After the introduction of highly active antiretroviral therapy (HAART) in 1996, several studies conducted in HIV seroconverter cohorts showed improvements in both survival and progression to AIDS [1–4]. Approximately a 25% reduction in the hazard of AIDS and a 40% reduction in survival were observed in the late 1990s [1–4]. However, there is less evidence about the long-term sustainability of these improvements [5,6]. In our previous study in the Spanish seroconverter cohort GEMES , we showed a clear effectiveness of HAART after 1998 and 1999. The aim of this paper is to explore the evolution of HAART effectiveness from 1999 to 2003.
Data from 1129 individuals with well-documented HIV seroconversion dates included in GEMES, the Spanish Multicenter Study Group of Seroconverters, were analysed. A seroconverter was defined as an individual who had an HIV-negative test within 3 years from the first HIV-positive test. Seroconversion was estimated as the mid-point between those tests. Current analyses have used data from four cohorts that have been described elsewhere . Follow-up was updated yearly at the recruiting centres and referral hospitals. Cross-checks with local or national AIDS and mortality registers were performed. The seroconversion dates run from 1983 up to the end of 2003 (median 1993.3). A total of 70% were exposed to HIV through intravenous drug users (IDU), 24% through sex between men, and 4% through sex between men and women; 21% were women. The median age at seroconversion was 25.9 (interquartile range 22.3–30.0).
Progression to AIDS and death from HIV seroconversion was analysed, allowing for late entry to the date of first HIV-positive test. Individuals who were AIDS-free and alive by January 2004 were censored. Individuals with pre-AIDS mortality were censored as AIDS-free at the moment of death for time to AIDS analyses. To analyse the effectiveness of HAART at the population level, the calendar year at risk was divided into different periods. The chosen reference period, 1996–1997, represented the introduction of HAART, 1998–1999 represented early HAART, and 2000–2003 the post-HAART era. The calendar period was modelled as a time-dependent so each individual contributed to the analyses with as many registers of time periods he/she has been at risk. The cumulative risk of AIDS and death was calculated by extended Kaplan–Meier estimates allowing for late entry. Cox proportional hazard models were use to examine the risk of AIDS and death in the previously described calendar periods adjusted for age at seroconversion, sex and transmission category and stratified by cohort. Analyses were performed in STATA 8.0, using robust methods to estimate confidence intervals.
Of 1129 individuals included in the analyses 201 (17.8%) died and 284 developed an AIDS-defining condition. The uptake of HAART by cohort members increased over time from 15% at the end of 1997 to approximately 50% at the end of 2003. The risk of AIDS decreased by calendar period after HAART (Fig. 1a). In 1998–1999 a hazard ratio (HR) of 0.63 [95% confidence interval (CI) 0.42–0.94] was observed. For 2000–2003, this hazard ratio diminished to 0.46 (95% CI 0.30–0.72) although differences between both periods were not statistically significant. IDU had a faster progression to AIDS than men who have sex with men; HR 2.28 (95% CI 1.47–3.54).
Similar results were observed for time to death (Fig. 1b). The initial reduction observed in 1998–1999 (HR 0.55; 95% CI 0.36–0.87) increased by 2000–2003 (HR 0.40; 95% CI 0.25–0.65), although again differences between periods were not statistically significant. Also IDU had faster progression to death; HR 2.17 (95% CI 1.22–3.87) than men who have sex with men.
This study confirms the sustainability of the population effectiveness of HAART in reducing the risk of AIDS and death in Spain, starting at 1998. This effect seems to be more pronounced after 2000, 3 years after the introduction of HAART, although the differences were not statistically significant. Similar results have been found elsewere [5,6], so has the poorer outcome observed in IDU. From the very beginning, HAART regimes have been free and available for all HIV patients in Spain. Despite the continued reduction in AIDS and death after the introduction of HAART, the differences detected in IDU could be explained by poorer access to treatment, worse adherence, undesirable delays to initiate HAART, and non-AIDS-related competing mortality such as hepatitis C virus co-infection and drug-related deaths. These results highlight the importance of monitoring HAART effectiveness over time, and the need to improve current public health strategies directed to IDU to reduce inequity in HIV infection care.
Sponsorship: This work was financed through grants from FIPSE (Fundación para la Investigación y la Prevención del SIDA en España) integrated by the Spanish Ministry of Health, Abbott Laboratories, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Merck Sharp and Dohme and Roche), (FIPSE 3023/99), FIS (Fondo de Investigación Sanitaria) (FIS 00/294, 02/0639).
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Coordinating Centre: Departamento de Salud Pública Universidad Miguel Hernández (UMH): I. Hernández Aguado, J. del Amo
Data Management Centre: Escuela Valenciana de Estudios para la Salud (EVES). Dpto Salud Pública Universidad Alicante: S. Pérez-Hoyos, I. Ferreros
Cohorte de los CIPS de la Comunidad Valenciana. Departamento de Salud Pública UMH. EVES: M. García de la Hera, I. Hurtado
Cohorte del Hospital Germans Trias i Pujol en Badalona: R. Muga, A. Sanvicens, B. Clotet, J. Tor
Cohorte de Madrid-Sandoval: J. del Romero, P. Raposo, C. Rodríguez, S. García, V. Soriano, y el Grupo de Seroconvertores de la Comunidad de Madrid
Cohorte de los Centros de Atención y Prevención de SIDA de Barcelona. Institut de Medicina i Salut de Barcelona. Cohorte IMSP: P. García de Olalla, J. Cayla, E. Masdeu, L. Caballé
Cohorte de las Prisiones de Cataluña: R. Guerrero, A. Marco
Cohorte de hemofílicos del Hospital La Paz: M. Quintana
Cohortes de hemofílicos del Hospital Vall d'Hebron: I. Ruiz
Cohortes de hemofílicos del Hospital Virgen del Rocío deSevilla: R. Pérez, J.M. Cisneros
Registro Nacional de SIDA: J. Castilla