Emtricitabin

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 product information of emtricitabine it is noted that concentrations (Cmax and Cmin) and mean AUC were higher in women compared to men but the differences were less than 20% and not considered clinically significant [1].

Effects

In a randomized study on HIV-1-infected adults (1040 men, 328 women) treated with rilpivirine or efavirenz and an NRTI backbone consisting of either tenofovir/emtricitabine or tenofovir/emtricitabine + zidovudine/lamivudine or abacavir/lamivudine no difference in response rate between men and women was found [2]. However, differences were found in the CASTLE study, where 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 lower in women than men in both treatment arms (67% of women and 77% of men on atazanavir/ritonavir and 63% of women and 71% of men on lopinavir/ritonavir). Discontinuation rates were higher in women than men in both treatment arms (22% of women and 15% of men on atazanavir/ritonavir and 29% of women and 18% of men on lopinavir/ritonavir) [3].

Adverse effects

The general differences in adverse events which have been described for antiretroviral regimens are that women have been reported to have 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.

In a randomized study on HIV-1-infected adults (1040 men, 328 women) treated with rilpivirine or efavirenz a backbone consisting of either tenofovir/emtricitabine or tenofovir/emtricitabine + zidovudine/lamivudine or abacavir/lamivudine nausea was more common in women than in men in both treatment groups while abnormal dreams/nightmares were more frequent in men [2].

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 diarrhoea and severe dyslipidaemia but more lipodystrophy [4] .

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% of patients 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 <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 [5].

In a study on glucose tolerance in HIV-infected adults on efavirenz, tenofovir, and emtricitabine (40 men, 30 women) half of the subjects were obese and these were matched with 30 obese HIV-negative controls. HIV-infected women had higher glucose tolerance and lower plasma metabolites associated with the development of diabetes compared with men with similar metabolic disease risk profiles. The relationship between patient’s sex and plasma metabolite levels did not significantly differ according to HIV-status among obese subjects, suggesting the observed sex differences may not be specific to HIV infection [6].

Reproductive health issues

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

Other information

In a retrospective follow-up study in a multisite cohort from the USA (4567 men, 806 women) a combination of efavirenz/emtricitabine/tenofovir was the most commonly prescribed initial antiretroviral treatment. Factors associated with modifying treatment regimen were female sex, intravenous drug use, and CD4 cell count less than 200 cells/μl [7].

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 [8]. It found women to have higher pre-treatment CD4+ and lower HIV-1 RNA compared to men. For atazanavir+didanosine/emtricitabine, women remained on treatment longer compared to men and were less likely to prematurely discontinue [8].

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 were also 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 [9].