Antiretroviral Treatment Interruption May Be a Viable Strategy if CD4 Cell Count Remains High

Several studies over the past few years have contributed to a growing body of evidence indicating that interruption of antiretroviral therapy (ART) is a potentially risky strategy.

In the large SMART trial, for example, participants who interrupted therapy while their CD4 count was above 350 cells/mm3 and resumed when it fell to 250 cells/mm3 not only had a higher rate of AIDS-related opportunistic disease or death due to any cause, but also were more likely to develop serious cardiovascular, liver, and kidney disease compared with patients who remained on continuous therapy.

Although one rationale for structured treatment interruption is avoidance of long-term toxicities and side effects, several studies have indicated that stopping therapy produced considerable risk but little of the expected benefit.

But treatment interruption may be a suitable strategy for certain patients who maintain high CD4 cell counts, according to results from the Italian LOTTI (LOng Term Treatment Interruption) trial reported in the April 27, 2009 issue of AIDS.

Franco Maggiolo and colleagues conducted a study comparing continuous combination ART versus CD4 count-guided scheduled treatment interruption. Unlike SMART, however, the threshold for resuming ART in LOTTI was 350 cells/mm3 (the current threshold for starting ART in current U.S. and European treatment guidelines).

A total of 329 participants enrolled in the study, making it the second largest treatment interruption trial after SMART. Nearly three-quarters were men and the mean age was 40 years. At baseline, they had a CD4 count above 700 cells/mm3, a CD4 nadir (lowest-ever level) no less than 200 cells/mm3, HIV viral load less than 50 copies/mL, and had been on a stable ART regimen (at least 3 drugs) for at least 6 months.

Participants were randomly assigned (1:1) to the 2 strategy arms. Treatment interruptions were individualized with the aim of keeping the CD4 cell count above 350 cells/mm3 with the shortest possible exposure to drugs. Patients in the treatment interruption arm stopped all their antiretroviral drugs at once. They generally resumed the same regimen they had stopped, but in either arm modifications were permitted due to drug-associated toxicity, clinical HIV disease progression, or to comply with changing treatment guidelines.

Participants were followed for a mean 4.2 years, contributing a total of 1388 person-years of follow-up data. The primary endpoint was development of an opportunistic disease, death from any cause, or the occurrence of non-opportunistic diseases requiring hospital admission. Secondary endpoints were major adverse effects, virological failure, and cost of therapy.

Results

• Participants in the scheduled treatment interruption group stopped therapy 1 to 5 times, for a total of 241 treatment interruption cycles; the mean duration of a treatment interruption cycle was 821 days.
• 109 patients interrupted treatment only once, either because they never reached the CD4 cell threshold to resume therapy (45 patients) or did not achieve the baseline CD4 cell count of 700 cells/mm3 after restarting therapy (64 patients).
• Patients in the scheduled treatment interruption arm were off therapy for an average of 65.3% of the follow-up period, compared with 1.7% in the continuous therapy arm.
• Treatment interruptions were always associated with a rapid increase in HIV RNA blood levels.
• However, patients generally promptly responded to ART reintroduction; 76.3% again had HIV RNA < 400 copies/mL within 2 months after reintroduction, and all but 1 had > 50 copies/mL within 8 months.
• 12.1% of patients in the scheduled treatment interruption arm and 11.6% in the continuous therapy arm reached one of the primary endpoints, which was not a significant difference (odds ratio [OR] 1.05).
• All deaths were due to myocardial infarction, and there was only 1 observed AIDS-defining event (progressive multifocal leukoencephalopathy in a patient who refused to restart therapy after reaching the CD4 reintroduction threshold).
• Several other clinical events not leading to hospitalization were observed (22 in the treatment interruption group vs 15 in the continuous therapy arm), most commonly herpes zoster, sexually transmitted infections, pneumonia, and acute hepatitis.
• A higher proportion of patients in the scheduled treatment interruption arm were diagnosed with pneumonia (P = 0.037).
• Conversely, clinical events associated with cardiovascular risk (diabetes, hypertension, elevated blood lipids) were significantly more frequent in the continuous therapy arm (P < 0.0001).
• 8 patients in the scheduled treatment interruption arm and 11 in the continuous therapy arm developed drug resistance mutations (4.8% vs 6.7%; OR 0.79).
• The mean daily cost of treatment was 9.07 Euro (about US$12) in the treatment interruption arm versus 20.29 Euro (about US$26) in the continuous therapy arm (P < 0.0001).

Based on these findings, the researchers concluded, "The two strategies may be considered clinically equivalent. CD4 cell-guided scheduled treatment interruptions seem a possible alternative for chronically infected individuals responding to HAART provided that CD4 cell decrements would be steadily maintained above a safe threshold."

"The results of LOTTI indicate that the long-term clinical outcome of a CD4 cell-guided STI strategy might be equivalent to continuous HAART," they wrote, suggesting that discrepancies between LOTTI and previous studies including SMART are likely due to the higher CD4 threshold.

In an accompanying editorial, Bernard Hirschel from Geneva University Hospital in Switzerland and Timothy Flanigan from Brown University Medical School sought to make sense of the disparate results of the LOTTI and SMART trials and their implications for clinical care.

With regard to higher cardiovascular risk in the treatment interruption arm of SMART but in the continuous therapy arm of LOTTI, the authors suggested that the cardiovascular benefits associated with less time on treatment may only become apparent later and therefore were not seen in SMART, which was stopped early (median follow-up of 16 months). They did not, however, discuss inflammation associated with ongoing HIV replication, which some recent studies implicate as playing a role in non-opportunistic disease in untreated patients.

"Many of our patients with high CD4 cell counts want to stop treatment," Hirschel and Flanigan wrote. "The LOTTI study does not justify a recommendation in that regard, but it does give clinicians useful information that it is probably safe to stop treatment within the limits of CD4 cell counts of LOTTI. Continued vigilance is needed so that excellent adherence is maintained when patients are on HAART to prevent the emergence of resistance."

4/24/09

References

F Maggiolo, M Airoldi, A Callegaro, and others. CD4 cell-guided scheduled treatment interruptions in HIV-infected patients with sustained immunologic response to HAART. AIDS 27(7): 799-807. April 27, 2009. (Abstract).

B Hirschel and T Flanigan. Is it smart to continue to study treatment interruptions? (Editorial comment). AIDS 27(7): 757-759. April 27, 2009.