Effects of Influenza Vaccine on the Immune Responses to SARS-CoV-2 Vaccination.

A number of studies have suggested that influenza vaccination can provide protection against COVID-19, but the underlying mechanisms that could explain this association are still unclear. In this study, the effect of the 2021/2022 seasonal influenza vaccination on the immune response to the booster dose of anti-SARS-CoV-2 vaccination was evaluated in a cohort of healthy individuals. A total of 113 participants were enrolled, 74 of whom had no prior COVID-19 diagnosis or significant comorbidities were considered for the analysis. Participants received the anti-influenza tetravalent vaccine and the booster dose of the anti-SARS-CoV-2 vaccine or the anti-SARS-CoV-2 vaccine alone. Blood was collected before and 4 weeks after each vaccination and 12 weeks after SARS-CoV-2 vaccination and analyzed for anti-flu and anti-spike-specific antibody titers and for in vitro influenza and SARS-CoV-2 neutralization capacity. Results indicated an increased reactivity in subjects who received both influenza and SARS-CoV-2 vaccinations compared to those who received only the SARS-CoV-2 vaccine, with sustained anti-spike antibody titers up to 12 weeks post-vaccination. Immune response to the influenza vaccine was evaluated, and individuals were stratified as high or low responders. High responders showed increased antibody titers against the SARS-CoV-2 vaccine both after 4 and 12 weeks post-vaccination. Conversely, individuals classified as low responders were less responsive to the SARS-CoV-2 vaccine. These data indicate that both external stimuli, such as influenza vaccination, and the host's intrinsic ability to respond to stimuli play a role in the response to the vaccine.

Reference curves for CD4 T-cell count response to combination antiretroviral therapy in HIV-1-infected treatment-naïve patients.

OBJECTIVES: The aim of this work was to provide a reference for the CD4 T-cell count response in the early months after the initiation of combination antiretroviral therapy (cART) in HIV-1-infected patients. METHODS: All patients in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) cohort who were aged ≥ 18 years and started cART for the first time between 1 January 2005 and 1 January 2010 and who had at least one available measurement of CD4 count and a viral load ≤ 50 HIV-1 RNA copies/mL at 6 months (± 3 months) after cART initiation were included in the study. Unadjusted and adjusted references curves and predictions were obtained using quantile regressions. RESULTS: A total of 28 992 patients were included in the study. The median CD4 T-cell count at treatment initiation was 249 [interquartile range (IQR) 150, 336] cells/µL. The median observed CD4 counts at 6, 9 and 12 months were 382 (IQR 256, 515), 402 (IQR 274, 543) and 420 (IQR 293, 565) cells/µL. The two main factors explaining the variation of CD4 count at 6 months were AIDS stage and CD4 count at cART initiation. A CD4 count increase of ≥ 100 cells/mL is generally required in order that patients stay 'on track' (i.e. with a CD4 count at the same percentile as when they started), with slightly higher gains required for those starting with CD4 counts in the higher percentiles. Individual predictions adjusted for factors influencing CD4 count were more precise. CONCLUSIONS: Reference curves aid the evaluation of the immune response early after antiretroviral therapy initiation that leads to viral control.

Higher rates of triple-class virological failure in perinatally HIV-infected teenagers compared with heterosexually infected young adults in Europe.

