Optimizing Treatment for Treatment-Experienced, HIV-Infected People

National Institute of Allergy and Infectious Diseases (NIAID)517 enrolled

Overview

The goal of anti-HIV therapy is to prevent HIV from replicating. Long-term control of HIV requires at least two anti-HIV drugs that are active against the virus. Drug resistance is a problem for many treatment-experienced, HIV-infected people. The purpose of this study was to determine the benefit of adding a nucleoside reverse transcriptase inhibitor (NRTI) to a new anti-HIV drug regimen for the suppression of HIV.

Two or more fully active antiretrovirals (ARVs) are recommended for successful suppression of HIV. In people infected with resistant HIV virus, finding two drugs that are fully active against HIV can be a challenge. However, the new generation of anti-HIV drugs has been designed to suppress drug-resistant HIV. These drugs include the FDA-approved protease inhibitors (PIs) darunavir and tipranavir, the investigational non-nucleoside transcriptase inhibitor (nNRTI) etravirine, the FDA-approved fusion inhibitor enfuvirtide, the recently FDA-approved CCR5 inhibitor maraviroc, and the investigational integrase inhibitor raltegravir. Also, it is not yet known whether multiple, partially-active drugs have the same rate of success in suppressing HIV. The purpose of this study was to use HIV resistance testing to predict the potency of a suggested ARV regimen using second generation ARVs and determine if the benefits of adding NRTIs to this new drug regimen outweigh the risks of drug toxicity and pill burden. All participants had treatment experience or resistance to NRTIs, nNRTIs, and PIs, and received novel agents. An active screening period (after enrollment but before randomization or treatment dispensation), occurred for up to 75 days for all participants, and study participation lasted an additional 96 weeks for those who qualified for either randomization or assignment (i.e. not randomized), to the study intervention. During active screening, all participants remained on their current drug regimen. During screening, phenotypic and genotypic HIV resistance tests were performed on participants' blood samples, as well as a coreceptor tropism assay. Using this information and medication history, the study team determined the best new regimen options for each participant. Each clinician, along with the study participant, then chose a new regimen based on the recommendations of the study team and the participant's preference. Evaluation for study outcomes began when participants started their new regimen as assigned by either randomization or determined assignment. Stratification between Arms A (Add NRTIs) and B (Omit NRTIs) or Arm C (Non-randomized to Add NRTIs) was based on predicted activity of the new regimen. Those assigned to a regimen with higher predicted activity were randomly assigned to Arm A (Add NRTIs) or B (Omit NRTIs); those assigned a regimen predicted to have lower activity were not randomized, but were assigned to Arm C (Add NRTIs). Participants in Arms A and C were instructed to take their newly assigned study regimen plus at least 2 NRTIs (personalized from expert recommendation and choice by local provider and participant) for 96 weeks. Participants in Arm B were instructed to take their newly assigned study regimen with no NRTIs for 96 weeks. Participants in all arms who met the primary efficacy outcome of regimen failure remained in the study in order to be followed for important secondary outcomes. All participants were scheduled to have 13 clinical visits, which included blood collection. At some visits, urine collection and quality of life and adherence questionnaires occurred. A neurocognitive assessment was performed for all participants at time of starting the new study regimen. Participants may also have consented to have cerebrospinal fluid collected via lumbar puncture following study treatment assignment and/or at Week 24. Those participants who consented to cerebrospinal fluid collection also had neurocognitive assessments at the times of collections. Participants were responsible for obtaining certain ARVs not provided by the study, including the ARVs they during the active screening period. The primary and secondary study objectives and comparisons relate to the randomized arms, and therefore, results are not provided for the non-randomized arm (C). The purpose of the non-randomized arm (C) was to include persons higher baseline resistance (and thus, lower activity scores) in order to address an exploratory objective related to the predictive power of these activity scores (and thus a larger range of scores by inclusion of arm C), on certain, virologic outcomes.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

517

Conditions

HIV Infections

Interventions

EnfuvirtideDRUG

90mg subcutaneously twice daily

RaltegravirDRUG

400 mg twice daily

DarunavirDRUG

Two 300-mg tablets twice daily, given with ritonavir 100mg twice daily (ritonavir not provided by the study)

