1. Home>
2. Specialties>
3. HIV/AIDS Clinical Care>
4. Feature

Serious Non-AIDS Conditions: Redefining the Spectrum of HIV-Related Disease

Non-AIDS conditions are increasingly common among HIV-infected patients. What are the implications of this trend for initiating antiretroviral therapy?

The Remarkable Success of ART
Combination potent antiretroviral therapy (ART) has transformed HIV infection from a rapidly progressive, often-fatal illness to a disease state characterized by common chronic conditions. During the early years of the epidemic, HIV-infected patients in the U.S. rarely lived more than several years beyond AIDS diagnosis. However, when PIs became the cornerstone of ART regimens in the mid-1990s, AIDS-related mortality rates began to fall rapidly. By 2003, ART was estimated to extend life expectancy beyond AIDS diagnosis by at least 14 years — a benefit exceeding that achieved with therapies for other chronic illnesses, such as coronary artery disease and certain cancers (ACC Jul 11 2006).¹ The clinical benefits associated with achieving potent virologic suppression and CD4-cell recovery early in the course of disease motivated some experts to suggest aggressive treatment strategies, such as the "hit early/hit hard" approach. Consistent with this philosophy, early treatment guidelines in the potent ART era recommended that ART be initiated when CD4 counts fell below 500 cells/mm³.

The Changing Spectrum of Morbidity and Mortality
Shortly after those guidelines were published, evidence began to emerge that the use of combination ART might be linked to seemingly new and unanticipated toxicities. Within the first 2 years of widespread PI use, case reports surfaced describing premature atherosclerotic cardiovascular disease among HIV-infected patients taking these drugs (ACC Jul 1 1998).² Insulin resistance, hypertriglyceridemia, lipodystrophy, and other metabolic complications associated with cardiovascular disease were also increasingly reported among patients taking PIs and certain NRTIs.³ Suddenly, the clinical benefits of ART had to be balanced against the long-term adverse effects. Indeed, treatment guidelines began to reflect this struggle, and the latest recommendations from both the International AIDS Society–USA and the U.S. Department of Health and Human Services are that ART be deferred until CD4 counts reach 200 to 350 cells/mm³. This CD4 range was chosen to minimize ART-associated toxicity while maximizing therapy’s beneficial effects. A large collaborative analysis⁴ demonstrated that a substantial reduction in AIDS-related events is achieved when ART is started at CD4 counts >200 cells/mm³, but little additional benefit is gained by starting ART at CD4 counts >350 cells/mm³.

Despite the movement toward a more conservative strategy for ART use, overall mortality rates among HIV-infected patients continued to show impressive declines. At the same time, causes of death in this population shifted from traditional AIDS-related illnesses to non-AIDS events (ACC Oct 2 2006),⁵ the most common being atherosclerotic cardiovascular disease, liver disease, end-stage renal disease, and non-AIDS–defining malignancies.

The Role of Immune Deficiency in Non-AIDS Conditions
Initially, the premature development of non-AIDS conditions during HIV infection was attributed to metabolic complications of ART and other drug-related toxicities. For example, in the DAD (Data collection of Adverse events of anti-HIV Drugs) study, an observational cohort of more than 23,000 HIV-infected patients, each additional year of ART use was associated with a 26% increased risk for myocardial infarction (ACC Jan 1 2004)⁶; most of this excess risk was attributable to PI use and dyslipidemia (ACC Apr 25 2007).⁷ However, additional analyses from this study also highlight the potential role of immunodeficiency in the development of non-AIDS diseases: The lower the latest CD4-cell count, the greater the risks for non-AIDS–related death in general and, more specifically, for fatal liver disease and fatal non-AIDS–related malignancies (ACC Sep 11 2006 and Apr 2 2007).^8,9

