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Abstract
ObjectiveRifampicin co-administration dramatically reduces plasma lopinavir concentrations. Studies in healthy volunteers and HIV-infected patients showed that doubling the dose of lopinavir/ritonavir (LPV/r) or adding additional ritonavir offsets this interaction. However, high rates of hepatotoxicity were observed in healthy volunteers. We evaluated the safety, effectiveness and pre-dose concentrations of adjusted doses of LPV/r in HIV infected adults treated with rifampicin-based tuberculosis treatment.MethodsAdult patients on a LPV/r-based antiretroviral regimen and rifampicin-based tuberculosis therapy were enrolled. Doubled doses of LPV/r or an additional 300 mg of ritonavir were used to overcome the inducing effect of rifampicin. Steady-state lopinavir pre-dose concentrations were evaluated every second month.Results18 patients were enrolled with a total of 79 patient months of observation. 11/18 patients were followed up until tuberculosis treatment completion. During tuberculosis treatment, the median (IQR) pre-dose lopinavir concentration was 6.8 (1.1–9.2) mg/L and 36/47 (77%) were above the recommended trough concentration of 1 mg/L. Treatment was generally well tolerated with no grade 3 or 4 toxicity: 8 patients developed grade 1 or 2 transaminase elevation, 1 patient defaulted additional ritonavir due to nausea and 1 patient developed diarrhea requiring dose reduction. Viral loads after tuberculosis treatment were available for 11 patients and 10 were undetectable.ConclusionOnce established on treatment, adjusted doses of LPV/r co-administered with rifampicin-based tuberculosis treatment were tolerated and LPV pre-dose concentrations were adequate.
Highlights
In resource constrained settings the second-line antiretroviral therapy (ART) regimen is based on ritonavir-boosted protease inhibitors (PIs), usually co-formulated lopinavir/ritonavir (LPV/r)
Once established on treatment, adjusted doses of LPV/r co-administered with rifampicin-based tuberculosis treatment were tolerated and LPV pre-dose concentrations were adequate
Adjusting doses of PIs to overcome induction by rifampicin resulted in very high rates of hepatotoxicity in healthy volunteers [5,6,7], but we have demonstrated that doubling the dose of LPV/r is relatively safe amongst HIV-infected patients established on LPV/r-based ART [4]
Summary
In resource constrained settings the second-line antiretroviral therapy (ART) regimen is based on ritonavir-boosted protease inhibitors (PIs), usually co-formulated lopinavir/ritonavir (LPV/r). Doubling the dose of LPV/r or adding additional ritonavir (so that LPV:ritonavir = 1:1) can overcome the inducing effect of rifampicin [3,4]. Adjusting doses of PIs to overcome induction by rifampicin resulted in very high rates of hepatotoxicity in healthy volunteers [5,6,7], but we have demonstrated that doubling the dose of LPV/r is relatively safe amongst HIV-infected patients established on LPV/r-based ART [4]. Standard tuberculosis treatment includes isoniazid [8,9], which inhibits CYP 3A4 and may attenuate the inducing effect of rifampicin on lopinavir metabolism. We prospectively followed-up patients on adjusted doses of LPV/r-based ART regimens who were treated with rifampicin-based regimens for tuberculosis
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