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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.

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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/mm3. 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/mm3 and mean HIV RNA copy number was 4.9 log10/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 log10 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).

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Some studies on untreated patients have shown a general correlation between plasma HIV copy number and plasma infectivity in in vitro models. Recent observations also indicate that HIV-RNA level is an important predictor of perinatal transmission and may also have a role in heterosexual transmission. To further analyse the correlation between HIV viral load and plasma infectivity, we studied the relationship between HIV-1 plasma copy number and plasma infectivity prior to and during treatment with antiretroviral combination regimens in HIV-1 infected adults. Plasma infectivity was assessed in vitro by coculture of plasma from HIV-positive patients with PHA-stimulated fresh PBMC from uninfected donors. A positive plasma isolation, in almost all cases (43/45) and irrespective of treatment status, was associated with an HIV viral load higher than 100000 copies per ml, with higher plasma HIV-1 RNA values in isolation-positive samples compared with isolation-negative samples (median values, 710000 vs. 37500 copies per ml, respectively). SI and NSI strains had similarly high viral load values (470000 vs. 790000 copies per ml), but CD4 counts were lower in the SI phenotype group. Our data indicate that low levels of viral load are only exceptionally associated with isolation from plasma in the in vitro model we used. This observation confirms indirectly the presence of an association between viral load and infectivity. The requisite of a high plasma viral load in order to obtain infectivity (i.e. positivity of HIV isolation from plasma) also seems maintained under antiretroviral treatment, adding confidence in the conclusion that reductions in viral load translate into reduction of plasma infectivity. Due to the extreme complexity of factors determining transmission, a very prudent interpretation of the results is essential when information from experimental studies has to be transferred to clinical situations requiring assessment of risks or clinical decisions.

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OBJECTIVES: To evaluate the quality of life outcomes in antiretroviral-naive patients randomized to zidovudine plus didanosine versus zidovudine plus didanosine plus nevirapine for treatment of advanced HIV disease (the Istituto Superiore di Sanità 047 trial). DESIGN: A 48-week randomized, double-blind trial. METHODS: Sixty patients were enrolled and evaluated over 24 weeks. Quality of life was assessed using a modified version of the Medical Outcomes Study-HIV Health Survey. For analysis, we calculated two summary scores reflecting the physical (PHS) and the mental (MHS) components of health. RESULTS: Although the three-drug combination was superior at inducing immunologic and virologic responses, the two-drug regimen was superior for both PHS and MHS, especially at week 8 where differences were both statistically and clinically significant (5.8 and 9.2 points, respectively, P< 0.02 for both). Quality of life changes paralleled trends in body weight and Karnofsky performance status score. CONCLUSION: Although a three-drug antiretroviral therapy regimen was superior in terms of short term virologic/immunologic response, the two-drug regimen was better in terms of quality of life. In general, triple therapy remains the most effective treatment option. However, quality of life assessments can yield results that may be discordant with and complementary to those obtained using conventional endpoints. Comparative trials should collect a comprehensive range of outcome measures, including patient-reported quality of life, in order to provide clinicians and patients with additional information that may influence treatment decisions.

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PURPOSE: To describe the cost of hospitalization and treatment in patients with very advanced disease who tart different regimens based on a protease inhibitor (PI). METHOD: An observational retrospective analysis was performed on data from a 48-week randomized, multicenter study. Analysis was based on a subgroup of centers that were geographically defined. Costs of ordinary hospital admissions and of antiretroviral treatment were considered. Incidence of hospitalization and number of days free from hospitalization during the period of observation were calculated. Cost and hospitalization measures were compared among patients receiving three different therapeutic regimens: only PI, PI plus one nucleoside, or PI plus two nucleosides. A multivariate analysis was used to assess cost differences, controlling for variables potentially able to influence outcome. RESULTS: Overall, among 166 patients starting PI (PI plus two nucleosides, 71;PI plus one nucleoside, 65; only PI, 30), 162 ordinary hospital admissions were observed during about 1 year of follow-up. Monthly rates of admission per person and incidence of first hospitalization on 100 person-months showed a clear inverse relationship with the number of drugs comprising the baseline treatment regimen, with the lower rates for the triple therapy group (0.06 and 3.9, respectively), intermediate values for the dual therapy group (0.10 and 8.1, respectively), and higher rates for the PI monotherapy group (0.15 and 13.7, respectively). The average number of days free from hospitalization per month was 29.5 in the triple therapy group, 28.6 in the dual therapy group, and 27.9 in the monotherapy group. The results of cost analysis showed, despite higher cost of antiretroviral treatment, that global costs were progressively lower using regimens of increasing potency: Compared to PI monotherapy, global cost (costs of antiretroviral treatment and of hospitalizations combined) per month per patient was 31.9% lower for the triple therapy group and 19.3% lower for the dual therapy. Global cost for the triple therapy was 15.7% lower compared to global cost for dual therapy. After adjustment for CD4 count, AIDS status, and Karnofsky score, both hospitalization costs and global costs were significantly lower for triple therapy compared to monotherapy (p =.002 and.039, respectively). CONCLUSION: In advanced and nucleoside-experienced patients, PI-containing regimens have a differential impact according to the overall strength of the regimen, with the best effects on both hospitalizations and treatment costs obtained using PI within potent combination regimens.

