Clinical trial NCT04050449: Assess Therapeutic Efficacy and Emergence of HIV Drug Resistance Following Initiation of TLD
Official title: 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
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: HIV-1-infection
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: United States President's Emergency Plan for AIDS Relief
First posted: 2019-08-08
Enrollment: 1339
Sex: ALL
Minimum age (years): 10
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Proportion of participants achieving virologic success at 6 months (Groups 1, 2, and 4)
timeFrame: 6 months +/- 3 months after starting TLD
measure: Proportion of participants achieving virologic success at end of TLD and RIF-Containing TB Treatment (Group 3)
timeFrame: 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 outcomes:
measure: Proportion of participants achieving virologic success
timeFrame: 6 months, 12 months, 24 months, and 36 months after starting TLD
measure: Proportion of participants with low HIV-1 RNA
timeFrame: 12months, 24 months, and 36 months.
measure: Time to confirmed virologic failure (VF)
timeFrame: At or after 6 months which is confirmed by the next HIV-1 RNA measurement
measure: Time to confirmed virologic failure with a new DTG resistance-associated mutation
timeFrame: From 0 to 36 months
measure: Time from start of TLD to TLD discontinuation
timeFrame: From 0 to 36 months
measure: Time from start of TLD to TLD discontinuation due to toxicity.
timeFrame: From 0 to 36 months
measure: Change in quality of life (QoL)
timeFrame: From study start to 6 months
measure: Time from start of TLD to first occurrence of a targeted clinical event
timeFrame: From 0 to 36 months
Other outcomes:
Locations:
city: Port-au-Prince
country: Haiti
facility: Les Centres GHESKIO CRS (30022)
state: Bicentaire
city: Port Au Prince
country: Haiti
facility: GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS (31730)
city: Eldoret
country: Kenya
facility: Moi University Clinical Research Center (MUCRC) CRS (12601)
city: Kericho
country: Kenya
facility: Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS (12501)
city: Kisumu
country: Kenya
facility: Kisumu Crs (31460)
city: Blantyre
country: Malawi
facility: Blantyre CRS (30301)
city: Lilongwe
country: Malawi
facility: Malawi CRS (12001)
city: Johannesburg
country: South Africa
facility: University of the Witwatersrand Helen Joseph (WITS HJH) CRS (11101)
state: Gauteng
city: Cape Town
country: South Africa
facility: Family Clinical Research Unit (FAM-CUR) CRS (8950)
state: West Cape
city: Cape Town
country: South Africa
facility: University of Cape Town Lung Institute (UCTLI) CRS (31792)
state: Western Cape
city: Durban
country: South Africa
facility: Durban Adult HIV CRS (11201)
city: Johannesburg
country: South Africa
facility: Soweto ACTG CRS (12301)
city: Kampala
country: Uganda
facility: Joint Clinical Research Centre (JCRC)/Kampala CRS (12401)
city: Harare
country: Zimbabwe
facility: Milton Park CRS (30313)
Study officials:
affiliation: Joint Clinical Research Centre (JCRC)/Kampala CRS
name: Cissy Kityo, MBChB; M.Sc.; Ph.D.
role: STUDY_CHAIR
References: