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The Kidney at CROI 2018
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Christina Wyatt MD - Associate Professor, Medicine/ Nephrology Icahn School of Medicine at Mount Sinai New York, NY
Updates on Tenofovir Alafenamide (TAF) and the Kidney
TAF-containing regimens are currently approved for individuals with CrCl 30 ml/min or higher, although small PK studies have evaluated the use of TAF in individuals with lower GFR. A small prospective study evaluated the safety and pharmacokinetics of E/C/F/TAF in 55 virologically-suppressed adults on chronic hemodialysis for at least 6 months [abstract 732]. Although nearly all participants reported at least one adverse event and one-third of participants experienced a serious adverse event over the 48-week study period, there were no study drug-related serious adverse events. Virologic suppression was documented in 45 of 55 participants at 48 weeks; among the remaining 10 participants, study drug was discontinued prior to 48 weeks in 7 participants (all with suppressed HIV-RNA at last assessment), 1 participant was missing HIV-RNA data at 48 weeks, and 2 participants had detectable HIV-RNA. Exposure to TFV and FTC as estimated by area under the curve (AUC) was much higher than previously observed in individuals with normal GFR, but TFV exposure was lower than observed in patients on chronic dialysis taking once weekly TDF. Participant satisfaction with the once-daily single tablet regimen was high and represents the primary rationale for considering the use of this regimen in ESRD. Concerns about the use of E/C/F/TAF in this population include the unknown impact of supratherapeutic TFV exposure on bone health and residual renal function, which are also concerns with the use of dose-adjusted TDF in these patients. In addition, clinicians should consider the potential challenges of ART management in kidney transplant candidates, particularly in the peri-transplant period. CROI: Safety and Efficacy of E/C/F/TAF in HIV-Infected Adults on Chronic Hemodialysis - (03/07/18)
Among 85 HIV-positive study participants who switched from TDF-containing combination regimens to dolutegravir monotherapy in the DOMONO trial, there was a significant improvement in urine albumin: creatinine ratio, urine protein: creatinine: ratio, and urine beta2-microglobulin from baseline to week 48 [poster 725]. A predictable decline in eGFR due to interference with tubular creatinine secretion was observed following the switch to dolutegravir, regardless of the baseline regimen. The effect was less pronounced among participants who switched from rilpivirine-containing regimens, consistent with previous in vitro and clinical observations that rilpivirine has a similar but less potent effect on tubular creatinine secretion. Whether the observed improvements in urine biomarkers reflect a reversal of subclinical kidney injury or a reversible effect of tenofovir exposure on proximal tubular transporters is still not known. http://www.croiconference.org/sites/default/files/posters-2018/1430_Wijting_725.pdf
Chronic Kidney Disease as a Risk Factor for Adverse Clinical Outcomes
In the general population, chronic kidney disease (CKD) is an important predictor of adverse outcomes, including cardiovascular disease and death. Using data from the European D:A:D cohort, Ryom et al. described clinical outcomes in 2,467 HIV-positive adults with CKD compared to D:A:D participants without CKD [oral abstract 75]. The incidence rate of end stage renal disease (ESRD), end stage liver disease, cardiovascular disease, malignancy, other AIDS events, and death were all significantly higher among participants with CKD, with a nearly 3-fold higher incidence rate for the combined endpoint (IR 68.9 versus 23.0/1000 person-years). Among participants with CKD, the most common adverse clinical outcomes were death, non-AIDS malignancy, and cardiovascular disease. Consistent with data in the general population, participants with CKD were at much higher risk for death and cardiovascular disease than for progression to ESRD, which occurred in only 3% of those with CKD, and lower eGFR was a strong independent predictor of both outcomes. Smoking was an important contributor to all of the clinical outcomes studied, with an estimated 6-11% of events attributed to smoking. Diabetes, poor HIV control, low body mass index, and dyslipidemia were also important contributors to adverse outcomes. The authors acknowledged several important limitations, including the relatively short follow-up time after incident CKD (median 2.7 years), and the lack of data on albuminuria, cause of CKD, and control of traditional risk factors such as diabetes and hypertension. In addition, the cohort was predominantly white MSM, and further studies are needed to characterize the prognosis associated with CKD in more diverse patient populations. CROI: SERIOUS CLINICAL EVENTS IN HIV-POSITIVE PERSONS WITH CHRONIC KIDNEY DISEASE (CKD) - D:A:D - (03/07/18)