OBJECTIVES: The aim of the study was to determine the time to, and risk factors for, triple-class virological failure (TCVF) across age groups for children and adolescents with perinatally acquired HIV infection and older adolescents and adults with heterosexually acquired HIV infection. METHODS: We analysed individual patient data from cohorts in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). A total of 5972 participants starting antiretroviral therapy (ART) from 1998, aged < 20 years at the start of ART for those with perinatal infection and 15-29 years for those with heterosexual infection, with ART containing at least two nucleoside reverse transcriptase inhibitors (NRTIs) and a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (bPI), were followed from ART initiation until the most recent viral load (VL) measurement. Virological failure of a drug was defined as VL > 500 HIV-1 RNA copies/mL despite ≥ 4 months of use. TCVF was defined as cumulative failure of two NRTIs, an NNRTI and a bPI. RESULTS: The median number of weeks between diagnosis and the start of ART was higher in participants with perinatal HIV infection compared with participants with heterosexually acquired HIV infection overall [17 (interquartile range (IQR) 4-111) vs. 8 (IQR 2-38) weeks, respectively], and highest in perinatally infected participants aged 10-14 years [49 (IQR 9-267) weeks]. The cumulative proportion with TCVF 5 years after starting ART was 9.6% [95% confidence interval (CI) 7.0-12.3%] in participants with perinatally acquired infection and 4.7% (95% CI 3.9-5.5%) in participants with heterosexually acquired infection, and highest in perinatally infected participants aged 10-14 years when starting ART (27.7%; 95% CI 13.2-42.1%). Across all participants, significant predictors of TCVF were those with perinatal HIV aged 10-14 years, African origin, pre-ART AIDS, NNRTI-based initial regimens, higher pre-ART viral load and lower pre-ART CD4. CONCLUSIONS: The results suggest a beneficial effect of starting ART before adolescence, and starting young people on boosted PIs, to maximize treatment response during this transitional stage of development.

Longitudinal analysis of the 90K glycoprotein in the Italian HIV-seroconversion study: temporal trend and predictability of the maturity of HIV infection.

OBJECTIVES: To evaluate the level of 90K as a predictor of AIDS; to describe 90K levels over time after HIV serconversion; and to evaluate the 90K level as a marker of the maturity of infection. DESIGN: Prospective incident cohort of HIV-infected individuals with documented dates of seroconversion. METHODS: Cox models were applied to estimate the crude and adjusted relative hazards (RH) of AIDS by level of 90K. Regression models were applied to describe the temporal trend and the correlates of the level of 90K over time after HIV-seroconversion. Logistic models were applied to evaluate the probability of a sample of 90K having been taken within a certain time period after HIV-seroconversion. RESULTS: The study population consisted of 150 participants of the Italian Seroconversion Study. A total of 429 measurements of 90K were taken. Both early and later measurements of 90K were highly predictive of AIDS, also when adjusting for CD4 lymphocyte count and HIV load. The 90K level (U/ml) increased by 10% annually (95% CI: 7%-13%); the increase over time was linear. IDUs had higher 90K levels than heterosexuals and homosexuals over the course of HIV disease. High 90K levels were highly predictive of distant seroconversions (age-adjusted probability, 74%), whereas were poorly predictive of recent seroconversions (age-adjusted probability, 5%); the results were similar for the predictability of CD4 lymphocyte count. CONCLUSIONS: The level of 90K is a useful prognostic tool for clinical purposes. As a marker of the maturity of infection, 90K is similar to the CD4 lymphocyte count, with the advantage of being able to use serum instead of fresh whole blood. It has a good capacity to identify distant infections.

Time to discontinuation of the first highly active antiretroviral therapy regimen: a comparison between protease inhibitor- and non-nucleoside reverse transcriptase inhibitor-containing regimens.

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.

Incidence of invasive cervical cancer in a cohort of HIV-seropositive women before and after the introduction of highly active antiretroviral therapy.

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.

Incidence of Kaposi's sarcoma and HHV-8 seroprevalence among homosexual men with known dates of HIV seroconversion. Italian Seroconversion Study.

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.

Cancer risk among men with, or at risk of, HIV infection in southern Europe.

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.

Does HHV-8 have a protective role on the development of HIV encephalopathy? Italian HIV-Seroconversion Study.

