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The Kidney at CROI 2014
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Christina M. Wyatt, MD Associate Professor, Medicine/ Nephrology Icahn School of Medicine at Mount Sinai New York, NY
Last year's meeting was marked by exciting reports of improved renal and bone safety in phase 2 studies of the new tenofovir prodrug TAF. Although enthusiasm remains high, investigators have recognized that it will be several years before the new drug will be widely available even if phase 3 clinical trials are successful. This year several studies focused on predicting renal outcomes with TDF and boosted PIs, while others investigated the safety of TDF in children and adolescents. In addition to studies focused on potential nephrotoxicity of ART, there were studies evaluating risk factors for atazanavir-related nephrolithiasis and renal adverse events with first generation triple therapy for HCV. New insights into the epidemiology of kidney disease in HIV-infected adults were provided by reports from several cohort studies and secondary analyses of randomized clinical trials.
Seeking to predict kidney disease outcomes with ART
Investigators from D:A:D and the US Veterans Health Administration evaluated the risk of kidney function decline in HIV-infected adults, with a focus on the role of specific ART agents. In the D:A:D cohort, Ryom and colleagues evaluated renal outcomes after progression to a confirmed CrCl < 70 mL/min (two consecutive measures separated by at least 3 months) (792). This CrCl cut-off was selected because of prior D:A:D analyses demonstrating a high rate of TDF discontinuation below this level and should not be interpreted as a threshold for the safe use of TDF, which the investigators were unable to identify in this cohort. Among 1237 participants with available data and with baseline creatinine clearance (CrCl) > 80 mL/min who progressed to confirmed CrCl < 70 mL/min, approximately 23% had a subsequent improvement in CrCl of > 10mL/min, 69% remained stable, and 8% had a further decline of > 10 mL/min at 12-24 months. In multivariate analysis, traditional CKD risk factors (older age and diabetes) and current use of TDF or ritonavir-boosted PI were associated with a lower chance of stabilization or improvement, while discontinuation of TDF > 12 months prior was associated with a higher chance of better renal outcomes (even when compared to never users). After reaching a confirmed CrCl < 70 mL/min, there was no consistent pattern of ART use or ART discontinuation associated with stabilization or improvement. The low rate of progression among patients with moderately reduced kidney function is reassuring and consistent with the very low prevalence of advanced CKD in this patient population with high rates of ART treatment and virologic control. The better renal outcomes observed in patients who had discontinued TDF > 12 months prior to reaching a CrCl < 70 mL/min may reflect a prolonged, gradual improvement in kidney damage following TDF discontinuation; however, it could also be a marker for earlier awareness and intervention to prevent comorbid CKD progression, including improved blood pressure and glycemic control, blockade of the renin-angiotensin system, and avoidance of other potential nephrotoxins.
CROI: Stopping TDF Before Renal Impairment Boosts Chance of Improving eGFR -
Using data from nearly 200,000 person-years of followup in the VA system, Scherzer and colleagues developed a score to predict the 5-year risk of eGFR < 60 mL/min/1.73m2 (confirmed on 2 consecutive measures at least 3 months apart) (798). Traditional CKD risk factors and CD4 cell count < 200 contributed to the final risk score, while HIV RNA did not. At all levels of predicted risk, the 5-year event rate was higher for patients on TDF; although the relative risk associated with TDF was greater in those with lower baseline risk scores, the absolute risk associated with TDF was highest among those with the highest baseline risk. The analysis did not consider the impact of other ART agents, such as boosted PI, on CKD risk. If validated in other populations, a risk score such as this one may be useful to identify patients at increased risk for CKD, both with and without TDF.
CROI: A Chronic Kidney Disease Risk Score to Determine Tenofovir Safety in a Prospective Cohort of HIV+ Male Veterans - (03/12/14)
Renal safety of TDF in children and adolescents
In a small cohort of children and adolescents with 96 weeks of follow-up on TDF-containing ART (n=35, mean age 16 years), Prasitsuebsai and colleagues demonstrated a small but significant reduction in median eGFR, which was associated with longer duration of TDF exposure and with concomitant protease inhibitor use (905). Transient or persistent elevations in at least one marker of proximal tubular dysfunction were observed in 57% of patients, with elevated urine beta-2 microglobulin seen most frequently. Isolated evidence of proximal tubular dysfunction was associated with higher mid-dose tenofovir concentrations. Although there were no clinical events requiring drug discontinuation in this population, these data reinforce the importance of close monitoring and further studies in children and adolescents exposed to TDF.