Serum cystatin C has been proposed as an alternative marker of GFR. Despite some potential for bias in the setting of inflammatory conditions such as HIV infection, prior studies have suggested that cystatin C may be a stronger predictor of cardiovascular risk and mortality than creatinine-based GFR estimates. Using pooled data from the MACS, VA, and Hawaii Aging cohorts, McLean et al. evaluated the association between different estimates of GFR and two surrogate markers of cardiovascular disease, carotid intima media thickness (CIMT) and coronary artery calcification (CAC) scores [abstract 688]. Among 562 participants with available data for CIMT, the combined creatinine-cystatin C GFR estimate was a significant independent predictor of CIMT after adjusting for demographics, traditional risk factors, and markers of HIV disease. In a smaller subgroup of 296 participants with available data for CAC score, the cystatin C-based GFR estimate was a significant independent predictor. Overall, age and traditional cardiovascular risk factors were the strongest predictors of CIMT and CAC score in this predominantly male cohort with relatively preserved kidney function. Whether CIMT and CAC scores have the same predictive value for clinical cardiovascular events in HIV-positive populations remains controversial. It is also possible that while GFR estimates within the normal range were not strong predictors of CIMT or CAC score in this analysis, lower GFR would be more strongly associated with these and other markers of cardiovascular disease. http://www.croiconference.org/sites/default/files/posters-2018/1430_McClean_688.pdf
Risk Factors for CKD in the Setting of HIV Infection
Several CKD risk scores have been proposed to predict the risk of CKD in HIV-positive individuals, with potential implications for ART regimen selection, frequency of monitoring, and control of traditional risk factors. Using data from OPERA, a large EHR-based clinical cohort, Mills et al. evaluated the performance of the D:A:D CKD risk score in a US population [abstract 730]. In a cohort of > 22,000 HIV-positive adults without previous exposure to potentially nephrotoxic ART, performance of the D:A:D risk score was similar to that observed in the European D:A:D cohort. Using the recommended CKD-EPI eGFR calculation, <1% of individuals categorized as low risk by the D:A:D risk score developed CKD over 5 years of follow-up, while > 20% of those with a high score developed CKD, with a nearly 5-fold increase in the incidence rate in the high-risk group. These results suggest that the D:A:D CKD risk score can be adapted for use in US populations despite the higher overall incidence of CKD and greater racial and ethnic diversity. The OPERA cohort plans to make the risk score available to participating clinicians through the EHR, and the D:A:D risk calculator is freely available to all clinicians online. http://www.croiconference.org/sites/default/files/posters-2018/1430_Mills_730.pdf
Black race/ African ancestry is a strong independent risk factor for CKD, with genetic susceptibility linked to variants in the APOL1 gene; this genetic association appears to be even more pronounced in the context of HIV infection. Previous studies have described differences in the frequency of the APOL1 high-risk genotype in different African populations, but limited data are available to compare the risk of CKD across these different populations. Among 8,334 HIV-positive black participants in the UK CHIC cohort, the risk of CKD Stage 3-5 (confirmed eGFR < 60 ml/min/1.73m2) was highest among those whose country of origin was in West Africa [abstract 731]. Regardless of stage, the risk of CKD was lowest among individuals from East Africa, intermediate among those from Southern Africa and the Caribbean, and highest among those from West Africa. The excess risk of CKD was most pronounced for Stage 5 CKD or ESRD, consistent with the established association between the APOL1 high-risk genotype and progressive kidney disease. This study provides strong support for the central role of genetic susceptibility in driving CKD risk among HIV-positive individuals of African descent, as participants of diverse African ancestry were exposed to a similar environment in the UK, including equal access to health care. http://www.croiconference.org/sites/default/files/posters-2018/1430_Hamzah_731.pdf
