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Background: Herpes simplex virus type 2 (HSV-2) infections may be a risk factor for the transmission of HIV. Data on the prevalence of HSV-2 infection among HIV-positive individuals are scarce., Goal: The goal was to study the seroprevalence of and risk factors for HSV-2 infection among a cohort of Italian HIV-positive individuals., Study Design: This was a cross-sectional study. HSV-2 serologic testing was performed for individuals with known date of HIV seroconversion, on the serum specimen obtained on the date closest to the estimated date of seroconversion. Antibodies to HSV-2 (anti-HSV-2) were detected by a gG2-specific ELISA., Results: A total of 380 HIV-positive individuals were tested for anti-HSV-2; 126 (33.2%) of them were positive. Older age at HIV seroconversion and homosexuality were significantly associated with HSV-2 infection in the multivariate analysis., Conclusions: These data stress the need for including anti-HSV-2 testing and therapy in the management of HIV positivity, especially for reducing the risk of transmission of HIV through herpetic lesions.

Data from a cohort of HIV-positive individuals who were antiretroviral naive at enrollment were analysed to estimate the probability of discontinuing the first highly active antiretroviral therapy (HAART) regimen, comparing protease inhibitor- and non-nucleoside reverse transcriptase-containing regimens. Of the 2002 individuals who began HAART, 857 (42.8%) discontinued their first regimen. No statistically significant difference was found in the time to discontinuation by specific type of regimen, either when considered overall or by specific reason.

To assess whether the incidence of invasive cervical cancer (ICC) has changed as a result of highly active antiretroviral therapy (HAART), we conducted a prospective cohort study on the incidence of ICC before and after the introduction of HAART among Italian women with a known duration of HIV infection. We estimated the incidence per 1000 person years of ICC as a first AIDS-defining disease for the periods 1981 through 1991, 1992 through 1995, and 1996 through 1998. We also estimated the incidence of other first AIDS-defining diseases. Kaplan-Meier and Cox models were applied to compare the periods 1981 through 1995 and 1996 through 1998 in terms of cumulative incidence and relative hazards (RHs). The analysis included 483 women (median follow-up: 7 years). In the period 1981 through 1995, a trend of increase was observed in the incidence of ICC and other AIDS-defining diseases; this trend has continued only for ICC, whereas the incidence of other AIDS-defining diseases has decreased since 1996. Compared with 1981 through 1995, the RH of ICC for 1996 through 1998 was 7.41 (95% confidence interval [CI]: 1.21--45.44); when adjusting for age at HIV seroconversion, the RH decreased to 4.75 (95% CI: 0.80--28.24). It remains to be determined whether the continued increase in ICC incidence after the introduction of HAART is attributable to a decreasing competitive mortality from other AIDS-defining diseases among HIV-infected women.

Objectives: To evaluate temporal trends of Kaposi's sarcoma (KS) and of the KS-related human herpesvirus (HHV-8) among homosexual men who seroconverted for HIV between 1984 and 1997., Methods: The study participants were 387 homosexual men. Changes over a period of time were assessed by estimating KS incidence rates per 1000 person-years for the periods 1984-1989, 1990-1992, 1993-1995, and 1996-1997. The proportional incidence of KS as the AIDS-defining disease for the same periods was also calculated. To evaluate a cohort effect of calendar period, Kaplan-Meier curves were used to estimate the risk of KS by period of HIV seroconversion [i.e. before 1990 (median year of seroconversion) versus later]. Relative hazards for the four periods were estimated using competitive-risks models. We also estimated HHV-8 seroprevalence over the study period., Results: Forty-eight participants developed KS. Between 1984 and 1995, the incidence rate of KS per 1000 person-years increased from 3.9 to 32.8, whereas the proportional incidence decreased from 33.3 to 24.3%. The risk of developing KS after HIV seroconversion did not change when comparing the seroconversion periods (i.e. before 1990 versus later). HHV-8 seroprevalence also remained stable. The rates of KS and the relative hazards dramatically decreased after 1995., Conclusions: Although KS incidence rates increased up to 1995, the proportional incidence decreased, due to the higher increase in rates of other AIDS-defining diseases. The finding that the risk of developing KS after HIV seroconversion remained stable over time is consistent with the stable trend of HHV-8 seroprevalence. The dramatic decrease in KS incidence rates after 1995 coincides with combined antiretroviral therapy.

