IDCRP is committed to reducing the impact of infectious diseases in the military population through collaborative clinical research Learn More >>

Human Immunodeficiency Virus

With approximately 350 new DoD HIV infections diagnosed annually and over 10,000 active duty military service members having been diagnosed cumulatively, HIV remains an important research priority in the U.S. military and IDCRP.  The estimated cost of lifetime HIV treatment is $379,668 (in 2010 dollars).  Although many gaps in understanding HIV in the military system have been addressed, recognition and understanding of non-AIDS outcomes and other issues with long term HIV infection and its treatment continue to develop and highlight research needs. The IDCRP HIV Research Area is focused on ensuring the long term health and function of infected service members and beneficiaries as well as primary HIV and secondary STI prevention efforts. To these ends, the HIV program actively fosters collaboration among DoD and non-DoD investigator partners, development of the next generation of clinical investigators, and maintaining flexibility to adapt to the evolving military environment.   

HIV and the US Military

Members of the U.S. military represent a unique opportunity to study HIV disease. HIV infection in the military is similar to HIV infection in the U.S. in that the virus disproportionately affects younger and more active populations to include African Americans, Hispanics and Latinos, Asian and Pacific Islanders, and men who have sex with men (MSM). However, the HIV epidemic in the military sector differs from the epidemic in the general population in that active duty (AD) service members (SM) have free access to health care and medications and on average have fewer social and economic barriers that prevent good medical care. Despite active HIV prevention programs to include routine HIV screens of all SM every two years (since 2004), there are approximately 350 new HIV infections in the U.S. DoD population per year. HIV infected troops typically remain healthy and continue to serve on active duty; however, in spite of successful treatment with HAART, many develop serious non-AIDS (SNA) events including neurocognitive disorders, cardiovascular diseases, renal diseases, and cancer.

Scientific Strategic Aims        

IDCRP is focused on current concerns for HIV infected military members, their care providers, and their commanders. The scientific strategic aims are as follows:

  1. Mitigate specific complications of HIV and highly active antiretroviral therapy (HAART) among military HIV-infected patients
    • Identify, treat and prevent HIV-associated neurocognitive disorders (HAND) in the US military health care system
    • Identify, treat and prevent serious non-AIDS in the U.S. military health care system
  2. Develop and employ predictive models to optimize individual management of HIV
  3. Improve therapeutic outcomes with the ultimate goal of functional cure of HIV infection
  4. Assess acquisition among HIV-infected active duty troops and how to prevent new infections

Benefitting from the unique racial/ancestral balance of the Military cohort (approx 45% European American, 45% AfricanAmerican, 8% Hispanic) as well as a setting with open access to healthcare, free medications, generally stable income, very low injection drug use, and a high level of education, this resource allows the program to address goals including 1) improving outcomes through understanding of factors associated with HIV infection and its treatment as well as complications of these, 2) understanding the safety and efficacy of non-HIV vaccine strategies important to the HIV-infected military and other relevant populations, and 3) understanding factors associated with HIV co-infections including STI and bidirectional effects on disease manifestations and progression.

Research Area Description

Within the DoD, approximately 350 new HIV infections are diagnosed each year with more than 10,000 active-duty service members diagnosed since the beginning of the epidemic.  In spite of successful lifelong antiretroviral therapy, long-term impacts of chronic HIV infection may include cognitive decline, renal insufficiency, cardiovascular disease, cancer, and mortality.

Although there has been substantial progress related to improved understanding of HIV in the Military Health System, data gaps still exist, including how to best ensure survival, minimize the development of non-AIDS comorbidities, and maximize fitness for those who are infected.  Further data are also needed to enhance HIV and sexually-transmitted infection prevention efforts, potentially through novel methods, such as antiretroviral pre-exposure prophylaxis (PrEP).  These critical issues constitute the scientific strategic aims of the HIV Research Area, which is focused on ensuring and restoring the long-term health and function of HIV-infected military personnel and beneficiaries. 

Since its inception in 1986, the U.S. Military HIV Natural History Study (NHS), led by Dr. Brian Agan, has been the centerpiece protocol of this research area, and continues to prove to be an invaluable resource for advancing the understanding of HIV both within the military and more broadly in civilian patients.  The NHS has enrolled over 6,000 individuals and provides a wealth of data and specimens for analysis of this disease among military active-duty and beneficiaries.  During 2017, efforts to increase the engagement of multiple lead investigators were successful, with growth to over 20 active analyses.  New collaborations were also developed with DoD investigators at USU, the U.S. Military HIV Research Program (MHRP), and the Naval Postgraduate School, as well as with academic collaborators.  A new area of investigation this year focused on patient centered outcomes, particularly health-related quality of life (HRQOL), which demonstrated that addressing modifiable mental and medical comorbidity factors may improve quality of life of HIV-infected patients.  Moreover, HRQOL was found to be predictive of subsequent hospitalization.  Additional analyses are ongoing in separate collaborations with Emory University and Atlanta Veterans Affairs, as well as with the Naval Postgraduate School. 

