Roberto Muga

When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study.

BACKGROUND Most clinical guidelines recommend that AIDS-free, HIV-infected persons with CD4 cell counts below 0.350 × 10(9) cells/L initiate combined antiretroviral therapy (cART), but the optimal CD4 cell count at which cART should be initiated remains a matter of debate. OBJECTIVE To identify the optimal CD4 cell count at which cART should be initiated. DESIGN Prospective observational data from the HIV-CAUSAL Collaboration and dynamic marginal structural models were used to compare cART initiation strategies for CD4 thresholds between 0.200 and 0.500 × 10(9) cells/L. SETTING HIV clinics in Europe and the Veterans Health Administration system in the United States. PATIENTS 20, 971 HIV-infected, therapy-naive persons with baseline CD4 cell counts at or above 0.500 × 10(9) cells/L and no previous AIDS-defining illnesses, of whom 8392 had a CD4 cell count that decreased into the range of 0.200 to 0.499 × 10(9) cells/L and were included in the analysis. MEASUREMENTS Hazard ratios and survival proportions for all-cause mortality and a combined end point of AIDS-defining illness or death. RESULTS Compared with initiating cART at the CD4 cell count threshold of 0.500 × 10(9) cells/L, the mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold. The corresponding hazard ratios were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively, for the combined end point of AIDS-defining illness or death. LIMITATIONS CD4 cell count at cART initiation was not randomized. Residual confounding may exist. CONCLUSION Initiation of cART at a threshold CD4 count of 0.500 × 10(9) cells/L increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 0.300 and 0.500 × 10(9) cells/L.

Effectiveness of highly active antiretroviral therapy in spanish cohorts of HIV seroconverters: differences by transmission category

Objective: To evaluate the population effectiveness of highly active antiretroviral therapy (HAART) in HIV progression and determine the heterogeneity of the effect of HAART in GEMES (Spanish multicenter study of seroconverters). Design: Multicenter cohort study. Methods: Data from 1091 persons with well-documented HIV seroconversion dates from 1980s to January 2000 were analysed. Risk of AIDS and death in subjects with same duration of HIV infection were compared in different calendar periods; before 1992, 1992–1995 (reference), 1996–1997, 1998 and 1999 with Kaplan–Meier methods and Cox proportional hazards models, allowing for late entry, fitting calendar period as time-dependent covariate and adjusting for transmission category, age and gender. Results: Statistically significant reductions in the risk of AIDS were first observed in 1998 [hazard ratio (HR), 0.59; 95% confidence interval (CI), 0.35–1.01] becoming more pronounced in 1999 (HR, 0.45; 95% CI, 0.24–0.84). Reduction in the risk of death was seen in 1997, though only reached borderline significance in 1999 (HR, 0.53; 95% CI, 0.26–1.07). Progression to AIDS and death was slower in women (HR, 0.68; 95% CI, 0.46–0.99 and HR, 0.53; 95% CI, 0.33–0.87, respectively). Compared with men who have sex with men (MSM), intravenous drug users (IDU) had lower reductions in the risk of AIDS and death. Conclusions: Reductions in incidence of AIDS and death in GEMES are seen after 1998 and 1999, respectively, compared with 1992–1995, being more pronounced in MSM compared with IDU, the commonest category in Spain.

Gender Differences in HIV Progression to AIDS and Death in Industrialized Countries: Slower Disease Progression Following HIV Seroconversion in Women

To evaluate sex differences in human immunodeficiency virus (HIV) disease progression before (pre-1997) and after (1997-2006) introduction of highly active antiretroviral therapy, the authors used data from a collaboration of 23 HIV seroconverter cohort studies from Europe, Australia, and Canada restricted to the 6,923 seroconverters infected through injecting drug use and sex between men and women. Within a competing risk framework, they used Cox proportional hazards models allowing for late entry to evaluate sex differences in time from HIV seroconversion to death, to acquired immunodeficiency syndrome (AIDS), and to each first AIDS-defining disease and death without AIDS. While no significant sex differences were found before 1997, from 1997 onward, women had a lower risk of AIDS (adjusted cumulative relative risk (aCRR) = 0.76, 95% confidence interval (CI): 0.63, 0.90) and death (adjusted hazard ratio = 0.68, 95% CI: 0.56, 0.82) than men did. Compared with men, women also had lower risks of AIDS dementia complex (aCRR = 0.23, 95% CI: 0.07, 0.74), tuberculosis (aCRR = 0.60, 95% CI: 0.39, 0.92), Kaposis sarcoma (aCRR = 0.27, 95% CI: 0.07, 0.99), lymphomas (aCRR = 0.47, 95% CI: 0.23, 0.96), and death without AIDS (aCRR = 0.74, 95% CI: 0.56, 0.98). Sex differences in HIV disease progression have become larger and statistically significant in the era of highly active antiretroviral therapy, supporting a stronger impact of health interventions among women.

