Immune Suppression While on Antiretroviral Therapy Predicts Risk of Non-Opportunistic Diseases

One of the biggest surprises of the SMART trial (also known as the Strategies for Management of Anti-Retroviral Therapy trial), which was first presented during the 13th Conference on Retroviruses and Opportunistic Infections (CROI 2006) in Denver last year¹ (and recently published in the New England Journal of Medicine²), was the high frequency of non-AIDS-related events among patients who had temporarily stopped antiretroviral therapy.

SMART had randomized HIV-infected individuals to two different strategies: one to completely suppress viral replication and the other to minimize patients' drug exposure while maintaining a reasonably elevated CD4+ cell count. What the researchers found was that individuals who discontinued antiretroviral therapy not only had more AIDS-related events, but also experienced an increased frequency of events not "typically" associated with HIV infection, such as cardiovascular events, liver toxicity or renal events.

The presentation of that data generated a lot of interest in understanding the role HIV itself had in driving those events. Previously, antiretroviral treatment had been blamed for any complication experienced by patients that was not an opportunistic infection or cancer.

The purpose of this study, presented at CROI 2007 by Jason Baker,³ was to look at the incidence of opportunistic infections and non-opportunistic infection events in the setting of a large CPCRA (Terry Beirn Community Programs for Clinical Research on AIDS) trial. The researchers used the FIRST trial, a trial which had randomized 1,397 patients to three different therapeutic strategies: a protease inhibitor (PI)-based regimen, a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, and a three-class regimen.

Approximately 470 patients were randomized to each strategy. The results of this trial were published last year in Lancet.⁴

The researchers classified the events as "opportunistic infections" (defined by U.S. Centers for Disease Control and Prevention modified AIDS criteria⁵) and "non-opportunistic infection" events. Non-opportunistic infections included liver events, cardiovascular events, renal events and all cancers.

Not surprisingly, opportunistic infection events tended to occur in individuals with detectable HIV viral loads and low CD4+ cell counts. Non-opportunistic events were also found to be more frequent in individuals with low CD4+ cell counts. Although these events decreased with treatment, their decrease after the initiation of antiretroviral therapy was found to be not as marked as the decrease of opportunistic infections. In individuals who had CD4+ cell counts of more than 200 cells/mm³, non-opportunistic infection events were even more common than opportunistic infection events.

I do not think anybody was surprised by the results of this study. Having ongoing HIV replication and a low CD4+ cell count are not good for anyone's health and put patients at risk not only for opportunistic infections, but also for other dangerous illnesses.

Switching to more potent treatment is recommended for anyone who is experiencing ongoing replication and a low CD4+ cell count. It's not a good idea to remain in this state for any extended period of time. The study investigators point out that non-opportunistic infection problems are very common among HIV-infected individuals and that clinicians need to pay attention to them and not assume that by taking care of the HIV the non-opportunistic infections will disappear on their own.

Footnotes

1. El-Sadr W, Neaton J, for the SMART Study Investigators. Episodic CD4-guided use of ART is inferior to continuous therapy: results of the SMART Study. In: Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colo. Abstract 106LB.

2. The SMART Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. November 30, 2006;355(22):2283-2296.

3. Baker J, Peng G, Rapkin J, et al, and Terry Beirn Community Prgms for Clin Res on AIDS (CPCRA). HIV-related immune suppression after ART predicts risk of non-opportunistic diseases: results from the FIRST Study. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Oral 37.
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4. MacArthur RD, Novak RM, Peng G, et al, for the CPCRA 058 Study Team and the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). A comparison of three highly active antiretroviral treatment strategies consisting of non-nucleoside reverse transcriptase inhibitors, protease inhibitors, or both in the presence of nucleoside reverse transcriptase inhibitors as initial therapy (CPCRA 058 FIRST Study): a long-term randomised trial. Lancet. December 16, 2006;368(9553):2125-2135.

5. Castro KG, Ward JW, Slutsker L, et al. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep. December 18, 1992;41(RR-17).