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The Kidney at CROI 2013
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Christina M. Wyatt, MD
Assistant Professor, Medicine/ Nephrology
Mount Sinai School of Medicine
New York, NY
Advanced chronic kidney disease and the role of antiretroviral therapy
At CROI 2007, investigators on the EuroSIDA cohort first reported a link between several antiretroviral agents and increased risk of chronic kidney disease (CKD), as defined by a confirmed creatinine clearance (CrCl) < 60. Since that time, several other groups have reported similar findings, linking TDF, atazanavir, and boosted lopinavir to moderate reductions in kidney function. In a recent analysis from the D:A:D cohort, all three agents were associated with glomerular filtration rate (GFR) < 70, but only boosted lopinavir was associated with GFR < 60 (Ryom et al, JID 2013). Expanding on that analysis in D:A:D (abstract 810), Ryom et al. demonstrated no increase in the risk of more advanced CKD (GFR < 30 or end-stage renal disease) associated with the use of these agents. The authors speculate that the frequent discontinuation of these specific antiretroviral agents, in particular TDF, in patients with declining GFR may have prevented progressive kidney injury.
Renal safety of TDF in HIV-infected adults
As in recent years, the dedicated session on renal disease was largely focused on the safety of TDF in HIV-infected adults. The only randomized trial data presented in the session were from a small substudy of ACTG A5202 comparing cART-naïve participants who were randomized to ABC/3TC versus TDF/FTC with open-label EFV or ATV/r (abstract 811). Among participants with GFR data at 96 weeks, the investigators reported greater improvement in estimated GFR and less increase in proteinuria/ albuminuria in those randomized to ABC/3TC versus TDF/FTC. In analyses stratified by HIV-RNA, there was also a greater improvement in those participants with HIV-RNA < 100,000 copies/mL who received EFV versus ATV/r. Based on a previous study comparing GFR estimates to a gold standard measure of GFR in HIV-infected adults (Inker et al, JAIDS 2012), the authors selected for their primary analyses an equation combining two clinically available markers, creatinine and cystatin C. The relationship between treatment allocation (which ARTs patients received) and change in GFR were similar when other creatinine-based GFR estimates were used, but not with the use of an equation based on cystatin C alone. In the absence of a gold standard GFR measure, it is not clear which equation provides the most relevant information in this setting. There are limited data on the performance of GFR estimates in cART-naïve individuals, and both creatinine and cystatin C may have unique limitations in this population. Future studies focused on this question would ideally include a gold standard measure of GFR in a subset of participants.
Investigators on the UK Collaborative HIV Cohort considered the important and understudied question of whether declines in GFR with TDF are reversible after discontinuation (abstract 813). While the majority of patients with available data recovered within 5% of baseline GFR, approximately 11% did not fully recover. Patients with steeper GFR decline on TDF or with a lower GFR at the time of TDF discontinuation were less likely to fully recover, as were older patients and patients with longer cumulative exposure to TDF. Because adequate data to evaluate recovery were available for only one-quarter of the patients who discontinued TDF, these findings should be used with caution to estimate the likelihood of full recovery in other populations.
Several abstracts reported data on kidney function among African or Asian individuals receiving TDF. Investigators and collaborators of IeDEA Southern Africa studied a large cohort of Zambian adults who initiated cART following the introduction of first-line TDF (abstract 816). Among patients with CrCl < 60 mL/min at baseline, mean CrCl improved with the inititation of cART with or without TDF. The improvement in kidney function with cART is consistent with previous studies in the US and Africa, and may reflect some underlying kidney disease related to HIV infection itself. In patients with normal or mildly reduced CrCl at baseline, progression to CrCl < 60 mL/min within the first year was more common among those who initiated TDF-containing regimens. Because of the cumulative nature of TDF toxicity, longer followup is needed to evaluate the longterm safety of TDF-containing cART in this population. Among African women randomized to TDF/FTC plus either nevirapine or boosted lopinavir in ACTG A5208 (abstract 152), renal adverse events (grade 3 or 4 creatinine elevation or a decline in CrCl that prompted a change in therapy) occurred in 3%. Randomization to boosted lopinavir was associated with a 3-fold increase in odds of the composite event, but was not associated with drug discontinuation.
