SMART Data Confirm Risk of CD4-guided Treatment Interruptions

By Liz Highleyman

Interruption of antiretroviral therapy is a potentially hazardous strategy associated with an increased risk of disease progression or death, according to data from the large international SMART (Strategies for Management of Antiretroviral Therapy) study.

The complete findings from the trial were published last week in the November 30, 2006 issue of the New England Journal of Medicine. Data from SMART were first reported at the 2006 Retrovirus conference last February, with additional updates presented at the 16th International AIDS Conference this summer in Toronto.

The SMART trial, which began in January 2002, included 5472 HIV positive adult participants at more than 300 sites in 33 countries, of whom 95% had prior antiretroviral treatment experience. The subjects, who started the study with CD4 cell counts above 350 cells/mm3, were randomly assigned to one of 2 treatment arms:

Drug conservation/treatment interruption (n = 2720): participants deferred or suspended antiretroviral therapy as long as CD4 cell counts remained above 350 cells/mm3, and started or resumed treatment when counts fell below 250 cells/mm3;

Viral suppression (n = 2752): participants remained on continuous antiretroviral therapy.

Going into the trial, researchers hypothesized that taking breaks from treatment might preserve future treatment options (by delaying drug resistance) and reduce the adverse side effects and long-term toxicities of antiretroviral therapy.

The drug conservation arm was prematurely discontinued in January 2006 after it became apparent that participants in that group had higher rates of opportunistic illness (OI) and death compared with those receiving continuous therapy.

While the increased OI rate was not entirely surprising, patients in the treatment interruption arm also had an unexpectedly higher rate of conditions such as cardiovascular, kidney, and liver problems, which are usually considered to be non-HIV/AIDS-related and are assumed to be associated with HAART.

Results

Baseline characteristics were similar in the 2 arms; the median CD4 cell count was 597 cells/mm3, median CD4 cell nadir was 250 cells/mm3, and 71.7% of participants had HIV viral loads of 400 copies/mL or less.

The average follow-up duration before the drug conservation arm was halted was 16 months.

Drug conservation participants were on therapy for 33.4% of the total follow-up time, compared with 93.7% in the continuous therapy arm.

CD4 counts decreased by an average of 87 cells/mm3 per month during the first 2 months in the drug conservation group, and thereafter continued to decline at a slower rate.

On average, throughout follow-up, the CD4 count was 206 cells/mm3 lower in the drug conservation group.

Participants in the drug conservation group spent 8.6% of follow-up time at CD4 counts below 250 cells/mm3, compared with 1.8% in the viral suppression group.

Within 2 months, the percentage of participants with HIV RNA below 400 copies/mL decreased from 71.8% to 6.0% in the drug conservation arm.

In both groups, the leading causes of death were non-opportunistic cancers, cardiovascular disease, substance abuse, and accidents/violence/suicide; 8% of deaths overall were due to opportunistic disease.

Opportunistic disease or death from any cause occurred in 120 participants (4.4%) in the drug conservation group, compared with 47 (1.7%) in the viral suppression group:

- deaths due to any cause: 55 vs 30;
- non-fatal disease: 65 vs 17;
- serious OIs: 13 vs 2;
- fatal or nonfatal kidney disease: 9 vs 2;
- fatal or non-fatal cardiovascular events: 48 vs 31.

The combined rate of OIs or death was 1.3 per 100 person-years in the drug conservation arm, compared with 3.3 per 100 person-years in the continuous therapy arm (hazard ratio 2.6; 95% CI 1.9-3.7; P < 0.001).

Adjusting for the most recent CD4 count and HIV RNA level reduced the hazard ratio from 2.6 to 1.5 (95% CI 1.0-2.1).

The hazard ratio for death from any cause was 1.8 (95% CI 1.2-2.9; P = 0.007).

The hazard ratio for serious OIs was 6.6 (95% CI 1.5-29.1; P = 0.01), while for non-serious OI-associated events it was 3.6 (95% CI 2.1-6.1; P < 0.001).

Significantly more participants in the drug conservation arm experienced at least 1 episode of major cardiovascular, kidney, or liver disease (65 vs 39; hazard ratio 1.7; 95% CI 1.1-2.5; P = 0.009).

Symptomatic Grade 4 adverse events occurred in 173 participants in the drug conservation group vs 148 in the viral suppression group (hazard ratio 1.2; 95% CI 1.0-1.5; P = 0.13)

Conclusion and Discussion

"Episodic antiretroviral therapy guided by the CD4+ count, as used in our study, significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy, largely as a consequence of lowering the CD4+ cell count and increasing the viral load," the authors concluded. "Episodic antiretroviral therapy does not reduce the risk of adverse events that have been associated with antiretroviral therapy."