Data from both the SMART study and the FIRST trial also support the potential influence of CD4-cell counts on the development of non-AIDS diseases. In the large international SMART (Strategies for Management of Antiretroviral Therapy) study, investigators attempted to minimize end-organ complications of ART by reducing exposure to antiretrovirals through CD4-guided treatment interruptions. The trial was stopped prematurely when the Data and Safety Monitoring Board determined that treatment interruption increased the risk not only for AIDS events but also for fatal and nonfatal cardiovascular, renal, and liver events (ACC Nov 29 2006).¹⁰ Some of this excess risk was attributable to the higher viral loads and lower CD4-cell counts associated with treatment interruption. In the FIRST (Flexible Initial Retrovirus Suppressive Therapies) trial, investigators evaluated the specific contribution of CD4-cell count to risk for both fatal and severe nonfatal non-AIDS conditions (atherosclerotic cardiovascular events, end-stage renal disease, cirrhosis, and non-AIDS–defining malignancies). Non-AIDS conditions occurred as frequently as AIDS events in patients whose latest CD4 counts were >200 cells/mm³, and higher latest CD4 levels were associated with decreased risk for non-AIDS conditions, even after adjustment for additional risk factors (ACC Apr 2 2007).¹¹ A recent meta-analysis provides further support for the role of immune suppression in the development of non-AIDS–defining malignancies.¹²

The underlying mechanisms by which HIV-related immune depletion may promote non-AIDS diseases should be a priority for future research. Immune activation is a hallmark of HIV infection and an important factor in the pathogenesis of viral replication and CD4-cell depletion. Many inflammatory biomarkers that are elevated during HIV infection are also associated with progression of renal disease and with risk for cardiovascular events and certain cancers. Coinfection with other viruses, such as human papillomavirus and hepatitis B or C, in the setting of long-standing impaired immune function may also facilitate a pro-oncogenic state or contribute to the progression of end-organ diseases.

It will be important to quantify more precisely the relative influence of ART on risk for non-AIDS conditions. Available observational data indicate that maintaining higher CD4-cell counts with ART may have a net positive effect on the risk for non-AIDS conditions. This benefit is modest compared to the effect that ART has in reducing traditional AIDS illnesses, especially when therapy is used at higher CD4 levels (>350 cells/mm³). Given the reality of limited healthcare resources, the cost-effectiveness of ART when initiated at increasingly higher CD4-cell counts must be carefully assessed, particularly in relation to established interventions for reducing non-AIDS diseases, such as smoking cessation and lipid- and blood-pressure–lowering therapy.

Implications for Initiating ART
For patients with access to potent ART, non-AIDS conditions are likely to dominate the HIV landscape for the foreseeable future, creating a need for treatment approaches that minimize the risk for both AIDS and non-AIDS diseases. Given that median survival after HIV diagnosis is now estimated to be more than 30 years (ACC Mar 12 2007),¹³ the rate of many non-AIDS conditions in this population will continue to increase. These events seem to occur at least as frequently as AIDS events, if not more so, when CD4 counts are >200 cells/mm³ (ACC Apr 13 2007).^11,14 Previous recommendations, in terms of when to start ART, have been based primarily on risk for AIDS or death. However, we must now ask whether initiating ART at higher CD4 counts (>350 cells/mm³) would be more beneficial for patients’ overall health.

Past pivotal ART trials generally evaluated the efficacy of treatment based on AIDS-defining events or HIV-related surrogate markers (viral loads or CD4-cell counts), with little emphasis on key non-AIDS clinical events. Furthermore, data are lacking on the risk for non-AIDS conditions before initiation of ART, when CD4-cell counts are declining and viral loads are high. We must determine whether starting ART at higher CD4-cell counts will indeed prevent non-AIDS events during this period, leading to further reductions in HIV-related morbidity and mortality. Earlier use of ART inherently means longer exposure to these medications, which appears itself to be a competing risk factor for some non-AIDS conditions.⁶

Potent ART has been remarkably effective for the treatment of HIV infection, saving countless lives and transforming the way we practice HIV medicine. However, after more than a decade of clinical experience, we still do not know the optimal time for starting ART, in terms of a patient’s comprehensive long-term health. Given the importance of this issue, further studies should focus on evaluating the overall long-term health effects of starting ART at higher CD4-cell counts.

