Nonnucleoside Analogues (Delavirdine, Efavirenz, Etravirine, Nevirapine)

CLASS

Chemical Structure

Discovered in 1990, nonnucleoside reverse transcriptase inhibitors (NNRTIs) are a structurally diverse group of compounds with potent and selective in vitro activity against human immunodeficiency virus (HIV)-1 (6,41, 42, 55, 56, 91, 103, 104, 153). A collection of chemically distinct agents, NNRTIs include dipyridodiazepinones such as nevirapine, bis(heteroaryl)piperazine compounds such as delavirdine, benzoxamines such as efavirenz, diarylpyrimidine (DAPY) compounds such as etravirine, benzophenone analogues such as GW4751, GW4511, and GW3011 (23), and trifluoromethyl-containing quinazolin-2(1H) compounds such as DPC-082, DPC-083, DPC-961, and DPC-963. The chemical structures of the four licensed NNRTIs are shown in Figure 1.

The four FDA-approved NNRTIs are nevirapine, delavirdine, efavirenz, and etravirine, and several compounds are in clinical development. The recently approved etravirine and several investigational agents, including GW4751, GW4511, GW3011, DPC-083, and rilpivirine (TMC-278) have all demonstrated in vitroactivity against strains of HIV resistant to the first three marketed NNRTIs, nevirapine, delavirdine, and efavirenz (23, 33). Etravirine is the first FDA-approved agent in the next generation of NNRTIs, demonstrating effectiveness in HIV-infected individuals with NNRTI-resistant virus. This review will focus on the commercially available NNRTIs, nevirapine, delavirdine, efavirenz, and etravirine, as data from human studies are available, and these compounds will continue to be developed and offer utility to the practicing clinician treating HIV-infected individuals.

Structure-Activity Relationship

Despite their diverse molecular compositions, NNRTIs share a common relationship between chemical structure and antiviral activity. Unlike nucleoside/tide reverse transcriptase inhibitors (N(t)RTIs), which are incorporated into viral DNA, all NNRTIs inhibit HIV-1 by binding directly to the reverse transcriptase molecule. Reverse transcriptase directs the polymerization of DNA from viral RNA, an essential step in viral replication. NNRTIs appear to inhibit polymerization allosterically by altering the position of critical amino acids within the catalytic site of the reverse transcriptase enzyme. The description of the crystal structure of reverse transcriptase by Kohlstaedt and colleagues in 1992 helped to demonstrate the binding of NNRTIs to the enzyme complex (74). The structure of reverse transcriptase is analogous to that of a right hand, with the p66 subdomain folded into several separate regions, often referred to as “fingers,” “palm,” and “thumb.” NNRTIs bind into a deep pocket that lies between the “palm” and the base of the “thumb.” This suggests a mechanism by which the inhibitors may act like sand in the gears of a machine, altering molecular movement essential for viral replication. The ability of etravirine, the most recent addition to the NNRTIs, to retain activity against NNRTI-resistant virus may be accounted for by the ability of the drug to bind to reverse transcriptase in a multitude of conformations as described by structure determination by crystallization and modeling  (34). The chemical reaction catalyzed by reverse transcriptase is significantly slowed in the presence of NNRTIs (11, 40, 125). This structure-activity relationship also explains the high degree of specificity of these agents for HIV-1 reverse transcriptase.

 

ANTIVIRAL ACTIVITY

Spectrum

The antiviral activity of all NNRTIs, except etravirine, is highly selective for HIV-1. Other than etravirine, the compounds do not exhibit activity against other viruses, including HIV-2 or other animal lentiviruses (75). Etravirine has demonstrated in vitro activity in the micromolar range against HIV-2 (IC50 = 3.5)(4) NNRTIs are highly potent antiretroviral drugs in vitro (6-8, 41, 42, 55, 56, 91, 103, 104, 153).  Inhibition of reverse transcriptase at nanomolar concentrations has been reported, with minimal cytotoxicity in a variety of cell lines. Synergy has been observed in vitro between NNRTIs and nucleoside analogs (20, 110).  NNRTIs are also active against some nucleoside-resistant strains; for example nevirapine is active against zidovudine-resistant HIV-1 in vitro (16). Inhibitory activities of nevirapine, delavirdine, efavirenz, and etravirine are shown in a variety of cell lines in Table 1. The nucleoside analogues zidovudine and didanosine leare also shown for comparison.

Pharmacodynamic Effects

Nevirapine

In vitro, nevirapine is active against HIV-1, including strains that are resistant to zidovudine, and is synergistic with zidovudine, didanosine, stavudine, lamivudine, and saquinavir (16).The in vitro 50% inhibitory concentration (IC50) ranges from 0.01 to 0.1 µM. To achieve 95% and 100% inhibition in vitro, nevirapine concentrations of approximately 1 and 10 µM, respectively, are necessary (110).  The relationship between in vitroinhibitory values and plasma concentration necessary to achieve sustained inhibition of HIV-1 replication is not known. Intracellular levels required for antiviral activity are also unknown. For example, nevirapine was administered in daily doses of 12.5, 50 and 200 mg to 62 HIV-infected persons with CD4 counts < 400 cells/µL. Steady-state trough concentrations at 12.5, 50, and 200 mg/day were 0.9, 4, and 7 µM, respectively, indicating that at the lowest dose trough concentrations were essentially above the in vitro IC50 at all times and were 70 times above at the highest dose. Yet, no patient achieved a sustained virologic response and all patients in the study had nevirapine-resistant HIV strains within 8 weeks of therapy initiation (25).

Clinical information on relationships between the plasma concentration of nevirapine and anti-HIV effect is available. Eighteen HIV-infected adults received 400 mg/d of nevirapine and were evaluated for virologic response, defined as at least a 50% reduction in immune complex-dissociated p24 antigen from baseline sustained for 8 weeks. Ten patients remained in the study for approximately 8 weeks and were available for response analysis: eight were classified as responders. The median trough nevirapine concentration was higher in responders than in the nonresponders (18 µM versus 12 µM, p=0.02) (66). In another study, 178 patients who received an antiretroviral regimen including nevirapine 400 mg/d were assessed to evaluate the relationship between nevirapine trough concentrations and the durability of viral suppression and the selection of nevirapine-associated primary resistance mutations (57). A nevirapine trough concentration of over 4,300 ng/ml (16.1µM) was associated with longer viral suppression, while a concentration of 3,100 to 4,300 ng/ml (11.6 to 16.1 µM ) was associated with a higher probability of developing primary resistance mutations versus concentrations above or below this range. These findings are supported by data from 74 HIV-infected patients that showed the average nevirapine trough concentration was lower in patients with virologic failure as compared to those with virologic response [2,572 ng/ml versus 4,550 ng/ml, (9.7 to 17.1 µM) respectively] (44). Ultimately, these data suggest that prospective monitoring of nevirapine plasma concentrations may be of some utility.

Delavirdine Mesylate

Delavirdine belongs to a class of compounds known as bisheteroarylpiperazines that have shown in vitroactivity against HIV-1 reverse transcriptase. Similar to nevirapine and efavirenz, delavirdine has no activity against the reverse transcriptase of HIV-2. The in vitro IC50 of delavirdine for HIV-1 averages 0.26 µM (42). Delavirdine has a high degree of selectivity for HIV-1 reverse transcriptase in that concentrations 2,000-fold higher are required to inhibit cellular polymerases in vitro. As with nevirapine and efavirenz, the relationship between concentrations required to inhibit HIV-1 replication in vitro and those necessary to achieve sustained inhibition in vivo is not known. The typical adult dose of 400 mg thrice daily produces average trough concentrations of approximately 16 µM, although there is considerable interpatient variability (50). While this trough is considerably greater than the average IC50, when adjusted for the high degree of binding to plasma proteins (average 98%), the free concentration of delavirdine would only be approximately 0.32 µM. Available data do support some clinical anti-HIV activity of delavirdine mesylate at the dose of 400 mg thrice daily. However, the effect appears quite weak, and perhaps not equivalent, when combined with zidovudine as compared to a nucleoside combination of zidovudine plus didanosine (35). One potential explanation for this weak antiretroviral effect may be the low ratio of free-drug plasma concentration to the in vitro inhibitory concentration.

Efavirenz

 Efavirenz belongs to the benzoxamine class of NNRTIs. The in vitro IC90 of efavirenz for HIV-1 ranges from 1.7 to 25 nM. After adjustment for protein binding these inhibitory concentrations range between 0.34 to 5 µM (17). Efavirenz has demonstrated synergistic activity against HIV-1 in cell culture when combined with NRTIs such as zidovudine, didanosine, and protease inhibitors (PIs), such as indinavir. Efavirenz exhibits a high degree of selectivity in that it does not inhibit HIV-2 or human cellular DNA polymerases alpha, beta, gamma and delta. As with other NNRTIs, the exact relationship between concentrations required to inhibit HIV-1 replication in vitro and those necessary to achieve sustained inhibition in vivo is unknown. The typical adult dose of efavirenz is 600 mg once daily. This regimen achieves typical values of 12.9 µM for Cmax, and 5.6 µM for Cmin. These data would suggest that in the majority of isolates, efavirenz concentrations in plasma will exceed the 90% in vitro inhibitory values by several fold; at the extreme of the susceptibility range, however, trough efavirenz concentrations may only approximate the protein binding adjusted 90% inhibitory concentration.

