, which is common to most of the group. Fortunately, as has been demonstrated with nevirapine and efavirenz, the effect of a single mutation may not be clinically relevant.²

Drugs Approved for Clinical Use

Nevirapine

Nevirapine was the first NNRTI to be licensed. It induces its own metabolism as well as that of other drugs such as protease inhibitors, oral contraceptives, rifampin, and rifabutin. Because of this, the initial adult dose of nevirapine, 200 mg daily, is escalated after 14 days to 400 mg daily in a divided or single dose. Nevirapine is not highly protein bound (60%), and it penetrates into all tissues, including the central nervous system (CNS).

The main adverse event associated with nevirapine is rash, occurring in 17% of patients. The rash is usually mild and self-limited and typically develops within the first one to eight weeks of therapy. Severe rashes have been reported in 7.6% of patients, including at least eight who developed Stevens-Johnson syndrome. If a rash develops, the dosage of nevirapine should not be escalated until it abates. If the rash is extensive, moist, involves the mucous membranes, or is associated with fever, nevirapine should be permanently discontinued. Hepatitis has also rarely been associated with nevirapine use. Whether patients intolerant to nevirapine can use other NNRTIs is unknown.

Nevirapine is approved for use in combination with nucleoside analogs for treatment of HIV-infected adults experiencing clinical or immunologic deterioration. Clinically, nevirapine has been used with nucleoside analogs in treatment-naive adults and with protease inhibitors in treatment-experienced adults.

The most recent guidelines issued by the International AIDS Society-USA recommend that initial therapy include a combination of two nucleoside analogs plus one protease inhibitor or one NNRTI such as nevirapine,³ a strategy supported by data from the INCAS trial. This international trial involved 151 treatment-naive and asymptomatic patients with CD4 cell counts of 200 to 600 per ml and a mean plasma HIV RNA concentration of 25,704 copies/ml. Patients received nevirapine plus ddI plus AZT, or nevirapine plus AZT, or AZT plus ddI. Plasma HIV RNA concentration decreased to below 20 copies/ml in 55% of patients for at least 52 weeks in the triple-therapy arm, compared with none of the patients in the other two treatment groups.⁴ This trial established that NNRTI activity is greatly enhanced when it is used in combination with at least two other drugs to which the patient is naive and to which the patient's virus is likely to be sensitive.³ Additionally, nevirapine resistance is probably prevented in those who achieve maximal viral suppression.⁵

Nevirapine produced significant if less dramatic virologic and clinical effects when used in a combination nucleoside regimen in treatment-experienced adult patients with more advanced disease. In ACTG 241, 398 nucleoside-experienced persons with less than 350 CD4 cells/ml and a baseline mean plasma HIV RNA concentration of 38,905 copies/ml received either nevirapine plus AZT plus ddI or AZT plus ddI. Plasma HIV concentration decreased in the triple-therapy group by 1.16 log, compared with 0.45 log for the double nucleoside group. After 48 weeks the triple-therapy group was just below the baseline value, whereas the combination nucleoside group was above baseline. The ddI-naive patients experienced a more pronounced virologic response, with the HIV RNA concentration declining to approximately 0.5 log below baseline at 48 weeks, illustrating the importance of adding more than one drug to a failing regimen.⁶

Nevirapine has been studied in a limited number of children. In one small study eight infants and children with maternally acquired HIV infection were treated with nevirapine plus AZT plus ddI. The plasma HIV RNA concentration was reduced by 0.5 to 1.5 log over a six-month period in five subjects. In two other patients plasma HIV RNA concentrations declined to undetectable levels. The treatment was well tolerated.⁷

Concomitant administration of nevirapine can reduce indinavir and saquinavir levels, but not ritonavir levels. In a pharmacokinetic study 24 asymptomatic HIV-infected patients received standard doses of indinavir plus nevirapine plus one or more nucleosides. After 24 weeks of therapy, the patients' CD4 cell counts had increased by a mean of 100, and plasma HIV RNA had decreased 1.2 log copies/ml, 90% to levels below the limits of assay detection. Nevirapine reduced the indinavir and saquinavir area-under-the-curve (AUC) by 28%, but apparently this did not alter their antiviral effect. Nevirapine plasma levels were not altered by any of the protease inhibitors.⁸

Delavirdine

Delavirdine was the second NNRTI to be approved. Unlike nevirapine, it inhibits hepatic metabolism and therefore may increase plasma concentrations of other drugs metabolized in the liver. Delavirdine has a plasma half-life of 5.8 hours and is prescribed at a dose of 400 mg three times daily. Very little penetrates into the CNS. Rash is reported in 18% of patients; 3.6% develop severe cases. As with nevirapine, the rash typically occurs within one to eight weeks of initiating therapy. In general, the rash is less intense than that seen with nevirapine. Elevated hepatic transaminase levels have been observed, particularly when delavirdine is used with saquinavir.

