Assess Therapeutic Efficacy and Emergence of HIV Drug Resistance Following Initiation of TLD

August 16, 2023 updated by: AIDS Clinical Trials Group

Observational Cohort to Assess Therapeutic Efficacy and Emergence of HIV Drug Resistance Following Initiation of Tenofovir-Lamivudine-Dolutegravir (TLD) for First- or Second-Line ART or With Rifampin-Containing TB Treatment: The Hakim Study

Tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD) is being used more widely across the world to treat HIV. This is an observational study (a type of study in which participants are observed and certain outcomes are measured). The aim of this study is to observe how successful TLD is at treating HIV, in the following groups of people:

  • People switching to TLD, after taking anti-HIV medication that contains a nonnucleoside reverse transcriptase inhibitor (NNRTI) drug (such as Efavirenz or Nevirapine) (Group 1).
  • People switching to TLD, after taking anti-HIV medication that contains a boosted protease inhibitor (PI) drug (such as Lopinavir or Atazanavir) (Group 2).
  • People taking TLD and receiving medication for TB that includes the drug rifampicin (RIF) (Group 3). These people must be starting one or both of these medications when they enter the study.
  • People starting TLD who have not taken anti-HIV medication before (Group 4).

Another goal of this study is to use genetic testing of the virus (HIV) to see how often HIV is resistant to TLD. Genetic testing of the virus is one way to see if the TLD medication is not working to treat a person's HIV infection.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
1339

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Haiti
      • Port Au Prince, Haiti
        • GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS (31730)
    • Bicentaire
      • Port-au-Prince, Bicentaire, Haiti, HT-6110
        • Les Centres GHESKIO CRS (30022)
  • Kenya
      • Eldoret, Kenya, 30100
        • Moi University Clinical Research Center (MUCRC) CRS (12601)
      • Kericho, Kenya, 20200
        • Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS (12501)
      • Kisumu, Kenya, 40100
        • Kisumu Crs (31460)
  • Malawi
      • Blantyre, Malawi
        • Blantyre CRS (30301)
      • Lilongwe, Malawi
        • Malawi CRS (12001)
  • South Africa
      • Durban, South Africa, 4013 SF
        • Durban Adult HIV CRS (11201)
      • Johannesburg, South Africa
        • Soweto ACTG CRS (12301)
    • Gauteng
      • Johannesburg, Gauteng, South Africa, 2193
        • University of the Witwatersrand Helen Joseph (WITS HJH) CRS (11101)
    • West Cape
      • Cape Town, West Cape, South Africa, 7505
        • Family Clinical Research Unit (FAM-CUR) CRS (8950)
    • Western Cape
      • Cape Town, Western Cape, South Africa, 7705
        • University of Cape Town Lung Institute (UCTLI) CRS (31792)
  • Uganda
      • Kampala, Uganda
        • Joint Clinical Research Centre (JCRC)/Kampala CRS (12401)
  • Zimbabwe
      • Harare, Zimbabwe
        • Milton Park CRS (30313)

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

10 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

HIV-infected adults and adolescents (>30 kg, ≥10 years of age) initiating or switching to TLD and receiving care through a President's Emergency Plan for AIDS Relief (PEPFAR)-supported treatment program.

Description

Inclusion Criteria:

  • Receiving care at a PEPFAR-supported site.
  • Documentation of HIV-1 infection acceptable to the local PEPFAR-supported program to allow ART to be initiated or continued.
  • Ability and willingness of participant or legal guardian/representative to provide informed consent to participate in the study.
  • Expectation that the participant will receive care within the local PEPFAR-supported program and will be able to be followed for study evaluations for at least 6 months and ideally for 36 months.
  • Group 1 participants: Receipt of an NNRTI-containing first-line ART regimen from a clinic in a PEPFAR-supported country for at least 6 consecutive calendar months prior to study entry. NOTE: ART treatment gaps are allowed, but treatment gaps should not exceed 14 consecutive days in the 6 calendar months prior to study entry.
  • Group 1 participants: HIV-1 RNA >1000 copies/mL obtained as part of standard of care or with a real-time test within 12 weeks prior to study entry at any network-approved non-US laboratory that operates in accordance with Good Clinical Laboratory Practices (GCLP) and participates in appropriate external quality assurance programs.
  • Group 2 participants: Receipt of a boosted PI-containing second-line ART regimen from a clinic in a PEPFAR-supported country for at least 6 consecutive calendar months prior to study entry. NOTE: ART treatment gaps are allowed, but treatment gaps should not exceed 14 consecutive days in the 6 calendar months prior to study entry.

  • Group 2 participants: HIV-1 RNA obtained as part of standard of care or with a real-time test within 12 weeks prior to study entry at any network-approved non-US laboratory that operates in accordance with Good Clinical Laboratory Practices (GCLP) and participates in appropriate external quality assurance programs.

