HIV affects over 40 million people of diverse racial and ethnic populations throughout the world . The global AIDS epidemic continues to grow and there is concerning evidence that some countries are seeing a resurgence in new HIV infection rates which were previously stable or declining. Although HIV infection is not yet curable, morbidity and mortality have significantly declined with the increased use of highly active antiretroviral therapy (HAART) [2–4]. However, certain subpopulations remain at increased risk. Racial and ethnic minority communities are disproportionately affected by HIV/AIDS. In 2005, estimated rates of HIV/AIDS cases per 100 000 in the United States were 54.1 in black, 18.0 in Hispanic, and 5.9 in white populations .
Numerous HIV treatment guidelines recommend efavirenz (EFV) as the preferred nonnucleoside reverse transcriptase inhibitor (NNRTI) component of HAART in HIV treatment-naive individuals [6,7]. Randomized, controlled trials and cohort studies in treatment-naive patients have all demonstrated superior or similar viral suppression in the EFV-treated patients compared with other regimens. Specifically, these studies compared EFV and two nucleoside reverse transcriptase inhibitors (NRTIs) with various protease inhibitor-based, nevirapine (NVP)-based, or triple NRTI-based regimens in treatment-naïve patients [8–15]. EFV has a long half-life (40–55 h after repeated dosing) that allows for a durable reduction in HIV RNA with once daily dosing . EFV pharmacokinetic profiles vary between individuals. Recent developments indicate an increasing role of pharmacogenetics and EFV metabolism, which has been demonstrated in different racial populations. The purpose of this review is to provide an overview of the available data to assess the impact of race/ethnicity on the clinical response to EFV.
Central nervous system effects and efavirenz exposure
EFV is widely distributed in body compartments and is, therefore, likely to be effective in protected tissues such as the central nervous system (CNS) and testes [17–19]. CNS side effects have been reported in 40–70% of patients who receive EFV . These side effects include dizziness, insomnia, impaired concentration, somnolence, abnormal dreams, and hallucinations, but are usually resolved within the first 2–4 weeks of treatment . In A5097s, a substudy  of the randomized, controlled AIDS Clinical Trials Group (ACTG) Study A5095, neurologic symptoms were correlated with EFV trough plasma concentrations at week 1 (P = 0.040), but not at weeks 4, 12, or 24. Six percent of patients discontinued treatment owing to CNS effects.
The adverse effects of CNS due to EFV are reported to be more frequent in patients with higher EFV plasma concentrations, although these effects diminish over time [23,24]. Other studies are less supportive of such a correlation. The initial large, multinational, randomized two nonnucleoside (2NN) study  did not show a significant difference in reported CNS adverse effects between EFV (600 mg) given once daily and NVP (200 mg) given twice daily. A substudy of 2NN  demonstrated that plasma concentrations of NVP and EFV were generally not related to adverse events. The only exception was a significant association between EFV exposure during the induction phase and the incidence of elevated liver enzymes within the first 6 weeks. No other correlations between adverse events and EFV pharmacokinetics or patient characteristics were identified.
A retrospective analysis of population pharmacokinetic data from 524 antiretroviral-naive patients in phase II/III clinical trials who received EFV (600 mg) once daily was evaluated in association with nervous system side effects (NSS). Of 295 patients (56%) who had NSS, 184 were mild in intensity, 97 were moderate, and 14 were severe. Presence and severity or absence of nervous system symptoms were not correlated with EFV plasma concentrations [area under curve (AUC) (P = 0.968) or Cmax (P = 0.694)]. Thus, on the basis of EFV pharmacokinetic parameters, there was no correlation with reports of NSS . In a study with 60 patients on an EFV-based regimen for at least 1 year, Fumaz et al. found no association between CNS adverse effects and EFV plasma levels. Mean EFV plasma levels (mg/l) were not significantly different between patients with (2.5 ± 1.1) and without (2.7 ± 0.7) neuropsychiatric disorders (P = 0.66). The mechanism of EFV-associated CNS adverse effects has not been determined. Although EFV metabolism may play a role, a clear relationship between EFV concentrations and CNS effects has not been demonstrated. Future studies should evaluate the relationship between EFV concentrations in the cerebrospinal fluid and CNS effects.
