Lopinavir

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 manufacturer does not report any pharmacokinetic differences between men and women and does not recommend any difference in dosing based on patients’ sex [1]. There are several published studies showing similar findings.A pharmacokinetic study of lopinavir/ritonavir treated HIV patients (78 men, 76 women) found no differences between men and women in pharmacokinetic variables of lopinavir [2]. Similarly, another study of lopinavir/ritonavir (9 men, 11 women) found no differences between men and women in pharmacokinetic variables [3]. A study of lopinavir pharmacokinetics performed in a TDM database (607 men, 150 women, 45 unknown) found weight to be inversely related with lopinavir concentrations and women to have higher lopinavir concentrations than men. However, in a multivariate analysis only body weight remained related to lopinavir concentrations [4]. In contrast, a pharmacokinetic study in pediatric HIV patients treated with lopinavir/ritonavir (90 boys, 67 girls) plasma clearance was found to increase with 39% after the age of 12 years for boys compared to girls [5]. 

A pharmacokinetic study in healthy volunteers measuring plasma drug concentrations after a single oral dose of lopinavir/ritonavir (8 men, 8 women) found no significant sex differences in oral bioavailability and systemic clearance of lopinavir or ritonavir after co-prandial administration if weight adjusted doses were used [6]. It is suggested by the authors that food would reduce the gastric physiological differences between men and women [7].

Effects

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 and lower in women than men in both treatment arms (63% and 71%, respectively of women and men on lopinavir/ritonavir) [8]. In contrast, a South African study in children with HIV randomized to continue ritonavir-boosted lopinavir-based antiretroviral treatment (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. Girls on nevirapine had more robust CD4 count improvement compared to boys and to girls remaining on ritonavir-boosted lopinavir [9].

Adverse effects

In general, 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 on various antiretroviral treatments [10-13]. In an analysis of the risk of lactic acidosis in a randomized open-label 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 [14]. The risk of lactic acidosis is commonly attributed to nucleoside reverse transcriptase inhibitors (NRTI) and nucleoside analogs.

Reproductive health issues

Lopinavir has not been reported to interact with oral contraceptives [15]. However, all lopinavir formulations are given as fixed combinations [15]. However, all lopinavir formulations are in fixed combination with ritonavir which adversely interacts with oral contraceptives and lowers the dose of both progesterone and estrogen component thus rendering them potentially ineffective [15, 16]. It is recommended that an alternative, effective and safe method of contraception should be used during treatment [16]. 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

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. Discontinuation rates were higher in women than men in each treatment arm (29% and 18%, respectively of women and men on lopinavir/ritonavir) [8].In a descriptive retrospective Brazilian study on HIV patients on highly active antiretroviral therapy those who modified their treatment within the first year of treatment were mostly men (52 men, 35 women). Efavirenz was the most often changed drug, followed by tenofovir, zidovudine and lopinavir/ritonavir [17].

An analysis of sex differences in a pharmacovigilance register (1547 men, 607 women) found women to be younger, less frequently HCV-co-infected, have less triglycerides alterations but a higher proportion of low HDL-cholesterol than men. Patients were treated with different combinations including lopinavir, atazanavir, tipranavir, fosamprenavir, and darunavir. Women had better immunological recovery and discontinued protease inhibitor (including lopinavir) treatment for adverse events and their own will more frequently [18].

In a South African study of children with HIV randomized to continue ritonavir-boosted lopinavir-based antiretroviral treatment (ART) or switch to nevirapine-based ART (168 boys, 155 girls) girls remaining on ritonavir-boosted lopinavir after a mean of 3.4 years had a higher total cholesterol:HDL ratio and lower mean HDL than boys on that treatment [9].

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 [19].