INSTI's For The Management of HIV-associated TB (INSIGHT)

A Phase 2b Study to Evaluate the Efficacy, Safety and PK of a Combination of Bictegravir, Emtricitabine, and Tenofovir Alafenamide Fumarate for Treatment of HIV-1 Infection in Patients With Drug-susceptible Tuberculosis on a Rifampicin-based Regimen

Johns Hopkins University, National Institute of Allergy and Infectious Diseases (NIAID), University of Cape Town, Medical Research Council, South Africa

This study is being conducted to assess the antiretroviral activity of a fixed-drug, single tablet, combination of Bictegravir 50mg/ Emtricitabine 200mg/ Tenofovir alafenamide 25mg (Biktarvy®) dosed twice daily in HIV-1 infected, ART-naïve patients with TB co-infection receiving a rifampicin-based tuberculosis (TB) treatment regimen. This study will assess the activity of Bictegravir and dolutegravir-containing ART regimens in patients with drug-susceptible TB through 48 weeks

Primary objective: To characterize viral suppression rates (proportion of patients with suppressed viral load) at week 24 in the BIC arm Secondary objectives: To characterize viral suppression rates at weeks 12, 24 and 48 in the standard of care treatment (SOC) arm (currently, TDF 300mg/3TC 300mg/DTG 50mg) and at weeks 12 and 48 in the BIC/FTC/TAF arm. To compare the pharmacokinetics (PK) of BIC when given twice daily and co-administered with Rifampicin during tuberculosis treatment vs when given alone after discontinuation of Rifampicin To assess the incidence of TB associated IRIS in each arm, through week 24. To characterize the tolerability of treatment in each arm by assessing frequency of clinician-initiated treatment interruptions or switches through week 48. To assess frequency of ART drug resistance mutations in participants with detectable viral load at study visit weeks 24 and 48.

Biktarvy® is a fixed dose combination, TLD- fixed-drug combination single tablet, Dolutegravir 50mg, HIV/AIDS, Tuberculosis, Pulmonary

80 participants for the Intervention Arm ART regimen which is a fixed-drug combination of a single tablet co-formulated regimen containing Bictegravir 50mg Emtricitabine 200mg and tenofovir alafenamide 25mg (BIC/FTC/TAF; Biktarvy®) that will be taken twice a day during rifampicin-containing TB treatment and 2 weeks after stopping TB treatment, thereafter the BIC/FTC/TAF single tablet co-formulation will be taken once daily. 40 participants in the Control ARM: Dolutegravir 50mg /Lamivudine 300mg/ Tenofovir 300mg (TLD- fixed-drug combination single tablet) plus Dolutegravir 50mg evening dose during TB treatment and for two weeks after completion of TB treatment, then TLD once daily thereafter- as per Standard of Care (SOC)

The Intervention Arm ART regimen is a fixed-drug combination of a single tablet co-formulated regimen containing Bictegravir 50mg Emtricitabine 200mg and tenofovir alafenamide 25mg (BIC/FTC/TAF; Biktarvy®) that will be taken twice a day during rifampicin-containing TB treatment and 2 weeks after stopping TB treatment, thereafter the BIC/FTC/TAF single tablet co-formulation will be taken once daily.

Dolutegravir 50mg /Lamivudine 300mg/ Tenofovir 300mg (TLD- fixed-drug combination single tablet) plus Dolutegravir 50mg evening dose during TB treatment and for two weeks after completion of TB treatment, then TLD once daily thereafter- as per Standard of Care (SOC)

Biktarvy® is a fixed dose combination, single tablet containing bictegravir (BIC), emtricitabine (FTC), and tenofovir alafenamide (TAF) for oral administration. BIC is an integrase strand transfer inhibitor (INSTI). FTC, a synthetic nucleoside analog of cytidine, is an HIV nucleoside analog reverse transcriptase inhibitor (HIV NRTI). TAF, an HIV NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. Each tablet contains 50 mg of BIC (equivalent to 52.5 mg of bictegravir sodium), 200 mg of FTC, and 25 mg of TAF (equivalent to 28 mg of tenofovir alafenamide fumarate) and the following inactive ingredients: croscarmellose sodium, magnesium stearate, and microcrystalline cellulose.

