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Truvada PrEP Did Not Cause Major Kidney Problems in HIV Prevention Trial

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Gay men who used Truvada (tenofovir/emtricitabine) for HIV pre-exposure prophylaxis (PrEP) were unlikely to develop impaired kidney function in the iPrEx study, according to a report in the February 4 advance edition of AIDS. Creatinine clearance decreased slightly on average among Truvada recipients, but returned to normal after stopping PrEP.

Tenofovir is one of the most widely used antiretroviral drugs for HIV treatment. Many studies have shown that it is generally safe and well-tolerated, but it can sometimes cause kidney problems and bone loss in people with HIV.

Marc Solomon and Robert Grant from UCSF's Gladstone Institutes and fellow iPrEx investigators evaluated the kidney safety of tenofovir among HIV negative participants in the trial.

As previously reported, iPrEx enrolled 2499 participants, mostly men who have sex with men and a small number of transgender women. Most were white, they were generally young (half being age 18-24), and only 5% were obese or had hypertension (high blood pressure). They were randomly assigned to receive once-daily oral Truvada or placebo. The primary analysis found that Truvada reduced new HIV infections by 44%. Further analysis showed that incidence fell by more than 90% among participants with measurable blood drug levels indicating good adherence.

The researchers measured serum creatinine and phosphorus levels during randomized treatment and after PrEP discontinuation. Creatinine clearance (CrCl) -- a common measure of kidney function -- was estimated using the Cockcroft-Gault equation. Indicators of proximal renal tubulopathy (excretion of phosphorus and uric acid, and protein and glucose in the urine) were measured in a substudy.

Results

  • There was a small but statistically significant decrease in creatinine clearance from baseline in the Truvada arm compared with the placebo arm, first observed at week 4 (mean change -2.4 vs -1.1 mL/min; P=0.02).
  • This difference persisted through the last on-treatment visit (mean change +0.3 vs +1.8 mL/min; P=0.02).
  • The decrease in creatinine clearance resolved after stopping Truvada PrEP (mean change -0.1 vs 0.0 mL/min; P=0.83).
  • The effect of Truvada on creatinine clearance did not vary according to race/ethnicity, age, or history of hypertension, all of which are traditional risk factors for kidney disease.
  • Creatinine elevation occurred with similar frequency in the Truvada and placebo groups.
  • There was no significant difference in serum phosphate levels between the Truvada and placebo arms.
  • Protein or glucose in the urine also occurred with similar frequency in both study arms.
  • 2 participants in the substudy who received placebo -- but none taking Truvada -- showed signs of proximal tubulopathy.

"In HIV-seronegative [men who have sex with men], randomization to [tenofovir/emtricitabine] was associated with a very mild non-progressive decrease in creatinine clearance that was reversible and managed with routine serum creatinine monitoring," the researchers concluded. "This study indicates that [tenofovir] use in PrEP may lead to mild and subclinical decline in creatinine clearance without proximal tubular dysfunction."

"In the current study, the mean decrease in creatinine clearance from baseline was of the order of 1-3 mL/min for the active arm when compared to placebo," they elaborated in their discussion. "Given that mean baseline creatinine clearance was approximately 117 mL/min, this small mean change represents approximately 2% loss in estimated creatinine clearance after taking the study drug for, on average, 81 weeks."

"Whereas some participants experienced greater decreases in creatinine clearance, the mean decline in creatinine clearance remained stable after week 4 despite continuation of [tenofovir/emtricitabine]," they continued. "Importantly, we observed a 3-5% downward drift in creatinine in both study arms, which was greater than the overall mean treatment effect."

While iPrEx enrolled mostly gay men, the authors noted, "a similar low incidence of renal injury was observed in heterosexual men and women in African PrEP studies."

These PrEP trials were limited to people with normal kidney function at baseline. This is also a requirement in the FDA-approved indication for Truvada PrEP, and kidney biomarkers should be monitored regularly while taking PrEP.

"Demonstration projects may also provide additional data on frequency of monitoring required or factors that will enable clinicians to identify those at greatest risk for renal effects of [tenofovir]," the researchers wrote. "The next step will be to monitor renal safety as PrEP is offered to broader populations with multiple comorbidities including pre-existing renal disease or predisposing risk factors for it (e.g. older age or diabetes) to determine whether [tenofovir/emtricitabine's] effects on renal function are similarly modest in these populations."

2/20/14

Reference

MM Solomon, JR Lama, DV Glidden, RM Grant, et al (iPrEx Study Team). Changes in renal function associated with oral emtricitabine/tenofovir disoproxil fumarate use for HIV pre-exposure prophylaxis. AIDS. February 4, 2014 (Epub ahead of print).