Continuing Education Activity

Ritonavir is a protease inhibitor used for the treatment of HIV/AIDS. It is seldom employed for its own antiviral activity but instead serves as a booster for other protease inhibitors. Although ritonavir was initially designed to inhibit HIV protease, studies have found that it also inhibits cytochrome P450-3A4. Because of its mechanism of action, ritonavir is currently under investigation for its use in treating some forms of cancer. In addition, it is used in combination with other medicines to treat Hepatitis C infection. This activity reviews the indications, dosage, administration, adverse event profile, mechanisms of action, toxicity, and contraindications for ritonavir as part of treating HIV/AIDS. This activity is pertinent for members of the interprofessional team involved in caring for patients with HIV/AIDS, including physicians, infectious disease specialists, nurses, pharmacists, physician assistants, and other healthcare providers.

Objectives:

• Describe the indications for ritonavir.
• Outline the potential adverse effects of ritonavir.
• Summarize the mechanism of action of ritonavir, both as an antiretroviral on its own and in its use with other agents.
• Outline the importance of collaboration and coordination among the interprofessional team to enhance the care of HIV patients when dosing with ritonavir to help limit side effects and improve patient outcomes.

Indications

In the United States, the Food and Drug Administration (FDA) approved ritonavir in 1996 to treat HIV. After saquinavir, it was the second approved protease inhibitor in the United States. Although ritonavir was initially designed to inhibit HIV protease, studies have found that it also inhibits cytochrome P450-3A4 (CYP450-3A4), which is its chief mechanism of action. It is currently used to augment HIV treatment by increasing the bioavailability of co-administered anti-retroviral (ARV) drugs. Combined with triple therapy, initial results for ritonavir showed increased CD4+ count and decreased HIV RNA levels in treatment naïve patients.[1] 

In combination with other standard ARV medications, lopinavir/ritonavir has provided significant virological suppression and better immune outcomes in both treatment-naive and treatment-experienced patients.[2] Because of its mechanism of action, ritonavir is currently under investigation for its use in treating some forms of cancer.[3] In 2014, the FDA approved a combination drug of ombitasvir/paritaprevir/ritonavir and dasabuvir to treat hepatitis C virus (HCV) genotype 1.[4] It is highly efficacious with minimal side effects. Additionally, lopinavir/ritonavir was FDA approved in early 2000. 

In combination with nirmatrelvir, ritonavir has received emergency use authorization as an investigational drug combination to treat COVID-19 in patients with mild-to-moderate severity. It is limited to the use in adults and children aged 12 years and older (weighing 88 pounds or more) with positive results of direct SARS-CoV-2 viral testing and at high risk for progression to severe COVID-19, including hospitalization or death. Some evidence exists for using ritonavir in combination with lopinavir to treat COVID-19 infection, but large clinical trials are needed to achieve more reliable results.[5]

Mechanism of Action

Ritonavir works by binding to HIV-1 protease. HIV-1 protease causes cleavage of protein precursors generating new viral particles. Protease inhibitors disrupt this cleavage process, interrupting the production of new viral particles.[6]

Perhaps the more important mechanism of action of ritonavir for the treatment of HIV and HCV is its inhibition of the liver enzyme cytochrome P450 3A4 (CYP450-3A4). This cytochrome pathway metabolizes other protease inhibitors. When ritonavir inhibits CYP450-3A4, the bioavailability of other antiretroviral drugs increases, and inhibition of this CYP450 pathway causes a decrease in the breakdown of ARVs, hence increasing serum drug levels. Ritonavir should be used carefully with other drugs metabolized through this pathway, including statins, anti-arrhythmic agents, anti-epileptic drugs, and anti-fungal agents.[7]

Administration

Ritonavir capsules and tablets are not bioequivalent. It is available in 100 mg tablets, capsules, powder packets, and 80 mg/ml oral solutions. Usually, it is used in the lopinavir/ritonavir combination of drugs used for HIV. The small amount of ritonavir increases the bioavailability of the lopinavir.[1] The standard route of administration is oral. It comes as a tablet, soft gel capsule, or oral suspension for adult and pediatric populations.[2] The typical regimen is dosed at 400 mg lopinavir/100 mg ritonavir orally twice daily. 

