SO MANY CONDITIONS,
SO MANY DRUGS

Living longer may lead to more drug interactions

BY STEPHANIE LYNCH, RPH AND ALICE TSENG, PHARMD

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People with HIV are living longer than ever before with improved antiretroviral (ARV) therapies. As patients age, however, other health conditions become more common, such as heart disease, high cholesterol, high blood pressure, diabetes, osteoporosis, kidney disease, and non-AIDS related cancers. These medical conditions may result from aging in general, long-term side effects of ARVs, risk factors that are more common in HIV-positive patients, or the virus itself.

With older age, the number of medications patients require tends to increase. They may also be taking vitamins, supplements, and complementary and alternative medicines (CAM) in addition to their prescription medications. As the number of medications grows, the potential for drug-drug interactions increases.

First things first

To better understand drug interactions, it’s helpful to know something about the chemical reactions that may cause them. Several ARVs may be more likely to cause drug interactions because of their effects on CYP (pronounced “sip”) enzymes.

Cytochrome P450 (CYP450) enzymes are a family of enzymes which work to break down medications in the liver.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are moderate inducers of CYP3A4 enzymes, which means they can speed up how quickly the liver breaks down drugs such as protease inhibitors (PIs) or other drugs that are broken down by this pathway. The concern is that if ARV drug levels become too low, this may lead to viral breakthrough (detectable viral load), development of ARV resistance, or less than ideal disease management.

Conversely, PIs are strong CYP450 inhibitors and can slow down the metabolism of other drugs resulting in increased drug concentrations. This in turn may lead to a greater chance of side effects.

multiple drugs and aging

Here in Toronto, we conducted a recent study, along with our colleagues, comparing the frequency of potential ARV interactions in HIV-positive people who were 50 years of age or older versus HIV-positive adults who were younger than 50. Fifty years of age was used as the definition of “older,” as patients with HIV may age prematurely.

The study included 914 HIV-positive patients attending the specialist-based immunodeficiency clinic in Toronto General Hospital. Fifty-four percent were younger than 50.

For every 10-year increase in age, the odds of identifying one or more potential drug-drug interactions was nearly two times higher.

When current medications were compared between older and younger patients, older patients were taking more medications than younger ones, nine compared to seven drugs, and this was a statistically significant difference. Older patients were also more likely to be on a ritonavir (Norvir)-boosted PI or an integrase inhibitor.

They were also taking a greater number of non-ARV medications. These non-HIV therapies included antibiotics, blood thinning agents, drugs for heart disease, antidepressants, mood stabilizers, sedatives, stomach medications, bone medications, narcotics and other painkillers, hormonal drugs, and CAM.

In this study, factors associated with the chance of having one or more potential drug-drug interaction (PDDI) included older age, greater number of non-ARV medications, use of drugs for heart disease, and use of a boosted or unboosted PI.

Moreover, for every 10-year increase in age the odds of identifying one or more PDDI was nearly two times higher (1.72) after taking into account gender, race, and type or number of ARVs.

In contrast, the use of an integrase inhibitor was associated with a decreased probability of one or more PDDI.

ARV effects

A common finding in published studies is that the use of PIs is associated with a higher risk of having an interaction. Ritonavir specifically may be involved in potential drug-drug interactions with a variety of drug classes because it is a potent inhibitor of CYP3A4 and p-glycoprotein (a substance that helps pump drugs and toxins out of cells). Ritonavir also induces numerous enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, and glucuronyltransferase.

The results of this study indicate almost half of the patients (44 percent) had PDDIs involving ritonavir, and patients on ritonavir-boosted PIs were 40 times more likely to have a PDDI than patients not taking these drugs.

On the other hand, integrase inhibitors, specifically raltegravir [Isentress], were associated with a decreased likelihood of a PDDI. This is not surprising given raltegravir’s lack of inducing or inhibiting effects on the CYP450 enzyme system.

The newest integrase inhibitor, dolutegravir [Tivicay], also does not significantly affect the cytochrome P450 enzyme system, and is also associated with a low risk of drug interactions.

In contrast, the integrase inhibitor elvitegravir [available only in Stribild] needs to be given with the booster cobicistat. Cobicistat acts similarly to ritonavir in inhibiting CYP3A4 and p-glycoprotein, and may therefore be associated with a higher risk of possible interactions.

Interactions

We found no statistically significant difference in “red flag” drug interactions by age. “Red flags” were defined as medication combinations that are contraindicated, or not to be taken together.

Older patients, however, were more likely to have one or more “orange flag” interactions. “Orange flags” included combinations that should not be taken together, could be given with dose adjustment or increased monitoring, or have not been studied for safety, efficacy, or clinical significance. Orange flag PDDIs were found for 71% of older people compared to 55% of younger individuals.

Patients with orange flag PDDIs were on more ARVs (four compared to three) and were more likely to be virally suppressed compared with patients without PDDIs (92 percent versus 87 percent), possibly due to the greater number of ARVs taken by this group.

