Ritonavir

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

Some studies have shown higher ritonavir exposure in women [1-5] while others show similar results in men and women [6]. The manufacturer does not recommend different dosing in men and women [7].

In a pharmacokinetic analysis of saquinavir with atazanavir or low-dose ritonavir (16 men, 15 women) women had higher exposure for all 3 protease inhibitors (PIs) compared to men after adjusting for weight [8]. As ritonavir is a potent inhibitor of cytochrome P450 3A4 isoenzyme (CYP 3A4) and P-glycoprotein (P-gp) and therefore used to boost other PIs (who are substrates of CYP3A4 and P-gp), the authors speculate that higher exposure of ritonavir in women could be the mechanism behind the higher AUC for the PIs [8].In a study of plasma concentration data from a randomized Phase III study (655 men, 131 women), ritonavir exposure was found to be higher in women [1]. A pharmacokinetic study of lopinavir/ritonavir treated HIV patients (78 men, 76 women) found women to have lower clearance and higher AUC of ritonavir [2]. A randomized open-label study of HIV-positive patients treated with atazanavir+ritonavir or efavirenz combined with abacavir/lamivudine or tenofovir/emtricitabine from the USA (1535 men, 322 women) found that women have lower ritonavir clearance, higher exposure, and higher pre-dose levels of ritonavir compared to men [3].In 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) girls remaining on ritonavir-boosted lopinavir had higher plasma concentrations of ritonavir than boys during post-randomization visits [4]. A pharmacokinetic study of ritonavir and saquinavir (9 men, 8 women) showed higher concentrations of both drugs in women [5].

In contrast, a study of steady-state concentrations of lopinavir/ritonavir in HIV-patients (9 men, 11 women) found no differences between men and women in pharmacokinetic variables [6]. Using data from Japanese patients with HCV population pharmacokinetic models were developed for paritaprevir, ombitasvir, and ritonavir (100 men, 157 women), and did not find patients’ sex to influence the pharmacokinetic parameters [9]. A Spanish PK study did not find any differences either in PK parameters for ritonavir (n=30) [10]. In a population pharmacokinetic analysis of cobistat or ritonavir boosted Elvitegravir (in all 1046 men, 410 women) patients’ sex did not affect pharmacokinetic variables [11]. A pharmacokinetic study in healthy volunteers measuring plasma drug concentrations after a single oral dose of lopinavir and ritonavir (8 men, 8 women) found no significant sex differences in oral bioavailability and systemic clearance of lopinavir and ritonavir after coprandial administration if weight adjusted doses were used [12]. It is suggested by the authors that food would reduce the gastric physiological differences between men and women [13].

Effects

Both men and women have been included in the pivotal studies but few sex-divided outcome measures have not been presented [7].

In 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 [4].

In the US study mentioned above in patients treated with atazananvir+ritonavir or efavirenz combined with abacavir/lamivudine or tenofovir/emtricitabine (1535 men, 322 women) women treated with ritonavir had a higher risk of virologic failure with either nucleoside reverse transcriptase inhibitor backbone than women assigned to efavirenz, or men assigned to atazanavir+ritonavir. In this study, more women than men reported black race which is a possible confounding [3].

Adverse effects

The differences in adverse events which have been described for different antiretroviral regimens are that in general women have been reported to have more nausea and gastrointestinal reactions, more lipodystrophy, a higher risk of developing kidney failure but a lower risk of LDL-level increase compared to men [3, 14-16].

A retrospective cohort study (438 men, 122 women) investigated if particular antiretroviral agents were associated with a higher risk of developing serious liver enzyme elevations in patients with HIV. An increased risk was found in women, use of first-line potent antiretroviral combination regimens in patients without prior NRTI treatment, recent start of nevirapine (HR, 9.6) or ritonavir, and in patients with higher baseline ALT levels, chronic HBV or HCV infection [17].

An American randomized open-label study of HIV-positive patients treated with atazanavir+ritonavir or efavirenz combined with abacavir/lamivudine or tenofovir/emtricitabine (1535 men, 322 women) found no difference between men and women in safety outcome between atazanavir+ritonavir and efavirenz treatment. Self-reported adherence did not differ significantly by sex. In this study, more women than men reported black race which is a possible confounding [3].

In 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) girls remaining on ritonavir-boosted lopinavir had a higher total cholesterol:HDL ratio and lower mean HDL than boys on that treatments [4].

Reproductive health issues

Ritonavir adversely interacts with oral contraceptives and lowers the dose of both progesterone and estrogen components thus rendering them potentially ineffective [7, 18].  It is recommended that an alternative, effective and safe method of contraception should be used during treatment [7]. Due to ritonavir having a high affinity for several cytochrome P450 isoforms the drug is prone to interaction. 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

Several studies report a higher rate of discontinuation from ART containing ritonavir boosted PI in women [19, 21]. A North American open label phase III study in HIV patients treated with darunavir+ritonavir in addition to an investigator-selected optimized background regimen (142 men, 287 women) found a higher discontinuation rate in women [19]. 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/emtricitabin. Discontinuation rates were higher in women than men in each treatment arm (29% and 18%, respectively of women and men on lopinavir/ritonavir) [20]. In a post-hoc analysis of data from a randomised 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 [21].

A descriptive retrospective Brasilian study of HIV patients on highly active antiretroviral therapy who modified their treatment within the first year of treatment (52 men, 35 women) found that efavirenz was the most often changed drug, followed by tenofovir, zidovudine and lopinavir/ritonavir [22].

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 [23].