Truvada PrEP Linked to Rare Case of Serious Kidney Disorder

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Researchers in Southern California have identified the first known case of Fanconi syndrome, a type of serious kidney dysfunction, in an otherwise healthy man taking Truvada (tenofovir/emtricitabine) for pre-exposure prophylaxis (PrEP), according to a poster presented at the 18th International Workshop on Co-morbidities and Adverse Drug Reactions in HIV last month in New York City. This case underlines the importance of regular kidney function monitoring while on PrEP.

Tenofovir disoproxil fumarate (Viread, also in several single-tablet regimens) is highly effective and generally safe for both HIV treatment and prevention, but it can cause a small amount of bone loss soon after starting therapy and lead to kidney problems in susceptible individuals. For this reason, people with pre-existing kidney function abnormalities are advised to avoid it.

Fanconi syndrome is an uncommon but serious kidney condition in which the proximal renal tubules are unable to properly reabsorb glucose, bicarbonate, phosphate, and other substances filtered out of the blood, and instead excretes them in the urine.

Cases of serious kidney toxicity have been seen in some HIV-positive people using tenofovir DF as part of combination antiretroviral therapy. Some studies have seen minor decreases in kidney function biomarkers among HIV-negative people using Truvada PrEP, but Fanconi syndrome had not previously been reported in this population.

M. Philip Dubéfrom the University of Southern California Keck School of Medicine and colleagues described the case of an HIV-negative study participant who developed reduced kidney function and features characteristic of Fanconi syndrome while taking Truvada for HIV prevention.

California Collaborative Treatment Group Study 595 (NCT01761643) was designed to evaluate whether a text messaging intervention could help improve adherence to daily Truvada PrEP in 400 high-risk gay men and transgender women.

The study protocol excluded people with pre-existing kidney problems and risk factors, including creatinine clearance less than 60 mL/min, dipstick proteinuria (protein in the urine), active hepatitis B, or use of other kidney-toxic drugs. Serum creatinine was measured at study entry and monitored at week 4, 12, and then every 12 weeks.

The participant in question was a 49-year-old white man with no ongoing medical problems who was on no other medications. However, he had a history of kidney stones 7 years earlier. At baseline he had an estimated creatinine clearance of 79.9 mL/min.

The man complained of no symptoms while taking Truvada, but routine monitoring at week 12 revealed that his creatinine clearance had decreased by 25%, to 58.9 mL/min -- just below the usual cutoff for using tenofovir DF. Additional testing showed that he had a low blood phosphate level, or hypophosphatemia (1.8 mg/dL) and elevated urinary phosphate excretion (fractional phosphate excretion of 26.6%), as seen in Fanconi syndrome. However, he did not have glucose, protein, or blood in the urine at any time.

The man then stopped Truvada, and 4 weeks later he had increased creatinine clearance (up to 69.1 mL/min) and improvement of phosphate abnormalities. His serum phosphate rose to 2.7 mg/dL (the low end of the normal range) and his fractional phosphate excretion fell to 12.2% (also within the normal range). By week 24 -- 12 weeks after going off Truvada -- his creatinine clearance had nearly returned to its baseline level (74.0 mL/min).

"Randomized trials have not documented an increase in renal tubular toxicity with [tenofovir DF/emtricitabine] based PrEP compared to placebo," the study authors wrote in their abstract. "However, we report a clear and significant reversible impairment in renal function accompanied by hypophosphatemia and renal phosphate wasting in an HIV-uninfected man receiving [tenofovir DF/emtricitabine]."

"Clinicians should be aware that this complication may still occur when [tenofovir DF] is used in HIV-uninfected individuals," they advised. "Although significant nephrotoxicity has been rarely reported, periodic renal monitoring is a reasonable recommendation in individuals receiving [tenofovir DF/emtricitabine] for PrEP"

This case demonstrates the value of kidney monitoring every 3 months, as was done in this study, allowing kidney function abnormalities to be detected early and Truvada to be discontinued before more serious toxicity occurs.

10/5/16

Reference

MP Dubé, CA Funk, K Corado, and S Morris. Tenofovir disoproxil fumarate associated Fanconi syndrome in an HIV uninfected man receiving HIV pre-exposure prophylaxis. 18th International Workshop on Co-morbidities and Adverse Drug Reactions in HIV. New York, September 12-13, 2016. Abstract P24.