Stefano Boros

Increasing survival time after AIDS in Italy : the role of new combination antiretroviral therapies

BACKGROUND In Italy, antiretroviral combination therapy was adopted in mid-1995 and protease inhibitors in mid-1996. OBJECTIVE To conduct a prospective, population-based, observational study to evaluate the effect of these therapies on the survival of persons with AIDS (PWA). METHODS PWA living in the Tuscany region diagnosed between 1985 and 31 March 1997 (National AIDS Registry) were studied. Information on antiretroviral drugs, prophylactic treatment, CD4 cell count, and AIDS-defining illnesses was collected for PWA still alive at 1 January 1996 and those diagnosed thereafter (analysis cut-off date, 30 November 1997). Kaplan-Meier curves were calculated by year of diagnosis. A Cox model was then used to estimate the adjusted (by sex, age, HIV exposure category, CD4 cell count, type and number of AIDS-defining illnesses) relative hazard (RH) of death by year of diagnosis and calendar date (considered as a time-dependent variable). Similar analyses were repeated for PWA diagnosed after 1989, having been stratified by disease-specific AIDS condition. A final analysis was performed for PWA still alive at 1 January 1996 or diagnosed thereafter for estimating the effect of single, double and triple combination therapy (time-dependent variables), having adjusted for the above variables and for prophylactic treatment. RESULTS A total of 1683 (79.5%) out of 2118 PWA died before 1 December 1997. Use of more potent combination therapies, including protease inhibitors, greatly increased during 1997. Median survival was 2.9, 12.3, 13.4, 11.4 and 17.6 months for diagnoses before 1987, in 1987-1990, 1991-1993, 1994 and 1995, respectively; an estimated 62% of those diagnosed in 1996-1997 had survived 15 months after diagnosis. The Cox model showed a trend of decrease of RH for calendar time starting in the first half of 1996, compared with 1994. When stratifying by specific AIDS-defining disease there was no statistically significant evidence that the improved overall survival was due to increased survival only for certain diseases. The final multivariate analysis for the 771 PWA still alive at 1 January 1996 or diagnosed thereafter estimated significant RH < 1.0 for double and triple therapy (RH, 0.61 and 0.36, respectively) compared with no therapy. CONCLUSIONS A significant reduction in risk of death after AIDS was observed from the second half of 1996, apparently due to the widespread use of antiretroviral combination therapies.

Cardiovascular risk profile and blood pressure control in Italian hypertensive patients under specialist care

Background Information on the association between high hypertension and metabolic risk factors in Italy is limited. Furthermore, data on the rate of blood pressure control in the Italian hypertensive population are restricted to some Italian regions only, and refer usually to surveys performed, in most instances, several years ago. Methods In the present study, a total of 4059 essential hypertensive patients were examined consecutively from March to June 2000 by 450 cardiovascular specialists (cardiologists, internists and diabetologists) operating throughout the Italian territory. Analysable data were obtained in 3812 patients. Results Blood pressure control by treatment (< 140/90 mmHg) was infrequent (11.9%), this being particularly the case for systolic as compared to diastolic blood pressure (15.1 versus 33.7%). Hypertension was the only risk factor in only 13.7% of the patients, the association with diabetes, hypercholesterolaemia or obesity characterizing the remaining cases. About 60% of the patients fell into the high or very high cardiovascular risk category of the World Health Organization/International Society of Hypertension (WHO/ISH) Guidelines. Compared to low or moderate cardiovascular risk, multiple antihypertensive drug treatment was more frequently used in individuals at high or very high risk. These conditions were frequently underdiagnosed by physicians. Conclusions Thus, in Italy, hypertension continues to be a poorly controlled condition. Despite being a Mediterranean country, the occurrence of hypertension is commonly associated with metabolic risk factors and often with a high or very high cardiovascular risk profile. This is not properly identified by specialist physicians.

Differential impact of combined antiretroviral therapy on the survival of italian patients with specific AIDS-defining illnesses.

