Safety, Efficacy and Pharmacokinetics of Ritonavir 400mg/Saquinavir 400mg Twice Daily plus Rifampicin Combined Therapy in HIV Patients with Tuberculosis

Valeria Cavalcanti Rolla; Maria A da Silva Vieira; Douglas Pereira Pinto; Maria C Lourenço; Carlos da Silva de Jesus; Mariza Gonçalves Morgado; Milton Ferreira Filho; Eduardo Werneck-Barroso


Clin Drug Invest. 2006;26(8):469-479. 

In This Article

Abstract and Introduction


Objective: To assess the drug concentrations, efficacy and safety of concomitant use of rifampicin and regimens containing ritonavir/saquinavir (400mg/400mg twice daily) in tuberculosis-HIV treatment-naive patients.
Design and methods: This was an open-label, non-randomised, multiple-dose study. On study day (D)1, tuberculosis treatment (rifampicin 600mg/isoniazid 400mg per day fasting plus pyrazinamide 2 g/day) was introduced in 30 patients. On D31, highly active antiretroviral therapy (HAART) consisting of two nucleoside analogues plus ritonavir/saquinavir 400mg/400mg twice daily was initiated (n = 20).
The pharmacokinetics were assayed with a validated reversed-phase HPLC method before the introduction of HAART on D30 (for rifampicin), after 30 days of HAART at D60 (for rifampicin plus ritonavir/saquinavir), and at the end of the study (without rifampicin) on D210 (for ritonavir/saquinavir). Clinical evaluations were performed on a monthly basis. CD4 counts and viral load were collected on D30, D60 and D180. Genotyping test for HIV was collected at baseline and at D180. Primary endpoints were drug concentration and viral load at D180 (<80 copies/mL). Secondary endpoints were presence of grade 3 and serious adverse events, clinical improvement, CD4 count and genotypic resistance to ritonavir/saquinavir.
Results: Ten patients dropped out of the study during tuberculosis therapy alone. Mean (± SD) baseline CD4 count (on D30) was 151.89 (± 146.77) cells/mm3 and viral load was 5.34 (± 0.4) log. During the antiretroviral therapy, 15 patients dropped out, 14 because of adverse events. One patient (of five) presented a viral load of <80 copies/mL at D180. All but one patient increased CD4 counts from baseline. No genotypic resistance was detected. Clinical improvement was evident in all five patients who tolerated the therapy. Serum concentrations of ritonavir/saquinavir and rifampicin remained within the therapeutic range.
Conclusions: Therapeutic concentrations of the studied drugs and reduction of viral load were achieved; adverse events are the main limitation of use of a ritonavir/saquinavir regimen in treatment-naive patients, but its clinical benefits were evident.


Tuberculosis is one of the most common opportunistic infections in HIV patients in Brazil.[1,2] Mycobacterium tuberculosis induces HIV replication, resulting in very severe forms of the disease, with associated high mortality rates.[3] Tuberculosis is considered difficult to manage, especially when associated with HIV, because of the number of drugs used, length of therapy and drug-drug interactions. Rifampicin, a key drug for tuberculosis treatment, is a potent inducer of cytochrome P450 (CYP) that results in a significant reduction in plasma concentrations of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs).[4] Ritonavir is one of the most potent inhibitors of CYP450 known to date, and that is the reason why it is increasingly used to enhance other concomitantly administered PIs.[5]

Based on a limited number of cases, it was suggested that the strong inhibiting effect of ritonavir on saquinavir metabolism could compensate for the enzyme-inducing effect of rifampicin.[6] With this information, most guidelines accepted this therapy for HIV patients with tuberculosis. This combination has not been well researched in the literature and needs further investigation. A careful assessment of the safety and efficacy of this combined therapy is of major importance in countries where tuberculosis is endemic and rifampicin is a first-line drug. It is important to offer patients and medical practitioners consistent data on the impact of the use of highly active antiretroviral therapy (HAART) concomitant with tuberculosis treatment, the efficacy of the drugs, the incidence of adverse events and the expected recovery.

The aim of this study was to assess the safety, efficacy and pharmacokinetics of concomitant treatment of HIV-1 and tuberculosis with rifampicin plus a HAART regimen containing ritonavir/saquinavir at a 400mg/400mg twice-daily dose.


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