As the first phase of an ongoing 48-week trial, Gilead Sciences evaluated safety and pharmacokinetics of the fixed dose formulation of TDF/FTC/elvitegravir/cobicistat in adolescents (n=14, median age 16 years) (909). Plasma elvitegravir concentrations and AUC were higher than that observed in clinical trials in the adult population, while exposure to the other components was similar to that observed in adults. Interestingly, the anticipated increase in serum creatinine with cobicistat was smaller than that observed in adults, a median increase of 0.06 mg/dL at week 12 from a median baseline of 0.78 mg/dL.
TDF pharmacokinetics and pharmacogenetics
In a small phase 1 open-label trial of HIV-infected adults with creatinine clearance 30 to < 50 mL/min (n=20), Cressey and colleagues demonstrated equivalent tenofovir exposure following DF 150 mg once daily versus standard every other day dosing of TDF 300mg (516). While awaiting phase 3 trials of TAF, which does not require dose reduction in patients with moderately reduced GFR, this dosing schedule could improve adherence and acceptability of TDF in this population.
In a pharmacogenetic study of 194 HIV-infected adults with creatinine clearance > 60 mL/min on TDF-containing ART, Calcagno and colleagues evaluated potential genetic influences on the urinary excretion of tenofovir as estimated by the ratio of urine: plasma tenofovir concentration (503). Real time PCR was used to identify single nucleotide polymorphisms (SNPs) in genes encoding renal transport proteins, including several that have been associated with TDF toxicity or proximal tubular dysfunction. In multivariate analysis, a polymorphism in the gene encoding MRP4, the primary regulator of tenofovir transport from proximal tubular cells into urine (ABCC4 3348 CC), was independently associated with increased urine: plasma tenofovir concentration. Although their preliminary data also suggest an association between higher urine: plasma tenofovir concentration and elevations in the proximal tubular injury marker retinol binding protein (RBP), the authors did not directly link this polymorphism to TDF toxicity.
In contrast, the HIV-NAT 114 Study Team demonstrated an association between polymorphisms in ABCC2 and ABCC10, but not ABCC4, and the development of proximal tubulopathy in TDF-treated adults (799). In this cross-sectional subgroup analysis, proximal tubulopathy was defined by the presence of at least 2 markers of proximal tubular dysfunction, including phosphaturia, uricosuria, or euglycemic glycosuria, in asymptomatic patients. Participants with overt proximal tubulopathy or eGFR decline were excluded from this analysis. In addition to polymorphisms in ABCC2 and ABCC10, other factors associated with proximal tubulopathy included diabetes and eGFR < 90 mL/min/1.73m2. The majority of pharmacogenetic studies of TDF-induced proximal tubulopathy have implicated polymorphisms in genes encoding MRP2, which is thought to be a minor contributor to the transport of tenofovir from proximal tubular cells into urine, and have not included patients with overt proximal tubular injury for whom risk prediction would be most valuable.
Atazanavir-related nephrolithiasis
Three abstracts described potential risk factors for nephrolithiasis in patients receiving atazanavir. In a small case-control study with atazanavir stones confirmed by spectroscopic stone analysis, LaFaurie and colleagues evaluated routinely available clinical characteristics as potential risk factors (795). Among 30 cases of confirmed atazanavir-induced nephrolithiasis, more than one-third presented with an eGFR < 60 mL/min/1.73m2. Routinely available clinical characteristics associated with increased odds of atazanavir stones included a history of nephrolithiasis, use of ritonavir, previous use of indinavir, longer exposure to atazanavir, and elevated serum bilirubin. In multivariate analysis, longer exposure to atazanavir and higher serum bilirubin remained independently associated with increased odds of atazanavir-induced nephrolithiasis.