Objective: To evaluate the cancer risk in southern European men with, or at risk of, HIV infection., Design: An analysis of longitudinal data to assess time-dependent rare events., Methods: Data from a cohort of HIV seroconverters, and from two hospital-based HIV seroprevalent cohorts were combined and analysed. The number of cancer cases observed was compared with the expected number, obtained from cancer incidence rates among men in the general population. Age-standardized incidence ratios (SIR) and their 95% confidence intervals (CI) were computed., Results: A total of 19,609 person-years of observation were accumulated among HIV-positive men, and 7957 person-years among HIV-negative men. Among HIV-positive men, statistically significant increased SIR were seen for Hodgkin's disease (HD) (SIR = 8.7), liver cancer (SIR = 11.0), and cancer of the salivary glands (SIR = 33.6). An excess of lung cancer was seen among intravenous drug users (IDU), but not among homosexual men. When the risk of all non-AIDS-defining cancers was considered, HIV-positive men had a nearly twofold excess (95% CI: 1.2-2.8). A risk of similar magnitude emerged among HIV-negative IDU (95% CI: 1.0-4.5), largely attributable to lung cancer and HD., Conclusion: These findings confirm that HIV infection increases the risk of HD, whereas they suggest that the risk of hepatocellular carcinoma may also be enhanced by HIV infection. The observation of an elevated risk of lung cancer in both HIV-positive and HIV-negative IDU points to personal behaviours unrelated to HIV infection.

A prospective study of 149 human immunodeficiency virus type 1 (HIV-1) seroconverters was conducted to describe trends and correlates of HIV-1 load after seroconversion and over time. HIV-1 load was quantified from frozen sera by reverse transcriptase-polymerase chain reaction. High early virus load was associated with lower CD4 cell counts and male sex but not with age at seroconversion or injection drug use. Early virus load predicted progression to clinical AIDS and AIDS/<200 CD4 cells/microL. Virus load exhibited a decline of 52% by 18 months after seroconversion then increased 23% annually (95% confidence interval, 13%-33%). Men and those developing AIDS during follow-up had higher virus loads over the course of disease. Persons who developed AIDS had a steeper virus load slope than those who were AIDS-free (P=.01). In long-term follow-up, virus load exhibited a gradual and sustained increase over time. Virus load and annual increase are strong predictors of disease progression.

Objective: To evaluate changes in survival among HIV-positive individuals with known date of seroconversion (SC)., Design: Prospective cohort study., Methods: Follow-up lasted from SC to death or to the end of 1997. A multivariate Cox model was applied to estimate relative hazards (RH) of death. The year of SC (as a categoric fixed variable) and calendar year (as a time-dependent variable) were considered to evaluate, respectively, cohort and prevalent changes in the rate of death. A separate Cox model was used to assess the association between survival and new combination therapies, using an "intention to treat" approach., Results: The study included 1535 individuals (53.9% injecting drug users, 25.3% homosexuals, 19.5% heterosexuals); 75.8% seroconverted between 1980 and 1991, and 24.2% seroconverted between 1992 and 1997. When adjusting for year of SC, the RH of death (and that of AIDS) was significantly lower in 1997, compared with before 1991 (RH = 0.54; 95% confidence interval, 0.30-0.98). Adjusted RHs of death were significantly lower for combination antiretroviral therapy, compared with no therapy. When combining the two Cox models, the 1997 reduction in risk of death was largely due to antiretroviral therapies; similar results were obtained when the endpoint was AIDS., Conclusions: A reduction in the risk of death, probably due to combination antiretroviral therapy, was observed in 1997 after having adjusted for age at SC and year of SC.