Clinical data do support relationships between efavirenz concentrations and anti-HIV response. In dose ranging studies conducted during the clinical development of efavirenz, treatment failure was found to be three times as frequent when efavirenz trough concentrations were < 3.5 µM (1.1 mg/L) than when trough concentrations were above this value. The probability of treatment success was estimated to be approximately 90% when trough concentrations were approximately 10 µM (3.2 mg/L), and was estimated to approach 100% when trough concentrations were approximately 20 µM (6.3 mg/L). In an analysis of efavirenz plasma concentrations in 130 HIV-infected individuals, concentrations obtained between 8 to 20 hours post dose (14 ± 2.7 hours) were found to predict both treatment failure and central nervous system (CNS) side effects (89). Virologic failure was observed in 50% of patients with efavirenz concentrations < 1 mg/L (≈ 3.2 µM), compared with failure rates of 22% and 18% in patients with concentrations between 1-4 mg/L or > 4 mg/L, respectively. CNS side effects were approximately three times more common in patients with efavirenz concentrations > 4 mg/L compared with patients who had concentrations between 1-4 mg/L.

Etravirine

Etravirine belongs to the diarylpyrimidine (DAPY) class of NNRTIs and has shown in vitro activity against HIV-1 and HIV-2 reverse transcriptase. The in vitro IC50 of etravirine for HIV-1 ranges from 0.9 to 5.5 nM. Furthermore, the in vitro IC50 of etravirine was less than 100 nM for 97% of over 1,000 NNRTI-resistant viruses (4). Etravirine has demonstrated synergistic activity against HIV-1 when combined with the NRTI, zidovudine, and an additive effect when combined with other NRTIs, including abacavir, didanosine, lamivudine, and stavudine, and PIs, specifically amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir. As with other NNRTIs, the exact relationship between concentrations required to inhibit HIV-1 replication in vitro and those necessary to achieve sustained inhibition in vivo is unknown. The typical adult dose of etravirine is 200 mg twice daily. This regimen achieves a mean trough level of 297 ng/ml (0.68 μM). These data suggest that the etravirine concentrations in plasma will exceed the in vitro IC50 by several fold, even after adjustment for protein binding.

There is little clinical information on the relationship between the plasma concentration of etravirine and anti-HIV effect. Sixteen HIV-infected adults, with documented virologic failure on a regimen comprised of at least two nucleoside analogues and either nevirapine or efavirenz, received 900 mg twice daily (formulation with lower bioavailability than the marketed formulation) of etravirine and were evaluated for HIV-1 viral load decay rate after 7 days of therapy (51). Fifteen patients remained in the study and were available for analysis; the viral load decay rate was 0.13 log10 RNA copies/ml per day. The mean trough level on the last day of treatment was 200 ng/ml (0.45 μM). No relationship was identified between the trough concentrations and the decrease in viral load. However, in vitro data suggest that such drug levels are above those necessary to inhibit 90% of resistant viruses; thus, no difference in response would be likely at such levels. Further work is necessary to elucidate the relationship between plasma concentration and anti-HIV effect of etravirine.

 

MECHANISM OF ACTION

Treatment for HIV infection has thus far largely focused on suppression of viral replication by inhibition of essential viral enzymes. HIV-1 reverse transcriptase remains an attractive target for antiretroviral therapy as there is no related cellular homolog for reverse transcriptase, and the enzyme is essential for viral replication. Reverse transcriptase controls multiple activities and is required prior to provirus production early in the life cycle of the virus. Clinical benefit has been demonstrated using the eight licensed nucleoside/tide analogues: zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, tenofovir and emtricitabine (101). All have exhibited the ability to suppress HIV-1 replication to varying degrees in vitro and in human studies.

The mechanism of action of NNRTIs is distinct from that of the nucleoside/tide analogues. N(t)RTIs constrain HIV replication by incorporation into the elongating strand of viral DNA, causing chain termination. In contrast, NNRTIs are not incorporated into viral DNA but inhibit HIV-1 replication directly by binding noncompetitively to HIV-1 reverse transcriptase (49, 115, 129, 152). The drugs bind to a hydrophobic pocket in the enzyme-DNA complex close to the active site catalytic residues (129) and slow the process of reverse transcription. NNRTIs do not interfere with nucleotide binding. Unlike nucleoside/tide analogs, NNRTIs do not inhibit human DNA polymerases. With their unique specificity for HIV-1, these agents are not active against other viruses, with the exception of the in vitro activity of etravirine against HIV-2.

Video: Mode of Action of NNRTIs

 

MECHANISM OF RESISTANCE

Organisms Commonly Resistant

As antiretroviral drug use becomes more widespread, there is an ever-increasing number of HIV-infected individuals who develop drug resistant virus. These viruses may be passed to others who acquire a drug resistant strain. The incidence of HIV drug resistance in new HIV infections is under constant scrutiny since it undermines therapeutic interventions and standardized recommendations for initial drug therapy. Resistance of HIV-1 to NNRTI s in recently infected patients, as evidenced by specific mutations in the RT gene (seen on genotypic assays) or resistance as measured in recombinant virus resistance assays (phenotypic assays), has been reported from a number of countries.(108) In recently infected persons in the US, Little et al (81) reported an increase in HIV resistance to NNRTIs from 1.7% in 1995-1998 to 7.3% in 1999-2000. The K103N substitution in the reverse transcriptase enzyme, most commonly associated with NNRTI resistance, was seen in 2% of the recently infected patients and significant levels of phenotypic drug resistance to the NNRTI class (>10 fold that of the reference strain) were found in 2-3% of new infections. Furthermore, Ross et al (116) retrospectively analyzed susceptibility data from over 300 antiretroviral-naïve patients from across the US and found that reduced susceptibility to at least one NNRTI was seen in 7% of patients, with 4% having reduced susceptibility to all NNRTIs. These trends support recommendations for the use of resistance testing in all HIV-infected patients entering into care (101).

On the other hand, up to 30 % of the viral isolates from antiretroviral naïve HIV infected patients may have low levels of drug resistance (IC50, 4-10 fold increased) or may show “atypical” substitutions of nucleotides within the reverse transcriptase gene. These substitutions are at the positions that are usually associated with NNRTI drug resistance mutations (e.g. 103) but other nucleic acid substitutions are present. Patients with these “atypical” substitutions or low-level resistance (<10 fold) show no worse virologic outcome with NNRTI use and they represent polymorphisms in the reverse transcriptase (RT) gene rather than true background drug resistance (29, 63).

Mechanisms of Resistance

As with all antiretroviral agents, the mechanism of development of resistance of HIV-1 to NNRTIs is by mutation of the reverse transcriptase gene in the viral genome. Suppression of wild-type virus during NNRTI therapy permits the outgrowth of minority populations of drug-resistant variants. The nucleic acid substitutions in the reverse transcriptase gene, which confer reduced susceptibility to NNRTIs, are located in the nonnucleoside binding pocket of the enzyme where the inhibitors physically interact (41, 74, 152). The molecular flexibility of etravirine allows anti-HIV activity to be maintained against virus resistant to the other three marketed NNRTIs. Etravirine has a higher genetic barrier to resistance, requiring multiple reverse transcriptase mutations in resistant strains as opposed to a single mutation for resistance to nevirapine, delavirdine, and efavirenz (147).

Both steric inhibition of drug binding and increased rates of dissociation of the enzyme drug-complex have been described, depending on the particular amino acid substitution involved (85, 128). These mutations appear to reduce viral fitness to a limited extent and most NNRTI-selected mutant viruses are both resistant and fit. In the presence of the drug, continued high-level replication of the drug-resistant mutant allows accumulation of additional mutations that achieve even higher levels of drug resistance (37). Such multiply-substituted viral strains are also more resistant to etravirine and the newer experimental NNRTIs that maintain activity against viruses with single or double mutations.

When NNRTIs are used as monotherapy for HIV-1 infection, drug resistance rapidly develops. In vitroresistance to nevirapine has been observed after only a few passages of infected cells in the presence of the drug (111).

Similarly, clinical trials of monotherapy with nevirapine (66) and delavirdine (102) have shown clinical and genotypic resistance within a few weeks of drug initiation. Drug resistance mutations have even been found after a single dose of nevirapine given for perinatal prophylaxis (71).

Initial in vitro and in vivo studies of NNRTIs suggested that there might be somewhat distinct reverse transcriptase mutations associated with viral resistance to each agent and gave hope that sequential use of NNRTIs would be possible. In the first clinical studies of nevirapine monotherapy, the most common reverse transcriptase mutation leading to drug resistance was a substitution of tyrosine with a cysteine at position 181 of the reverse transcriptase gene (Y181C). By week 12 of therapy 100% of the 24 subjects in this study had >100 fold increased IC50 and 19 (80%) of them had the Y181C. A substitution at V106A was also noted with continued nevirapine use (66). However, when thymidine analogs were used in combination with nevirapine, the majority of drug-resistant isolates developed a K103N mutation, with subsequent accumulation of substitutions at Y188L and G190S (38).