Over the past several years, we have made substantial efforts to increase repository-based collaborations with the goal of fully leveraging this unique resource of the NHS.  This was successful in 2017 with new grant applications, increased publications, and new collaborations.  In one of the repository-based analyses, the immunological response of HIV-infected individuals to hepatitis B vaccine was examined, extending past NHS work in this area.  Individuals who responded to the hepatitis B vaccine had an immune profile consistent with a better Type 1 T helper cell (adaptive immunity) response.  In addition, two new repository-based collaborations with investigators at the National Institute of Neurological Disorders and Stroke are in protocol development.  One will utilize cerebrospinal fluid to investigate biomarkers for HIV-associated neurocognitive disorders (HAND) and HIV-associated dementia, while the other will evaluate the effect of antiretroviral drugs on human endogenous retrovirus K, which is a presumed cause of amyotrophic lateral sclerosis, including among HIV-infected individuals.   

This past year also saw progress with other protocols in the HIV Research Area.  In particular, the HIV Associated Neurocognitive Disorders (ALLHANDS) protocol continued enrollment of HIV-infected individuals and recruitment of the HIV+ cohort and HIV- controls was completed.  Approximately half of the subjects have already completed their second annual visit.  Preliminary baseline data from the cohort were presented at the NIH NeuroHIV Retreat, which is a conference that brings together scientists and program officers from at least seven NIH Institutes.

The HIV Virtual Cohort Study is moving forward following approval from the USU IRB, as well as for a data sharing agreement with the Defense Health Agency.  Initial abstraction of data through the Military Health System Data Repository for the analysis is forthcoming.   For the Rifaximin study, led by Dr. Anuradha Ganesan, data collection for the randomized control trial was completed and analysis of the data is underway.   Having completed the analysis related to the study’s primary objective, the Strategic Timing of Anti-Retroviral Therapy (START) protocol was modified to simplify visits and extend follow-up beyond 2017.  Lastly, an amendment to collaborate with MHRP on the CD4 Zeta protocol, led by COL Naomi Aronson, to examine the HIV reservoir and persistence of the gene therapy modified cells has been approved and is underway.

We anticipate the coming year to be successful in our expanding areas of HIV research.  Non-AIDS outcomes, including the study of HAND, remain a priority.  With the possibility of a functional cure, we are also working with MHRP to initiate a trial of a therapeutic HIV vaccine.

Key Studies

IDCRP-000: DoD HIV Natural History Study (NHS)

The HIV NHS protocol and sub-analyses constitute the core of the IDCRP HIV Research Program. The NHS is an ongoing, longitudinal, observational cohort study designed to collected retrospective and prospective data with the United States (U.S.) military active duty and Department of Defense (DoD) health care beneficiary HIV infected population. Data collected and tissue samples contained within the U.S. Military HIV Natural History Study Repository (NHSR) represent a unique national scientific resource. The NHSR is an invaluable resource. The NHS has been instrumental in the growth of knowledge concerning how to prevent, diagnose and treat HIV and AIDS. This study dates back to 1986 when it began and has continued since that time.

IDCRP-008: Immune Reconstitution Syndrome (IRIS) Study 

In collaboration with the Military HIV Research Program (MHRP), the IRIS study is an international observational cohort being conducted in Thailand, Kenya and the U.S. to evaluate the predictors, incidence, clinical presentation and immunopathogenesis of IRIS. IRIS is a serious diagnosis that develops due to worsening of infectious and non-infectious diseases shortly after antiretroviral therapy (ART) initiation. After starting treatment, these patients experience an excessive inflammatory response. The syndrome primarily has been observed in HIV+ patients who begin treatment at low CD4 levels and who have existing opportunistic infections; however, the exact etiology of IRIS is unclear.

IDCRP-016: Prevalence and Predictors of Neurocognitive Impairment Study

The neurocognitive impairment study is an observational pilot study with the objective to determine the prevalence of neurocognitive impairment within the active duty HIV+ military population. Neurocognitive impairment remains a major concern for those infected with HIV on and off treatment.  HIV-associated neurocognitive disease (HAND) has been one of the main reasons cited that restricts active duty from piloting aircraft, personal reliability program positions (i.e. nuclear missile launch) and deployment. This was the first military study comparing neurocognitive impairment between active duty HIV-infected and HIV-uninfected groups, now being continued through a larger protocol – the ALLHANDS DoD study described below.