Viral suppression rate (HIV-1 RNA <50 copies/mL) at week 24 in the BIC arm (using the FDA snapshot algorithm)

Viral suppression rates (HIV-1 RNA <50 copies/mL) in the DTG arm and at 12 and 48 weeks in the BIC arm

BIC drug levels (AUC) when given twice daily and co-administered with Rifampicin vs. during TB treatment vs when given alone after TB treatment completion

BIC drug levels (Cmax) when given twice daily and co-administered with Rifampicin vs. during TB treatment vs when given alone after TB treatment completion

BIC drug levels ( Ctrough) when given twice daily and co-administered with Rifampicin vs. during TB treatment vs when given alone after TB treatment completion

To characterize the tolerability of treatment in each arm by assessing frequency of clinician-initiated treatment interruptions or switches through week 48

Inclusion Criteria: Adults ≥ 18 years of age with Karnofsky score ≥ 70 Confirmed rifampicin-susceptible tuberculosis and/or On first-line rifampicin-based tuberculosis treatment (not > 8 weeks at the time of enrolment) Documented HIV-1 infection, ART-naïve OR ART non-naïve (patients to have no exposure to ART medication at least ≥ 3 months at the time of enrollment) Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m2 Alanine aminotransferase (ALT) ≤3 times the upper limit of normal (ULN) Total bilirubin ≤2.5 times ULN Creatinine ≤2 times ULN Hemoglobin ≥ 7.0 g/dL (6.5 g/dL for females) Platelet count ≥ 50,000/mm3 Absolute Neutrophil Count (ANC) ≥650/mm3 Able and willing to provide written informed consent Female patients agree to use both a barrier and a non-barrier form of contraception during the study, starting at least 14 days prior to enrolment Exclusion Criteria: Pregnancy or breastfeeding (or planned pregnancy within 12 months of study entry) Prior use of antiretroviral drugs for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP) < 3 months at the time of enrolment Hepatitis B surface antigen positive OR Hepatitis B virus (HBV) infection OR active systemic infections (other than HIV-1 infection) requiring systemic antibiotic or antifungal therapy current or within 30 days prior to baseline that could, in the opinion of the investigator, interfere with study procedures or assessment of study outcomes Participants with a CD4+ cell count of < 50 cells/ μl Any verified Grade 4 laboratory abnormality, with the exception of, Grade 4 triglycerides. A single repeat test is allowed during the Screening period to verify a result Patients on metformin (> 500mg, 12hourly) Patients with an uncontrolled psychiatric co-morbidity. Patients who, in the investigator's judgment, pose a significant suicidality risk. Recent history of suicidal behavior and/or suicidal ideation may be considered as evidence of serious suicide risk Other condition or circumstance deemed by clinician/investigators to be detrimental to patient safety or study conduct Unwilling to be part of the main pharmacokinetic (PK) study and have PK blood draws done (NB there is a semi-intensive PK substudy which is optional)

Data generated under this project will be shared in accordance with CAPRISA, and NIH-SAMRC policies, including the NIH Data Sharing Policy. Research data that documents, supports, and validates research findings will be made available after the main findings from the final research data set have been accepted for publication.

Not longer than 12 months after first publication of results. In accordance with WHO stipulations, summary results or a link to summary results will be reported within the trial registration record within 12 months of the study completion date.

Access to databases and associated software tools generated under the project will be available for educational, research, and non-profit purposes from bona-fide researchers and/or research organisations.

Naidoo A, Dooley KE, Naidoo K, Padayatchi N, Yende-Zuma N, Perumal R, Dorse G, Boodhram R, Osuala EC. INSTIs for the management of HIV-associated TB (INSIGHT study): a phase 2b study to evaluate the efficacy, safety and pharmacokinetics of a combination of bictegravir, emtricitabine and tenofovir alafenamide fumarate for the treatment of HIV-1 infection in patients with drug-susceptible tuberculosis on a rifampicin-based treatment regimen: a phase 2b open-label randomised controlled trial. BMJ Open. 2022 Nov 10;12(11):e067765. doi: 10.1136/bmjopen-2022-067765.