A randomized trial comparing the introduction of ritonavir or indinavir in 1251 nucleoside-experienced patients with advanced HIV infection.

ISS-IP1, a multicenter, randomized, 48-week open trial, was designed to compare the introduction of ritonavir or indinavir in patients with previous nucleoside experience and CD4 + cell counts below 50/mm 3. Concomitant antiretroviral treatment with nucleoside analogs was allowed. Primary efficacy measures were survival and time to a new AIDS-defining event or death, analyzed through the whole period of observation by the intention-to-treat approach. Primary toxicity measures were time to treatment discontinuation and adverse events, grade at least 3/serious, analyzed by an on-treatment approach. Evaluation of efficacy also included CD4 + cell and RNA response. The trial enrolled 1251 patients in 5 months. At baseline, mean CD4 + cell count was about 20 cells/mm 3 and mean HIV RNA copy number was 4.9 log 10/ml in both groups. Overall, 402 patients in the ritonavir group and 250 patients in the indinavir group permanently discontinued the assigned treatment (relative risk, 1.96; 95 % CI, 1.68-2.30; p = 0.0001), with most of this difference dependent on a higher number of discontinuation for adverse events in the ritonavir group. After a mean follow-up of 307 days (ritonavir, 304; indinavir, 309), 124 deaths (ritonavir, 61; indinavir, 63; relative risk, 0.96; 95% CI, 0.67-1.36; p = 0.80) and 330 new AIDS-defining events (ritonavir, 170; indinavir, 160; relative risk, 1.05; 95% CI, 0.85-1.31; p = 0.60) were observed. CD4 + cell counts increased in both groups in patients still receiving treatment, with about 100 cells gained by week 24 and 150 cells gained by week 48. Body weight also increased over time in both groups. Analysis of RNA response showed a decrease of 1.5 log 10 or higher in both treatment groups. Overall, 400 patients in the ritonavir group and 338 patients in the indinavir group developed at least one grade 3/serious new adverse event during follow-up (relative risk, 1.48; 95% CI, 1.28-1.72; p = 0.0001). Favorable CD4 + cell and RNA responses at 24 and 48 weeks were observed in both groups of patients remaining on treatment. Indinavir showed slightly better effects in sustaining RNA, CD4 + cell, and body weight responses. Ritonavir and indinavir results were comparable in terms of clinical outcome (survival and AIDS-defining events)

Treatment of cytomegalovirus esophagitis in patients with acquired immune deficiency syndrome: A randomized controlled study of foscarnet Versus ganciclovir

Objective: Although several uncontrolled studies have shown that the response rate to ganciclovir and foscarnet for all forms of cytomegalovirus (CMV) infection in immunocompromised patients is almost similar, to date, no controlled clinical trial has been specifically designed to compare these two agents in the treatment of CMV esophagitis. The aim of this study was, therefore, to compare the efficacy and safety of these two drugs in the induction therapy of CMV esophagitis in patients with acquired immunodeficiency syndrome (AIDS). Methods: Thirty-nine of 211 (18%) consecutive AIDS patients undergoing endoscopy for esophageal symptoms had macroscopic esophagitis that proved to be sustained by CMV based on the documentation of typical intranuclear inclusions at histology; 23 were considered eligible for this study and were randomized to receive foscarnet 90 mg/kg b.i.d. or ganciclovir 5 mg/kg b.i.d. for 21 days. Twelve patients received foscarnet, whereas 11 were treated with ganciclovir. Clinical and laboratory evaluation was performed weekly, and endoscopy was repeated at the end of therapy. The two treatment groups were well balanced as to the following characteristics at entry: age, sex, absolute number of CD4 cells, duration of AIDS, Karnofsky score, frequency of concomitant Candida esophagitis (grade I or II), and severity of esophageal symptoms. Results: Marked endoscopic improvement (complete disappearance of macroscopic lesions or significant reduction of the endoscopic score) was observed in eight of 11 (73%) of foscarnet and seven of 10 (70%) of ganciclovir-treated patients, and inclusion bodies disappeared from follow-up biopsies in 55% and 50% of patients, respectively. The symptomatic response was also similar for both treatments: 82% of patients who received foscarnet and 80% of those treated with ganciclovir had a complete or at least a good clinical response. Frequency of adverse events was comparable with both drugs: only one patient in each group suspended treatment because of severe side effects. Conclusions: Foscarnet and ganciclovir appear to be similarly effective and safe in the induction therapy of AIDS-related CMV esophagitis. Consequently, the choice of the anti-CMV agent should be tailored to the individual patient according to the different toxicity profiles of the two drugs

Risk factors and occurrence of rash in HIV-positive patients not receiving nonnucleoside reverse transcriptase inhibitor: data from a randomized study evaluating use of protease inhibitors in nucleoside-experienced patients with very low CD4 levels (<50 cells/microL)

BACKGROUND: Most of the studies evaluating rash in HIV-positive patients have focused on nonnucleoside reverse transcriptase inhibitors (NNRTI), particularly nevirapine, and little is known about the occurrence of rash and the risk factors for its development in patients receiving regimens not based on NNRTI. METHODS: We evaluated all cases of rash observed during a 48-week randomized multicentre trial in 1251 nucleoside-experienced patients who started treatment with protease inhibitors (ritonavir or indinavir) at CD4 counts below 50 cells/microL. Incidence rates for rash were calculated according to gender, clinical status, age, use of highly active antiretroviral therapy (HAART), Pneumocystis carinii pneumonia (PCP) prophylaxis and use of individual antiretroviral drugs at enrollment. Differences between groups defined according to the above characteristics were tested for statistical significance using the log-rank test in a Kaplan-Meier survival analysis. All factors that gave results in the univariate analyses below the significance level of 0.05 were included in a multivariate analysis using a Cox regression model. RESULTS: During a follow-up period of 9690 person-months, 66 patients (5.3%) developed rash (0.68 events/100 person-months). In the univariate analyses, risk of rash did not differ with trial treatment (indinavir or ritonavir), clinical status, PCP prophylaxis, or age. During follow-up, rash was observed in 7.5% of enrolled women and in 4.5% of enrolled men (P=0.03). Serious rash occurred in 4.5% of enrolled women and in 1.6% of enrolled men (P=0.003). Use of HAART (P<0.001) and inclusion of zidovudine and of zalcitabine in the prescribed regimen (P=0.02) appeared to be associated with a lower risk of rash. In the multivariate analysis, the variables that remained significantly predictive of rash were gender (risk for women compared to men: 1.65, 95% confidence interval (CI): 1.00-2.72, P=0.048) and use of a non-HAART regimen (risk for non-HAART patients compared to HAART: 2.73, 95% CI: 1.49-5.02, P=0.001). CONCLUSIONS: In our study, about 5% of HIV-positive patients who started treatment with protease inhibitors at very low CD4 counts developed rash, generally in the first few weeks after treatment. Risk was significantly higher in women and in patients who did not receive a HAART regimen. Our data indicate that women have a higher risk of rash than men, also with regimens that do not include NNRTI

Epidemiology of cryptosporidiosis among European AIDS patients

Objective: To study epidemiology and possible risk factors associated with the development of cryptosporidiosis among European patients with AIDS. Methods: An inception cohort of 6548 patients with AIDS, consecutively diagnosed from 1979 to 1989, from 52 centres in 17 European countries was studied. Data on all AIDS defining events were collected retrospectively from patients' clinical records. Kaplan-Meier estimates, log rank tests and Cox proportional hazard models were used to examine for possible risk factors associated with cryptosporidiosis. Results: Cryptosporidiosis was diagnosed in 432 (6.6%) patients, 216 at time of the AIDS diagnosis and 216 during follow-up. The probability of being diagnosed with cryptosporidiosis at AIDS diagnosis was significantly lower for intravenous drug users (1.3%) than for homosexual men (4.1%) and for patients belonging to other transmission categories (4.0%) (p < 0.001). The probability was also higher for patients from Central Europe compared with patients from South Europe (4.1% versus 2.5%, p = 0.005). The rate of developing cryptosporidiosis after the diagnosis of AIDS was 3 per 100 patient years of follow-up. The rate was significantly lower for intravenous' drug users than for homosexual men (relative risk 0.34, 95% confidence limits 0.22-0.54) and for women compared with men (RR 0.43 (0.21-0.87)). The risk was higher in North Europe than in South and Central Europe. In a multivariate analysis only transmission category remained a significant predictor for the development of cryptosporidiosis. Conclusion: The development of cryptosporidiosis in AIDS patients may be associated with sexual risk behaviour

Virologic and immunologic response to regimens containing nevirapine or efavirenz in combination with 2 nucleoside analogues in the Italian Cohort Naive Antiretrovirals (I.Co.N.A.) study

This nonrandomized study compared the virologic and immunologic responses to potent regimens containing either efavirenz or nevirapine after considering potential systematic differences between patients receiving these drugs. Virologic failure was defined as the first of 2 consecutive measurements of virus load > 500 human immunodeficiency virus RNA copies/mL. Of the 694 patients included in the analysis, 460 (66.3%) started nevirapine and 234 (33.7%) started efavirenz. The adjusted relative hazard of virologic failure for patients who started nevirapine, compared with those who started efavirenz, was 2.08 (95% confidence interval, 1.37-3.15; P = .0006). In addition, patients receiving efavirenz tended to recover 5 CD4 cells/\u3bcL more per quarter (P = .05). Although comparisons of drug efficacy in nonrandomized studies should be viewed with caution, no results from randomized controlled comparisons of these drugs are thought to be available. The findings of this study are in agreement with those of other observational studies