Compared to a cohort in London, the rate of GFR decline and the risk of GFR<60 were greater among Indian adults initiating TDF-containing cART (abstract 814). Older age and concomitant use of boosted PI were associated with increased risk of GFR < 60, and there was high prevalence of traditional CKD risk factors (diabetes, hypertension, and HCV) in the small subgroup of patients who required treatment discontinuation. In a small Japanese study (abstract 812), evidence of proximal tubular dysfunction was observed in 10% of adults on stable TDF-containing cART. Factors significantly associated with increased risk of proximal tubular dysfunction included older age, lower GFR, and lower body weight. Low body weight was also associated with an increased risk of creatinine clearance decline (25% or greater) among Thai adults receiving TDF/FTC (Abstract 815). Compared to historical controls treated with received AZT, a difference in the risk of creatinine clearance decline was noted only among adults with body weight < 60kg.
Renal safety of TDF in HIV-infected children
The importance of body weight has prompted the development of weight based dosing algorithms for use in pediatric patients. In a small open-label study of Thai children age 3-18 years (abstract 972), weight based dosing of TDF was not associated with any clinically relevant renal toxicity at 48 weeks. There was a greater decline in bone mineral density compared to children on TDF-sparing cART.
Renal safety of TDF-containing pre-exposure prophylaxis
With the 2012 approval of TDF/FTC for HIV pre-exposure prophylaxis, there remains concern about the potential for subclinical kidney and bone toxicity in HIV-uninfected individuals. In an analysis of data from iPrEx (abstract 998), there was a small but statistically significant decline in creatinine clearance in men randomized to active PrEP, similar to observations in HIV-infected adults receiving TDF-containing cART (Cooper et al, CID 2010). The difference between treatment arms resolved after discontinuation of study drug. Consistent with the small number of graded creatinine elevations reported in the primary publication, the difference between study arms was driven largely by small declines in creatinine clearance in the majority of participants, rather than by clinically relevant declines in a smaller number of participants. In a substudy, there was no difference in markers of subclinical proximal tubular injury between treatment arms. While these results are reassuring, they were not adjusted for adherence to study drug and may not be generalizable to women, who are more likely to have low body weight and higher tenofovir exposure.
Predictors of higher tenofovir exposure
Several studies focused on predictors of tenofovir exposure in HIV-infected adults on stable TDF-containing cART, hypothesizing that higher exposure is a risk factor for toxicity. In a rigorous PK study of 101 WIHS participants (abstract 522), Baxi et al. explored predictors of steady state tenofovir exposure as measured by log-transformed area under the curve (AUC). Factors independently associated with higher tenofovir exposure in women included ritonavir use, older age, lower body mass index, and GFR < 70. Menopausal status was not associated with tenofovir exposure in this study or in a smaller study comparing 22 postmenopausal women and 28 premenopausal women (abstract 900). Higher serum creatinine and lower body weight were predictors of plasma tenofovir levels in both pre- and postmenopausal women, and in a separate study 100 men and women with baseline creatinine clearance > 80 mL/min performed by the same investigators (abstract 523). The relationship with body weight was stronger among women than men, with more than 2-fold higher mean plasma tenofovir levels in women weighing < 50kg. Both higher plasma tenofovir level and older age were independently associated with a higher incidence of adverse events (proteinuria, decline in GFR, or decrease in bone density). Among women, body weight < 50kg was also associated with a higher incidence of adverse events. In contrast, PK data from randomized trials of Stribild (abstract 524) demonstrated no relationship between tenofovir AUC and changes in GFR or markers of proximal tubular function (proteinuria, glycosuria, and serum phosphorus), which were rare. As previously reported, there were no significant changes in measured GFR despite an early decline in estimated GFR in participants assigned to cobicistat.
