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Efavirenz

Classification: A

Drug products: Atripla, Efavirenz Aurobindo, Efavirenz Sandoz, Efavirenz Teva, Efavirenz/Emtricitabine/Tenofovir disoproxil Krka, Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan, Efavirenz/Emtricitabine/Tenofovir disoproxil Teva, Emtenef, Padviram, Stocrin®

ATC code: J05AG03, J05AR06

Substances: efavirenz

Summary

Women have been shown to have higher concentrations of efavirenz given the same dose as men. While some studies report no sex differences others have reported better effect in women/girls. The risk of nausea, lipodystrophy, kidney failure, lactic acidosis, and drug induced liver injury has been reported to be higher in women Men experience more diarrhoea, CNS toxicity, and dysglycemia.
 
In our opinion, the described differences do not motivate differentiated dosing or treatment in men and women.

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 the SPC no difference in dosing depending on patient’s sex is recommended [1]. However, there are several smaller studies showing omen to have higher plasma concentrations of efavirenz compared to men, given the same dose.

In a pharmacokinetic study of HIV patients treated with efavirenz in combination with stavudine and lamivudine (26 men, 48 women) women had higher concentrations of efavirenz compared to men. Presence of the CYP2B6*6 allele was also associated with high efavirenz concentrations [2]. Some studies have found women to have higher CYP2B6 activity compared to men [3, 4].A population pharmacokinetic analysis in HIV patients with tuberculosis (TB) receiving an efavirenz-based and a rifampicin-containing anti-TB regimen (60 men, 125 women) the following was found: CYP2B6*6 and *18 variant alleles, weight and sex explain the major part of inter-individual variability in efavirenz clearance and women had a 22% higher clearance than men [5].Efavirenz plasma concentration data from 32 adult healthy subjects and 29 HIV-1-infected, treatment-naïve patients (31 men, 30 women) found HIV/AIDS patients to have 30% lower relative bioavailability (95% CI 18.7, 40.7) than healthy subjects. Women had a 2-fold higher volume of distribution and a 2-fold longer elimination half-life than men [6].

In a TDM database study of efavirenz concentrations (189 men, 66 women) women had higher concentrations compared to men (4.0 mg/L vs 2.8 mg/L) [7]. Persons of non-caucasian race also had higher concentrations [7].

In a bioequivalence study of different formulations of oral efavirenz (6 men, 8 women) the efavirenz absorption rate differed between the formulations only in men [8].

Effects

Conflicting results of differences in effect between men/boys and women/girls have been reported.

Sex differences reported

An observational Thai study in HIV-infected naive children (132 boys, 142 girls) treated with nevirapine (66%) or efavirenz (34%) based antiretroviral therapy found predictors of immune recovery at week 96 to be younger, to have female sex, higher baseline CD4%, and sustained virologic suppression after week 24 [10]. In a cross-sectional observational study from Zimbabwe in non-pregnant or non-breast-feeding HIV patients (32 men, 86 women) on treatment with an nucleoside reverse transcriptase inhibitor (NRTI) backbone and nevirapine or efavirenz, women also had a lower risk of treatment failure [11]. In an observational study in East African children (51 boys, 58 girls) treated with a NRTI backbone and efavirenz, virological non-suppression was more common in children older than 8 years and in children younger than 8 years. Boys had a 5.3 times higher risk of virological non-suppression than girls [12].

No sex differences reported

In contrast, a British study (853 men, 141 women) reported no sex difference in effect of efavirenz or nevirapine [13]. In a randomized study on HIV-1-infected adults treated with rilpivirine or efavirenz with an NRTI backbone (1040 men, 328 women) no difference between men and women was found in virological response rate [14]. 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 the efavirenz-based treatment regimen was more effective in suppressing viral load, with no differences seen between men and women [15]. Another small study (38 men, 26 women) did not find any sex difference either in effect of triple-nucleoside-based versus efavirenz-based regimens [16].

Similarly in the ACTG study A5202 (1535 men, 322 women) found women on atazanavir to have an increased risk of virological failure compared to men and compared to women on efavirenz [17]. In chart reviews of patients treated with efavirenz or a protease inhibitor (atazanavir, lopinavir, darunavir or fosamprenavir) (in all 358) no differences between men and women were reported for discontinuation or virological response in those treated with efavirenz. Women on a protease inhibitor had a higher discontinuation rate (46 vs 38%) and lower virological response (79 vs 90%) compared to men and compared to women on efavirenz also in this analysis [17].

Adverse effects

Different adverse reaction patterns in men and women treated with efavirenz-containing antiretroviral regimens have sometimes, but not always, been reported. If this reflects the different treatment regimens, differences between populations or is due to chance is difficult to discern.

The differences in adverse events which have been described for various antiretroviral regimens are that, women report more nausea and gastrointestinal reactions, more lipodystrophy, a higher risk of developing kidney failure and lactic acidosis but a lower risk of LDL-level increase compared to men [14, 19-21]. Also, the risk of drug induced liver injury has been reported to be higher in women on efavirenz-containing antiretroviral treatment regimens. Men have more diarrhoea, CNS toxicity, and dysglycemia.

