Safety considerations for nirmatrelvir/ritonavir (Paxlovid®) use in persons living with HIV whether or not on antiretroviral treatment, or persons at risk of HIV while on PrEP who are diagnosed with COVID-19 infection

The COVID-19 therapy Paxlovid® consists of the antiviral medication nirmatrelvir co-packaged with the pharmacokinetic enhancer (“booster”) ritonavir, taken as a twice daily, oral, five-day treatment course, with dosage adjustment required for renal impairment (see prescribing information).

Nirmatrelvir/ritonavir treatment is initiated as soon as possible following a positive SARS-CoV-2 test result. Eligibility criteria for nirmatrelvir/ritonavir vary between Canadian provinces and will likely evolve over time. Also, eligibility in British Columbia may be expanded as drug supply increases. Therefore, prescribers are strongly encouraged to refer to current nirmatrelvir/ritonavir prescribing information and local guidelines for treatment eligibility and general contraindications/precautions. In British Columbia, see the BC Centre for Disease Control website: http://www.bccdc.ca/health-professionals/clinical-resources/covid-19-care/clinical-care/treatments

On March 3, 2021, the BC Provincial Laboratory Medicine Services released an information bulletin stating that some lab results for markers of kidney function have been affected by production issues with analytical reagents. Some serum creatinine measurements (SCr) may show higher than expected results, and calculated glomerular filtration rate values (eGFR) may be lower than expected

The shift towards higher SCr values is associated with some batches of reagents used in Roche chemistry analyzers for serum creatinine.  This problem has been reported internationally.  In BC, the affected sites are LifeLabs, Valley Medical Laboratories, and some Northern Health laboratories.  The upward shift in SCr results affects samples drawn in November 2020 to March 2021.

Affected laboratories have posted additional information on their websites and/or have added interpretation notes to affected test results, and are communicating with healthcare providers.  For information updates:

• To view the BC Provincial Laboratory Medicine Services bulletin, click here. (Updated March 15, 2021)
• To view BC LifeLabs notification and alert updates, click here.
• To view Valley Medical Laboratories news updates, click here.

Note that a variety of analytical systems are employed by BC laboratories, and this issue only affects the Roche serum creatinine assay (not the plasma creatinine assay).

Implications for antiretroviral safety monitoring:

• Use caution when making renal dose adjustments to antiretroviral medications (e.g. lamivudine, tenofovir DF).  Excessive dose reduction based on a falsely low eGFR result could result in inadvertent under-dosing.
• When monitoring kidney function, be aware that affected laboratories may report SCr values an average of 9 μmol/L higher than previous samples, and corresponding eGFR values may be an average of 8 mL/min/1.73 m² lower.  Consider the overall clinical picture and results of serial monitoring.

Update: The affected laboratories advised that the issue with the manufacturer’s serum creatinine reagent was resolved in mid-March 2021.

In July 2019 new information was presented at the International AIDS Society meeting (Mexico City) regarding the use of dolutegravir in pregnancy. Background: In May 2018, preliminary findings from an observational study in Botswana identified a potential increased risk of neural tube defects among infants born to women who had been treated with dolutegravir at the time of conception. Warnings were issued by Health Canada and other health agencies in response to this safety signal, and the Oak Tree Clinic at BC Women’s Hospital developed interim dolutegravir prescribing guidelines.

In July 2019 newly published studies reported that, although the risk of neural tube defects may be somewhat higher if dolutegravir is taken at the time of conception compared to other antiretroviral drugs, the difference in risk between dolutegravir and other antiretrovirals is lower than suggested by the preliminary analysis. In response to this new data, the Oak Tree Clinic at BC Women’s Hospital and Health Centre, in collaboration with the BC-CfE, has REVISED the Dolutegravir prescribing guidelines for pregnancy and women of reproductive potential.

Click here to view the most recent updates to the Oak Tree Clinic resources for healthcare providers (scroll down the page to Antiretroviral Drug Information).

On December 20th, 2018 Health Canada issued an information update: Antiretroviral products containing darunavir 800 mg – cobicistat 150 mg for once daily administration (Prezcobix™, Symtuza™) are not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy.

Results from a small clinical trial found administration of darunavir 800 mg with cobicistat 150 mg once daily, in combination with other antiretrovirals, resulted in substantially lower exposure of darunavir and cobicistat during the second and third trimesters of pregnancy compared to the postpartum (non-pregnant) state. The Prezcobix™ and Symtuza™ product monographs recommend use of an alternative antiretroviral regimen for women who become pregnant during therapy with these products.

For more information Click here to go to the Health Canada’s Health Product InfoWatch bulletin

For information on antiretroviral prescribing during pregnancy Click here to view the Oak Tree Clinic, BC Women’s Hospital guidelines (scroll down the page to “British Columbia Guidelines for the Care of HIV Positive Pregnant Women & Interventions to Reduce Perinatal Transmission”)

On September 28th, 2018 – Health Canada issued an information update regarding labeling changes in the product monograph for fluorometholone acetate (Flarex^TM) eye drops. Systemic corticosteroid adverse reactions such as Cushingoid symptoms or adrenal suppression may occur after intensive or long-term, continuous fluorometholone use in persons treated with CYP3A4 inhibitors including ritonavir (Norvir^TM, Kaletra^TM ) or cobicistat (in Prezcobix^TM, Stribild^TM, Genvoya^TM), which are used as antiretroviral ‘boosters’ in the treatment of HIV.

