Deborah Yoong

Severe Anemia Secondary to a Probable Drug Interaction between Zidovudine and Valproic Acid

A 42-year-old man with human immunodeficiency virus (HIV) infection and a history of complex partial seizures developed severe anemia after the addition of valproic acid to his stable antiretroviral regimen of zidovudine, lamivudine, and abacavir. The inhibition of zidovudine glucuronidation by valproic acid and the resultant zidovudine hematologic toxicity is the proposed mechanism of the interaction.

Outcomes of Dosage Adjustments Used to Manage Antiretroviral Drug Interactions

Dosage adjustments are often used to manage HIV drug interactions, but little is known about their clinical significance. We examined patients from the Ontario HIV Cohort Study to assess the effects of dosage adjustments on plasma viral load. A significant reduction (0.67 log10 copies/mL) in viral load was associated with adjustments to manage efavirenz-based interactions (95% confidence interval, -1.33 to -0.01) but was not observed after adjustments to manage rifabutin-based (difference in viral load, 0.03 log10 copies/mL; 95% confidence interval, -0.71 to 0.77) or nevirapine-based interactions (difference in viral load, 0.09 log10 copies/mL; 95% confidence interval, -0.83 to 1.01).

A Potential Drug–Herbal Interaction between Ginkgo biloba and Efavirenz

Efavirenz (EFV) is primarily metabolized by cytochrome P450 (CYP) 2B6 and to a lesser extent by CYP3A4. Drugs that significantly inhibit or induce these enzymes would then be expected to increase or lower the levels of EFV potentially resulting in toxicity or therapeutic failure, respectively. The constituents of Ginkgo biloba extract have been demonstrated to induce gene expression of the CYP450 enzymes. We report a case in which a potential drug–herb interaction may have led to virological breakthrough in a patient that was maintained on the same regimen for 10 years. Therefore, a drug–herbal interaction may be expected when these agents are taken concurrently, and we advise clinicians to avoid this combination when possible.

Non-occupational post-exposure prophylaxis for HIV at St Michael's Hospital, Toronto: a retrospective review of patient eligibility and clinical outcomes:

Stringent eligibility criteria, drug costs and antiretroviral toxicities are challenges in delivering HIV non-occupational post-exposure prophylaxis (nPEP). We reviewed patients’ nPEP eligibility and clinical outcomes at St Michaels Hospital, Toronto, Canada to identify opportunities for improvement. Of 241 patients, 59%, 36% and 6% presented for high- (receptive anal/vaginal, blood), medium- (insertive anal/vaginal) and low-risk (oral) sexual exposures, respectively, and nearly all (93%) presented within 72 hours. Of 205 patients given nPEP, 20 were known to have discontinued nPEP prematurely: three due to costs but none due to toxicities. Two HIV seroconversions occurred in patients with suspected ongoing potential exposures. Five asymptomatic syphilis diagnoses were made among 71 tested. Only 39% and 19% of nPEP patients returned to our institution for follow-up at 3–4 and six months, respectively. Our findings underscore the feasibility and importance of nPEP programmes to HIV and sexually transmitted infection control, while identifying opportunities for improvement.

A case of a potential drug interaction between clobazam and etravirine-based antiretroviral therapy.

The cytochrome P450 isoforms primarily involved in clobazam metabolism are CYP3A4 and 2C19. Drugs that modulate these enzymes would then be expected to alter the exposure of clobazam and its major metabolites. Etravirine, a second-generation non-nucleoside reverse transcriptase inhibitor has been shown to induce CYP3A4, while inhibiting CYP2C9 and CYP2C19. We report a case in which a potential drug interaction between clobazam and etravirine may have led to increased concentrations of clobazam and its pharmacologically active metabolite, N-desmethylclobazam, causing neurotoxic symptoms.

Canadian guideline on HIV pre-exposure prophylaxis and nonoccupational postexposure prophylaxis

KEY POINTS New HIV infections occur every year in Canada,[1][1] highlighting the need for integrated prevention programs. Pre-exposure prophylaxis (PrEP) and nonoccupational postexposure prophylaxis (nPEP) are two important strategies for preventing HIV that should be considered standard of care and

Preparing for pre-exposure prophylaxis: perceptions and readiness of Canadian pharmacists for the implementation of HIV pre-exposure prophylaxis.

Pre-exposure prophylaxis (PrEP) has been shown to reduce the risk of HIV transmission but has the potential to cause harm if not used properly. Pharmacists are well-positioned to foster PrEP’s efficacy but little is known whether they would endorse it as an HIV prevention tool. The objective of the study was to determine Canadian HIV pharmacists’ support for PrEP and to identify current barriers to promoting PrEP. Canadian pharmacists with experience in HIV care were invited to complete an online survey about their experiences, opinions, and learning needs regarding PrEP from December 2012 to January 2013. Among the 59 surveys received, 48 met criteria for final analysis. Overall, 33 (69%) respondents would provide education positively supporting the use of PrEP and 26 (54%) believed Health Canada should approve PrEP for use in Canada. Familiarity with the concept of PrEP and practice characteristics examined did not appear to be significantly associated with support for PrEP in univariable analyses. The principal barriers to promoting PrEP included inadequate drug coverage and insufficient knowledge to educate others. Many Canadian HIV pharmacists would endorse PrEP for high-risk patients; however, wider dissemination of information and lower drug costs may be needed to make PrEP more widely promoted.