Sex differences reported

In a randomized study on HIV-1-infected adults (1040 men, 328 women) treated with rilpivirine or efavirenz with an NRTI backbone, nausea was more common in women and abnormal dreams/nightmares were more frequent in men. Diarrhea was more frequent in men in the efavirenz group [14].

In an analysis of the risk of lactic acidosis in a randomized open-label study of stavudine/lamivudine-based versus didanosine/zidovudine-based therapy and lopinavir/ritonavir-based versus efavirenz-based therapy in HIV-infected individuals (1204 men, 567 women) 13 cases of lactic acidosis were found (3 men, 10 women). The risk of lactic acidosis was higher in women (OR 7.19, 95% CI 1.84-40.75; P=0.001) regardless of therapy choice. Higher body mass index was also a risk factor [22].

A cohort study from Zimbabwe in HIV patients experiencing CNS toxicity on efavirenz treatment (62 men, 133 women) found this ADR to be more common in men [23].

In a retrospective chart review of HIV-patients treated with efavirenz or nevirapine (223 men, 75 women) liver toxicity was more frequently associated with nevirapine (12%) than with efavirenz (4%) (p =.016) and female sex was an independent risk factor [24]. Similar findings come from a case series of HIV patients with efavirenz induced liver injury (DILI) from South Africa (22 men, 59 women) where multivariate analyses showed that women had higher risk of DILI [25]. Also, in a study in HIV-patients treated with blinded NRTI and nevirapine or efavirenz (156 men, 229 women) early hepatotoxicity occurred in 17% in the nevirapine group but 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 [26].

However, in a prospective observational study from Uganda of liver enzyme elevation in HIV-infected patients on antiretroviral therapy with lamivudine+stavudine and nevirapine (74%) or lamivudine+stavudine and efavirenz and zidovudine (26%) (in all 169 men, 377 women) male sex was associated with AST elevation [27].

In an analysis of the effect on cholesterol levels in an open-label study of treatment with efavirenz+zidovudine+lamivudine, efavirenz+indinavir, or indinavir+zidovudine+lamivudine (509 men, 126 women) increased cholesterol was more common in the efavirenzefavirenz +indinavir group. Women had higher HDL baseline levels. In the efavirenzefavirenz group HDL cholesterol increased in both men and women but in the other groups the increase was only seen in women [28].

In a South African prospective observational study (199 men, 653 women) multivariate analysis found male sex , older age, higher CD4 count, and use of efavirenz to be associated with dysglycemia [30].

A global randomized study on sex differences in antiretroviral treatment with efavirenz+lamivudine-zidovudine, atazanavir+didanosine/emtricitabine or efavirenz+emtricitabine-tenofovir (832 men, 739 women) has been performed [31]. It found women assigned to efavirenz plus lamivudine-zidovudine to be more likely to have a primary safety event compared to men, a difference driven by an increased rate of neutropenia among women. As this adverse effect is commonly associated with zidovudine, this safety difference may be due to the zidovudine component of this regimen and not to efavirenz efavirenz [31].

Safety and tolerability were evaluated in a European HIV cohort (958 men, 336 women). Women had a higher risk of treatment discontinuation than men. Compared to men, women had less diarrhoea and severe dyslipidaemia but more lipodystrophy [32].

No sex differences reported

In an observational study from Nigeria in HIV-patients treated with zidovudine/lamivudine, stavudine/ lamivudine, or tenofovir/lamivudine in combination with either nevirapine or efavirenz (944 men, 1706 women) men and women reported ADRs in the same frequency (64%) [33]. Most ADRs were mild.In a US randomized open-label study of HIV-positive patients treated with atazanavir+ritonavir or efavirenz in combination with abacavir/lamivudine or tenofovir/emtricitabine (1535 men, 322 women) women treated with abacavir/lamivudine had a higher (32%) safety risk (more gastrointestinal adverse events) compared to men. Self-reported adherence did not differ significantly by sex. In this study, more women than men reported black race which is a possible confounding factor [20].

Reproductive health issues

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

Other information

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

A descriptive retrospective Brazilian study on HIV patients on highly active antiretroviral therapy who modified their treatment within the first year of treatment (52 men, 35 women) found that changes were more common in men. Efavirenz was the most often changed drug, followed by tenofovir, zidovudine and lopinavir/ritonavir [34].

A questionnaire based study on discontinuation with efavirenz treatment in HIV patients (635 men, 193 women) found higher risk in women. Other risk factors were unemployment, having a steady sexual partner and multiple episodes of depression [35]. The global randomized study reported by Firnhaber (832 men, 739 women) also found men to have a higher risk of premature study discontinuation or stopping antiretroviral therapy [31]. In contrast, in a retrospective Italian study, patients with efavirenz containing HIV treatment (391 men, 162 women) men were found to have a lower risk of efavirenz discontinuation [36].

A retrospective study on the prevalence of high sensitivity CRP (hsCRP) levels in HIV patients treated with zidovudine+lamivudine and abacakvir and/or efavirenz (145 men, 51 women) there was no difference in hsCRP between men and women at baseline. At week 96 higher levels were seen in women compared to men [37].

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 [38].

Updated: 2019-02-26

Date of litterature search: 2018-07-18

References

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Authors: Mia von Euler, Linnéa Karlsson Lind

Reviewed by: Karin Schenck-Gustafsson, Jaran Eriksen

Approved by: Karin Schenck-Gustafsson