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

HIVSome studies have shown higher ritonavir exposure and lower ritonavir clearance in women [1-5] while others show similar results in men and women [6-9]. The original manufacturer does not recommend different dosing in men and women [10].In a pharmacokinetic analysis of low-dose ritonavir (16 men, 15 women) women had higher exposure for all 3 protease inhibitors (PIs) (ritonavir, atazanavir, saquinavir) compared to men after adjusting for body weight [11]. As ritonavir is a potent inhibitor of CYP 3A4 and P-glycoprotein (P-gp) and therefore used to boost other PIs (being  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 [11].

Effects

HIVBoth men and women have been included in the pivotal studies but few studies have presented sex-divided outcome measures [10]. 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 [4].Women treated with ritonavir+atazanavir had a higher risk of virologic failure than men assigned to ritonavir+atazanavir in a US study (1535 men, 322 women) [3].

COVID-19A phase 2/3 trial conducted by the original manufacturer showed that a similar proportion of men and women treated with nirmatrelvir/ritonavir (520 men, 519 women) had COVID-19-related hospitalization or death from any cause at day 28 [12].

Adverse effects

Specific for ritonavir in HIVAn American randomized open-label study of HIV-positive patients (1535 men, 322 women) found no sex difference in safety outcome between atazanavir+ritonavir and efavirenz treatment. Self-reported adherence did not differ significantly by patient’s sex [3].In a South African study in children with HIV (168 boys, 155 girls), girls on ritonavir-boosted lopinavir had a higher total cholesterol:HDL ratio and lower mean HDL than boys [4].Treatment with lopinavir/ritonavir was associated with incident hypertension in men but not in women, according to a retrospective study in a Zambian population of people with HIV (106 men, 201 women) [13].

Antiretroviral agents in general in HIVFor antiretroviral regimens 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].

COVID-19Sex differences in adverse event reports from nirmatrelvir/ritonavir have been analyzed using the FDA Adverse Event Reporting System (FAERS). Of the 11 997 reports, 59.5% of the adverse events were reported in women. The distribution of specific adverse events was similar in men and women [18].

Reproductive health issues

Ritonavir adversely interacts with oral contraceptives and lowers the dose of both progesterone and estrogen components thus rendering them potentially ineffective [10, 19].  It is recommended that an alternative, effective and safe method of contraception should be used during treatment [10]. 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 RCT trials report a higher rate of discontinuation from ART containing ritonavir boosted PI in women [20-22].

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].