Antiretroviral Therapy in HIV-infected Adults: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Nevirapine, Delavirdine, and

The first NNRTI, nevirapine (NVP) (Viramune®, Boehringer Ingelheim), was approved in June 1996. Delavirdine (DLV) (Rescriptor®, Pharmacia & Upjohn) received approval in April 1997, and EFV was approved in September 1998. Studies with NNRTIs, in particular with EFV, have received considerable attention. NVP has been extensively studied in resource-poor countries as an affordable alternative to short-course ZDV in the prevention of perinatal HIV transmission.

The NNRTIs inhibit the reverse transcriptase enzyme of HIV-1 isolates; unlike the NRTIs, however, they are not structural analogues of the naturally occurring nucleosides. Members of this class of drugs bind directly to reverse transcriptase, thereby blocking the RNA-dependent and DNA-dependent DNA polymerase activities in a noncompetitive manner. HIV-2 reverse transcriptase and human cellular DNA polymerases are not inhibited by NNRTIs. The NNRTIs are indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection.

Resistance

Resistance develops rapidly when NNRTIs are given as monotherapy, and significant cross-resistance between the NNRTIs is evident. K103N and Y188L are key primary mutations that are shared by all three agents (NVP, DLV, and EFV), which can reduce the clinical utility of all currently approved NNRTIs. A total of 13 clinical isolates that were previously characterized as EFV-resistant were also pheno-typically resistant to NVP and DLV in vitro compared with baseline evaluations. Clinically derived ZDV-resistant HIV-1 isolates tested in vitro remained susceptible to EFV. In four patients, ZDV-resistant isolates tested in vitro retained susceptibility to NVP; in six patients, NVP-resistant isolates were susceptible to ZDV and ddI. official canadian pharmacy

Finally, because NNRTIs and HIV protease inhibitors (PIs) have different target enzymes, cross-resistance between the two is considered unlikely.

Contraindications

NVP, DLV, and EFV are contraindicated in patients with clinically significant hypersensitivity to any of their respective components.

Warnings and Precautions

NVP is associated with severe and life-threatening skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Discontinuation is recommended in cases of severe rash or rash accompanied by constitutional symptoms, such as fever, blistering, oral lesions, conjunctivitis, swelling, muscle or joint aches, or general malaise. Severe or life-threatening hepatotoxicity, including fatal fulminant hepatitis, has occurred in patients treated with NVP. It is recommended that therapy be temporarily discontinued if moderate or severe elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) occur and permanently discontinued if liver function abnormalities recur upon rechal-lenge. In patients with persistent elevations of serum trans-aminases to greater than five times the upper limit of the normal range, the benefit of continued therapy needs to be weighed against the risk of significant liver toxicity.

EFV is strongly associated with central nervous system (CNS) and psychiatric manifestations, including severe symptoms such as acute depression, suicidal ideation or attempts, and delusions. A total of 52% of patients reported having some sort of CNS side effect that included dizziness, impaired concentration, somnolence, abnormal dreams, or insomnia. Reportedly, 2.6% of patients had to discontinue therapy because of CNS side effects. Most CNS symptoms occur within the first few days of therapy and resolve within two to four weeks. Patients taking EFV should avoid alcohol because of the potential for additive CNS effects.

Adverse Effects

Selected adverse effects of the NRTIs are shown in Table 4.

Table 4 Serious or Frequent Adverse Effects Occurring with Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Nevirapine (Viramune®)	Delavirdine (Rescriptor®)	Efavirenz ()
• Rash	• Rash	• Rash
• Toxic epidermal necrolysis	• Increased transaminase levels	• Central nervous system symptoms
• Increased transaminase levels	• Headache	• Increased transaminase levels
• Hepatotoxicity, including fulminant	• Nausea	• False-positive cannabinoid test
hepatitis		• Teratogenic effects in monkeys
• Nausea		• Fatigue
Data from Panel on Clinical Practices for Treatment of HIV;6 product information for Viramune®, Roxane;29 product information for Rescriptor®, Pharmacia & Upjohn;30 and product information for Sustiva®, Bristol-Myers Squibb Virology.31

Drug Interactions

Nevirapine (NVP) is a CYP-3A inducer and may result in lower plasma concentrations of other concomitantly administered drugs that are extensively metabolized by the CYP-3A enzyme system.

Coadministration of delavirdine (DLV) with certain non-sedating antihistamines, sedative hypnotics, antiarrhythmic agents, calcium-channel blockers, ergot alkaloid preparations, and amphetamines may result in potentially serious or life-threatening adverse events. Because of the inhibitory effect of DLV on CYP-3A and CYP-2C9, coadministration with drugs primarily metabolized by these liver enzymes may result in increased DLV plasma concentrations.