Background: The incidence of Kaposi's sarcoma (KS) is increased severalfold in individuals infected with human immunodeficiency virus-1 (HIV). Human herpesvirus 8 (HHV8) has also been implicated in KS. We investigated several factors that may determine the onset of KS, particularly HHV8 infection in individuals after becoming seropositive for HIV., Methods: We studied 366 individuals belonging to different HIV-exposure categories (i.e., homosexual activity, intravenous drug use, and heterosexual contact) for whom a negative HIV serologic test and then a positive HIV serologic test were available within a 2-year period. HHV8 antibody testing was performed by use of an immunofluorescence assay on the first serum sample available after the first positive HIV test. Actuarial rates of progression of KS and of other acquired immunodeficiency syndrome (AIDS)-defining diseases were estimated by use of time-to-event statistical methods. All statistical tests were two-sided., Results: Twenty-one of the 366 study participants developed AIDS-related KS, and 83 developed AIDS without KS. One hundred forty (38.3%) participants had detectable anti-HHV8 antibodies. The actuarial progression rate to KS among persons co-infected with HIV/HHV8 was nearly 30% by 10 years after HIV seroconversion. Increasing HHV8 antibody titers increased the risk of developing KS (for seronegative versus highest titer [1:125 serum dilution], adjusted relative hazard [RH] = 51.82; 95% confidence interval [CI] = 6.08-441.33) but not of other AIDS-defining diseases (adjusted RH = 1.14; 95% CI = 0.72-1.80). HHV8-seropositive homosexual men compared with HHV8-seropositive participants from other HIV-exposure categories showed an increased risk of KS that approached statistical significance (adjusted RH = 6.93; 95% CI = 0.88-54.84)., Conclusions: Approximately one third of individuals co-infected with HIV/HHV8 developed KS within 10 years after HIV seroconversion. Progression to KS increased with time after HIV seroconversion. Higher antibody titers to HHV8 appear to be related to faster progression to KS but not to other AIDS-defining diseases.

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.

To determine the frequency and the determinants of use of antiretroviral drugs and prophylaxis for Pneumocystis carinii Pneumonia (PCP) among HIV-infected individuals before AIDS diagnosis, a questionnaire was sent to all physicians reporting at least one AIDS case during the first six months of 1994 to the Italian National AIDS Registry. Information on cases diagnosed between 1 January and 31 March 1995 was collected. Information was obtained for 878 (66.4%) of the 1323 persons with AIDS: 447 (50.9%) had received antiretroviral drugs and 343 (39.1%) PCP prophylaxis, whereas 303 cases (34.5%) had received both. Individuals who became aware of being HIV-positive shortly before AIDS diagnosis were less likely to have started antiretroviral therapy (adjusted odds ratio (AOR): 0.05, 95% CI: 0.03-0.09). Homosexual men and heterosexuals were more likely to begin therapy (AOR: 1.40, 95% CI: 0.83-2.37 and AOR: 1.79, 95% CI: 1.05-3.05, respectively) compared to injecting drug users. Individuals living in Southern Italy and foreigners were less likely to start therapy (AOR: 0.75, 95% CI: 0.49-1.16 and AOR: 0.40, 95% CI: 0.15-1.09, respectively) compared to those living in Northern Italy. Results were similar for PCP prophylaxis. Lack of awareness of HIV infection, HIV exposure category, and geographical area were the most important factors associated with treatment before AIDS diagnosis.

