HIV-1 coreceptor switch during 2 years of structured treatment interruptions.

The purpose of this investigation was to determine the impact on human immunodeficiency virus (HIV) tropism of uncontrolled virus exposure during 2 years of intermittent highly active antiretroviral therapy (HAART). The Istituto Superiore di Sanità-Pulsed Antiretroviral Therapy (ISS-PART) randomized study compared the outcome of 2 years of structured treatment interruptions (STIs) versus standard continuous treatment in first-line HAART responder subjects. The STI schedule consisted of five STIs of 1, 1, 2, 2, and 3 months, respectively, separated by four periods of 3-month therapy. In the present study, coreceptor tropism was assessed in 12 patients of the STI arm at different time points over a period of 2 years. Tropism was determined on DNA and RNA by V3 loop region sequencing. The Geno2pheno algorithm (false-positive rate, FPR: 20%) was used for data interpretation. At baseline, 9/12 subjects (75.0%) had CCR5-tropic viruses in their HIV. Three had a CXCR4-tropic virus. Ten patients maintained the same coreceptor in DNA after 2 years, whereas in two patients, a shift occurred (one R5-X4, one X4-R5). In a patient with an R5 virus at baseline, a transient change to X4 tropism was seen in the rebounding virus during STI. Changes in tropism were not associated with the amplitude and duration of virus exposure during STIs, residual viremia at baseline, or the development of resistance mutations in the RT region. Our preliminary results suggest that viral replication, observed after short periods of treatment interruption, is not enough to drive the evolution of HIV tropism.

Virological failure at one year in triple-class experienced patients switching to raltegravir-based regimens is not predicted by baseline factors.

We evaluated rates and determinants of virological failure in triple-class experienced patients receiving raltegravir-based regimens from a national observational study over 48 weeks, defined by any one of the following: (1) no HIV-RNA suppression to undetectable levels (<50 copies/mL) during follow-up; (2) detectable viral load after obtaining undetectable levels; and (3) leaving the study before 48 weeks. Among 101 eligible patients, 26 (25.7%; 95% CI 17.2-34.2) had virological failure. No significant differences between patients with and without virological failure were observed for gender, age, route of transmission, baseline CD4/HIV-RNA, CDC group, hepatitis B or C co-infections, resistance (based on the last genotype available), type and number of concomitant drug classes, concomitant use of darunavir, atazanavir, etravirine, enfuvirtide or maraviroc, and health-related quality-of-life measures. A high rate of treatment response was observed. The analyses did not identify any baseline factor associated with failure, including resistance status. Even if we cannot exclude the presence of pre-existing minority resistant variants not captured by genotypic tests, the lack of baseline predictors of failure suggests the need to monitor patients closely during follow up for other factors, such as potential drug interactions and reduced levels of adherence, which may favour virological failure.

The mutational archive in proviral DNA does not change during 24 months of continuous or intermittent highly active antiretroviral therapy.

OBJECTIVES: The aim of the study was to determine the modifications of the mutational archive in proviral HIV-1 DNA occurring during 24 months of intermittent or continuous highly active antiretroviral therapy (HAART). METHODS: The study population included subjects enrolled in the Istituto Superiore di Sanità Pulsed Antiretroviral Therapy (ISS PART) clinical trial. All of these patients were on first-line HAART and had plasma HIV-1 RNA below 50 HIV-1 RNA copies/mL. A genotypic resistance test was performed on HIV-1 DNA extracted from peripheral blood mononuclear cells (PBMC) at baseline and after 24 months of follow-up. Resistance-associated mutations (RAMs) were defined according to the International AIDS Society (IAS) USA classification. RESULTS: Sixty-nine subjects were included in the study [36 enrolled in arm A of the ISS PART (continuous HAART) and 33 enrolled in arm B (intermittent HAART)]. No major modifications of the mutational archive were found in either group after 24 months of follow-up, in terms of both the proportion of subjects with mutations and the total number of mutations. CONCLUSIONS: In this patient population, the mutational archive in HIV-1 DNA extracted from PBMC was stable for 24 months, irrespective of HAART modality, whether continuous or intermittent.

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.

HIV-related morbidity and mortality in patients starting protease inhibitors in very advanced HIV disease (CD4 count of < 50 cells/microL): an analysis of 338 clinical events from a randomized clinical trial.

BACKGROUND: AIDS defining events occur infrequently in the presence of CD4 counts above 200 cells/microL. It is, however, uncertain for most of the AIDS defining conditions whether this threshold can be considered equally safe in patients with a previously very low CD4 nadir. METHODS: We evaluated in detail all the AIDS defining events observed during a 48-week clinical trial in 1251 nucleoside reverse transcriptase inhibitor-experienced patients who started protease inhibitors (PIs) at CD4 counts below 50 cells/microL. The type of event, immunological status at the moment of event and time between start of PI treatment and event occurrence were analysed cumulatively and by event type; event rates were calculated. RESULTS: Concomitant data on CD4 counts were available for 338 AIDS defining events (81% of total events). Median time between start of treatment with PI and event was 94.5 days and median absolute CD4 value at the occurrence of event was 20 per microL. Only 14 events (in 12 patients) were observed above the threshold of 200 CD4 cells/microL. An analysis of the 67 deaths with concomitantly available CD4 counts (57%) showed a median CD4 count of 10 cells/microL, with only four deaths occurring in the presence of a CD4 count above 100 cells/microL. CONCLUSIONS: Very few clinical AIDS defining conditions were observed in patients who start PIs at very low CD4 counts and with treatment restore absolute values in CD4 counts above 200 cells/microL. This threshold can therefore be considered a clinically effective goal of treatment with respect to occurrence of all AIDS defining conditions in patients starting PIs in very advanced HIV disease.

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/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).

Quality of life outcomes of combination zidovudine- didanosine-nevirapine and zidovudine-didanosine for antiretroviral-naive advanced HIV-infected patients.

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.

Hospitalizations and costs of treatment for protease inhibitor-based regimens in patients with very advanced HIV-infection (CD4 < 50/mm(3)).

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.

A randomized, double-blind trial on the use of a triple combination including nevirapine, a nonnucleoside reverse transcriptase HIV inhibitor, in antiretroviral-naive patients with advanced disease.

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.

Evaluation of a simplified test for the rapid detection of antibody to the human immunodeficiency virus (HIV-1).

We describe a new simplified solid phase immunoassay for the detection of anti-HIV antibodies. The results obtained analyzing a panel of sera from subjects showing a different pattern of reactivity on enzyme immunoassays and on Western blot demonstrated high sensitivity and specificity. The test does not require experienced laboratory staff nor the use of costly laboratory instruments.