Age at Time of Seroconversion Reported to be Key Prognostic Factor in Era Before HAART in Newly Published Study
In the April 1 2000 (volume 355; pages 1131-1137)
issue of the Lancet a study was published reported on the affect of age at
seroncenversion on survival and time to AIDS events. The study title is:
from HIV-1 seroconversion to AIDS and death before widespread use of
highly-active antiretroviral therapy: a collaborative re-analysis.
Authors: Collaborative Group on AIDS Incubation and
HIV Survival* including the CASCADE EU Concerted Action
findings of this study reported that following HIV seroconversion the incidence
of AIDS increased and survival time decreased with age. This study reported that
individuals who seroconverted at ages 25-34 progressed to AIDS in a median 9.8
years compared to individuals 65 or older who progressed to AIDS in a median 5.0
years. The rate of progression to AIDS is about double. Similar findings are
reported from this study on differences in survival time when comparing between
age groups. Individuals aged 25-34 survived a median of 10.9 years while
individuals 65 or older survived a median of 4.0 years. When looking at a middle
age group of 45-54 years of age, the survival in years was a median of 7.9 and
the time to AIDS was 7.7 years. A further breakdown on age groups is listed
below. The study group looked at a number of factors that might contribute to
progression to AIDS and death such as means of exposure to HIV (hemophilia, IVDU,
sex, etc). These factors were found to have at best a very small effect on
survival or the time to development of AIDS. In this study, age at
seroconversion was the most powerful predictor of the time to AIDS or death
(p<0.001). The authors of this study reported that the reduction in survival
that came with increasing age, that the study found, was not due to increase in
mortality that comes with aging.
Are The Implications Of These Findings??
the first questions that comes to my mind after reading this information is --what
is the effect of age in the era of HAART? Do the treatment guidelines need
to be re-addressed? Does the CD4 count and viral load prior to starting therapy
accurately reflect disease stage and considerations of when to begin therapy
regardless of age? Are there qualitative differences in CD4s based on age, that
may not be reflected in the absolute number of CD4s or in the CD4 percent?
treatment start earlier for individuals infected at older ages? Are the effects
of HAART so potent that they overcome the age effect? In other words, the age
effect may become virtually meaningless after HAART is used.
the status of the study has changed, the AIDS Clinical Trials Group (ACTG) is
planning a study to look at the effects of a HAART regimen (d4T+FTC+ABT-378/r)
on changes in CD4 between two different ages groups. The last study status I saw
was planning to compare individuals >50 years with those <30 years of age.
So, a study like this might uncover if the response to therapy differs between
older and younger individuals. The study might uncover that age-related factors
may affect the quantity or quality of the CD4 response from antiretroviral
following information include excerpts from the published article.
The natural history of HIV disease can only be accurately determined if the data at serocenversion for individuals is known. This study, which pooled data from 38 studies including 13,000 patients from 15 countries, provides data on the time it takes from HIV infection to AIDS to death in the era before potent antiretroviral therapy.
Reliable estimates of AIDS incubation period, survival time after HIV-1 seroconversion, and factors that influence them are essential to enable us to understand the natural history of HIV-1 disease and to plan health-care resources. Follow-up studies of HIV-1-infected individuals whose dates of sero-conversion can be estimated with reasonable accuracy have been the major source of information for these estimates to date.
already been learnt about the determinants of HIV-1 disease progression. Age at
seroconversion is recognised as a crucial factor, with younger age being
predictive of slower progression. Also, the route through which infection is
acquired might affect the rate of disease progression. However, differences
between cohort studies in their
and the range of ages at seroconversion and exposure group of their participants
have prevented a full understanding of such effects, leading to apparent
inconsistencies. Several specific questions remain unanswered. Does
age at seroconversion predict HIV-1 disease progression in all exposure
categories? Is the effect of age equally strong in the different exposure
categories? After controlling for age at seroconversion, does the mode through
which infection is acquired affect the rate of disease progression or mortality?
Is the effect of age at seroconversion quantitatively similar throughout the
whole period after seroconversion?
The authors are reporting on an international collaboration established to bring together data from all seroconverter cohorts in Europe, North America, and Australia. The main objective was to provide accurate estimates based on all available data of the time from HIV-1 seroconversion to AIDS and death for people infected at different ages, in different periods, and in different ways, while controlling for the effects of other factors and accounting for differences in methods where appropriate and possible. We report the analyses done to assess the effect of age at seroconversion and exposure category on HIV-1 progression before the advent of highly-active antiretroviral therapy. Additional information, including details of the methods of data collection and the effects of other covariates, will be given elsewhere.
of This Study
Methods 38 studies of HIV-1-infected individuals whose dates of seroconversion could be reliably estimated were included in the analysis. Individual data on 13,030 HIV-1-infected individuals from 15 countries were collated, checked, and analysed centrally. We calculated estimates of mortality and AIDS incidence rates and estimated the proportions of individuals surviving and developing AIDS at each year after seroconversion from the numbers of observed deaths or cases of AIDS and the corresponding person-years at risk. Analyses were adjusted for age at seroconversion, time since seroconversion, and other factors as appropriate.
from these 38 studies on HIV-1-infected individuals with reliably estimated
dates of seroconversion were assembled in similar formats. Mortality and AIDS
incidence increased strongly with time since seroconversion and age at
seroconversion.Median survival varied from 12.5 years for those aged 15-24 years
at seroconversion to 7.9 years for
those aged 45-54 years at seroconversion, whereas for development of AIDS it
took 11.0 years (for those aged 15-24) and 7…7 years (for those 45-54 aged).