Lopinavir/Ritonavir Formulation                                 

• Tablet: 100 mg/25 mg, 200 mg/50 mg
• Oral Solution: 400 mg/100 mg per 5 mL

HIV-1

• 400 mg/100 mg orally twice daily, or 800 mg/200 mg by mouth once daily in patients with less than three lopinavir resistance-associated substitutions
• Increase the dose to 500 mg/125 mg orally twice daily in tablet formulation or 520 mg/130 mg (6.5 mL) solution by mouth twice daily if used with efavirenz, fosamprenavir, nelfinavir, or nevirapine

HIV Post-exposure Prophylaxis

• 400 mg/100 mg orally twice daily

Pediatric Population

14 days to 12 months

• 16 mg/4 mg/kg orally twice daily

Treatment naïve patients, age over 13 months, less than 15 kg

• 12 mg/3 mg/kg orally twice daily or 230 mg/57.5mg/m^2
• Increase the dose to 300 mg/75 mg/m^2 when used with efavirenz, fosamprenavir, nelfinavir, or nevirapine.

Treatment naïve patients, greater than 13 months, 15 to 40 kg

• 10mg/2.5 mg/kg by mouth twice daily OR 230 mg/57.5 mg/m^2
• Increase the dose to 300 mg/75 mg/m^2 when used with efavirenz, fosamprenavir, nelfinavir, or nevirapine.

Treatment-experienced patients older than 13 months, under 15 kg

• 13 mg/3.25 mg/kg orally twice a day. Max dose is 400 mg/100 mg twice daily or 300 mg/75 mg/m^2
• Increase the dose to 300 mg/75 mg/m^2 when used with efavirenz, fosamprenavir, nelfinavir, or nevirapine

Treatment-experienced patients, over 13 months, 15 to 45 kg

• 11 mg/2.75 mg/kg by mouth two times daily. Max dose is 400 mg/100 mg twice daily or 300 mg/75 mg/m^2
• Increase the dose to 300 mg/75 mg/m^2 when used with efavirenz, fosamprenavir, nelfinavir, or nevirapine.

Treatment experienced patients older than 13 months, weight greater than 45 kg

• 400 mg/100 mg/kg orally twice daily
• Increase to 500 mg/125 mg orally twice daily or 520 mg/130 mg solution twice daily with efavirenz, fosamprenavir, nelfinavir, or nevirapine.

Special Patient Population

Patients with Hepatic Impairment

• In case of moderate or severe hepatic impairment, use ritonavir with monitoring. As per the manufacturer's labeling, avoid using in patients with severe hepatic impairment.

Pregnancy Considerations

• 400 mg/100 mg oral dosing twice daily
• Increase the dose to 500 mg/125 mg orally twice daily when used with efavirenz, fosamprenavir, nelfinavir, or nevirapine.
• Healthcare providers are encouraged to register patients to Antiretroviral Pregnancy Registry (APR), which monitors pregnancy outcomes in women exposed to ritonavir during pregnancy. The oral solution contains around 27% propylene glycol and 43% ethanol; hence the use is not recommended during pregnancy.

Breastfeeding Considerations

• The CDC recommends against HIV-infected mothers breastfeeding their infants to prevent postnatal transmission of HIV, developing viral resistance (when HIV-negative infants), and serious adverse drug reactions. There is no information available on the effects of the ritonavir on milk production or the effects on the breastfed infant. There are no adverse reactions reported in infants.[8]

COVID-19 Emergency Use Authorization

• Administer 300 mg nirmatrelvir with 100 mg ritonavir by mouth twice daily (in the morning and the evening) for five days. For each dose, it is a must to take all three tablets at the same time. The dose for patients with a renal impairment needs to be adjusted based on renal function. For eGFR ≥30 to <60 mL/min, decrease the dose to 150 mg nirmatrelvir and 100 mg ritonavir twice daily for five days. Use is not recommended for patients with eGFR <30 mL/min.[9]

Adverse Effects

Ritonavir has several constitutional side effects, including malaise, dizziness, and insomnia, gastrointestinal side effects including nausea, vomiting, abdominal pain, and diarrhea, and metabolic side effects such as hyperlipidemia, hypertriglyceridemia, transaminitis, and rhabdomyolysis.[2] Although there are reports of QT prolongation with the use of protease inhibitors, studies have not established them as independent culprits.[10]

Because of the metabolic side effects of ritonavir, lipid-lowering agents might also be indicated along with protease inhibitors to reduce cardiovascular disease risk. Other serious adverse effects are pancreatitis, diabetes mellitus, renal failure, hypersensitivity reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), hepatotoxicity, leukopenia, and neutropenia.[6] 

It requires cautious use with other medications that inhibit the CYP450-3A4 enzyme, causing an increase in serum drug levels. Ritonavir should also not be given to patients on pharmacological agents that act as CYP inducers. These can cause drastically reduced levels of ritonavir, resulting in potential drug resistance.[6] 

Fat Redistribution and/or accumulation, including dorsocervical fat enlargement (buffalo hump), central obesity, peripheral wasting, breast enlargement, facial wasting, and "cushingoid appearance," have been observed in patients receiving antiretroviral therapy, but causal relationships haven't been established.