Prevalence and distribution of Hhv-8 in different subpopulations, with and without Hiv infection, in Spain

ObjectiveTo estimate the seroprevalence of HHV-8 in several Spanish subpopulations with different risk levels of acquiring HIV-1 infection and from different geographical regions. DesignCross-sectional seroprevalence study. MethodsA total of 1699 serum samples from blood donors (613), children under the age of 12 years (100), injecting drug users (IDU) (382), heterosexuals attending a sexually transmitted disease (STD) clinic (273) and homosexual men attending a STD clinic or a HIV-based hospital unit (331) were analysed for anti-HHV-8 antibodies. The presence of antibodies against HHV-8 was tested with an indirect immunofluorescence assay (IFA). A subsample of HHV-8-positive samples was also tested for antibody titre against HHV-8. ResultsThe overall seroprevalence of antibodies against HHV-8 for the blood donor population was 6.5% (7.0% in Andalusia, 8.0% in Catalonia and 4.5% in the Basque Country). None of the children tested positive for HHV-8. The HHV-8 prevalence was 86.7% in HIV-positive homosexual men and 28.0% in HIV-negative homosexual men (P < 0.001). Of heterosexual men attending STD clinics, 17.2% tested positive for HHV-8; 11.5% of IDU tested positive for HHV-8. HHV-8 antibody titres by groups parallel the distribution of HHV-8 prevalence. No association between HHV-8 antibody titres and CD4 cell count or HIV viral load was identified. ConclusionsThe HHV-8 prevalence among blood donors in Spain is higher than in Northern Europe and the USA, but is similar to that in Northern Italy. The distribution of HHV-8 is compatible with a sexually transmitted agent. The distribution of HHV-8 correlates with that of Kaposis sarcoma but factors other than HHV-8 seem to explain the Kaposi sarcoma distribution.

Effect of HCV Infection on Cause-Specific Mortality After HIV Seroconversion, Before and After 1997

BACKGROUND & AIMS Individuals with human immunodeficiency virus (HIV) infection frequently also are infected with hepatitis C virus (HCV) (co-infection), but little is known about its effects on the progression of HIV-associated disease. We aimed to determine the effects of co-infection on mortality from HIV and/or acquired immune deficiency syndrome (AIDS), and hepatitis or liver disease, adjusting for the duration of HIV infection. METHODS We analyzed data from the 16 cohorts of the Concerted Action on Seroconversion to AIDS and Death in Europe (CASCADE) collaboration, which included information on HCV infection and cause of death. A competing-risks proportional subdistribution hazards model was used to evaluate the effect of HCV infection on the following causes of death: HIV- and/or AIDS-related, hepatitis- or liver-related, natural, and non-natural. RESULTS Of 9164 individuals with HIV infection and a known date of seroconversion, 2015 (22.0%) also were infected with HCV. Of 718 deaths, 395 (55.0%) were caused by HIV infection and/or AIDS, and 39 (5.4%) were caused by hepatitis or liver-related disease. Among individuals infected with only HIV or with co-infection, the mortality from HIV infection and/or AIDS-related causes and hepatitis or liver disease decreased significantly after 1997, when combination antiretroviral therapy became widely available. However, after 1997, HIV and/or AIDS-related mortality was higher among co-infected individuals than those with only HIV infection in each risk group: injection drug use (adjusted hazard ratio [aHR], 2.43; 95% confidence interval [CI], 1.14-5.20), sex between men and women or hemophilia (aHR, 3.43; 95% CI, 1.70-6.93), and sex between men (aHR, 3.11; 95% CI, 1.49-6.48). Compared with individuals infected with only HIV, co-infected individuals had a higher risk of death from hepatitis or liver disease. CONCLUSIONS Based on analysis of data from the CASCADE collaboration, since 1997, when combination antiretroviral therapy became widely available, individuals co-infected with HIV and HCV have had a higher risk of death from HIV and/or AIDS, and from hepatitis or liver disease, than patients infected with only HIV. It is necessary to evaluate the effects of HCV therapy on HIV progression.

