Award

Challenging and Expanding Paradigms of Aging with HIV

Description: Project Narrative People living with HIV are living longer, primarily due to effective treatment, and age-related diseases are becoming more common in people with HIV, specifically heart attacks, kidney disease and cancers. This research will examine: 1) differences in the age at diagnosis of these conditions in HIV-infected and - uninfected people; 2) the role of traditional risk factors (i.e. smoking and high blood pressure) and HIV-related risk factors (i.e. hepatitis C and antiretroviral therapy use) in the occurrence of these conditions in HIV-infected people; and 3) how the timing of antiretroviral treatment initiation can effect these conditions. This research will impact the public health of people living with HIV by identifying ways to reduce their risk of these age-related conditions. __SpecificAimsTextDelimiter__ Specific Aims By 2015, it is estimated >50% of HIV-infected individuals in the United States (US) will be e50 years of age. Given the 6.5 per 100,000 population incidence of HIV-infection in older adults, it can be assumed the vast majority of HIV-infected individuals aged e50 years were infected when they were younger and are aging with HIV. In the US and other countries with access to highly active antiretroviral therapy (HAART) since the mid- 1990s, death from age-related comorbidities is now more common than AIDS-related death. Age-related, non- AIDS-related comorbid conditions, particularly myocardial infarction (MI), end-stage renal disease (ESRD) and cancer (heretofore referred to as comorbidities) are of critical and growing importance in HIV research. Three prominent paradigms regarding aging with HIV have emerged from the growing research field of aging with HIV. First, biological evidence of "accelerated aging" of the immune system and epidemiologic studies of a younger median age at diagnosis of comorbidities compared to the general population has resulted in a paradigm of earlier age at comorbidity diagnosis in HIV-infected individuals. The appropriate comparison group of HIV-uninfected individuals with similar demographic characteristics and prevalence of risk factors for comorbidities proves to be elusive at a sample size large enough to capture an adequate number of comorbid events. The question remains: Is the younger age at comorbidities diagnosis in HIV-infected individuals real or an artifact of the comparison group? Second, due to the increased prevalence of some traditional risk factors for comorbidities in HIV-infected individuals, it is thought the majority of the risk of comorbidities in HIV-infected individuals can be attributed to traditional risk factors. HIV-related risk factors that have been shown to increase the risk of comorbidities include low CD4 T-lymphocyte (CD4) count, hepatitis C co-infection, use of protease inhibitor (PI)-based HAART regimens, exposure to specific antiretroviral drugs and longer duration of HAART use. These HIV-related risk factors continue to increase in prevalence, begging the question: Are traditional or HIV-related risk factors for comorbidities driving the increasing rates of comorbidities? Finally, if the current CD4 count threshold for HAART initiation was increased from <350 to <500 cells/mm3, the duration of HAART use would increase. The increased risk of comorbidities associated with increasing duration of HAART leads to the question: How does the risk of comorbidities impact the "when to start" question? These three important questions, that challenge and expand upon current aging with HIV paradigms and have public health and clinical practice implications, will be investigated as follows: Aim 1: To estimate the difference in risk of comorbidities in HIV-infected and similar -uninfected individuals in the US in clinical care, by age at comorbidity diagnosis. Hypothesis 1.1: The estimated mean age at diagnosis of comorbidities will be <10 years younger in HIV-infected compared to -uninfected individuals. Hypothesis 1.2: The risk of comorbidities will be greater in the HIV-infected compared to HIV-uninfected individuals at younger ages, but similar at older ages. Aim 2: To determine the attributable fraction of traditional and HIV-related risk factors on comorbidities in HIV-infected individuals in clinical care in the US and Canada. Hypothesis 2.1: The attributable fraction of HIV-related risk factors will be less than that of traditional factors. Hypothesis 2.2: The difference in the attributable fraction of traditional and HIV-related risk factors will narrow over calendar time. Aim 3: To determine the risk of first comorbid event after HAART initiation by CD4 count at HAART initiation in HIV-infected individuals in clinical care in the US and Canada. Hypothesis3.1: Individuals initiation HAART at a CD4 count e500 will have a reduced risk of comorbidities as compared to those who initiate HAART with a CD4 count <500 cells/mm3. Hypothesis 3.2: Individuals who initiate HAART at a CD4 count e500 cells/mm3will have a reduced risk of comorbidities as compared to those who defer HAART initiation until CD4 count <500 cells/mm3. The VACS enrolled >100,000 HIV-infected and -uninfected individuals from 1997 to 2004 matched on calendar year of entry, age at entry, race, sex, and geographical location and is the ideal study population to investigate Aim 1. The NA-ACCORD is a collaboration of 21 interval and clinical cohorts in the United States and Canada, pooling information on >115,000 HIV-infected individuals collected from 1985 to the present calendar year and is uniquely-positioned to investigate Aims 2 and 3 with adequate sample size. Causal inference methodology, a cutting-edge and continually evolving area of observational epidemiologic research, will be utilized, incorporating competing risks and dynamic marginal structural models to estimate average causal effects. This proposed research will impact public health policy and clinical practice guidelines by potentially demonstrating the need for age-specific screening mechanisms for HIV-infected individuals, informing prevention interventions by determining the risk factors with the greatest attributable risk, and expanding the "when to start" question to incorporate morbidity outcomes.

Funder: National Institute of Allergy and Infectious Diseases

Funding type: career_development

Funder scheme: K01

Start date: 2011-09-08

End date: 2017-08-31

Investigator: KERI NICOLE ALTHOFF

Institution: JOHNS HOPKINS UNIVERSITY