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IAS 2013: Kidney Problems Linked to Tenofovir Use, Improve with Switch to Abacavir

Indian people with HIV who took tenofovir had a higher rate of kidney impairment than westerners, according to a study presented at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013) this month in Kuala Lumpur. A related study found that switching from tenofovir to abacavir reduced kidney risk.

Tenofovir (Viread, also in Truvada and other coformulations) is a component of preferred first-line antiretroviral therapy (ART) in U.S. treatment guidelines, and is increasingly used in resource-limited and middle-income countries due to its good efficacy and tolerability compared with older agents such as zidovudine (AZT, Retrovir) or stavudine (d4T, Zerit). Tenofovir can, however, cause kidney problems in susceptible individuals.

Ameet Dravid and colleagues assessed changes in kidney function, determined by declines in estimated glomerular filtration rate (GFR), among people taking tenofovir. They also looked at acute kidney injury and recovery of kidney function.

Most tenofovir kidney studies to date have been done in the U.S. and Europe, and clinical trials have typically excluded people with pre-existing kidney problems and do not reflect a "real world" population, the researchers noted as background.

This retrospective cohort analysis included 743 patients seen at Ruby Hall Clinic -- a tertiary HIV/AIDS clinic in Pune in western India -- who started first-line ART or switched to a regimen containing tenofovir between March 2009 and March 2013 and had available serum creatinine and creatinine clearance data. They were compared against 340 clinic patients who used tenofovir-free regimens.

About two-thirds of tenofovir recipients were men and the average age was 43 years. The median baseline CD4 count was low, at 168 cells/mm³. Most participants (79%) took tenofovir with non-nucleoside reverse transcriptase inhibitors (NNRTIs), while 21% did so with protease inhibitors, usually atazanavir (Reyataz).

Mean GFR at baseline among tenofovir recipients was 96 ml/min using the MDRD equation, or about 90 ml/min using the CockcroftGault method. About 23% had GFR (by MDRD) of 60-90 ml/min, while just 2% had low values in the 30-60 ml/min range. Individuals who started tenofovir with creatinine clearance <50 ml/min were excluded, as this is a considered a contraindication to using the drug. Those who fell below 60 ml/min during the first 6 months of therapy had tenofovir discontinued. The average duration of follow-up was just under 2 years.

Results

• Overall, estimated GFR declined by 6.9 ml/min (by MDRD) after 12 months of follow-up.
• The decline was 5.5 ml/min for those taking tenofovir with NNRTIs, compared with 11.8 ml/min for those taking tenofovir with protease inhibitors.
• Declines continued but were smaller during subsequent years of tenofovir use. Looking at the entire follow-up period, annualized declines in GFR (by MDRD) were 5.3 ml/min per year among all participants exposed to tenofovir, 4.2 ml/min per year for those taking tenofovir with NNRTIs, and 9.2 ml/min per year for those taking tenofovir with protease inhibitors.
• In comparison, GFR fell by just 1.3 ml/min per year among individuals on tenofovir-sparing regimens -- similar to the normal age-related GFR decline, averaging about 1.0 ml/min/year, in the HIV negative general population.
• Significant predictors of greater GFR decline were baseline CD4 count below 100 cells/mm³ and diabetes, with age over 50 years falling just short of statistical significance.
• 36 tenofovir recipients (5%) developed acute kidney injury, defined as serum creatinine >2 mg/dl, creatinine clearance falling to <50 ml/min, or a GFR decrease of more than 50% from baseline.
• Most people (44%) did so within the first 6 months on tenofovir, but 19% did so after 24 months.
• 3 of these patients (8%) required kidney dialysis and 4 people (11%) died.
• Significant risk factors for acute kidney injury included low baseline creatine clearance, CD4 count below 100 cells/mm³, using tenofovir with protease inhibitors as opposed to NNRTIs, use of other nephrotoxic drugs, and co-existing obstructive kidney disease (for example, kidney stones or benign prostate enlargement).
• 18 individuals with acute kidney injury were followed for at least 6 months after stopping tenofovir, during which half showed recovery of kidney function but the other half developed chronic kidney disease (GFR remaining <60 ml/min); none, however, required long-term dialysis.

"Renal function decline in patients on tenofovir-based ART was much higher than [in] patients taking tenofovir-sparing ART," the researchers concluded.

They added that the 5% rate of acute kidney injury among tenofovir recipients seen in this Indian population was higher than the 1% rate seen in most studies done in high-income western countries. This difference could be attributable to lower baseline creatinine clearance, lower CD4 count, and higher incidence of co-morbid conditions in this cohort, they suggested.

Furthermore, they continued, "management of tenofovir nephrotoxicity in resource-limited settings like India is tough due to limited access to routine laboratory monitoring, renal replacement therapy [dialysis], and alternate antiretroviral drugs like abacavir."

Switch from Tenofovir to Abacavir

Turning to a western setting, Silvia Guillemi from St. Paul's Hospital in Vancouver looked at kidney function changes among people who switched from a tenofovir-containing regimen to one containing abacavir (Ziagen, also in the Epzicom coformulation).

This retrospective analysis included 225 HIV positive adults in the British Columbia Centre for Excellence in HIV/AIDS Drug Treatment Program who switched from a suppressive regimen containing tenofovir plus either emtricitabine (the drugs in Truvada) or lamivudine (3TC, Epivir) to one containing abacavir plus lamivudine (the drugs in Epzicom), while staying on the same third drug.

Most participants (80%) were men, the median age was 47 years, and the median CD4 count was relatively high at 440 cells/mm³. A majority (56%) were taking atazanavir as their third drug, which can cause kidney stones.

Serum creatinine declined slightly after the switch, falling from 100 mcmol/l at baseline to 90 mcmol/l at 3 months, 89 mcmol/l at 6 months, and 87 mcmol/l at 12 months. Estimated GFR (by MDRD) rose in turn, from 69 ml/min at baseline to 78 ml/min at 3 months and 81 ml/min at 6 and 12 months. Serum phosphorus levels also increased. Changes in these parameters were not significantly different between people who took atazanavir and those who used other third agents.

In patients who switched from tenofovir-based to abacavir-based ART, "there was a significant improvement in renal function...without significant changes in plasma HIV RNA," the researchers concluded. "Similar trends were observed whether or not the third drug in the regimen was atazanavir."

7/15/13

References

A Dravid, A Sadre, S Dhande, et al. Tenofovir nephrotoxicity in resource-limited setting of western India: higher rate of renal function decline, acute kidney injury and progression to chronic kidney disease compared to western data. 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Kuala Lumpur, June 30-July 3, 2013. Abstract WEAB0201.

M Harris, S Guillemi, K Chan, et al. Effects on renal function of a switch from tenofovir (TDF)- to abacavir (ABC)-based highly active antiretroviral therapy (HAART), with or without atazanavir. 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Kuala Lumpur, June 30-July 3, 2013. Abstract WEAB0202.