Drug products: Kaletra, Lopinavir/Ritonavir Accord, Lopinavir/Ritonavir Mylan, Norvir, Paxlovid, Ritonavir Accord, Ritonavir Mylan
ATC code: J05, J05AE03, J05AR10
In the treatment of HIV, few analyses of sex differences in effect of ritonavir specifically have been presented. Diarrhea and severe lipid disturbances are reported to be more common in men while lipodystrophy, nausea, and liver injuries are more common in women with ritonavir-based combination treatment.
In the treatment of COVID-19, nirmatrelvir/ritonavir show similar efficacy in men and women.
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 .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 . 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 .
HIVBoth men and women have been included in the pivotal studies but few studies have presented sex-divided outcome measures . 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 .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) .
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 .
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 .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 .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) .
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 .
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 .
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 . 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).
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 .
Date of litterature search: 2023-01-12
- Venuto CS, Mollan K, Ma Q, Daar ES, Sax PE, Fischl M et al. Sex differences in atazanavir pharmacokinetics and associations with time to clinical events: AIDS Clinical Trials Group Study A5202. J Antimicrob Chemother. 2014;69(12):3300-10. PubMed
- Umeh OC, Currier JS, Park JG, Cramer Y, Hermes AE, Fletcher CV. Sex differences in lopinavir and ritonavir pharmacokinetics among HIV-infected women and men. J Clin Pharmacol. 2011;51(12):1665-73. PubMed
- Smith KY, Tierney C, Mollan K, Venuto CS, Budhathoki C, Ma Q et al. Outcomes by sex following treatment initiation with atazanavir plus ritonavir or efavirenz with abacavir/lamivudine or tenofovir/emtricitabine. Clin Infect Dis. 2014;58(4):555-63. PubMed
- Shiau S, Kuhn L, Strehlau R, Martens L, McIlleron H, Meredith S et al. Sex differences in responses to antiretroviral treatment in South African HIV-infected children on ritonavir-boosted lopinavir- and nevirapine-based treatment. BMC Pediatr. 2014;14(1):39. PubMed
- Schmitt C, Kaeser B, Riek M, Bech N, Kreuzer C. Effect of saquinavir/ritonavir on P-glycoprotein activity in healthy volunteers using digoxin as a probe. Int J Clin Pharmacol Ther. 2010;48(3):192-9. PubMed
- Ofotokun I, Chuck SK, Binongo JN, Palau M, Lennox JL, Acosta EP. Lopinavir/Ritonavir pharmacokinetic profile: impact of sex and other covariates following a change from twice-daily to once-daily therapy. J Clin Pharmacol. 2007;47(8):970-7. PubMed
- Gopalakrishnan SM, Polepally AR, Mensing S, Khatri A, Menon RM. Population Pharmacokinetics of Paritaprevir, Ombitasvir, and Ritonavir in Japanese Patients with Hepatitis C Virus Genotype 1b Infection. Clin Pharmacokinet 2016 Jun 17; PubMed
- Curran A, Martí R, López RM, Pérez M, Crespo M, Melià MJ et al. Darunavir and ritonavir total and unbound plasmatic concentrations in HIV-HCV-coinfected patients with hepatic cirrhosis compared to those in HIV-monoinfected patients. Antimicrob Agents Chemother. 2015;59(11):6782-90. PubMed
- Custodio JM, Gordi T, Zhong L, Ling KH, Ramanathan S. Population Pharmacokinetics of Boosted-Elvitegravir in HIV-Infected Patients. J Clin Pharmacol. 2016;56(6):723-32. PubMed
- Norvir (ritonavir). Summary of Product Characteristics. European Medicines Agency (EMA); 2018.
- King JR, Kakuda TN, Paul S, Tse MM, Acosta EP, Becker SL. Pharmacokinetics of saquinavir with atazanavir or low-dose ritonavir administered once daily (ASPIRE I) or twice daily (ASPIRE II) in seronegative volunteers. J Clin Pharmacol. 2007;47(2):201-8. PubMed
- EMA. Assessment report Paxlovid. EMA [www]. [updated 2021-12-16, cited 2022-04-14]. EMA
- Masenga SK, Povia JP, Mutengo KH, Hamooya BM, Nzala S, Heimburger DC et al. Sex differences in hypertension among people living with HIV after initiation of antiretroviral therapy. Front Cardiovasc Med. 2022;9:1006789. PubMed
- Hodder S, Arasteh K, De Wet J, Gathe J, Gold J, Kumar P et al. Effect of gender and race on the week 48 findings in treatment-naïve, HIV-1-infected patients enrolled in the randomized, phase III trials ECHO and THRIVE. HIV Med. 2012;13(7):406-15. PubMed
- Kumar PN, Rodriguez-French A, Thompson MA, Tashima KT, Averitt D, Wannamaker PG et al. A prospective, 96-week study of the impact of Trizivir, Combivir/nelfinavir, and lamivudine/stavudine/nelfinavir on lipids, metabolic parameters and efficacy in antiretroviral-naive patients: effect of sex and ethnicity. HIV Med. 2006;7(2):85-98. PubMed
- Mocroft A, Lundgren JD, Ross M, Law M, Reiss P, Kirk O et al. Development and validation of a risk score for chronic kidney disease in HIV infection using prospective cohort data from the D:A:D study. PLoS Med. 2015;12(3):e1001809. PubMed
- Wit FW, Weverling GJ, Weel J, Jurriaans S, Lange JM. Incidence of and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy. J Infect Dis. 2002;186(1):23-31. PubMed
- Li M, Zhang QS, Liu XL, Wang HL, Liu W. Adverse Events Associated with Nirmatrelvir/Ritonavir: A Pharmacovigilance Analysis Based on FAERS. Pharmaceuticals (Basel). 2022;15(12). PubMed
- Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A, European/Australasian Stroke Prevention in Reversible Ischaemia Trial Study Group. Risk indicators for development of headache during dipyridamole treatment after cerebral ischaemia of arterial origin. J Neurol Neurosurg Psychiatry. 2009;80:437-9. PubMed
- Currier J, Averitt Bridge D, Hagins D, Zorrilla CD, Feinberg J, Ryan R et al. Sex-based outcomes of darunavir-ritonavir therapy: a single-group trial. Ann Intern Med. 2010;153:349-57. PubMed
- Squires KE, Johnson M, Yang R, Uy J, Sheppard L, Absalon J et al. Comparative gender analysis of the efficacy and safety of atazanavir/ritonavir and lopinavir/ritonavir at 96 weeks in the CASTLE study. J Antimicrob Chemother. 2011;66(2):363-70. PubMed
- Gallant J, Moyle G, Berenguer J, Shalit P, Cao H, Liu YP et al. Atazanavir Plus Cobicistat: Week 48 and Week 144 Subgroup Analyses of a Phase 3, Randomized, Double-Blind, Active-Controlled Trial. Curr HIV Res. 2017;15(3):216-224. PubMed
- Else LJ, Taylor S, Back DJ, Khoo SH. Pharmacokinetics of antiretroviral drugs in anatomical sanctuary sites: the male and female genital tract. Antivir Ther. 2011;16(8):1149-67. PubMed
- Statistikdatabas för läkemedel. Stockholm: Socialstyrelsen. 2021 [cited 2022-03-15.] länk
- VAL-databasen. Region Stockholm. 2021 [cited 2023-01-20.] länk
Reviewed by: Diana Rydberg
Approved by: Karin Schenck-Gustafsson