Extensive Bruising and Elevated Rivaroxaban Plasma Concentration in a Patient Receiving Cobicistat-Boosted Elvitegravir:

Rivaroxaban, a direct oral anticoagulant (DOAC) that is dosed without the need for close monitoring, is vulnerable to pharmacokinetic drug interactions that could result in failure or toxicity. It is partially metabolized by cytochrome P450 (CYP) 3A4 (18%), CYP2J2 (14%), CYP-independent mechanisms (14%), and over a third of the dose is excreted unchanged in the urine via permeability-glycoprotein (P-gp) and breast cancer resistance protein (BRCP) transporters. Cobicistat is used as a pharmacokinetic enhancer to improve the exposure of protease inhibitors or the integrase inhibitor elvitegravir; it inhibits the CYP3A4 enzyme and the P-gp, BCRP, multidrug and toxin extrusion-1 (MATE1), and organic anion transporter polypeptides (OATP) transporters. We report the first case of a patient who was receiving elvitegravir-cobicistat-emtricitabine-tenofovirdisoproxil-fumarate (EVG/c/FTC/TDF) and experienced extensive bruising after being prescribed rivaroxaban. A 69-year-old HIV-infected man stable on EVG/c/TDF/ FTC for more than 2 years presented to the emergency department with new-onset atrial fibrillation. After being cardioverted back to sinus rhythm, he was prescribed rivaroxaban 20 mg daily. He was assessed at a cardiac clinic 6 days later, and rivaroxaban was continued, along with his chronic medications candesartan, atorvastatin, and EVG/c/ FTC/TDF. At his routine HIV appointment 2 months later, he denied any symptoms of abnormal bleeding but did note extensive bruising on his left thigh from a minor injury 2 days earlier. No additional medications were added. To determine the extent of the drug interaction and to minimize any further risk, blood tests were arranged and repeated 1 month after switching the antiretrovirals (Table 1). There was no significant decline in his hemoglobin or platelets, and his estimated creatinine clearance was consistently >80mL/min. Follow-up visits were uneventful. We suggest that the bruising and elevated rivaroxaban concentration that occurred in our patient was likely a result of a drug interaction from cobicistat. Drug interactions between rivaroxaban and antiretrovirals have been reviewed and have resulted in serious adverse events. There have been no published data on the extent of a drug interaction between cobicistat and rivaroxaban. Based on its inhibitory effects, cobicistat would be predicted to significantly increase rivaroxaban’s exposure; however, prescribing information for EVG/c/FTC/TDF and other resources do not warn of this interaction. The rivaroxaban plasma concentration obtained in our patient was 210 ng/mL—nearly 3-fold higher than the predicted concentrations at the same time point (75 ng/mL)—and subsequently decreased after elvitegravir-cobicistat was replaced with dolutegravir, an antiretroviral that exhibits no effects on the CYP enzymes or the P-gp transporter. Similarly, the anti-Factor Xa concentration, a quantitative assessment of rivaroxaban, exhibited the same decline after the interaction was removed. Although an elevated concentration does not translate to more intense anticoagulation, hemorrhagic events have occurred when rivaroxaban concentrations were increased. The ideal sampling schedule would have been to collect blood 2 hours after observed administration and before, during, and after the concomitant medication use; but despite this limitation, the interaction was calculated as probable. Rivaroxaban has simplified dosing; however, regular follow-up that includes the assessment for potential drug interactions is necessary for safe and effective use. Without an established rivaroxaban therapeutic range, dose adjustments to manage drug interactions are challenging and may not be effective. Our case highlights that the use 702677 AOPXXX10.1177/1060028017702677Annals of PharmacotherapyYoong et al letter2017

A Case of a Potential Drug Interaction between Phenobarbital andDarunavir-based Antiretroviral Therapy

The cytochrome P450 isoform that is primarily involved in the metabolism of darunavir is CYP3A4. Drugs that modulate this enzyme would then be expected to alter the pharmacokinetics of darunavir.Phenobarbital, a traditional antiepileptic has been shown to have broad induction effects on CYP450 and glucuronidation systems and would be expected to affect any drug, including antiretrovirals that are handled by these systems. We report a case in which we believe decreased serum concentrations of darunavir may have been a result of a drug interaction with phenobarbital.

Re: “Erythema Annulare Centrifugum due to Pegylated Interferon-α-2a plus Ribavirin Combination Therapy in a Patient with Chronic Hepatitis C Virus Infection”

BACKGROUND: Pegylated interferon-α combined with ribavirin is the current standard treatment for chronic hepatitis C virus infection. During interferon and ribavirin therapy, both local and generalized mucocutaneous adverse reactions have been reported. Erythema annulare centrifugum induced by this therapy regimen has not been reported previously. CASE REPORT: A 29-year-old woman was referred to our clinic for a 1-week history of slightly pruritic annular erythematous eruptions on the lower extremities and hands. The eruptions had first occurred on the hands 3 to 4 days after pegylated interferon-α-2a plus ribavirin combination therapy for hepatitis C virus infection. Histopathologic examination supported the diagnosis of erythema annulare centrifugum. The lesions completely regressed within 2 weeks after the cessation of treatment but recurred on similar localizations within 24 hours with the same therapy. It was thought that erythema annulare centrifugum was induced by pegylated interferon-α-2a plus ribavirin combination therapy. CONCLUSION: Erythema annulare centrifugum is considered an inflammatory skin disease with unknown etiology. It is thought to represent a hypersensitivity reaction to some triggering factors, including infections, immunologic disorders, malign neoplasms, foods, pregnancy, and drugs. We report the first case of erythema annulare centrifigum induced by pegylated interferon-α-2a plus ribavirin combination therapy.