In vitro studies showed the major drug resistance mutation of delavirdine was a P236L substitution in the reverse transcriptase. Interestingly, this mutation sensitized the virus to nevirapine (43). Yet, the delavirdine monotherapy trial (ACTG 260) showed the P236L mutation developed in less than 10% of patients with delavirdine resistance(39). Demeter’s group has shown the P236L mutation leads to reduced replication fitness relative to K103N, which may explain the emergence of the K103N rather than the P236L mutant (52). In the ACTG 260 trial, the K103N was seen alone (48%) or in association with the Y181C mutation (30%) while 19% of patients had Y181C alone (39).

In the phase II combination trials of efavirenz with zidovudine and lamivudine or efavirenz with indinavir, therapeutic failure was associated with the emergence of an reverse transcriptase mutation at K103N (90%). Subsequently, these subjects developed additional mutations including L100I, V108I, or P225H. The Y181C mutation that does not cause high level efavirenz resistance was not seen (9). Viruses carrying the L100I or K103N mutations have a 20- to 30-fold increase in their efavirenz IC50. The combination of K103N with another substitution as L100I, V108I or P225H leads to more than a 100-fold increase in the IC50. Those patients failing efavirenz without a K103N develop Y188L and/or G190S mutations.

Preliminary analyses of data from the two randomized, double-blind, placebo-controlled trials that formed the primary basis for the approval of etravirine suggest that the presence of three or more of 13 specific mutations was associated with decreased virologic response to etravirine. The 13 mutations associated with decreased response include V90I, A98G, L100I, K101E, K101P, V106I, V179D, V179F, Y181C, Y181I, Y181V, G190A, and G190S (77, 84). In both trials, the most prevalent NNRTI resistance-associated mutations were K103N, Y181C, and G190A. Table 2 shows the spectrum of mutations in the reverse transcriptase gene associated with drug resistance to nevirapine, delavirdine, efavirenz, and etravirine (31, 77, 84).

Mutations in reverse transcriptase correlate with clinical and/or virologic failure of the NNRTI. There is a close correlation between the codon substitutions and reduced in vitro susceptibility. Reduced in vitro susceptibility has been observed to varying degrees with each codon mutation. Fold decrease in susceptibility for some commonly selected mutations as compared to wild-type virus are shown in Table 3 (106, 147).

More recently, in vitro evidence suggests that a Y318F mutation in the 3’ end of reverse transcriptase caused NNRTI resistance. This led to a search for clinical isolates with this mutation. Review of data from a large phenotypic-genotypic database (Virco) showed decreased NNRTI susceptibility in 85% of clinical isolates with Y318F. There was also significant association of these isolates with past delavirdine and nevirapine use. Combinations of this mutation with other NNRTI-associated resistance mutations further reduced viral susceptibility (64).

Recombinant in vitro susceptibility assays express drug susceptibility as fold change of the IC50 of the patient isolate compared to a wild-type reference virus. Recently, investigators have noted that some patient isolates appear in vitro more susceptible to select antiretroviral agents, i.e., less drug is needed to inhibit viral replication. These viruses are referred to as “hypersusceptible”. NNRTI-naïve patients with prior N(t)RTI exposure, who have isolates with resistance mutations and phenotypic resistance to N(t)RTIs, appear more likely to have hypersusceptibility to the NNRTI class of drugs (150). The clinical significance of this phenomenon, e.g. improved treatment response to NNRTIs, has recently been investigated by several groups (124).  Haubrich et al (65) found that patients with longer duration of exposure to and reduced susceptibility to N(t)RTIs were more likely to have efavirenz hypersusceptibility. In their patients treated with efavirenz, the mean fall in HIV RNA and mean CD4 rise was greater in those who had hypersusceptibility to efavirenz than those who did not.

Methods to Overcome and Prevent Resistance

As with other antiretroviral agents, methods to prevent HIV drug resistance have utilized combinations of antiretrovirals. While dual combination of a NNRTI and a single nucleoside analog have not resulted in sustained virologic suppression (25), triple drug combinations with two effective N(t)RTIs plus an NNRTI have proven quite effective with prolonged viral suppression to undetectable levels (58, 95, 133).

In fact, efavirenz in combination with two N(t)RTIs has emerged as one of the preferred initial treatment regimens for HIV infection (101). A large open label randomized trial, referred to as the 2 NN study, compared two triple drug combinations: stavudine and lamivudine plus either nevirapine or efavirenz to the quadruple regimen of stavudine and lamivudine plus both nevirapine and efavirenz. There were over 1,200 subjects randomized and 84% completed 48 weeks of the trial. Analysis of viral loads showed 67.8% of efavirenz recipients, 63.6% of nevirapine twice daily, 65% nevirapine once daily, and 61.7% of the 2 NNRTI arm achieved virologic success (RNA<50 copies/mL). No significant differences were shown among the study groups in terms of virologic success (RNA<50 copies/mL) or increase in CD4 cells. The 2 NNRTI regimen, nevirapine plus efavirenz, was associated with the highest rates of clinical adverse events. Thus, the combination of nevirapine plus efavirenz did not result in increased efficacy but did cause more adverse events (145). At this time, there are no data to support the use of double NNRTIs in an antiretroviral regimen, and such use is not recommended (101).

Studies that have evaluated the efficacy of NNRTI plus PI combinations have been completed but are limited. The double drug combination of efavirenz and the PI, indinavir, was tested in nucleoside-naïve and nucleoside-experienced patients and showed that durable virus suppression was achieved in 53% to 66% of patients treated in the intent-to-treat analysis (112, 133). A recent study within the AIDS Clinical Trials Group (ACTG) examined the NNRTI + PI combination of efavirenz + lopinavir/ritonavir. ACTG 5142 was a multi-center, open-label randomized 96-week study of 753 antiretroviral-naive patients who received one of three regimens: lopinavir/ritonavir 533/133 mg twice daily plus efavirenz 600 mg once daily, or lopinavir/ritonavir 400/100 mg twice daily plus two N(t)RTIs, or efavirenz 600 mg once daily plus two N(t)RTIs (113). At week 96, 89% of the efavirenz group achieved a viral load of <50 copies/ml compared to 77% for lopinavir/ritonavir and 83% for lopinavir/ritonavir plus efavirenz. CD4 cell response, however, was superior for the lopinavir/ritonavir containing regimens compared with efavirenz. The new formulation of lopinavir/ritonavir tablets were not studied in this trial. Additionally, the ability to extrapolate the lopinavir/ritonavir plus efavirenz regimen currently is uncertain because the lopinavir/ritonavir dose of 533/133 (of the capsule formulation) is no longer available. ACTG 5116 was another randomized, open-label study was conducted to evaluate the combination of efavirenz plus lopinavir/ritonavir plus two N(t)RTIs versus efavirenz plus two N(t)RTIs. Similar to the ACTG 5142 study, the new formulation of lopinavir/ritonavir tablets were not used in this trial. After approximately 2 years of follow-up of over 200 patients, there was a higher rate of virologic failure (defined as RNA>200 copies/mL) and a higher rate of drug-related toxicity, primarily increased triglycerides, in those a receiving efavirenz plus lopinavir/ritonavir (48).

In patients who have failed treatment with nevirapine, the detection of only a Y181C mutation in the reverse transcriptase gene suggests the possibility of susceptibility to efavirenz. Unfortunately, efavirenz in vitrosusceptibility was only found in half of the nevirapine failures and resulted in HIV suppression in only 17% of subjects at three months (5). In a report by Shulman, patients with Y181C had an initial virologic response to efavirenz, but this was lost by 12 weeks (124). In another report by Casado, 47 nevirapine-experienced patients with HIV RNA >1000 copies/mL were placed on an efavirenz-based salvage regimen. Only 19% achieved undetectable levels of viral RNA and these were patients with shorter periods of nevirapine therapy (21).

In most resource-limited countries, a single-dose nevirapine regimen for women in labor and their infants is the foundation for prevention of mother-to-child transmission and has been shown to significantly decrease transmission (60, 72, 96, 135, 136).  However, resistance to nevirapine is found in 20 to 69% of women and 50 to 87% of infants after the use of a single-dose nevirapine regimen (45, 47, 71, 78, 121). Limited data suggest that the incidence of nevirapine resistance may be decreased if other antiretroviral agents are given during the delivery and for a short period post-partum to cover the prolonged period (or tail) of nevirapine elimination from the body. A study was conducted to evaluate the development of nevirapine resistance in infants who received either single-dose nevirapine alone or single-dose nevirapine plus zidovudine, regardless of whether the mother received intrapartum nevirapine (46). Among 78 infants, the development of nevirapine resistance was lowest among those who received single-dose nevirapine plus zidovudine and whose mothers did not receive nevirapine (27%). The rate of nevirapine resistance among those who received single-dose nevirapine plus zidovudine and whose mothers also received single-dose nevirapine versus those who received single-dose nevirapine whose mothers did not receive nevirapine versus those who received single-dose nevirapine plus receipt of single-dose nevirapine by their mother was 57, 74, and 87%, respectively. Of note, infants who received single-dose nevirapine alone and whose mothers did not receive nevirapine had a higher incidence of HIV infection versus the other three groups. A study in South Africa demonstrated an absolute reduction of 50% in the development of nevirapine resistance when zidovudine plus lamivudine was given in addition to single-dose nevirapine during labor and then continued for 4 to 7 days after delivery (90). Another study in Africa evaluated women who received zidovudine plus lamivudine at ≥ 32 weeks of gestation, an extra dose of zidovudine plus lamivudine in addition to single-dose nevirapine at beginning of labor, then zidovudine plus lamivudine for 3 days post-partum. The infants received zidovudine for 7 days plus single-dose nevirapine on day 2 (22).  The overall frequency of nevirapine resistance was 1.14%. Although these data are promising both in terms of preventing transmission and decreasing the development of nevirapine resistance, the optimal regimen and duration are unknown.

