hreshold of 500 msec.
Modest prolongation of the PR interval was also noted in subjects receiving ritonavir in the same study on Day 3. The mean changes from baseline in PR interval ranged from 11.0 to 24.0 msec in the 12 hour interval post dose. Maximum PR interval was 252 msec and no second or third degree heart block was observed (see section 4.4).
Resistance
Ritonavir-resistant isolates of HIV-1 have been selected in vitro and isolated from patients treated with therapeutic doses of ritonavir.
Reduction in the antiretroviral activity of ritonavir is primarily associated with the protease mutations V82A/F/T/S and I84V. Accumulation of other mutations in the protease gene (including at positions 20, 33, 36, 46, 54, 71, and 90) can also contribute to ritonavir resistance. In general, as mutations associated with ritonavir resistance accumulate, susceptibility to select other PIs may decrease due to cross-resistance. The Summary of Product Characteristics of other protease inhibitors or official continuous updates should be consulted for specific information regarding protease mutations associated with reduced response to these agents.
Clinical pharmacodynamic data
The effects of ritonavir (alone or combined with other antiretroviral agents) on biological markers of disease activity such as CD4 cell count and viral RNA were eva luated in several studies involving HIV-1 infected patients. The following studies are the most important.
Adult Use
A controlled study completed in 1996 with ritonavir as add-on therapy in HIV-1 infected patients extensively pre-treated with nucleoside analogues and baseline CD4 cell counts 100 cells/μl showed a reduction in mortality and AIDS defining events. The mean average change from baseline over 16 weeks for HIV RNA levels was -0.79 log10 (maximum mean decrease: 1.29 log10) in the ritonavir group versus-0.01 log10 in the control group. The most frequently used nucleosides in this study were zidovudine, stavudine, didanosine and zalcitabine.
In a study completed in 1996 recruiting less advanced HIV-1 infected patients (CD4 200-500 cells/μl) without previous antiretroviral therapy, ritonavir in combination with zidovudine or alone reduced viral load in plasma and increased CD4 count. The mean average change from baseline over 48 weeks for HIV RNA levels was -0.88 log10 in the ritonavir group versus -0.66 log10 in the ritonavir + zidovudine group versus -0.42 log10 in the zidovudine group.
The continuation of ritonavir therapy should be eva luated by viral load because of the possibility of the emergence of resistance as described under section 4.1 Therapeutic indications.
Paediatric Use
In an open label trial completed in 1998 in HIV infected, clinically stable children there was a significant difference (p = 0.03) in the detectable RNA levels in favour of a triple regimen (ritonavir, zidovudine and lamivudine) following 48 weeks treatment.
In a study completed in 2003, 50 HIV-1 infected, protease inhibitor and lamivudine naïve children age 4 weeks to 2 years received ritonavir 350 or 450 mg/m2 every 12 hours co-administered with zidovudine 160 mg/m2 every 8 hours and lamivudine 4 mg/kg every 12 hours. In intent to treat analyses, 72% and 36% of patients achieved reduction in plasma HIV-1 RNA of 400 copies/ml at Week 16 and 104, respectively. Response was similar in both dosing regimens and across patient age.
In a study completed in 2000, 76 HIV-1 infected children aged 6 months |