For individuals with Kaposi's sarcoma rates were calculated separately.
In the table immediately below you can see the vast difference in individuals <34 years of age and individuals >55 yrs of age in survival and time to AIDS.
|At Seroconversion||Survivial (years)||Time To AIDS (years)|
|15-24 years||12.5 yrs||11.0 yrs.|
By The Authors
Seroconverter studies from around the world have contributed substantially to knowledge about HIV-1 disease progression. Nevertheless, there are still questions about the effect of exposure category and age at seroconversion on disease progression that individual studies have not been able to resolve. Studies of people with haemophilia and transfusion recipients have, for instance, consistently reported that individuals infected at younger ages progress at a slower rate than those infected at older ages.6-9,11 However, several cohort studies of homosexual men and injecting drug users, typically characterised by a narrow range of ages at seroconversion, have previously failed to report such an effect.19-21 Injecting drug users and people with haemophilia, who are parenterally infected, might have a slower progression than individuals infected by sexual routes,3,12 but this hypothesis has been difficult to study because most cohorts have predominantly included individuals from one exposure category, and injecting drug users have tended to be younger at seroconversion than homosexual men.2,12,22 Finally, a differential age effect has been suggested at different times since seroconversion, but again, there is no agreement on the periods for which age at seroconversion is important.2,4,23
large quantity of data assembled by this international collaboration has the
advantage of including substantial numbers of individuals belonging to different
exposure categories with a wide range of ages at seroconversion, and is based on
individuals with well-estimated dates of seroconversion. This collaboration
therefore provides a unique opportunity to overcome the potential limitations of
individual cohorts in addressing these questions.
Our analyses have confirmed that age at seroconversion is an important risk factor with a large effect seen in every exposure category. For those aged 15-54 years at seroconversion the effect of age at seroconversion was well summarised by a constant multiplicative factor and, after controlling for the effect of age at seroconversion, there was no appreciable effect of mode of infection on survival or on the proportion developing AIDS (excluding Kaposi's sarcoma). Thus, irrespective of exposure category, a 10-year increase in age at seroconversion was associated with a 1…47-fold increase in the risk of death and a 1…32-fold increase in the risk of developing AIDS (excluding Kaposi's sarcoma). For people with haemophilia the factors were slightly larger, especially for mortality. This is perhaps not surprising given that virtually all HIV-1-infected patients with haemophilia are known to have been infected with the hepatitis C virus, commonly many years before HIV-1 infection. Mortality from liver disease in haemophilia patients co-infected with HIV-1 and hepatitis C virus is higher than in those who are not co-infected24,25 and older age is a risk factor in liver disease progression.25,26 There is no evidence among individuals aged 15-54 years at seroconversion that the effect of age at seroconversion varies with time since seroconversion either for mortality or for development of AIDS.
no evidence of a difference in survival or time to the diagnosis of AIDS for
individuals who seroconverted in 1983-96. The apparently better survival for
individuals seroconverting before 1983 may be an artefact, because these
individuals seroconverted before the discovery of HIV-1 as the causative agent
for AIDS. Such findings may, therefore, be due to methodological issues such as
the under-ascertainment of deaths in these individuals. We also found no strong
evidence of differences between men and women in terms of survival or of time to
the diagnosis of AIDS.
data form a baseline with which data from other groups can be compared in the
future. For example, comparisons with data from developing countries and
children infected through mother-to-infant transmission may give insights into
the variability of the effects of HIV-1 infection in different populations. In
the light of recent advances in anti-HIV-1 therapy, it will be important to
continue to monitor disease progression and survival in seroconverters, and
these studies should ultimately provide information on the long-term effect of
highly-active antiretroviral therapy.
(Additional Articles To Read on This Subject)
1 Phillips AN, Lee CA, Elford J, et al. More rapid progression to AIDS in older HIV-infected people: the role of CD4+ T-cell counts. J Acquir Immune Defic Syndr 1991; 4: 970-75 [PubMed].
Mariotto AB, Mariotti S, Pezzotti P, Rezza G, Verdecchia A. Estimation of the
immunodeficiency syndrome incubation period in intravenous drug users: a comparison with male homosexuals. Am J Epidemiol 1992; 135: 428-37 [PubMed].
3 Rosenberg PS, Goedert JJ, Biggar RJ, Multicenter Hemophilia Cohort Study, International Registry of Seroconverters. Effect of age at seroconversion on the natural AIDS incubation distribution. AIDS 1994; 8: 803-10 [PubMed].