Cross-resistance among nevirapine, delavirdine, and efavirenz is common and is shown in Table 3, as measured using a recombinant virus phenotypic assay (Virco) (67).  Fortunately, there is little overlap with mutations that confer resistance to N(t)RTIs or PIs. However, the combination of tenofovir and didanosine with either efavirenz or nevirapine has been associated with a high incidence of early virologic failure. These failures are often associated with high initial viral loads and mutation at G190S/E in combination with other NNRTI drug resistance associated mutations at virologic failure (79, 142). Yet this combination was not associated with high failure rates when used as a simplification regimen in patients who were already suppressed (14).

Additionally, etravirine, the most recently marketed NNRTI, represents a new generation of this class, demonstrating efficacy against HIV-1 resistant to the other NNRTIs. Two multinational, randomized, double-blind, placebo-controlled trials, DUET-1 and DUET-2, evaluated etravirine plus an optimized background regimen (including darunavir/ritonavir in all patients) in treatment-experienced patients with virologic failure (RNA>5000 copies/mL on current antiretroviral therapy), at least three primary PI mutations, and at least one NNRTI resistance mutation. The most common NNRTI resistance mutations in both trials were K103N, Y181C, and G190A. At week 24, virologic success (RNA<50 copies/mL) was achieved for 56% and 62% of patients receiving etravirine in DUET-1 and DUET-2, respectively, versus 39% and 44% of patients receiving placebo in DUET-1 and DUET-2, respectively (77, 84). These studies demonstrate that etravirine represents a treatment option in treatment-experienced patients with resistance to other NNRTIs.

 

PHARMACOKINETICS

Nevirapine

Nevirapine is well absorbed after oral administration. Absolute bioavailability appears > 90% and maximum concentrations are generally achieved by 4 hours after an oral dose. Absorption was not affected by concomitant administration with a high fat breakfast, antacids, or didanosine (16). Nevirapine is widely distributed in humans; it is highly lipophilic, essentially not ionized at physiologic pH, and is approximately 60% bound to plasma proteins. Nevirapine concentrations in the cerebrospinal fluid of 6 individuals were 45% ± 5% of corresponding plasma values: this ratio is approximately equivalent to the unbound fraction in plasma (54). Nevirapine readily crosses the placenta. This may be attributed to its low degree of protein binding (60%), a lower molecular weight (266), a relatively favorable degree of lipophilicity (log octanol:water partition coefficient 1.81) and/or because it is reportedly not a substrate of P-glycoprotein (88). One 200 mg oral dose of nevirapine administered to an HIV-positive mother during labor and a single 2 mg/kg dose administered to the newborn at 48-72 hours after birth maintains serum concentrations above 100 µg/L (10 times the in vitro 50% inhibitory concentration against wild-type HIV) throughout the first week of life. This regimen has been shown to reduce vertical transmission of the virus by nearly 50% in mothers and infants receiving no other antiretroviral therapy (60,93). For women receiving a single 200 mg dose of nevirapine, cord blood concentrations will exceed 100 µg/L provided the baby is delivered at least 1-2 hours after maternal administration (94). Nevirapine is present in breast milk. In 20 Ugandan women who received a single 200-mg dose of nevirapine during labor, the median nevirapine concentration in breast milk 1 week after delivery was 103 ng/ml (25-309 ng/ml) (99). Although nevirapine concentrations in breast milk were maintained above 100 µg/L in this study, the total amount of drug provided to a nursing infant was small, approximately 0.06 mg/kg on day 2 of life and 0.02 mg/kg on day 7.

Nevirapine is extensively metabolized by the cytochrome P450 system, principally by CYP 3A4 and CYP2B6. In a mass balance study in healthy volunteers, > 90% of a radiolabeled dose was recovered, mostly from the urine (81%) as glucuronidated metabolites (16). Renal excretion contributes little to the elimination of the parent compound. Nevirapine is also an inducer of cytochrome P450 enzymes, including those associated with its own metabolism. This autoinduction is characterized by a decrease in the terminal elimination half-life from approximately 45 hours after a single dose to 25-30 hours after 14 days of multiple doses, a 1.5 to 2-fold increase in apparent oral clearance, and a fall in trough concentrations (24, 66). Furthermore, recent data suggest that the CYP2B6-G516T genotype is associated with altered nevirapine pharmacokinetics in adults and children of different races (105, 117, 118). Available data do not indicate race-related differences in the oral clearance of nevirapine (116). Data do indicate that the oral clearance of nevirapine is slower in women than in men (154). Pharmacokinetic studies of nevirapine in children do indicate that oral clearance is higher in children than in adults. Children receiving multiple-doses of nevirapine at 120-240 mg/m2/day had an oral clearance of approximately 0.08 mL/kg/d, a value two-fold greater than that found for adults (83).

Delavirdine Mesylate

Delavirdine mesylate is a weak base with very low solubility at pH > 3. While the drug is usually rapidly absorbed after oral administration, reaching maximum concentrations within 1.5 hours following a dose, absorption can be delayed and reduced by an increase in gastric pH (49, 122). For example, simultaneous administration with an antacid reduced the delavirdine area under the concentration curve (AUC) by 48% (49). Food and didanosine also appear to delay and reduce delavirdine absorption, although under steady-state conditions these interactions do not appear to be clinically significant and patients can be allowed to take delavirdine with a meal, and with didanosine (97). In general, gastric hypoacidity or therapeutic agents that raise gastric pH should be expected to decrease delavirdine absorption and reduce plasma concentrations; delavirdine administration under these conditions should be avoided until proven otherwise.

Delavirdine is highly (98%) protein bound, which restricts systemic distribution (3). The penetration of delavirdine into cerebrospinal fluid appears quite low and likely clinically insignificant; in 5 adults, cerebrospinal fluid concentrations were 0.4% of corresponding plasma concentrations (3, 35).  Delavirdine is extensively metabolized, and renal clearance of unchanged drug is a negligible route of elimination. The cytochrome P450 system and isozymes of the 3A family are a significant pathway of metabolism for delavirdine. Delavirdine is not only a substrate for this enzyme system but is also a potent inhibitor. Thus, delavirdine (and/or its metabolites) can actually inhibit its own metabolism, and this appears responsible for the nonlinearities observed in delavirdine pharmacokinetics (27). These nonlinearities are characterized by a decrease in oral clearance, an increase in the terminal elimination half-life, and a greater than proportional increase in plasma concentrations with higher doses of delavirdine. Steady-state plasma concentrations, for example, at 600 mg daily, average 9.2 µMand 2.3 µM for maximum and minimum, respectively. A two-fold increase in dose to 1200 mg daily produced a four-fold increase in maximum concentrations to 36 µM and a seven-fold increase in minimum values to 16 µM (49). Moreover, delavirdine pharmacokinetics are highly variable between patients. As one illustration of this variability, the range in delavirdine trough concentrations in patients receiving 1200 mg daily appears to be from < 5 µM to approximately 50 µM, a more than ten-fold difference. This high degree of variability in delavirdine pharmacokinetics is consistent with known interpatient differences in cytochrome P450 activity. Furthermore, delavirdine metabolism has been shown to be circadian in nature, causing trough concentrations to be higher in the morning versus those in the evening. The clinical significance of this finding is unknown but is an important consideration, particularly for therapeutic drug monitoring (126).

Delavirdine pharmacokinetics have not been studied in individuals under 16 or over 65 years. The median delavirdine AUC was shown to be 31% higher in 12 females compared with 55 males receiving the standard dose of 400 mg thrice daily (3). At this time, dosing recommendations are the same for females and males. No significant racial difference in delavirdine trough concentrations has been reported.

Efavirenz

Efavirenz is well absorbed after oral administration. Peak efavirenz concentrations of 1.6-9.1 µmol/L were attained by 5 hours following single oral doses of 100-1600 mg to uninfected volunteers. In HIV-infected patients, 600 mg daily doses produced an average Cmax of 12.9 µmol/L, Cmin of 5.6 µmol/L, and oral clearances of 0.18 L/hr/kg.(133) Steady state plasma concentrations were reached in 6-10 days. The administration of efavirenz tablets and capsules with a high-fat meal (>54 g fat) should be avoided as it results in an increase in efavirenz AUC and Cmax and may increase the incidence of CNS adverse effects. At standard adult doses, efavirenz exhibits linear pharmacokinetics. Efavirenz is highly protein bound (approximately 99%). CSF concentrations in 10 patients receiving 600 mg daily averaged 35.1 nM, significantly higher than the reported IC90 for wild-type HIV-1. The penetration of efavirenz into the CSF ranged from 0.26-0.99% of total plasma concentrations, generally consistent with unbound concentration in plasma (138). Efavirenz has a terminal half-life of 52-76 hours after a single dose and 40-55 hours after multiple doses, as a result of autoinduction. CYP3A4 and CYP2B6 are the major isoenzymes responsible for the metabolism of efavirenz. Less than 1% of unchanged drug is excreted in the urine (17), therefore no dosage adjustment is required for reduced renal function. A study of a single 400 mg dose of efavirenz in 10 patients with chronic liver disease demonstrated a 35% decrease in Cmax and an increased half-life compared to healthy volunteers; however, there was no significant change in AUC. Monitoring for toxicity in these patients is warranted.

