Observational Cohorts: What they have taught us about HIV disease

The observational cohort study design has served HIV clinicians and our patient communities for over 30 years by teaching us a great deal about HIV disease and its complications.

While randomized controlled trials (RCT) remain the gold-standard in medical research, they are often impractical or in some cases unethical to perform when it comes to HIV-related clinical questions. Since the first observational cohort was started in 1984 (MACS — see below), the research community has garnered a vast amount of information from groups of HIV-infected men and women who have been followed longitudinally. They have answered many question related to HIV pathogenesis and natural history. There are now numerous HIV cohorts that provide basic science and clinical information in persons living long-term with HIV and many of the associated co-morbidities. The majority of these studies are still recruiting new participants. What follows is an overview of some of the key HIV observational cohorts.

Multicenter AIDS Cohort Study (MACS)

The MACS began recruiting participants in 1984 when 4,954 gay or bisexual HIV-positive men were enrolled from clinical sites in Baltimore (Johns Hopkins), Chicago (Northwestern), Pittsburgh (University of Pittsburgh), and Los Angeles (UCLA).

They were followed with data collection, including laboratory and clinical parameters performed on a semi-annual basis. The MACS was the first to look at the natural history of untreated HIV disease. Early data gathered from this cohort includes anal intercourse as a risk for HIV infection, rates of CD4+/T-cell decline, use of prophylaxis for Pneumocystis, progression to AIDS, and survival from time of diagnosis.

In more recent years the MACS has expanded to including several sub-studies. These include aging with HIV, co-morbidities of cancer, cardiovascular and neurological diseases, and oral health. Funding for the MACS is primarily from the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health. Over 1,400 papers have been published from the MACS, including most recently those noted below:

• Peckham-Gregory EC, et al. MicroRNA-related polymorphisms and non-Hodgkin lymphoma susceptibility in the Multicenter AIDS Cohort Study (MACS). Cancer Epidemiol. Oct.1, 2016; 45:47-57.
• Zhang L. et al. Vitamin D Deficiency and Metabolism in HIV-infected and -uninfected Men in the Multicenter AIDS Cohort Study (MACS). AIDS Res Hum Retroviruses. Oct. 2016.
• Akhtar-Khaleel WZ, et al. Long-Term Cigarette Smoking Trajectories among HIV-Seropositive and Seronegative MSM in the Multicenter AIDS Cohort Study (MACS). AIDS Behav. 2016; 20(8):1713-21.
• Slama L et al. Longitudinal Changes Over 10 Years in Free Testosterone among HIV-Infected and HIV-Uninfected Men. J Acquir Immune Defic Syndr. 2016; 71(1):57-64.

Women’s Interagency HIV Study

The Women's Interagency HIV Study (WIHS) was established in August 1993 to carry out wide-ranging investigations on the impact of HIV infection and its clinical, laboratory, and psychosocial effects in women.

The WIHS began enrolling patients in October 1994 and the initial cohort included 2,625 women (2,056 HIV-positive and 569 HIV-negative). The original WIHS sites included Bronx, NY, Los Angeles, CA, Chicago, IL, San Francisco/Oakland CA, and Washington DC and is the largest and longest ongoing study of HIV-infected women in the U.S.

Participants have follow-up visits at six-month intervals. Information obtained from these women include socio-demographics, sexual behaviors, gynecological, obstetrical and contraceptive history, as well as alcohol, tobacco and drug use. Some key data from WIHS has been cervical and lung cancer risks in HIV-positive women.

WIHS is co-sponsored by five NIH Institutes including the NIAID, National Cancer Institute (NCI), Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute on Drug Abuse, and the National Institute of Mental Health. More recently, new sites were added that better reflect the demographics of the HIV epidemic include Atlanta, GA, Chapel Hill, NC, and Jackson, MS. Over 600 publications have come out of the WIHS cohort, including these recent papers:

• Dale SK et al. Abuse, nocturnal stress hormones, and coronary heart disease risk among women with HIV. AIDS Care. October 2016; 13:1-5.
• Vance DE et al. Aging and Neurocognitive Functioning in HIV-Infected Women: a Review of the Literature Involving the Women's Interagency HIV Study. Curr HIV/AIDS Rep. October 2016.
• Weitzmann MN et al. Bone Loss among Women Living With HIV. Curr HIV/AIDS Rep. Sept 2016.
• Torre P et al. Speech audiometry findings from HIV+ and HIV- adults in the MACS and WIHS longitudinal cohort studies. J Commun Disord. July 2016.

North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD)

The NA-ACCORD was founded in 2006 as a regional representative of the International epidemiologic Databases to Evaluate AIDS (IeDEA).

NA-ACCORD is composed of 25 cohorts (including the WIHS and MACS) from the U.S. and Canada. Over 200 sites from all 50 states, three U.S. territories and nine Canadian Provinces contribute data on over 130,000 HIV-infected patients. These sites include both academic and community-based facilities that deliver primary and specialty HIV care.

The NA-ACCORD combines epidemiological and clinical HIV cohorts, includes both HIV-seropositive and seronegative persons, and is complemented by specimen repositories for conducting translational research. Funding for the NA-ACCORD is from NIAID and the NCI. According to their website, NA-ACCORD is open to collaboration with additional clinical sites.