Background: A decrease in HIV‐related mortality and morbidity has been observed since 1996 in most developed countries as a consequence of the extensive use of combined antiretroviral therapies. The purpose of this study was to investigate whether combined antiretroviral therapies had a differential impact on the survival of patients with different AIDS‐defining illnesses (ADIs). Methods: In total, 35,318 persons representing all the adults with AIDS (PWAs) diagnosed in Italy from January 1, 1990 to August 31, 1998 were studied. Actuarial life tables and the Kaplan‐Meier method were used to estimate the cumulative probability of survival; the multivariate Cox proportional hazards model was used to estimate adjusted relative hazard of death (RH). Results: Among PWAs diagnosed after 1995, the proportion of survivors 24 months after diagnosis was more than doubled (66%) compared with that of PWAs diagnosed before the end of 1995 (31%). Significantly decreased RHs for some ADIs were observed as early as 1996 (i.e., esophageal candidiasis, Pneumocystis carinii pneumonia, brain toxoplasmosis, HIV‐wasting syndrome, and pulmonary tuberculosis). In the last period (1997‐1998), the decrease was marked and significant for almost all the ADIs, ranging from 55% to 80% compared with the RHs of the reference year (1995). Conversely, primary lymphoma of the brain and Burkitts lymphoma showed a low and not statistically significant decrease; these were the ADIs with the worst outcome. Conclusions: After 1995, there was a rather uniform increase in the survival of PWAs diagnosed with most specific ADIs but not for patients affected by primary brain lymphoma and Burkitts lymphoma. The determinants of this differential effect need to be investigated.

Increasing proportion of late testers among AIDS cases in Italy, 1996–2002

Abstract In recent years, the proportion of individuals who are unaware of being infected with HIV when diagnosed with AIDS (defined as ‘late testers’) has dramatically increased in several European countries, including Italy. We evaluated the extent and determinants of late testing and its impact in terms of AIDS-defining illnesses among AIDS cases reported to the Italian National AIDS Registry since 1996. Late testers were defined as those persons whose first positive HIV test result was within six months of the AIDS diagnosis. Late testers were more likely to be heterosexual contacts or MSWM, as opposed to IDUs. They were also more likely to come from low prevalence areas of Italy or from foreign countries. At AIDS diagnosis, late testers were less likely to be undergoing HAART or prophylaxis against PCP/toxoplasmosis, compared to non-late testers. The mean CD4 cell count at AIDS diagnosis was significantly lower among late testers. PCP, toxoplasmosis and Kaposis sarcoma were more frequently diagnosed as an AIDS-defining illness in late testers, who also had a significantly higher risk of presenting with multiple concomitant AIDS-defining illnesses. In conclusion, late testing results in missed opportunities for preventing and treating HIV infection, leading to an increased risk of developing preventable opportunistic infections and death.

Molecular Diversity of HIV in Albania

Little information is available on circulating human immunodeficiency virus (HIV) subtypes and resistance to antiretroviral drugs in Albania. To fill this gap, we studied 72 plasma samples from HIV-infected individuals from throughout the country. Subtype classification and genotypic resistance analysis were performed on the HIV pol gene region. The analysis was successfully performed on 66 (91.6%) plasma samples and showed that 43 (65.2%) strains were non-B subtypes (mostly subtype A, as determined by analysis of pol gene sequences). No major mutations in the protease gene were found, whereas analysis of the reverse transcriptase gene revealed a few major mutations associated with resistance. In conclusion, non-B subtypes are predominant in Albania, and the prevalence of resistance to antiretroviral drugs is still low.