Delavirdine is also approved for use in combination with nucleoside analogs to treat HIV-infected adults experiencing clinical or immunologic deterioration. Since delavirdine has only recently been licensed, little is known of its clinical use.

The clinical antiretroviral activity of delavirdine has been evaluated in two large multicenter trials referred to as Protocols 0021 and 0017. In 0021, 718 patients with CD4 cell counts between 200 and 500 and less than six months of prior AZT therapy (68% were treatment naive) received AZT alone or in combination with delavirdine (200 mg, 300 mg, or 400 mg three times daily). Patients receiving the 300-mg or 400-mg doses of delavirdine had CD4 cell count increases of 20 to 30, compared with only 10 for those taking AZT alone. No significant difference in plasma HIV RNA concentration was noted after a year.⁹

In Protocol 0017, 1,190 patients with unlimited prior AZT use and less than four months of ddI were randomized to receive either ddI alone or ddI plus delavirdine (400 mg three times daily). Subjects had symptomatic disease and CD4 cell counts less than 300. The combination group achieved a greater mean increase in CD4 cell counts during the first 12 weeks of the study, but the increase was not sustained after that time. By week four the plasma HIV RNA concentration decrease for the combination group was twice that of the ddI monotherapy group, but this difference disappeared after four weeks. The study was closed early on the advice of an independent monitoring board that concluded that no clinical outcome difference was likely to be achieved. Although Protocols 0021 and 0017 did not demonstrate an obvious benefit, delavirdine was licensed for use in adults. The relatively unimpressive observations were likely attributable to the study design and not to lack of viral activity.¹⁰

Delavirdine's effect on protease inhibitors has been studied in HIV-negative volunteers. In single-dose studies, it increased indinavir concentrations by twofold and saquinavir concentrations by four- to sixfold. However, many patients receiving delavirdine plus saquinavir had minor but significant elevations in hepatic transaminase levels. Further safety data are required before a recommendation can be made on combining delavirdine with a protease inhibitor.

Drugs in Development

Loviride

Loviride, studied primarily in Europe, is prescribed at 100 mg three times daily. Its effect on hepatic metabolism is not well characterized.

Loviride has been studied in the CAESAR trial, which enrolled 1840 3TC- and NNRTI-naive subjects with CD4 cell counts between 25 and 250. Patients were randomized to add placebo, 3TC alone, or 3TC plus loviride to their baseline regimen of nucleoside analogs. The final results revealed that 20% in the placebo group and 9% in both the 3TC and 3TC plus loviride groups reached a clinical endpoint of either an AIDS-defining condition or death. Mortality was also significantly less in the 3TC-containing arms. Clinical outcome did not differ for patients assigned to 3TC alone, compared with those assigned to 3TC plus loviride. The 3TC plus loviride group achieved a slightly higher CD4 count and slightly lower plasma HIV RNA level, compared with the other two groups. However, this modest difference disappeared after 12 weeks. The results were certainly underwhelming compared with those obtained by including a protease inhibitor in the regimen.¹¹

In the AVANTI trial, 106 treatment-naive persons were randomized to receive AZT plus 3TC or AZT plus 3TC plus loviride. At baseline the median plasma HIV RNA level was 63,000 copies. After 52 weeks of therapy, plasma HIV RNA concentrations decreased by approximately 2.0 log copies in each group. Only 11% of the AZT plus 3TC and 20% of the AZT plus 3TC plus loviride group achieved undetectable levels of plasma HIV RNA at week 52.¹²

Currently there are no plans to market loviride in either Europe or the United States.

Efavirenz

Efavirenz (DMP 266) is a very potent NNRTI currently under development. Although it is highly protein bound (99.5%), expected plasma trough levels of free drug effectively inhibit HIV reverse transcriptase. In vitro, efavirenz is active in MT-4 cells, peripheral blood mononuclear cells, and macrophages. High-level resistance develops more slowly with efavirenz than with other NNRTIs, although the mutations significantly overlap. At least two mutations are required in order for phenotypic resistance to develop. The half-life of efavirenz is 40 to 50 hours, and all of the unbound drug crosses the blood-brain barrier.

Efavirenz has been studied in approximately 500 patients for at least four months at 600 mg once daily. The most common adverse reactions are CNS complaints such as dizziness, which can usually be alleviated by administering 300 mg twice daily. Rash is reported infrequently.

Like nevirapine, efavirenz induces the hepatic P450 system. Drug interaction studies have been completed with indinavir, nelfinavir, saquinavir, AZT, 3TC, clarithromycin, fluconazole, famotidine, and Mylanta. Concomitant efavirenz administration decreases indinavir's AUC by approximately 36% and saquinavir's by 39%, but it increases the nelfinavir AUC by 15% to 24%. The only other significant interaction is with clarithromycin. This combination is poorly tolerated clinically, and the clarithromycin AUC is reduced by 44%.

