Oral Acyclovir and Acute Kidney Injury? Is There a Risk?

Dr Ngan LamDrug safety is a critical concern in medicine. A recent trend is the late discovery of drug complications after the drug’s approval. A recent study published in the May issue of the American Journal of Kidney Diseases looks at a novel method for detecting specific drug complications after a drug is released. Lead author Dr. Ngan N. Lam (NL) discusses this report with Dr. Joel Topf (eAJKD), eAJKD Advisory Board member.

eAJKD: Can you describe the novel approach your team took to assess the safety of acyclovir and valacyclovir?

NL: We were interested in acute kidney injury (AKI) after outpatient prescription of acyclovir, valacyclovir, and famciclovir. These three drugs are used to treat the herpes virus. We retrospectively followed these people for 30 days after their initial prescription to see whether or not they required hospitalization for AKI. We had access to unique administrative databases that allowed us to answer a lot of questions that you might not be able to get from conventional observational or randomized control studies.

eAJKD: Was your assumption that there was no known risk of AKI with the oral use of these agents?

NL: It is known that intravenous (IV) forms of acyclovir cause AKI, and is related to the speed and route of drug administration. The drug crystallizes in the renal tubules causing damage. This has been shown in randomized control trials, observational studies, and case reports. When you look at oral acyclovir, only a few case reports and some small observational studies have reported a risk of AKI. There’s not a lot of literature out there about the actual risk of oral acyclovir at the population-based level.

eAJKD: Why did you choose to use an active control group rather than a placebo control group?

NL: There are three drugs used to treat the herpes virus in older patients. The indications for using these drugs are similar, and one drug is not favored over another. Famciclovir has not been shown to cause AKI while both acyclovir and valacyclovir are thought to cause AKI. We considered whether or not to use a subset of patients who had the herpes virus, but did not get treatment. We would then have to rely on diagnostic codes for the herpes virus diagnoses. To compare it to a group that doesn’t have the herpes virus and didn’t get the treatment is also a challenge, because then you’re not comparing apples to apples. You’re comparing a group of patients with this disease who received treatment with a group of patients that didn’t have the disease and didn’t get a drug. You’re not quite sure whether or not your outcome is related to the drug, or to the disease itself, confounding the results. We thought that the cleanest and most effective way of measuring this outcome was to compare the two drugs that can cause AKI with the one drug that’s not thought to cause AKI.

eAJKD: Going forward, how should population studies like this fit into our overall safety scheme to protect the public from dangerous drugs?

NL: These types of studies provide information about the safety and trends in the use of these drugs. I don’t think they are going to replace the gold standard of randomized control trials quite yet. There are some limitations to this study design, the main thing being that these are observational retrospective cohort studies. We are really only able to draw associations, and not able to say with confidence that the causality of the relationship like you would if you were to do randomized control trials.

Population-based studies can really complement the information from randomized controlled trials in that they are formed from encounters based on real-world routine practice. Also, randomized controlled trials are often only powered for the efficacy outcome, and do not have enough power to detect adverse drug events. This is where the large numbers in datasets, such as the ones we used, can be quite useful. In this study, we analyzed over 160,000 patients that were prescribed these drugs between 1997 and 2011.

eAJKD: What do you want our readers to take away from this study?

NL: If you are being treated with acyclovir or valacyclovir as an outpatient, your risk of hospitalization for AKI within 30 days of that prescription is no higher than if you had been treated with famciclovir.

To view the article abstract or full-text (subscription required), please visit AJKD.org.

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