Significant reductions of HIV prevalence but not of hepatitis C virus infections in injection drug users from metropolitan Barcelona: 1987–2001

OBJECTIVES To characterize trends from 1987 to 2001 in the prevalence of HIV and HCV infections among 2219 injection drug users (IDUs) starting treatment for substance abuse in two large hospitals in metropolitan Barcelona. METHODS The study population comprised IDUs with HIV tests completed from 1987 to 2001 and admitted for detoxification. Testing for HCV started in 1991 (n=1132). Characterization of temporal trends was carried out using logistic regression methods. Stratification was used to describe possible heterogeneities of the temporal trends. RESULTS The overall prevalence of HIV, HCV, and HBV (HBsAg+) was 55%, 88%, and 7%, respectively. Adjusted by duration of IDU, sex, and age at initiation, the prevalence of HIV infection declined significantly (p<0.001) from 1989 to 2004. The substantially higher prevalence of HCV showed a decline (p=0.065) of lesser magnitude. The decline of HIV infection was consistently observed among those with duration of IDU of less than 10 years. In turn, the decline of HCV was restricted to those with short duration of IDU (<4 years) because the prevalence of HCV infection was close to 100% for durations longer than 4 years in all calendar periods. CONCLUSIONS Preventive interventions and treatment for substance abuse might have contributed to the waning of the HIV epidemic in Spain. However, the extremely high levels of HCV infection and the underlying prevalence of HIV might lead to a large health burden of liver disease.

Changes in the incidence of tuberculosis in a cohort of HIV-seroconverters before and after the introduction of HAART.

Objective:To analyse incidence and determinants of tuberculosis in HIV-seroconverters before and after the introduction of HAART. Methods:Data from a multicenter cohort study of 2238 HIV-seroconverters between the 1980s and 2004 were analysed and censored by December 2004. Calendar year at risk intervals were pre-1992, 1992–1996 and 1997–2004. Incident tuberculosis was calculated as cases per 1000 person-years (p-y). Survival analyses using Kaplan–Meier and multivariate Cox regression allowing for late-entry were used. Proportional hazards assumptions were checked with tests based on Schoenfeld residuals. Results:Overall, 173 (7.7%) patients developed tuberculosis over 23 698 p-y at a rate of 7.3 cases per 1000 p-y [95% confidence interval (CI), 6.3–8.5]. Incident tuberculosis was higher in intravenous drug-users (IDUs), 12.3 per 1000 p-y compared with persons infected sexually, 3.8 per 1000 p-y (P < 0.001), and persons with clotting disorders (PCD), 2.7 per 1000 p-y (P < 0.001). A decreasing tuberculosis incidence trend was observed from 1995 in all categories. Highest tuberculosis rates, 44 per 1000 p-y, were observed prior to 1997 in IDUs infected with HIV for 11 years. In multivariable analyses women were less likely to develop tuberculosis [relative hazard (RH), 0.62; 95% CI, 0.41–0.96; P < 0.05) and IDUs were more likely to develop tuberculosis (RH, 3.0; 95% CI, 1.72–5.26, P < 0.001). In the HAART era, the hazard of developing tuberculosis was 70% lower (RH, 0.31; 95% CI, 0.17–0.54; P < 0.001). Before 1997, the risk of tuberculosis increased with time since HIV seroconversion, whereas it remained nearly constant in the HAART era. Conclusions:Since the mid-1990s important decreases in tuberculosis have been observed in HIV-seroconverters that probably reflect the impact of both HAART and tuberculosis control programmes.

Impact of hepatitis C infection on long-term mortality of injecting drug users from 1990 to 2002: differences before and after HAART.

Objective:To assess the impact of HIV and hepatitis C virus (HCV) infection on long-term mortality in injecting drug users (IDU). Design:Community-based prospective cohort study. Methods:Mortality data from follow-up in clinical sites and the Mortality Registry by December 2002 were collected for 3247 IDU who attended three centres for voluntary counselling and testing for HIV/AIDS, HCV and hepatitis B virus (HBV) in 1990–1996. Mortality rates by Poisson regression were adjusting for age, sex, duration of drug use, education, HBV and calendar period (1990–1997 and 1998–2002). Results:Overall, 11.2% were HIV/HCV negative, 43.7% positive only for HCV and 45.1% positive for both. During 26 772 person-years of follow-up, 585 deaths were detected (2.19/100 person-years). Before 1997, HIV/HCV-positive subjects had a five-fold increase in risk of death [relative risk (RR), 5.4; 95% confidence interval (CI), 2.5–11.4] compared with those negative for both; after 1997, a three-fold increase was observed (RR, 2.7; 95% CI, 1.7–4.2). Being HCV positive/HIV negative was not associated with an increase in the risk of death either before (RR, 1.3; 95% CI, 0.6–2.9) or after (RR, 1.2; 95% CI, 0.8–1.9) 1997 compared with HCV/HIV negative. While increases in mortality were seen in those HCV/HIV negative (RR, 1.6; 95% CI, 0.7–3.7) and those only positive for HCV (RR, 1.5; 95% CI, 1.0–2.1), a 20% reduction among coinfected IDUs was observed after 1997 (interaction P = 0.033). Conclusions:HCV/HIV coinfection has had a large impact on mortality in IDU. After 1997, mortality increased in HIV negative/HCV positive subjects and decreased in HIV positive/HCV positive.

