protease inhibitor

Pfizer begins pediatric trial of COVID-19 antiviral

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Pfizer announced Wednesday that it has initiated a phase 2/3 study of its COVID-19 antiviral for pediatric patients.

Paxlovid, which contains tablets of the protease inhibitor nirmatrelvir and a low dose of ritonavir, is already available for patients aged 12 years or older under an emergency use authorization issued by the FDA in December.

Source: NIAID
Pfizer initiated a phase 2/3 study of its COVID-19 oral treatment Paxlovid for pediatric patients.

The new pediatric trial is an open-label, multicenter, single-arm study that will enroll approximately 140 participants aged younger than 18 years.

Initial enrollment will include two cohorts of participants aged 6 to 17 years. The first will include children weighing at least 40 kg, who will receive 300 mg of nirmatrelvir and 100 mg of ritonavir orally twice daily for 5 days — the currently authorized dose for patients aged 12 years and older weighing at least 40 kg. A second cohort of children weighing between 20 kg and 40 kg will also receive the therapy orally twice daily for 5 days, but with a reduced dose of nirmatrelvir (150 mg).

Mikael Dolsten, MD, PhD, Pfizer’s chief scientific officer and president for worldwide research, development and medical, said the antiviral may fill a “significant unmet need” for outpatient treatments for children and adolescents with COVID-19.

“Since the beginning of the pandemic, more than 11 million children under the age of 18 in the United States alone have tested positive for COVID-19, representing nearly 18% of reported cases and leading to more than 100,000 hospital admissions,” Dolsten said in a press release.

“Paxlovid is already authorized or approved in many countries around the world, with more than 1.5 million treatment courses delivered thus far and 30 million expected by July to help combat this devastating disease,” he said. “We are proud to expand studies of our novel COVID-19 treatment to include pediatric participants to further evaluate the safety and efficacy of this treatment in this important population.”

A final analysis of data from the Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-HR) trial demonstrated that Paxlovid reduced COVID-19-related hospitalizations and deaths by almost 90% among adults. The new trial is called EPIC-PEDS.

“Data from the EPIC-PEDS study will provide further support for the dose recommendations in this population, as well as potentially expand the indication to younger age groups and lower weights,” Pfizer said.

Viekira Pak Approved for Hepatitis C.

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The FDA on Friday approved a new, all-oral, interferon-free treatment for patients with hepatitis C genotype 1, including those with cirrhosis. Viekira Pak includes a combination ombitasvir/paritaprevir/ritonavir tablet (two tablets taken once daily) plus a dasabuvir tablet (taken twice daily).

Ombitasvir is an NS5A inhibitor, paritaprevir a protease inhibitor, and dasabuvir a non-nucleoside polymerase inhibitor. (Ritonavir is a previously approved HIV-1 protease inhibitor used to boost levels of paritaprevir.) Viekira Pak may be used with or without ribavirin.

In clinical trials of patients with chronic HCV infection with or without cirrhosis, 91% to 100% of Viekira Pak recipients achieved a sustained virologic response.

The New York Times reports that the wholesale price of Viekira Pak will be roughly $83,000 for 12 weeks of therapy — “less than the $94,500 for 12 weeks of [the recently approved] Harvoni, but probably not enough of a discount to allay complaints about high prices.”

Infectious disease expert Paul Sax told Physician’s First Watch: “The key factor whether people will choose this regimen is going to be price/payer coverage. It’s definitely more complex than what’s been approved already.

Single-Pill Regimens for HIV-1 Infection.

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In the latest Clinical Therapeutics review, a 52-year-old man with a history of HIV-1 infection and poor medication adherence presents for evaluation. A single-pill regimen is considered. For some patients with HIV-1 infection, combination regimens consisting of one pill to be taken daily can improve adherence.

With the advent and refinement of combination ART [antiretroviral therapy], the life expectancy of HIV-infected patients has risen dramatically. In addition to benefiting infected persons, ART almost completely blocks HIV-1 transmission to uninfected sexual partners. If we were able to treat most or all HIV-infected patients and thereby prevent new infections, “the beginning of the end of AIDS” would be in sight.

