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Cited by 269HIV-related health complications and treatmentsHIV Research and TreatmentHIV/AIDS Research and Interventions

The role of HIV in serious diseases other than AIDS.

Open access
Phillips, Andrew N, Neaton, James, Lundgren, Jens D·2008·AIDS
DOI 10.1097/qad.0b013e3283174636PMC PMC2679976
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Abstract

Introduction Now that we are over 10 years into the HAART era in resource-rich countries the major clinical impact of this therapy on reduced AIDS events and AIDS deaths has been well described [1] and in the past few years the focus has turned to describing and understanding what residual clinical disease remains in populations of HIV-infected individuals. As death rates may be still falling in HIV-infected patients [2,3], at 0.5–1.0% per year, there is still a considerable excess risk compared with the general population. The breakdown of causes of death of patients has been described based on a study of deaths occurring in 2005 in France [4]. AIDS diseases were responsible for only 36% of deaths, with a further 5% due to non-AIDS infections. Other leading causes of death were non-AIDS cancers (16%), liver disease (15%), cardiovascular disease (9%), and suicide (5%). In a United States study, Lau et al.[5] found that risk of death from non-AIDS conditions was greater than that for AIDS conditions for persons with CD4 count above 200/mm3. Now with fewer AIDS deaths we have of course observed an increase in the proportion of deaths due to non-AIDS causes, however, this does not mean to say that there has been an increase in the rate of non-AIDS – quite the reverse in fact. Unpublished data from EuroSIDA on trends over calendar time in rates of non-AIDS death (Fig. 1) indicate that the start of the HAART era was actually accompanied by a decline in the rate of death from non-AIDS causes ([6] and Personal communication), a finding that has been observed in other studies [7]. This at first somewhat puzzling observation suggests that perhaps HIV may be playing a role in other diseases well beyond the 26 diseases which characterize AIDS. As we keep people with HIV alive for longer there will be an ever-growing number of people with HIV. If HIV is influencing risk of these events, particularly if it does so in the higher CD4 count range where the majority of treated patients hopefully will be, then it is very important to be aware of this and to study it. In this article we briefly consider what rationale (i.e., potential mechanisms) there might be to hypothesize that HIV may play a role in causing diseases such as non-AIDS malignancy, liver cirrhosis, end stage renal disease and serious cardiovascular events (e.g., myocardial infarction, stroke and surgery for coronary artery disease). Collectively, we refer to these as serious non-AIDS events. We then go on to review studies, which have data on incidence of serious non-AIDS disease, death, or both, from these diseases to build up a picture of the current state of knowledge. We finish by suggesting the implications for future research and current clinical care of patients. This review is not intended to consider adverse effects due to antiretroviral drugs (ART), although it is recognized that it is not always easy to separate the effects of HIV from the effects of ART.Fig. 1: Rate of non-AIDS death by calendar time: EuroSIDA. Adapted with permission from [6].Potential mechanisms There are a range of plausible mechanisms by which HIV might lead to raise risk of non-AIDS morbidity and mortality. As well as causing immunodeficiency, HIV also causes a generalized immune activation and leads to increased T cell turnover [8,9] which is perhaps linked to what has been referred to as microbial translocation, resulting early from depletion of CD4 lymphocytes in lymphoid tissue in the gut [10] which could have consequences for the speed of pathogenic processes leading to a variety of conditions of the cardiovascular and digestive system. Thinking specifically of CVD, whereas, HIV infection seems to lead to a decrease in total cholesterol, it also causes decreases in HDL-cholesterol (e.g., [11–13]) and results in increases in markers of inflammation (e.g., C-reactive protein), endothelial activation and damage (e.g., intercellular adhesion molecule, ICAM and vascular cell adhesion molecule, VCAM), and in fact also of coagulation (e.g., D-dimer) – factors which have been linked to increased risk of cardiovascular disease in the general population [11,14–21]. Considering liver disease, there is fairly well established evidence that HIV-infection results in faster progression of fibrosis and increased risk of hepatocellular cancer in people with hepatitis B and C virus although the mechanism is not entirely clear [22–25]. Whether HIV can affect progression of fibrosis due to an effect on adaptive immunity to HCV, alteration of the dominant HCV subtype or increased hepatocyte apoptosis is not certain. Recent work suggests a possible role of decreased interferon gamma production by HCV-specific CD4 cells in coinfected patients [26]. With regard to renal disease, HIV associated nephropathy (HIVAN), a glomerulopathy demonstrating focal segmental glomerulosclerosis with collapsing features, is a condition well established as being related to HIV [27,28], and possible mechanisms ha

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  • Long-term treated HIV-infected adults have excess risk of a number of HIV-associated, non-AIDS (HANA) conditions, including many typically associated with advancing age, such as cardiovascular disease, kidney disease, liver disease, osteoporosis, cancer, and cognitive impairment.

