OBJECTIVE:

To assess the efficacy and safety of switch to dolutegravir and lamivudine (DTG/3TC) single tablet regimen from bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) in persons living with HIV aged 60 years old or more.

METHODS:

This is a phase 3b, multi-center, open-label, single-arm clinical trial over 96 weeks. The study will take place at two sites in Kenya: Kenyatta National Hospital (KNH) and Jaramogi Oginga Odinga Teaching and Referral Hospital (JOOTRH). Study visits will take place at screening, baseline, and weeks 4, 12, 24, 36, 48, 60, 72, 84, and 96 (with a 6-week extension as required for confirming HIV-1 RNA levels). A target of 240 participants from the ongoing B/F/TAF Elderly Switch Study will be enrolled. Eligible participants will be switched from B/F/TAF to DTG/3TC at enrollment and followed up for 96 weeks. The primary endpoint will be the proportion of participants with plasma HIV-1 RNA ≥ 50 copies/mL (Snapshot algorithm) at Week 48. Analysis of the primary endpoint will be performed for the intention to treat - exposed (ITT-E) population using the FDA snapshot method.

BACKGROUND:

Three drug regimens for the treatment of HIV are widely used and successful in achieving viral suppression. However, they are associated with various adverse events including renal and bone disease, anaemia, mitochondrial toxicity, and possible association with increased cardiovascular events. Data from the ongoing B/F/TAF Elderly Switch Study has demonstrated high rates of renal insufficiency and osteoporosis in people living with HIV aged 60 years or more, hence the need for safe treatment options. Two drug regimens (2DR) have demonstrated non-inferiority to three drug regimens in patients who are treatment-naïve as well as in those who are virally suppressed on a first-line regimen and potentially have lower toxicity, fewer adverse drug events and a lower drug burden.

OVERALL STRATEGY:

This is a phase 3b, multi-centre, open-label, single-arm clinical trial over 96 weeks describing the efficacy of switching virally suppressed HIV-1 infected adults to DTG/3TC dual therapy from their current B/F/TAF regimen. The primary efficacy endpoint is the proportion of participants with viral load (VL) ≥ 50 copies/ml at week 48.

The study will take place at two sites in Kenya: Kenyatta National Hospital (KNH, the largest teaching and referral hospital in Kenya), and Jaramogi Oginga Odinga Teaching and Referral Hospital (JOOTRH, the largest teaching and referral hospital in the Nyanza region of Kenya). The outpatient HIV clinics at these sites currently provide antiretroviral therapy (ART) to over 15,000 persons living with HIV (PWH) combined. These two sites are currently participating in the B/F/TAF-elderly study.

Study visits will take place at screening, baseline, and weeks 4, 12, 24, 36, 48, and 96 (with a 6-week extension as required for confirming HIV-1 RNA levels within the FDA snapshot window). HIV-1 RNA viral load will be performed at screening and weeks 4, 12, 24, 48 and 96. If HIV-1 RNA is ≥ 50 copies/ml then a repeat test will be performed at least 2 weeks after the detectable result to confirm virological failure. If the repeat HIV-1 RNA result is ≥ 50 copies/ml this confirms protocol-defined virological failure (PDVF) and genotypic resistance testing will be performed for any repeat viral load ≥ 500 copies/ml. Other routine study investigations will include CD4 count, complete blood count, serum Cr, renal biomarkers, alanine transaminase (ALT), aspartate aminotransferase (AST), fasting lipids, fasting glucose and patient satisfaction questionnaires (HIVTSQ).

METHODS:

The anticipated sample size is 240 participants started on study treatment among patients on B/F/TAF therapy for at least 24 weeks and no prior virological failure (defined as two consecutive HIV-1 RNA viral loads ≥ 50 copies/ml separated by at least 2 weeks), with a viral load of < 50 copies/ml for at least 12 weeks, and aged 60 years or above.

All participants will be recruited from the pool of patients who are exiting the B/F/TAF-elderly trial at the two study sites. Those who provide written informed consent will be assessed for eligibility through review of their medical records, history and physical examination.

Patients who provide informed consent and meet all eligibility criteria after screening investigations will be enrolled in the study within 28 days of the screening investigations and will complete baseline investigations (CD4 count, fasting lipid profile and fasting glucose). During the enrollment visit participants will be switched to DTG/3TC two drug regimen.

Participants will be engaged in the study for 96 weeks plus up to 28 days between screening and enrolment, and a follow-up visit up to 28 days beyond the week 96 visit if required to confirm HIV-1 RNA within the FDA snapshot window.

Inclusion Criteria:

• Able and willing to understand and comply with the protocol requirements, instructions and restrictions
• Able and willing to give informed consent
• Have been randomised to the B/F/TAF arm and completed the B/F/TAF-elderly study. Participants should be on B/F/TAF until day 1 of entry into the current study
• HIV-1 RNA viral load &lt; 50 copies/ml at screening (within 28 days prior to enrollment)

Exclusion Criteria:

• Confirmed treatment failure as defined by two consecutive HIV-1 RNA viral loads ≥ 50 copies/ml separated by at least 2 weeks, after at least 6 months on ART or after a documented HIV-1 RNA viral load &lt; 50 copies/ml

• Using any protocol-defined prohibited medicine where the participant is unwilling or unable to switch to an alternative (see Section 5.2. under Prohibited medications and non-drug therapies)

• Evidence of hepatitis B virus (HBV) infection based on the results of testing at screening for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), hepatitis B surface antibody (anti-HBs) and HBV DNA as follows:

  1. Participants positive for HBsAg are excluded;
  2. Participants negative for anti-HBs but positive for anti-HBc (negative HBsAg status), whether negative or positive for HBV DNA, are excluded;
  3. Participants positive for anti-HBc (negative HBsAg status) and positive for anti-HBs (past and/or current evidence) are immune to HBV and are not excluded.

• Has AST and/or ALT at least 5-times greater than the upper limit of normal

• Severe hepatic impairment (Class C) as determined by Child-Pugh classification

• Has an estimated creatinine clearance (CrCl) below 30 ml/min (as estimated using the Cockcroft-Gault estimate for glomerular filtration rate)

• Documented opportunistic infection within 4 weeks prior to the study enrolment

• Any condition (including illicit drug use or alcohol abuse) or laboratory results which, in the investigator's opinion, interfere with assessments or completion of the study

• Untreated syphilis infection (positive rapid plasma reagin [RPR] at Screening without clear documentation of treatment). Participants who are at least 7 days post completed treatment are eligible.

• History or presence of allergy or intolerance to the study treatment or their components or drugs of their class or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.

• Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal or penile intraepithelial neoplasia.

• Participants who in the investigator's judgment, poses a significant suicidality risk. Participant's history of suicidal behavior and/or suicidal ideation should be considered when evaluating for suicide risk

• Any evidence of any major 3TC resistance associated mutations (M184V/I and/or K65R and/or MDR) or presence of any major INSTI resistance associated mutation

We will share the individual patient data (IPD) that underlie the results reported after de-identification (text, tables, figures and appendices)

Beginning 6 months after publication of the final manuscript and for a period of 36 months

Access to IPD will be subject to the University of Nairobi data sharing requirements. Written requests should be submitted to the Principal Investigator providing a brief description of the individual or group making the request and detailing the reason for the same. Prior to sharing the data, the requestor will be required to sign a data access and sharing agreement.