4 Touloumi G, Hatzakis A, Rosenberg PS, O'Brien TR, Goedert JJ, Multicenter Hemophilia Cohort Study. Effects of age at seroconversion and baseline HIV RNA level on the loss of CD4+ cells among persons with hemophilia. AIDS 1998; 12: 1691-97 [PubMed].
5 UK Register of HIV Seroconverters Steering Committee. The AIDS incubation period in the UK estimated from a national register of HIV seroconverters. AIDS 1998; 12: 659-67 [PubMed].
6 Altisent C, Montoro JB, Ruiz I, Lorenzo JI. Long-term survivors and progression of human immunodeficiency virus infection. N Engl J Med 1996; 334: 1065-66 [PubMed].
7 Operskalski EA, Stram DO, Lee H, et al. Human immunodeficiency virus type 1 infection: relationship of risk group and age to rate of progression to AIDS. J Infect Dis 1995; 172: 648-55 [PubMed].
8 Darby SC, Ewart DW, Giangrande PL, Spooner RJ, Rizza CR. Importance of age at infection with HIV-1 for survival and development of AIDS in UK haemophilia population. Lancet 1996; 347: 1573-79.
9 Kopec Schrader E, Tindall B, Learmont J, Wylie B, Kaldor JM. Development of AIDS in people with transfusion-acquired HIV infection. AIDS 1993; 7: 1009-13 [PubMed].
10 CarrČ N, Meyer L, Boufassa F, et al. High risk of HIV disease progression after infection through a sexual partner with AIDS. AIDS 1996; 10: 77-80 [PubMed].
11 Goedert JJ, Kessler CM, Aledort LM, et al. A prospective study of human immunodeficiency virus type 1 infection and the development of AIDS in subjects with hemophilia. N Engl J Med 1989; 321: 1141-48 [PubMed].
12 Multicohort Analysis Project Workshop. Immunologic markers of AIDS progression: consistency across five HIV-infected cohorts, part 1. AIDS 1994; 8: 911-21 [PubMed].
13 CarrČ N, Deveau C, Belanger F, et al. Effect of age and exposure group on the onset of AIDS in heterosexual and homosexual HIV-infected patients. AIDS 1994; 8: 797-802 [PubMed].
Pehrson P, Lindb”ck S, Lidman C, Gaines H, Giesecke J. Longer survival after
HIV infection for injecting drug users than for homosexual men: implications for
immunology. AIDS 1997; 11: 1007-12 [PubMed].
Anonymous. New case definition. Lancet 1993; 341: 441 [PubMed].
Centers for Disease Control. 1993 revised classification system for HIV
infection and expanded surveillance case definition for AIDS among adolescents
and adults. MMWR 1992; 41 (RR-17): 1-19.
SM, Carlin JB, Stewart KI, Luca CR, Hoy JF. Predictive value of CD4 lymphocyte
numbers for the development of opportunistic infections and malignancies in
HIV-infected persons. J Acquir Immune Defic Syndr 1991; 4: 770-76 [PubMed].
Office of Population Censuses and Surveys. Mortality statistics: review of the
Registrar General on deaths in England and Wales, 1990. Series DH1 no 24.
London: HM Stationery Office, 1990.
Brettle RP, McNeil AJ, Burns S, et al. Progression of HIV: follow-up of
Edinburgh injecting drug users with narrow seroconversion intervals in
1983-1985. AIDS 1996; 10: 419-30 [PubMed].
Hessol NA, Koblin BA, van Griensven GJP, et al. Progression of human
immunodeficiency virus type 1 (HIV-1) infection among homosexual men in
hepatitis B vaccine trial cohorts in Amsterdam, New York City, and San
Francisco, 1978-1991. Am J Epidemiol 1994; 139: 1077-87 [PubMed].
Veugelers PJ, Page KJ, Tindall B, et al. Determinants of HIV disease progression
among homosexual men registered in the Tricontinental seroconverter study. Am J
Epidemiol 1994; 140: 747-58 [PubMed].
Overbeck J, Egger M, Davey Smith G, et al. Survival in HIV infection, do sex and
category of transmission matter? AIDS 1994; 8: 1307-13 [PubMed].
Longini IM, Clark WS, Gardner LI, Brundage JF. The dynamics of CD+4 T-lymphocyte
decline in HIV-infected individuals: a Markov modelling approach. J Acquir
Immune Defic Syndr 1991; 4: 1141-47 [PubMed].
Eyster ME, Diamondstone LS, Lien JM, Ehmann WC, Quan S, Goedert JJ. Natural
history of hepatitis C virus infection in multitransfused hemophiliacs: effect
of coinfection with human immunodeficiency virus. J Acquir Immune Defic Syndr
1993; 6: 602-10 [PubMed].
SC, Ewart DW, Giangrande PLF, et al. Mortality from liver cancer and liver
disease in haemophilic men and boys in UK given blood products contaminated with
hepatitis C. Lancet 1997; 350: 1425-31 [PubMed].
Poynard T, Bedossa P, Opolon P, for OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC
groups. Natural history of liver fibrosis progression in patients with chronic
hepatitis C. Lancet 1997; 349: 825-32 [PubMed].