Pegylated Interferon alfa-2a monotherapy results in suppression of HIV type 1 replication and decreased cell-associated HIV DNA integration

Abstract

Background: Antiretroviral therapy (ART)-mediated immune reconstitution fails to restore the capacity of the immune system to spontaneously control human immunodeficiency virus (HIV) replication.

Methods: A total of 23 HIV type 1 (HIV-1)-infected, virologically suppressed subjects receiving ART (CD4(+) T-cell count, >450 cells/μL) were randomly assigned to have 180 μg/week (for arm A) or 90 μg/week (for arm B) of pegylated (Peg) interferon alfa-2a added to their current ART regimen. After 5 weeks, ART was interrupted, and Peg-interferon alfa-2a was continued for up to 12 weeks (the primary end point), with an option to continue to 24 weeks. End points included virologic failure (viral load, ≥ 400 copies/mL) and adverse events. Residual viral load and HIV-1 DNA integration were also assessed.

Results: At week 12 of Peg-interferon alfa-2a monotherapy, viral suppression was observed in 9 of 20 subjects (45%), a significantly greater proportion than expected (arm A, P = .0088; arm B, P = .0010; combined arms, P < .0001). Over 24 weeks, both arms had lower proportions of subjects who had viral load, compared with the proportion of subjects in a historical control group (arm A, P = .0046; arm B, P = .0011). Subjects who had a sustained viral load of <400 copies/mL had decreased levels of integrated HIV DNA (P = .0313) but increased residual viral loads (P = .0078), compared with subjects who experienced end-point failure.

Conclusions: Peg-interferon alfa-2a immunotherapy resulted in control of HIV replication and decreased HIV-1 integration, supporting a role for immunomediated approaches in HIV suppression and/or eradication.

Clinical trials registration: NCT00594880.

Figure 1.

Trial schema and subject disposition. A, Schema of the trial visit and relative activities (top row) during the 14 visits scheduled to occur over 49 weeks. Treatment is represented by dark grey boxes (pegylated [Peg] interferon alfa-2a at 180 or 90 μg/week), light grey boxes (antiretroviral therapy [ART], as previously treated), or white boxes (ART interruption, Peg–interferon alfa-2a monotherapy). B, CONSORT (Consolidated Standards of Reporting Trials) flow diagram of the study subject disposition. PHQ2/9, Patient Health Questionnaire 2/9.

Figure 2.

CD4⁺ T-cell count response to Peg–interferon alfa-2a. CD4⁺ T cell count was assessed at each study visit for arm A (closed circles) and arm B (open squares). Treatment is represented by black (antiretroviral therapy [ART]) or white horizontal boxes (Peg–interferon alfa-2a). The left panel represents visits up to failure or study end point. The right panel represents visits after ART resumption.

Figure 3.

Viral load (VL) response to Peg–interferon alfa-2a. The VL was assessed at each visit and is represented as the Kaplan–Meier plot of the viral response to Peg–interferon alfa-2a treatment. The vertical axis represents the fraction of subjects in arm A (solid line) and arm B (dotted line) with a VL of <400 RNA copies/mL. The dashed line represent the comparator historical structured treatment interruption (STI) group [21]. Abbreviation: ART, antiretroviral therapy.

Figure 4.

Assessment of integrated HIV DNA levels per circulating CD4⁺ T cell. A, Integrated HIV DNA was measured by Alu–polymerase chain reaction, as described in the Methods section. The number of integrated HIV DNA copies/CD4⁺ T cell are represented. The left panel shows 6 subjects experiencing protocol failure (viral load, ≥400 HIV RNA copies/mL) before the 12-week end point. Assessed are protocol week 8 (antiretroviral therapy [ART]), week 13 (ART + Peg–interferon alfa-2a), and after failure (after ART resumption). The right panel shows 7 subjects experiencing protocol-defined success (a sustained viral load of <400 copies/mL until the 12-week end point). Assessed are protocol week 8 (ART), week 13 (ART + Peg–interferon alfa-2a; subject 1 = not done), and week 25 (Peg–interferon alfa-2a monotherapy), as indicated. P values calculated by the Wilcoxon signed rank test are indicated. B, Boxes represent the median, quartiles, and extremes of the distribution of end point:baseline ratios of integrated DNA copies/CD4⁺ T cell in subjects with virological failure or success. Individual values are superimposed as open circles. A P value calculated by the Wilcoxon rank sum test is indicated.