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:

Time 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

The 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.

What Are The Implications Of These Findings??

Commentary:

One of 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?

Should 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.

Unless 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 therapy.

The following information include excerpts from the published article.

Introduction

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.

Much has 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

methods 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.

Methods 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.

RESULTS

Data 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.

Discussion 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

The 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.

We found 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.

These 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.

References (Additional Articles To Read on This Subject)

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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].

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