Since older patients have been shown to be more adherent to ARVs, this may be another reason for increased virological suppression in patients with orange flag PDDIs in this study as compared to other published research.

Specific interactions

In total, 1,718 potential drug-drug interactions (PDDIs) were identified in 63 percent of patients. Of those, 24% occurred between ARVs and the majority, 76%, were between ARVs and non-ARVs.

A total of 31 red flag PDDIs were identified in three percent of patients. Fourteen involved a PI and an NNRTI which could have resulted in reduced PI levels and viral breakthrough. Seven patients had a red flag PDDI between salmeterol and a PI. Three patients were on combination ritonavir and Levitra (vardenafil), whereas two patients were on Lexiva (fosamprenavir) and Valium (diazepam). The remaining patients had a red flag interaction between a PI and Cordarone (amiodarone), for atrial fibrillation, Zocor (simvastatin), and Halcion (triazolam).

Of a total of 571 orange flag PDDIs found in 62 percent of patients, the most common were:

  • between PIs and nucleosides (28%)
  • medications for heart disease (23%)
  • narcotics (17%)
  • and antidepressants (13%)

The most common examples were combinations of ritonavir and analgesics or narcotics (17%), Reyataz (atazanavir) and Viread (tenofovir) (13%), and ritonavir with antidepressants (10%).

Older patients were more likely to have PDDIs involving:

  • Sustiva or Atripla (containing efavirenz) or Intelence (etravirine) with Lipitor (atorvastatin)
  • PIs with calcium channel blockers or statins (heart and cholesterol medications), and
  • ritonavir with beta-blockers (high blood pressure drugs)

An overall look

Overall, this study demonstrated that HIV-positive patients at a specialty clinic treated with ARV therapy are at high risk for experiencing a PDDI. Two-thirds of the patients on ARV therapy had one or more PDDIs identified, with a median of two PDDIs per patient (half of the patients had more than this and half had less). Potential consequences of these interactions included higher risk of drug toxicity or reduced drug effectiveness.

The rate of orange flag interactions was found to be slightly higher in this study when compared to other studies. This may be due to the fact that PDDIs with questionable clinical significance were included; around 8% of orange flag PDDIs in this study fell into that category.

In this study, older patients were significantly more likely than younger patients to be male, men who have sex with men, white and non-immigrants, have a history of an AIDS-defining illness, and have been HIV-positive and on ARV treatment longer. In the study overall, 78 percent of study participants were male and 90 percent were virologically suppressed.

The study is limited by the fact that PDDI frequency rates may be underestimated, as potential interactions between non-ARV medications were not analyzed. Secondly, orange flag PDDIs that were already taken into account through dose adjustments were included.

Finally, given the multifactorial nature of PDDIs on patient outcomes, it was not possible to quantify the clinical impact of a PDDI on individual patient health.

Recommendations for patients

Where available, referral to an expert HIV pharmacist for a medication review and assessment of PDDIs is recommended in order to optimize drug treatments. Patients are highly encouraged to use one pharmacy to fill all of their prescription medications so that drug-drug interactions can be promptly identified.

It is also recommended that patients check with their physician or pharmacist before starting any new prescription medication, over-the-counter drugs, vitamins, supplements, or complementary and alternative medicines to ensure there are no potential drug-drug interactions with their current medication regimen.

Conclusions

Older patients are at a higher risk of experiencing potential drug-drug interactions due to a greater number of non-ARV medications, specifically medications for heart diseases. Increased vigilance should be taken in the care of HIV-positive patients of at least 50 years of age on ARV therapy to prevent drug-drug interactions, to maximize ARV and non-ARV efficacy, and to minimize toxicity.


Reference

Tseng A, Szadkowski L, Walmsley S, et al. Association of Age With Polypharmacy and Risk of Drug Interactions with Antiretroviral Medications in HIV-Positive Patients. Ann Pharmacother 2013;47(11): 1429-1439.

Stephanie Lynch, RPh, is a pharmacist and doctoral student of pharmacy at the University of Toronto. She graduated from Dalhousie University with a Bachelor of Science in pharmacy in 2011 and completed an accredited Canadian pharmacy residency program at the Moncton Hospital, Horizon Health Network in 2012.

Alice Tseng, PharmD, is a pharmacist at the Immunodeficiency Clinic, Toronto General Hospital and assistant professor with the faculty of pharmacy, University of Toronto. She is an editor of two popular websites on HIV and hepatitis C drug interaction and pharmacology information—hivclinic.ca and hcvdruginfo.ca. She is also a reviewer of this year’s drug guide.

Websites such as hivclinic.ca/main/drugs_interact.html, hiv-druginteractions.org or hivinsite.ucsf.edu/insite?page=ar-00-02 are frequently-updated sources of ARV drug interaction information which can be used by physicians and patients to help identify potential drug-drug interactions (PDDIs).

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