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The Kidney at CROI 2015
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Lene Ryom PhD
CHIP, Department of Infectious Diseases and Rheumatology, Section 2100, Rigshospitalet - University of Copenhagen, Denmark
Christina Wyatt MD
Associate Professor, Medicine/ Nephrology Icahn School of Medicine at Mount Sinai New York, NY
Phase 3 studies of tenofovir alafenamide (TAF)
As reported in a press release last fall, the primary efficacy outcomes of GS 104 and 111 demonstrated non-inferiority of a fixed dose combination of elvitegravir/ cobicistat/ emtricitabine with TAF versus TDF [Abstract 113LB]. Paul Sax reported the results of the pre-specified safety analyses, which were consistent with observations in the phase 2 studies [Abstract 143LB]. There were no cases of proximal tubulopathy in either treatment group. Study drug was discontinued because of renal adverse events in 4 participants in the TDF arm and none in the TAF arm. At 48 weeks, there was a small but statistically significant difference in eGFR decline (as estimated by CKD-EPI) and in the prevalence of proteinuria (defined as urine: protein: creatinine ratio > 200 mg/g) and albuminuria (urine albumin: creatinine ratio > 30 mg/g) favoring the TAF regimen. Urine beta2-microglobulin and retinol binding protein, markers of proximal tubular function, followed a similar pattern. Although differences between the groups are of limited clinical significance, they are consistent with the suggestion that TAF may have less potential for kidney toxicity, based on exposure of proximal tubular cells to significantly lower circulating levels of the active drug tenofovir. The clinical utility of switching from TDF to TAF will be investigated in upcoming studies.
Prior PK studies have demonstrated therapeutic plasma concentrations of the active drug tenofovir with once daily dosing of TAF in patients with eGFR 30-50mL/min, suggesting that dose reduction is not necessary in these patients. Fordyce et al. evaluated the safety of full dose TAF in 242 patients with creatinine clearance < 70mL/min [Abstract 795]. Participants were switched from TDF or abacavir to TAF 25mg daily and followed for 24 weeks. There was no significant change in eGFR following the switch to TAF; consistent results were observed in a small subgroup undergoing direct GFR measurement by iohexol clearance. There was a decline in proteinuria and albuminuria following the switch. There was also a rapid decline in both beta2-microglobulin and retinol binding protein from baseline to the first post-switch study visit at 1 week. These reductions were sustained, and were of greater magnitude in participants whose initial regimen included TDF. The mechanism of this very rapid decline is not known, but seems too early to reflect recovery of proximal tubular injury. Overall, the results of this small phase 3 study suggest that full dose TAF is safe and well tolerated in adults with decreased kidney function, which may open the door to fixed dose combination regimens for this patient population.
CROI: Tenofovir Alafenamide (TAF) in a Single-Tablet Regimen in Initial HIV-1 Therapy - (02/26/15)
CROI: TAF easier on kidney and bone signals than TDF in 48-week trials - written by Mark Mascolini - (02/27/15)
CROI: Renal and Bone Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate - (02/27/15)
CROI: Safety of Tenofovir Alafenamide in Renal Impairment - (02/27/15)
CROI: GILEAD ANNOUNCES SVR12 RATES FROM PHASE 3 STUDY EVALUATING HARVONI® FOR THE TREATMENT OF CHRONIC HEPATITIS C IN PATIENTS CO-INFECTED WITH HIV - (02/27/15)
Pharmacokinetic Studies of TDF
Prior studies have demonstrated an association between higher plasma concentrations of tenofovir and increased risk of kidney injury. In the Women's Interagency HIV Study (WIHS), Baxi et al. observed a strong relationship between lower eGFR levels and higher tenofovir area-under-the-time-concentration-curves in 105 HIV-positive women undergoing 24-hour PK sampling after witnessed tenofovir intake [Abstract 792 poster]. These results expand on the findings in prior studies and provide additional rationale for the potential safety benefits of TAF.
In an open-label PK study of 40 adults with CrCl 30-50mL/min on dose-reduced TDF, co-administration of ritonavir-boosted PIs was associated with a significant increase in plasma tenofovir concentrations compared to concomitant use of NNRT, despite similar intracellular concentrations [Abstract 511 poster].
In a phase 3 study of ledipasvir-sofosbuvir for the treatment of Hepatitis C virus co-infection in TDF-treated patients (n=355), there were no renal adverse events during 12 weeks of treatment [Abstract 152LB Êwebcast]. Although these data are reassuring given the previously demonstrated increase in tenofovir plasma concentrations with coadministration of ledipasvir, no participants were receiving TDF in combination with a ritonavir-boosted PI.
