Elsevier

The Lancet HIV

Volume 3, Issue 10, October 2016, Pages e463-e472
The Lancet HIV

Articles
Combined effect of Vacc-4x, recombinant human granulocyte macrophage colony-stimulating factor vaccination, and romidepsin on the HIV-1 reservoir (REDUC): a single-arm, phase 1B/2A trial

https://doi.org/10.1016/S2352-3018(16)30055-8Get rights and content

Summary

Background

Immune priming before reversal of latency might be a component of a functional HIV cure. To assess this concept, we assessed if therapeutic HIV immunisation followed by latency reversal would affect measures of viral transcription, plasma viraemia, and reservoir size in patients with HIV on suppressive antiretroviral therapy.

Methods

In this single-arm, phase 1B/2A trial, we recruited adults treated at the Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark (aged ≥18 years) with successfully treated HIV-1 with plasma RNA loads of less than 50 copies per mL for the previous year and CD4 counts of at least 500 cells per μL. Exclusion criteria included CD4 counts of less than 200 cells per μL within the past 2 years, active hepatitis B or C infections, and clinically significant cardiac disease, including QTc prolongation. Participants received six therapeutic intradermal HIV-1 immunisations with 12 mg/mL Vacc-4x and 0·6 mg/mL rhuGM-CSF over 12 weeks (at 0 weeks, 1 week, 2 weeks, 3 weeks, 11 weeks, and 12 weeks) before receiving 5 mg/m2 intravenous romidepsin once a week for 3 weeks. This procedure was followed by analytical treatment interruption. Coprimary outcomes were changes in copies of HIV-1 DNA (total and integrated) per million CD4 T cells and infectious units per million (IUPM) resting memory CD4 T cells established by viral outgrowth, assessed in all patients receiving at least one dose of active treatment with assessable data. We assessed total HIV-1 DNA at screening, before romidepsin treatment, and 6 weeks after romidepsin treatment. We assessed integrated viral DNA at baseline, before romidepsin treatment, and 8 weeks after romidepsin treatment. We assessed IUPM at screening, 2 weeks before romidepsin treatment, and 6 weeks after romidepsin treatment. This trial is registered at ClinicalTrials.gov, number NCT02092116.

Findings

Between May 19, 2014, and Oct 8, 2014, we enrolled 20 individuals, of whom 17 completed all Vacc-4x and rhuGM-CSF administrations and romidepsin infusions. 16 of 17 had assessable total HIV-1 DNA, 15 of 17 had assessable integrated HIV-1 DNA, and six of 17 had assessable IUPM at baseline and at one or more timepoints after study treatment. Total HIV-1 DNA declined from screening to 6 weeks after romidepsin treatment (mean reduction 39·7%, 95% CI −59·7 to −11·5; p=0·012). The decrease in integrated HIV-1 DNA from baseline to 8 weeks after romidepsin treatment was not significant (19·2%, −38·6 to 6·3; p=0·123). Among the six assessable participants, the mean reduction in IUPM from screening to 6 weeks after romidepsin treatment was 38·0% (95% CI −67·0 to −8·0; p=0·019). Of 141 adverse events, 134 (95%) were grade 1 and seven (5%) were grade 2–3.

Interpretation

This in-vivo combinatorial approach provides the first evidence for the feasibility of a combined shock and kill strategy, but also emphasises that further optimisation of this strategy is needed to achieve a sizeable effect on the latent reservoir that will translate into clinically measurable benefits for people living with HIV-1.

Funding

Bionor Pharma, the Research Council of Norway, and SkatteFUNN.

Introduction

Antiretroviral therapy (ART) leads to potent and durable suppression of HIV-1 replication, but does not cure infection. For this reason, lifelong treatment is needed to prevent virus rebound and disease progression. Furthermore, chronic HIV-1 infection and ART are associated with increased mortality and morbidity.1 For these reasons, a curative therapy for HIV-1 remains an important goal.

Early in HIV-1 infection, a latent reservoir is established when activated CD4 T cells become infected before reverting into a resting memory state.2, 3 These long-lived cells containing proviral genomes persist in a latent transcriptionally silent state in which the proviruses remain non-susceptible to ART and unrecognisable to the immune system.4, 5 Although a large proportion of integrated HIV-1 DNA is defective, replication-competent proviruses persist in all individuals who receive ART and they drive rapid viral rebound after discontinuation of ART.6, 7, 8 This latent reservoir is widely recognised as the primary barrier to eradication of infection.

