3rd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 23-26 October 2001, Athens, Greece

Nephrotoxicity in patients randomized to zidovudine/ lamivudine combined with either indinavir 800 mg three times a day or indinavir/ritonavir 800/100 mg twice a day: 64- week outcome

Antiviral Therapy 2001; 6(Suppl. 4):8 (abstract no. 10)

M Boyd^1,2, E Hassink^1,3, F Cox³, J Tromp³, O van Ruler³, M Felderhof³, A Mahanontharit¹, C Duncombe^1,2, K Ruxrungtham¹, M Stek⁴, J Lange³, D Cooper², P Phanupak¹ and P Reiss^3
1HIV-NAT, Thai Red Cross AIDS Research Centre, Bangkok, Thailand; ²NCHECR. Sydney, Australia; ³IATEC, Amsterdam, The Netherlands;and ⁴Merck Et Co., Whitehouse Station, NJ, USA

BACKGROUND: Indinavir sulfate three times a day is associated with indinavir crystalluria, nephrolithiasis and impaired renal function. A ritonavir-boosted indinavir twice a day strategy may influence nephrotoxicity.

OBJECTIVE: To compare urinary tract signs and symptoms (UTSS) and changes in renal function in patients randomized to zidovudine/lamivudine with indinavir 800 mg three times a day or indinavirl ritonavir 800/100 mg twice a day.

METHODS:Over 64 weeks, UTSS (dysuria, renal colic, flank pain, back pain with microscopic haematuria, pyelonephritis), haematuria (>3 cells/µl), leucocyturia (>3 cells/µl), indinavir crystalluria and serum creatinine were assessed. Wilcoxon signed ranks test, t-test, repeated measurements and logistic regression were performed.

RESULTS: One-hundred-and-four patients commenced therapy: 67 males, mean (SD) BMI 28 (3) kg/m², and age 35 (6) years. UTSS occurred in 28% (15/54) zidovudine/lamivudine with indinavir and 34% (17/50) indinavirlritonavir (P=0.49), most commonly dysuria (18%) and flank pain (11%). Five patients (two zidovudine/lamivudine with indinavir, three indinavir/ ritonavir) required drug interruptions due to UTSS but no permanent drug-discontinuations occurred. Occurrence of leucocyturia, haematuria and indinavir crystals did not differ significantly between arms. However, from baseline to week 64, leucocyturia (17-46%; P<0.001) and haematuria (6-12%; P=0.03) increased significantly. At week 64, indinavir crystals were observed in 16% of the patients. On multivariate analysis females were more likely to develop leucocyturia OR (95% CI): 2.0 (1.3-3.2), haematuria 3.2 (1.6-6.3), and crystalluria 2.3 (1.3-4.2). Weeks on therapy was associated with increased leucocyturia 1.02 (1.01-1.03) and haematuria 1.02 (1.00-1.03). Higher BMI decreased the risk of leucocyturia 0.89 (0.83-0.96). At week 64, median reduction (IQR) in creatinine-clearance was -11.1 (-25.3 to 8.7) ml/min (P=0.0l). Twenty-seven percent of patients had at least a 25% reduction in creatinine clearance without a significant difference between arms. Creatinine-clearance was more impaired in females than in males (P<0.01). Reduced creatinine-clearance (≤100 ml/min) at baseline was not associated with worse renal function by week 64 (P=0.50).

CONCLUSIONS: Nephrotoxicity was similar for both arms with female gender, lower BMI, and longer duration of therapy noted as risk factors. Monitoring renal function is appropriate for patients on indinavir regimens. Effective management of nephrotoxicity was seen in these patients with no permanent discontinuations, although limited treatment options undoubtedly influenced trial retention.

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