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HIV & Aging Clinical Recommendations
Antiretroviral therapy (ART) has led to improved survival and reduced disease progression in PLWH.1 According to CDC estimates, 47% of PLWH in the United States are 50 years or greater and 16% are 65 years or greater.2 With increased longevity due to effective viral suppression, chronic conditions such as kidney disease have largely replaced HIV-related complications as leading causes of mortality.3 PLWH are at increased risk of acute kidney injury (AKI) and chronic kidney disease (CKD) as a result of HIV-related kidney disease, medication nephrotoxicity, coinfections and comorbidities.4 In addition, the aging HIV population is at a disproportionately increased risk due to age-related GFR decline, prolonged ART exposure and an increased burden of traditional CKD risk factors such as diabetes and hypertension.
The Aging Kidney
With the incorporation of GFR estimating equations in the evaluation of kidney function, there has been an increase in the number of older adults diagnosed with CKD. However, changes occur in the kidney as part of the typical aging process.5 Biopsies taken from healthy kidney donors have demonstrated an increase in the prevalence of glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arteriosclerosis with increasing age, independent of kidney function.6 In addition to these structural changes, there is also a functional decline in GFR that occurs with aging. Longitudinal studies have observed a GFR decline of 7.5-9.5 mL/min per decade of life in the general population and approximately 50% of adults over the age of 70 years have a GFR less than 60 mL/min per 1.73 m2.7,8 This decline in GFR is relevant in older adults because low GFR, regardless of age, has been associated with increased mortality and risk of end-stage kidney disease (ESKD).9,10
HIV infection may accelerate the aging process through chronic immune system activation, leading to a faster GFR decline in PLWH.11 In the AgehIV cohort study, there was a higher prevalence of CKD and faster CKD progression in HIV-infected middle aged individuals 48-59 years old compared to HIV-negative controls.12 Age-related renal cellular senescence makes the kidneys more susceptible to AKI, CKD and medication toxicity from accumulation of renally excreted metabolites and should be taken into consideration with drug dosing.
Causes of CKD in Older PLWH
Numerous risk factors may influence the development CKD and CKD progression in older PLWH including comorbidities, age, race, genetic predisposition, and HIV-related factors.
Although the prevalence of CKD in the HIV population varies widely, it is expected to rise in the aging HIV population due to increased burden of traditional CKD risk factors.13 Diabetes mellitus (DM) and hypertension are the leading causes of ESKD (end stage kidney disease) in the United States.14 Large population-based studies have demonstrated an increased prevalence of DM and hypertension in PLWH compared to HIV-negative controls.15 HIV infection and prolonged ART exposure may contribute to the development of DM and hypertension and when combined, may substantially increase the risk of CKD and progression. In the Veterans Aging Cohort Study, the coexistence of HIV and DM were shown to have an additive effect on CKD progression compared to either diagnosis alone.16 Hypertension in PLWH has also been associated with increased risk for cardiovascular events and all-cause mortality compared to HIV-negative controls.17,18
Approximately 30% of PLWH are coinfected with hepatitis C and 10% are coinfected with hepatitis B.19 Multiple cohort studies have demonstrated hepatitis B and hepatitis C coinfection are independent predictors of progressive CKD in PLWH on ART.20,21 Hepatitis C with active viremia has been associated with increased risk of developing CKD compared to individuals with cleared infection or HIV-monoinfected patients.22 Additionally, individuals with hepatitis C coinfection have been shown to have reduced survival on dialysis and inferior kidney transplant outcomes compared to HIV-monoinfected individuals.23,24
Early initiation of ART is associated with initial improvement in kidney function.25 However, lifelong exposure to ART may increase the risk of nephrotoxicity and development of CKD.26,27 This risk is magnified in older individuals with reduced renal reserve and numerous risk factors for CKD, highlighting the importance of careful selection of the ART regimen, drug dosing adjustment for GFR, and close monitoring of kidney function.
