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Pegylated Interferon May Maintain HIV Suppression and Reduce Viral DNA Integration

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Adding pegylated interferon alfa to antiretroviral therapy (ART) for HIV may help some people control viral replication when they interrupt treatment, according to a small study reported at this year's Conference on Retroviruses and Opportunistic Infections (CROI 2012) and published in the October 26, 2012, advance online edition of the Journal of Infectious Diseases.

Most people with HIV are unable to control the virus long-term without treatment. Studies such as SMART have shown that ART interruption is harmful overall; however, researchers must attempt brief treatment interruptions to determine whether various cure approaches are able to maintain viral suppression or achieve viral eradication.

Livio Azzoni and Luis Montaner from the Wistar Institute in Philadelphia and colleagues looked at 23 HIV positive individuals who were on ART with suppressed viral load < 50 copies/mL and CD4 T-cells counts > 450 cells/mm3.

Study participants were randomly assigned to add either 90 or 180 mcg/week pegylated interferon alfa-2a (Pegasys) -- the latter being the dose typically used to treat chronic hepatitis C -- to their current ART regimen. After 5 weeks, patients stopped ART and continued on pegylated interferon alone for up to 12 weeks (the primary endpoint), with an option to continue through 24 weeks.

Results

  • At 12 weeks, 9 of 20 participants (45%) who stayed on pegylated interferon monotherapy maintained viral suppression < 400 copies/mL.
  • Looking at all 23 randomized participants, 39% remained suppressed.
  • In both analyses, people in both dose arms were significantly more likely to maintain viral suppression than expected based on prior ART-interruption studies without interferon.
  • Among 8 participants who continued on pegylated interferon alone through 24 weeks, 6 had < 400 and 3 had < 50 copies/mL.
  • Here too, people in both dose arms were significantly less likely to experience viral load rebound than historical controls not using interferon.
  • People who maintained viral load < 400 copies/mL had significantly reduced levels of integrated HIV DNA in CD4 cells.
  • However, these participants had increased residual viral load compared to people with virological failure.

Based on these findings, the study authors summarized, "[Pegylated interferon alfa-2a] immunotherapy resulted in control of HIV replication and decreased HIV-1 integration, supporting a role for immune-mediated approaches in HIV suppression and/or eradication."

Participants on ART with good immunological recovery likely had restored immune cell subsets including natural killer cells and CD8 T-cells, as well as activation of host antiviral factors, enabling type 1 interferons to stimulate immune responses against HIV, they explained in their discussion.

"Our approach may have contributed to [decreased integrated HIV DNA] by allowing residual HIV replication to trigger immune responses restored by long-term ART, and capable of clearing infected cells expressing HIV proteins," they continued. "[O]ne hypothesis is that [pegylated interferon alfa] resulted in an immune-mediated reduction in the size of the cellular latent reservoir."

"It will be important for future studies to determine whether [pegylated interferon alfa] treatment can stabilize the viral setpoint to these low levels, sustaining viral control over time," they added.

"Our study provides a proof-of-concept that immunotherapy can be pursued in HIV-infected ART-dependent subjects to reach a status of viral control beyond ART and could complement current research approaches to current 'functional cure' and eradication," the researchers concluded.

In an accompanying editorial, Lucy McNamara and Kathleen Collins from the University of Michigan at Ann Arbor wrote, "Although the results of the present study need to be confirmed in a larger cohort, the clinical implications of this research are promising.

"[Azzoni and colleagues] have demonstrated that it is possible to subject participants to [structured treatment interruptions] without increasing the reservoir of HIV DNA in the peripheral blood," they continued. "[T]his result suggests that [interferon alfa] administration before and during [structured treatment interruptions] could provide a safer way to evaluate viral control in the absence of HAART."

11/9/12

References

L Azzoni, AS Foulkes, E Papasavvas, LJ Montaner, et al. Pegylated interferon-alpha-2a mono-therapy results in suppression of HIV-1 replication and decreased cell-associated HIV DNA integration. Journal of Infectious Diseases. October 26, 2012 (Epub ahead of print).

L McNamara and K Collins. Interferon-alpha therapy: towards an improved treatment for HIV. Journal of Infectious Diseases. October 26, 2012 (Epub ahead of print).