It has been postulated that patients with a history of psychiatric disorders or substance abuse or both may have a higher incidence of CNS effects with EFV use. Observational cohort studies which evaluated the short-term incidence of adverse events and treatment interruptions of patients using EFV showed that intravenous drug users had higher treatment discontinuation rates due to intolerance of side effects than nonintravenous drug users (22.6 vs. 6.6%) . Similar results were observed in patients taking methadone as a substitution treatment (19.1 vs. 7.9%) . However, studies which examined abuse of other substances (cocaine, ethanol, cannabis) found no significant differences in CNS side effects or discontinuation rates between recreational substance users and nonusers [31,32]. A review by Halman  determined that a history of mental health disorders is not in and of itself a risk factor for the emergence of EFV-related psychiatric side effects, particularly if the mental health disorder is being adequately treated. The available data indicate that prior psychiatric history or recreational substance abuse is not a contraindication to the use of EFV. However, EFV use in patients with a history of substance abuse should be weighed against underlying lifestyle issues pertinent to this patient population, such as nonadherence and potential drug interactions, which may further increase the probability of CNS side effects.
Impact of race/ethnicity on clinical response to efavirenz therapy
A post-hoc analysis of 1228 patients from study DMP266-006  was performed to determine the incidence of NSS by racial categories after 96 weeks of treatment. The percentage of NSS in 763 white, 256 black, and 209 Hispanic patients treated with EFV and indinavir (IDV) was 57% white, 43% black, 57% Hispanic; EFV, zidovudine (ZDV) along with lamivudine (3TC), 60% white, 56% black, 56% Hispanic; or IDV, ZDV together with 3TC, 30% white, 25% black, 17% Hispanic. Most NSS adverse events were mild (grade 1), and occurred during the first 4 weeks regardless of race. The observed differences were not statistically significant (P > 0.05). There were no racial differences in EFV discontinuation rates overall or in those patients with NSS. Another post-hoc analysis of the same cohort was made to determine the durability of response measured by time to virologic failure (TVF) and time to treatment failure (TTF). In the EFV-containing arms, no significant differences in TVF were observed between the three racial groups. The only significant difference in the EFV-containing regimens was TTF between Hispanics and whites in the EFV–ZDV–3TC arm (P < 0.05). No significant differences in TVF and TTF between blacks and whites were detected .
A study by Sension et al. assessed the impact of race on efficacy and the occurrence of new onset NSS in virologically suppressed patients who simplified their treatment regimens to once daily EFV-based HAART. Through week 48, virologic suppression rates (<50 copies/ml) were similar for whites (82%), blacks (77%), and Hispanics (82%). When patients new to EFV were assessed, 35% white, 40% black, and 53% Hispanic reported at least one NSS. There was no difference in the overall occurrence of NSS between races (P = 0.32, all grades). The pharmacokinetics of EFV metabolism was not reported.
The United States Military's Tri-Service AIDS Clinical Consortium sought to determine whether the effectiveness of HAART (time to AIDS and time to death from HIV seroconversion) differs in HIV-infected patients in European-Americans and African-Americans, and to evaluate whether differences in healthcare access had an effect on treatment outcomes regardless of race. Racial/ethnic differences were not observed for years between the last negative and first positive HIV visit, overall follow-up time, and overall AIDS and death rates (P > 0.15). The distribution of first AIDS defining events were similar between groups (P = 0.829). In the United States, the data show a continuing increase in AIDS incidence in blacks, despite the availability of interventions and treatments that have reduced the number of AIDS cases and deaths overall. The authors postulate that the increased AIDS burden in blacks is unlikely to be due to major population-level differences in HAART effectiveness, but more likely attributable to economic or social disparities resulting in a decreased access to healthcare and higher incidence of HIV .
Phase I studies with EFV provided an early suggestion of population pharmacokinetic variability where a lower clearance with Asians and blacks relative to whites and slightly lower plasma clearance in women relative to men was observed . However, the sex and race differences identified were moderate and interpretations of these data are limited by the narrow demographic diversity of the pooled phase I data. An evaluation of 166 patients treated with EFV–ZDV–3TC in study DMP266-006  found no correlation between EFV pharmacokinetics and race or sex.
