Patrizio Pezzotti

Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive patients

Objective:To evaluate the frequency of discontinuation of the first highly active antiretroviral regimen (HAART) and the factors predictive of discontinuing for toxicity and failure in a population-based cohort of HIV-positive individuals in Italy, naïve from antiretrovirals at enrolment. Methods:The study population consisted of individuals who initiated HAART and had at least one follow-up visit. The primary end-points were discontinuation of any component of HAART for drug toxicity and discontinuation for failure. Survival analyses were performed to identify predictive factors for reaching the two end-points. Results:Eight hundred and sixty-two individuals initiated HAART; in 727 of them (84.3%) this consisted of two nucleoside reverse transcriptase inhibitors (NRTI) and one protease inhibitor (PI). Over a median follow-up of 45 weeks, 312 patients (36.2%) discontinued therapy: 182 (21.1%) discontinued due to toxicity, 44 (5.1%) due to failure. The probability of discontinuing HAART at 1 year was 25.5% [95% confidence interval (CI), 21.9–28.9] due to toxicity and 7.6% (95% CI, 4.9–10.3) due to failure. Independent factors associated with discontinuation for toxicity were: gender [relative hazard (RH) = 0.51; 95% CI, 0.32–0.80 for men versus women], type of treatment (indinavir-containing regimens, RH = 1.94; 95% CI, 1.10–3.41 and ritonavir-containing regimens, RH = 3.83; 95% CI, 2.09–7.03 versus hard-gell saquinavir) and time spent on treatment (RH = 0.89; 95% CI, 0.80–0.98 for each additional month). Discontinuation due to failure was independently associated with the most recent HIV-RNA (RH = 3.20; 95% CI, 1.74–5.88 for log10 copies/ml higher), and with type of treatment (indinavir-containing regimens, RH = 0.21; 95% CI, 0.06–0.78 and ritonavir-containing regimens, RH = 0.23; 95% CI, 0.04–1.26 versus hard-gell saquinavir). Conclusions:If the current HAART regimen caused no toxicity, less than 10% of naïve patients discontinue their first HAART regimen because of failure after 1 year from starting therapy.

Self-reported symptoms and medication side effects influence Adherence to highly active antiretroviral therapy in persons with HIV infection

Objectives: To identify variables predictive of nonadherence to highly active antiretroviral therapy (HAART) and to assess whether self‐reported symptoms or medication side effects are related to adherence. Design: Cross‐sectional multicenter study Adherence Italian Cohort Naive Antiretrovirals [AdICONA] within the Italian Cohort Naive Antiretrovirals (ICONA). Methods: Participants receiving HAART completed a 16‐item self‐administered questionnaire to assess nonadherence in the last 3 days as well as the type and intensity of 24 common HIV‐ and HAART‐related symptoms experienced during the last 4 weeks. Results: From May 1999 to March 2000, 358 persons were enrolled: 22% reported nonadherence and were less likely to have HIV RNA <500 copies/ml (odds ratio = 0.51; 95% confidence interval: 0.31‐0.85). Frequency of moderate/severe symptoms or medication side effects in nonadherent participants ranged from 3.6% to 30%. On univariate analysis, nausea, anxiety, confusion, vision problems, anorexia, insomnia, taste perversion, and abnormal fat distribution were significantly associated with nonadherence. Nonadherent persons had a higher mean overall symptom score (12.3 ± 9.2 versus 8.1 ± 6.6; p < .001) and mean medication side effect score (2.9 ± 2.7 versus 1.9 ± 1.9; p < .001) when compared with adherent participants. In the multivariate analysis, nausea (p = .003); anxiety (p = .006); younger age (p = .007); unemployment (p < .001); not recalling name, color, and timing of drugs (p = .009); running out of pills between visits (p = .002); and being too busy (p = .03) were independently associated with nonadherence in the last 3 days. Conclusions: In addition to patient characteristics, medication‐related variables, and reasons for nonadherence, patient‐reported symptoms and medication side effects were significantly associated with adherence to HAART.

