Do IL-2 and Hydroxyurea Facilitate Structured Treatment Interruption?

By Liz Highleyman

Among the topics that generated the most interest at this years Conference on Retroviruses and Opportunistic Infections was a series of reports indicating that CD4 cell count-guided structured treatment interruptions of antiretroviral therapy not only do not appear to be beneficial, but may actually be harmful.

Treatment interruption has been proposed as a strategy for stimulating the immune response to HIV, forcing the virus to revert to the more drug-susceptible wild-type, reducing long-term toxicities associated with antiretroviral therapy, and giving patients a break from taking pills every day.

However, as reported at the February conference, the treatment-interruption arms of three trials¾SMART, DART, and Trivican¾were stopped early after it was observed that participants in these arms were significantly more likely to experience serious illness or death; in the SMART study, patients who interrupted therapy also experienced more cardiovascular, liver, and kidney problems. In his plenary address, John Bartlett, MD, of Johns Hopkins University declared that treatment interruption studies to date have been disappointing.

Two studies published in the June 2006 Journal of Acquired Immune Deficiency Syndromes evaluated structured treatment interruption augmented by adjunct therapies, either the cytokine interleukin-2 (IL-2) or hydroxyurea (also known as hydroxycarbamide, brand name Hydrea).

Interleukin-2

Keith Henry, MD, and colleagues reported data from AIDS Clinical Trials Group (ACTG) A5102, a pilot study evaluating three cycles of IL-2 before antiretroviral treatment interruption. The researchers noted that treatment interruption is limited by concerns about virological failure, selection of drug-resistance mutations, and HIV disease progression. They sought to determine whether boosting CD4 cell counts using IL-2 could safely prolong the duration of CD4-guided interruptions.

The study included 47 HIV positive patients on potent HAART with CD4 cell counts of at least 500 cells/mm³ and HIV RNA levels less than 200 copies/mL. Subjects were randomly assigned to one of two arms:

• Arm A: HAART plus three 5-day cycles of IL-2 (4.5 million units by subcutaneous injection twice daily) every 8 weeks
• Arm B: HAART alone for 18 weeks

At the end of this first phase, patients with CD4 cells counts of 500 cells/mm³ or more stopped antiretroviral therapy until their CD4 counts dropped below 350 cells/mm³, at which point they resumed HAART. The researchers analyzed the time to virological rebound and emergence of drug-resistance mutations.

Results

• Patients receiving IL-2 maintained higher CD4 cell counts during treatment interruption for 48 weeks, with a waning of this effect by week 72.
• A sustained CD4 count of more than 350 cells/mm³ and longer (more durable) treatment interruption were associated with a higher nadir (lowest ever) CD4 cell count before starting HAART, and with a higher naïve CD4 count at study entry.
• After treatment interruption, a higher viral set-point and drug-resistance mutations at the time of virological rebound were associated with a shorter time until CD4 cell count fell below 350 cell/mm³.
• There were no differences in the magnitude of virological rebound or the steady-state HIV RNA level after week 8 of the treatment interruption phase.
• At week 8 of the treatment interruption phase, the median HIV viral load was 4.23 log₁₀ in Arm A and 4.21 log₁₀ in Arm B.

Conclusion

The authors concluded that administration of IL-2 before structured treatment interruption did not prolong the time it took for CD4 cell counts to fall below 350 cells/mm³. A treatment interruption strategy utilizing a CD4 cell threshold of less than 350 cells/mm³ for restarting HAART “appears generally safe,” they said, with most subjects in both arms remaining off antiretroviral therapy for more than one year. The researchers added that the implications of their results include the potential advantage of starting HAART at a higher CD4 cell counts while avoiding drug resistance, and recommended further evaluation of immunomodulators or drugs to reduce T-cell activation and virological rebound during treatment breaks.

Hydroxyurea

Mark Bloch, MB BS, and colleagues evaluated the role of hydroxyurea in enhancing virological control during structured treatment interruptions in patients with primary (acute) HIV infection. The researchers noted that such interruptions have been proposed as a way to improve virological control during primary infection by stimulating HIV-specific T-lymphocyte immunity; addition of hydroxyurea may reduce viral production from activated CD4 cells.

This study included 68 patients (all gay men) with primary HIV infection. The median baseline viral load was 5.73 log₁₀ copies/mL and the median CD4 cell count was 517 cells/mm³. For up to 12 months, all subjects received a standardized antiretroviral regimen consisting of:

• 800 mg twice-daily indinavir (Crixivan)
• 100 mg twice-daily ritonavir (Norvir)
• 400 mg once-daily ddI (didanosine, Videx), and
• either 40 mg twice-daily d4T (stavudine, Zerit) or 150 mg twice-daily 3TC (lamivudine, Epivir).

In addition, subjects were randomly assigned to either receive or not receive 500 mg twice-daily hydroxyurea. If virological suppression was achieved (< 50 copies/mL), up to three structured treatment interruptions were undertaken. Two antiretroviral cycles were permitted after each interruption if viral load rebounded to more than 5000 copies/mL. Treatment success was defined as maintaining a viral load below 5000 copies/mL for six months after interruption of antiretroviral therapy.

Results

• Treatment success rates did not differ significantly between individuals receiving and not receiving hydroxyurea.
• 9 patients in each arm (26% and 27%, respectively) maintained viral loads less than 5000 copies/mL (P = 0.88).
• 11 out of 59 patients (19%) achieved virological control after one treatment interruption, 1 of out 41 (2%) after two interruptions, and 6 out of 36 (17%) after three interruptions.
• Serious adverse events were observed in 9 out of 35 patients (26%) using hydroxyurea, and 3 out of 33 (9%) in the HAART-only group (P = 0.28).
• CD4 cell increases were significantly blunted in the hydroxyurea arm compared with the HAART-only group after the initial treatment phase (101 vs 196 cells/mm³, respectively; P = 0.006).

Conclusion

The authors concluded that hydroxyurea was not found to be beneficial when used in association with structured treatment interruption during primary HIV infection.

Together, these studies suggest that adjunct therapies tested to date do not facilitate safe treatment interruption. IL-2 did not prolong the time it took for CD4 cell counts to fall below 350 cells/mm³, and hydroxyurea was actually associated with smaller CD4 cell increases. While structured treatment interruption appeared relatively safe, these studies were small and were conducted before the latest disappointing results from much larger trials were announced.

6/23/06

Reference

K Henry, D Katzenstein, DW Cherng, and others. A Pilot Study Evaluating Time to CD4 T-cell Count <350 cells/mm³ after Treatment Interruption Following Antiretroviral Therapy +/- Interleukin 2: Results of ACTG A5102. Journal of Acquired Immune Deficiency Syndromes 42(2): 140-149. June 2006.

M Bloch, T Mark, FP Dip, and others. The Role of Hydroxyurea in Enhancing the Virologic Control Achieved through Structured Treatment Interruption in Primary HIV Infection: Final Results from a Randomized Clinical Trial (Pulse). Journal of Acquired Immune Deficiency Syndromes 42(2): 192-202. June 2006.