IDCRP-038: Strategic Timing of AntiRetroviral Treatment (START) Study

The Strategic Timing of AntiRetroviral Treatment (START) trial is an international, multi-site trial, designed to answer the question, “When should HIV treatment with medicines be started?”  Although current recommendations suggest beginning treatment as soon as possible, there are risks and benefits for both starting treatment early versus later. This study seeks to investigate differences in the risk of acquiring serious illnesses and AIDS between groups that begin treatment at CD4+ counts above 500 cells/mm3 or at CD4+ counts below 350 cells/mm3.

IDCRP-063: Rifaximin Study

The Rifaximin Study is a randomized control trial investigating the effects of oral Rifaximin on gut microbial translocation. Bacteria in the gut are one of the suspected causes of chronic immune activation observed in HIV-infected individuals that remains even with modern therapies. This study seeks to determine whether Rifaximin treatment reduces levels of markers of immune system activation.

IDCRP-078: ALLHANDS DoD Study

ALLHANDS DoD is an observational study seeking to understand the natural history of HIV-associated neurocognitive disease (HAND).  The study is being conducted in conjunction with the National Institute of Health’s (NIH’s) similar ALLHANDS study.  ALLHANDS DoD and ALLHANDS NIH studies follow HIV-infected and HIV-uninfected individuals over 5 years.  Two important aims of this study are to validate a neuropsychological test to identify those presenting with HAND and identify markers of immune activation in the central nervous system – a possible reservoir for latent HIV infection.

Military Impact

Our current HIV research portfolio is designed with military impact as a central goal. Through our investigations, we continue to support the Military Health System by evaluating clinical care and serious outcomes among people with HIV. The HIV Virtual Cohort Study seeks identifiable or modifiable risk factors for adverse effects of HIV that may enable early diagnosis, treatment, or prevention. Our current work to evaluate the ‘cascade of care’ among active-duty found to be newly HIV positive will identify potential areas for military care improvement and is a first step in the evaluation of HIV care quality in the DoD. We anticipate that the ALLHANDS study may have policy implications to allow active-duty members with HIV to expand job functions and increase rank. Lastly, our work with sexually-transmitted infections among HIV-infected subjects continues to generate data that may inform policy to improve diagnosis and treatment of these infections, as well as improve understanding of transmission to support prevention efforts in the military. 

Hilights and Key Findings

  • First year that National Institutes of Health Research Project R01 funding for HIV research was awarded to the IDCRP
  • Reached target of 200 consented subjects for ALLHANDs protocol and a higher than expected proportion of subjects elected to participate in optional procedures critical to addressing research aims
  • Evaluation of patient centered outcomes determined that highly active antiretroviral therapy (HAART) was not associated with HRQOL; however, the presence of medical and mental comorbidities was negatively associated with physical functional health.  This work resulted in a PhD being awarded to a trainee.
  • As part of collaboration with the UNAIDS Working Group collecting seroconverter data from multiple cohorts, the NHS supplied data from 3053 NHS subjects as part of the development of a model detailing the CD4+ cell decline following HIV-1 infection; data demonstrated regional and age-specific differences which will support future HIV models  

Partners and Collaborators

The IDCRP HIV research program is primarily funded by the National Institute of Allergy and Infectious Diseases (NIAID). The program is complementary to other DoD HIV research and surveillance efforts.

Publications 

Mangal TD; UNAIDS Working Group on CD4 Progression and Mortality Amongst HIV Seroconverters including the CASCADE Collaboration in EuroCoord.  Joint estimation of CD4+ cell progression and survival in untreated individuals with HIV-1 infection.  AIDS. 2017;;31(8):1073-1082.

Fink E, Fuller K, Agan B, et al.  Humoral Antibody Responses to HIV Viral Proteins and to CD4 Among HIV Controllers, Rapid and Typical Progressors in an HIV-Positive Patient Cohort.  AIDS Research and Human Retroviruses. 2016;32(12):1187-1197.

Lodi S, Sharma S, Lundgren JD, et al.  The per-protocol effect of immediate vs. deferred ART initiation in the START randomized trial.  AIDS. 2016;30(17):2659-2663.

Perkins M, Bradley W, Lalani T, et al. Prevalence of Post-Treatment Controller Phenotype is Rare in HIV-infected Persons after Stopping Antiretroviral Therapy. Journal of Acquired Immune Deficiency Syndromes. 2017;75(3):364-369.