In a second case-control study, Nishijima and colleagues considered the role of genetic factors in the risk of atazanavir-related nephrolithiasis (796). Cases included atazanavir-treated patients with nephrolithiasis confirmed by stone passage or imaging (n=24) or flank pain in the setting of new onset hematuria (n=7).
Polymorphisms in 5 genes involved in the absorption and metabolism of atazanavir were considered. In models adjusted for age, sex, and HCV status, polymorphisms in the UGT1A1 gene were significantly associated with their case definition. The results were qualitatively similar when only confirmed cases were included.
In a series of 273 consecutive atazanavir-treated patients, Gervasoni and colleagues demonstrated an association between atazanavir trough concentration and drug-related adverse effects, including hyperbilirubinemia, dyslipidemia, and kidney stones (511). Overall, kidney stones were the least common adverse event, reported in 13/273 (4.8%) patients; the mean atazanavir concentration in these cases was significantly higher than that observed in patients without drug-related adverse events. Although differences among the adverse events were not significant, the mean plasma trough concentration was highest among patients with kidney stones. This is consistent with the putative mechanism of atazanavir-related stones. Ritonavir boosting and concomitant rosuvastatin use were independently associated with higher atazanavir trough concentration.
CROI: Correlation between atazanavir concentrations, clinical covariates and side effects - (03/14/14)
Renal adverse events with currently approved triple therapy for HCV
Although newly approved and emerging agents for the treatment of HCV infection and HIV-HCV co-infection took center stage, several sessions focused on the experience with first generation HCV protease inhibitors. Secondary analysis of the TelapreVIH study demonstrated a link between declines in eGFR and clinically significant anemia with the addition of telaprevir to IFN/ ribavirin in genotype 1 patients with HIV-HCV co-infection (664). The analysis focused on the initial phase of the trial, which included 4 weeks of IFN/ ribavirin followed by 12 weeks of triple therapy with telaprevir. The investigators observed a decline in eGFR and a corresponding increase in ribavirin concentrations with the addition of the telaprevir. Both eGFR (baseline and week 8) and elevated ribavirin concentration were associated with treatment-emergent anemia at week 8.
CROI: Telaprevir Increases Ribavirin Toxicity Through eGFR Decrease in HIV-HCV Coinfected Patients - (03/24/14)
In a retrospective analysis of HCV mono-infected patients treated with bocepravir/ IFN/ ribavirin (n=97) and IFN-sparing sofusbuvir/ ribavirin (n=60), Townsend and colleagues demonstrated a higher rate of adverse events in patients receiving triple therapy (661). Subjects were treatment-naïve adults with genotype 1 infection. DAIDS grade 1 or 2 creatinine elevations occurred in 8% of patients on triple therapy compared to 2% of those on IFN-sparing therapy (p < 0.001). No grade 3-4 creatinine events occurred in either group. These results are consistent with the excellent renal safety demonstrated in clinical trials of IFNs-sparing therapy with sofusbuvir.
Epidemiology of chronic kidney disease in HIV: Cohort studies
Post and colleagues provided new information on the spectrum of biopsy-proven kidney disease and the outcomes of end-stage renal disease (ESRD) in HIV-infected adults in the UK. In a series of 250 native kidney biopsies performed during a 14-year period, 67 were diagnostic for HIV-associated nephropathy (HIVAN, 27%), 56 for HIV immune complex kidney disease (HIVICK, 22%), and 32 (13%) for other immune complex kidney disease, including lupus nephritis and IgA nephropathy (793). Compared to patients with HIVAN, those with HIVICK were less likely to be black and had higher CD4 cell count and estimated glomerular filtration rate (eGFR) at the time of biopsy. Similar to a prior study from Baltimore [Foy et al. CJASN 2013], progression to ESRD was significantly more common among patients with HIVAN. In a parallel analysis of the UK CHIC cohort, black race and detectable HIV RNA were risk factors for both HIVAN and HIVICK. Future studies should consider the role of HIV infection and ART in the pathogenesis and natural history of HIVICK, which is responsible for a growing proportion of kidney disease in HIV-infected individuals.