Progress in the development of the new prodrug tenofovir alafenamide (TAF)
Unlike TDF, which is rapidly metabolized to tenofovir, the new prodrug TAF (formerly GS 7340) has a much longer half-life in plasma, allowing for increased uptake and concentration in target cells. As a result, higher intracellular levels can be achieved with lower doses and plasma levels, theoretically decreasing the potential for kidney and bone toxicity. In a small phase 2 study of cART-naïve adults randomized 1:2 to Stribild versus a fixed dose combination including the same components with TAF 10 mg in place of TDF 300 mg (abstract 99), Zolopa et al. confirmed that tenofovir AUC was much lower in participants randomized to the TAF-containing regimen. There was a decline in estimated GFR in both arms at 2 weeks, consistent with the effect of cobicistat. At 24 weeks, declines in estimated GFR and bone density were significantly less in the TAF arm. Changes in markers of proximal tubular function also suggested less subclinical proximal tubular dysfunction with TAF. There were no discontinuations for renal adverse events in either arm of the study.
Previous studies have shown that renal elimination of TAF is minimal. In a small PK study of 14 subjects with creatinine clearance 15-29 mL/min and 13 with normal GFR who received a single dose of TAF 25 mg (abstract 529), there was no significant difference in TAF exposure as measured by area under the curve (AUC). Tenofovir exposure was nearly 6-fold higher among those with kidney impairment; however, the AUC for tenofovir was substantially lower than previously documented following a single dose of TDF 300mg in adults with creatinine clearance in this range. Tenofovir exposure was similar to that observed in adults with normal kidney function following a single dose of TDF 300mg, suggesting that dose reduction may not be necessary in patients with impaired kidney function. The final decision should consider emerging data on the relationship between tenofovir exposure and risk of nephrotoxicity.
Gilead also presented in vitro data on proximal tubular cell uptake of TAF (abstract 540). Overexpression of the established transporters for tenofovir, OAT1 and OAT3, did not substantially increase the uptake of TAF into cells and only minimally increased the cytotoxicity of TAF. As previously reported, overexpression of OAT1, and to a lesser extent OAT3, significantly increased the cellular accumulation and cytotoxicity of tenofovir in the same system. Although it is possible that other tubular cell transporters could transport TAF into proximal tubular cells, the absence of uptake with the organic anion transporters in vitro is consistent with the minimal renal elimination of TAF observed in human volunteers.
Taken together, the data presented at CROI suggest that TAF may have a more favorable renal safety profile than TDF for the treatment of HIV infection. Phase 3 studies in HIV-infected adults are currently enrolling. Additional studies are needed to determine the efficacy and safety of TAF for other indications, including HIV pre-exposure prophylaxis and treatment of Hepatitis B virus infection.
Chronic kidney disease in HIV-infected adults
The literature on chronic kidney disease (CKD) in HIV is complicated by a lack of consensus on the most appropriate estimate of glomerular filtration rate (GFR). Recent data suggest that the CKD-EPI equation provides the most accurate estimate of true GFR in stable HIV-infected adults, but the clinical significance of differences between the GFR estimates is not known. In a longitudinal analysis of data from the EuroSIDA cohort (abstract 808), clinically relevant differences between the CKD-EPI GFR and Cockcroft-Gault creatinine clearance were more common in Europeans with traditional CKD risk factors, including older age, non-white race, higher HIV-RNA, and comorbid hypertension. The estimated incidence of moderate CKD (eGFR < 60) was higher when Cockcroft-Gault was used to estimate GFR. Based on prior studies comparing GFR estimates to a gold standard measure of GFR [Inker et al, JAIDS 2012], it is likely that the incidence of moderate CKD is overestimated by Cockcroft-Gault. Nonetheless, modest reductions in creatinine clearance were more strongly associated with all-cause mortality than were similar reductions in CKD-EPI GFR, suggesting that both equations may have a role in epidemiologic studies.
Two large studies compared the risk of CKD between HIV-infected and -uninfected adults. Using nationally representative data for HIV-infected adults from the Medical Monitoring Project and uninfected adults from NHANES (abstract 809), Garg et al. demonstrated an increased prevalence of CKD (eGFR < 60) in HIV-infected adults. The greatest difference in CKD prevalence was observed in adults under age 60 years, with no relevant difference in older adults.
