Ritonavir (Norvir)

Published January 25, 2001; Updated October 2016
Susa Coffey, MD
http://hivinsite.ucsf.edu/InSite?page=ar-03-02
Selected References
10. Walmsley  S, Bernstein  B, King  M, Arribas  J, Beall  G, Ruane  P, Johnson  M, Johnson  D, Lalonde  R, Japour  A, Brun  S, Sun  E; M98-863 Study Team.
Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med. 2002 Jun;346(26):2039-46
[PubMed ID: 12087139]
Abstract:
BACKGROUND: Lopinavir is a newly developed inhibitor of human immunodeficiency virus (HIV) protease that, when formulated with ritonavir, yields mean trough plasma lopinavir concentrations that are at least 75 times as high as that needed to inhibit replication of wild-type HIV by 50 percent. METHODS: We conducted a double-blind trial in which 653 HIV-infected adults who had not received antiretroviral therapy for more than 14 days were randomly assigned to receive either lopinavir-ritonavir (400 mg of lopinavir plus 100 mg of ritonavir twice daily) with nelfinavir placebo or nelfinavir (750 mg three times daily) with lopinavir-ritonavir placebo. All patients also received open-label stavudine and lamivudine. The primary efficacy end points were the presence of fewer than 400 HIV RNA copies per milliliter of plasma at week 24 and the time to the loss of virologic response through week 48. RESULTS: At week 48, greater proportions of patients treated with lopinavir-ritonavir than of patients treated with nelfinavir had fewer than 400 copies of HIV RNA per milliliter (75 percent vs. 63 percent, P<0.001) and fewer than 50 copies per milliliter (67 percent vs. 52 percent, P<0.001). The time to the loss of virologic response was greater in the lopinavir-ritonavir group than in the nelfinavir group (hazard ratio, 2.0; 95 percent confidence interval, 1.5 to 2.7; P<0.001). The estimated proportion of patients with a persistent virologic response through week 48 was 84 percent for patients receiving lopinavir-ritonavir and 66 percent for those receiving nelfinavir. Both regimens were well tolerated, with the rate of discontinuation related to the study drugs at 3.4 percent among patients receiving lopinavir-ritonavir and 3.7 percent among patients receiving nelfinavir. Among patients with more than 400 copies of HIV RNA per milliliter at some point from week 24 through week 48, resistance mutations in HIV protease were demonstrated in viral isolates from 25 of 76 nelfinavir-treated patients (33 percent) and none of 37 patients treated with lopinavir-ritonavir (P<0.001). CONCLUSIONS: For the initial treatment of HIV-infected adults, a combination regimen that includes lopinavir-ritonavir is well tolerated and has antiviral activity superior to that of a nelfinavir-containing regimen.
11. Clotet  B, Bellos  N, Molina  JM, Cooper  D, Goffard  JC, Lazzarin  A, Wöhrmann  A, Katlama  C, Wilkin  T, Haubrich  R, Cohen  C, Farthing  C, Jayaweera  D, Markowitz  M, Ruane  P, Spinosa-Guzman  S, Lefebvre  E; POWER 1 and 2 study groups.
Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet. 2007 Apr;369(9568):1169-78
[PubMed ID: 17416261]
Abstract:
BACKGROUND: The continuing, randomised, multinational, phase IIB POWER 1 and 2 studies aim to evaluate efficacy and safety of darunavir in combination with low-dose ritonavir in treatment-experienced HIV-1-infected patients. We did a pooled subgroup analysis to update results at week 48 for patients receiving the recommended dose of darunavir-ritonavir compared with those receiving other protease inhibitors (PIs). METHODS: After 24-week dose-finding phases and primary efficacy analyses, patients randomised to receive darunavir-ritonavir were given 600/100 mg twice daily, and patients receiving control PIs continued on assigned treatment into the longer-term, open-label phase; all patients continued on optimised background regimen. We assessed patients who had reached week 48 or discontinued earlier at the time of analysis; for the darunavir-ritonavir group, only patients who received 600/100 mg twice daily from baseline were included. Analyses were intention-to-treat. The POWER 2 study (TMC114-C202) is registered with ClinicalTrials.gov (NCT00071097). FINDINGS: At week 48, 67 of 110 (61%) darunavir-ritonavir patients compared with 18 of 120 (15%) of control PI patients had viral load reductions of 1 log10 copies per mL or greater from baseline (primary endpoint; difference in response rates 46%, 95% CI 35%-57%, p<0.0001). Based on a logistic regression model including stratification factors (baseline number of primary PI mutations, use of enfuvirtide, baseline viral load) and study as covariates, the difference in response was 50% (odds ratio 11.72, 95% CI 5.75-23.89). In the darunavir-ritonavir group, rates of adverse events were mostly lower than or similar to those in the control group when corrected for treatment exposure. No unexpected safety concerns were identified. INTERPRETATION: Efficacy responses with darunavir-ritonavir 600/100 mg twice daily plus optimised background regimen were greater than those with control PI and were sustained to at least week 48, with favourable safety and tolerability in treatment-experienced patients. This regimen could expand the treatment options available for such patients.