Low dose 200/100 IDV/RTV managed by TDM in substudy of co-infected patients

A substudy of six patients coinfected with HIV and either chronic hepatitis B (HBV) or chronic hepatitis C (HCV) concludes that low dose treatment with indinavir (IDV, Crixivan) and ritonavir (RTV, Norvir) appears to be effective and safe.

The poster presentation by Dr G Peytavin on behalf of colleagues in Paris, looked at six patients from the larger GEOPHAR study, which is evaluating the benefits of therapeutic drug monitoring (TDM) in association with genotypic resistance testing to optimise treatment in multi-experienced patients.

In five patients with HCV, one with HBV and a control group of 16 without chronic hepatitis, treatment with IDV/RTV low doses (400/100 mg bid) combination plus two NRTIs was selected upon results of the resistance genotyping test, treatment history, and drug tolerance. A month after starting the new regimen, HIV-1 RNA level was measured and IDV Cmin was performed by using an HPLC assay. The researchers considered plasma concentrations as adequate if values of IDV Cmin determined 12 hours after the last intake were in the therapeutic range of 150 to 675 ng/mL.

In the six patients with chronic hepatitis, IDV plasma concentrations were very high, and all Cmin but one were < 675 ng/mL (median value: 1,440 ng/mL; range: 650 to 2,310 ng/mL). In all patients, a viral load < 200 copies/mL was achieved. Despite high IDV Cmin in these patients, no side effects were noted. After a therapeutic adjustment within a month (IDV/RTV 200/100 mg bid), adequate IDV Cmin were obtained and remained stable in five patients until the end of the study (at week 24: median value: 277 ng/mL; range: 150-320 ng/mL). The patient with HCV, who had an adequate Cmin, was lost to follow-up. HIV-1 RNA level remained undetectable until the end of the study.

The researchers conclude: “The results of this study suggest that the IDV/RTV low dose (200/100 mg bid) appears to be effective and safe in patients co-infected with HIV and HCV or HBV. The benefit of TDM in association with genotypic resistance testing and expert advice to optimise subsequent therapy in HCV or HBV co-infected patients receiving the combination IDV/RTV appeared crucial in this GENOPHAR substudy.”

Ref: P. Bossi, G. Peytavin, C. Lamotte et al. High indinavir plasma concentrations in HIV-1 patients co-infected with hepatitis B or C virus receiving indinavir and ritonavir low dosages: a GENOPHAR substudy. 10th CROI, 10–14 February 2003, Boston. Abstract 546

Comment

There is no report in the abstract on what stage of liver disease these six patients were at. Did they have advanced disease where the liver might be less functional thus leading to higher IDV drug levels or did they have earlier stage disease where the liver may be more functional leading to more normal IDV drug levels?

This small study exemplifies the role of the liver in clearing certain classes of anti-HIV drugs, particularly the PIs and NNRTIs. Most NRTIs are cleared by the kidneys (and hence dose adjustments in renal impairment). Unlike renal impairment, where creatinine clearances can be easily calculated or measured, hepatic clearance of drugs is difficult to predict or measure. Thus, therapeutic drug monitoring may be the only way of ascertaining drug levels of PIs and NNRTIs in patients with hepatitis co-infections and advanced liver disease and such drug dose adjustments need to be made on an individual basis. No data on co-medications was provided in this study.

The authors’ conclusion that low doses of ritonavir-boosted indinavir is safe and effective in co-infected patients may not be valid for all patients and indeed, may not apply to other liver cleared anti-HIV drugs. Safe and effective dose-reduction is only possible by TDM on an individual basis.