Table 5 Drug Interactions between Efavirenz and Selected Drugs

Coadministered Drug		Effect on AUC	Comment
Indinavir sulfate (, Merck)		IDV decreased 31% EFV unaffected	Dose: IDV 1,000 mg every 8 hours, standard EFV dose
Ritonavir (, Abbott)		RTV increased 18% EFV increased 21%	Dose: RTV 600 mg b.i.d. (500 mg b.i.d. for intolerance), standard EFV dose
Saquinavir mesylate-soft-gel capsule (SGC) (Fortovase®, Roche)		SQV decreased 62% EFV decreased 12%	Coadministration is not recommended
Amprenavir (Agenerase®, GlaxoSmithKline)		AMP decreased 36% EFV not affected	Dose: AMP 1,200 mg t.i.d. as single PI or 1,200 mg b.i.d. + RTV 200 mg b.i.d., standard EFV dose
Lopinavir/ritonavir (Kaletra®, Abbott)	•	LPV decreased 40% EFV not affected	Consider LPV/RTV 533/133 mg b.i.d., standard EFV dose
Rifabutin (Mycobutin®, Pharmacia & Upjohn)	•	Rifabutin decreased 35% EFV not affected	Dose in a non-PI-containing regimen: rifabutin 450 mg to 600 mg every day or 600 mg two to three times per week, standard EFV dose
Clarithromycin (, Abbott)	•	Clarithromycin canadian decreased 39% EFV not affected	Selecting an alternative agent is recommended.
AMP = amprenavir; AUC = area under the curve; b.i.d. = twice a day; EFV = efavirenz; IDV = ; LPV = lopinavir; LPV/RTV = lopinavir/ ; PI = protease inhibitor; RTV = ritonavir; SQV = saquinavir; t.i.d. = three times a day.Data from Panel on Clinical Practices for Treatment of HIV Infection6 and product information for Sustiva®, Bristol-Myers Squibb Virology.

Efavirenz canadian (EFV) should not be coadministered with mid-azolam (e.g., Versed®, Roche), triazolam (e.g., Halcion®, Pharmacia), or ergot derivatives because of competition for the CYP-3A4 enzyme system, which might lead to inhibition of metabolism of these drugs and create the potential for serious or life-threatening adverse events. In vitro studies have shown that EFV also inhibits the CYP-450 isoenzymes 2C9 and 2C19, but not 2E1, in the range of observed plasma concentrations. There is also in vivo evidence that EFV causes hepatic enzyme induction of the CYP-3A4 isoenzyme. Hence, EFV has the potential for many serious interactions, and several studies have documented EFV-drug interactions (Table 5).

Pharmacokinetics

The comparative pharmacokinetic properties of NNRTI agents are presented in Table 6.

Table 6 Comparative Pharmacokinetics of Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

	Nevirapine (Viramune®)	Delavirdine (Rescriptor®)	Efavirenz (Sustiva canadian)
Absorption	Oral bioavailability > 90%	Mean oral bioavailability 85%	Steady-state C = 12.9 ± 3.7 micromoles / max Steady state C i = 5.6 ± 3.2 micromoles / min AUC 184 + 73 micromoles/hour in a sample of 35 patients
Protein binding	Approximately 60%	Approximately 98% protein-bound, primarily to albumin	Approximately 99.5%-97.5% to human plasma proteins, predominantly albumin
Serum half-life	25-30 hours	5.8 hours	40-55 hours
Metabolism	Metabolized by CYP-450 (3A inducer)	Metabolized by CYP-450 (3A inhibitor)	Metabolized by CYP-450 (3A mixed inducer/ inhibitor); capable of autoinduction of metabolism
Elimination	80% excreted in urine as glucoronidated metabolites (<5% unchanged); 10% in feces	51% excreted in urine (<5% unchanged), 44% in feces	14%-34% excreted in urine, mostly as gluco-ronidated metabolites (<1% unchanged; 16%-61% excreted in feces

Clinical Trials Nevirapine

A randomized, double-blind, placebo-controlled trial was conducted to compare NVP + zidovudine canadian (ZDV) + cialis professional (ddI) with ZDV + ddI. A total of 68 patients who had CD4
counts below 200/mm³ or an AIDS-defining diagnosis were monitored for 48 weeks. Patients were randomly assigned to receive NVP + ZDV+ ddI (n = 32) or ZDV + ddI (n = 36). Efficacy was monitored by HIV RNA levels and the peripheral CD4 count. The median HIV RNA values before therapy were similar in both groups, with the triple-therapy arm having 5.8 log₁₀ copies/ml and the double-therapy arm beginning with 5.7 log₁₀ copies/ml. Results are shown in Table 7.

The authors concluded that the triple-drug regimen of NVP + ZDV + ddI induced sustained virologic and immunologic responses in HIV-positive patients with low CD4 cell counts or a previous AIDS-defining diagnosis. Data from the AIDS Clinical Trial Group (ACTG 241) support this finding. Delavirdine

A total of 373 HIV-1 positive patients were randomly assigned to three treatment groups:

delavirdine (DLV) + zidovudine (ZDV) + lamivudine (3TC)
zidovudine (ZDV) + cialis professional (3TC)
delavirdine (DLV) + zidovudine (ZDV)

In this blinded study, the mean CD4 cell count was 354 to 360 cells/mm³, and the mean viral load was 22,000 to 31,000 copies/ml. Patients were monitored for an average of a year.