There is substantial variation in the metabolism and elimination of EFV, leading to 16–23% intraindividual variation and 55–84% interindividual variation in EFV pharmacokinetics [39,40]. Clearance of EFV appears slower in blacks and Hispanics than in whites, leading to higher EFV plasma concentrations [38,41]. The impact of sex on EFV metabolism is inconclusive. In some studies, there was no correlation with sex and EFV pharmacokinetics [39,41], whereas others reported increased EFV levels in female patients compared with male patients [42,43].
Pharmacogenetics and efavirenz metabolism
EFV is subject to extensive metabolism, mainly by the cytochrome P450 (CYP) family of drug-metabolizing enzymes. In human liver microsomes, Ward et al. demonstrated that the CYP2B6 isoform is the principal catalyst of the sequential hydroxylation of EFV to 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz. Wide interindividual variability in the expression of CYP2B6 was seen at the level of mRNA, protein, and catalytic activity.
Genetic polymorphisms have been identified in all the main cytochromes P450 that contribute to metabolism of drugs. Lang et al. first identified nine exonic CYP2B6 single-nucleotide polymorphisms (SNPs) and haplotype analysis revealed six different allelic variants: CYP2B6*2 (64C>T), CYP2B6*3 (777C>A), CYP2B6*4 (785A>G), CYP2B6*5 (1459C>T), CYP2B6*6 (516G>T and 785A>G), and CYP2B6*7 (516G>T, 777C>A, and 1459C>T). Currently, 29 alleles and over 100 SNPs have been described for CYP2B6 (http://www.cypalleles.ki.se/cyp2b6.htm). Further analysis has shown that extensive linkage disequilibrium among the SNPs has produced complex haplotype structures and variants with unknown functional significance .
Pharmacogenetic studies are identifying CYP2B6 polymorphisms that affect the pharmacokinetic profiles of EFV (Table 1). Analysis of the 516G>T SNP (which is a marker of CYP2B6*6) has been investigated in numerous studies. A cohort of 100 HIV-infected patients receiving EFV revealed that 52% had the wild-type genotype (G/G), 43% had the heterozygous genotype (G/T), and 5% had the homozygous genotype (T/T). When genotype was correlated with plasma EFV concentrations, the lowest concentrations were found in patients homozygous for the wild-type alleles G/G and the highest concentrations were found in the T/T variant. The median (range) EFV concentrations were 1.71 (1.09–2.53) mg/ml for the wild-type G/G, 2.6 (1.73–3.5) mg/ml for the G/T genotype, and 3.57 (2.55–6.07) mg/ml for the T/T genotype . The Swiss HIV group  demonstrated that the T/T genotype was associated with higher plasma and intracellular EFV levels, and the presence of the T/T variant was two to three times more frequent among patients describing sleep or mood disorders, although a positive correlation between EFV plasma levels and toxicity was not found.
Haas et al. assessed the impact of the CYP2B6 516G>T SNP on EFV clearance in a study that included patients of several races. The T/T genotype was more common in African-Americans (20%) than in European-Americans (3%). A significant reduction in the metabolism of EFV was observed in patients with G/T and T/T genotypes relative to the G/G genotype. EFV plasma clearance was 23% lower with the G/T genotype and 54% lower with the T/T genotype (P = 0.0001). G/T and T/T genotypes were also associated with CNS symptoms compared with the G/G genotype at week 1 (P = 0.036), but not at week 24 (P = 0.76).
Data from more extensive analyses of CYP2B6 genetic diversity with respect to race have recently been reported. Klein et al. analyzed sequences from a total of 238 healthy individuals of African-American, Ghanaian, Japanese, Taiwanese, and Korean origin. The frequencies of the wild-type CYP2B6*1 allele were highest among Koreans (76.1%) and lowest among Ghanaians (39.1%) compared with 50.7% in Caucasians. Frequencies for CYP2B6*6 were 46.9% in Ghanaians, 25.6% in Caucasians, and 18.9% in Asians (overall). The CYP2B6*5 allele (1459C>T) was found at a 1.0% frequency in Asians as compared with 10.9% in Caucasians, and at a frequency of 1.6% in Ghanaians compared with 8.6% in African-Americans [49,50].
