Impact of early versus deferred antiretroviral therapy on estimated glomerular filtration rate in HIV-positive individuals in the START trial

Abstract

Background Both untreated HIV infection and antiretroviral therapy (ART) have been associated with worsening kidney function. The impact of earlier ART initiation on kidney function has not been studied. Methods The START trial was a randomized comparison of immediate versus deferred ART initiation among HIV+ persons with CD4+ counts >500 cells/mm3. Serum creatinine and urine dipstick protein were measured at baseline, months 1, 4, 8, 12, and annually thereafter. We compared the two arms for changes in estimated glomerular filtration rate (eGFR, using the CKD-EPI equation) over time using longitudinal mixed models. Findings Of 4685 START participants, 4629 (n=2294 in immediate and 2335 in deferred arm) individuals were included. Median baseline CD4 and eGFR were 651 cells/mm3 and 111.5 mL/min/1.73m2. ART was initiated in 2271 participants (99%) in the immediate and 1127 participants (48%) in the deferred arm, accounting for over 94% and 19% of follow-up time, respectively. Overall, 89% started ART using a tenofovir-based regimen. Over a median follow-up of 2.1 years, the mean eGFR was 0.56 (95% CI: 0.003–1.11) mL/min/1.73m2 higher in the immediate arm than the deferred arm. This difference was more prominent after adjustment for current use of tenofovir or boosted-protease inhibitors (1.85, 95% CI: 1.21–2.50), and was more prominent in participants of black race (30% overall) (3.90, 95% CI: 2.84–4.97) compared to non-black (1.05, 95% CI: 0.33–1.77) (p<0.001 for interaction). Relative risk for proteinuria in the immediate vs. deferred arm was 0.74 (95% CI: 0.55–1.00), P=0.049. The incidence of chronic kidney disease as defined by eGFR < 60 or dipstick proteinuria was low, and there was no significant difference between treatment arms (incidence rate ratio 0.79, 95% CI 0.59–1.05). Conclusion In the short-term, immediate ART initiation was associated with a modestly higher eGFR and lower risk of proteinuria as opposed to deferring ART- a difference more pronounced in those with black race. Whether this early benefit translates into a lower risk of chronic kidney disease requires further follow-up.

Renal dysfunction by baseline CD4 cell count in a cohort of adults starting antiretroviral treatment regardless of CD4 count in the HIV Prevention Trials Network 071 [HPTN 071; Population Effect of Antiretroviral Therapy to Reduce HIV Transmission (PopART)] study in South Africa

“…The overall incidence rate of eGFR < 60 mL/min (1.9 cases/100 PY) was lower than that reported in a previous study (5.9 cases/100 PY) with a lower baseline median CD4 count that reported on the same endpoint . Also in contrast to previous studies, this study did not find an association between baseline CD4 count and average eGFR or renal dysfunction after ART initiation after adjustment for key baseline characteristics . Notably, analysis of incident eGFR < 60 mL/min – restricted to individuals with a normal baseline renal function – showed a low incidence rate of eGFR < 60 mL/min of 1.1 cases/100 PY (95% CI 0.6–1.8 cases/100 PY) and no incident cases among individuals with baseline CD4 counts > 500 cells/μL.…”

“…These studies reported less renal dysfunction following ART initiation among individuals with baseline CD4 counts > 200 cells/μL compared with lower values . Recently published results from the Strategic timing of antiretroviral treatment (START) trial showed higher mean eGFR after ART initiation among individuals starting ART at baseline CD4 counts > 500 cells/μL compared with those with baseline CD4 counts of 350–500 cells/μL . There are, however, limited data from programmatic studies to confirm these findings.…”

Rapid initiation of antiretroviral therapy for people living with HIV

“…We excluded several studies as they assessed the effect of ART initiation related to CD4 threshold rather than initiating ART soon after HIV diagnosis (Achhra 2017; Danel 2015; Iwuji 2017; Sabapathy 2017; Larmarange 2016; Plazy 2016; Temprano 2015). We further excluded studies that specifically assessed timing of ART in participants who had oppurtunistic infections such as cryptococcal meningitis or tuberculosis meningitis (Bisson 2013; Blanc 2011; Boulware 2014; Degu 2012; Grant 2010; Havlir 2011; Laurelliard 2013; Makadzange 2010).…”

Changes in renal function with long‐term exposure to antiretroviral therapy in HIV‐infected adults in Asia

“…Nadir CD4 counts were significantly associated with CKD, suggesting that initiating ART early may help in reducing this risk. For example, early initiation of ART in the Strategic Timing for Antiretroviral Therapy (START) study was associated with a modestly higher eGFR and lower risk of proteinuria . In addition, TDF use may be best avoided among patients with lower baseline eGFR as is recommended by some guidelines …”

“…For example, early initiation of ART in the Strategic Timing for Antiretroviral Therapy (START) study was associated with a modestly higher eGFR and lower risk of proteinuria. 22 In addition, TDF use may be best avoided among patients with lower baseline eGFR as is recommended by some guidelines. 23 Estimated GFR can be affected by ethnicity and body composition.…”