During Phase II trials of efavirenz, Black and Pacific Island races were noted to have reduced clearance of efavirenz compared to Caucasians, but this was not found in the analysis of Phase III trial data (13). A recent study by Burger and colleagues identified consistently higher plasma efavirenz concentrations in female and non-Caucasian patients (18). Further studies evaluating the effect of race and gender on the pharmacokinetics of efavirenz are warranted. Similar to nevirapine, the CYP2B6-G516T genotype has been shown to significantly alter the pharmacokinetics of efavirenz in adults and children of different races (62, 109, 114, 117, 118, 143, 148). Conversely, the effect of the CYP2B6-G516T genotype is greater for efavirenz as compared to nevirapine because CYP2B6 is the primary isoenzyme responsible for the metabolism of efavirenz (149). Efavirenz has demonstrated inhibiting and inducing abilities for several isoenzymes in the cytochrome system, which will be discussed further in the drug interactions section.

Etravirine

The absolute oral bioavailability of etravirine is unknown, but the systemic exposure to etravirine is decreased in a fasting state. Thus, etravirine should be taken following a meal. In HIV-infected patients, peak etravirine concentrations are reached by 4 hours following the dose after 7 days of treatment (51). Steady state plasma concentrations are reached in 4-6 days (51, 59). Etravirine is highly protein bound (over 99%). CNS penetration and CSF disposition of etravirine are unknown. Etravirine has an elimination half-life of approximately 30 to 40 hours (59). CYP3A4, CYP2C9, and CYP2C19 are the major isoenzymes responsible for the metabolism of etravirine; etravirine is eliminated as glucuronide conjugates and therefore is a substrate for uridine glucuronosyl transferase. Etravirine is primarily eliminated in the feces. No unchanged drug is excreted in the urine. The pharmacokinetics of etravirine have not been studied in patients with renal impairment. The steady state pharmacokinetics of etravirine were not significantly altered in patients with mild to moderate hepatic impairment. Etravirine has not been studied in severe hepatic impairment. Reduced clearance of etravirine is seen in patients coinfected with HIV and hepatitis B/C, but no dosage adjustment is warranted in these patient populations due to the favorable safety profile. Race and gender do not appear to affect the pharmacokinetics of etravirine, though a limited number of women were included in the evaluation of sex differences in pharmacokinetics. Etravirine has demonstrated inhibition and induction of several isoenzymes in the cytochrome system, which will be discussed further in the drug interactions section. Pharmacologic parameters of nevirapine, delavirdine, efavirenz, and etravirine are shown in Table 5.

 

DOSAGE (TABULAR)

Adults and Children

 

Adult Dosing 

The usual adult doses of nevirapine, delavirdine efavirenz, and etravirine are shown in Table 6.

Pediatric Dosing 

Nevirapine and efavirenz have both been clinically evaluated in children, and nevirapine is approved for use in children 2 months of age and older, and efavirenz is approved for use in children three years of age and older. For both drugs, children require a higher dose on a weight or body surface area basis than adults to maintain acceptable plasma concentrations. In a pharmacokinetic study of multiple-dose nevirapine, children 2 months to 13 years of age were administered 240 mg/m2/day of nevirapine following an induction-phase dose of 120 mg/m2/day. Oral clearance rates correlated with age and, consistent with enzymatic activity predictions, children 2 years of age and younger had the highest rates of nevirapine clearance, which was double the adult rate. The FDA approved doses of nevirapine for use in children are: for children 2 months up to 8 years of age, 4 mg/kg once daily for the first 14 days followed by 7 mg/kg twice daily thereafter. For children 8 years and older, the recommended dose is 4 mg/kg once daily followed by 4 mg/kg twice daily thereafter. The DHHS Panel for the Use of Antiretroviral Agents in Pediatric HIV Infection recommends mg/m2 dosing of nevirapine, with a maintenance dose of 150-200 mg/m2 twice daily. The basis for this recommendation is that the FDA-approved approach results in a substantial decrease in exposure when the eighth birthday is reached (a decrease in the maintenance dose from 7 to 4 mg/kg). Dosing based on body surface area provides a more consistent level of exposure in children and is the recommended dosing strategy. It is recommended that the total nevirapine dose not exceed 400 mg (16).  Safety and effectiveness of delavirdine have not been established in HIV-1 infected individuals younger than 16 years of age (3).

Efavirenz has been shown to be a highly effective drug in children and adolescents and has a relatively low incidence of adverse effects, and a prolonged half-life allowing once daily dosing. The FDA approved efavirenz dose ranges between 10-20 mg/kg/day for children three years of age or older and weighing between 10 and 39 kg, which is about double the recommended adult dose, reflecting the higher clearance of efavirenz on a weight basis in children compared with adults (132). Efavirenz dosing for pediatric patients 3 years of age or older and weighing between 10 and 39 kg is listed in Table 7 (17).

The recommended dosage of efavirenz for pediatric patients weighing 40 kg or more is 600 mg once daily.

The safety and effectiveness of etravirine have not been established in HIV-1 infected individuals younger than 18 years of age in comparative (e.g. versus protease inhibitors) controlled trials (141). Noncomparative investigations of efavirenz in children 2 years of age and older demonstrate safety and effectiveness consistent with that in HIV-infected adults (131, 132).

Renal Failure

Dose adjustment for renal insufficiency (mild to severe < 30 mL/min), does not appear necessary for nevirapine. However, subjects requiring dialysis exhibited a 44% reduction in nevirapine AUC over a one-week exposure period and an additional 200 mg dose following each dialysis is recommended (17, 69, 70, 139).  Dose adjustment for renal insufficiency for delavirdine has not been well studied but does not appear to be necessary (3). The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal and dose adjustment for renal insufficiency does not appear necessary (17). A case report of efavirenz use in chronic peritoneal dialysis found no need for dose adjustment (53).  The pharmacokinetics of etravirine have not been studied in patients with renal impairment. As suggested for efavirenz, because no unchanged etravirine is excreted in the urine, the impact of renal insufficiency on the elimination of etravirine should be negligible.

Hepatic Failure

In the majority of patients with mild or moderate hepatic impairment, no significant changes in the pharmacokinetics of nevirapine were seen in a single dose study but an increase in the AUC of nevirapine has been observed in one patient with Child-Pugh Class B and ascites. This suggests that patients with severe hepatic function and ascites may be at risk of accumulating nevirapine and the manufacturer recommends that nevirapine not be administered to patients with severe hepatic impairment (16). It is also recognized that the risk for hepatotoxicity from nevirapine is increased in persons with chronic hepatitis.

The pharmacokinetics of delavirdine, and efavirenz have not been evaluated in patients with hepatic dysfunction. Nevertheless, these agents are metabolized primarily by the liver and should be used with caution in patients with impaired hepatic function.

No dosage adjustment is required for etravirine in patients with mild (Child-Pugh Class A) to moderate (Child-Pugh Class B) hepatic impairment. The pharmacokinetics of etravirine have not been studied in patients with severe (Child-Pugh Class C) hepatic impairment. However, because etravirine is metabolized primarily by the liver, caution should be advised when using etravirine for these patients.

Body Composition

Neither weight nor age (range 18-68 years) appears to affect dosing requirements of nevirapine for adults (16, 98). However, none of the NNRTIs have been extensively evaluated in patients beyond the age of 65 years.

Ascites/Edema

The effect of ascites or edema on pharmacokinetic disposition has also not been evaluated for any of the NNRTI agents

Diarrhea, Malabsorption

Nevirapine has similar absorption whether taken with a fatty meal or administered with antacids or fasting (16).

Delavirdine tablets may be administered with or without food. HIV-infected subjects with gastric hypoacidity significantly malabsorb delavirdine so patients with achlorhydria should take this drug with an acidic beverage (e.g., orange or cranberry juice). Delavirdine administration with acidic beverages improves, but dose not normalize, absorption in these subjects (123).

It is recommended that efavirenz be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of this drug with food might lead to an increase in frequency of CNS side effects (17).

Etravirine should be taken with a meal. The systemic exposure is significantly decreased if taken in a fasting state. The caloric content of the meal does not appear to affect the pharmacokinetics of etravirine (141).

Malnutrition

It is not known whether malnutrition alters the pharmacokinetics of nevirapine, delavirdine, efavirenz, or etravirine.

Pregnancy

No dosage adjustment is recommended for NNRTI therapy during pregnancy. Nevirapine and delavirdine are FDA Category C. Delavirdine has demonstrated ventricular septal defects in rodent teratogenicity studies. Efavirenz is category D and caused malformations in 3 of 20 fetal cynomolgous monkeys including anencephaly, anophthalmia and microphthalmia. Four reports were received by the FDA of neural tube defects in infants born to mothers who took efavirenz during the first trimester; therefore, efavirenz should not be administered during pregnancy. Etravirine is FDA Category B. Reproduction studies in rats and rabbits have not revealed any evidence of fetal harm, but studies in humans are lacking.