Cardio- and cerebrovascular events in HIV-infected persons

Objective: Recent results from the D:A:D Study indicated that the incidence of myocardial infarction (MI) increased by 26% per year of exposure to combination antiretroviral treatment (CART). The present study was performed to investigate whether this risk was similar when including other cardio- and cerebro-vascular disease events (CCVE). Design: D:A:D is an international collaboration of 11 cohorts, following 23 468 HIV-infected patients prospectively at 188 clinics in 21 countries situated in Europe, USA and Australia. Methods: The end-point was the occurrence of a first CCVE during prospective follow-up, defined as the first of: acute MI, invasive cardiovascular procedures, stroke, or death from other cardiovascular disease. Relative rates (RR) for CCVE from Poisson regression models and 95% confidence intervals (CI) are reported. All models are adjusted for other risk factors for CCVE, including age, gender, ethnicity, family history, body mass index, and smoking status as well as cohort and HIV transmission group. Results: Over 36 145 person-years of follow-up, 207 patients experienced at least one CCVE (23.7% fatal). The first event was MI in 126 patients, invasive cardiovascular procedure in 39 patients, stroke in 38 patients, and death from other cardiovascular disease in four patients. The incidence of first CCVE was 5.7 per 1000 person-years [95% confidence interval (CI) 5.0–6.5] and increased with longer exposure to CART (RR per year of exposure, 1.26; 95% CI, 1.14–1.38; P < 0.0001). Conclusion: CART increases the risk of CCVD, and this increase is comparable with how CART affects the risk of MI. This finding is consistent with the hypothesis that atherosclerosis is a side-effect of CART.

Delayed presentation and late testing for HIV: Demographic and behavioral risk factors in a multicenter study in Italy

Summary:Ensuring timely access to care for persons with HIV is an important public health goal. To identify factors associated with delayed presentation to medical care after testing HIV-positive or with late HIV testing, we studied 968 patients at their first HIV care visit, enrolled in a multicenter study in Italy from 1997–2000. Patients completed a questionnaire on HIV-testing history, sexual behavior, and drug use behavior. Delayed presenters were patients with >6 months between their first HIV-positive test and presentation for HIV care; late testers were patients with CD4 count < 200 /mm3 or clinically defined AIDS at their first HIV-positive test. Among the study patients, 255 (26.3%) were delayed presenters, and 280 (28.9%) were late testers. In multinomial logistic regression analysis, injection drug use significantly increased (odds ratio [OR]= 5.04) the probability of delayed presentation but reduced (OR = 0.55) the chance of late testing. A previous HIV-negative test was associated with a reduced risk of both delayed presentation (OR = 0.39) and late testing (OR = 0.36). Unemployment was positively associated with delayed presentation and increasing age with late testing, whereas HIV counseling at the time of first positive HIV test strongly (OR = 0.42) reduced the odds of delayed presentation. Interventions aimed at promoting timely access to care of HIV-infected persons should consider differentiated programs for delayed presentation and late testing.

AIDS–related focal brain lesions in the era of highly active antiretroviral therapy

Objective: To compare the years since the introduction of highly active antiretroviral therapy (HAART) with the pre-HAART era for trends in the proportions of HIV-related focal brain lesion–causing disorders. Methods: A prospective, single-center study of all consecutive HIV-infected patients with a neurologic presentation and focal brain lesions observed between January 1991 and December 1998 was undertaken. Results: The major diagnoses in the 281 patients were toxoplasmic encephalitis (36.4%), primary CNS lymphoma (26.7%), progressive multifocal leukoencephalopathy (18.2%), and focal HIV encephalopathy (5.0%). During the HAART period, patients were less likely to be male, contracted HIV more often through heterosexual exposure, had fewer previous AIDS-defining events, received anti-Toxoplasma prophylaxis less frequently, had a CD4+ lymphocyte count 2.5 times higher, and had diagnosis based more often on PCR assays from CSF, reducing the need for brain biopsy and enhancing the likelihood of in vivo diagnosis. Using all patients hospitalized per year as reference population, the risk of focal brain lesions strongly increased during the pre-HAART period and declined significantly during the HAART years. In the HAART period a relevant decline of primary CNS lymphoma was found (OR for 1998, 0.25; p for trend = 0.03) and the effect of progressive calendar year was confirmed on multivariable analysis (OR, 0.52; 95% CI, 0.28 to 0.97). The frequency of toxoplasmic encephalitis decreased during the pre-HAART era and was stable afterwards. For progressive multifocal leukoencephalopathy, a slight increase was seen over time. Focal white matter lesions without enhancement or mass effect increased between 1991 and 1998. Conclusions: During the HAART era, AIDS-related primary CNS lymphoma showed a strong decline, toxoplasmic encephalitis remained stable, and progressive multifocal leukoencephalopathy showed a slight increase. Focal white matter lesions without mass effect or contrast enhancement became the most frequently seen focal brain lesion. For differential diagnosis, PCR-based assays from CSF led to a shift from brain biopsy toward a minimally invasive approach with an augmented likelihood of in vivo diagnosis.