Objectives: To evaluate the association between time since initiation of pre-AIDS antiretroviral therapy [mainly with zidovudine (ZDV)] and AIDS-free survival in a cohort of HIV seroconverters, and to assess possible differences in this association and in the use of antiretroviral therapy by HIV exposure group., Design: Observational study of HIV-infected individuals, both those treated with antiretroviral therapy and those untreated, enrolled in an ongoing prospective cohort (median follow-up, 5.3. years)., Setting: Sixteen HIV outpatient clinics throughout Italy., Patients: A total of 1,078 individuals infected with HIV through injecting drug use or homo-/heterosexual activity, and with accurately estimated dates of seroconversion., Main Outcome Measures and Methods: Kaplan-Meier estimates of the probability of receiving antiretroviral therapy before AIDS. Crude and adjusted relative hazards of AIDS and of death from AIDS using Cox regression models., Results: The cumulative incidence of beginning pre-AIDS antiretroviral therapy within 7 years of seroconversion was 49.2%. Injecting drug users (IDU) were less likely to undergo antiretroviral treatment before AIDS than homosexual men and heterosexual contacts. The adjusted relative hazard of developing AIDS for patients treated with ZDV (relative hazard adjusted for occurrence of acute HIV disease, pre-AIDS HIV-related diseases, CD4 count, and use of prophylaxis for Pneumocystis carinii pneumonia) was 0.57 within the first year of starting zidovudine and 0.92 after 1 year of therapy. Stratifying by HIV exposure category, the adjusted relative hazards of AIDS for individuals who started ZDV less and more than 1 year before AIDS were 0.74 and 0.99 among IDU, 0.31 and 0.89 among homosexual men, and 0.69 and 0.72 among heterosexuals, respectively. Similar results were obtained when using death from AIDS as an endpoint., Conclusions: IDU began pre-AIDS antiretroviral therapy significantly later than homosexual men and heterosexuals, even after adjusting for CD4 count. Results from this non-randomized study confirm that antiretroviral treatment has only a short-term clinical benefit. There was a stronger association between antiretroviral treatment and lower risk of AIDS in homosexual men than in IDU.

We prospectively examined a cohort of HIV-positive persons with an accurately estimated date of HIV seroconversion who were infected through injecting drug use or sexual contact to estimate the proportion of long-term nonprogressors (LTNP), considering four definitions of LTNPs. We also evaluated whether factors such as gender, age, and HIV-exposure category were associated with being LTNP; we determined the overlap among the definitions and compared the CD4 and CD8 counts and the CD4/CD8 decline among LTNPs and "moderate" and "fast" progressors. Of the 528 persons selected for analysis, 2 to 4% were considered LTNPs, depending on the definition. The proportion of LTNPs varied by definition, and there was little overlap among definitions. The LTNPs did not appear to differ from "moderate" and "fast" progressors with regard to main demographic characteristics, and they showed a better trend of immunological parameters, appearing to have a slower progression rather than a permanently arrested infection.

A prospective study of 1,198 individuals who seroconverted to human immunodeficiency virus (HIV) was conducted to estimate the incidence and determinants of herpes zoster and to determine whether herpes zoster can accelerate the progression to AIDS. Herpes zoster was diagnosed for 48 individuals (4%). After adjusting for the CD4 cell count, individuals acquiring HIV infection through sexual contact were more likely to have herpes zoster than were injection drug users (relative hazard, 1.50). The crude relative hazard of AIDS for individuals who had herpes zoster compared with those without herpes zoster was 2.44; the adjusted relative hazard was 1.08. After adjusting for the CD4 cell count, fever was the only specific characteristic of herpes zoster that was significantly associated with a more rapid progression to AIDS (relative hazard, 6.52). Data suggest that herpes zoster occurs more frequently in individuals acquiring HIV infection through sexual transmission. There was no evidence that herpes zoster per se is an independent cofactor of progression of HIV disease, although febrile episodes of herpes zoster may predict a faster progression to AIDS.