Consecutive Epidemics of Q Fever in a Residential Facility for Drug Abusers: Impact on Persons with Human Immunodeficiency Virus Infection

Two large outbreaks of Q fever occurred in 1987 and 1988 in an agricultural community for the rehabilitation of drug users. Approximately 40% of the residents were human immunodeficiency virus (HIV)-positive. Two hundred thirty-five residents presented with clinical evidence of a flulike syndrome that was confirmed to be Q fever; moreover, a large proportion of residents developed an asymptomatic infection. Clinical signs and symptoms were rather nonspecific: fever, malaise, and muscle pain that were often associated with pulmonary symptoms. Single or multiple opacities were detected, with mild interstitial inflammation evident on chest roentgenograms. The source of infection was the sheepfold, which is part of the stock-farming activity of the community. Both outbreaks occurred just after lambing had begun. Residents who were exposed during the first epidemic were protected in the second one. The attack rate among HIV-positive residents was significantly higher than that among HIV-negative residents in the first outbreak, whereas only a slight, marginally significant difference was observed in the second outbreak. The clinical features of Q fever did not differ between HIV-positive and HIV-negative individuals. No cases of relapse or chronic disease were observed.

Survival after AIDS diagnosis in Italy, 1999-2006: a population-based study.

Objectives:To provide survival estimates of Italian people with AIDS (PWA) in the highly active antiretroviral therapy era and to identify prognostic factors at diagnosis and illnesses present at death. Design:Longitudinal study with all-cause mortality as end point. Methods:The vital status and illnesses present at death of the 9662 Italian PWA diagnosed from 1999 to 2005 were evaluated through a record linkage with the Italian mortality database. The survival was estimated through Kaplan-Meier method, whereas hazard ratios were computed to identify prognostic factors in the first 12 months or later. Results:80.6% of PWA survived 1 year, 75.2% 2 years, and 66.4% 5 years. Elevated death risks emerged among older individuals, injection drug users, and those with a CD4+ cell count <200. Non-Hodgkin lymphoma at AIDS diagnosis was the strongest negative prognostic factor, particularly in the first 12 months after AIDS (hazard ratio = 9.2, for primary brain lymphoma). At death, non-AIDS-defining illnesses increased from 38.4% in 1999 to 56.9% in 2006, with non-AIDS-defining cancers rising from 3.7% to 8.7%. Conclusions:Our study documented the prolonged survival of Italian PWA, the strong impact of non-Hodgkin lymphoma on mortality, and the increasing frequency of non-AIDS-defining illnesses at death.

Incidence of Human Herpesvirus 8 (HHV-8) infection among HIV-uninfected individuals at high risk for sexually transmitted infections

BackgroundThe occurrence of, and risk factors for, HHV-8 infection have yet to be definitively determined, particularly among heterosexual individuals with at-risk behavior for sexually transmitted infections (STI). The objective of this study was to estimate the incidence and determinants of HHV-8 infection among HIV-uninfected individuals repeatedly attending an urban STI clinic.MethodsSera from consecutive HIV-uninfected individuals repeatedly tested for HIV-1 antibodies were additionally tested for HHV-8 antibodies using an immunofluorescence assay. To identify determinants of HHV-8 infection, a nested case-control study and multivariate logistic regression analysis were performed.ResultsSera from 456 HIV-uninfected individuals (224 multiple-partner heterosexuals and 232 men who have sex with men (MSM]) were identified for inclusion in the study. The HHV-8 seroprevalence at enrollment was 9.4% (21/224; 95% C.I.: 6.0–14.2%) among heterosexuals with multiple partners and 22.0% (51/232; 95% C.I.: 16.9–28.0%) among MSM. Among the 203 multiple-partner heterosexuals and 181 MSM who were initially HHV-8-negative, 17 (IR = 3.0/100 p-y, 95% C.I.: 1.9 – 4.8) and 21 (IR = 3.3/100 p-y, 95% C.I:.2.1 – 5.1) seroconversions occurred, respectively. HHV-8 seroconversion tended to be associated with a high number of sexual partners during the follow-up among MSM (> 10 partners: AOR = 3.32 95% CI:0.89–12.46) and among the multiple-partner heterosexuals (> 10 partner; AOR = 3.46, 95% CI:0.42–28.2). Moreover, among MSM, HHV-8 seroconversion tended to be associated with STI (AOR = 1.80 95%CI: 0.52–7.96).During the study period the HIV-1 incidence was lower than that of HHV-8 among both groups (0.89/100 p-y among MSM and 0.95/100 p-y among multiple-partner heterosexuals).ConclusionThe large difference between the incidence of HHV-8 and the incidence of HIV-1 and other STIs may suggest that the circulation of HHV-8 is sustained by practices other than classical at-risk sexual behavior.

