Supporting renal health in PLHIV

This article has been commissioned and funded by ViiV Healthcare
Authors: Dr Marta Boffito, Chelsea and Westminster Hospital, London and Prof Bruce Hendry, King's College London

People living with HIV (PLHIV) are particularly vulnerable to renal impairment and its effects1 – but why? In this editorial, we will discuss renal risk factors in PLHIV, consider how to identify those most likely to be affected and look at management options, including antiretroviral drug choice.

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Monitoring and maintenance of renal function should be an important part of the clinical management of PLHIV. Renal function should be monitored on a regular basis, along with ongoing assessment of risk factors for renal injury.

Careful consideration of combination antiretroviral therapy (cART) is also necessary. In patients with existing renal impairment and those at risk, regimens containing tenofovir (as tenofovir disoproxil fumarate, TDF) and/or protease inhibitors (PIs) should be used with caution, and avoided where possible. A two-drug regimen consisting of Tivicay® (dolutegravir) plus lamivudine has been shown to be non-inferior to a three-drug regimen in achieving an undetectable viral load, and may be an option for patients in whom renal function is a concern.2

My top tips for maintaining renal health in PLHIV
Dr Marta Boffito

  1. Achieve and maintain HIV RNA undetectability
  2. Ensure relevant co-morbidities are being actively managed by an appropriate member of the multidisciplinary team
  3. Avoid drugs associated with renal toxicity in PLHIV who have existing renal impairment or risk factors
  4. Know when and how to refer to a nephrologist

Kidneys and HIV

The prevalence of chronic kidney disease (CKD) is higher in PLHIV than in the general population and is associated with poor clinical outcomes.1

The global prevalence of CKD in PLHIV is around 4-12%,* depending on the methodology used, with the highest regional prevalence in Africa (Modification of Diet in Renal Disease [MDRD]: 7.9%, versus 3.7% in Europe).3 Co-morbidities such as hypertension and diabetes significantly increase the risk of CKD; its prevalence in PLHIV with these co-morbidities has been estimated at 20.7% and 19.4%, respectively.3

Renal disease in PLHIV presents in a number of ways, including HIV-associated nephropathy, drug-related nephrotoxicity and disease secondary to concomitant conditions.1

Risk factors for renal impairment in PLHIV include:

  • Co-morbidities, such as diabetes and hypertension1,3
  • Advancing age
  • Race and ethnicity, with risk being greatest in black PLHIV1,4,5
  • Poorly controlled viral load5
  • Use of certain antiretroviral agents, including:1,6-8
    • TDF, particularly in regimens containing a pharmacological boosting agent
    • Atazanavir (ATZ)
    • Boosted PIs
  • Co-infection with hepatitis C1,5

PLHIV are living longer, with life expectancy now approaching that of the general population.9 Increasingly, this exposes PLHIV to the effects of ageing and the risk of developing age-related diseases, such as CKD and cardiovascular disease.10 Combined with the importance of viral suppression and immune reconstitution in avoiding acute kidney injury,10 paying close attention to renal function should be a central part of the overall care plan for PLHIV.

*Based on a literature review of 61 articles published between 1982-2016, including 209,078 HIV patients across 60 countries. CKD defined as estimated glomerular filtration rate (eGFR) <60 mL/min using MDRD, Chronic Kidney Disease Epidemiology (CKD-EPI) or the Cockcroft-Gault (CG) equations. The overall prevalence of CKD was 6.4% using MDRD, 4.8% using CKD-EPI and 12.3% using CG.

Identifying patients at risk of renal impairment

It is important to monitor renal function on an ongoing basis in PLHIV, but also to regularly assess for additional risks such as hypertension, diabetes and other co-morbidities. This is particularly true for PLHIV who have additional demographic factors that are associated with risk.

In PLHIV with hypertension or diabetes, ask: are blood pressure and glycated haemoglobin (HbA1c) being actively managed in line with the latest guidelines?11 Are there additional modifiable risks, or is the patient taking any non-antiretroviral medications (e.g. anti-inflammatory drugs) that could adversely affect renal function?