Eligibility

Sex: ALLMin age: 16 Years

Medical Language ↔ Plain English

Inclusion Criteria: * HIV-1 infection * Triple-class drug experience or resistance. More information on this criterion can be found in the protocol. * Currently on a failing PI-containing regimen that includes 2 other ARVs with no regimen change for 8 weeks prior to study screening * HIV viral load of 1000 copies/ml or more * Hepatitis B surface antigen negative within 90 days of study entry * Able to obtain NRTIs and ritonavir and have required ARVs at time of starting study intervention * Willing to use acceptable forms of contraception * Parent or legal guardian willing to provide consent, if applicable * CD4 count result from a specimen drawn within 120 days prior to study entry * If any previous HIV-1 viral co-receptor tropism result is available, then most recent specimen date and the tropism result of that specimen AND specimen date and tropism result of any test with either X4 or D/M result, if different from the first specimen, must be available Inclusion Criteria continued: * Receipt of successful phenotype/genotype resistance results within 105 days prior to study treatment intervention assignment * Study team identification of a study regimen and at least 2 NRTIs for participant to take * Certain abnormal laboratory values. More information on this criterion can be found in the protocol. Exclusion Criteria: * Chronic, active hepatitis B virus infection (hepatitis B surface antigen positive or HBV DNA positive) * Taking certain medications. More information on this criterion can be found in the protocol. * Known allergy/sensitivity to components of two or more of the study-provided drugs or their formulations. For maraviroc, this includes hypersensitivity or history of allergy to soy lecithin or peanuts. * Active drug or alcohol use that, in the opinion of the investigator, may interfere with the study * Pregnancy or breastfeeding * Use of any immunomodulator (interferons, interleukins, systemic corticosteroids, or cyclosporine), vaccine, or investigational therapy within 30 days prior to study treatment allocation/assignment * Require certain medications prohibited with study treatment * Serious illness requiring systemic treatment or hospitalization. Participants who complete therapy or are clinically stable on therapy for at least 14 days prior to study treatment allocation are not excluded.

Locations (64)

Outcomes

Primary Outcomes

Percent of Participants With Regimen Failure, Defined as a Confirmed Virologic Failure or Discontinuation of Randomized NRTI Component of Study Treatment

Virologic failure defined as confirmed plasma HIV-1 RNA meeting 1 of the following 4 criteria: \< 1.0 log10 copies/mL reduction from baseline level and \>= 200 copies/mL at or after week 12 evaluation; \>= 200 copies/mL after 1 measurement \< 200 copies/mL; absence of any values \< 200 copies/mL by and including week 24 evaluation; \>= 200 copies/mL at week 48 evaluation. Discontinuation of Randomized NRTI component of Study Treatment is defined as permanently stopping all NRTIs among those randomized to add NRTIs, or starting any NRTI among those randomized to omit NRTIs. Subjects leaving the study for reasons other than death, relocation, incarceration, or site closure were reviewed for the discontinuation outcome by a blinded, independent panel. Additionally, any participant failing to start study treatment after randomization and prior to closure was also reviewed. Results report percent of participants reaching regimen failure outcome by week 48 evaluation using Kaplan-Meier method.

Time frame: From study entry to end of Week 48 evaluation window

Secondary Outcomes

Time From Treatment Dispensation to First Grade 3 or Higher (and at Least One Grade Higher Than Baseline) Signs/Symptom or Laboratory Abnormality

Events following permanent discontinuation of NRTI assignment are excluded (i.e. censoring at time of this event, if applicable). Week 96 study visit could occur up to 110 weeks following randomization. Censoring time was the latest study visit when participant was evaluated or when NRTI assignment was discontinued (when applicable). Event time was the exact number of weeks following treatment initiation when the qualifying sign/symptom started (for those safety events triggered by a sign/symptom), or exact number of weeks following treatment initiation when specimen from qualifying laboratory result was drawn (for those safety events triggered by a laboratory abnormality).

Time frame: From treatment dispensation to week 96 study visit

Time From Treatment Dispensation to First Study ARV Modification (Excluding NRTIs, if Applicable)

Data from ClinicalTrials.gov

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