Gender differences in progression to AIDS and death from HIV seroconversion in a cohort of injecting dug users from 1986 to 2001

Background: Although the consensus is that gender does not influence HIV progression, its relevance may depend on the setting. Aim: To study gender differences in HIV progression to AIDS and death from 1986 to 2001 in a cohort of injecting drug user (IDU) seroconverters in Spain. Methods: Risk of AIDS and death in persons infected for the same length of time were compared through Kaplan-Meier, allowing for late entry, and Cox regression adjusting for gender, age, and calendar period (before 1992, 1992–1995, 1996–1998, 1999–2001) fitted as time dependent covariates. Results: Of 929 IDU, 24.7% were women. Median seroconversion year was 1993.3 for men and women. 44% of women and 34% of men received antiretroviral therapy. Risk of AIDS was lower in women in univariate (hazard ratio (HR) 0.72; 95%CI:0.51 to 1.01) and multivariate analyses (HR 0.73 95%CI:0.52 to 1.03). A 46% reduction in risk of AIDS for period 1999–2001 compared with 1992–1995 was seen in both men and women (HR: 0.56 (95%CI:0.36 to 0.87). As for mortality, women’s risk of death was lower univariately (HR 0.67 95%CI:0.45 to 0.99) although compared with 1992–95, men experienced a 34% reduction in mortality during 1999–2001 (HR 0.66 95%CI:0.40 to 1.01), which was not statistically significant in women. Conclusions: HIV progression was lower in female IDU before and after 1997 and their uptake of antiretroviral therapy was higher than male IDU. The inability to detect a reduction in mortality for women during 1999–2001 is probably attributable to lack of power. Differences in severity of addiction, drug using patterns, and competing causes of death may explain these findings.

Survival of HIV-Infected Injection Drug Users (IDUs) in the Highly Active Antiretroviral Therapy Era, Relative to Sex- and Age-Specific Survival of HIV-Uninfected IDUs

BACKGROUND In the era of highly active antiretroviral therapy (HAART), it remains unclear whether human immunodeficiency virus (HIV)-infected injection drug users (IDUs) have durations of survival similar to those for comparable HIV-uninfected IDUs. The goal of this study was to compare survival durations of HIV-infected and HIV-uninfected IDUs for the period 1987-2004.Methods. Demographic data, drug use characteristics, and biological markers were obtained at the time of admission to a substance abuse treatment program. The outcome of interest was the duration of survival after admission, and the primary exposure was HIV infection. Vital status was ascertained by means of the mortality register by the end of 2004. Three calendar periods, which were defined on the basis of use of specific therapies, were considered: 1987-1991 (the antiretroviral monotherapy era), 1992-1996 (the dual combination therapy era and the era when methadone was introduced in Spain), and 1997-2004 (the era of HAART and of established methadone programs). We used Cox regression methods allowing for late entries to handle the contribution of persons who survived a given period and entered the following period with nonzero time. We compared HIV-uninfected and HIV-infected IDUs with adjustments for age, sex, and duration of follow-up after admission. RESULTS A total of 1209 IDUs were admitted to the hospital during the period from January 1987 through December 2004, and 1181 were eligible for the study. The majority (81.3%) of patients were men. The mean age (+/- standard deviation) at admission was 27.8+/-5.6 years, and the mean duration of injection drug use (+/- standard deviation) was 7.6+/-5.0 years. The prevalences of HIV and hepatitis C virus infections were 59.0% and 92.3%, respectively, and the total duration of follow-up was 10.116 person-years. Although survival duration for HIV-uninfected IDUs in 1997-2004 was similar to the duration in earlier periods, the duration for HIV-infected IDUs improved significantly since 1997 (P<.01). Furthermore, among patients admitted in the last period, the survival durations for HIV-uninfected and HIV-infected IDUs was virtually the same (relative hazard, 0.89; 95% confidence interval, 0.44-1.81). CONCLUSIONS The duration of survival of HIV-infected IDUs has improved substantially since 1997, reaching rates similar to the rates for HIV-seronegative IDUs who accessed the health care system in the era of HAART.