Uses
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Treatment of HIV Infection
Ritonavir is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults, adolescents, and pediatric patients older than 1 month of age.
Concomitant use of low-dose ritonavir and certain other HIV protease inhibitors (PIs) results in increased plasma concentrations of the other PI and is used to therapeutic advantage (ritonavir-boosted PIs) in PI-based regimens used in antiretroviral-naive (have not previously received antiretroviral therapy) and antiretroviral-experienced patients (received prior antiretroviral therapy). Regimens that contain full-dose ritonavir or ritonavir as the sole HIV protease inhibitor (PI) are not recommended for initial treatment because of a high pill burden, GI intolerance, and metabolic toxicity.
The most appropriate antiretroviral regimen cannot be defined for each clinical scenario, and selection of specific antiretroviral agents for use in such regimens should be individualized based on current knowledge regarding antiretroviral potency, potential rate of development of resistance, known toxicities, and potential for pharmacokinetic interactions as well as virologic, immunologic, and clinical characteristics of the patient. For information on the general principles and guidelines for use of antiretroviral therapy, including specific recommendations for initial therapy in antiretroviral-naive patients and recommendations for changing antiretroviral regimens, see .
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Ritonavir-boosted Therapy
Low-dose ritonavir is used in conjunction with other PIs to decrease metabolism of and increase plasma concentrations of the other PI. Use of low-dose ritonavir in conjunction with another PI has been referred to as ritonavir pharmacokinetic enhancement or ritonavir-boosted therapy. The antiretroviral activity of these regimens is due to the other PI since a therapeutic dosage of ritonavir is not administered. A fixed-combination preparation of lopinavir and low-dose ritonavir is commercially available (lopinavir/ritonavir); other ritonavir-boosted regimens involve administration of a specific dosage of ritonavir and the other PI recommended for the combined regimen.
Regimens that include low-dose ritonavir in conjunction with another PI have been recommended for use in antiretroviral-naive and antiretroviral-experienced patients.
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Antiretroviral-naive Adults and Adolescents
The US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents states that several PI-based regimens that include a ritonavir-boosted PI and 2 HIV nucleoside reverse transcriptase inhibitors (dual NRTIs) are recommended or alternative regimens for initial treatment in antiretroviral-naive adults and adolescents.
PI-based regimens that are recommended by these experts for initial treatment in antiretroviral-naive adults and adolescents regardless of pretreatment viral load or CD4 T-cell count are ritonavir-boosted atazanavir or ritonavir-boosted darunavir in conjunction with tenofovir disoproxil fumarate (tenofovir DF) and emtricitabine (or lamivudine).Ritonavir-boosted atazanavir in conjunction with abacavir and lamivudine (or emtricitabine) is another recommended regimen for initial treatment in antiretroviral-naive adults and adolescents, but should be used only in those with pretreatment plasma HIV RNA levels less than 100,000 copies/mL who are human leukocyte antigen (HLA)-B*5701 negative.
Alternative PI-based regimens recommended by these experts for initial treatment in antiretroviral-naive adults and adolescents include ritonavir-boosted darunavir or lopinavir/ritonavir in conjunction with certain dual NRTIs.
Ritonavir-boosted fosamprenavir, ritonavir-boosted indinavir, ritonavir-boosted saquinavir, and ritonavir-boosted tipranavir are not recommended for initial treatment regimens in antiretroviral naive adults and adolescents.
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Clinical Experience
Safety and efficacy of ritonavir for antiretroviral therapy in antiretroviral-naive adults was initially evaluated in a randomized, double-blind study (study 245) that used regimens that are no longer considered standard of care (monotherapy, 2-drug regimens). Patients in this study had mild to moderate HIV infection (mean baseline CD4 T-cell counts 364/mm) and were randomized to receive monotherapy with oral ritonavir (600 mg twice daily), monotherapy with oral zidovudine (200 mg 3 times daily), or a 2-drug regimen of oral ritonavir (600 mg twice daily) and oral zidovudine (200 mg 3 times daily). During the double-blind phase of the study, ritonavir monotherapy was associated with greater mean increases in CD4 T-cell count from baseline to week 12 compared with the zidovudine arms; mean CD4 T-cell count then appeared to plateau through week 24 in those receiving ritonavir monotherapy, but gradually diminished through week 24 in those receiving zidovudine monotherapy or the regimen that included both drugs. From baseline to week 2, greater mean decreases in plasma HIV-1 RNA levels were observed in those receiving ritonavir or the 2-drug regimen containing ritonavir compared with those receiving zidovudine monotherapy. After week 2 and through week 24, mean plasma HIV-1 RNA levels remained stable in those receiving ritonavir or zidovudine monotherapy or gradually rebounded toward baseline in those receiving both drugs.
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Antiretroviral-experienced Adults and Adolescents
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Clinical Experience
Safety and efficacy of ritonavir for use in previously treated HIV-infected patients was initially evaluated in a randomized, double-blind study with open-label follow-up (study 247) that used regimens that are no longer considered standard of care (monotherapy, 2-drug regimens). The study involved 1090 patients with advanced HIV infection (baseline CD4 T-cell count 100/mm or less; mean baseline count 32/mm) who had received at least 9 months of NRTI therapy. Oral ritonavir (600 mg twice daily) or placebo was added to the patient's existing regimen (i.e., no antiretroviral therapy, monotherapy with zidovudine, zalcitabine (no longer commercially available in the US), didanosine, or stavudine, or therapy with zidovudine and zalcitabine, didanosine, or stavudine) and efficacy was assessed by disease progression or death over the following 6 months.