OBJECTIVE: To evaluate risk factors for HIV encephalopathy and whether Kaposi's sarcoma (KS) and coinfection with human herpesvirus 8 (HHV-8) protect against this disease in a cohort of HIV seroconverters. METHODS: Individuals with known dates of HIV seroconversion belonging to different HIV exposure categories (intravenous drug users, homosexual men, heterosexual contacts) were recruited by 17 clinical centers throughout Italy. Antibodies to HHV-8 lytic antigens were detected in a subgroup of participants using an immunofluorescence assay. Risk factors for HIV encephalopathy were evaluated using Cox proportional models. The association between KS or HHV-8 infection and HIV encephalopathy was evaluated using standard statistical techniques. RESULTS: During the study period, 485 of the 1,520 participants developed acquired immunodeficiency syndrome, 38 of whom developed HIV encephalopathy. HHV-8 serologic status was determined for 390 participants. Male gender, injecting drug use, and low CD4 T-cell count were associated with HIV encephalopathy; none of the 63 participants with KS developed this disease. The risk of HIV encephalopathy did not differ significantly by HHV-8 serologic status. CONCLUSIONS: HIV encephalopathy was found to be associated with male gender and intravenous drug use. The risk increased at lower CD4 T-cell counts. Although HIV encephalopathy occurred less frequently in patients with KS, no association with HHV-8 infection was found.

Temporal changes in the rate of progression to death among Italians with known date of HIV seroconversion: estimates of the population effect of treatment. Italian HIV Seroconversion Study (ISS).

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.

Human herpesvirus 8 seropositivity and risk of Kaposi's sarcoma and other acquired immunodeficiency syndrome-related diseases.

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.

Longitudinal human immunodeficiency virus type 1 load in the italian seroconversion study: correlates and temporal trends of virus load.

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.

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.

Serum IgG antibodies to human herpesvirus-6 (HHV-6) do not predict the progression of HIV disease to AIDS. Italian Seroconversion Study group.

OBJECTIVES: To evaluate if different levels of human herpesvirus 6 (HHV-6) antibodies can predict HIV disease progression. DESIGN: Longitudinal study of individuals with a documented date of HIV seroconversion. SETTING: Clinical centers located throughout Italy. PATIENTS: Individuals who serconverted for HIV between 1983 and 1995 in Italy. METHODS: Sera were tested for IgG antibodies to HHV-6 using a commercial enzyme immunoassay. A serum sample with an optical density (OD) > or =242 (i.e. the mean value of 10 negative controls +4x standard deviation) was considered as HHV-6 positive; the progression of HIV disease was evaluated estimating the relative hazards (RH) of AIDS (by Cox models) for individuals with higher levels vs. lower levels of HHV-6 antibodies or considering levels of antibodies based on 10% increase of the distribution (deciles). Rates of CD4 decline fitting linear regression were also estimated. RESULTS: A total of 381 persons were followed for a median time of 4 years (range: 0.15-9 years) following the date of collection of the serum sample. The median OD value of HHV-6 antibodies was 306, with an interquartile range of 241-440 and a range of 48-2330. A slight inverse correlation was found between HHV-6 antibody levels and age of the individual at the time of serum collection (Spearman rank correlation coefficient, -0.16; p = 0.0013). No association was found between HHV-6 and CD4 level or between HHV-6 and CD8 level at the date of serum collection. The unadjusted RH of progression to AIDS was 0.63 (95% CI: 0.42-0.96) for HHV-6 positive individuals vs. HHV-6 negative; when adjusting for possible confounders (CD4, age, pre-AIDS HIV-related pathologies at the date of sera collection, and previous anti-herpes treatment), the RH of AIDS increased to 0.80 (95% CI: 0.51-1.23). No particular association with HIV disease progression was found when using the deciles of the distribution of HHV-6 antibodies. The median CD4 cell loss was 5.0x10(6) cells/l per month among HHV-6 positive individuals and 5.7x10(6) cells/l per month among the others. CONCLUSIONS: The presence of high levels of HHV-6 antibodies does not seem to predict the clinical or immunologic progression of HIV disease.

Frequency and determinants of use of antiretroviral and prophylactic therapies against Pneumocystis carinii Pneumonia (PCP) before AIDS diagnosis in Italy.

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.

How many HIV-infected individuals may be defined as long-term nonprogressors? A report from the Italian Seroconversion Study. Italian Seroconversion Study Group (ISS)

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.

Antiretroviral treatment and progression to AIDS in HIV seroconverters from different risk groups. HIV Italian Seroconversion Study.

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.