Rotger et al. genotyped a cohort of 169 HIV-infected patients to compare specific CYP2B6 allelic variants with EFV plasma concentrations. Two new loss or diminished function alleles were identified in individuals with median AUC levels of 188.5 μg h/ml. CYP2B6*27 (593T>C) resulted in an 85% decrease in enzyme activity and CYP2B6*28 (1132C>T) resulted in a protein truncation at amino acid 378. Both of these alleles were found only in black patients at a very low frequency (0.6%). The observed frequencies of their results for CYP2B6*5 and CYP2B6*6 were in good agreement with previously published data, with allele *6 more frequent among black individuals than whites, and *5 more frequent among whites than blacks. However, the high frequencies found in Asians for these alleles are not consistent with other reports. As with previous studies on the 516G>T polymorphism, significantly higher plasma EFV levels were found for the G/T genotype (P = 0.01) and the T/T genotype (P < 0.0001) compared with the wild-type G/G [24,47]. Using a panel of human liver microsomes that were genotyped and phenotyped for CYP2B6 protein expression, Desta et al. demonstrated in vitro that the CYP2B6*6 allele was significantly associated with a decrease in CYP2B6 expression and activity, as well as a low rate of EFV 8-hydroxylation, representing a first step toward elucidating the mechanism by which this allele identifies patients exhibiting very high EFV plasma concentrations.
Significantly reduced levels of EFV were observed for the CYP2B6*4 allele, which had the highest frequency in Hispanics (14.3%) . Another study  showed no decrease in EFV levels associated with this allele. Reports have linked the CYP2B6*5 (1459C>T) allele to reduced CYP2B6 protein levels [42,45]; however, no difference in plasma EFV levels were observed in individuals with this allele [43,54]. Accordingly, a decrease in CYP2B6 protein was observed in human liver microsomes with *1/*5 and *5/*6 genotypes, but this did not result in significant reduction of EFV metabolism, probably due to differences in specific activity of the protein variants .
A study by Ribaudo et al. investigated the relationship of slower EFV clearance in individuals with the 516T/T genotype after discontinuation of EFV-containing HAART. Treatment discontinuation in patients with slower plasma EFV clearance could potentially result in functional EFV monotherapy, increasing the risk for selection of low-frequency EFV-resistant virus. The results suggested that CYP2B6 516T/T homozygotes have a higher probability of experiencing more-prolonged plasma EFV exposure following discontinuation of antiretroviral therapy than do G/G homozygotes or G/T heterozygotes. A standard strategy for stopping EFV-containing HAART would not be feasible for all individuals. HIV treatment guidelines describe options for staggered component discontinuation, such as stopping EFV but continuing the other agents for a period of time, or substitute a protease inhibitor for EFV and continue the protease inhibitor with dual NRTIs . However, the optimal duration for continuation has not been determined. Measuring EFV plasma levels in real-time several days apart after therapy is stopped could be used to determine when to stop treatment with other agents in the regimen. Nevertheless, strategies to safely discontinue EFV-containing regimens should not differ on the basis of race or ethnicity, as there is considerable overlap between EFV pharmacokinetic profiles among different racial and ethnic groups .
The impact of CYP2B6 516 G>T SNP on EFV pharmacokinetics and its association with adverse events has been most widely evaluated. In summary, higher EFV plasma and intracellular concentrations were noted in patients with a T/T genotype and these patients were more likely to be identified as African-American. Although a long-term association with genotype and CNS adverse effects was not observed, CNS adverse events after 1 week of therapy were higher in patients with a G/T or T/T genotype. These genotypes could prove to be a significant development in the identification of individuals at risk of high-plasma concentrations of EFV, and those who may be more at risk to develop CNS side effects [24,48,53].
The MDR1 gene encodes P-glycoprotein (P-gp), which is an energy-dependent drug efflux transporter in the intestine, liver, kidney, and blood–brain barrier . The polymorphism 3435C>T in MDR1 has been associated with low expression of P-gp. Studies attempting to correlate MDR1 polymorphisms with antiretroviral metabolism or treatment outcome with race have produced mixed results. Previously published work suggests that MDR1 polymorphisms predict EFV concentrations and therapy outcome. Fellay et al. noted an association between EFV serum levels and allelic variations in the MDR1 gene. However, EFV is not known to be a P-gp substrate . Minimal involvement of P-gp in EFV transport was demonstrated in vivo by intravenous administration of 14C-EFV to wild-type mdr1a/1b+/+ or P-gp-deficient mdr1a/1b−/− mice . In a study  examining genetic variations and their effect on EFV pharmacokinetics, MDR1 SNPs 2677G>T/A and 3435C>T had no impact on EFV plasma exposure, although the MDR1 allelic frequencies differed between African-Americans and European-Americans (2677G>T, 11.0 and 44.0%; 3435C>T, 22.0 and 55.6%, respectively) (P < 0.0001).