Increasing Proportion of AIDS Diagnoses among Older Adults in Italy

We evaluated the impact of AIDS among older persons in Italy and compared these cases with cases among younger persons. The data source was Italys National AIDS Registry. We considered adults diagnosed with AIDS between 1982 and 2005. Older adults were defined as those aged 50 years or older at diagnosis. Of the total adult cases, 8.8% were among older adults. This proportion increased over time, from 4.9% in 1982-1990 to 15.9% in 2000-2005. Among older adults, the most represented exposure category (80.8%) was sexual intercourse (heterosexual and homosexual). At AIDS diagnosis, older adults, compared to younger adults, had a higher risk of developing AIDS dementia complex or wasting syndrome, and of presenting multiple AIDS-defining illnesses. A significantly lower proportion of older adults were undergoing antiretroviral therapy, compared to younger adults. Among older adults, 67.2% were late testers, compared to 32.8% of younger adults. Most of the older adults acquired the infection through sexual contact; approximately two thirds of them were diagnosed late (i.e., first HIV-positive test 6 months or less before AIDS diagnosis); and only one fourth were undergoing antiretroviral therapy at diagnosis. These observations stress the need to more seriously consider the possibility of HIV infection among older individuals and to collect more detailed information on their sexual behavior.

response to Highly Active Antiretroviral Therapy According to Duration of Hiv Infection

Objective: To evaluate whether duration of HIV‐1 infection influences the response to highly active antiretroviral therapy (HAART). Design: Prospective study of individuals (Italian Seroconversion Study cohort) with well‐estimated dates of HIV‐1 seroconversion. Methods: This analysis included 277 participants who began HAART (defined as three antiretroviral drugs used in combination). Cox regression models were used to evaluate the association between duration of infection (as categorical variable [≤3, 3‐7.5, >7.5 years from seroconversion] or continuous variable) and an immunologic (rise in CD4 count >100 cells/mm3) and a virologic (decline in plasma HIV‐RNA to unquantifiable levels) outcome. All analyses were stratified by center of recruitment and adjustment, when used, was for gender, age at inception of HAART, injection drug use, previous antiretroviral therapy, lag‐time between positive and negative HIV test result, year of starting HAART, clinical stage, CD4 count, and HIV‐RNA at time of HAART. Results: HAART was initiated a median of 6.4 years after seroconversion. There was a median follow‐up of 1.6 years after starting HAART to the calendar cut‐off (November 1999). One‐hundred‐eighty‐one (65.3%) patients experienced a decline in viral load to below quantifiable levels and 184 (66.4%) experienced a rise in CD4 >100 cells/mm3. In the Cox models, by 1‐year increase in duration of infection, we estimated a lower crude hazard of achieving a CD4 count increase >100 cells (relative hazard [RH], 0.96; 95% confidence interval [CI], 0.92‐1.01; p = .09), and a lower hazard of reaching an unquantifiable level of plasma HIV‐RNA (RH, 0.97; 95%CI, 0.93‐1.02; p = .20). After adjustment, these values became 0.99 (95%CI, 0.93‐1.04; p = .62) and 0.98 (95%CI, 0.93‐1.04; p = .48), respectively. When duration of HIV infection was considered as a categorical variable, the results were consistent with those already described. Conclusions: These results suggest that the duration of HIV infection does not seem to play an important independent role in determining the virologic and immunologic responses to HAART.