BOSTON — Recent findings discussed at CROI 2016 suggest extended use of Truvada could clinically impact renal function, with patients who demonstrated higher levels of adherence to the pre-exposure prophylaxis treatment experiencing the most severe declines.
This finding is most relevant in older patients and in people who demonstrate reduced renal function before PrEP initiation, according to the researchers, as they may require more frequent creatinine clearance (CrCl) screening than currently recommended by the CDC.
“These are healthy people who don’t need medication for their treatment of HIV,” Monica Gandhi, MD, MPH, professor of medicine and associate division chief of the HIV, infectious diseases and global medicine division at the University of California San Francisco, said during a press event. “It’s often said that these are such low declines that it doesn’t matter. But PrEP studies have not monitored people for as long as treatment studies have, and HIV clinicians have all seen issues with Truvada in patients on treatment. I think it matters a lot to monitor for toxicities when you don’t have infection … especially as they get closer to dangerous territory.”
Increased screening for older patients with renal deficiency
To study renal function among PrEP users, Gandhi and colleagues examined participant data from the iPrEx open-label extension (iPrEx OLE) study, which enrolled a cohort of HIV-negative men who have sex with men and transgender women who have sex with men to receive Truvada (emtricitabine/tenofovir disoproxil fumarate, Gilead Sciences; FTC/TDF). Serum creatinine was measured every 12 weeks, and estimated CrCl or glomerular renal function (eGFR) was determined using the Cockcroft-Gault or MDRD equation. The researchers assessed changes in CrCl in relationship with exposure data obtained from hair samples, which were collected every 12 weeks and analyzed for tenofovir (TFV) and FTC concentrations via liquid chromatography and tandem mass spectrometry.
“Hair analysis gives us about a month’s worth of exposure, so hair levels really represent cumulative exposure instead of recent exposure, and thus can be less susceptible to ‘white-coat effects’ or other day-to-day variation in adherence,” Gandhi said.
The researchers analyzed hair and creatinine data collected from 202 participants followed for a median 16.8 months (1,144 person-visits). The median age of participants was 29 years, and they were predominantly Latino or mixed race. The average serum creatinine was 0.89 mg/dL at baseline, while median CrCl was 112 mL/min.
Participants demonstrated decreasing eGFR with PrEP use during the study period. Researchers identified a direct relationship between renal function and hair concentrations of TFV (P = .008) and FTC (P = .006), with enrollees in the highest quartile of adherence demonstrating a mean –5.6% decline from baseline eGFR (compared with a 2.5% decline in all-comers). In addition, participants who were aged 40 years or older or had a low baseline CrCl (< 90 mL/min) before starting PrEP were at increased risk for having their renal function fall to a clinically relevant level where closer monitoring is indicated (CrCl < 70 mL/min).
“The monitoring guidelines [recommended] by the CDC are to monitor every 6 months for creatinine,” Gandhi said. “However, for those who start out with a CrCL of less than 90, or who are older, you may want to consider more frequent monitoring. If I see someone with a creatinine clearance of 70, I’m going to monitor them more frequently — I’m not going to wait 6 months.”
Modest declines in renal function
This conclusion was reaffirmed by another study presented by Albert Y. Liu, MD, MPH, of the San Francisco Department of Public Health. Liu and colleagues examined renal function among participants in the open-label U.S. PrEP Demonstration Project.
Albert Y. Liu
“We wanted to see whether kidney toxicity was different in a more real-world setting,” Liu said during the press event.
In their analysis, the researchers enrolled 557 HIV-negative MSM and transgender women who have sex with men from the cohort. All participants demonstrated CrCl of 60 mL/min or more at baseline, and were given 48 weeks of TDF/FTC. Similar to the study presented by Gandhi, creatinine was monitored every 12 weeks. To determine exposure and adherence, however, Liu and colleagues measured TFV-diphosphate (DP) levels in dried blood spots collected regularly from a subset of patients.
The median age of the enrolled participants, who were primarily white (48%) or Latino (35%), was 33 years, and 12% had pre-existing hypertension or diabetes. Baseline median creatinine was 0.92 mg/dL, and baseline eGFR was 97 mL/min. Dried blood spots were collected from 294 participants at 1,067 visits, with 82% of visits demonstrating TFV-DP levels consistent with four or more doses of PrEP each week.
Liu and colleagues observed a small but statistically significant decline in mean eGFR of 2.8% from baseline to week 12, which then remained stable through week 48. Only three participants had FTC/TDF held due to elevated creatinine, and these elevations were not confirmed on repeat testing and did not recur when FTC/TDF was restarted. TFV-DP levels indicating four or more doses per week were associated with greater declines in eGFR (4% from baseline). During the study, 12% developed a new onset eGFR of less than 70 mL/min. Liu said that onset of clinically relevant eGFR was most common among older participants whose baseline eGFR was less than 90.
“On average, there were very modest declines in kidney function with starting Truvada in our cohort, and more importantly it was nonprogressive over the course of the study,” Liu said. “Similar to iPrEx OLE, people who start with low function — particularly older people — may warrant additional monitoring.” – by Dave Muoio
Gandhi M, et al. Abstract 866. Presented at: Conference on Retroviruses and Opportunistic Infections; Feb. 22-25, 2016; Boston.
Liu AY, et al. Abstract 867. Presented at: Conference on Retroviruses and Opportunistic Infections; Feb. 22-25, 2016; Boston.
Disclosures: Gandhi and Liu report no relevant financial disclosures. Gilead Sciences provided the study drug for these trials, but did not contribute other financial support and had no role in data interpretation.