Potential for kidney toxicity with currently approved ART
A number of studies, including earlier observational data from D:A:D, EuroSIDA, and the VA Medical Center, have associated the use of tenofovir, indinavir, and boosted atazanavir and lopinavir with increased risk of CKD. These data were extended by the D:A:D study group [Abstract 142 webcast] by demonstrating a cumulative nature of the association between each of these ARVs with CKD over time; after five years of exposure the relative risk of CKD related to use of tenofovir was 1.74 (1.33 - 2.27), for boosted atazanavir 3.27 (2.32 - 4.61) and for boosted lopinavir 2.11 (1.62 - 2.75). Consistent results were seen after censoring for any co-administered ARVs. Furthermore, data suggested that once tenofovir use was discontinued, the relative risk of CKD development declined with time since discontinuation. Follow-up time was insufficient to evaluate the risk of newer boosted protease inhibitors such as darunavir. Likewise, considerably longer follow-up (>6 years) is needed to determine if risk plateaus or continues to increase with longer exposure.
In a series of 265 kidney biopsies performed in HIV-positive individuals at 8 UK clinics between 2000-2012, Hamzah et al. focused on the subgroup of cases with tubular and interstitial damage that could reflect drug toxicity. The authors identified 54 (20%) cases of renal tubular disease, including 22 cases of acute tubular injury, 20 cases of tubulointerstitial nephritis, and 12 cases of interstitial fibrosis/tubular atrophy [Abstract 794 poster]. Compared with 64 cases of immune complex disease, the investigators found that a diagnosis of acute tubular injury was associated with current and recent use of tenofovir, boosted atazanavir and lopinavir.
During a median of 16 months follow-up, a 5% incidence rate of CKD was observed among 443 HIV-positive women starting 2nd line ART in Cameroon, Senegal or Burkina Faso [Abstract 793]. Overall, the use of tenofovir in combination with boosted lopinavir or darunavir was well tolerated by the large majority of participants based on changes in median eGFR.
CROI: Impact of TDF + PI/r on Renal Function in Sub-Saharan Africa (2LADY/ANRS 12169) - (03/30/15)
Inflammation and kidney disease
The association between markers of inflammation and immune activation in HIV-positive individuals with development of kidney disease was investigated in two US studies. In a cross-sectional study of 96 HIV-positive individuals on ART in the Hawaii Ageing with HIV-cohort, albuminuria was observed in as many as 19% [Abstract 796 poster]. Presence of albuminuria was associated with older age, hypertension, use of ACE-inhibitors/ARBs, non-classical monocyte subset and the urine pro-fibrotic markers TGF-ß1 and collagen IV, but was independent of diabetes and use of tenofovir and ritonavir.
Among 434 ART-treated HIV-positive males and 200 HIV-negative controls in the Multicenter AIDS Cohort Study (MACS) [Abstract 797] Abraham et al. found that markers of immune activation including sTNF-receptor-2, sIL 2-receptor-α, sCD27 and sCD14 were associated with proteinuria (urine protein:creatinine > 200). These inflammatory markers were elevated amongst the HIV-positive individuals despite an 80% rate of viral suppression on ART. These findings suggest a need for further studies to confirm the observed association between inflammation and CKD and to determine whether inflammation contributes to the increased risk of CKD in HIV.
CROI: Kidney Dysfunction and Markers of Inflammation in the Multicenter AIDS Cohort Study - (03/06/15)
CKD as a predictor of cardiovascular disease
Several abstracts reinforced the strong association between CKD and adverse cardiovascular outcomes in HIV-positive adults. Analyses from two large cohorts, D:A:D and NA-ACCORD, demonstrated a strong association between CKD and cardiovascular events. Among 34,793 individuals in the D:A:D cohort, Ryom et al. observed that by five years almost one in four with eGFR<30 were estimated to have developed a centrally adjudicated cardiovascular event, with an increasing 28-day fatality rate as eGFR levels declined [Abstract 742] . While the association between eGFR and cardiovascular events was largely explained by older age at higher eGFR levels, the association with eGFR < 30 remained strong in fully adjusted models.
CROI: Confirmed kidney deficit tied to rising cardiovascular disease incidence in D:A:D......."need intensified monitoring for all types of emerging cardiovascular disease, in particular in older individuals with continuously low eGFR levels, and cincreased focus on applying different renal and cardiovascular preventive measures in HIV-positive persons" - (03/11/15)
Drozd et al. described risk factors for acute myocardial infarction (MI) in 24,919 participants in NA-ACCORD, distinguishing primary MI attributed to acute coronary plaque rupture (n=262) from MI secondary to increased demand. All MI cases were centrally adjudicated. In adjusted analysis, Stage 4-5 CKD (eGFR < 30) was a significant independent predictor of primary myocardial infarction [Abstract 748].