Reports of increased bleeding, spontaneous skin hematomas, and hemarthrosis in patients with hemophilia type A and B treated with protease inhibitors. Still, causal relationships between protease inhibitor therapy and these events are not established.

Reports of varying degrees of cross-resistance among protease inhibitors have been observed. Continued use of ritonavir 1200 mg daily following a loss of viral suppression might increase the risk of cross-resistance with other protease inhibitors.

Contraindications

Ritonavir contraindications include patients with a known allergic reaction to either ritonavir or any of its components. Hypersensitivity reactions include Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).

There is a boxed warning for drug-drug interactions of ritonavir leading to potentially serious and/or life-threatening reactions when co-administered with drugs such as antiarrhythmics (amiodarone, dronedarone, flecainide, propafenone, quinidine), sedative-hypnotics (triazolam, orally administered midazolam), HMG-COA reductase inhibitors (lovastatin, simvastatin) or an ergot alkaloid (dihydroergotamine, ergotamine, methylergonovine). Healthcare providers should review medications taken by patients before prescribing ritonavir or when prescribing other drugs to patients already taking ritonavir. It also has significant drug interaction when taken with alfuzosin, ranolazine, voriconazole, colchicine, lurasidone, pimozide, cisapride, lomitapide, or sildenafil (for the treatment of pulmonary arterial hypertension).

Ritonavir is contraindicated with potent CYP3A inducers (e.g., apalutamide, St. John's wort), which can significantly reduce ritonavir plasma concentrations and may be associated with the potential for loss of virologic response, possible resistance, and cross-resistance.[6]

Monitoring

Because ritonavir use correlates with hepatotoxicity, monitoring liver function tests before initiation of therapy, 2 to 8 weeks after starting treatment, and subsequently every 3 to 6 months is recommended. Ritonavir has also demonstrated associations with hypercholesterolemia, so a lipid profile is recommended at baseline and every 6 to 12 months. Because a rise in lipids increases the risk for cardiovascular disease, lipid-lowering agents may be required. Patients on ritonavir are also susceptible to diabetes mellitus, so recommendations include baseline fasting glucose levels followed by screening every 12 months. Although there is weak evidence of QT prolongation and Torsades de Pointes in patients on ritonavir, the measurement of electrolyte levels, including magnesium, should occur at baseline, 2 to 8 weeks after starting treatment, and every 3 to 6 months after that.[10] The pediatric population should also have similar screening.

The oral solution of lopinavir/ritonavir contains alcohol, so it should be avoided in neonates less than 42 weeks postmenstrual age and less than 14 days old. Infants, particularly premature infants, are at increased risk of central nervous system complications.

Toxicity

Because there is a small quantity of ritonavir in the combination of lopinavir/ritonavir, there are few reports of ritonavir toxicity. However, a few case reports have suggested retinal toxicity secondary to ritonavir. One such case showed an improvement after discontinuing ritonavir after 2 and 4 weeks.[11][12]

Because most of the neurological and gastrointestinal side effects are directly associated with higher ritonavir concentrations, the dosage should be monitored and titrated down in patients with side effects. This titration could result in increased tolerability of the drug and a decrease in treatment failure.[13]

Enhancing Healthcare Team Outcomes

Since ritonavir is a potent CYP450-3A4 inhibitor, clinicians must be cautious when adding it to a patient's regimen with multiple comorbidities and medications. Dosing, patient education, and subsequent monitoring should be the purview of an interprofessional healthcare team that includes clinicians (MDs and DOs), mid-level practitioners (NPs and PAs), nurses, and pharmacists. For instance, cobicistat and ritonavir are both used as pharmacokinetic boosters with similar inhibition of CYP450-3A4. However, in the presence of inducers such as rifamycin or anti-convulsants, the inhibition of CYP450-3A4 is markedly different.[14] It might be easy to extrapolate data from ritonavir and apply it to cobicistat; however, a person on a stable dose of another medication can experience an increase or decrease in serum drug concentrations. The pharmacist should perform thorough medication reconciliation and report any concerns to the prescribing clinician and nursing staff to implement corrective measures.

In addition to standard drug monitoring for a particular regimen by the primary care provider/nurse practitioner, dose adjustment or additional monitoring might be necessary if a drug-drug interaction is suspected. The oncology pharmacist should assist the team in review and management.[14] Nursing is in the best position to evaluate and emphasize the importance of patient compliance with their antiretroviral regimen, assess treatment progress, and monitor for adverse reaction, informing the prescriber of their findings. Any antiretroviral regimen, including those with ritonavir, requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists collaborating across disciplines to achieve optimal patient results. [Level 5]