The product monographs for other potent ophthalmic corticosteroids, including difluprednate (Durezol^TM) and dexamethasone (Maxidex^TM, Maxitrol^TM, Tobradex^TM) include similar drug interaction warnings with ritonavir and cobicistat.

The combination of potent corticosteroid eye drops with ritonavir or cobicistat should be avoided unless the benefit outweighs the increased risk, in which case patients should be monitored for systemic corticosteroid adverse reactions.

For more information: Click here to view the Health Canada advisory

The drug interaction between ritonavir or cobicistat and other corticosteroid products such as inhalers, nasal sprays, and intra-articular injections is well documented.

For more information about how to manage or monitor the drug interaction between ritonavir or cobicistat and ophthalmic/ inhaled/ injectable corticosteroids, Click here to download the BC-CfE Pharmacovigilance Safety Alert Bulletin (June 2010) on this topic.

On June 7, 2018 – Health Canada issued a warning regarding the possible risk of neural tube defects associated with dolutegravir use during early pregnancy. This warning is based on preliminary findings from an observational study in Botswana, which identified 4 infants with neural tube defects born to women who had been treated with dolutegravir at the time of conception.

For more information: Click here to view the Health Canada advisory

In collaboration with the BC Centre for Excellence in HIV/AIDS, the Oak Tree Clinic at BC Women’s Hospital and Health Centre has developed Dolutegravir prescribing guidelines for pregnancy and women of reproductive potential.

Amendment: On July 31, 2019, the Oak Tree Clinic guidelines were updated to reflect new information. Click here to view the most recent updates to the Oak Tree Clinic resources for healthcare providers (scroll down the page to Antiretroviral Drug Information)

June 2017 – Drug interactions between antiretroviral drugs and other medications can result in loss of therapeutic efficacy or drug toxicity. Selected proton pump inhibitors and inhaled corticosteroids recently became available as non-prescription products in BC. These, and other non-prescription medications, can have clinically important interactions with certain antiretroviral drugs. This bulletin summarizes clinically important antiretroviral drug interactions with non-prescription drugs.

For more information: Click here to download the BC-CfE Safety Alert (PDF)

November, 2015 –At least three B.C. patients have developed new integrase resistance mutations affecting dolutegravir and/or raltegravir and elvitegravir which emerged during treatment with dolutegravir 50 mg daily plus abacavir-lamivudine. Two of the three patients also developed new resistance to lamivudine and abacavir. One patient was treatment naïve and two were treatment experienced. None had previously documented drug resistance. Two of these patients achieved virologic suppression followed by rebound, while one never achieved a viral load <40 c/mL. Drug resistance emerged within 8-12 months after starting the dolutegravir-based regimen. Incomplete medication adherence appeared to be a contributing factor.

For more information: Click here to download the BC-CfE Safety Alert (PDF)

On February 19th, 2014 Health Canada issued an information update regarding labeling changes in the fosamprenavir (Telzir™) product monograph. The update includes a strengthened warning to avoid co-administration of fosamprenavir with certain medications used for regulating the rhythm of the heart. This labeling change does not represent a new safety concern.

For more information: Click here to view the Health Canada advisory

September 17, 2012 – The Pharmacovigilance Initiative at the BC Centre for Excellence in HIV/AIDS has received reports of patients seeing nevirapine 400 mg XR (extended release) tablets or tablet fragments in their feces (stools). In BC, approximately 4% of patients treated with nevirapine XR have reported seeing tablet remnants in their stool.

Nevirapine 400 mg XR tablets are formulated in a non-digestible cellulose-based matrix, with the drug dispersed throughout the matrix. When tablets are swallowed, nevirapine is released into the gastrointestinal tract and absorbed into the body and the inactive tablet matrix is eliminated in the feces. Softened tablet remnants may sometimes resemble “whole” tablets, but laboratory testing has shown that the remnants are primarily inactive ingredients – the nevirapine dose has been released. The manufacturer acknowledges that reports of nevirapine XR tablet remnants in the feces have been documented among clinical trial participants and during post-marketing monitoring in other countries.

To date, there have been NO known cases of treatment failure associated with the observation of nevirapine XR tablet remnants in feces (including “whole” tablets) either in British Columbia or in the manufacturer’s global database. Quality control tests of tablet samples have confirmed that nevirapine XR tablets meet all the product specifications for dissolution performance.

There is currently no safety concern associated with the observation of nevirapine XR tablets or tablet fragments in the stool under normal physiological conditions. Nevirapine 400 mg XR tablets are available to treatment-eligible patients through the BC-CfE Drug Treatment Program.

For more information: Click here to download the BC-CfE Safety Alert (PDF)