Cidofovir in addition to antiretroviral treatment is not effective for AIDS-associated progressive multifocal leukoencephalopathy: a multicohort analysis

Objective:To establish the effectiveness of cidofovir for AIDS-related progressive multifocal leukoencephalopathy (PML) in patients concomitantly receiving combination antiretroviral therapy. Design:Analysis of raw data pooled from one prospective and five cohort studies. Setting:Tertiary care centers for the treatment of HIV-associated complications. Patients:Three hundred seventy HIV-infected PML patients diagnosed from 1996 treated with combination antiretroviral therapy with or without cidofovir. All studies had already published their results but for four of them, additional patients and follow-up data are included in this report. Follow-up was started from the date of first abnormal neuroimaging; those treated with cidofovir were entered at risk at the date of cidofovir initiation.Main study outcomes were time to PML-related death and odds of 12-month moderately severe to severe disability (Rankin score ≥4). Results:Sixty-four percent of the PML cases were confirmed by histopathology or JC virus DNA detection in cerebrospinal fluid; 185 (50%) received cidofovir (median five cycles). During 463 person-years of follow-up, 167 PML-related deaths occurred (36.6 per 100 person-years of follow-up). Estimated 1 year survival was 0.56 (95% confidence interval, 0.50–0.61). In multivariate models stratified by cohort and adjusted for type of diagnosis and relevant prognostic confounders, cidofovir treatment was not associated with survival (hazard ratio for death 0.93, 0.66–1.32). Results were similar using time to death from any cause as the outcome. Furthermore, 12-month moderately severe to severe disability was not associated with the use of cidofovir. Conclusion:In combination antiretroviral therapy-treated PML patients, cidofovir use did not influence PML-related mortality or residual disability. New treatments for AIDS-related PML are urgently needed.

Precision and Accuracy of a Procedure for Detecting Recent Human Immunodeficiency Virus Infections by Calculating the Antibody Avidity Index by an Automated Immunoassay-Based Method

ABSTRACT We evaluated the precision and accuracy of a procedure for detecting recent human immunodeficiency virus (HIV) infections, specifically, the avidity index (AI) calculated using a method based on an automated AxSYM HIV 1/2gO assay (Abbott). To evaluate precision, we performed multiple replicates on eight HIV-positive serum samples. To evaluate the accuracy in identifying recent infections (i.e., within 6 months of seroconversion), we used 216 serum samples from 47 persons whose dates of seroconversion were known. To evaluate the sensitivity and specificity of the procedure for different AI cutoff values, we performed receiver operating characteristic (ROC) analysis. To determine the effects of antiretroviral treatment, advanced stage of the disease (i.e., low CD4-cell count), and low HIV viral load on the AI, we analyzed 15 serum samples from 15 persons whose dates of seroconversion were unknown. The precision study showed that the procedure was robust (i.e., the total variance of the AI was lower than 10%). Regarding accuracy, the mean AI was significantly lower for samples collected within 6 months of seroconversion, compared to those collected afterwards (0.68 ± 0.16 versus 0.99 ± 0.10; P < 0.0001), with no overlap of the 95% confidence intervals. The ROC analysis revealed that an AI lower than 0.6 had a sensitivity of 33.3% and a specificity of 98.4%, compared to 87.9 and 86.3%, respectively, for an AI lower than 0.9. Antiretroviral treatment, low CD4-cell count, and low viral load had no apparent effect on the AI. In conclusion, this procedure is reproducible and accurate in identifying recent infections; it is automated, inexpensive, and easy to perform, and it provides a quantitative result with different levels of sensitivity and specificity depending on the selected cutoff.

When to start highly active antiretroviral therapy in chronically HIV-infected patients: evidence from the ICONA study.