Globally, tenofovir disoproxil fumarate (TDF) is the most widely prescribed ART agent. It is eliminated via glomerular filtration and proximal tubule secretion. Though TDF is well tolerated in most patients, a small but significant percentage experience proximal tubular injury characterized by glycosuria, low molecular weight proteinuria, renal phosphate wasting, and/or reduced eGFR. Large observational studies have shown TDF is associated with increased risk of AKI, proteinuria, and CKD.28 Discontinuation of TDF often leads to recovery of kidney function but this may be incomplete, especially in older individuals at higher risk for CKD.29 The use of TDF is not recommended in individuals greater than 60 years of age with an eGFR less than 60 mL/min per 1.73 m2 or in those who experience a greater than 25% decline in GFR to below 60 mL/min per 1.73 m2.1 Tenofovir alafenamide (TAF) was FDA approved in 2015 and allows for similar efficacy against HIV with significantly lower plasma levels of tenofovir and less nephrotoxicity. Randomized trials have demonstrated a significantly smaller decline in eGFR in individuals treated with TAF compared to TDF as well as increased eGFR at 96 weeks in those switched from TDF to TAF.30,31 Although long term follow-up studies are needed, TAF should be the preferred agent in individuals greater than 60 years of age who are considered at increased risk for CKD.
Some protease inhibitors (PI) have been associated with adverse kidney outcomes. Both atazanavir and indinavir have been associated with interstitial nephritis and crystalluria due to their low solubility in urine.32,33 The Data collection on Adverse events of Anti-HIV Drugs (D:A:D) Study demonstrated longer cumulative exposure of ritonavir-boosted atazanavir and lopinavir was associated with increased incident CKD.27 In contrast, recent studies have shown individuals changed from ritonavir-boosted atazanavir or lopinavir to darunavir experienced improvement in kidney function and prolonged darunavir exposure does not appear to be associated with excess CKD risk.34,35 In older individuals at increased risk for CKD, darunavir should be preferentially used.
HIV-related kidney diseases
HIV-associated nephropathy (HIVAN) is characterized by rapidly progressive kidney failure and severe proteinuria in the context of untreated, late stage HIV infection. HIVAN is almost exclusively observed in individuals of African ancestry largely due to variants in the APOL1 gene. African Americans and South Africans with APOL1 high-risk genotypes have 29- and 89-fold increased risk of HIVAN, respectively and in these individuals, the lifetime risk of HIVAN approaches 50% in the absence of ART.36 In the era of ART, the prevalence of “classic” HIVAN, characterized by severe proteinuria and rapid progression to ESRD, has dramatically decreased but persons with APOL1 high risk genotypes treated with ART may present with more a indolent form of focal segmental glomerulosclerosis (FSGS).37 In addition to HIVAN and FSGS, immune complex glomerulonephritis (ICGN) is commonly found on kidney biopsy in PLWH. ICGN represents a wide spectrum of glomerular diseases associated with HIV and coinfection with hepatitis B or C. Unlike HIVAN, ICGN is more frequently observed in individuals receiving ART, is not associated with APOL1 risk variants, and follows a milder course.38 Because of the varied types of glomerular disease observed in HIV infection, individuals with significant proteinuria and/or hematuria should undergo a kidney biopsy to guide management.