Other studies investigated the impact of race and the correlation between the MDR1 3435C>T polymorphism and the efficacy of therapy. In a study reported by Myles et al., a cohort of 361 HIV-1-infected US military healthcare beneficiaries receiving HAART, of which 99 were receiving EFV-containing regimens, the 3435C>T polymorphism was assessed. The cohort contained 177 (49%) whites and 143 (39.6%) blacks. The frequency of 3435C>T genotypes differed by race (C/C: 22.4% whites, 64.9% blacks; C/T: 54.1% whites, 30.6% blacks; T/T: 23.5% whites, 4.5% black). Neither MDR1 3435C>T genotype nor race correlated with time to virologic failure in the entire cohort, or the subset of the cohort receiving EFV.
Haas and colleagues  examined the potential MDR1 and CYP2B6 genetic correlates of long-term response to EFV in patients enrolled in ACTG Study 384. Patients were followed up for as long as 3 years. For MDR1 3435C>T, the frequencies of genetic variants differed between the white, black, and Hispanic patients, 55.5, 17.1, and 40.9%, respectively (P < 0.0001). CYP2B6 516G>T was associated with increased plasma EFV exposure, the median values of the area under the 24-h EFV concentration–time curve were approximately two times higher in T/T homozygotes than in G/G homozygotes (P < 0.0001). The association between CYP2B6 516G>T and EFV exposure was consistent in white, black, and Hispanic patients analyzed separately. Somewhat surprisingly, no associations were observed between CYP2B6 SNPs and long-term responses to EFV. In contrast, the MDR1 3435T/T genotype was associated with significantly less virologic failure on EFV. No differences among genotypes were observed for treatment failure due to toxicity or all-cause treatment failure. The MDR1 3435T/T genotype was also a significant predictor of decreased likelihood of virologic failure with emergence of EFV resistance (P = 0.008), with an odds ratio of 0.6 per T allele, whereas age, race, sex, baseline CD4+ cell count, and baseline plasma viral load were not significant predictors. A recent analysis of the ACTG 384 study  suggests that multilocus genetic interactions involving polymorphisms in both MDR1 and CYP2B6 may predict clinical responses to EFV.
Overall, the 3435C>T polymorphism at the MDR-1 gene has been examined to elucidate its influence on HIV disease progression and response to therapy. There is no concordance between the different studies. Although some have described a relationship between the C/C genotype and earlier virologic failure, others have not found any difference in host susceptibility to HIV disease progression or in the CD4 recovery following initiation of antiretroviral therapy.
Virologic failure, race and adherence
In ACTG A5095, 765 HIV-infected patients randomized to either a three-drug or four-drug EFV-containing regimen were followed for a median of 144 weeks . The primary efficacy end point, time to virologic failure, was not significantly different between the two treatment groups. Patients included 164 Hispanic (21%), 271 black (35%), and 314 white (41%). Post-hoc analyses were conducted to understand the differences in efficacy, safety, and adherence by race/ethnicity. Although virologic response rates were high in all race/ethnicity groups, there was a significantly shorter time to virologic failure in black patients compared with white patients (P = 0.003). This disparity in treatment outcome could not be explained by differences in baseline CD4+ cell count or baseline drug resistance. Blacks had a significantly shorter time to discontinuation of their initial EFV-containing regimen than whites (P = 0.03). The most common reason was virologic failure. There was no significant difference in time to study discontinuation (P = 0.22). Black patients reported missing at least one dose of medication over the prior 4 days significantly more often than whites at week 4 (P = 0.01) and week 12 (P = 0.01), and blacks had a significantly shorter time to virologic failure than similarly adherent whites (P < 0.001 by log-rank test). Interaction of race/ethnicity, adherence, and treatment was seen at week 12 (P = 0.05), but not at week 4 (P = 0.34). There were no significant differences at weeks 24 and 48 in self-reported adherence rates among the racial/ethnic groups (P > 0.20). The authors hypothesize that the CYP2B6 516G>T polymorphism and corresponding higher plasma EFV concentrations may provide an explanation for the observed racial differences by virtue of an increase in adverse events leading to incomplete adherence, development of drug resistance, and, ultimately, virologic failure. However, no pharmacokinetic or genotype analysis was performed to support or refute this hypothesis.
