Changes in the Risk of Death After HIV Seroconversion Compared With Mortality in the General Population
Krishnan Bhaskaran, MSc; Osamah Hamouda, MD; Mette Sannes, MLabTech;Faroudy Boufassa, MD; Anne M. Johnson, MD; Paul C. Lambert, PhD; Kholoud Porter, PhD; for the CASCADE Collaboration
JAMA. July 2, 2008;300(1):51-59.
“…..To our knowledge, no study to date has made a comparison of mortality among HIV-infected and uninfected individuals adjusted for duration of HIV infection, and our results provide estimates, hitherto unavailable, of the cumulative excess probability of death as duration of HIV infection increases…..we found that by 2004-2006, the risk of death in the first 5 years following seroconversion was similar to that of the generalpopulation, with the excess probability of death becoming apparent only later in the course of infection, particularly evident in those infected for 10 years or more….Our long-term cumulative mortality estimates for 2004-2006 include data from individuals infected in the mid-1990s or earlier who may have started antiretroviral treatment later in the course of infection and with regimensinferior to those currently available; thus, such estimates may be pessimistic in terms of the long-term outlook for more recently infected individuals…..Indeed, we found a lower uptake of HAART among those exposed through IDU compared with other groups, while lower therapy adherence among such individuals has been described in the literature…..Although we matched by age, sex, calendar time, and country, it is likely that HIV-infected individuals in our study differ from the general population in other ways. Rates of smoking have been shown to be high among some HIV-infected populations30; other risk behaviors, socioeconomic factors, and race/ethnicity are also likely to differ among HIV-infected persons. Those exposed through IDU in particular are likely to be at higher risk of mortality than the general population regardless of HIV infection, and we have presented our estimates of the cumulative excess mortality proportion excluding this group. Nonetheless, our results are interpretable as estimates of the excess mortality among HIV-infected individuals, who may differ from a general population not only in being infected with HIV but also in other factors……A second limitation is that HIV seroconverters are not representative of the total HIV-infected population; mortality estimates derived from seroconverters, by definition diagnosed and monitored from an early stage, are likely to be optimistic compared with the experience of the wider HIV-infected population….
……We found that the gap in mortality rates between HIV-infected individuals in our study and the general population narrowed in every calendar period from 1996 onward. Considering the first years following the widespread introduction of HAART, we haveestimated an 88% reduction in excess mortality in 2000-2001 compared with pre-1996, corresponding closely to the 87% reduction in the standardized mortality ratio in 1997-2001 compared with pre-1996, as reported by the Swiss HIV cohort.7 Our more recentdata show that reductions have continued to 2004-2006, with excess mortality in this period 94% lower than pre-1996 levels. Corresponding to these reductions, the uptake of HAART increased, and though this leveled off after 2001, there followed an increasing use of NNRTI-based HAART as the first-line treatment regimen and a substantial increase in the boosting of PI-based regimens……Despite the major reductions in excess mortality, a significantly increased risk of death remained among individuals of all ages in 2004-2006…..we aimed to evaluate changes over calendar time in the excess mortality of HIV-infected individuals comparedwith expected mortality in the general uninfected population, adjusting for duration of HIV infection. We further aimed to assess changes over calendar time in the effects of prognostic factors and in the overall and excess probability of death at various stages of HIV infection. We also report corresponding changes over time in the uptake and use of HAART in our population…..excess mortality decreased dramatically from 1996 onward. By 2004-2006, there was no evidence of any excess mortality to 5 years from seroconversion in any age group. However, in the longer term, some excess mortality was still evident, with the cumulative excess probability of death in the first 10 years from seroconversion estimated to be 4.8% (95% CI, 2.5%-8.6%) in those aged 15 to 24 years and 4.3% (95% CI, 0.0%-10.5%) in those 45 years or older at seroconversion….The median time from HIV seroconversion to starting HAART was 1.6 (IQR, 0.7-3.5) years in 1996-1997 and 1.4 (IQR, 0.6-3.4), 1.8 (IQR, 0.7-5.6), 2.4 (IQR, 0.8-6.7), and 2.2 (IQR, 1.0-4.8) years in 1998-1999, 2000-2001, 2002-2003, and 2004-2006, respectively…”
Context Mortality among human immunodeficiency virus (HIV)–infected individuals has decreased dramatically in countries with good access to treatment and may now be close to mortality in the general uninfected population.
Objective To evaluate changes in the mortality gap between HIV-infected individuals and the general uninfected population.
Design, Setting, and Population Mortality following HIV seroconversion in a large multinational collaboration of HIV seroconverter cohorts (CASCADE) was compared with expected mortality, calculated by applying general population death rates matched on demographic factors. A Poisson-based model adjusted for duration of infection was constructed to assess changes over calendar time in the excess mortality among HIV-infected individuals. Data pooled in September 2007 were analyzed in March 2008, covering years at risk 1981-2006.
Main Outcome Measure Excess mortality among HIV-infected individuals compared with that of the general uninfected population.