In their discussion, the authors wrote, "contrary to available data and to the assumptions underlying our study design, participants in the drug conservation group had a higher rate of major cardiovascular, renal, or hepatic disease than did those in the viral suppression group. On the basis of prior findings, and as a consequence of less exposure to antiretroviral therapy in the drug conservation group, we expected the rate of cardiovascular disease to be 15% lower in the drug conservation group than in the viral suppression group."

"Some antiretroviral drugs have been associated with adverse hepatic and renal events, but recent findings indicate that these events are also related to the level of immunodeficiency and that antiretroviral therapy improves these outcomes either directly by inhibiting viral replication or indirectly by improving immune function," they continued. "Our data support these findings. Adjustment for the latest CD4+ count reduced the hazard ratio in the drug conservation group versus the viral suppression group for death from causes other than opportunistic disease, confirming that immunosuppression increases the risk of death among patients with diseases not traditionally believed to be opportunistic in nature."

They also noted that while some subgroups (e.g., black and Latino patients, those with lower viral loads) had higher rates of disease progression or death, the benefits of the continuous therapy strategy were evident across the board.

"In summary, our findings provide clear and compelling evidence that the episodic antiretroviral strategy, guided by the CD4+ count, used in the SMART study is deleterious," they concluded. "Much, but not all, of the difference in the rates of opportunistic disease or death from any cause between the drug conservation group and the viral suppression group was explained by differences in the CD4+ count and HIV RNA level during follow-up…The reasons for the remaining excess risk are not clear."

Commenting on the results, SMART co-chair Wafaa El-Sadr, MD, said, "Quite unexpectedly, our results show that interrupting therapy increases the risk of serious non-AIDS-related events…This is a major lesson learned for designing any HIV/AIDS treatment trial: It is important to evaluate all causes of death, not just death from AIDS, and to also evaluate other major non-fatal clinical diseases, not just those considered AIDS-related opportunistic diseases."

"Treatment may increase the risk" of cardiovascular, liver, and kidney disease, added co-chair James Neaton, PhD, "but the absence of treatment appears to increase the risk even more."

While the reason for the increased rate of conditions usually not considered to be AIDS-related is unclear, experts have suggested that chronic inflammation associated with HIV infection may play a role, in ways that are not yet fully understood.

Editorial

In an accompanying editorial, Judith Currier, MD, and Lindsey Baden, MD, discussed the clinical implications of the SMART findings.

"The design of the SMART trial was controversial," they recalled. "In 2000 through 2002, when the study was on the drawing board, the scientific community was divided as to the appropriateness of the question. Some believed that it was hazardous to stop antiretroviral therapy in patients with a history of AIDS, whereas others thought there was equipoise between the risk of disease progression and the risk of toxic effects from the use of medication in the setting of close monitoring. In the end, the majority of the scientific community agreed that answering the question was critical."

The rate at which patients developed opportunistic diseases in the drug conservation group was "not completely unexpected," they said. "However, the overall rate of death and the higher-than-expected rate of major cardiovascular, renal, or hepatic disease in the drug conservation group exceeded predictions…It is notable that the increase in mortality in the drug conservation group as compared with the viral suppression group was not clearly associated with traditional HIV-related events; the cause of more than a quarter of the deaths in the drug conservation group was unknown."

"The most unexpected finding was that the rates of non-opportunistic disease and death were higher in the drug conservation group than in the viral suppression group," they continued. "The drug conservation group should have been relatively protected from events that are usually considered to be side effects of treatment…This observation raises questions about the contribution of
uncontrolled HIV replication to short-term cardiovascular risk."

Finally, they asked whether the SMART findings should end research on intermittent antiretroviral therapy, given than other trials -- some of which used different interruption strategies, including higher CD4 cell cut-offs -- have produced conflicting results.

Intermittent strategies may be appropriate in certain circumstances, they suggested, such as for patients with acute HIV infection or women with CD4 counts above 350 cells/mm3 who receive antiretroviral therapy to prevent mother-to-child HIV transmission. Shorter periods of treatment interruption may also be safe for some individuals.

"We may learn that the only people in whom therapy can be safely interrupted for long periods are those who do not require it in the first place," they concluded. "Given the deleterious effects of uncontrolled HIV replication, we must continue to re-evaluate the optimal criteria for the initiation of antiretroviral therapy. In the future, we can only hope to be smart enough to identify ways to make antiretroviral therapy less costly and less toxic."

12/05/06

References

W M El-Sadr, J D Lundgren, J Neaton, and other (the SMART Study Group). CD4+ Count-Guided Interruption of Antiretroviral Treatment. New England J Medicine 355(22): 2283-2296. November 30, 2006.

J S Currier and L R Baden. Getting Smarter -- The Toxicity of Undertreated HIV Infection. New England J Medicine 355(22): 2359-2361. November 30, 2006.