In an analysis of data from nearly 100,000 US veterans in the VACS virtual cohort (abstract 59), Althoff et al. reported an increased incidence of end-stage renal disease (ESRD) in HIV-infected compared to matched HIV-uninfected veterans. Despite the increase in incidence of both ESRD and myocardial infarction in HIV-infected veterans, there was no significant difference in the mean age at diagnosis either before or after adjusting for demographics and traditional risk factors. The authors speculate that prior studies demonstrating a younger age at diagnosis among HIV-infected individuals may have been confounded by differences in the population age structure, with HIV-infected individuals being younger on average. Both of these studies demonstrate a clinically relevant increase in the risk of CKD and ESRD in HIV-infected US adults, highlighting the importance of early recognition and risk factor modification.
Increased CKD risk with HIV-Hepatitis C virus (HCV) co-infection
Recent studies have demonstrated an independent relationship between HIV-HCV co-infection and increased risk of CKD outcomes [Mocroft et al, PLoS ONE 2012; Peters et al, AIDS 2012]. More recently, two studies have suggested an association between HCV viremia and increased risk of CKD or CKD progression in HIV-infected adults. In an analysis of data from NA-ACCORD (abstract 718), Lucas et al. confirmed the previously reported association between HIV-HCV co-infection (as determined by HCV antibody status) and increased risk of CKD. While the risk of both Stage 3 and Stage 5 CKD (eGFR < 60 and <15 for at least 90 months, respectively) was increased in participants with HIV-HCV co-infection, there was no significant difference in risk between those with and without HCV viremia after adjusting for demographics, comorbid conditions, use of potentially nephrotoxic cART, and markers of HIV disease severity. Differences between these findings and those of prior studies may be partly explained by differences in patient population and active injection drug use, and should be the subject of future studies.
In an analysis of data from the HIV Research Network (abstract 720), the overall rate of hospital admissions and the rate of admission for renal disease were both higher among those with HCV co-infection, who represented 20% of the population. This study did not consider the role of HCV viremia.
Increased mortality and morbidity associated with CKD in HIV-infected adults
Similar to data in the general population, CKD has previously been associated with adverse clinical outcomes in HIV-infected individuals, including AIDS and non-AIDS mortality and cardiovascular disease. In a cohort of HIV-infected veterans with and without HCV co-infection (abstract 723), a diagnosis of CKD was associated with an approximately 50-60% increase in the risk of mortality. (from Jules: HCV treatment reduced mortality risk by over 60%)
In a cross-sectional analysis of participants in the ACTG Longitudinal Linked Randomized Trial cohort (abstract 460), Kalayjian et al. reported a novel association between prevalent proteinuria and neurocognitive impairment. Participants with a urine protein: creatinine ratio ≥ 0.2 were more likely to have neurocognitive impairment as assessed using standardized instruments. The authors speculate that this association may reflect similar pathogenic mechanisms for albuminuria and neurocognitive impairment in HIV-infected individuals.
In vitro studies: the kidney as a potential reservoir
In an autopsy study of 5 HIV-infected individuals (abstract 373), integrated HIV DNA was found in kidney and brain tissue, supporting a hypothesized role of local HIV infection in the pathogenesis of both neurocognitive impairment and CKD, and providing further evidence that these non-lymphoid tissues may serve as latent HIV reservoirs. Local HIV infection of the kidney has an established role in the pathogenesis of HIV-associated nephropathy (HIVAN), and previous in vitro studies have supported cell-cell transfer of replication-competent virus from T-cells to renal epithelial cells through virologic synapses. In a series of co-culture experiments, Blasi et al (abstract 195) confirmed the ability of T-cells to transfer infectious virus to renal tubular epithelial cells. Co-culture of infected tubular cells with uninfected T-cells further demonstrated transfer of infectious virus to T-cells. These data suggest bidirectional transfer of HIV between T-cells and renal epithelial cells, an important step in establishing the kidney as a potential viral reservoir.
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