Darunavir/Cobicistat and Dolutegravir to Maintain Virologic Suppression and Reduce NRTI-associated Toxicity

NRTIs have been a stalwart for treatment in both the pre- and post-ART eras. However, NRTIs
have numerous toxicities partly due to the fact that they are analogs of naturally occurring
nucleotides and interfere with the activity of numerous cellular functions. In highly
treatment-experienced individuals with more than two active drugs in their salvage regimens,
an NRTI-sparing regimen has been shown to be non-inferior to an NRTI-containing regimen
[33]. However, studies with NRTI-sparing regimens not consisting of more than two active
medications have generally been disappointing.

One limitation of earlier NRTI-sparing regimens has been a higher pill burden than more
standard regimens. However, the approvals of DTG and the co-formulated DRV/COBI, both with
well-established antiviral activities, may allow for a compact, effective, NRTI-sparing
regimen. A switch to DTG/DRV/COBI in virologically suppressed HIV-infected individuals has
the potential to avoid NRTI-associated toxicity while maintaining virologic suppression.

Inclusion Criteria:

1. HIV-1 infection, as documented by any licensed ELISA test kit and confirmed by Western
blot at any time prior to study entry. A second antibody test by a method other than ELISA
is acceptable as an alternative confirmatory test or a previous detectable HIV RNA level.

2 .Age ≥ 18 years

3. HIV-1 RNA <50 copies/mL while on a stable antiretroviral regimen for at least 6 months
prior to study entry excluding blips (i.e., a single measurement <200 copies/mL preceded
and followed by measurements <50 copies/mL)

4. At screening, patient on a stable antiretroviral regimen containing at least one NRTI
and a PI, NNRTI, or INSTI

5. No changes in antiretroviral regimen in the six months prior to screening (except for a
switch to a coformulated tablet from the component tablets)

6. A desire to switch off current antiretroviral therapy due to: a) Renal dysfunction
(microalbuminuria/proteinuria or CrCl<70 mL/min/1.73 m2) on tenofovir disoproxil fumarate
(TDF) of tenofovir al; b) Osteopenia or osteoporosis on a TDF-containing regimen (i.e.,
lowest T-score ≥1.0 standard deviation below the young adult mean measured by dual-energy
x-ray absorptiometry); c) Peripheral neuropathy or lipoatrophy at least partially
attributable to ongoing NRTI use; d) Intermediate or high Framingham risk (i.e., ≥10%
10-year risk) on an abacavir-containing regimen; e) Patient preference.

7. Laboratory values within six months of screening visit

- Hemoglobin ≥8.0 g/dL

- Platelet count ≥40,000/mm3

- AST, ALT, and alkaline phosphatase ≤5 × ULN

- Total bilirubin ≤2.5 x ULN (except for those on atazanavir-containing regimens)

- Calculated creatinine clearance (CrCl) ≥45 mL/min as estimated by the Cockcroft-Gault
equation:

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

*For women, multiply the result by 0.85 = CrCl (mL/min)

8. For women of reproductive potential, negative serum or urine pregnancy test at
screening and a negative urine pregnancy test at the entry visit prior to randomization
and also 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)

Exclusion Criteria:

1. Current CD4+ T-cell count <200 cells/µL

2. Current antiretroviral regimen consisting of three of more antiretroviral classes

3. History of genotypic resistance, phenotypic resistance or intolerance to either DRV
or DTG.

Prohibited protease mutations: V11I, V32I, L33F, I47V/A/L, I50V, I54T/S/L/M, T74P,
L76V, V82F, I84V, or L89V

Prohibited INSTI mutations: E92Q, E92K/A, G140S/A/C, Q148H/R/K or Q148 substitution
plus any of the following: L74I/M, E138A/D/K/T, G140A/S, Y143H/R, E157Q,
G163E/K/Q/R/S, or G193E/R.

4. History of virologic failure while on an INSTI prior to study enrollment

5. Severe hepatic impairment (Child Pugh Class C)

6. Hepatitis B Surface Antigen Positive

7. Breastfeeding, pregnancy, or plans to become pregnant during the study

8. Known allergy/sensitivity to any study drug or their formulations.

9. Receipt or planned receipt of prohibited concomitant medications (See section 5.2.1)

10. Active drug or alcohol use or dependence that, in the opinion of the site
investigator, would interfere with adherence to study procedures and treatment.

11. Serious medical illness that, in the opinion of the site investigator, precludes safe
participation in the study.