Zidovudine

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.Zidovudine is a nucleoside reverse transcriptase inhibitor, indicated for the prevention of maternal-fetal HIV-1 transmission and for adults and children in combination with other antiretroviral agents for the treatment of HIV-1 infection [1].

Pharmacokinetics and dosing

The pharmaceutical company does not recommend any difference in dosing between men and women [1]. A pharmacokinetic study on oral or i.v. zidovudine (18 men, 20 women) found no difference between men and women in plasma concentration although men had higher intracellular levels [2]. However, a population pharmacokinetic analysis of zidovudine and lamivudine (47 men, 28 women) showed that women had higher zidovudine concentrations than men due to men having a higher clearance [3]. Similarly, a small pharmacokinetic/pharmacodynamic sub study of a prospective, randomized, open-label trial (29 men, 4 women) triphosphate concentrations were found to be 2.3-fold higher in women [4]. These women also reached an HIV-RNA level under 50 copies/ml twice as fast as men [4]. The clinical relevance of this is unclear.

Effects

A register based Italian study on HIV patients treated with zidovudine (1102 men, 366 women) did not find any sex difference in risk of developing AIDS in multivariate analyses [5].

A randomized study on HIV-1-infected adults treated with rilpivirine  or efavirenz+tenofovir/emtricitabine, or tenofovir/emtricitabine, zidovudine/lamivudine or abacavir/lamivudine (1040 men, 328 women) found no difference between men and women in response rate [6]. Furthermore, there was no difference between men and women in effect on T-lymphocyte count after post-exposure prophylaxis including zidovudine, zidovudine plus lamivudine, or zidovudine, lamivudine, and indinavir [7].

Also, in a cross-sectional observational study from Zimbabwe of HIV patients (32 men, 86 women) on stavudine, tenofovir or zidovudine combined with lamivudine and nevirapine or efavirenz women were found to have a lower risk of treatment failure [8].

An observational study of Chinese HIV-positive patients (278 men, 258 women) following antiretroviral treatment for 3 years found that women, but not men, initiating stavudine-based versus zidovudine-based regimens were more susceptible to virological failure, HIV drug resistance, and adverse events [9].

In a cross-sectional surveillance study from KwaZulu-Natal, South Africa (324 men, 960 women) found no differences between men and women at 12-15 months in HIV drug resistance [10]. In multivariate analysis of the risk of virologic failure male sex, advanced WHO stage at initiation of treatment, and use of stavudine or zidovudine versus tenofovir were factors associated independently [10].

Adverse effects

A global randomized study on sex differences in efficacy outcome of treatment failure of antiretroviral treatment (832 men, 739 women) women assigned to efavirenz plus lamivudine-zidovudine were more likely to have a primary safety event compared to men [11]. This difference was driven by an increased rate of neutropenia among women. Neutropenia is an adverse effect commonly associated with zidovudine [11].

A large 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%) [12]. Most ADRs were mild [12].

In contrast, a randomized study on HIV-1-infected adults treated with rilpivirine or efavirenz+tenofovir/emtricitabine, or tenofovir/emtricitabine, zidovudine/lamivudine or abacavir/lamivudine (1040 men, 328 women) nausea was more common in women than in men in all treatment groups while abnormal dreams/nightmares were more frequent in men [6]. Similarly, a study of side effects in persons receiving post-exposure treatment with zidovudine, lamivudine, and tenofovir found women at higher risk for nausea [13].

There are also several studies of the risk of lactic acidosis in patients treated with nucleoside analogs describing a higher risk in overweight women [1, 14-16]. 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 (EFV)-based therapy in HIV-infected patients (1204 men, 567 women) 13 cases (3 men and 10 women) of lactic acidosis were found [14]. The risk of lactic acidosis was significantly higher in women regardless of therapy choice. Higher body mass index was also a risk factor [14]. In a systematic review of case reports of lactic acidosis, 90 patients were taking nucleoside reverse transcriptase inhibitors at the time of the episode [15]. Among the 83 patients with details of their antiretroviral therapy regimen 29 zidovudine, 51 patients were taking stavudine, 27 didanosine, and 25 lamivudine. Estimated, based on the infection and sex distribution, lactic acidosis is concluded to be more common in women [15].

A study in patients treated with zidovudine/ lamivudine combined with different protease or non-nucleoside reverse transcriptase inhibitors found increased age and male sex to be independently associated with lower limb fat and abdominal subcutaneous tissue, but more visceral adipose tissue [17].

In an analysis of cholesterol levels in an open-label study of treatment with efavirenz + zidovudine + lamivudine, efavirenz + indinavir, and indinavir + zidovudine + lamivudine (in all 509 men, 126 women) increased cholesterol was more common in the efivarenz+indinavir group. Women had higher HDL baseline levels and HDL cholesterol increased significantly in women in all groups but only in the efavirenz-containing arms in men [18]. An East African registry based study of lipid profiles in patients with HIV (55 men, 176 women) treated with zidovudine (76%), efavirenz (66%), zidovudine+efavirenz+lamivudine (42%), zidovudine+lamivudine+neverapine (34%), or 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 [19].

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 [11]. It found women to have higher pretreatment CD4+ and lower HIV-1 RNA compared to men. Women assigned to efavirenz plus lamivudine-zidovudine were 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, it seems likely that the safety difference may be due to the zidovudine component of this regimen [11].

In a prospective follow-up study (57 men, 55 women) of HIV-infected patients treated with zidovudine, zalcitabine, lamivudine, didanosine, stavudine, or a combination of didanosine+stavudine 29% developed polyneuropathy, more commonly in the didanosine+stavudine combination-treatment group and in women [20].

Reproductive health issues

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

Other information

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 [21].