Clinical Pearls

• What are the currently available single-pill combinations marketed for HIV-1 treatment?

There are currently three single-pill combinations marketed for HIV-1 treatment, each containing the same combination of one nucleotide reverse-transcriptase inhibitor and one nucleoside reverse-transcriptase inhibitor (NRTIs): tenofovir disoproxil fumarate (TDF) at a dose of 300 mg and emtricitabine (FTC) at a dose of 200 mg, respectively. The first agent (Atripla, Bristol-Myers Squibb and Gilead Sciences), released in 2006, is a single pill that combines TDF-FTC with 600 mg of the nonnucleoside reverse-transcriptase inhibitor (NNRTI) efavirenz (EFV). The second agent (Complera, Gilead Sciences), approved in 2011, combines TDF-FTC with 25 mg of the NNRTI rilpivirine (RPV). The third agent (Stribild, Gilead Sciences), released in 2012, consists of TDF-FTC combined with 150 mg of the integrase strand-transfer inhibitor (INSTI) elvitegravir (EVG) and 150 mg of the pharmacoenhancer cobicistat (which boosts serum EVG levels). A fourth single-pill combination has not yet been approved for clinical use. This agent would combine two NRTIs — abacavir (ABC) at a dose of 600 mg and lamivudine (3TC) at a dose of 300 mg — with 50 mg of the recently approved INSTI dolutegravir DTG).

• In which patient populations should single-pill combinations be generally avoided?

Single-pill combinations should be avoided in patients with clinically significant renal disease because TDF, TC, and FTC all require dose reductions or elimination when the estimated creatine clearance is less than 50 ml per minute. The inability to adjust the dose of individual drug components in patients with renal insufficiency is an important limitation of single-pill combinations. In addition, patients who have drug-resistant HIV-1 infection often require agents that are not included in single-pill combinations.

Morning Report Questions

Q: When should a regimen containing a protease inhibitor be used?

A: None of the current single-pill combinations contain protease inhibitors, which should be used in patients with known viral resistance to NNRTIs or INSTIs. In addition, because transmitted resistance to protease inhibitors is uncommon and resistance to this class emerges relatively slowly, protease inhibitors are often favored when treatment decisions are required before resistance-testing results are available — for example, in the case of patients with acute HIV-1 infection or opportunistic infections. Protease inhibitors are also sometimes considered in patients with inconsistent adherence because multiple viral mutations are required to compromise the activity of these agents.

Q: How do currently available anchor medications for once daily regimens compare?

A: EFV, the anchor drug in EFV-TDF-FTC, is potent and, in recent years, the drug to which every newly developed anchor antiretroviral agent has been compared. EFV may cause neuropsychiatric effects (e.g., vivid dreams, insomnia, somnolence, and depression) or rash, although symptoms typically diminish over time. EFV is the preferred NNRTI during pregnancy, when initiated 8 weeks after conception. Rilpivirine (RPV)-based regimens are not recommended for patients whose pretherapy HIV-1 RNA level is more than 100,000 copies per milliliter or whose CD4+ T-cell count is 200 per cubic millimeter or less. RPV must be taken with a solid meal (greater than or equal to 390 kcal) and requires stomach acid for adequate absorption, precluding the concomitant use of proton-pump inhibitors. In addition to its use in initial therapy, RPV-TDF-FTC may have a role in patients with virologic suppression during treatment with a protease inhibitor-containing regimen who have a reason to change medications: in a recent trial, switching such patients to RPV-TDF-FTC maintained high rates of virologic suppression and improved lipid levels. Cobicistat-boosted EVG does not have neuropsychiatric effects and does not commonly cause rash. However, cobicistat inhibits tubular secretion of creatinine without reducing the creatine clearance. As a result, patients may have a mild increase in the serum creatinine level, typically less than 0.4 mg per deciliter (35 micromoles per liter), with this medication initially.