ObjectivesTo compare the response to highly active antiretroviral therapy (HAART) in individuals starting HAART at different CD4 cell counts. DesignThe mean increase in CD4 cell count and rate of virological failure after commencing HAART were measured in antiretroviral-naive patients (1421) in a large, non-randomized multicentre, observational study in Italy (ICONA). Clinical endpoints were also evaluated in a subset of patients who started HAART with a very low CD4 cell count. ResultsAfter 96 weeks of therapy, the mean rise in CD4 cell count was 280, 281 and 186 × 106 cells/l in patients starting HAART with a CD4 cell count < 200, 201–350 and > 350 × 106 cells/l, respectively. Patients starting HAART with a CD4 cell count < 200 × 106 cells/l tended to have a higher risk of subsequent virological failure [relative hazard (RH), 1.15; 95% confidence interval (CI), 0.93–1.42] compared with patients starting with > 350 × 106 cells/l. There was no difference in risk between the 201–350 and the > 350 × 106 cells/l groups (RH, 1.0; 95% CI, 0.79–1.29). The incidence of new AIDS-defining diseases/death in patients who started HAART with a CD4 count < 50 was 0.03/person-year (95% CI, 0.10–0.33) during the time in which the patients CD4 cell count had been raised to > 200 × 106 cells/l. ConclusionsThere was no clear immunological or virological advantage in starting HAART at a CD4 cell count > 350 rather than at 200–350 × 106 cells/l. The increase in CD4 cells restored by HAART is meaningful in that they are associated with reduced risk of disease/death.

Discontinuation of Maintenance Therapy for Cryptococcal Meningitis in Patients with AIDS Treated with Highly Active Antiretroviral Therapy: An International Observational Study

We conducted a retrospective, multicenter study evaluating the safety of discontinuing maintenance therapy for cryptococcal meningitis after immune reconstitution. Inclusion criteria were a previous definitive diagnosis of cryptococcal meningitis, a CD4 cell count of >100 cells/microL while receiving highly active antiretroviral therapy (HAART), and the subsequent discontinuation of maintenance therapy for cryptococcal meningitis. The primary end point was relapse of cryptococcal disease. As of July 2002, 100 patients were enrolled. When maintenance therapy was discontinued, the median CD4 cell count was 259 cells/microL and the median plasma virus load was <2.30 log10 copies/mL, and serum cryptococcal antigen was undetectable in 56 patients. During a median follow-up period of 28.4 months (range, 6.7-64.5; 262 person-years), 4 events were observed (incidence, 1.53 events per 100 person-years; 95% confidence interval, 0.42-3.92). Three of these patients had a CD4 cell count of >100 cells/microL and a positive serum cryptococcal antigen test result during the recurrent episode. In conclusion, discontinuation of maintenance therapy for cryptococcal meningitis is safe if the CD4 cell count increases to >100 cells/microL while receiving HAART. Recurrent cryptococcal infection should be suspected in patients whose serum cryptococcal antigen test results revert back to positive after discontinuation of maintenance therapy.

Risk of invasive cervical cancer among women with, or at risk for, HIV infection.

Although invasive cervical cancer (ICC) has been included among the AIDS‐defining conditions since 1993, it remains controversial whether HIV infection increases the risk of developing such neoplasm. In this study, ICC risk was longitudinally investigated among 1,340 HIV‐positive intravenous drug user (IDU), 811 HIV‐negative IDU, and 801 HIV‐positive heterosexual women. These women, aged 15–49 years, were followed up at the Italian HIV Seroconverter Study, at the San Patrignano Community (Rimini, North Italy), and in South‐eastern France (the DMI‐2 study). The number of observed cases of ICC was compared with the expected one, based on ICC incidence rates among women of the same age in the general population of Italy or France, and standardized incidence ratios (SIR) were computed; 9,070 person‐years of observation were accumulated among HIV‐positive women and 2,310 among HIV‐negative ones. Ten cases of ICC were diagnosed among HIV‐positive women (SIR = 12.8): ICC risk was apparently higher among HIV‐positive IDU (SIR = 16.7) than among heterosexual women (SIR = 6.7). No cases of ICC were diagnosed among HIV‐negative IDU women admitted to the San Patrignano Community (0.15 cases were expected). Our findings confirm previous suggestions showing an increased risk of ICC among HIV‐infected women and have important implications at the individual and public health levels. Int. J. Cancer 82:334–337, 1999.