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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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HIV-1-infection

Participation Criteria
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Eligibility Criteria
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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. 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. 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. 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. 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.

Ages Eligible for Study
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Minimum Age: 10 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group 1: Switch to TLD from NNRTI first-line regimen<br>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<br>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<br>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<br>Antiretroviral therapy (ART)-naïve participants initiating therapy with TLD | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants achieving virologic success at 6 months (Groups 1, 2, and 4) | 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) | 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants achieving virologic success | 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 | Plasma HIV-1 RNA ≤1000 copies/mL | 12months, 24 months, and 36 months. | 
| Time to confirmed virologic failure (VF) | 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 | 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 from start of TLD to TLD discontinuation | From 0 to 36 months | 
| Time from start of TLD to TLD discontinuation due to toxicity. | Time from start of TLD to TLD discontinuation due to toxicity. | From 0 to 36 months | 
| Change in quality of life (QoL) | 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 from start of TLD to first occurrence of a targeted clinical event | From 0 to 36 months |