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The immunologic and virologic activity of nevirapine in combination with two nucleosides (zidovudine [ZDV] and didanosine [ddI]) was evaluated in antiretroviral-naive patients with a CD4 count <200/mm3 or clinical AIDS. In all, 68 patients were enrolled in a 48-week double-blind, placebo-controlled trial. A group of 32 patients received ZDV + ddI + nevirapine, and 36 patients received ZDV + ddI. Primary efficacy parameters were the activity on HIV-1 RNA and on peripheral blood CD4+ cells, with differences between groups analyzed by the Wilcoxon's nonparametric two-sample test. Baseline RNA was high in both treatment groups (median values, 5.8 and 5.7 log10). RNA and CD4 responses were significantly higher with the triple combination (median RNA reductions, 2.69 versus 1.05 log10 at 24 weeks and 1.97 versus 1.20 log10 at 48 weeks; median CD4 increases, 81 versus 64 cells/mm3 at 24 weeks and 101 versus 27 cells/mm3 at 48 weeks). This study demonstrates that a triple combination of ZDV + ddI + nevirapine used as first-line regimen in antiretroviral-naive patients can induce sustained virologic and immunologic response in patients with low CD4 count or a previous diagnosis of AIDS.

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OBJECTIVES: To extend the range of CD4 counts in which a plasma viral load nadir (pVL) <20 copies/ml was known to be predictive of the duration of virologic response. To determine whether baseline pVL is predictive of virologic response during the study periods. METHODS: A meta-analysis was conducted of the original individual patient data from two randomized controlled trials comparing zidovudine (ZDV)/didanosine (ddI) with ZDV/ddI/nevirapine (NVP). RESULTS: In total, 87 patients received ZDV/ddI and 83 received ZDV/ddI/NVP. Study subjects on triple therapy with baseline pVL <100,000 copies/ml were more likely to achieve a pVL <400 copies/ml (odds ratio [OR] = 2.49; p = .02) and <20 copies/ml (OR = 4.76; p = .001) during the trial than those with baseline pVL > 100,000 copies/ml. Among triple therapy patients, the relative risk of virologic failure was higher for patients with higher baseline pVL (rate ratio [RR] = 2.51/log10 copies/ ml; p = .01), after controlling for compliance and pVL nadir. The relative risks of virologic failure associated with pVL nadir <20 copies/ml and between 21 and 400 copies/ml were .04 (p = .0001) and .56 (p = .26), respectively, compared with patients with a pVL nadir >400 copies/ml. CONCLUSIONS: We have extended our earlier results that achieving a pVL nadir <20 copies/ml is important for maintaining virologic suppression. In particular, we have demonstrated that a pVL nadir <20 copies/ml is at least fivefold more protective against virologic failure than achieving a pVL nadir between 20 and 400 copies/ml. Baseline pVL is significantly associated with the probability of achieving and sustaining virologic suppression.

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In this multicenter study (ISS 902), 554 previously untreated patients with <500 CD4 cells/mm3 and mildly symptomatic human immunodeficiency virus disease were randomized to receive zidovudine or didanosine (ddI). After a mean follow-up of 20 months, 80 patients (40 zidovudine, 40 ddI) had died and 146 had at least one AIDS-defining event (73 zidovudine, 73 ddI). Overall, no difference was found between treatments with respect to progression to AIDS or death. The analysis of relative risk (RR) of progression over time, however, showed an initially minor risk for zidovudine patients and an inversion in the zidovudine-ddI RR in the second and third years of follow-up. Didanosine showed a greater effect on CD4 cell count response. The two drugs confirmed the toxicity patterns already reported in other trials, with a low occurrence of pancreatitis (ddI 1.3%, zidovudine 0.4%). The overall results suggest that, in this population, zidovudine and ddI monotherapies have comparable long-term clinical efficacy and that more powerful regimens should be preferred.

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