Schackman et al. examined virologic failure differences by race from A5095 patients according to missing zero vs. greater than one dose in the past 4 days and alternative adherence definitions. Adherence was measured by self-report at weeks 4, 12, 24, and 24 weeks thereafter. Results show a higher failure rate in patients with recent nonadherence than in those with recent good adherence by all four adherence tests (P < 0.02). The analysis showed that treatment failure occurred in significantly higher proportions of nonadherent blacks than in nonadherent whites. There is evidence of an adherence–race interaction over time on, with a greater effect of nonadherence on virologic failure with blacks than whites.
Research on human genome variation increasingly challenges the applicability of the term ‘race’ to human population groups, forcing a paradigm shift from ‘race’ to ‘human genome variation’ . Responses to medical therapies, such as drugs, are often compared among populations that are categorized according to race or ethnicity. Allelic variation tends to be shared widely among populations, so race will often be an inaccurate predictor of response to drugs or other medical treatments . One such instance is that, on average, hypertensive African-Americans showed less response than hypertensive European-Americans to angiotensin-converting enzyme (ACE) inhibitors, and that these differences are often highlighted in practice guidelines. Meta-analysis revealed the differences were small when compared with the variation within each race . Therefore, in practice, effective antihypertensive therapy might be denied to a specific group of patients based solely on population averages. The use of race or ethnicity for classification in trials or practice is further complicated by heterogeneity among Europeans and among African-Americans who may have approximately 25% European genes compared with sub-Saharan Africans who are more genetically homogeneous . Ideally, human genome variation, not race should be used as a descriptor for both clinical studies and treatment decisions.
When looking at race and human genome variation, this dissimilitude can be seen in the volumes of EFV pharmacokinetic data. Some outcomes of EFV pharmacokinetic studies investigating sex and ethnicity agree and many do not. Despite a trend for slower EFV clearance rates in blacks and Hispanics, there was also tremendous overlap in EFV exposures within each racial group . Furthermore, after adjusting for the 516G>T genotype, differences in EFV pharmacokinetic profiles between whites and blacks were not evident, reinforcing the suggestion that genotype and not race explains this pharmacokinetic finding . Yet, there are limits blocking the use of pharmacogenetic data in the care of HIV-infected patients treated with EFV. There is presently no commercially available means to identify the SNPs associated with increased EFV plasma concentrations. Progress is being made toward commercial availability of identifying SNPs in the gene for CYP2B6, as a significant number of drugs are substrates of this enzyme. Even with commercial availability of assays for SNPs, cost remains an issue – particularly in resource poor settings.
Clinical evidence has demonstrated variability in EFV metabolism although there is no established direct correlation of EFV concentrations and symptoms. Understanding how genetic variation affects EFV metabolism and influences CNS adverse effects becomes more important as HIV incidence and use of antiretrovirals increases worldwide. The 516T/T genotype has been observed at a greater frequency in Americans of African descent than in those descended from Europeans and is associated with higher plasma levels of EFV and NVP, and with CNS symptoms at week 1 of EFV-containing antiretroviral therapy. All studies to date have consistently found the 516G>T polymorphism to be associated with higher plasma EFV concentrations, an effect observed regardless of ethnic background. This genotype could prove to be a significant development in the identification of individuals at risk of high-plasma concentrations of EFV, and those who may be more at risk to develop CNS side effects. Above all, the evidence maintains that providers should not withhold treatment of HIV infection with EFV on the basis of racial or ethnic categorizations.
We thank Stacey Shehin, PhD, i3 Statprobe (Ann Arbor, Michigan, USA), for assistance in preparation and editing of this manuscript.
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