Key points are not available for this paper at this time.
There is currently great interest in the combination of a small dose of ritonavir with other protease inhibitors, such as indinavir or saquinavir, in order to increase drug potency by improving trough plasma levels 1. However, the use of ritonavir is associated with a higher risk of hepatotoxicity compared with other protease inhibitors 2,3, in particular in those HIV-1-infected patients co-infected with hepatitis C (HCV) 4–7. This study includes 19 consecutive HIV-1-infected patients (17 men and two women) co-infected with HCV (n = 18) or hepatitis B (HBV) (n = 1), who have been treated for at least 6 months with indinavir combined with two nucleoside analogues. The protease inhibitor treatment of these patients was next modified through the addition of ritonavir 100 mg twice a day (n = 17) or 200 mg twice a day (n = 2) and a decrease in the indinavir dosage from 800 mg three times a day to 800 mg twice a day. Liver function tests were performed at baseline and after an average follow-up period of 179 days (range 67–313 days) after treatment modification. The median age of the study population was 40 years. HIV infection was acquired through intravenous drug use in 13 patients, homosexual contact in four patients and heterosexual contact in two patients. At the time of the study, 14 patients were included in a methadone substitution programme. The diagnosis of HCV infection was based on the presence of anti-HCV antibodies and that of chronic HBV infection was based on the detection of HBs antigen. Zidovudine plus lamivudine (n = 6) or stavudine plus lamivudine (n = 7) were the most frequent nucleoside analogue combinations. All patients were naive for ritonavir. Before the addition of ritonavir, the baseline median plasma viraemia and CD4 cell counts were 1.84 log10 RNA copies/ml (range 1.0–5.33) and 439 CD4 T cells/mm3 (range 39–945). After the 179 day follow-up period, viraemia (median 2.53 log10 RNA copies/ml, range 1.0–5.2) and CD4 T cell counts (median 317 cell/mm3, range 40–976) were in the same range. The median baseline values for aspartate transaminase (AST) and alanine transaminase (ALT) were 55 U/l (range 15–350) and 51 U/l (range 6–391), respectively (Fig. 1). Liver toxicity was recorded on an individual basis according to the ratio of follow-up values over baseline values for AST and ALT. The median of the ratios was 0.91 for AST (range 0.09–2.11) and 1.40 for ALT (range 0.06–2.74). In one patient, there was a 2.1- and 2.7-fold increase in AST and ALT values, respectively. There was no case of discontinuation of medication.Fig. 1.: Liver function tests at baseline and a median of 179 days after switch from a triple-drug regimen containing indinavir three times a day to indinavir twice a day with low dosage ritonavir. Normal values for aspartate transaminase (AST) and alanine transaminase (ALT) were 10–34 and 10–44 U/l, respectively.Long-term treatment with indinavir has been associated with the impairment of renal function, as observed in 18.6% of patients having a 20% increase in creatinine levels, nephrolithiasis and hyperbilirubinemia 8,9. In our patients, we monitored the renal function and total bilirubin levels from the onset of treatment with indinavir at the dosage of 800 mg three times a day. The average treatment duration with indinavir was 931 days (range 378–1360). Before the initiation of indinavir treatment, median values for creatinine were 76 μmol/l (range 58–103) and reached 83 μmol/l (range 59–143) after 931 days. Two patients had a gradual 1.6- and twofold increase in creatinine levels during the total duration of indinavir treatment from 89 to 143 μmol/l and from 68 to 141 μmmol/l, respectively. During the period of treatment with the indinavir–ritonavir-based regimen, three patients experienced one episode of nephrolithiasis that resolved with increased fluid intake. This was accompanied in one patient by a slight increase in creatinine levels from 112 to 143 μmol/l. There was no change in the bilirubin levels during the whole period of indinavir treatment. The median baseline total bilirubin levels were 24 μmol/l (range 8–94) before the onset of indinavir-based highly active antiretroviral therapy and 23 μmol/l (range 8–112) at the end of the study period. In HIV-infected patients co-infected with HCV treated with indinavir and nucleoside analogues for a median of 32 months, a switch from indinavir three times a day to indinavir twice a day in association with a low dose of ritonavir does not result in the impairment of liver function tests during a follow-up of approximately 6 months. Samir Voraa Christophe Michona Christian Junetb Jean-François Balavoinec Catherine Renold-Moynierd Sabine Yerlya Luc Perrina
Michon et al. (2000) studied this question.