Screening and Monitoring of CKD in Older PLWH
Early detection and diagnosis of kidney disease is essential to slow decline in kidney function. Serum creatinine is the preferred biomarker to estimate GFR. Although GFR estimating equations have not been well validated in the HIV population, studies have shown the creatinine based CKD-EPI equation is more accurate than the Modification of Diet in Renal Disease equation for GFR estimation in PLWH and should be preferentially used.39-41 Creatinine may overestimate GFR in older individuals with reduced muscle mass or protein intake. Additionally, the ART medications dolutegravir, rilpivirine, and pharmacoenchancer cobicistat reduce tubular secretion of creatinine, leading to small reductions in creatinine clearance.42 Cystatin C is an alternative biomarker that is freely filtered and may be considered in individuals receiving medications that alter the tubular secretion of creatinine. Cystatin C is less affected by muscle mass and age and may be more predictive of cardiovascular events and all-cause mortality compared to serum creatinine.43 However, cystatin C has been shown to be elevated with systemic inflammation so its value must be interpreted cautiously.44
The 2013 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend stratifying risk of CKD progression by CKD etiology, GFR category, and albuminuria category.45 GFR and albuminuria have been shown to be independent predictors of CKD progression and ESRD and should both be used to evaluate CKD risk.46 The 2014 Infectious Disease Society of America practice guidelines recommend monitoring kidney function at least twice yearly using a creatinine-based GFR estimate and assessing proteinuria annually with urinalysis or quantitative measurement of albuminuria in stable PLWH.47 GFR trajectories rather than single GFR values should be used to identify a decline in kidney function. Individuals with CKD Stage 3A (GFR less than 60 mL/min per 1.73 m2), greater than 300mg albuminuria, or those who experience a 25% decline in GFR to less than 60 mL/min per 1.73 m2 should be referred for nephrology evaluation.47
Management of CKD in Older PLWH
There are often multiple contributors to CKD in older individuals, making determination of the underlying cause challenging. In older adults with significant proteinuria and/or hematuria, a kidney biopsy should be considered to differentiate HIV and non-HIV related kidney disease. Although studies examining the impact of blood pressure and glycemic control and CKD progression in PLWH are lacking, guidelines for the general population should be followed. Individuals with greater than 300mg of albuminuria should be treated with an angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker.45,47 Since older individuals are at increased risk of polypharmacy and medication nephrotoxicity, medications should be carefully reviewed, dose reduced or discontinued as appropriate for level of GFR. A nephrologist should be part of the care team in older adults with established CKD Stage 3B or 4 (GFR less than 30-45 mL/min per 1.73 m2) for prevention of CKD progression and for advanced CKD planning including dialysis preparation and kidney transplant evaluation when the GFR is less than 20 mL/min per 1.73 m2.45,47
In the ART era, survival of PLWH on dialysis has dramatically improved and parallels that of HIV-negative individuals.48 Observational studies demonstrate similar rates of survival in PLWH on hemodialysis compared to peritoneal dialysis, thus selection of dialysis modality should be based on patient preference.49 Although dialysis outcomes have improved, kidney transplant offers a significant survival advantage compared to remaining on dialysis, regardless of age or HIV status.50,51 Because transplant offers improved survival and quality of life, older individuals with well-controlled HIV infection and advanced CKD (eGFR less than 20 mL/mins per 1.73 m2) should be referred for transplant evaluation.52,53
One challenge in the transplantation of PLWH has been the significant drug-drug interactions between ART and maintenance immunosuppression. Protease inhibitors slow the metabolism of calcineurin inhibitors (CNI) and when coadministered, their use has been associated with increased rates of acute rejection, CNI toxicity, and increased risk of allograft loss in the first year.54 Integrase inhibitors and nucleoside reverse transcriptase inhibitors do not interact with CNIs and are the preferred ART agents to maintain steady-state drug levels.
Despite complex drug-drug interactions and increased rates of rejection, contemporary patient and allograft outcomes in PLWH are similar to HIV-uninfected individuals who undergo transplant. A national study demonstrated excellent 1- and 3-year patient and allograft survival rates, falling between the rates for the overall U.S. transplant population and subgroup of recipients greater than 65 years old.55 Registry data of outcomes at 5- and 10- years also show similar patient and allograft survival compared to HIV-negative controls.56 In an effort to expand the organ donor pool, there has been increased interest in HIV-positive to HIV-positive transplantation. South Africa demonstrated similar 3- and 5- year patient and allograft survival in PLWH who received kidneys from HIV-positive deceased donors compared to HIV-negative donors.57 In 2015, the US HIV Organ Policy Equity Act was passed, allowing the use of organs from HIV-positive donors in approved research programs and more recently, the first living HIV-positive donor to HIV-positive recipient kidney transplant was performed.58