CROI: Incidence and Risk of Myocardial Infarction (MI) by Type in the NA-ACCORD - (03/23/15)
Association between CKD and neurocognitive decline
Two small observational studies demonstrated an association between markers of kidney function and objective measures of neurocognitive decline. A subgroup analysis of 191 participants in the CHARTER cohort with sustained virologic suppression identified eGFR < 50 as the strongest independent predictor of neurocognitive decline [Abstract 469 poster]. A more detailed summary of the CHARTER analysis is available online http://www.natap.org/2015/CROI/croi_05.htm.
In a cross-sectional analysis of 77 HIV-positive adults over age 50 years, higher levels of serum cystatin C were associated with neurocognitive impairment [Abstract 484]. Because cystatin C has been shown to reflect both GFR and systemic inflammation in the setting of HIV infection, future studies are needed to confirm this association and to evaluate the relationship with decreased kidney function.
Lipids and lipid-lowering therapy: impact on the kidney
A prospective cohort study of ART-naïve adults initiating ART in South Africa demonstrated a significant association between elevated total cholesterol and risk of decreased kidney function (eGFR< 90) [Abstract 781 poster]. In a small single-center study of rosuvastatin use among adults without conventional indications for statin therapy but with evidence of coronary artery plaque, eGFR was stable in participants randomized to the active treatment arm, in contrast to a small decline in the placebo arm [Abstract 136 poster]. The differences did not reach statistical significance, but were consistent with observations in the SATURN trial. The impact of statins on kidney function should be evaluated in larger studies with adequate power to detect a clinically meaningful effect.
CKD in the setting of Hepatitis C virus (HCV) infection
Previous studies have demonstrated an association between HCV infection and increased risk of CKD in both HIV-infected and HIV-negative adults. Analyses from two large cohort studies evaluated this association in the context of HCV treatment and recent HCV seroconversion. In an analysis of 5407 HIV-HCV co-infected individuals in the MASTER cohort, Leone et al identified cirrhosis as a significant independent predictor of Stage 3-5 CKD (eGFR < 60) [Abstract 655 poster]. Achievement of sustained virologic response with IFN/ ribavirin did not significantly impact the risk of CKD. Future studies should evaluate the impact of IFN-sparing antiviral therapy on CKD risk. In an analysis of HCV mono-infected US Veterans, Butt et al. demonstrated that chronic HCV infection was associated with increased incidence and faster progression to Stage 3-5 CKD [Abstract 642]. Although recent seroconversion was also associated with CKD in univariate analysis, this association was attenuated after adjustment for demographic and clinical characteristics.
Kidney transplantation in HIV infection
Risk factors for acute (<1 year) kidney allograft rejection were investigated by Gathogo et al. in the HIV/Kidney Transplant Cohort study between 2005-2013 [Abstract 798 poster ]. Patient and graft survival rates were generally high (96.8% and 95.3% ), although 36% experienced biopsy-proven acute allograft rejection.
Use of the calcineurin inhibitor tacrolimus was the only factor independently associated with lower levels of acute rejection as compared to use of cyclosporine.
In a 21-center US study among 150 HIV-positive individuals and controls, Roland et al. described the 5-year outcomes after kidney transplantation [Abstract 799 poster]. The authors observed an 11.3% mortality rate and 20.7% non-fatal graft loss rate among the HIV-positive kidney transplant recipients. Compared to risk-and demographic matched registry controls, there was a trend towards increased graft loss and no difference in patient survival.
Pediatric studies in kidney disease and kidney function assessment
Serum cystatin C has been proposed as a more sensitive marker of GFR decline, but studies in adults have suggested that systemic inflammation may confound the interpretation of cystatin C in the setting of HIV infection. In a cohort of 88 HIV-infected adolescents (mean age 12.7 years), serum cystatin C levels correlated with both GFR and markers of inflammation [Abstract 934 poster]. These results are consistent with those in HIV-infected adults, and suggest that cystatin C should not be used alone to estimate GFR in HIV-positive children and adolescents.
Polymorphisms in the APOL1 gene have been strongly linked to kidney disease in the general population and to both HIVAN and proteinuria in HIV-infected adults. In a case-control study nested within the PHACS cohort, carriage of two APOL1 risk alleles was also strongly associated with the presence of CKD in perinatally infected children (defined by the presence of proteinuria or GFR < 60 on at least 2 serial measures) [Abstract 933 poster].
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