Nevirapine is the best studied and best tolerated antiretroviral agent used to prevent perinatal transmission and its use is recommended by the several consensus guidelines (1).

 

ADVERSE EFFECTS

Nevirapine

The most common adverse effects associated with nevirapine therapy are rash and hepatitis. Severe, life threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis and hepatic failure, have been reported (16). Serious hepatic events occur most frequently during the first 12-16 weeks of therapy although may occur at any time during treatment. Patients with signs or symptoms of hepatitis should be evaluated promptly with liver function testing and be advised to discontinue nevirapine as soon as possible. A higher frequency of hepatic events has been seen in women with pretreatment CD4 cell counts above 250 cells/mm3 and in men with pretreatment CD4 cell counts above 400 cells/mm3. Thus, nevirapine should not be used in these individuals.(101). Serious hepatotoxicity (including liver failure requiring transplantation in one instance) has even been reported in HIV-uninfected individuals receiving multiple doses of nevirapine in the setting of post-exposure prophylaxis (120).

Co-infection with hepatitis B and/or C, a CD4+ T cell count of more than 350 cells/mm3 prior to the start of antiretroviral therapy and female gender all seem to be associated with increased risk of hepatic adverse events with nevirapine.

Rash has been reported with nevirapine therapy in 15 – 30% of patients and may require discontinuation in about 7% (12, 16, 98). A 14-day lead-in period of 200 mg/day (4 mg/kg/day in pediatric patients) has been shown to reduce the frequency of rash and is generally recommended (26). If rash is observed during the lead-in period, dose escalation should not occur until the rash has resolved. The rash is most commonly maculopapular and mild to moderate. Although the precise mechanism is unclear, skin biopsies have demonstrated nonspecific inflammatory changes and some have shown perivascular infiltration consistent with a drug eruption. Immune complex deposition has not been observed. Rash typically occurs within six weeks of initiation of treatment and, in general, the rashes are self-limiting and rarely require treatment although antihistamines and topical steroid therapy can be used. However, severe, life-threatening skin reactions, including fatal cases, have been reported with nevirapine treatment and include Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Some of the risk factors for developing serious cutaneous reactions include failure to follow the initial dosing of 200 mg daily during the 14-day lead-in period and delay in stopping the nevirapine treatment after the onset of the initial symptoms. Women appear to be at higher risk than men of developing rash with nevirapine. Additionally, CD4+ T-cell count may be associated with the risk of rash with nevirapine. A recent study of over 900 antiretroviral-naïve patients with a CD4 cell count < 250 cells/mm3 who were started on a nevirapine-containing regimen demonstrated that patients with higher baseline CD4 cell counts had a higher probability of nevirapine-associated rashes (87).

In a clinical trial, concomitant prednisone use was associated with an increase in incidence and severity of rash during the first 6 weeks of nevirapine therapy and is therefore not recommended to prevent rash (151).

Delavirdine Mesylate

Rash is also a common adverse effect observed to date with delavirdine therapy with an overall incidence around 35% (3). The rash associated with delavirdine is also maculopapular occurring between 7 and 15 days after initiating treatment. The occurrence, but not severity, of the rash appears to correlate with CD4+ T-cell count and occurs more frequently in patients with <100 CD4 cells/mm3. Like nevirapine, the incidence of rash appears unrelated to dose or blood level of delavirdine. Pruritus occurs in one third of patients who develop rash though other symptoms have not been observed. Clinical trial experience has demonstrated that continuing treatment is possible in >85% of patients who develop rash (49). Dosing through the rash with medication for symptomatic relief, or dose interruption with resumption at a lower dose that is increased over two weeks, have both been successful. Severe skin reactions are rare with delavirdine. Other adverse effects are headache, fatigue, and gastrointestinal complaints, including occasional increase in transaminase levels (3).

Efavirenz

The most common adverse effects with efavirenz therapy are central nervous system symptoms, rash and hepatitis. Nervous system symptoms have been reported by 53% of subjects receiving efavirenz in controlled trials compared to 25% receiving control regimens (17). These symptoms include (in order of frequency): dizziness, insomnia, impaired concentration, somnolence, abnormal dreams, and hallucinations. Generally mild to moderate and self-limiting (within 2 – 4 weeks), these symptoms led to discontinuation of therapy in only 2% of cases. Dosing at bedtime may improve the tolerability of these nervous system symptoms and patients should be alerted to the potential for additive central nervous system effects when efavirenz is used concomitantly with alcohol or psychoactive drugs, and to avoid potentially hazardous tasks such as driving or operating machinery. Limited data exist regarding an association between an increased prevalence of central nervous system effects and ethnicity, and this relationship is likely due to higher plasma concentrations seen in these racial groups due to a CYP2B6 allelic variant (61).

Serious psychiatric adverse experiences have also been reported including severe depression, suicidal ideation, non-fatal suicide attempts, aggressive behavior, paranoid reactions and manic reactions. Patients with a history of psychiatric disorders may be at greater risk of these serious psychiatric adverse experiences, and many providers avoid using the drug in patients at risk. As with the other drugs in this class, rash can occur in up to 26% of patients. Severe rash is rare; the median time to onset of rash in adults was 11 days and the median duration was 16 days (17). Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash.

Unlike other antiretroviral drug classes, the NNRTIs are not commonly associated with metabolic complications after long-term therapy. The exception to this is the potential contribution of efavirenz to HIV-associated dyslipidemia although the mechanism underlying this is not known (130, 137).

Etravirine

The most common adverse event observed to date with etravirine is rash, with an overall incidence of 9% versus 3.1% with placebo (141). The rash associated with etravirine is maculopapular, occurred within the first few weeks of therapy, and resolved within a few weeks of continued therapy. The occurrence, but not severity, of the rash appears to correlate with gender, occurring more frequently in female patients (84). Severe skin reactions are rare with etravirine. Clinical trial experience has demonstrated no significant differences in neuropsychiatric events or laboratory abnormalities for etravirine versus placebo.

Overdose

There are no known antidotes for overdosing with nevirapine, delavirdine, efavirenz, or etravirine. Cases of nevirapine overdose at doses ranging from 800 to 1800 mg per day for up to 15 days have been reported (16). Treatment of over dosage with NNRTIs includes general supportive measures and elimination of unabsorbed drug by emesis, gastric lavage, or administration of activated charcoal, if indicated. Since delavirdine, efavirenz, and etravirine are extensively metabolized by the liver and highly protein bound, dialysis is unlikely to result in significant removal of the drugs.

MONITORING REQUIREMENTS

Therapeutic Drug Monitoring

In general, antiretroviral agents meet most of the characteristics of agents that can be considered as candidates for a therapeutic drug monitoring (TDM) strategy. For NNRTIs, the rationale for TDM arises in particular from data showing considerable interpatient variability in concentrations among patients who take the same dose, and data indicating relationships between the concentration of drug in the body, the anti-HIV effect and in some cases, toxicity. The data describing relationships between anti-HIV agents and response have been reviewed in various publications (2, 10, 19, 32, 144).

There are limitations and unanswered questions in these data; however, the data do provide a framework for the potential implementation of TDM for NNRTIs and consensus guidelines of US and European clinical pharmacologists have been published (100). The recommended threshold trough concentration for patients with wild-type virus susceptibility to nevirapine is 3.4 mg/L. Support for this value arises in large part from the INCAS trial that demonstrated patients with nevirapine concentrations above 3.4 mg/L (12.7 µM) reached undetectable levels of HIV-1 RNA in plasma more rapidly than those who had lower trough concentrations. In this study, the median nevirapine plasma concentration was significantly correlated with success of therapy after 52 weeks (146). These findings were similar to those of an observational cohort study evaluating 189 HIV-infected patients receiving nevirapine. This study showed that patients with a nevirapine trough level of 3 mg/L (11.2 µM) or less were significantly more likely to have virologic failure (36). Although data from the 2NN study show that the risk of virologic failure with nevirapine started to increase with a trough level less than 3.1 mg/L, there was no cutoff value below which a statistically significant increased risk occurred, suggesting that the use of a trough level for the sole purpose of predicting virologic failure is questionable(80). The recommended threshold trough concentration for efavirenz is 1.0 mg/L (3.2µM) in patients with wild-type virus susceptibility. In a study of 130 patients with HIV on an efavirenz-based antiretroviral regimen, 50% of patients with an efavirenz trough of less than 1 mg/L experienced virologic failure versus 22% in patients with efavirenz concentrations between 1-4 mg/L. This same study showed that CNS toxicity was approximately three times more frequent in patients whose efavirenz levels exceed 4 mg/L (89). These findings were corroborated by the 2 NN study, which showed that patients with predicted efavirenz trough levels of at least 1.1 mg/L were less likely to experience virologic failure (80). Guidelines for the collection of blood samples and other practical suggestions can be found in a position paper published by the Adult AIDS Clinical Trials Group Pharmacology Committee (2, 100).  Nov 15;47(10):1339-44.

