Association between antiretroviral exposure and renal impairment among HIV-positive persons with normal baseline renal function: the D:A:D study

Abstract

Background: Several antiretroviral agents (ARVs) are associated with chronic renal impairment, but the extent of such adverse events among human immunodeficiency virus (HIV)-positive persons with initially normal renal function is unknown.

Methods: D:A:D study participants with an estimated glomerular filtration rate (eGFR) of ≥ 90 mL/min after 1 January 2004 were followed until they had a confirmed eGFR of ≤ 70 mL/min (the threshold below which we hypothesized that renal interventions may begin to occur) or ≤ 60 mL/min (a value indicative of moderately severe chronic kidney disease [CKD]) or until the last eGFR measurement during follow-up. An eGFR was considered confirmed if it was detected at 2 consecutive measurements ≥ 3 months apart. Predictors and eGFR-related ARV discontinuations were identified using Poisson regression.

Results: Of 22 603 persons, 468 (2.1%) experienced a confirmed eGFR of ≤ 70 mL/min (incidence rate, 4.78 cases/1000 person-years of follow-up [95% confidence interval {CI}, 4.35-5.22]) and 131 (0.6%) experienced CKD (incidence rate, 1.33 cases/1000 person-years of follow-up [95% CI, 1.10-1.56]) during a median follow-up duration of 4.5 years (interquartile range [IQR], 2.7-6.1 years). A current eGFR of 60-70 mL/min caused significantly higher rates of discontinuation of tenofovir (adjusted incidence rate ratio [aIRR], 1.72 [95% CI, 1.38-2.14]) but not other ARVs compared with a current eGFR of ≥ 90 mL/min. Cumulative tenofovir use (aIRR, 1.18/year [95% CI, 1.12-1.25]) and ritonavir-boosted atazanavir use (aIRR, 1.19/year [95% CI, 1.09-1.32]) were independent predictors of a confirmed eGFR of ≤ 70 but were not significant predictors of CKD whereas ritonavir-boosted lopinavir use was a significant predictor for both end points (aIRR, 1.11/year [95% CI, 1.05-1.17] and 1.22/year [95% CI, 1.16-1.28], respectively). Associations were unaffected by censoring for concomitant ARV use but diminished after discontinuation of these ARVs.

Conclusions: Tenofovir, ritonavir-boosted atazanavir, and ritonavir-boosted lopinavir use were independent predictors of chronic renal impairment in HIV-positive persons without preexisting renal impairment. Increased tenofovir discontinuation rates with decreasing eGFR may have prevented further deteriorations. After discontinuation, the ARV-associated incidence rates decreased.

Figure 1.

Antiretroviral discontinuation rates and current estimated glomerular filtration rates (eGFRs). Models adjusted for baseline eGFR (per 5-mL/min increase), age (per 10-year increase), sex, ethnicity (white, African ancestry, or unknown), mode of human immunodeficiency virus (HIV) transmission (male-male sex, heterosexual, injection drug use, unknown, or other), nadir CD4⁺ T-cell count, enrollment cohort, prior AIDS-defining illness, and baseline date. Hepatitis B virus (HBV) positivity (defined as detection of HBV surface antigen, detection of HBV e antigen, or detection of HBV DNA plus antibody to HBV e antigen), hepatitis C virus (HCV) positivity (defined as detection of antibody to HCV plus detection or unknown presence of HCV RNA), current smoker, hypertension, diabetes, cardiovascular disease, CD4⁺ T-cell count (per doubling), HIV load (per log₁₀ copies/mL increase), and cumulative exposure (per year) to unboosted atazanavir, ritonavir-boosted atazanavir (atazanavir/r), ritonavir-boosted lopinavir (lopinavir/r), tenofovir, abacavir, indinavir, and other ritonavir-boosted protease inhibitors were included as time-updated variables. Abbreviations: CI, confidence interval; IRR, incidence rate ratio.

Figure 2.

