Safety, Tolerability, and Mechanisms of Antiretroviral Activity of Pegylated Interferon Alfa-2a in HIV-1- Monoinfected Participants: A Phase II Clinical Trial

David M. Asmuth () 2 Robert L. Murphy 0 Susan L. Rosenkranz 6 Juan J. L. Lertora 5 Shyam Kottilil 5 Yoninah Cramer 6 0 Northwestern University , Evanston, Illinois 1 University of California , San Diego 2 University of California-Davis Medical School , Sacramento 3 University of Pittsburgh , Pittsburgh, Pennsylvania 4 SAIC-Frederick, Frederick, Maryland 5 National Institutes of Health Clinical Center , Bethesda 6 Harvard School of Public Health , Boston, Massachusetts 7 Frontier Science and Technology Research Foundation , Amherst, New York 8 Duke University , Durham, North Carolina Background. To our knowledge, the antiviral activity of pegylated interferon alfa-2a has not been studied in participants with untreated human immunodeficiency virus type 1 (HIV-1) infection but without chronic hepatitis C virus (HCV) infection. Methods. Untreated HIV-1-infected volunteers without HCV infection received 180 mg of pegylated interferon alfa-2a weekly for 12 weeks. Changes in plasma HIV-1 RNA load, CD4+ T cell counts, pharmacokinetics, pharmacodynamic measurements of 2 ,5 -oligoadenylate synthetase (OAS) activity, and induction levels of interferoninducible genes (IFIGs) were measured. Nonparametric statistical analysis was performed. Results. Eleven participants completed 12 weeks of therapy. The median plasma viral load decrease and change in CD4+ T cell counts at week 12 were 0.61 log10 copies/mL (90% confidence interval [CI], 0.20-1.18 log10 copies/ mL) and 44 cells/mL (90% CI, 95 to 85 cells/mL), respectively. There was no correlation between plasma viral load decreases and concurrent pegylated interferon plasma concentrations. However, participants with larger increases in OAS level exhibited greater decreases in plasma viral load at weeks 1 and 2 (r p 0.75 [90% CI, 0.93 to 0.28] and r p 0.61 [90% CI, 0.87 to 0.09], respectively; estimated Spearman rank correlation). Participants with higher baseline IFIG levels had smaller week 12 decreases in plasma viral load (0.66 log10 copies/ mL [90% CI, 0.06-0.91 log10 copies/mL]), whereas those with larger IFIG induction levels exhibited larger decreases in plasma viral load ( 0.74 log10 copies/mL [90% CI, 0.93 to 0.21 log10 copies/mL]). Conclusion. Pegylated interferon alfa-2a was well tolerated and exhibited statistically significant anti-HIV-1 activity in HIV-1-monoinfected patients. The anti-HIV-1 effect correlated with OAS protein levels (weeks 1 and 2) and IFIG induction levels (week 12) but not with pegylated interferon concentrations. Trial registration. ClinicalTrials.gov identifier: NCT00078442. - Interferon a is produced predominantly by B lymphocytes, null lymphocytes, macrophages, and dendritic cells after exposure to foreign eukaryotic, tumor, or virus-infected cells. Interferons have potent and diverse immunoregulatory effects, which include induction of other cytokines, activation of macrophages and dendritic cells, augmentation of natural killer cell cytotoxicity, antibody-dependent cellular cytotoxicity and T cell cytotoxicity, and alterations of cell trafficking [13]. Studies of both RNA and DNA viruses indicate that inhibition of translation and virion assembly appears to be the principal mode of the antiviral effects of interferons [46]. Several enzyme systems that are induced by interferon (interferon-inducible genes [IFIGs]) have been shown to interfere with viral replication. These include, among others, 2 ,5 -oligoadenylate synthetase (OAS), which catalyzes the synthesis of oligonucleotides that activate the endoribonuclease RNAse L, which in turn produces cleavage of viral RNA. Interferon a inhibits both early human immunodeficiency virus type 1 (HIV-1) replication and integration [7] and latestage assembly and packaging of viral particles [8]. Over 30 different IFIGs have been implicated as playing a potential role in the inhibition of various viruses [5, 6, 9, 10]. Measurement of IFIGs has provided insight into the antiviral effects of interferon therapy in the setting of treatment of hepatitis C virus (HCV) infection and may play a role in predicting response to treatment [11]. Pegylated interferon alfa-2a (peginterferon alfa-2a) is a commercial preparation of recombinant interferon alfa-2a covalently attached to a branched mobile 40-kDa polyethylene glycol moiety, which inhibits enzymatic degradation of interferon alfa2a and allows for weekly administration. The pegylation increases the half-life of interferon alfa-2a for a sustained virological response, compared with nonpegylated interferon alfa2a [12, 13]. Peginterferon alfa-2a is approved for the treatment of HCV and hepatitis B virus (HBV) infections and has a more favorable pharmacokinetic and safety profile than those of previously available interferon alfa formulations [14, 15]. Pegylated interferon alfa-2b and peginterferon alfa-2a have only been tested for the treatment of HIV-1 infection in the setting of acute HIV1 infection in conjunction with highly active antiretroviral therapy [16, 17]. This study was therefore undertaken to test the antiviral activity, safety, and tolerability of peginterferon alfa2a (Pegasys) in HCV-uninfected, HIV-1infected volunteers who are not currently receiving antiretroviral therapy. MATERIALS AND METHODS Participants were eligible to enroll in the AIDS Clinical Trials Group Protocol 5192 if they had a CD4+ T cell count of 300 cells/mL, had a plasma HIV-1 RNA load of 5000 copies/mL, and were antiretroviral therapynaive or were antiretroviral therapyexperienced but currently not receiving therapy for at least 12 weeks. The patients must have tested negative for HBV surface antigen and HCV antibody and have had transaminase levels of grade !1 at entry. Exclusion criteria included a history of severe psychiatric illness or any history of a chronic illness, such as a cardiopulmonary disorder, that could be worsened by interferon therapy or its known toxicities. All participants expressed a willingness to defer initiation (or reinitiation) of antiretroviral therapy until after the completion of the study, although a safety clause for withdrawal from the study for a CD4+ T cell count of 200 cells/mL was stipulated in the toxicity management section of the protocol. Filgrastim (Neupogen; provided by Amgen), a granulocyte colony-stimulating factor analogue, was available for the treatment of neutropenia through the study for providers to use according to local standard-ofcare practices. Written informed consent was obtained from all participants. The primary end points were change in plasma HIV-1 RNA load from baseline to week 12 and safety and tolerability of peginterferon alfa-2a (provided by Roche Pharmaceuticals) at 180 mg given subcutaneously weekly by study personnel for 12 weeks. A post hoc decision was made to include analyses at weeks 1 and 2, when the largest decreases in HIV-1 RNA load were observed. Secondary objectives included assessment of HIV-1specific CD4+ T cell immunity while receiving treat (...truncated)