A sentinel publication that came out of this cohort was the 2009 paper [MM Kitahata et al. Engl J Med 2009; 360:1815-1826] that found early initiation of antiretroviral therapy before the CD4+ count fell below 350 and 500 cells/mm3 significantly improved survival, as compared with deferred therapy. Recent publications from NA-ACCORD include:

• Buchacz K et al. Incidence of AIDS-Defining Opportunistic Infections in a Multicohort Analysis of HIV-infected Persons in the U.S. and Canada, 2000-2010. J Infect Dis. 2016 15; 214(6):862-72.
• Klein MB et al. Risk of End-Stage Liver Disease in HIV-HCV Coinfected Persons in North America from the Early to Modern Antiretroviral Therapy Eras. Clin Infect Dis. 2016 1; 63(9):1160-1167.
• Koethe JR et al. Rising Obesity Prevalence and Weight Gain among Adults Starting Antiretroviral Therapy in the United States and Canada. AIDS Res Hum Retroviruses. 2016 Jan; 32(1):50-58.

Veterans Aging Cohort Study (VACS)

The VACS is a prospective, observational cohort of HIV- positive and HIV-negative veterans in care with the Veterans Administration health system in the United States.

The primary aim of the VACS is to understand the role of comorbid medical and psychiatric diseases and their effects on HIV-related clinical outcomes. The VACS is primarily funded by the National Institute on Alcoholism and Alcohol Abuse. The principle investigator of the VACS is Dr. Amy Justice from the VA Connecticut Healthcare System and Yale University School of Medicine.

The VACS consists of two ongoing cohorts. The first began in 1997 and includes 40,000 HIV- positive veterans and a one-to-two matched sample of uninfected controls. The VACS also has a sub-study cohort of patients from nine VA medical centers (“VACS-9”) that include Atlanta, Baltimore, Bronx, Dallas, and Los Angeles.

When new veterans with HIV infection present for care, they are offered enrollment in one of the two cohorts. A key research tool of the VACS is the “VACS Index” — a clinical scoring system that predicts all-cause mortality, cause specific mortality, and other outcomes in those living with HIV infection. The VACS Study Index creates a score by summing pre-assigned points for age, CD4 count, HIV-1 RNA, hemoglobin, platelets, hepatic function, renal function, and viral hepatitis C infection. Several recent published studies by the VACS include:

• Kahler CW et al.Direct and Indirect Effects of Heavy Alcohol Use on Clinical Outcomes in a Longitudinal Study of HIV Patients on ART. AIDS Behav. July 2016.
• Marquine MJ, et al. The Veterans Aging Cohort Study (VACS) Index and Neurocognitive Change: A Longitudinal Study. Clin Infect Dis. 2016; 63(5):694-702.
• Montoya JL, et al. Elevated Biomarkers of Inflammation and Coagulation in Patients with HIV Are Associated with Higher Framingham and VACS Risk Index Scores. PLoS One. 2015; 10(12).

Data Collection on Adverse events of Anti-HIV Drugs (D:A:D)

D:A:D: is a prospective multi-cohort study primarily focused on the recognition of adverse events related to HIV disease and also complications specifically related to ART.

The original study population of 23,000 patients was enrolled between December 1999 and April 2001. The data center is based in Denmark and is composed of 11 cohorts including EuroSIDA, Aquitaine, ATHENA, and ICONA. The U.S. member of D:A:D is the Community Programs for Clinical Research on AIDS (CPCRA). The total current enrolment is approximately 50,000 patients that represent 212 clinics from 33 countries.

According to the D:A:D web site, funding comes from 'The Oversight Committee for The Evaluation of Metabolic Complications of HAART', and several pharmaceutical companies that produce anti-retroviral drugs.

The data collection for D:A:D takes place about every eight months and is merged to a central database in Copenhagen. Core data in D:A:D is information o­n incident cases of cardiovascular disease, which are reported immediately to the coordinating office.

The data collection also includes information o­n risk factors for cardiovascular disease, such as previous myocardial infarction or stroke, diabetes, dyslipidemia, family history, hypertension, and smoking. In more recent years, D:A:D has collected information on non-AIDS defining malignancies, renal disease, liver disease and death.

A sentinel study from D:A:D was the 2007 publication noting an increased risk of myocardial infarction from certain HIV therapies including protease inhibitors. [Friis-Moller N, N Engl J Med. 2007 Apr 26; 356(17):1723-35]. The D:A:D Study has produced several hundred key papers and presentations since 2003 and continues to do so. Some recent publications from the D:A:D include:

• Boettiger DC, et al. Is nelfinavir exposure associated with cancer incidence in HIV-positive individuals? AIDS. 2016 Jun 19; 30(10):1629-37. D:A:D Study Group.
• Mocroft A et al. Cumulative and current exposure to potentially nephrotoxic antiretrovirals and development of chronic kidney disease in HIV-positive individuals with normal baseline estimated GFR. Lancet HIV. 2016; 3(1):e23-32. D:A:D Study Group.
• Ryom L et al. Use of antiretroviral therapy and risk of end-stage liver disease and hepatocellular carcinoma in HIV-positive persons. AIDS. 2016; 30(11):1731-43. D:A:D Study Group.
• Achhra AC et al. Short-term weight gain after ART initiation and subsequent risk of CVD and diabetes. HIV Med. 2016; 17(4):255-268. D:A:D Study Group.

ABOUT THE AUTHOR:

Jeffrey T. Kirchner, DO, FAAFP, AAHIVS is Medical Director at Penn Medicine/LGHP Comprehensive Care at Lancaster General Hospital, Lancaster, PA. He chairs the HIV Specialist Editorial Advisory Group.