Antiretroviral therapy and the kidneys

Several anti-HIV medications have the potential to adversely affect renal function.1,6-8 The antiretrovirals most associated with nephrotoxicity are certain PIs and TDF.1,6-8

Importantly, the concomitant use of TDF with pharmacological boosters, such as cobicistat and ritonavir, may increase exposure to tenofovir and, consequently, amplify the risk of renal toxicity.1 Use of TDF is associated with proximal tubulopathy, renal tubular proteinuria, decreased bone density and impaired glomerular filtration.1,6,12

These findings prompted the development of tenofovir alafenamide fumarate (TAF), which is associated with a lower incidence of renal-related adverse events than TDF.7,13-15 Similarly, abacavir (ABC) has minimal effect on renal function.16 However, patients with renal disease are at increased risk of CV disease;1,4,17 this should be taken into consideration when using ABC.18

Many antiretrovirals and/or their metabolites are renally eliminated and require dosage adjustment in PLHIV with impaired renal function.8,19 For example, the dosage of 3TC should be reduced in patients with an eGFR <50 ml/min. 19 ATZ has the potential to induce urolithiasis and crystalluria, and its use has been linked to a high incidence of proximal tubular dysfunction, nephrotoxicity and CKD.20

In PLHIV with renal impairment or at high risk of renal impairment, nephrotoxic drugs should be avoided. Among antiretrovirals, this may be the case for TDF when combined with a boosted third agent (e.g. a boosted PI or elvitegravir/cobicistat). Boosted PIs should be avoided when possible.

The GEMINI trials

In GEMINI-1 and GEMINI-2 trials, treatment with a two-drug cART regimen consisting of DTG plus 3TC in antiretroviral-naive PLHIV was shown to be non-inferior to conventional three-drug cART [DTG/FTC (emtricitabine)/TDF] in achieving viral undetectability (HIV RNA <50 copies/mL).2 The proportion of patients with an undetectable viral load after 48 weeks was 91% for DTG plus 3TC, compared with 93% for the three-drug regimen (DTG/FTC/TDF); the difference was not statistically significant.2

Encouragingly, virological withdrawal in patients who received the two-drug regimen was not associated with resistance-associated mutations.2

The clinical use of DTG is associated with increased serum creatinine levels. However, these changes are not considered to be clinically significant,21 or to reflect alterations in GFR,21 as confirmed by the cystatin C estimates of GFR in the GEMINI trials (see Table below).

Changes in renal biomarkers statistically favoured the two-drug over the three-drug regimen (Table),2 although the total numbers of reported renal and urinary adverse events were similar in both treatment groups (4%).22 Additionally, fewer patients in the two-drug arm of the trial experienced a drug-related adverse event or discontinued study treatment because of such an event, compared with those in the three-drug arm.2

Table: Renal results of the GEMINI-1 and -2 trials comparing DTG plus 3TC versus DTG/FTC/TDF in treatment-naive PLHIV2

Renal biomarker    Adjusted mean change from baseline P value
  DTG plus 3TC (two-drug regimen) DTG/FTC/TDF (three-drug regimen)  
Creatinine (umol/L) 10.4 13.5 <0.0001
GFR from creatinine,
CKD-EPI (mL/min/1.73 m2)
-12.1 -15.5 <0.0001
Cystatin C (mg/L) -0.1 0.0 <0.0001
GFR from cystatin C,
CKD-EPI (mL/min/1.73 m2)
6.3 4.1 0.0004

These data suggest that a two-drug regimen consisting of DTG plus 3TC allows PLHIV to achieve and maintain undetectability, while simultaneously reducing the number of antiretrovirals (versus standard three-drug cART) and supporting renal function.  

Case example

Name: L.S.
Gender: Female
Ethnicity: British-African
Age: 54 years old
Body mass index: 29.1 kg/m2

Medical history

  • Type 2 diabetes (T2D) since 2009, on metformin + sitagliptin
    • HbA1c 8.1% [reference (non-diabetic) value <6.0%23]
  • History of recurrent urinary tract infection: pyelonephritis in 2005
  • Diagnosed with HIV in 2013 following visit to Sierra Leone
    • Started cART immediately, with TDF/FTC/EFV (efavirenz)
    • HIV viral load undetectable at 3 months, but severe dizziness and insomnia were experienced due to EFV
    • Subsequently switched to, and still maintained on, darunavir/ritonavir (DRV/r) + FTC/TDF
  • Her eGFR (Cockcroft-Gault) is 65 mL/min and she has a urinary protein-creatinine ratio (uPCR) of 55 mg/mmol (values >15 mg/mmol are abnormal)
  • Current medication: cART, antidiabetics, ibuprofen as needed for back pain

What would you do to support her renal function?

