In this large multicenter cohort of HIV-infected patients in routine care with a median follow-up duration of 4.8 years on ART, we observed a significantly slower rate of eGFR decline associated with antiretroviral treatment. We also observed a significantly higher risk of developing CKD in association with lower time-varying CD4 cell count and higher plasma viral load. This suggests that effective ART lowered the rate of eGFR decline and lowered the risk of CKD, and the magnitude of this protective effect increased in a dose-dependent manner with increasing severity of kidney disease. We also observed a significantly higher risk of moderate CKD associated with tenofovir and a rPI (HOR 3.35 for eGFR less than 60 ml/min per 1.73 m2, compared with a regimen that included a NNRTI without tenofovir). Despite this high risk, however, moderate CKD was uncommon in association with this regimen-type, developing in 5.7% of patients after 4 years of exposure. Furthermore, regimens containing tenofovir and a rPI were not associated with a significantly increased risk of more severe kidney disease in the context of usual care that included regular toxicity monitoring, although the small number of cases may have limited our ability to detect such an association. Of note, we did not observe a significantly increased risk of CKD at any eGFR threshold in patients, who initiated tenofovir plus a NNRTI.
Previous studies have demonstrated kidney function improvements in patients with HIVAN [1
], and in observational cohorts of HIV-infected with renal insufficiency [2
]. In some studies, this improvement was associated with viral load suppression on ART [2
]. Consistent with two large multicenter cohort studies showing higher risk of ESRD associated with lower last CD4 cell count on ART [38
], we extend these findings by demonstrating a significantly higher risk of CKD with lower time-varying CD4 cell count and higher time-varying plasma viral load on ART. These results provide additional evidence for the benefits of ART on kidney function in HIV-infected patients.
Many studies have found modest nephrotoxicity associated with tenofovir [10
]. In a meta-analysis of 17 studies, the magnitude of this effect was −3.9 ml/min over a median of 48 weeks [16
]. Atazanavir was also independently associated with nephrotoxicity in one large study, and with enhanced nephrotoxicity when combined with tenofovir. Ritonavir may enhance tenofovir-associated nephrotoxicity by increasing tenofovir plasma levels, possibly via enhanced intestinal absorption [40
]. In two clinical trials and two observational cohorts, greater eGFR declines were observed over 48 weeks to 24 months with tenofovir and a rPI, versus a NNRTI [20
]. In contrast to our study, however, six observational studies did not find evidence of increased nephrotoxicity with tenofovir when it was combined with a rPI, including two that examined CKD risk and four that examined eGFR changes [10
]. In the present study, the CKD risk associated with atazanivir–ritonavir did not appear to be different from that of other rPIs, mainly lopinavir–ritonavir. Although the reasons for discrepancies between the present study and several others are not apparent, it is possible that by examining outcomes associated with initial ART regimens only, we avoided obscuring associations with the drug exposures of interest with residual nephrotoxicity due to previous ART exposure [43
]. Furthermore, we may have been better able to detect additive or synergistic toxicities by examining ART regimens within a small number of mutually exclusive categories rather than evaluating drug combinations or interactions between numerous individual drugs. Finally by excluding indinavir, the ART-associated nephrotoxicity that we observed may be more representative of current ART regimens.
The strong association between black race and severe CKD highlights the disproportionate and substantial burden of kidney disease among African Americans, as has previously been documented, particularly in association with advanced kidney disease [37
]. The present study also identifies an important contribution by hepatitis C to the risk of severe CKD in persons with HIV disease, extending recent associations found with modest eGFR declines and heavy proteinuria among HCV coinfected patients [45
]. It is possible that other factors associated with past or current injection drug use may confound associations between hepatitis C and CKD.
Consistent with a previous study, we observed a significantly slower rate of eGFR decline on ART [6
]. Although eGFR improved with each ARTregimen-type, such improvement was significant only in association with tenofovir and a rPI, a regimen-type that was also associated with significantly higher risk of CKD. A possible explanation for these findings may be that tenofovir and a rPI does not adversely affect kidney function in most patients, but may only affect a subset of patients. In support of this, despite the high relative risk of CKD associated with this regimen, CKD developed in less than 6% of patients after 4 years of exposure. Risk factors for tenofovir-associated renal tubular toxicity in previous studies include older age, lower body mass index, and lower eGFR at the start of therapy [17
]. Among all baseline factors, we detected an interaction between ART regimen and race, which was of uncertain significance given the small sample size that warrants further study.
This study was conducted among patients in routine care whose initial ART regimen was not randomly assigned. Thus, differences in baseline characteristics among patients receiving different types of initial ART could contribute to confounding by indication, which has the potential to minimize apparent toxicities associated with tenofovir for example, if patients, who were at greater risk for kidney disease were also less likely to receive this drug. In addition, changes in ART regimens in routine care limit the ability to directly examine associations between drug-exposure and CKD risk. Therefore, we examined CKD risk associated with initial ART regimen using marginal structural logistic regression models to control for confounding by indication and potential bias due to informative censoring that may occur if ART changes were made before eGFR declines fell below event-defining thresholds, resulting in missed CKD events. Thus, this analysis provides more reliable estimates of CKD risk with initial ART than the standard Cox proportional hazards analysis. These models could only control for measured variables that were included in the analysis, however, and residual confounding from unmeasured factors may remain.
It is notable that we observed only 16 cases of severe incident CKD in this cohort with over 10 000 person-years of follow-up on ART. Although this small number of events limited our ability to detect associations with ART, it argues against a general risk of severe nephrotoxicity by any ART regimen-type in the context of usual care with regular toxicity monitoring, given the large sample size and the long follow-up duration of this cohort. Consistent with a recent large study from the Veteran’s Administration, we found that tenofovir-containing regimens were not associated with increased risk of more severe CKD defined by eGFR thresholds below 45 or 30 ml/min per 1.73 m2
In conclusion, we observed a significantly slower rate of eGFR decline in association with treatment with ART, and lower risk of CKD with higher time-varying CD4 cell count and lower time-varying plasma viral load on ART. Despite these benefits, initial ART regimens that included tenofovir and a rPI were associated with significantly higher risk of CKD compared with a regimen that included a NNRTI without tenofovir, but this developed in less than 6% of patients after 4 years of exposure to such a regimen. Many factors contribute to kidney disease in persons living with HIV infection. These findings suggest durable benefits of ART-associated immunologic and virologic improvements in reducing the risk of kidney disease, while also delineating contributions by ART-specific toxicities, demographic factors and comorbidities to this important complication.