Paris RM, Milagres LG, Moysi E, et al.  Lower Baseline Germinal Center Activity and Preserved Th1 Immunity Are Associated With Hepatitis B Vaccine Response in Treated HIV Infection.  Pathogengs & Immunity. 2017;2(1):66-88.

Emuren L, Welles S, Evans AA, et al.  Health-related quality of life among military HIV patients on antiretroviral therapy.  PLoS One. 2017;12(6):e0178953.

Presentations 

ID Week 2016, October 26-30, 2016, New Orleans, LA:

  1. Oral Presentation: O'Bryan T, Olsen C, Rahman S, et al.  Calculated Globulin Levels Predict Hepatitis B Vaccine Response in HIV-Infected Persons with Viremic Suppression and High CD4 Cell Count.
  2. Poster #478: Macalino G, Wang X, Ganesan A, et al.  How does changing sexual risk behaviors impact incident sexually transmitted infections (STIs) in a cohort of HIV+ Military beneficiaries? 
  3. Poster #709: Crum-Cianflone N, Won S, Lee R, et al.  Do Low Vitamin D Levels Explain Poorer Influenza Vaccine lmmunogenicity among HIV­ Infected and HIV-Uninfected Adults?
  4. Poster #1534: O'Bryan T, Olsen C, Ganesan A, et al.  Baseline Albumin/Globulin Ratio Predicted Progression to AIDS Among Persons with Stage 1 HIV Disease in the Pre-Combination Antiretroviral Therapy Era. 
  5. Poster #2158: O'Bryan T, Freiberg M, Tracy R, et al.  Relationship of Albumin/Globulin Ratio with Biomarkers of Inflammation and Coagulation in HIV-Infected Persons Before and After Combination Antiretroviral Therapy. 
  6. Poster #2198: Pomerantz H, Xu X, White J, et al.  Evaluation of Quantitative Varicella-Zoster Virus Antibody Levels as a Predictor of Zoster Reactivation in HIV-infected Persons. 

Conference on Retroviruses and Opportunistic Infections, February 13-16, 2017, Seattle, WA:

  1. Poster #540: Deiss R, Moore RC, Crum-Cianflone NF, et al. Post-traumatic Stress Disorder and Neurocognitive Impairment in a U.S. Military Cohort.
  2. Poster #668: Agan BK, Won SH, Schofield CM, et al. VACS Index as a Predictor for Non-AIDS Defining Conditions in a Longitudinal Cohort.
  3. Poster #865: Ganesan A, Wang X, Deiss R, et al.  Incident Syphilis Infections Declined in a Well Characterized Cohort of HIV+ Persons.
  4. Poster #932: Joya C, Won SH, Kronmann K, et al. Low-Level Viremia is Associated with Virologic Failure in a Large Military Cohort. 

International AIDS Society, July 23-26, 2017, Paris, France:

  1. Poster # WEPEB0535: Sheikh V, Sawe F, Shaffer D, et al.  IL-27 is Independently Associated with IRIS: Results of a Multicenter International Prospective Study. 

Military Health System Research Symposium, Aug 27-30, 2017, Kissimmee, Florida:

  1. Poster #182: Joya C, Won SH, Okulicz J, et al.  Low level viremia is associated with virologic failure in a large military cohort.

ID Week 2017, October 4-8, 2017, San Diego, CA:

  1. Oral Presentation: Eickhoff CA, Wang X, Deiss R, et al.  Gonorrhea (GC) and Chlamydia (CT) Infection in a Large, Well-Characterized Military Cohort: Prevalence, Incidence, Site of Infection, and Patient Characteristics.
  2. Poster #560: Joya C, Won SH, Deiss R, et al.  The Impact of Continuous Virologic Suppression on the Development of Non-AIDS Diagnoses. 
  3. Poster #585. Gilbert L, Wang X, Deiss R, et al.  Incidence of Herpes Zoster in a Large Cohort of Persons Living with HIV.
  4. Poster #597: Wood S, Byrne M, Deiss R, et al. The Incidence and Risk Factors Associated with Chronic Liver Enzyme Elevation (cLEE) in HIV-Monoinfected Persons.
  5. Poster #2222: O'Bryan T, Olsen C, Rahman S, et al.  Calculated Globulin Adds Predictive Value to Hepatitis B Vaccine Response in HIV-infected Persons Independently of HIV Viral load and CD4 Cell Count. 
  6. Poster #2261: Pannebaker D, Larson D, Wang X, et al.  High-risk behavior among U.S. military HIV-Infected Active-Duty and Retired Personnel.