Inge C. Gyssens

Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal.

BACKGROUNDnThe extent to which mortality differs following individual acquired immunodeficiency syndrome (AIDS)-defining events (ADEs) has not been assessed among patients initiating combination antiretroviral therapy.nnnMETHODSnWe analyzed data from 31,620 patients with no prior ADEs who started combination antiretroviral therapy. Cox proportional hazards models were used to estimate mortality hazard ratios for each ADE that occurred in >50 patients, after stratification by cohort and adjustment for sex, HIV transmission group, number of antiretroviral drugs initiated, regimen, age, date of starting combination antiretroviral therapy, and CD4+ cell count and HIV RNA load at initiation of combination antiretroviral therapy. ADEs that occurred in <50 patients were grouped together to form a rare ADEs category.nnnRESULTSnDuring a median follow-up period of 43 months (interquartile range, 19-70 months), 2880 ADEs were diagnosed in 2262 patients; 1146 patients died. The most common ADEs were esophageal candidiasis (in 360 patients), Pneumocystis jiroveci pneumonia (320 patients), and Kaposi sarcoma (308 patients). The greatest mortality hazard ratio was associated with non-Hodgkins lymphoma (hazard ratio, 17.59; 95% confidence interval, 13.84-22.35) and progressive multifocal leukoencephalopathy (hazard ratio, 10.0; 95% confidence interval, 6.70-14.92). Three groups of ADEs were identified on the basis of the ranked hazard ratios with bootstrapped confidence intervals: severe (non-Hodgkins lymphoma and progressive multifocal leukoencephalopathy [hazard ratio, 7.26; 95% confidence interval, 5.55-9.48]), moderate (cryptococcosis, cerebral toxoplasmosis, AIDS dementia complex, disseminated Mycobacterium avium complex, and rare ADEs [hazard ratio, 2.35; 95% confidence interval, 1.76-3.13]), and mild (all other ADEs [hazard ratio, 1.47; 95% confidence interval, 1.08-2.00]).nnnCONCLUSIONSnIn the combination antiretroviral therapy era, mortality rates subsequent to an ADE depend on the specific diagnosis. The proposed classification of ADEs may be useful in clinical end point trials, prognostic studies, and patient management.

Determinants of recurrent toxicity-driven switches of highly active antiretroviral therapy. The ATHENA cohort

Background Toxicity is the most important reason for premature switching of highly active antiretroviral therapy (HAART). In order to optimize the benefit–risk ratio of HAART, guidelines for toxicity management are needed. Objective An observational cohort study to estimate the incidence and identify determinants of toxicity-driven switches on second-line HAART after having switched first-line HAART despite successful viral suppression. Methods Patients were selected from those in the ATHENA cohort (n = 2470) who switched the initial HIV protease inhibitor (PI)-containing HAART while plasma HIV-1 RNA was ⩽ 500 copies/ml (n = 775). One-year cumulative incidences of subsequent toxicity-driven switches and adjusted relative risks (RR) for potential determinants were calculated. Results The 1-year cumulative incidence of toxicity-driven switches of the second regimen was 24% [95% confidence interval (CI), 21–28], mostly because of gastrointestinal toxicity and neuropathy. Those who had switched from first HAART because of toxicity were at an increased risk of a recurrent toxicity-driven switch (RR, 2.5; 95% CI, 1.7–3.5). Switching from PI to nevirapine while continuing the other antiretroviral drugs was more protective against a subsequent switch because of further toxicity than changing to another PI-containing regimen (RR, 0.2; 95% CI, 0.1–0.6). Conclusions As for first-line HAART, toxicity is responsible for the majority of switches during second-line HAART. Prior switching for toxicity increased the risk of having to switch the subsequent regimen for toxicity, but this risk is reduced when switching to nevirapine rather than to an alternative PI. The latter should be taken into account when designing toxicity-management guidelines.

Persistent leukocyturia and loss of renal function in a prospectively monitored cohort of HIV-infected patients treated with indinavir.

Symptomatic nephrotoxicity is a well-known complication of indinavir treatment. However, little is known about the relevance of other abnormalities, such as leukocyturia during use of indinavir. We determined the prevalence, risk factors, and consequences of persistent leukocyturia in a prospectively monitored cohort of indinavir users in three adult outpatient clinics. Patients were monitored for nephrotoxicity at regular visits (every 3 months) between August 1998 and September 2000. Monitoring involved urine dipstick analysis and microscopy for pH, erythrocytes, leukocytes, and indinavir crystals. The urine albumin concentration/creatinine concentration ratio and serum creatinine and indinavir plasma concentrations were measured, and urinary tract infection was excluded. Urologic symptoms were retrieved from medical records. Of 184 patients with at least one assessment, 35% had leukocyturia (i.e., >75 cells/&mgr;L) at least once during the study period, which coincided with mild increase in the serum albumin level, erythrocyturia, and crystalluria. Thirty-two (24%) of 134 patients with two or more assessments had persistent leukocyturia (i.e., on two or more occasions). Risk factors were indinavir plasma concentration of >9 mg/L, urine pH of >5.7, and crystalluria. Persistent leukocyturia was associated with a gradual loss of renal function but not with urologic symptoms. The data show that leukocyturia is a frequent finding and emphasize the need for monitoring renal function during indinavir treatment, even in the absence of urologic symptoms.

Indinavir crystallization around the loop of Henle: experimental evidence.

Objective: To determine the probable site of the nephron and the plasma indinavir (IDV) concentration at which intrarenal IDV crystallization occurs. Design: We performed in vitro crystallization experiments in IDV solutions simulating conditions found in the nephron. Methods: To determine intrarenal IDV concentrations at which conditions in the nephron allow crystallization, several concentrations of IDV basic solutions (0‐800 mM) were titrated from pH 4.0 to higher pH values until crystals formed within 1 minute. Based on the combination of pH and ionic strength at which crystals formed, we determined the site of the nephron at which this combination was first attained. Based on the capacity for concentration at that site, we were able to measure the corresponding plasma IDV concentration. Results: Under conditions normally found at the proximal tubule (i.e., pH 6.7 and ionic strength of 200 mM), IDV crystallized at 200 mg/L. Under conditions applying to the loop of Henle, pH 7.4 and ionic strength of 200 mM, IDV crystallized at 125 mg/L, which would correspond to a plasma IDV concentration of 8 mg/L. Conclusions: IDV crystallization is most likely in the loop of Henle and may already start at plasma IDV concentrations as low as 8 mg/L. Increasing hydration does not reduce the risk of IDV crystallization in the loop of Henle but instead prevents IDV crystallization and aggregation in the lower urinary tract. It remains to be confirmed whether prevention of high IDV plasma concentrations will reduce the risk of IDV crystallization in the loop of Henle.