Antiretroviral exposure (per year) and incidence rate ratios of progression to confirmed estimated glomerular filtration rates (eGFRs) of ≤70 mL/min and CKD from an eGFR of ≥90 mL/min. Models adjusted for baseline eGFR (per 5-mL/min increase), age (per 10-year increase), sex, ethnicity (white, African ancestry, or unknown), mode of human immunodeficiency virus (HIV) transmission (male-male sex, heterosexual, injection drug use, unknown, or other), nadir CD4⁺ T-cell count, enrollment cohort, prior AIDS-defining illness, and baseline date. Hepatitis B virus (HBV) positivity (defined as detection of HBV surface antigen, detection of HBV e antigen, or detection of HBV DNA plus antibody to HBV e antigen), hepatitis C virus (HCV) positivity (defined as detection of antibody to HCV plus detection or unknown presence of HCV RNA), current smoker, hypertension, diabetes, cardiovascular disease, CD4⁺ T-cell count (per doubling), HIV load (per log₁₀ copies/mL), and cumulative exposure (per year) to unboosted atazanavir, ritonavir-boosted atazanavir (atazanavir/r), ritonavir-boosted lopinavir (lopinavir/r), tenofovir, abacavir, indinavir, and other ritonavir-boosted protease inhibitors were included as time-updated variables. Abbreviations: CI, confidence interval; IRR, incidence rate ratio.

Figure 3.

Antiretroviral exposure and rates of progression to a confirmed estimated glomerular filtration rate (eGFR) of ≤70 mL/min from an eGFR of ≥90 mL/min. Models adjusted for baseline eGFR (per 5-mL/min increase), age (per 10-year increase), sex, ethnicity (white, African ancestry, or unknown), mode of human immunodeficiency virus (HIV) transmission (male-male sex, heterosexual, injection drug use, unknown, or other), nadir CD4⁺ T-cell count, enrollment cohort, prior AIDS-defining illness, and baseline date. Hepatitis B virus (HBV) positivity (defined as detection of HBV surface antigen, detection of HBV e antigen, or detection of HBV DNA plus antibody to HBV e antigen), hepatitis C virus (HCV) positivity (defined as detection of antibody to HCV plus detection or unknown presence of HCV RNA), current smoker, hypertension, diabetes, cardiovascular disease, CD4⁺ T-cell count (per doubling), HIV load (per log₁₀ copies/mL increase), and cumulative exposure (per year) to unboosted atazanavir, ritonavir-boosted atazanavir (atazanavir/r), ritonavir-boosted lopinavir (lopinavir/r), tenofovir, abacavir, indinavir, and other ritonavir-boosted protease inhibitors were included as time-updated variables. Abbreviations: CI, confidence interval; IRR, incidence rate ratio.

Figure 4.

Other predictors of confirmed estimated glomerular filtration rates (eGFRs) of ≤ 70 mL/min and ≤60 mL/min, CKD, from an eGFR of ≥90 mL/min. Models adjusted for baseline eGFR (per 5-mL/min increase), age (per 10-year increase), sex, ethnicity (white, African ancestry, or unknown), mode of human immunodeficiency virus (HIV) transmission (male-male sex, heterosexual, injection drug use, unknown, or other), nadir CD4⁺ T-cell count, enrollment cohort, prior AIDS-defining illness, and baseline date. Hepatitis B virus (HBV) positivity (defined as detection of HBV surface antigen, detection of HBV e antigen, or detection of HBV DNA plus antibody to HBV e antigen), hepatitis C virus (HCV) positivity (defined as detection of antibody to HCV plus detection or unknown presence of HCV RNA), current smoker, hypertension, diabetes, cardiovascular disease, CD4⁺ T-cell count (per doubling), HIV load (per log₁₀ copies/mL increase), and cumulative exposure (per year) to unboosted atazanavir (ATV), ritonavir-boosted ATV, ritonavir-boosted lopinavir, tenofovir, abacavir, indinavir, and other ritonavir-boosted protease inhibitors were included as time-updated variables. Abbreviations: CI, confidence interval; IDU, injection drug use; IRR, incidence rate ratio