Results Of 16 534 individuals with median duration of follow-up of 6.3 years (range, 1 day to 23.8 years), 2571 died, compared with 235 deaths expected in an equivalent general population cohort. The excess mortality rate (per 1000 person-years) decreased from 40.8 (95% confidence interval [CI], 38.5-43.0; 1275.9 excess deaths in 31 302 person-years) before the introduction of highly active antiretroviral therapy (pre-1996)to 6.1 (95% CI, 4.8-7.4; 89.6 excess deaths in 14 703 person-years) in 2004-2006 (adjusted excess hazard ratio, 0.05 [95% CI, 0.03-0.09] for 2004-2006 vs pre-1996). By 2004-2006, no excess mortality was observed in the first 5 years following HIV seroconversion among those infected sexually, though a cumulative excess probability of death remained over the longer term (4.8% [95% CI, 2.5%-8.6%] in the first 10 years among those aged 15-24 years).
Conclusions Mortality rates for HIV-infected persons have become much closer to general mortality rates since the introduction of highly active antiretroviral therapy. In industrialized countries, persons infected sexually with HIV now appear to experience mortality rates similar to those of the general population in the first 5 years following infection, though a mortality excess remains as duration of HIV infection lengthens.
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A number of studies have reported the dramatic decreases in mortality among individuals infected with human immunodeficiency virus (HIV) since the widespread introduction of highly active antiretroviral therapy (HAART) in industrialized countries.1-2 It is important to provide up-to-date and robust estimates of expected mortality as anti-HIV drugs and strategies continue to improve. Such estimates help policy makers and those planning health care to monitor the effectiveness of treatments at a population level and provide an indicator of the ongoing and likely future impact of HIV disease on health care needs.
With mortality among HIV-infected individuals decreasing to relatively low levels compared with the pre-HAART era and with patients living to older ages, it is also of increasing interest to assess how mortality rates of HIV-infected individuals compare with those of the general uninfected population, ie, the “excess mortality.”3Overall mortality of HIV-infected individuals is likely to be increasingly influenced by deaths that would haveoccurred regardless of HIV infection, and mortality in the general uninfected population provides a natural reference point for taking this into account. This concept has been used in studies of other diseases in which successfully treated patients frequently live for many years, such as Hodgkin disease4 and thyroid5 and other6cancers.
A few studies have compared HIV-infected and uninfected populations in industrialized countries, reporting reductions in the standardized mortality ratio in the early years of HAART availability7 and estimating a reduced life expectancy of 17 years for HIV-infected individuals compared with that of the uninfected population.8 Two further studies specifically considering those with a good initial response to treatment found an increased mortality risk, even in this subgroup.9-10
These studies have not been able to adjust for duration of HIV infection, which is a key factor influencing mortality risk and could confound other relationships. Using a large data set of individuals with well-estimated HIV seroconversion dates—thus avoiding biases that can occur when duration of infection is unknown11—we aimed to evaluate changes over calendar time in the excess mortality of HIV-infected individuals comparedwith expected mortality in the general uninfected population, adjusting for duration of HIV infection. We further aimed to assess changes over calendar time in the effects of prognostic factors and in the overall and excess probability of death at various stages of HIV infection. We also report corresponding changes over time in the uptake and use of HAART in our population.
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Data were used from CASCADE (Concerted Action on Seroconversion to AIDS and Death in Europe), which has been described elsewhere.12 It is currently a collaboration of 23 cohorts of individuals with well-estimated dates of HIV seroconversion from Europe (20 cohorts from Denmark , France , Germany , Greece , Italy , the Netherlands , Norway , Spain , Switzerland , and the United Kingdom ), Australia (2 cohorts), and Canada (1 cohort). All eligible individuals are recruited, both prospectively and retrospectively, to the constituent cohorts through the clinical centers where they receive their HIV care, and an enrollment date is recorded for each participant. Of the 23 cohorts, 3 regional and 6 national cohorts collect data on individuals from a number of HIV clinical centers across the region or country, through the abstraction of medical records for all participants from routine clinic visits. These data are recorded on clinic report forms and then entered into the individual cohort database. Data are then extracted according to an agreed-on standardized data exchange protocol and submitted to the CASCADE coordinating center (Medical Research Council Clinical Trials Unit, London, United Kingdom) on an annual basis,where they are pooled. The remaining 14 single-clinic cohorts abstract data directly from their clinic database according to the same standardized data exchange protocol and forward the data to the coordinating center. Enrollment averaged 317 individuals per year overall from 1985-1987 and increased to 801 per year over the 19-year period 1988-2006. Six cohorts included in the analysis had ceased recruitment of new seroconvertersin 1992, 1997 (2 cohorts), 2000, 2002, and 2004. These 6 cohorts make up 7.7% of data included in the analyses. A subgroup of participants represented by the UK cohort data presented herein were evaluated in a previous study estimating changes in survival over calendar time after HIV seroconversion in a UK setting.13
All cohorts received approval from their individual ethics review boards except for the Danish cohort, which received approval from the National Data Registry Surveillance Agency because Danish law allowed collection and pooling of anonymized clinical data with approval from this agency alone. Two ethics review boards deemed their cohort participants exempt from providing signed informed consent. Signed informed consent was obtained from all others. Approval was also given by all ethics review boards to pool anonymized data for analyses and dissemination.
Estimates of HIV seroconversion dates are accurate to within 18, 12, and 6 months for 100%, 87%, and 63% of individuals, respectively, and are based on documented evidence of seroconversion. In 95% of cases, this evidence comprised a documented negative HIV antibody test result, which must be dated fewer than 3 yearsbefore the first positive result, and seroconversion date is estimated as the midpoint between the last negative and first positive test results. For the remaining 5% of cases, alternative documented laboratory evidence of seroconversion is available (real-time polymerase chain reaction positivity in the absence of HIV antibodies, or antigen positivity with