Nevirapine

Additional information

Antiretrovirals for treatment of HIV are always given as a combination of at least three medicines. Cobicistat is used to boost the effect of other antiretroviral drugs. As studies on HIV patients always include patients receiving combination therapy it is difficult to know which of the studied medicines that cause changes in effect and/or adverse events.

Pharmacokinetics and dosing

In pharmacokinetic analyses (686 men, 391 women), women were found to have 14% lower clearance and 20-30% higher through concentrations of nevirapine [1]. The manufacturer recommends the same starting dose in men and women [1].

In a study of nevirapine biotransformation (33 men, 20 women) the plasma concentrations of nevirapine and the metabolite 3-hydroxy-nevirapine, as well as the proportions of the metabolites 12-hydroxy-nevirapine and 3-hydroxy-nevirapine, were higher in women, when adjusted for body weight [2].

Effects

Conflicting results have been reported whether women may have a better effect of nevirapine or if there are no differences between the sexes in effect. 

Sex differences reported

In a study of efficacy and tolerability in HIV patients receiving nevirapine-based versus efavirenz-based combination antiretroviral therapy in Botswana (199 men, 451 women) women had a higher probability of survival (12% vs men 6%). Nevirapine-treated women had higher virologic failure rates than efavirenz-treated women. Efavirenz-treated and nevirapine-treated males having more favorable outcomes [3].

An observational cohort study of treatment regime modification in Thai patients treated with a combination of stavudine, lamivudine and nevirapine (461 men, 453 women) found female sex to be a predictor of regimen modification due to lipodystrophy. Female sex, older age, and having HLA-B*40:01 had protective effects on treatment failure-related regimen modification [4]. Another observational Thai study in HIV-infected treatment naive treated with nevirapine- (66%) or efavirenz-based (34%) antiretroviral therapy children (132 boys, 142 girls) found predictors of immune recovery at week 96 to be younger age, female sex, higher baseline CD4%, and sustained virologic suppression after week 24 [5]. Similarly, a South African study in children with HIV randomized to continue ritonavir-boosted lopinavir (LPV/r)-based ART or switch to nevirapine-based ART (168 boys, 155 girls) no sex differences in risk of virological failure were observed within either treatment group but girls on nevirapine had more robust CD4 count improvement compared to boys [6].

In a cross-sectional observational study from Zimbabwe in non-pregnant or breast-feeding HIV patients (32 men, 86 women) on stavudine, tenofovir or zidovudine combined with either lamivudine and nevirapine or efavirenz, women were found to have a lower risk of treatment failure [7].

No sex differences reported

In contrast to the studies above, a British study (853 men, 141 women) reported no sex difference in effect of efavirenz or nevirapine [8]. Similarly, in an observational study from Uganda in HIV-patients (157 men, 325 women) of which 74% were treated with nevirapine+stavudine+lamivudine and 26% with efavirenz+zidovudine+lamivudine no sex differences were described but the efavirenz-based treatment regimen was found to be more effective in suppressing viral load in both men and women [9].

Adverse effects

There is a risk of hepatotoxicity and serious cutaneous reactions with nevirapine that needs to be considered when starting the treatment and the risk is higher in girls/women [1]. Skin reactions (rashes and also Steven Johnson syndrome) are known adverse effects of nevirapine. Several studies have found skin reactions and rashes to be more common in women [10-15]. Several, but not all studies have reported a higher risk of liver enzyme elevation and drug induced liver injury in nevirapine treated women compared to men [16-20].

In a retrospective Indian study nevirapine toxicity in children with HIV who were switched from efavirenz or were treatment naive (122 boys, 101 girls) the risk of nevirapine toxicity was found to be higher in girls and particularly those with high CD4 count [21]. This is in contrast to an observational study from Nigeria in HIV-patients treated with either nevirapine or efavirenz in combination with lamivudine and zidovudine, stavudine, or tenofovir (944 men, 1706 women) where men and women reported ADRs in the same frequency (64%) [22]. Most ADRs were mild [22].    

Hepatotoxicity

A retrospective chart review of HIV-patients treated with efavirenz or nevirapine (223 men, 75 women) found that liver toxicity to be more frequently associated with nevirapine (12%) than with efavirenz (4%) and female sex to be an independent risk factors [16]. Similarly in a retrospective cohort study (438 men, 122 women) investigating whether particular antiretroviral agents were associated with a higher risk for developing serious liver enzyme elevations in patients with HIV an increased risk was found in women and in those with higher baseline ALT levels, chronic HBV or HCV infections, the use of first-line potent antiretroviral combination regimens in patients without prior NRTI treatment, and recent start of nevirapine or ritonavir [17].

Also a study in HIV-patients treated with blinded lamivudine or emtricitabine, stavudine, and nevirapine or efavirenz (156 men, 229 women) early hepatotoxicity occurred in 17% in the nevirapine group and none in the efavirenz group and was balanced between the lamivudine and emtricitabine arms. Multivariate analysis found women to be at higher risk, as were patients with body-mass index (BMI) <18.5, serum albumin level <35 g/L, mean corpuscular volume 185 fL, plasma HIV-1 RNA load <20,000 copies/mL, aspartate aminotransferase level <75 IU/L, and lactate dehydrogenase level <164 IU/L [19].

A study from India in HIV patients (677 men, 148 women) found the risk impaired liver function to be increased in women and in patients using nevirapine. The women had lower weight and the authors hypothesize that cumulative exposure may explain the higher risk in women [18].