    1. If Group 2b reaches its enrollment target of 360 participants, the protocol team will notify sites that the following criteria will be implemented: For Group 2 participants, an HIV-1 RNA >1000 copies/mL will need to be obtained as part of standard of care or with a real-time test within 12 weeks prior to study entry.
    2. If Group 2a reaches its enrollment target of 180 participants, the protocol team will notify sites that the following criteria will be implemented: For Group 2 participants, an HIV-1 RNA ≤1000 copies/mL will need to be obtained as part of standard of care or with a real-time test within 12 weeks prior to study entry.
  • Group 4 participants: No current or prior ART treatment. NOTE: Women who received ART regimens only during pregnancy and/or breastfeeding for prevention of mother-to-child transmission but who have not taken any ART drugs for at least 6 calendar months immediately prior to study entry will be allowed.
  • For Group 1, 2, and 4 participants, expected initiation of TLD taken once daily within 7 days after study entry. NOTE: Group 1, 2, and 4 participants may not be on, or expected to start, RIF-containing TB treatment at the time of study entry.
  • For Group 3 participants already on RIF-containing TB treatment but not on TLD at study entry, expected initiation of TLD taken once daily with an additional daily dose of DTG 50 mg. This must be started within 7 days after study entry AND within 56 days after the start of RIF-containing TB treatment. These participants may be ART-naïve, or may be switching from a first- or second-line ART regimen. NOTE: For ART-naïve participants who start RIF-containing TB treatment first and then start TLD at a later date, screening must occur within 14 days before the intended TLD start date.
  • For Group 3 participants not already on RIF-containing TB treatment but already on TLD at study entry, receipt of TLD for at least 6 consecutive calendar months prior to study entry AND expected initiation of RIF-containing TB treatment within 7 days after study entry.
  • For Group 3 participants not already on RIF-containing TB treatment or TLD at study entry, expected initiation of TLD and RIF-containing TB treatment within 7 days after study entry. These participants may be ART-naïve, or may be switching from a first- or second-line ART regimen.
  • For Group 1 participants, HIV-1 RNA >1000 copies/mL obtained as part of standard of care or with a real-time test within 12 weeks prior to study entry at any network-approved non-US laboratory that operates in accordance with Good Clinical Laboratory Practices (GCLP) and participates in appropriate external quality assurance programs.

  • For Group 2 participants, HIV-1 RNA obtained as part of standard of care or with a real-time test within 12 weeks prior to study entry at any network-approved non-US laboratory that operates in accordance with Good Clinical Laboratory Practices (GCLP) and participates in appropriate external quality assurance programs.

    1. If Group 2b reaches its enrollment target of 360 participants, the protocol team will notify sites that the following criteria will be implemented: For Group 2 participants, an HIV-1 RNA >1000 copies/mL will need to be obtained as part of standard of care or with a real-time test within 12 weeks prior to study entry.
    2. If Group 2a reaches its enrollment target of 180 participants, the protocol team will notify sites that the following criteria will be implemented: For Group 2 participants, an HIV-1 RNA ≤1000 copies/mL will need to be obtained as part of standard of care or with a real-time test within 12 weeks prior to study entry.

Exclusion Criteria:

  • Weight ≤30 kg.
  • For participants already on ART in Groups 1, 2, and 3, known to have had an ART interruption encompassing the entire 14 day window (≥14 consecutive days) immediately prior to study entry.
  • For Group 3, if a participant is already taking TLD at the time of study entry, HIV-1 RNA >1000 copies/mL within the past 9 months while taking TLD with no subsequent HIV-1 RNA ≤1000 copies/mL.
  • Prior enrollment in any group in this study.
  • For Group 3 participants, already on concomitant TLD and RIF-containing TB treatment prior to study entry.
  • For Group 2 participants with HIV-1 RNA >1000 copies/mL from a host country in which treatment guidelines require a genotypic test prior to switching patients on a boosted PI-containing second-line ARV regimen to TLD, 65R RT mutation within 12 weeks prior to study entry.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Group 1: Switch to TLD from NNRTI first-line regimen
Participants switching to TLD from a first-line regimen containing a NNRTI. These participants will be divided into two subgroups based upon their HIV-1 RNA level in a sample obtained at entry, before starting TLD. Group 1a will include participants with viremia (HIV-1 RNA >1000 copies/mL at start of TLD) and Group 1b will include participants with suppressed viral load (HIV-1 RNA ≤1000 copies/mL at start of TLD).
Group 2: Switch to TLD from boosted PI second-line regimen
Participants switching to TLD from a second-line regimen containing a boosted PI. These participants will be divided into two subgroups based upon their HIV-1 RNA level in a sample obtained at entry, before starting TLD. Group 2a will include participants with viremia (HIV-1 RNA >1000 copies/mL at start of TLD) and Group 2b will include participants with suppressed viral load (HIV-1 RNA ≤1000 copies/mL at start of TLD).
Group 3: Concomitant TLD and RIF-containing TB treatment
Participants initiating concomitant TLD and RIF-containing TB treatment, with an additional daily dose of dolutegravir (DTG) 50mg. For participants already on RIF-containing TB treatment when TLD treatment is started, TLD treatment must be started within 8 weeks (56 days) of the start of RIF-containing TB treatment. Group 1, 2, or 4 participants who start RIF-containing TB treatment after enrollment will have additional evaluations at the start and end of concomitant HIV and TB treatment but will not be co-enrolled in Group 3 (their additional evaluations will, however, be considered when analyzing data from Group 3).
Group 4: ART-naive initiating TLD therapy
Antiretroviral therapy (ART)-naïve participants initiating therapy with TLD

