Atazanavir

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

The producer reports no differences between men and women in pharmacokinetic variables and does not recommend differences in dosing according to patient’s sex [1].

A pharmacokinetic study in ritonavir-boosted atazanavir treated HIV patients (48 men, 26 women) found atazanavir/ritonavir steady-state pharmacokinetics to be comparable in men and women, despite women having lower body weight and thus higher weight adjusted atazanavir doses [2]. However, a retrospective analysis of routine analyses of atazanavir trough concentrations (255 samples from 179 patients) found female sex and co-treatment with tenofovir to be independently associated with higher atazanavir concentrations [3]. Similarly, in a study of atazanavir plasma concentration data from a randomized phase III study (655 men, 131 women), atazanavir clearance was shown to be around 10% lower in women after accounting for body weight [4]. Ritonavir exposure was also higher in women which may affect the result.

In a pharmacokinetic analysis of saquinavir with atazanavir or low-dose ritonavir (16 men, 15 women) women  had a higher exposure for all 3 protease inhibitors compared to men after adjusting for weight [5]. As ritonavir is a potent inhibitor of cytochrome P450 3A4 isoenzyme and P-glycoprotein, through which protease inhibitors are metabolized and transported the authors speculate that higher exposure of ritonavir in women could be the mechanism behind the higher AUC for the protease inhibitors [5].

Effects

Women seem to have an increased risk of virological failure in studies of antiretroviral therapies including atazanavir. In the CASTLE study, treatment-naive adult HIV-patients (606 men, 277 women) were randomized to receive either atazanavir/ritonavir or lopinavir/ritonavir with fixed-dose tenofovir/emtricitabine. At week 96, virological response was higher in women and men receiving atazanavir/ritonavir than those receiving lopinavir/ritonavir but lower in women than men in both treatment arms [6]. In the ACTG study A5202 (1535 men, 322 women) women on atazanavir had an increased risk of virological failure compared to men and compared to women on efavirenz [7]. How much imbalances in baseline characteristics influenced this finding is unclear and the results should therefore be interpreted with caution [7].

Adverse effects

Differences in adverse events have been described for different antiretroviral regimens, in general women  report more nausea and gastrointestinal reactions, a higher risk of developing renal failure, and more lipodystrophy but less risk of diarrhea and LDL-level increase [8-11]. 

Safety and tolerability were evaluated in a European HIV cohort (958 men, 336 women). Women had a higher risk of treatment discontinuation than men (hazard ratio [HR], 1.54; 95%CI: 1.28, 1.85) but no increased risk of virological failure (HR, 1.06; 95%CI: 0.85, 1.33). Compared to men, women had less diarrhea and severe lipid but more lipodystrophy [12]. 

In the CASTLE study, treatment-naive adult HIV-patients (606 men, 277 women) were randomized to receive either atazanavir/ritonavir or lopinavir/ritonavir with fixed-dose tenofovir/emtricitabine. Discontinuation rates were higher in women than men in each treatment arm (22% of women and 15% of men on atazanavir/ritonavir). In both women and men jaundice and hyperbilirubinemia occurred more frequently in the atazanavir/ritonavir group [6]. 

Reproductive health issues

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

Other information

A global multicenter randomized study on sex differences in treatment failure of antiretroviral treatment with efavirenz plus lamivudine-zidovudine, atazanavir plus didanosine-emtricitabine or efavirenz plus emtricitabine-tenofovir-didanosine (832 men, 739 women) found women to have higher pretreatment CD4+ and lower HIV-1 RNA compared to men [13]. For atazanavir plus didanosine-emtricitabine, women remained on treatment longer and were less likely to prematurely discontinue treatment compared to men [13]. 

In contrast to this a retrospective observational Italian cohort study of predictive factors for in durability and therapeutic failure of atazanavir-based antiretroviral regimens with or without ritonavir (r) in HIV patients treated with atazanavir (727 men, 303 women)  found the risk of discontinuing with atazanavir was higher among women [14]. Similarly, an analysis of differences between men and women treated with combinations including lopinavir, atazanavir, tipranavir, fosamprenavir, and darunavir in a pharmacovigilance register (1547 men, 607 women) women had a better immunological recovery to discontinue protease inhibitor treatment due to adverse events and at their own will more frequently [15]. In a post-hoc analysis of data from a randomized phase-III trial in HIV patients treated with atazanavir boosted with either cobicistat or ritonavir in combination with emtricitabine/tenofovir disoproxil fumarate (574 men, 118 women) found more discontinuations due to withdrawal of consent and pregnancies in women receiving atazanavir+ritonavir compared to atazanavir+cobicistat [2].

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 [16].