An interim analysis at 24 weeks revealed HIV RNA reductions of 2.2 log₁₀ copies/ml in the DLV + ZDV + 3TC arm, 1.3 log₁₀ copies/ml in the ZDV + 3TC arm, and 0.6 log₁₀ copies/ml in the DLV + ZDV arm. The triple-therapy group included significantly more patients with values below the limit of detection (HIV RNA below 400 copies/ml) than did the ZDV + 3TC arm at all time points from weeks 8 to 52. At 52 weeks, the triple-therapy group included 68% of patients with viral loads remaining below the limits of detection; the ZDV + 3TC group included 22% of patients with viral loads remaining at this level.

Table 7 Comparison of Nevirapine Triple Therapy with NRTI Double Therapy

Median HIV RNA Reduction (log|0 Copies/ml)

Median CD4 Cell Count Increase (Cells/mm3)

Drug Regimen

24 48 weeks weeks

24 48

weeks weeks

NVP + ZDV + ddl ZDV + ddl

2.69 1.97 1.05 1.20

81 101 64 27

The mean CD4 cell count increase over weeks 24 to 52 was 88 to 122 cells/mm³ (DLV + ZDV + 3TC), 72 to 77 cells/mm³(ZDV + 3TC), and 13 to 18 cells/mm³ (DLV + ZDV). The percentage of patients who achieved viral loads of less than 400 copies/ml was significantly greater in the triple-drug therapy arm than in either dual-therapy group.

The authors concluded that therapy with DLV + ZDV + 3TC is associated with a superior and significant reduction in viral burden than either of the dual therapies, as measured by the mean change from baseline and by the percentage of patients with HIV RNA levels below the limits of detection. The findings of the AIDS Clinical Trial Group (ACTG 261) confirm these results. Efavirenz

DuPont 266-006. This trial resulted in the addition of the first non-PI-containing regimen to the list of first-line therapies, according to the U.S. Department of Health and Human Services (DHHS) guidelines. This was an open-label study of 450 patients who were randomly assigned to one of three treatment arms:

cialis professional (ZDV) + lamivudine (3TC) + efavirenz (EFV)
zidovudine (ZDV) + lamivudine canadian (3TC) + indinavir sulfate (IDV)
indinavir sulfate (IDV) + efavirenz (EFV)

Patients were new to treatment with PIs, NNRTIs, and 3TC. Mean baseline HIV-1 RNA levels were 4.77 ± 0.57 log₁₀copies/ml, and mean CD4 cell counts were 345.3 ± 202.7 cells/mm³. Efficacy results are outlined in Table 8. On the basis of the study results, the authors concluded that EFV + AZT + 3TC conferred superior efficacy with durability of response to at least 48 weeks as well as greater dosing convenience compared with IDV + ZDV + 3TC.

Table 8 Suppression of Plasma HIV-1 RNA Levels at 48 Weeks

		Treatment Group
Efficacy Parameter at 48 Weeks	EFV + ZDV+ 3TC	IDV + ZDV + 3TC	EFV + IDV
Percentage of patients with suppression of plasma HIV-1 RNA to undetectable levels (<400 copies/ml), as intent-to-treat population	71	48	53
Percentage of patients with suppression of plasma HIV-1 RNA to undetectable levels (<400 copies/ml), as treated population	98	86	83
Percentage of patients with suppression of plasma HIV-1 RNA to <50 copies/ml, as intent-to-treat population	65	44	47

DMP 266-005. The authors of this study concurred that a regimen of EFV + ZDV + 3TC was effective in reducing viral loads and in increasing CD4 cell counts.

The ACTG Study. In this trial, 195 NRTI treatment-experienced patients were randomly assigned to one of three treatment arms: (1) NFV + EFV, (2) NFV, or (3) EFV, in addition to two nucleoside analogues. The baseline characteristics of the patients were similar among the three treatment groups, but the sample comprised predominantly non-Hispanic white men. The median baseline CD4 cell count was 350 cells/mm³, and the mean age of all patients was 41.1 years.

The results showed that NFV + EFV + two NRTIs brought about a higher rate of viral suppression at 40 and 48 weeks than the other two regimens did (P = .001). Comparison of the EFV and NFV arms at 40 and 48 weeks showed that the EFV group had a significantly greater reduction in viral load than the NFV group (P = .008).

Although the results of the quadruple-therapy arm in the setting of treatment-experienced patients is encouraging, a high pill burden is involved. The reproducibility of these results outside of the setting of a clinical trial remains to be seen.

Category: HIV

Tags: adults, Antiretroviral Therapy, HIV-infected