Among nearly 28,000 patients followed in UK CHIC between 2000 and 2012, 0.4% had ESRD requiring renal replacement therapy (800). Risk factors for ESRD included expected factors such as older age, black race, lower CD4, and co-infection with HBV or HCV. Interestingly, higher HIV RNA was associated with a decreased risk of progression to ESRD, an effect that was not explained by differences in the use of TDF or other potentially nephrotoxic ART. Although the reason for this unexpected finding is unclear, it is consistent with findings in the D:A:D cohort published earlier this year [Ryom et al AIDS 2014]. The incidence of ESRD was stable over the study period, with rising prevalence among blacks reflecting excellent survival with ESRD. Kidney transplantation was offered more frequently in the later years of the study period, and patients who were considered transplant candidates had better outcomes than those who were not considered suitable for transplantation, regardless of whether they received a transplant or remained on the waiting list.
CROI: End-stage kidney disease and kidney transplantation in HIV positive patients - (03/12/14)
CROI: HIV-Immune Complex Kidney Disease: Risk Factors and Progression to End-Stage Kidney Disease - (03/12/14)
In an analysis of data from the MACS cohort, Gabuzda and colleagues demonstrated an association between heavy use of nitrate inhalants (daily or weekly use of "poppers") and kidney and cardiovascular disease in US men (740). Among Caucasians with at least 5 years of followup, heavy use of nitrate inhalants was associated with eGFR < 60 on at least two visits. Preliminary results suggest that the association with kidney disease is independent of cocaine and heroin use, which have been previously associated with kidney disease risk.
CROI: Heavy Popper Use in Gay MACS Cohort Linked to New Heart Disease, Cancer - (03/12/14)
Renal outcomes in randomized controlled trials
In a secondary analysis of the ACTG A5175 trial, Touzard Romo and colleagues evaluated renal safety of AZT/3TC/efavirenz versus TDF/FTC efavirenz (794). Renal adverse events were defined as DAIDS grade 3-4 creatinine elevation (creatinine > 1.9 mg/dL) and/ or CrCl < 50 mL/min. A total of 21 participants met one or both criteria (10 with DAIDS grade 3-4 creatinine and 16 with a CrCl < 50 mL/min); although approximately 70% of events occurred in the TDF arm, there was no significant difference between the groups. Factors associated with the development of a renal adverse event included traditional kidney disease risk factors, older age, diabetes, and lower baseline CrCl. Enrolling countries included the US and 8 low- or middle-income countries; outcomes were not significantly different between countries. These results may help to identify patient subgroups likely to benefit most from targeted monitoring in resource-limited settings where routine toxicity monitoring is not feasible.
In an a priori secondary analysis of the A5224s substudy of ACTG 5202, Longenecker and colleagues evaluated changes in serum cystatin C and inflammatory biomarkers in ART-naïve participants randomized to blinded ABC/3TC versus TDF/FTC with open-label ATV/r or efavirenz (797). At baseline, cystatin C was correlated with biomarkers of inflammation, and observed declines in cystatin C were correlated with improvement in most of these inflammatory biomarkers. Although cystatin C improved in all treatment arms, assignment to TDF/FTC or ATV/r was associated with a less significant improvement.
The SATURN-HIV investigators reported a significant decrease in serum cystatin C and creatinine-based eGFR in HIV-infected adult participants randomized to rosuvastatin 10 mg daily versus placebo (743). Participants were on stable ART with LDL ≤ 130 mg/dL and with evidence of immune activation. The treatment groups were balanced with respect to baseline eGFR, cystatin C, and prevalence of microalbuminuria (17% in each group). Elevated baseline cystatin C was associated with biomarkers of inflammation, including soluble TNF-α receptors I and II (TNFR), and with abnormal carotid intima media thickness, a marker of cardiovascular risk. Over 24 weeks of treatment, cystatin C decreased significantly in the rosuvastatin arm and correlated with changes in TNFR. This finding is consistent with other studies suggesting that cystatin C is a marker of both GFR and inflammation in HIV-infected individuals. At the same time, both cystatin C and creatinine-based eGFR improved with rosuvastatin treatment, suggesting that this approach may have both anti-inflammatory effects and related or unrelated benefits for the kidney. Future studies should target participants with abnormal kidney function who would have greater potential to benefit from this approach.
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