Abstract
Introduction
Cobicistat, a component of stribild (STB), is known to inhibit renal creatinine secretion. A detailed analysis of the renal safety profile of STB in two Phase 3b switch studies of virologically-suppressed individuals on stable therapy: STRATEGY(S)-PI (STB vs a RTV-boosted protease inhibitor [PI] with emtricitabine and tenofovir DF [FTC/TDF]); and STRATEGY(S)-NNRTI (STB versus a non-nucleoside reverse transcriptase inhibitor [NNRTI] with FTC/TDF) is herein described.
Materials and Methods
Baseline eGFR ≥70 mL/min was an inclusion criterion. The renal safety profile of STB was examined by baseline eGFR through week 48 (i.e., changes in eGFR, renal tubular laboratory abnormalities, investigator-reported renal adverse events leading to discontinuation and unreported subclinical proximal renal tubulopathy [PRT]). Subclinical PRT was defined as a confirmed serum-creatinine increase ≥0.4 mg/dL and two or three markers of renal tubular dysfunction (hypophosphatemia, normoglycemic glycosuria, proteinuria) occurring at the same visit at least once and with no alternative etiologies.
Results
In S-PI, 433 subjects (STB 293; PI 140) and in S-NNRTI, 434 subjects (STB 291; NNRTI 143) were randomized and treated. Most (>85%) STB subjects had a baseline eGFR ≥90 mL/min. STB subjects with baseline eGFR <90 mL/min had smaller declines in eGFR compared to those with baseline eGFR ≥90 mL/min and similar occurrences of renal tubular laboratory abnormalities (Table 1). Rate of renal adverse events leading to study drug discontinuation were similar for the STB group (one PRT in a subject with baseline tubular laboratory abnormalities consistent with underlying PRT and one isolated increase in serum creatinine) and PI group (one isolated decrease in eGFR); none in the NNRTI group. The case of PRT improved after study drug discontinuation. There were no cases of unreported subclinical PRT in any group.
Conclusions
In this virologically suppressed patient population, the renal safety of STB did not differ by baseline eGFR. The renal discontinuation rate was low in the STB group, similar to the RTV-boosted PI group, and consistent with published historical rates.
Table 1.
Changes in eGFR at week 48 and tubular laboratory abnormalities by baseline eGFR
| S-PI Study Arm | STB | STB | PI+RTV | PI+RTV |
|---|---|---|---|---|
| Baseline eGFR (mL/min) category | <90 (n=40) | ≥90 (n=253) | <90 (n=27) | ≥90 (n=113) |
| Changes from baseline at week 48: eGFR (mL/min), median (IQR) | −3.8 (−8.1 to 1.2) | −8.9 (−16.9 to 0.4) | −0.2 (−4.5 to 5.0) | 0.5 (−9.1 to 7.3) |
| Hypophosphatemia* | 0 | 0.4% (1) | 0 | 0 |
| Normoglycemic glycosuria* | 0 | 0 | 0 | 0 |
| Proteinuria* | 5.0% (2) | 9.5% (24) | 11.1% (3) | 7.1% (8) |
| S-NNRTI Study Arm | STB | STB | PI+RTV | PI+RTV |
| Baseline eGFR (mL/min) category | <90 (n=43) | ≥90 (n=248) | <90 (n=20) | ≥90 (n=123) |
| Changes from baseline at week 48: eGFR (mL/min), median (IQR) | −8.0 (−11.6 to 0.9) | −12.6 (−21.2 to −6.3) | 7.4 (1.9 to 14.4) | −1.7 (−10.9 to 5.8) |
| Hypophosphatemia* | 4.7% (2) | 0 | 0 | 1.6% (2) |
| Normoglycemic glycosuria* | 2.3% (1) | 1.2% (3) | 0 | 0 |
| Proteinuria* | 9.3% (4) | 6.9% (17) | 10% (2) | 4.9% (6) |
≥1-grade increase from baseline observed at two consecutive post-baseline visits (within 30 days after last dose date).