Back HIV Prevention Pre-exposure (PrEP) Truvada for PrEP Not Linked to Kidney Impairment, Resistance Is Rare

Truvada for PrEP Not Linked to Kidney Impairment, Resistance Is Rare

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Truvada (tenofovir/emtricitabine) used for pre-exposure prophylaxis (PrEP) was not associated with clinically relevant declines in kidney function through 36 months in a large clinical trial, researchers recently reported. A related study found that drug resistance is rare among PrEP users, but it can occur in people who have acute HIV infection when they start Truvada and those who become infected despite PrEP.

Pre-exposure prophylaxis using tenofovir/emtricitabine has been shown to dramatically reduce the risk of HIV infection. The iPrEx trial of mostly gay and bisexual men found that daily Truvada reduced the risk of HIV infection by 42% overall, rising to 92% among participants with blood drug levels indicating regular use. The Partners PrEP and TDF2 trials, which looked at heterosexual couples in Africa, found that Truvada or tenofovir PrEP reduced the risk of HIV acquisition by about 65%-75%.

Kidney Function

Tenofovir disoproxil fumarate (TDF)and emtricitabine are generally safe and well-tolerated, but tenofovir can cause bone loss shortly after starting therapy and kidney dysfunction in susceptible individuals. Most studies of tenofovir toxicities, however, have looked at HIV positive patients on combination antiretroviral therapy (ART), not people taking tenofovir or Truvada for PrEP.

As described in the December 22 edition of JAMA Internal Medicine, Kenneth Mugwanya from the University of Washington/Makerere University and fellow investigators with the Partners PrEP Study Team conducted a safety analysis of changes in estimated glomerular filtration rate (eGFR) -- a measure of kidney function -- among study participants.

Partners PrEP enrolled 4747 serodiscordant heterosexual couples in Kenya and Uganda between July 2008 and November 2010. To be eligible, the HIV negative partner had to have normal kidney function at baseline, defined as a serum creatinine level <1.3 mg/dL for men or <1.1 mg/dL for women and creatinine clearance of >60 mL/min (Cockcroft-Gault equation). They also did not have diabetes or clinically significant cardiac disease and were not receiving other drugs known to cause kidney toxicity.

Among at the HIV negative partners, about 60% were men and 40% were women, with a median age of 35 years. They were randomly assigned to receive 300 mg tenofovir alone, Truvada, or placebo, all once-daily.

Results

  • At baseline the mean eGFR of the HIV negative partners was 130 mL/min/1.73 m2, indicating good kidney function.
  • During a median follow-up of 18 months, the mean changes in eGFR were +0.14 in the tenofovir-only group, -0.22 in the Truvada group, and +1.37 mL/min/1.73 m2 in the placebo group.
  • This translated into average declines in eGFR attributable to PrEP vs placebo of -1.23 and -1.59 mL/min/1.73 m2 for tenofovir alone and for Truvada, respectively.
  • The difference in mean eGFR between the PrEP and placebo groups appeared by 1 month after starting PrEP, was stable through 12 months, and then appeared to diminish.
  • 1.3% of participants in the tenofovir-only group and 1.2% in the Truvada group developed a clinically significant confirmed 25% or greater decline in eGFR from baseline by 12 months; 1.8% and 2.5%, respectively, did so by 24 months.

"In this large randomized, placebo-controlled trial among heterosexual persons, with median follow-up of 18 months and maximum follow-up of 36 months, daily oral [tenofovir]-based PrEP resulted in a small but non-progressive decline in eGFR that was not accompanied by a substantial increase in the risk of clinically relevant (>25%) eGFR decline," the study authors concluded.

These findings support current recommendations that Truvada PrEP is safe overall, but that kidney function should be monitored regularly and people with pre-existing kidney dysfunction should not use tenofovir or Truvada.

Drug Resistance

Along with kidney toxicity, another common concern about Truvada PrEP is the development of drug resistance.

As described in the January 13 Journal of Infectious Diseases, Dara Lehman and colleagues with the Partners PrEP teamtested blood plasma from participants who seroconverted for resistance mutations associated with emtricitabine (K65R and M184IV) or tenofovir (K65R and K70E).

Of of 121 seroconverters, 25 received Truvada, 38 received tenofovir alone, and 58 received placebo; 26 of these individuals had plasma drug levels indicating that PrEP was used during or after HIV infection.

Among these participants, 5 had virus with PrEP-associated resistance mutations. Of these, 3 had unrecognized acute HIV infection at the time of PrEP randomization and 2 were HIV negative at enrollment. Of note, resistance was more frequent in the Truvada group (4 of 7 people) than in the tenofovir-only group (1 of 19 people), because the M184IV emtricitabine mutation develops readily while tenofovir has a higher barrier to resistance

"These results suggest that resistance selected by PrEP is rare but can occur both with PrEP initiation during acute seronegative HIV infection and in PrEP breakthrough infections and that [emtricitabine] is associated with a greater frequency of resistance mutations than [tenofovir]," the researchers concluded."

In an accompanying editorial, iPrEx principle investigator Robert Grant of the Gladstone Institutes and Teri Liegler of UCSF argued that while resistance is possible, the benefits of PrEP for preventing HIV infection outweigh the risks.

"There are ways to minimize the risk of drug resistance during PrEP use," they wrote. "Highly sensitive viral tests that detect RNA or antigen can rule out acute infection prior to starting PrEP...If testing for HIV RNA or antigen is not available or not affordable, deferring PrEP in people with an acute viral syndrome will help, as the majority of acute HIV infections are symptomatic. Inviting PrEP users to inform providers about their stopping and starting of PrEP is important and provides an opportunity to arrange timely HIV testing. Home testing may make test access easier."

"Some practices used to minimize the risk of HIV resistance are ill advised: attempting to restrict access to PrEP is expected to foster intermittent dosing, hoarding of medications, sharing among friends and partners, and other unsupervised use," they added. "Fomenting fear of drug resistance is also misguided if it distracts us from fear of HIV itself, by far the greater threat to human health."

1/29/15

References

KK Mugwanya, C Wyatt, C Celum, J Baeten, et al (Partners PrEP Study Team). Changes in Glomerular Kidney Function Among HIV-1-Uninfected Men and Women Receiving Emtricitabine-Tenofovir Disoproxil Fumarate Preexposure Prophylaxis - A Randomized Clinical Trial. JAMA Internal Medicine. December 22, 2014 (Epub ahead of print).

DA Lehman, JM Baeten, CO McCoy, et al (Partners PrEP Study Team). Risk of Drug Resistance Among Persons Acquiring HIV Within a Randomized Clinical Trial of Single- or Dual-Agent Preexposure Prophylaxis. Journal of Infectious Diseases. January 13, 2015 (Epub ahead of print).

RM Grant and T Liegler. Weighing the Risk of Drug Resistance With the Benefits of HIV Preexposure Prophylaxis (Editorial Commentary). Journal of Infectious Diseases. January 13, 2015 (Epub ahead of print).