Effect of Reducing Nucleotide Exposure on Bone Health (ReNew)

Philip Grant

Status and phase: Withdrawn; Phase 2

Conditions: Osteopenia; HIV-1-infection; HIV/AIDS

Treatments: Drug: Current tenofovir alafenamide (TAF)-containing ART regimen; Drug: Dolutegravir (DTG) 50MG/lamivudine (3TC) 300MG FIXED DOSE COMBINATION (FDC)

Study type: Interventional

Funder types: Other

Identifiers

NCT03549689

43453

Details and patient eligibility

About

This is an open-label, randomized pilot study to assess the effect on bone mineral density (BMD) of a switch from a tenofovir alafenamide-containing antiretroviral regimen to dolutegravir/lamivudine vs. a continuation of the tenofovir alafenamide-containing regimen.

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. HIV-1 infection, as documented by a positive 4th generation assay or by any licensed ELISA test kit confirmed by Western blot at any time prior to study entry.

2. Age ≥18 years

3. HIV-1 RNA BLQ (e.g., <20 copies/mL or other threshold based on the local viral load assay used) for at least 12 months prior to study entry excluding blips (i.e., a single measurement <200 copies/mL preceded and followed by measurements BLQ)

4. On a stable TAF-containing ART that also includes at least 2 other antiretrovirals, with no changes in the 12 months prior to entry (except for a switch to a co-formulated tablet from the component tablets or a switch from ritonavir to cobicistat)

5. Lumbar spine, femoral neck or total hip BMD T-score ≤-1.0 from a DXA scan within the past 48 weeks

6. If receiving testosterone or estrogen replacement therapy, on a stable dose for ≥3 months prior to enrollment without plan to change dose during the study period.

7. Acceptable blood laboratory values at screening visit:

   • CD4+ T-cell count ≥200 cells/µL

   • Phosphate ≥2mg/dL

   • 25-hydroxyvitamin D level ≥10 ng/ml

   • Calculated creatinine clearance (CrCl) ≥50 mL/min as estimated by the Cockcroft-Gault equation*:

     • For men = CrCl (mL/min) = (140 - age in years) x (body weight in kg) ÷ (serum creatinine in mg/dL x 72)

   For women, multiply the above result by 0.85

8. For women of reproductive potential, negative serum or urine pregnancy test prior to screening and a negative urine pregnancy test at the entry visit prior to randomization and agreeable to using a contraceptive of choice during the study period.

"Women of reproductive potential" are defined as women who have not been post-menopausal for at least 24 consecutive months (i.e., who have had menses within the preceding 24 months) and have not undergone surgical sterilization (i.e., hysterectomy, bilateral oophorectomy, or tubal ligation; participant report sufficient)

Exclusion criteria

1. Current systemic glucocorticoid use
2. Lumbar spine, femoral neck or total hip BMD T-score <-3.0
3. Previous, current pharmacologic treatment, or plan for initiation of therapy for osteoporosis (i.e., bisphosphonates, teriparatide, denosumab, tamoxifen or raloxifene)
4. Previous fragility fracture (i.e., any fall from a standing height or less that resulted in a fracture)
5. History of genotypic resistance or phenotypic resistance to either DTG or 3TC. The interpretation of genotypic resistance is based on output from the Stanford HIV Resistance Database (available at https://hivdb.stanford.edu). Isolates with an interpretation of low-level resistance or higher are considered resistant.
6. History of virologic failure (i.e., confirmed HIV-1 RNA level ≥200 copies/mL after over 6 months of therapy) while on an integrase inhibitor (i.e., raltegravir, elvitegravir, bictegravir, or dolutegravir) or on lamivudine/emtricitabine prior to study enrollment. Any antiretroviral history (even before routine virologic monitoring became standard of care) that would suggest the presence of the M184V mutation should be considered exclusionary
7. ALT ≥5 X ULN, OR ALT ≥3xULN and bilirubin ≥1.5xULN (with >35% direct bilirubin)
8. Severe hepatic impairment (Child Pugh Class C)
9. Anticipated need for antiviral therapy for HCV
10. Hepatitis B surface antigen positive or Hepatitis B DNA positive
11. Weight >300 pounds, precluding safe DXA testing
12. Breastfeeding, pregnancy, or plans to become pregnant during the study
13. Known allergy/sensitivity to DTG or 3TC.
14. Receipt or planned receipt of prohibited concomitant medications (See section 5.4)
15. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study procedures and treatment.
16. Any serious medical or psychiatric illness that, in the opinion of the site investigator, precludes safe participation or adherence to study procedures.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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0 participants in 2 patient groups

Switch

Experimental group

Description:

Dolutegravir (DTG) 50MG/ lamivuidne (3TC) 300MG FIXED_DOSE COMBINATION (FDC) DAILY at randomization for 96 weeks

Treatment:

Drug: Dolutegravir (DTG) 50MG/lamivudine (3TC) 300MG FIXED DOSE COMBINATION (FDC)

Continuation

Active Comparator group

Description:

Continue current tenofovir alafenamide (TAF)-containing ART regimen from weeks 0 to 96.

Treatment:

Drug: Current tenofovir alafenamide (TAF)-containing ART regimen