Preliminary data from an ongoing phase II study of 21 patients treated with indinavir plus efavirenz demonstrate that plasma HIV RNA declines to undetectable levels in 80% of patients. Other pilot trials suggest that efavirenz is a potent drug when used with nucleoside analogs or protease inhibitors. Studies in treatment-naive and treatment-experienced patients and in pediatric patients are underway or in the planning stages.

HBY 097

HBY 097, a quinoxaline derivative, is the first compound in its chemical class known to inhibit HIV reverse transcriptase. The half-life of HBY 097 is between 10 and 12 hours, and studies have used doses from 250 to 750 mg three times daily. Early phase II data suggest an antiviral response,¹³ and a dose-ranging phase II study is currently underway. The most common adverse events associated with HBY 097 are gastrointestinal complaints and rash. This drug unpredictably affects the P450 hepatic enzyme system. In animal models, it appears to cross the blood-brain barrier. More data should be available later this year. Until then, it is too early to comment on the possible clinical use of this compound.

— Robert L. Murphy, MD

Dr. Murphy is Associate Professor of Medicine in the Division of Infectious Diseases at Northwestern University. He has received both research and consulting support from Boehringer-Ingelheim, Dupont-Merck, and Pharmacia and Upjohn.

Published in AIDS Clinical Care October 1, 1997

Citation(s):

1. Murphy R and Montaner J. Nevirapine: a review of its development, pharmacological profile and potential for clinical use. Exp Opin Invest Drugs 1996 5 1183-1199.

2. Byrnes VW et al. Comprehensive mutant enzyme and viral variant assessment of human immunodeficiency virus type 1 reverse transcriptase resistance to nonnucleoside inhibitors. Antimicrob Agents Chemother 1993 37 1576-1579.

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3. Carpenter CCJ et al. Antiretroviral therapy for HIV infection in 1997: updated recommendations of the International AIDS Society- USA Panel. JAMA 1997 277 1962-1969.

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4. Conway B et al. Randomised, double-blind one-year study of the immunological and virologic effects of nevirapine, didanosine and zidovudine combinations among antiretroviral-naive AIDS-free patients with CD4+ cell counts of 200-600uL. In: Program and Abstracts of the Third International Congress on Drug Therapy in HIV Infection, Abstract OP7.1., Birmingham, England, November 3-7 1996 .

5. Wainberg MA and Birch C, for the Boehringer-Ingelheim 1046 Study Team (INCAS Trial). Phenotypic and genotypic resistance emergent of reverse transcriptase inhibitors. In: Programs and Abstracts of the Third International Congress on Drug Therapy in HIV Infection, Abstract OP7.2., Birmingham, England, November 3-7 1996 .

6. D'Aquila RT et al. Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. Ann Intern Med 1996 124 1019-1030.

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7. Luzuriaga K et al. Combination treatment with zidovudine, didanosine, and nevirapine in infants with human immunodeficiency virus type 1 infection. N Engl J Med 1997 336 1343-1349.

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8. Murphy RL et al. Effect of nevirapine on pharmacokinetics of indinavir and ritonavir in HIV-1 patients. In: Abstracts of the 4th Conference on Retroviruses and Opportunistic Infections, Abstract 374, Washington, D.C., January 22-26 1997 .

9. Freimuth WW et al. Delavirdine (DLV) in combination with zidovudine (ZDV) causes sustained antiviral and immunologic effects in HIV-1 infected individuals. In: Programs and Abstracts of the 3rd Conference on Retroviruses and Opportunistic Infections, Abstract LB8a, Washington, D.C., January 28-February 1 1996 .

10. Freimuth WW et al. Delavirdine (DLV) + didanosine (ddI) combination therapy has sustained surrogate marker response in advanced HIV-1 populations. In: Program and Abstracts of the 3rd Conference on Retroviruses and Opportunistic Infections, Abstract LB8b, Washington, D.C., January 28-February 1 1996 .

11. CAESAR Coordinating Committee. Randomised trial of addition of lamivudine or lamivudine plus loviride to zidovudine-containing regimens for patients with HIV-1 infection: the CAESAR trial. Lancet 1997 349 1413-1421.

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12. Rozenbaum W. AVANTI 1: a randomized, double-blind, comparative trial to evaluate the efficacy, safety and tolerance of combination antiretroviral regimens for the treatment of HIV infection. In: Abstracts of the 4th Conference on Retroviruses and Opportunistic Infections, Abstract 368, Washington, D.C., January 22-26 1997 .

13. Rubsamen-Waigmann H et al. Second-generation non-nucleoside reverse transcriptase inhibitor HBY097 and HIV-1 viral load. Lancet 1997 349 1517-1517.

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