Other Laboratory Monitoring

Liver function tests should be monitored in patients on NNRTI therapy, especially during the first few weeks of therapy. The optimal frequency of monitoring during this time period has not been established but most experts recommend clinical and laboratory monitoring at baseline, prior to nevirapine dose escalation and at two weeks post-dose escalation. After the initial treatment period, periodic laboratory monitoring should continue about every 3 months. Monitoring of cholesterol and triglycerides should be considered in patients treated with efavirenz.

 

DRUG INTERACTIONS

Nevirapine

Nevirapine is an inducer of hepatic cytochrome P450 3A; maximal induction seems to occur within two to four weeks of multiple dosing. Thus, nevirapine has the potential ability to decrease concentrations of other agents metabolized by these same isozymes. For example, nevirapine has been shown to decrease saquinavir maximum concentrations by 29% and the AUC by 27% and this combination should be avoided (16). The effect of nevirapine on the pharmacokinetics of indinavir has been evaluated in 24 HIV-infected persons. The indinavir AUC was 28% lower, peak concentration 11% lower, and trough concentration 38% lower when administered with nevirapine (16). These results appear consistent with the known ability of nevirapine to induce the hepatic cytochrome enzyme 3A. An increase in the dose of indinavir to 1000 mg every 8 hours, or the addition of ritonavir is recommended if indinavir and nevirapine are to be co-administered; however, the clinical safety, tolerance, and antiviral effect of this combination has not been evaluated. The effect of nevirapine on the pharmacokinetics of ritonavir has also been evaluated. This combination was studied in 24 HIV-infected persons, although only 14 had evaluable data. Results indicate that the ritonavir AUC was 11% less, peak concentrations were 10% lower, and trough concentrations 9% lower when given with nevirapine. These differences were not statistically significant, and no changes in the ritonavir dosing regimen are recommended (15). Neither indinavir nor ritonavir affected the pharmacokinetics of nevirapine. The AUC of nelfinavir may also be reduced necessitating an increased nelfinavir dose, but clear guidelines are lacking for these combinations. The effect of nevirapine on lopinavir/ritonavir (400/100 mg) has been studied and shown to lower the AUC, peak concentration, and trough concentration by 27, 19, and 51%, respectively (16). When used in combination, lopinavir/ritonavir should be increased to 600/150 mg twice daily in treatment-experienced patients. The lopinavir/ritonavir 400/100 mg tablets may be given twice daily in treatment-naïve patients. Lopinavir/ritonavir should not be administered as a once daily regimen with nevirapine.

As an inducer of metabolism, nevirapine has a theoretical ability to decrease the plasma concentrations of oral contraceptive agents and increase the risk of contraceptive failure. Concomitant administration of nevirapine at steady state and ethinyl estradiol/norethindrone resulted in a 29% reduction in ethinyl estradiol AUC and an 18% reduction in norethindrone AUC in 10 HIV-infected women (92). Therefore, oral contraceptives should not be the primary method of birth control in women of childbearing potential who are treated with nevirapine. Several case reports have described methadone withdrawal of varying degrees in patients receiving nevirapine therapy. Pharmacokinetic studies support these findings, with 40-50% reductions in methadone AUC in patients initiated on a nevirapine-containing antiretroviral regimen. There is however, wide inter-individual variability, and not all patients require increases in methadone dosage(28, 134). Nevirapine has been shown to induce the metabolism of itraconazole, causing a decrease in the Cmax, AUC, and half-life of itraconazole of 38%, 61%, and 31%, respectively. In contrast, itraconazole did not have an effect on the pharmacokinetics of nevirapine (73). Nevirapine can reduce zidovudine plasma concentrations by approximately 25%(30). This interaction is most likely a result of induction of glucuronyl transferase activity by nevirapine. Nevirapine has had no effect on the pharmacokinetics of either didanosine or zalcitabine (16).

Nevirapine is extensively metabolized by the cytochrome P450 system and is a substrate for isozymes from the 3A family. Therefore, the metabolism of nevirapine has the potential to be increased by inducers, or decreased by inhibitors of these enzymes. Rifampin and rifabutin are well-known enzyme inducers and have been shown to reduce steady-state nevirapine trough concentrations by 37% and 16%, respectively (16). Clinical studies suggest that nevirapine-based combination regimens in patients receiving rifampin are reasonably effective and well tolerated. Nevirapine is considered an acceptable alternative to efavirenz when rifabutin is not available (86). Ketoconazole is an enzyme inhibitor, and was shown in in vitro experiments to inhibit nevirapine metabolism. However, pharmacokinetic studies in 11 patients receiving nevirapine and ketoconazole found no apparent inhibition of nevirapine metabolism. These contradictory findings seem to warrant additional clinical investigation, especially because cimetidine and macrolide antibiotics have both been shown to inhibit nevirapine metabolism and increase trough concentrations by 21% and 12%, respectively (16). Co-administration of nevirapine plus darunavir/ritonavir (400/100 mg twice daily) led to increases in the nevirapine AUC, peak concentration, and trough concentration of 27, 18, and 47%, respectively. However, these drugs can be co-administered without any dosage adjustments (140).

Delavirdine Mesylate

Like nevirapine, the metabolism of delavirdine is mediated by hepatic cytochrome enzymes including those of the 3A family. Thus, there exists the potential for the clearance of delavirdine to be affected by inducers or inhibitors of these isozymes. Concomitant administration of delavirdine with rifabutin decreased delavirdine concentrations by five-fold, while administration with rifampin decreased concentrations by 27-fold (49). Neither rifabutin nor rifampin should be co-administered with delavirdine. Fluconazole and clarithromycin are inhibitors of hepatic drug metabolism. Clinical investigations have found that fluconazole did not affect delavirdine metabolism, and there was no overall significant interaction between delavirdine and clarithromycin. However, clarithromycin does have some ability to inhibit delavirdine metabolism, and there may be certain patients particularly susceptible to this interaction. While there is no apparent contraindication to concomitant administration of these two agents, careful clinical monitoring of delavirdine tolerance is recommended.

Delavirdine, in contrast to nevirapine, is a potent inhibitor of hepatic metabolism. In healthy volunteers, delavirdine increased the AUC of indinavir by approximately 70 to 90% (3). On the basis of these data, the dose of indinavir would need to be reduced from the approved 800 mg every 8 hours if delavirdine and indinavir are given as combination therapy. An indinavir dose of 400 or 600 mg every 8 hours has been suggested, but clinical safety and efficacy data in HIV-infected patients are lacking. Delavirdine also inhibits the metabolism of saquinavir, increasing the steady-state concentration an average of six-fold (3). There appears to be considerable interpatient variability in the magnitude of this interaction, however, as individual trough saquinavir concentrations were increased from two- to 15-fold. Delavirdine did not demonstrate inhibition of ritonavir metabolism, nor did ritonavir affect the metabolism of delavirdine in a study in healthy volunteers. There are no available data on the combination of delavirdine and nelfinavir. Perhaps the most serious potential interactions with delavirdine exist in concomitant use with certain non-sedating antihistamines, such as terfenadine and astemizole, and other cytochrome P450 3A substrates like cisapride. Combinations of these agents and other inhibitors of cytochrome P450 3A have lead to significant arrhythmias that can be fatal (68, 107). The mechanism of this interaction is inhibition of metabolism of the parent drug, leading to accumulation of the parent drug, which can be cardiotoxic. Delavirdine is contraindicated for concomitant use with these agents.

Efavirenz

Efavirenz is principally metabolized by CYP 2B6 and 3A4 to hydroxylated metabolites with subsequent glucuronidation. In vitro, efavirenz is an inhibitor of CYP3A4, CYP2C9, and CYP2C19. However, its effect on CYP3A4 is mixed, as it has also been shown to induce this enzyme. Efavirenz also induces its own metabolism.

When indinavir 800 mg thrice daily is co administered with efavirenz, the indinavir AUC is decreased by approximately 31% and Cmax decreased by 16%. It is therefore suggested that patients receive 1000 mg of indinavir thrice daily when used concomitantly with efavirenz, or have ritonavir added to their regimen (66, 133). Similarly, when co administered with efavirenz, lopinavir AUC and trough concentration are reduced by 19 and 39%, respectively (17). Thus, a dose increase of lopinavir/ritonavir is warranted when used in combination with efavirenz. However, the recommended increased dose of lopinavir/ritonavir is 533/133 mg, which is no longer possible with the new tablet formulation; therefore, the dose of lopinavir/ritonavir should be increased to 600/150 mg twice daily. Saquinavir AUC and Cmax were reduced by 62% and 50% respectively when dosed with efavirenz in a study of 12 healthy volunteers. Therefore, use of saquinavir as a single protease inhibitor with efavirenz is not recommended, but co-administration of saquinavir with ritonavir could be considered (17). Atazanavir AUC, peak concentration, and trough concentration were decreased by 74, 59, and 93%, respectively, when co-administered with efavirenz. In contrast, when atazanavir is boosted with ritonavir 100 mg the AUC, peak concentration, and trough concentration increase by 39, 14, and 48%, respectively, as compared to atazanavir alone. Thus, in treatment-naïve patients, the recommended daily dose of atazanavir is 300 mg with ritonavir 100 mg when co-administered with efavirenz. The dosage adjustments in treatment-experienced patients have not been delineated. Co-administration of darunavir/ritonavir (300/100 mg twice daily) with efavirenz leads to reductions in the AUC of 13%, the peak concentration of 15%, and the trough concentration of 31%. Conversely, the efavirenz AUC and trough concentration were increased by 21 and 17%, respectively. The significance of this interaction has not been established, and this combination should be used with caution.