  • Refer her to a diabetologist or endocrinologist?
  • Refer to a nephrologist?
  • Change her anti-HIV or pain medication?
  • Watch and wait: continue with routine follow-up, including monitoring of renal function?

My approach

  • PIs and TDF should be used with caution in patients with, or at risk of, renal impairment. In particular, the use of a boosting agent (in this case, ritonavir) in combination with TDF should be avoided in this setting
  • Consequently, L.S. was switched to DTG plus 3TC, to eliminate both TDF and the boosted PI from her regimen
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen are potentially nephrotoxic; she was therefore switched to paracetamol
  • Additionally, her HbA1c and uPCR suggested suboptimal diabetic control and diabetic nephropathy, respectively; she was referred to an endocrinologist for review
  • DTG increases metformin concentrations,21 so this was highlighted in the referral letter
  • L.S. was advised to monitor her glucose levels more closely than normal for several weeks and asked to take her readings with her to her endocrinology appointment

Follow-up

  • At 3 months, L.S. maintained her undetectable viral load and reported no side effects from treatment
  • Her eGFR was stable at 65 mL/min, and her HbA1c was now 7.5%; no changes to her metformin dosage had been made  

 

Ask the nephrologist
Prof Bruce Hendry

  • What should I be doing to optimise renal health in PLHIV?
    • Assess renal status at baseline and on follow-up using a creatinine-based measure of eGFR, usually CKD-EPI, and by quantifying proteinuria [either urinary albumin-creatinine ratio (uACR) or uPCR]. Repeat measurements at least annually, and more frequently if there are adverse results or trends
    • Recognise important co-morbidities as relevant to renal risk, particularly cardiovascular disease, diabetes and hypertension
    • Guard against over-the-counter use of potentially nephrotoxic agents, such as NSAIDs
    • Ensure diabetes and hypertension are detected and well-managed, in collaboration with the full multidisciplinary team. Investigate suspected cardiovascular disease
    • Where renal issues or risk are identified, choose renal-friendly antiretrovirals and avoid TDF and boosted PIs
    • Diets high in protein and creatine are unlikely to be a risk for healthy kidneys, but I would advise against them in PLHIV with, or at high risk of, CKD. These diets may slightly increase serum creatinine
  • What advice/information should I give PLHIV around renal function, whether or not they have evidence of renal impairment?
    • Always stay well hydrated before routine blood tests
    • Your care team will regularly assess your kidney function, taking into account other factors that might affect how well they are working
    • They will tell you what you can do to help maintain the health of your kidneys and will take steps to ensure your HIV treatment does not cause harm
    • Be sure to discuss all your medications and therapies with your care team so that they can help you make choices that will support your overall health
    • Keeping your heart healthy is important for your kidney health and vice versa. Always report any symptoms like shortness of breath, chest pain or swollen ankles to your healthcare team
  • When should I refer to a nephrologist?
    • Always refer to a nephrologist if the eGFR is <30 mL/min, or if proteinuria is grade A3 (e.g. uACR >30 mg/mmol or uPCR >50 mg/mmol)
    • When eGFR is 30-60 mL/min or proteinuria is grade A2, a referral may be appropriate if there is no renal diagnosis or if trends are negative and treatment choices are unclear
    • Haematuria should always be investigated to establish the cause
    • Unexplained abnormalities of renal imaging (e.g. multiple cysts) or of biochemistry (e.g. hyperkalaemia) should be investigated and referred as appropriate, sometimes to nephrology

About the authors

Dr Marta Boffito, MD, PhD, FRCP, is Consultant Physician, HIV Service Lead and Clinical Research Lead at the Chelsea and Westminster Hospital in London, and is a Reader at Imperial College London. In addition to her clinical duties, Dr Boffito is the lead investigator on a number of major HIV clinical trials and has a special interest in antiretroviral pharmacology.

Prof Bruce Hendry, MD, PhD, FRCP, is Emeritus Professor of Renal Medicine at King’s College London and Chair of the South-West Thames Institute for Renal Research (SWTIRR). He has over 25 years’ experience as a clinical nephrologist and has a special interest in the kidney health of PLHIV.  

Dr Marta Boffito

Prof Bruce Hendry 

 

 

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PM-GB-DLM-WCNT-190002 | October 2019