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Proportion of participants achieving virologic success at 6 months (Groups 1, 2, and 4)
Time Frame: 6 months +/- 3 months after starting TLD
Proportion of participants on TLD at 6 months achieving virologic success, defined as suppression of plasma HIV-1 RNA to ≤1000 copies/mL. This will be based on the measurement closest to exactly 6 months (i.e., 183 days) after the date of start of TLD, within the window of 6 months ±3 months (specifically 92 to 274 days, inclusive).
6 months +/- 3 months after starting TLD
Proportion of participants achieving virologic success at end of TLD and RIF-Containing TB Treatment (Group 3)
Time Frame: 4 weeks before to 6 months after end of TLD and RIF-containing TB treatment (expect to end concomitant treatment within 12 months of study entry)
Proportion of participants achieving virologic success, defined as suppression of plasma HIV-1 RNA to ≤1000 copies/mL at the end of concomitant TLD and RIF-containing TB treatment. This will be the measurement closest to the end of concomitant treatment within the window of 4 weeks (28 days) before the end to 6 months (183 days) after the end, inclusive.
4 weeks before to 6 months after end of TLD and RIF-containing TB treatment (expect to end concomitant treatment within 12 months of study entry)

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Proportion of participants achieving virologic success
Time Frame: 6 months, 12 months, 24 months, and 36 months after starting TLD
Based on the FDA Snapshot algorithm modified to use the HIV-1 RNA threshold of 1000 copies/mL (instead of the usual 50 copies/mL) at 6 months, 12 months, 24 months, and 36 months after starting TLD in each of Groups, 1a, 1b, 2a, 2b, and 4; and at the end of concomitant TLD and RIF-containing TB treatment, 12 months, 24 months, and 36 months after starting concomitant TLD and RIF-containing TB treatment in Group 3.
6 months, 12 months, 24 months, and 36 months after starting TLD
Proportion of participants with low HIV-1 RNA
Time Frame: 12months, 24 months, and 36 months.
Plasma HIV-1 RNA ≤1000 copies/mL
12months, 24 months, and 36 months.
Time to confirmed virologic failure (VF)
Time Frame: At or after 6 months which is confirmed by the next HIV-1 RNA measurement
Time to confirmed virologic failure (VF), defined as the time from start of TLD to the first HIV-1 RNA >1000 copies/mL at or after 6 months which is confirmed by the next HIV-1 RNA measurement also being >1000 copies/mL
At or after 6 months which is confirmed by the next HIV-1 RNA measurement
Time to confirmed virologic failure with a new DTG resistance-associated mutation
Time Frame: From 0 to 36 months
DTG resistance-associated mutation as detected in population-based sequencing. New is a mutation not present in the last population-based sequence obtained prior to initiating TLD).
From 0 to 36 months
Time from start of TLD to TLD discontinuation
Time Frame: From 0 to 36 months
Time from start of TLD to TLD discontinuation
From 0 to 36 months
Time from start of TLD to TLD discontinuation due to toxicity.
Time Frame: From 0 to 36 months
Time from start of TLD to TLD discontinuation due to toxicity.
From 0 to 36 months
Change in quality of life (QoL)
Time Frame: From study start to 6 months
Change in quality of life (QoL), defined as the difference in the summary scores obtained from the ACTG SF-21 at 6 months from the scores obtained at study entry
From study start to 6 months
Time from start of TLD to first occurrence of a targeted clinical event
Time Frame: From 0 to 36 months
Time from start of TLD to first occurrence of a targeted clinical event
From 0 to 36 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
AIDS Clinical Trials Group

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Institute of Allergy and Infectious Diseases (NIAID)
United States President's Emergency Plan for AIDS Relief

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Chair: Cissy Kityo, MBChB; M.Sc.; Ph.D., Joint Clinical Research Centre (JCRC)/Kampala CRS

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 28, 2019

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 31, 2023

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 31, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 5, 2019

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 7, 2019

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 8, 2019

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 21, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 16, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2023

More Information

Terms related to this study

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • ACTG A5381
  • UM1AI068636 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Individual participant data that underlie results in the publication, after deidentification.

IPD Sharing Time Frame

Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH.

IPD Sharing Access Criteria

  • With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group.
  • For what types of analyses? To achieve aims in the proposal approved by the AIDS Clinical Trials Group.
  • By what mechanism will data be made available? Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://actgnetwork.org/about-actg/templates-and-forms. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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