Rifamycins are commonly used in the treatment of mycobacterial infections associated with HIV disease. Rifabutin is often selected because it is a less potent inducer of CYP3A than the other rifamycins, thereby lessening the chances of reduced concentrations of antiretrovirals. However, rifabutin Cmax and AUC are reduced by 32% and 38% respectively when given with efavirenz. An increase in rifabutin dose to 450-600 mg daily may be warranted if patients are on an antiretroviral regimen that contains efavirenz and no protease inhibitor. Rifampin has been shown to decrease the Cmax and AUC of efavirenz by 20 and 26% respectively. It had been advised to increase the efavirenz dose to 800 mg when concomitant treatment with rifampin is necessary (82), especially for patients weighing more than 60 kg. However, this increased dose is not currently recommended (101).

Methadone AUC is reduced by approximately 50% when administered with efavirenz. But, like nevirapine, reduced methadone concentrations do not always correlate with clinical effect. Physicians should monitor patients receiving methadone-maintenance who are initiating an efavirenz-based antiretroviral regimen for symptoms of withdrawal.

Oral contraceptive concentrations are increased by efavirenz, but the clinical significance of this interaction is unknown.

Etravirine

Etravirine is primarily metabolized by the CYP3A4, CYP2C9, and CYP2C19 isoenzymes. Etravirine has been shown to be an inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19.

Concomitant administration of etravirine with either atazanavir or indinavir without ritonavir results in decreased levels of the PI. Etravirine administration with atazanavir/ritonavir may decrease the atazanavir trough level by about 38% and increase the etravirine exposure by 100% due to CYP3A4 induction by etravirine and CYP3A4/2C9 inhibition by atazanavir, respectively. This combination is not recommended. Etravirine significantly increases the amprenavir AUC, peak concentration, and trough concentration by 69, 62, and 77%, respectively, when given with fosamprenavir/ritonavir. Because the dose adjustment of fosamprenavir has not been determined, this combination is not recommended. Etravirine should not be co-administered with the standard dose of ritonavir (600 mg bid) because ritonavir significantly decreases the plasma concentrations of etravirine. Administration of tipranavir/ritonavir plus etravirine results in significantly decreased levels of etravirine due to induction of CYP3A4, and co-administration is not recommended. Likewise, darunavir/ritonavir decreases exposure to etravirine, but due to the favorable results of the DUET-1 and DUET-2 studies, in which patients received etravirine in combination with darunavir/ritonavir, the FDA has not recommended a dose adjustment for this combination. However, for patients who are dissimilar to those in the DUET studies (i.e., would not meet inclusion criteria), the clinical significance of this interaction is unknown. Lopinavir/ritonavir results in an 85% increase in systemic exposure of etravirine; this combination should be administered with caution.

Although clarithromycin exposure was decreased by etravirine, the concentrations of the active metabolite, 14-hydroxy-clarithromycin were increased. The clinical effect of this interaction is unknown, but alternatives to clarithromycin, such as azithromycin, are preferred. Rifampin is a potent inducer of CYP3A4 isoenzyme, and co-administration with etravirine is not advised. However, rifabutin may be used with etravirine at a dose of 300 mg once daily if a boosted PI is not part of the antiretroviral regimen.

Atorvastatin and etravirine may be co-administered, but the clinical response to atorvastatin should be closely monitored.

Concomitant administration of etravirine and methadone is permitted (119). Clinicians should monitor patients receiving methadone-maintenance who are initiating an etravirine-based antiretroviral regimen for symptoms of withdrawal.

 

CLINICAL INDICATIONS

All four licensed NNRTIs are indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. These indications are based on clinical trials demonstrating prolonged suppression of HIV-RNA (3, 16, 17, 77, 84). Unlicensed uses of these drugs include prevention of perinatal transmission, prevention of occupational exposure, and prevention of non-occupational exposure (1).  Nevirapine is not recommended for post-exposure prophylaxis because of reported cases of hepatotoxicity (120), and efavirenz may be problematic because of the central nervous system side effects and also potential teratogenicity in female health care workers of child bearing potential (17). Efavirenz and delavirdine should also be avoided during pregnancy because of teratogenic potential. Etravirine is indicated for treatment of HIV-1-infected patients with virologic failure and resistance to NNRTIs and other antiretrovirals. Etravirine is the first NNRTI to show activity in treatment-experienced patients with NNRTI-resistant virus.

 

CONCLUSIONS

NNRTIs have an established and important role in the treatment of HIV-1 infection. High antiviral potency, high specificity, and minimal metabolic complications have all contributed to the popularity of NNRTI-based regimens. The combination of efavirenz plus abacavir and lamivudine or efavirenz plus emtricitabine and tenofovir (now available in a single combination product, Atripla) are the preferred NNRTI-based regimens, providing pill burdens that were once unimaginable. With the exception of etravirine, the major vulnerability of this class is the potential for rapid emergence of resistance with almost universal cross-resistance between nevirapine, delavirdine, and efavirenz. Other promising second generation compounds are in development, which may further expand the usefulness of the class of antiretroviral agents.

 

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Tables

Figure 1.  Structural Formulae of Nevirapine, Delavirdine, Efavirenz

Table 1.  Inhibitory Activities of the Nonnucleoside Reverse Transcriptase Inhibitors Nevirapine, Delavirdine and Efavirenz in A Variety of Cell Lines.  The Nucleoside Analogues Zidovudine and Didanosine are also Shown for Comparison.

Inhibitory activities of nucleoside and nonnucleoside RT inhibitors in a variety of cell lines
Compound	IC50 (µM)*	Reference
Zidovudine	0.027	61
Didanosine	0.05	35
Nevirapine	0.010-0.040	60
Delavirdine	0.066	35
Efavirenz	0.34-5	92

*IC50 corresponds to the drug concentration required to inhibit HIV-1 replication and cytopathicity by 50% in culture.

Table 2.   Mutations in the Reverse Transcriptase (RT) Gene Associated with Drug Resistance To NNRTI. 

HIV-1 RT Codons Associated with Drug Resistance
Agent	L100I	K103N	V106A	V1081	Y191C/I	Y188C/L/H	G190A/S	P225H	P236L
Nevirapine	X	X	X	X	X	X	X
Delavirdine		X			X				X
Efavirenz	X	X		X	X	X	X	X

 

Table 3. Fold Increase of IC50 For Some Commonly Selected Mutations as Compared to Wild-Type Virus.

RT Mutant	NVP	DLV	EFV
L100l	3.1	30	10
K103N	55	52	26
Y181C	161	35	3
Y188L	> 500	9	109
G190A	75	0.5	7.6
K103N, Y181C	> 500	> 250	31
K103N, G190A	> 500	37	213

 

   Table 4.  NNRTI Cross-Resistance – Virco Database N=5000 (50). 

NVP	DLV	EFV	%
R	S	S	3%
R	R	S	12%
R	S	R	6%
R	R	R	79%

 R = Resistant; S = Sensitive

% refers to the proportion of the 5,000 isolated in the Virco database

Table 5.  Pharmacologic Parameters of Nevirapine, Delavirdine, and Efavirenz. 

Drug Approximate Plasma	In VitroSusceptibility	F %	Vd/F (L/Kg) Cmax/Cmin	T ½ (hr)	CL/F (L/kg/h) (Range, µm)	Adult Dose
Nevirapine daily	0.01-0.1 27/16	90	1.4	25	0.04	200 mg twice
Delavirdine daily	0.001-0.69 36/16	85*	1.0	7	0.07	400 mg twice
Efavirenz	0.34-5	NA	NA 13/6	40-55	0.18	600 mg once daily

 * not available  

        

Abbreviations:  F, bioavailability; Vd/F, apparent steady-state distribution volume;         

T1/2, elimination half-life; CL/F, oral clearance; Cmax, maximum plasma concentration; Cmin, minimum plasma concentration

 

Table 6. The Usual Adult Doses of Nevirapine, Delavirdine, and Efavirenz.    

Usual Adult Dose
NVP (12)	200 mg bid after 200 mg/day lead in for 2 weeks. Patients who interrupt nevirapine dosing for more than 7 days should restart with lead-in.
DLV (2)	400 mg tid
EFV (14)	600 mg daily

  NVP = nevirapine   DLV = delavirdine   EFV = efavirenz   bid=twice daily   tid=three times a day

Table 7. Efavirenz Pediatric Dose.

Body Weight in Kg	Efavirenz Once Daily Dose
10 kg to < 15 kg	200 mg
15 kg to < 20 kg	250 mg
20 kg to < 25 kg	300 mg
25 kg to < 32.5 kg	350 mg
32.5 kg to < 40 kg	400 mg

 

What's New

Gutiérrez-Valencia A, López-Cortés LF, et al. Stepped-Dose vs. Full-Dose Efavirenz for HIV Infection and Neuropsychiatric Adverse Events: A Randomized Trial. Ann Intern Med. 2009 Jul 6. [Epub ahead of print]

FDA.  New intelence labeling: severe skin and hypersensitivity reactions. 

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