Kidney transplantation
Using the national ESRD database, Tourret et al. evaluated the impact of HIV status on the time to kidney transplantation [abstract 728]. The authors assembled a cohort of 225 HIV-positive patients and 476 matched HIV-negative controls who initiated renal replacement therapy in France between 2006-2010. Over a median follow-up of more than 5.6 years, the cumulative probability of wait listing for kidney transplantation was lower among the HIV-positive patients. While wait-listing was delayed in HIV-positive candidates throughout the study period, there was a significant interaction with the time of cohort entry, with some improvement in the time to listing among HIV-positive candidates over time. In contrast, there was no evidence that the observed delay in receipt of a kidney transplant improved over the study period. The results were similar in a subgroup of participants with available data who were on ART and/ or had documented virologic suppression. HIV-positive and HIV-negative candidates were matched on several important characteristics, including age, sex, year of dialysis initiation, country of birth, and diagnosis of diabetic nephropathy. The authors are currently evaluating the impact of living donation on their results, in particular the time to transplantation. Overall, these results suggest a need for continued education of nephrologists and HIV-positive patients with ESRD to ensure equal access to kidney transplantation. http://www.croiconference.org/sites/default/files/posters-2018/1430_Abgrall_728.pdf
With successful outcomes of kidney donation from HIV-positive donors to HIV-positive recipients in South Africa, studies of this approach are ongoing in the United States and other countries. One concern with the use of HIV-positive deceased donors is the potential transmission of viral resistance, which is more common in the United States. Bismut et al successfully characterized ART resistance and viral tropism in 31 of a series of 36 potential HIV-positive deceased donors using blood obtained from organ procurement organizations [poster 553]. Among the potential donors whose organs were ultimately accepted for transplantation, one of four had NRTI resistance and all three who were successfully characterized had CCR5-tropic virus. Among the remaining potential donors, 7 of 27 had virus resistant to at least one antiretroviral class, while 12 of the 22 who were successfully characterized had dual tropic virus. Future studies are needed to determine the clinical impact of these findings in HIV-positive transplant recipients who accept organs from HIV-positive donors. http://www.croiconference.org/sites/default/files/posters-2018/1430_Bismut_553.pdf
Urine biomarkers of kidney injury and inflammation
In a small cross-sectional study of 198 ART-naïve participants from the MACS and WIHS cohorts, Muiru et al. explored a panel of 14 urine biomarkers of kidney injury and the association with traditional CKD risk factors [abstract 729]. Different risk factors were associated with different patterns of kidney injury, providing a potential rationale for biomarker selection in future studies. http://www.croiconference.org/sites/default/files/posters-2018/1430_Muiru_729.pdf
In a case-control study of HIV-positive, virologically suppressed adults, pre-ART levels of the inflammatory biomarker suPAR were independently associated with increased odds of non-AIDS events, including cardiovascular and cerebrovascular events, non-AIDS malignancy, serious bacterial infections, and death [abstract 763]. Although suPAR has also been hypothesized to play a potential pathogenic role in the development or progression of focal segmental glomerulosclerosis, the underlying histologic lesion of HIV-associated nephropathy, the composite endpoint did not include kidney disease. http://www.croiconference.org/sites/default/files/posters-2018/1430_Hoenigl_763.pdf
Despite increased genetic susceptibility to kidney disease in some African populations, routine screening for kidney disease is not always feasible in resource-limited settings. While dipstick proteinuria was relatively common among HIV-positive pregnant women in Zambia, and in itself may have important implications for maternal health, the presence of dipstick proteinuria was poorly correlated with decreased GFR and is not a useful surrogate for serum creatinine testing [abstract 808]. http://www.croiconference.org/sites/default/files/posters-2018/1430_Holmes_808.pdf
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