Objective: To estimate the frequency of acute retroviral syndrome associated with HIV infection among injecting drug users (IDU), and to determine the extent to which acute retroviral syndrome predicts a faster rate of progression to AIDS and immunosuppression in this population., Design: Prospective study of HIV seroconverters (median follow-up, 50.5 months)., Setting: Sixteen clinical centres throughout Italy established to study the natural history of HIV infection., Patients: Three hundred and ninety-one IDU for whom the date of HIV seroconversion was established with a 9-month precision., Main Outcome Measures and Methods: Incidence of acute retroviral syndrome with signs and symptoms that included fever (temperature > 38 degrees C) occurring within 6 months prior to the time of first positive HIV test, progression to AIDS, crude and adjusted relative hazard of AIDS using survival analysis techniques, and trajectories of CD4+ cell counts using a piece-wise linear regression model incorporating the degree of dependency of within-person measurements., Results: Of 391 HIV seroconverters, 39 (10.0%) were diagnosed with acute retroviral syndrome. During follow-up, 13 seroconverters with acute retroviral syndrome and 24 asymptomatic seroconverters developed AIDS. The Kaplan-Meier estimates for the cumulative AIDS incidence during 4.5 years of follow-up were 26.8 and 6.5%, respectively; the relative hazard of developing AIDS for acute retroviral syndrome was 5.59 (95% confidence interval, 2.79-11.20) after adjustment for age, sex and year of seroconversion. Although CD4+ level within the first year from seroconversion was similar, the rate of CD4+ cell decline after 1 year from seroconversion was faster in individuals with acute retroviral syndrome than in those without this syndrome (P < 0.001)., Conclusions: Among HIV-infected IDU, a distinct acute retroviral syndrome is apparent and associated with a faster rate of clinical progression to AIDS and HIV-related immunosuppression.

Objective: To compare the progression of HIV-1 infection in men and women followed up for up to nine years after an accurately estimated date of seroconversion., Design: Prospective observational study., Setting: 16 HIV outpatient clinics across Italy., Subjects: 321 women and 533 men infected with HIV through injecting drug use or heterosexual sex and with accurately estimated dates of seroconversion., Main Outcome Measures: Progression to severe CD4 lymphocytopenia (CD4 lymphocyte count < 200 x 10(6)/l), development of AIDS defining diseases, and death from AIDS., Results: Thirty two women and 67 men developed AIDS at Kaplan-Meier progression rates of 25% (95% confidence interval 13.8% to 35.5%) and 23% (15.6% to 30.4%), respectively, 7 years after seroconversion. In a Cox proportional hazards model the relative hazard was 0.93 (that is, a slightly lower hazard in women) before and 1.10 (0.70 to 1.72) after adjusting for age, HIV exposure group, and year of seroconversion. When CD4 lymphocytopenia and death from AIDS were used as end points the results were similar, with adjusted relative hazards of 0.95 (0.63 to 1.42) and 0.72 (0.48 to 1.79) respectively. In both women and men the risk of developing AIDS before the CD4 lymphocyte count had declined below 200 x 10(6)/l was small (3% in women, 6% in men). The estimated median count at which AIDS developed in women (34 x 10(6)/l; 10 x 10(6) to 44 x 10(6)) was similar to that for men (44 x 10(6)/l; 22 x 10(6) to 60 x 10(6))., Conclusion: There seems to be little evidence for appreciable differences in the natural course of HIV infection between men and women followed up from the time of seroconversion.

We used data from different sources to estimate the extent and the trend of the epidemic of drug use in Italy in the second half of the '80s. During the study period, the number of subjects attending drug dependency units increased from 13,905 to 61,689. Mortality and morbidity indicators showed an increase in both drug related deaths (mainly from overdose) and AIDS cases reported in injecting drug users, particularly among older subjects. However, the number of young adults detected as drug users at the army recruitment remained virtually stable from 1986 on. These findings suggest that both demand and availability of treatment increased through the years 1985-89, and that clinical consequences of drug use related behaviour have become an important public health priority.