— Jason Baker, MD, MS, and Keith Henry, MD

Dr. Baker is an Assistant Professor of Medicine at the University of Minnesota and a staff physician in HIV medicine and Infectious Diseases at Hennepin County Medical Center in Minneapolis. Dr. Henry is a Professor of Medicine at the University of Minnesota and is the Director of HIV Clinical Research at Hennepin County Medical Center.

Published in AIDS Clinical Care July 30, 2007

Citation(s):

1. Walensky RP et al. The survival benefits of AIDS treatment in the United States. J Infect Dis 2006 Jul 1; 194:11-9.

• Medline abstract (Free)

2. Henry K et al. Severe premature coronary artery disease with protease inhibitors. Lancet 1998 May 2; 351:1328.

• Medline abstract (Free)

3. Morse CG and Kovacs JA. Metabolic and skeletal complications of HIV infection: The price of success. JAMA 2006 Aug 16; 296:844-54.

• Original article (Subscription may be required)
• Medline abstract (Free)

4. Egger M et al. Prognosis of HIV-1–infected patients starting highly active antiretroviral therapy: A collaborative analysis of prospective studies. Lancet 2002 Jul 13; 360:119-29. [Erratum in: Lancet 2002 Oct 12; 360:1178.]

• Medline abstract (Free)

5. Sackoff JE et al. Causes of death among persons with AIDS in the era of highly active antiretroviral therapy: New York City. Ann Intern Med 2006 Sep 19; 145:397-406.

• Original article (Subscription may be required)
• Medline abstract (Free)

6. Friis-Møller N et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003 Nov 20; 349:1993-2003. [Erratum in: N Engl J Med 2004 Feb 26; 350:955.]

• Original article (Subscription may be required)
• Medline abstract (Free)

7. DAD Study Group. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med 2007 Apr 26; 356:1723-35.

• Original article (Subscription may be required)
• Medline abstract (Free)

8. Weber R et al. Liver-related deaths in persons infected with the human immunodeficiency virus: The D:A:D study. Arch Intern Med 2006 Aug 14/28; 166:1632-41.

• Original article (Subscription may be required)
• Medline abstract (Free)

9. d’Arminio Monforte A et al. HIV-induced immunodeficiency and risk of fatal AIDS-defining and non-AIDS-defining malignancies: Results from the D:A:D study. Presented at: 14th Conference on Retroviruses and Opportunistic Infections; February 27 , 2007; Los Angeles. Abstract 84.

10. Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count–guided interruption of antiretroviral treatment. N Engl J Med 2006 Nov 30; 355:2283-96.

• Original article (Subscription may be required)
• Medline abstract (Free)

11. Baker J et al. HIV-related immune suppression after ART predicts risk of non-opportunistic diseases: Results from the FIRST study. Presented at: 14th Conference on Retroviruses and Opportunistic Infections; February 26 , 2007; Los Angeles. Abstract 37.

12. Grulich AE et al. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: A meta-analysis. Lancet 2007 Jul 7; 370:59-67.

• Medline abstract (Free)

13. Lohse N et al. Survival of persons with and without HIV infection in Denmark, 1995–2005. Ann Intern Med 2007 Jan 16; 146:87-95.

• Original article (Subscription may be required)
• Medline abstract (Free)

14. Lau B et al. Risk of non–AIDS-related mortality may exceed risk of AIDS-related mortality among individuals enrolling into care with CD4⁺ counts greater than 200 cells/mm³. J Acquir Immune Defic Syndr 2007 Feb 1; 44:179-87.

• Medline abstract (Free)