At week 24, patients who received ritonavir in conjunction with their existing regimen had clinically important increases in CD4 T-cell counts and decreases in plasma HIV-1 RNA levels; there were no improvements in these surrogate markers in patients randomized to receive placebo in addition to their existing regimen. The cumulative incidence of clinical disease progression or death during the double-blind phase (median duration 6 months) was 26% in patients randomized to receive ritonavir in conjunction with their existing regimen and 42% in those randomized to receive placebo with the existing regimen. The cumulative mortality through the end of the open-label follow-up phase (median duration 13.5 or 14 months) was 18 or 26% in patients randomized to receive ritonavir or placebo, respectively, in conjunction with their existing regimen. Results of this study indicated that, in patients with advanced HIV infection who have received long-term NRTI therapy, addition of ritonavir to the regimen increased the probability of survival and was associated with certain clinical benefits such as decreased incidence and severity of opportunistic infections (e.g., esophageal candidiasis, Kaposi's sarcoma, cytomegalovirus retinitis or other cytomegalovirus infections, Pneumocystis carinii pneumonia, Mycobacterium avium complex infections, HIV-associated wasting syndrome). During the double-blind phase of the study, increases in CD4 T-cell counts were observed at week 2 and 4 in those receiving ritonavir, and mean CD4 T-cell count then appeared to plateau from week 4 through week 24. In contrast, there was no apparent change in mean CD4 T-cell count at any visit between baseline and week 24 in patients randomized to placebo.
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Pediatric Patients
Ritonavir is used in conjunction with other antiretroviral agents for the treatment of HIV-1 infection in children older than 1 month of age.
For initial treatment in antiretroviral-naive pediatric patients, the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children recommends a PI or HIV nonnucleoside reverse transcriptase inhibitor (NNRTI) in conjunction with 2 NRTIs. These experts state that the preferred PI-based regimens for initial treatment in antiretroviral-naive pediatric patients are lopinavir/ritonavir and 2 NRTIs (used only in those 14 days of age or older and postmenstrual age at least 42 weeks [i.e., time elapsed since first day of the mother's last menstrual period to birth plus time elapsed after birth]) or ritonavir-boosted atazanavir and 2 NRTIs (used only in those 6 years of age or older). Alternative PI-based regimens recommended by these experts for initial treatment are ritonavir-boosted darunavir (twice-daily) and 2 NRTIs (used only in those 3 years to less than 12 years of age) and ritonavir-boosted darunavir (once daily) and 2 NRTIs (used only in those 12 years of age or older without darunavir-associated resistance substitutions). These experts state that regimens that contain full-dose ritonavir or ritonavir as the sole PI are not recommended for initial therapy in pediatric patients because of GI intolerance and metabolic toxicity.
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Clinical Experience
Safety and efficacy of ritonavir in children 2-17 years of age was evaluated in a randomized, phase 2 study (PACTG 338) that used regimens that are no longer considered standard of care (monotherapy, 2-drug regimens). In this study, HIV-infected children who had received prior antiretroviral therapy (86% had previously received zidovudine alone or in conjunction with didanosine) were randomized to receive a 2-drug regimen of zidovudine and lamivudine, a 2-drug regimen of ritonavir and stavudine, or a 3-drug regimen of zidovudine, lamivudine, and ritonavir (350 mg/m twice daily). At week 12, interim analysis indicated that only 14% of those receiving zidovudine and lamivudine had undetectable levels of plasma HIV-1 RNA (i.e., less than 400 copies/mL) whereas 57 or 61% of those receiving the 2- or 3-drug regimen containing ritonavir, respectively, had undetectable levels. In the subgroup of children who had undetectable plasma HIV-1 RNA levels at study entry, 27% of those receiving the 2-drug ritonavir regimen and 42% of those receiving the 3-drug ritonavir regimen had undetectable levels at 48 weeks. The virologic response to the ritonavir-containing regimens was lower in those with a higher viral load at study entry. In the subgroups of children who had baseline plasma HIV-1 RNA levels of 2.6-3, 3-4, 4-5, or 5-6 log10 copies/mL, plasma HIV-1 RNA levels were undetectable at 48 weeks in 69, 44, 32, or 19%, respectively, in those receiving the 2- or 3-drug ritonavir regimens.
Efficacy of ritonavir in conjunction with zidovudine and lamivudine was evaluated in an open-label, phase 1 and 2 study in HIV-infected infants 1-24 months of age who had not previously received therapy with a PI. At week 16, 36 of 43 children who continued study treatment (as-treated analysis) had plasma HIV-1 RNA levels less than 400 copies/mL. At week 104, durable viral suppression was maintained in 46% of children (as-treated analysis).
The efficacy, safety, and pharmacokinetics of ritonavir have been evaluated in a multicenter phase 1 and 2 study in HIV-infected children 6 months to 18 years of age who were treatment-naive or who had become refractory or intolerant to previous antiretroviral therapy. These children received ritonavir monotherapy (250-400 mg/m twice daily) for the first 12 weeks, then zidovudine (90 mg/m every 6 hours) and/or didanosine (90 mg/m twice daily) was added to the regimen. Interim analysis at 24 weeks of data from children 2 years of age or older (younger children were excluded from this analysis) indicate that regimens that included ritonavir in a dosage of 300 mg/m twice daily in conjunction with zidovudine and/or didanosine were associated with a mean increase in CD4 T-cell counts of 263/mm from baseline counts and a mean decrease in plasma HIV-1 RNA levels of 0.4 logs/mL from baseline levels. Ritonavir was well tolerated, and additional studies have been initiated and are ongoing to further evaluate safety and efficacy of the drug in pediatric patients.
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