Tenofovir does not increase risk of kidney disease in those at low risk

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Antiretroviral treatment containing the older formulation of tenofovir (TDF) did not increase the risk of chronic kidney disease in previously untreated people with HIV at low risk for kidney disease, a large US cohort study led by researchers at the New York University Langone Health Centre, AIDS Healthcare Foundation, Epividian, Durham, Merck & Co, Kenilworth and Duke University, Durham reported at the 17th European AIDS Conference in Basel, Switzerland.

However, analysis of a large randomised trial carried out in South Africa showed that the newer formulation of tenofovir (TAF) was associated with a significantly lower risk of reduced kidney function. The study also found that treatment containing TAF was associated with a lower risk of osteopenia (bone loss).

Chronic kidney disease in the OPERA cohort study – Tenofovir disoproxil (TDF), the older formulation of tenofovir, has been associated with an increased risk of developing chronic kidney disease, especially in people who receive tenofovir as part of a combination that includes a boosting agent (ritonavir or cobicistat). Tenofovir is known to have a harmful effect on the kidney tubules and boosting agents may raise levels of tenofovir in the kidneys, exacerbating the harmful effects of the drug.

Tenofovir alafenamide (TAF) is a newer formulation which is less likely to cause kidney dysfunction. However, it is unclear if a switch to TAF is necessary in all patients. Given the increasing availability of low-cost generic versions of TDF, it is important to know whether some groups of people can continue taking TDF without increased risk of chronic kidney disease.

To investigate the risk of chronic kidney disease, the researchers looked at 9,802 people who started antiretroviral treatment with normal kidney function (eGFR ≥60 ml/min/1.73m2 within 12 months prior to starting treatment). The cohort was stratified by prior risk of developing chronic kidney disease according to a scoring system developed by the D:A:D cohort study and clinical trial investigators, which draws on known, non-antiretroviral risk factors for chronic kidney disease.

Some antiretroviral drugs including dolutegravir, rilpivirine and cobicistat inhibit tubular creatinine secretion without harmful effects, leading to a lower eGFR result. In this study, the investigators corrected eGFR scores according to the reductions in eGFR observed in trials of third agents in the patient regimen.

In this cohort, 6,222 people started treatment with a regimen containing TDF and were followed for median of 29 months, while 3,580 started a non-TDF containing regimen and were followed for a median of 19 months.

There was very little difference in the proportion of people at medium or high risk of chronic kidney disease among those who included or avoided TDF in their first-line regimen (8% at high risk in both groups, 16% of the TDF group and 13% of the non-TDF group at medium risk), but those with medium and high risk were older, more likely to be women and initiated ART earlier, regardless of TDF use.

People not taking TDF were more likely to be taking an integrase inhibitor; people taking
TDF were more likely to be taking a non-nucleoside reverse transcriptase inhibitor.
In the low risk group, the incidence of chronic kidney disease (two eGFR measures < 60, at least 90 days apart) did not differ according to exposure to TDF (incidence rate 0.4 cases per 1,000 person years in both the TDF and non-TDF groups).

Chronic kidney disease developed most frequently in people at highest risk of chronic kidney disease at baseline (incidence rate 12.4 cases per 1000 person years of follow-up in those not exposed to TDF and 18.6 cases per 1000 person years).

People at high risk of kidney disease not taking TDF were almost 20 times more likely to develop chronic kidney disease during the follow-up period (adjusted odds ratio 19.8, 95% CI 7.35-52.00) compared to those at low risk. Among those taking TDF, those at highest risk were almost 13 times more likely to develop kidney disease compared to those at low risk (aOR 12.84, 95% CI 4.57-36.07)

There was no difference in the incidence of chronic kidney disease by TDF use or by use of a boosting agent.

The ADVANCE study by researchers at Imperial College London, Wits Reproductive Health and HIV Institute at the University of the Witwatersrand and Liverpool University, compared efavirenz with two dolutegravir-containing regimens, one paired with TDF, the other with TAF. The 96-week study monitored kidney function by measuring creatinine and tubular markers of kidney function (beta 2 microglobulin, retinol binding protein and the ratio of urine albumin to creatinine). The study monitored bone mineral density by DXA scan at baseline, week 48 and week 96 in all participants.
The incidence of treatment-emergent osteopenia in the hip was lowest in the TAF/emtricitabine+dolutegravir arm at week 96 (6.3%), compared to 11.1% in the TDF/emtricitabine+dolutegravir arm and 30% in the TDF/emtricitabine/efavirenz arm (p < 0.001). Treatment-emergent osteopenia in the spine was lowest in the TAF arm (18%) versus 23% and 30% in the TDF and efavirenz arms respectively, but this difference was not statistically significant.

There was no difference in the 10-year risk of hip fractures in participants aged 40 and over between the three study arms but participants in the efavirenz arm had a significantly higher 10-year of major fractures (p=0.05). However, the absolute 10-year risk of a major fracture was 0.36% in the efavirenz arm.