Research in context

Evidence before this study

We searched PubMed and Scopus for articles published up to April 16, 2016, in any language, that reported clinical studies that aimed to reduce the size of the HIV reservoir through reversal of HIV latency with the search terms “HIV cure”, “HIV reactivation”, “HIV reservoir”, “HIV latency”, and “HIV eradication”, and we reviewed the results for relevance. Investigators of human studies of the histone deacetylase inhibitor vorinostat and antialcoholic abuse agent disulfiram have successfully shown increased HIV-1 expression measured as increased cellular HIV-1 RNA levels in latently infected cells. Investigators of two clinical trials of the potent histone deacetylase inhibitor panobinostat and romidepsin, in addition to showing an increase in cellular HIV-1 expression, showed increased levels of viral HIV-1 particles in plasma during histone deacetylase inhibitor dosing with standard clinical assays. Investigators of none of these studies found a significant effect of the interventions on the size of the latent HIV-1 reservoir, measured as total DNA, integrated DNA, or quantitative viral outgrowth.

Added value of this study

We report the first clinical trial of a combinatorial approach in which latency reversal is preceded by immunotherapy for improved targeting of the HIV-1 reservoir. In this phase 1B/2A trial, therapeutic HIV-1 immunisation with Vacc-4x and rhuGM-CSF combined with the histone deacetylase inhibitor romidepsin resulted in about a 40% reduction in the size of the HIV-1 reservoir from baseline to follow-up, a statistically significant reduction of not only the proviral HIV-1 reservoir on a cohort level, but also the replication-competent HIV-1 reservoir in a subset of individuals. Additionally, despite marked increases in histone acetylation and cell-associated unspliced HIV-1 RNA shortly after each romidepsin infusion, only four of 17 individuals pretreated by immunisation with Vacc-4x and rhuGM-CSF had quantifiable plasma HIV-1 RNA immediately after one of the romidepsin infusions, raising the possibility that priming of the immune system before latency reversal induced an immune pressure on virus-producing cells leading to their killing and therefore limited extracellular release of viral particles during romidepsin treatment. However, although these findings indicate that the size of the viral reservoir was diminished, the combined so-called shock and kill intervention did not seem to prolong median time to virus rebound during ART interruption.

Implications of all the available evidence

A combined approach to a shock and kill strategy for HIV cure is feasible, but optimisation of this strategy is needed to achieve a sizeable effect on the latent reservoir that will translate into clinically measurable benefits for people living with HIV-1.

One strategy to cure HIV-1 aims to purge the reservoir by reactivating virus transcription with a latency-reversing agent, in turn allowing elimination of infected cells by viral cytopathic or immune effector mechanisms.2 Findings from clinical trials9, 10, 11, 12, 13, 14 with latency-reversing agents show that viral reactivation is indeed possible. However, latency reversal has not produced measurable reductions in the size of the reservoir, possibly because of insufficient immune-mediated killing of infected cells (eg, inadequate CD8 cytotoxic T-lymphocyte or natural killer cell responses).15 Hence, great interest exists in interventions to improve antiviral immune responses in combination with latency reversal; the ultimate goal is eradication of latently infected CD4 T cells to sustain long-term drug-free remission of HIV-1.

We present the results of part B of the REDUC trial. Part A, showing latency reversal by the histone deacetylase inhibitor romidepsin alone, has been published.10 The trial's overall objective was to assess the effect on the size of the latent HIV-1 reservoir of the combination of a peptide-based therapeutic HIV-1 vaccine (Vacc-4x; a synthetic p24 gag peptide vaccine) and recombinant human granulocyte macrophage colony-stimulating factor (rhuGM-CSF) as local adjuvant followed by treatment with the latency-reversing agent romidepsin.

Section snippets

Study design and participants

In this single-arm, phase 1B/2A trial, we enrolled, by invitation letter, adults (aged ≥18 years) with HIV-1 infections and on ART with plasma viral RNA loads of less than 50 copies per mL for the previous year (with a minimum of two viral load measurements taken) and a CD4 count of at least 500 cells per μL treated at the Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark. Exclusion criteria included a CD4 count of less than 200 cells per μL within the past 2 years,

Results

Between May 19, 2014, and Oct 8, 2014, we enrolled 20 individuals with HIV-1 infections (figure 2, table 1). Three individuals discontinued the trial during the immunisation phase: one because of potential Vacc-4x-related AEs, one moved out of the study area, and one relapsed into alcohol abuse. 17 individuals completed the assigned investigational drugs. 16 of 17 had assessable total HIV-1 DNA, 15 of 17 had assessable integrated HIV-1 DNA, and six of 17 had assessable IUPM at baseline and at

Discussion

In this phase 1B/2A trial, therapeutic HIV-1 immunisation with Vacc-4x and rhuGM-CSF combined with the histone deacetylase inhibitor romidepsin resulted in three important findings. First, this dual intervention significantly reduced the HIV-1 reservoir as evidenced by a decrease in total HIV-1 DNA and replication-competent virus in patients for whom data were assessable, although the decrease in integrated HIV-1 DNA was not significant. Second, despite marked increases in histone acetylation

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