    “When compared to HIV-uninfected persons, long-term treated HIV-infected adults have excess risk of a number of HIV-associated, non-AIDS (HANA) conditions, including many typically associated with advancing age (e.g., cardiovascular disease, kidney disease, liver disease, osteoporosis, cancer, and cognitive impairment) (46).”

    From HIV and Aging: State of Knowledge and Areas of Critical Need for Research. A Report to the NIH Office of AIDS Research by the HIV and Aging Working Group (2012) · cites this paper as [46]

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Research works printed but not linked: 6

  1. [21]Kuller L the SMART Study Group Cardiovascular risk, mortality and TB complicating HIV infections 15th Conference on Retroviruses and Opportunistic Infections Feb 3–6 2008 Boston, USA Abstract 139
  2. [22]Eyster ME Diamondstone LS Lien JM Natural-history of hepatitis-C virus infection in multitransfused hemophiliacs – effect of co-infection with HIV JAIDS 1993 6 602 610 8098752
  3. [33]Gupta S Franceschini N Szczech LA Smurzynski M Kalayjian R The effects of HIV-1 viral suppression and non-viral factors on clinically significant proteinurea in the HAART era 15th Conference on Retroviruses and Opportunistic Infections Feb 3–6 2008 Boston, USA Abstract 974
  4. [57]Marin B Thiebaut R Rondeau V Costagliola D Dorrucci M Bucher H on behalf of the CASCADE Collaboration Association between CD4 and HIV RNA with non AIDS-related causes of death in the era of combination Antiretroviral Therapy (cART) 4th IAS Conference on HIV Pathogenesis and Treatment July2007 Sydney
  5. [60]d’Arminio Monforte A The incidence of fatal AIDS-defining (ADM) and non-AIDS-defining (nADM) malignancies in the D:A:D study, and their relationship with immunodeficiency 14th Conference on Retroviruses and Opportunistic Infections 2007 Los Angeles
  6. [62]Kirk O Mocroft A d’Arminio Monforte A Hansen AB Gatell J Caplinskas S Deterioration in renal function associated with current level of immunodeficiency 15th Conference on Retroviruses and Opportunistic Infections Feb 3–6 2008 Boston, USA Abstract 971

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Authors
Phillips, A. N., Neaton, J., & Lundgren, J. D.
Affiliations
  • The Royal Free Hospital (GB)
  • University of Minnesota (US)
  • University of Copenhagen (DK)
Corresponding author
Phillips, Andrew N
ORCID
Venue
AIDS
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2008-11-30
Volume
22
Issue
18
Pages
2409-2418
ISSN
0269-9370 (ISSN-L)
DOI
10.1097/qad.0b013e3283174636
PMC
PMC2679976
OpenAlex
W2083751424
Cited by
269
References
74
Citations by year
2026: 3 · 2025: 5 · 2024: 4 · 2023: 3 · 2022: 8 · 2021: 19 · 2020: 10 · 2019: 10 · 2018: 8 · 2017: 17 · 2016: 10 · 2015: 21 · 2014: 17 · 2013: 30 · 2012: 40
FWCI
4.32
Type
journal article
Language
en
Open access
Locations
  • AIDS (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders
National Institute of Allergy and Infectious Diseases (U01AI068641)
Topics
  • Health Sciences › Medicine › Emergency Medicine › HIV-related health complications and treatments
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS Research and Interventions
Keywords
HIV, non-AIDS events, liver cirrhosis, end-stage renal disease, cardiovascular disease, myocardial infarction, stroke, coronary artery disease, highly active antiretroviral therapy, CD4 count, HIV-associated liver disease, HIV-associated nephropathy, HIV-associated cardiovascular disease, HIV-associated cancer
MeSH terms
Cardiovascular Diseases, Digestive System Diseases, Humans, Kidney Diseases, Neoplasms, RNA, T-Lymphocytes, HIV-1, HIV Infections, Randomized Controlled Trials as Topic, CD4 Lymphocyte Count, Antiretroviral Therapy, Highly Active

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