In people with low bone mineral density, people with low body mass are at higher risk of fractures than people with higher body mass. “Any weight gain associated with antiretroviral treatment would ameliorate the increased fracture risk,” Dr Michelle Moorhouse said.

There was no significant difference in grade 3 or 4 creatinine elevations or CKD adverse events between study arms, but TAF recipients were significantly less likely to experience elevations above the upper limit of normal in tubular markers of kidney dysfunction.

Abstract 1
Purpose: Given recent evidence that the risk of renal toxicities with TDF may increase with coadministration of a pharmacoenhancer (Hill 2018), we assessed the risk of chronic kidney disease (CKD) associated with TDF and non‐TDF containing regimens by D:A:D CKD risk and boosting.
Method: ART‐naïve adults initiating treatment with eGFR≥60 mL/min/1.73 m2 (last eGFR within 12 months pre‐initiation) were identified in the OPERA cohort. CKD was defined as≥2 consecutive eGFR<60 mL/min/1.73 m2, >90 days apart. The associations between TDF use, baseline D:A:D CKD risk, and incident CKD were assessed with unadjusted incidence rates (IR, Poisson regression) and adjusted survival analyses (pooled logistic regression). Secondary analysis evaluated the contribution of pharmacoenhancers.

Results: Of 9,802 PLWH included, 6,222 initiated TDF (76% low‐risk D:A:D CKD score, 16% medium‐risk, 8% high‐risk) and 3,580 did not (79% low‐risk, 13% medium‐risk, 8% high‐risk; Table 1); 40–47% initiated a boosted regimen (Table 2). Overall, 125 incident CKD events occurred over 24,382 person‐years of follow‐up. Within strata of D:A:D risk score, IRs were similar by TDF exposure, with high baseline CKD risk associated with highest incidence regardless of TDF use (Figure 1). Compared to the low‐risk group without TDF, there was no statistical difference in odds of incident CKD in the medium‐risk group without TDF (aOR: 2.32, 95% CI: 0.72, 7.52) or the low‐risk group with TDF (aOR: 0.55, 95% CI: 0.19, 1.54; Figure 2). Odds of incident CKD did not differ by pharmacoenhancer exposure, with or without TDF.
Conclusion: In this large cohort of ART‐naïve PLWH, incident CKD following ART initiation was relatively infrequent and was strongly associated with baseline CKD risk. TDF‐containing regimens did not appear to increase the risk of CKD in those with a low baseline D:A:D CKD risk, the largest group of naïve PLWH, and may remain a viable treatment option.

Authors
R Hsu, L Brunet, J Fusco, A Beyer, G Prajapati, C Wyatt, M Wohlfeiler, G Fusco

Abstract 2
Purpose: In previous clinical trials and cohort studies, tenofovir disoproxil fumarate (TDF) has been associated with decreased bone mineral density (BMD) and renal function. One of the aims of the ADVANCE study was to determine whether BMD and renal changes over 96 weeks differed in HIV‐infected persons taking TDF‐containing regimens versus those taking tenofovir alafenamide fumarate (TAF)‐containing regimens.
Method: We conducted a 96‐week, open‐label randomised trial in South Africa, comparing TAF/FTC+DTG, TDF/FTC+DTG and TDF/FTC/EFV. Inclusion criteria included age ³ 12 years, no prior ART>30 days, creatinine clearance>60 mL/min (>80 mL/min if <19 years), and HIV‐1 RNA>500 copies/mL. Investigators were blinded to renal tubular markers and DXA scans unless patient safety concerns were an issue. Based on WHO classifications of BMD T‐scores, treatment emergent osteopenia and osteoporosis was assessed across the three treatment arms.

Results: The TDF‐containing arms had most impact on hip and spine DXA‐assessed bone density and renal markers. Creatinine changes were minor (Table 1). Treatment emergent osteopenia for hip was lowest in the TAF/FTC+DTG arm (7%) versus 16% in the TDF/FTC+DTG and 18% in the TDG/FTC/EFV arms (p<0.001). Similarly, treatment emergent osteopenia for spine was lowest in the TAF/FTC+DTG arm (18%) versus 23% and 22% in the TDF/FTC+DTG and TDF/FTC/EFV arms respectively. However, there was no statistical difference seen between the arms. Grade 3–4 renal adverse events (AEs) and bone fractures were rare. None of the fractures were related to the study drugs. Tubular markers above the upper limit of normal (ULN) were higher in TDF‐containing arms than in the TAF arm. (Table 1)
Conclusion: In the ADVANCE study, TAF/FTC+DTG had less impact on bone density and renal function than the TDF‐containing regimens.

Authors
A Qavi, M Moorhouse, S Sokhela, WDF Venter, C Serenata, B Simmons, K McCann, A Hill

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EACS 2019 abstract book

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