Also in a study in HIV-patients treated with blinded lamivudine or emtricitabine, stavudine, and nevirapine or efavirenz (156 men, 229 women) early hepatotoxicity occurred in 17% in the nevirapine group and none in the efavirenz group. Multivariate analysis found women to be at higher risk, as were patients with low body-mass index (<18.5), serum albumin level <35 g/L, mean corpuscular volume 185 fL, plasma HIV-1 RNA load <20,000 copies/mL, aspartate aminotransferase level <75 IU/L, and lactate dehydrogenase level <164 IU/L [19].

However, in a prospective observational study from Uganda of liver enzyme elevation in HIV-infected patients on antiretroviral therapy with lamivudine+nevirapine and stavudine (74%) or efavirenz and zidovudine (26%) (in all 169 men, 377 women) male sex was associated with AST elevation [20]

A retrospective analysis from a HIV-treated cohort (848 men, 67 women) found co-infection with Hepatitis C to increase the risk of nevirapine induced liver toxicity. In Hepatitis C negative patients women with CD4+ T-cell counts of > or =250/mm3 and men with CD4+ T-cell counts of > or =400/ mm3 had a higher risk [23].

Skin reactions

In a case series and matched case–control analysis from South Africa of severe skin reactions occurring in patients on antiviral treatment 169 cases were identified of which 141 (83%) were women and half of the reactions Steven Johnson syndrome/toxic epidermal necrolysis. There was an independent association between severe skin reaction and nevirapine use. Pregnancy was also identified as a risk factor [10].

A retrospective observational study of the risk of rash in HIV patients treated with antiretroviral therapy containing nevirapine (283 men, 146 women) found the risk of rash to be higher in women and also in those with prophylactic use of glucocorticoids or antihistamines [11]. This is in concordance with a long term follow up in patients treated with nevirapine (366 men, 207 women) where discontinuation because of cutaneous reaction was more common in women [12]. Also a retrospective cohort study from Ghana on the risk of non-nucleoside reverse transcriptase inhibitor associated rash (1272 men, 2727 women) found the risk to be associated with nevirapine use and higher in women and in those with lower baseline CD4 counts [13]. 

A post-hoc analysis within a randomized trial in HIV patients treated with regimes containing nevirapine, efavirenz, or both, in addition to stavudine and lamivudine (772 men, 444 women) found the incidence of rash in the nevirapine group to be higher in women with higher CD4 cell counts [14]. In a multicenter, retrospective cohort study of HIV patients treated with nevirapine (263 men, 95 women) severe rash was more common in women than in men. Women were more likely to discontinue nevirapine therapy because of rash [15].

Lipid profiles

An east African registry based study of lipid profiles in patients with HIV (55 men, 176 women) treated with zidovudine (76%), efavirenz (66%), zidovudine and efavirenz in combination with lamivudine (42%), zidovudine and lamivudine in nevirapine (34%), and the remaining tenofovir-based treatments (24%) found increased LDL in 60% of the patients with no difference between men and women. However, men were twice as likely to have decreased HDL-C [24].A retrospective database review off HIV patients treated with nevirapine (137 men, 180 women) found little hepatic and metabolic impact of the treatment. Women with high CD4 count and men with low CD4 count were more prone to develop dyslipidemia [25].

Reproductive health issues

Due to the induction of CYP3A4 there is a risk of lower estradiol exposure in women on oral contraceptives and nevirapine. In a clinical trial with 10 HIV-1-infected a 29% reduction in the (single-dose) ethinyl estradiol exposure and a 18% reduction in norethistrerone exposure in terms of AUC was seen [26]. Regarding drug-drug interactions aspects, please consult Janusmed Interactions (in Swedish, Janusmed interaktioner).

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan). 

Other information

Adherence to therapy has in some studies been reported to be higher in women, in other in men. Adherence to antiretroviral therapy may be more dependent on socioeconomic- and geographical determinants and thus the population studied.

A review has described drug exposure in the genital tract of men and women which is of interest in viral transferal and in effect of pre-exposure prophylactic treatment. In men, concentrations in seminal fluid were described to be highest for nucleoside analogues and lowest for protease inhibitors and efavirenz. Seminal accumulation of raltegravir and maraviroc was defined as moderate. The rank order of accumulation presented in the review is nucleoside/nucleotide reverse transcriptase inhibitors [lamivudine/zidovudine/tenofovir/didanosine > stavudine/abacavir] > raltegravir > indinavir/maraviroc/nevirapine >> efavirenz/protease inhibitors [amprenavir/atazanavir/darunavir > lopinavir/ritonavir > saquinavir] > enfuvirtide. In the female genital tract, the nucleoside analogues also were described as having high accumulation ratios, whereas protease inhibitors have limited penetration; however, substantial variability exists. Second generation non-nucleoside reverse transcriptase inhibitor etravirine, and maraviroc and raltegravir, have been found to demonstrate effective accumulation in cervicovaginal secretions. The rank of accumulation presented in the review is nucleoside/nucleotide reverse transcriptase inhibitor [zidovudine/lamivudine/didanosine > emtricitabine/tenofovir] > indinavir > maraviroc/raltegravir/darunavir/etravirine > nevirapine/abacavir > protease inhibitors [amprenavir/atazanavir/ritonavir] > lopinavir/stavudine/efavirenz > saquinavir [27].