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About
Antiretroviral therapy (ART) can reduce HIV to very low levels in the blood, but it cannot cure HIV infection because a small amount of virus remains in cells as a hidden (latent) form. The purpose of this study was to evaluate the safety and efficacy of single dose and multiple dose administration of romidepsin (RMD) in HIV-infected adults.
Full description
A major challenge in eradicating HIV-1 infection is the persistence of virus in long-lived cells, such as latently infected memory CD4 T cells. One approach for eliminating the HIV-1 reservoir is to activate viral replication in these latently infected CD4 T cells by targeting cellular mechanisms that repress proviral transcription. Histone deacetylase inhibitors (HDACis), such as RMD, induce HIV-1 expression by increasing acetylation and facilitating transcriptional activation of HIV-1. RMD administered in combination with ART may serve as an important component of a strategy to eradicate the HIV-1 latent reservoir. The purpose of this study was to evaluate the safety and efficacy of single dose and multiple dose administration of RMD in HIV-infected adults.
Participants were sequentially enrolled into four cohorts and randomly assigned to receive either RMD or placebo. The cohorts differed in the dose of RMD given. Participants in Cohorts 1, 2, and 3 had one intravenous (IV) infusion of RMD or placebo at Day 0. Participants in Cohort 4 had four IV infusions of RMD or placebo at Days 0, 14, 28, and 42.
For participants in Cohorts 1, 2, and 3, study duration was 4 weeks. For participants in Cohort 4, study duration was a minimum of 24 weeks and a maximum of 48 weeks.
Participants attended several study visits, which could include a physical examination, blood and urine collection, pharmacokinetic (PK) sampling, and an electrocardiogram (ECG).
Enrollment
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Inclusion and exclusion criteria
Inclusion Criteria: Cohorts 1, 2, & 3
HIV-1 infection, documented by any licensed rapid HIV test or HIV E/CIA test kit at any time prior to study entry & confirmed by a licensed Western blot or a 2nd antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen or plasma HIV-1 RNA
Receiving 2 (or more) nucleoside or nucleotide reverse transcriptase inhibitors with raltegravir, dolutegravir, or efavirenz for at least 90 days prior to study entry with no intention to change for the duration of the study
Documentation of at least 2 historical HIV-1 RNA measurements <50 copies/mL while on ART obtained by standard ultrasensitive assay. Documentation of the 1st measurement must be from a result obtained between 365-91 days, inclusive, prior to study entry. Documentation of the 2nd measurement must be from a result obtained between 730-366 days, inclusive, prior to study entry. In addition, there must be no HIV-1 RNA values ≥50 copies/mL for at least 365 days prior to study entry.
CD4 cell count ≥300 cells/mm^3 obtained within 90-50 days prior to study entry at any US laboratory that has a CLIA certification or equivalent
HIV-1 RNA level of <50 copies/mL obtained by standard ultrasensitive assay within 90-50 days prior to study entry
HIV-1 RNA level of ≥0.4 copies/mL obtained by SCA within 90-50 days prior to study entry. This result must be available prior to the pre-entry visit
The following laboratory values obtained within 21-0 days prior to study entry by any laboratory that has a CLIA certification or equivalent
The following laboratory values obtained within 21-7 days prior to study entry by any laboratory that has a CLIA certification or equivalent
HCV antibody negative result within 90-50 days prior to study entry or, for study candidates who are HCV antibody positive (based on testing performed at any time prior to study entry), a negative HCV RNA result obtained within 90-50 days prior to study entry
Negative HBsAg result obtained within 90-50 days prior to study entry or a positive HBsAb result at any time prior to study entry
For females of reproductive potential, negative serum or urine pregnancy test (latter with sensitivity of ≤25 mIU/mL) at the screening visit, pre-entry visit within 21-7 days prior to study entry, & at entry prior to romidepsin infusion, by any US laboratory that has a CLIA certification or equivalent
Female candidates of reproductive potential must refrain from participating in active attempts to become pregnant, &, if participating in sexual activity that could lead to pregnancy, must agree to use at least 2 reliable forms of contraception that are non-estrogen based. All female participants of reproductive potential must be instructed to use contraceptives for 6 months/180 days after completing RMD or placebo infusion
Karnofsky performance score ≥80 within 21-7 days prior to study entry
Men and women age ≥ 18 years
Ability & willingness to provide written informed consent
Investigator anticipates that a fully active alternative ART regimen could be constructed in the event of virologic failure on the current ART regimen
Exclusion Criteria: Cohorts 1, 2, & 3
Inclusion Criteria: Cohort 4, Step 1
HIV-1 infection, documented by any licensed rapid HIV test or HIV E/CIA test kit at any time prior to study entry & confirmed by a licensed Western blot or a 2nd antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen or plasma HIV-1 RNA
Receiving 2 or more nucleoside or nucleotide reverse transcriptase inhibitors with raltegravir or dolutegravir for at least 90 days prior to study entry with no intention to change for the duration of the study
Documentation of at least 2 historical HIV-1 RNA measurements <50 copies/mL while on ART obtained by standard ultrasensitive assay. Documentation of the first measurement must be from a result obtained between 365-61 days, inclusive, prior to study entry. Documentation of the second measurement must be from a result obtained between 730-366 days, inclusive, prior to study entry. In addition, there must be no HIV-1 RNA values ≥50 copies/mL for at least 365 days prior to study entry
CD4 cell count ≥300 cells/mm^3 obtained between 36-60 days prior to study entry (screening visit) at any US laboratory that has a CLIA certification or equivalent
HIV-1 RNA level of <50 copies/mL obtained by standard ultrasensitive assay at screening (between 36-60 days prior to study entry)
The following laboratory values obtained at pre-entry (between 3-14 days prior to study entry) by any laboratory that has a CLIA certification or equivalent
HCV antibody negative result at screening (between 36-60 days prior to study entry) or, for study candidates who are HCV antibody positive (based on testing performed at any time prior to study entry), a negative HCV RNA result obtained at screening
Negative HBsAg result obtained at screening (between 36-60 days prior to study entry) or a positive HBsAb result at any time prior to study entry
For females of reproductive potential, negative urine pregnancy test (with a sensitivity of ≤25 mIU/mL) at screening (between 36-60 days prior to study entry), at pre-entry (between 3-14 days prior to study entry), & at entry prior to infusion, by any US laboratory that has a CLIA certification or equivalent
Female candidates of reproductive potential must refrain from participating in active attempts to become pregnant, &, if participating in sexual activity that could lead to pregnancy, must agree to use at least 2 reliable forms of contraception that are non-estrogen based. All participants of reproductive potential will be instructed to use contraceptives for 6 months or 180 days after completing RMD/placebo infusion
Karnofsky performance score ≥80 at pre-entry (between 3-14 days prior to study entry)
Men and women age ≥ 18 years
Ability & willingness to provide written informed consent
Investigator anticipates that a fully active alternative ART regimen could be constructed in the event of virologic failure on the current ART regimen
Exclusion Criteria: Cohort 4, Step 1
See the protocol for Inclusion and Exclusion Criteria for Cohort 4, Steps 2, 3, and 4.
Primary purpose
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Interventional model
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59 participants in 8 patient groups, including a placebo group
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Data sourced from clinicaltrials.gov
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