Ritonavir;

Why do some patients with Covid-19 develop a rebound after completing a course of Paxlovid (nirmatrelvir/ritonavir) and how common is it?

FA Manian MD, MPH, , , , , , Leave a comment

Covid-19 rebound, characterized by the recurrence of Covid-19 symptom or a new positive viral test after having tested negative, is a poorly understood phenomenon that can occur after completion of therapy with Paxlovid, Molnupiravir (another antiviral Covid-19 drug) and even in patients with acute Covid-19 who never received any specific antiviral therapy. 1-6

Based on very limited number of studies, it appears that rebound is not caused by emergence of drug resistance or absence of neutralizing immunity, rather resumption of SARS-CoV-2 replication following completion of therapy, triggering a secondary immune-mediated response that’s associated with clinical symptoms.2,3

Recent studies suggest that rebound following Paxlovid treatment may not be as common as one may think.  In a cohort of 483 high-risk patients treated with Paxlovid for Covid-19, 0.8% experienced rebound of symptoms within 30 days of diagnosis, which were generally mild at a median of 9 days after treatment, all resolving without additional antiviral therapy.3  In this study, the median age was 63 years and 93% were fully vaccinated; there were no hospitalization related to rebound or deaths. In another study (pre-print) involving over 11,000 patients treated with Paxlovid, rebound symptoms occurred in 2.3% and 5.9% of patients  7 and 30 days following therapy, respectively, with similar rates reported in patients treated with Molnupiravir.4

Interestingly, a preprint article involving 568 untreated patients with mild-moderate Covid-19 found that 27% had symptom rebound after initial improvement with 12% having viral rebound based on nasal swabs with ≥0.5 log viral RNA copies/ml. 5 So antiviral therapy for Covid-19 is not a prerequisite for rebound symptoms.

Although some have suggested that insufficient drug exposure either due to individual pharmacokinetics or insufficient duration may be the cause of rebound in treated patients,2   there is currently no evidence that additional treatment for Covid-19 is needed in these patients.6

Despite reports of rebound, Paxlovid should still be considered in selected patients with mild-moderate Covid-19 at high risk of complications to minimize the risk of hospitalization and death from Covid-19. 

Bonus Pearl: Did you know that, according to CDC, Covid-19 rebound often occurs between 2-8 days following initial recovery? 1

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References

  1. Covid-19 rebound after paxlovid treatment. May 24, 2022. COVID-19 Rebound After Paxlovid Treatment (cdc.gov)
  2. Carlin AF, Clark AE, Chaillon A, et al. Virologic and immunologic characterization of Coronavirus Disease 2019 recrudescence after nirmatrelvir/ritonavir treatment. Clin Infec Dis 2022 (June 20). Virologic and Immunologic Characterization of Coronavirus Disease 2019 Recrudescence After Nirmatrelvir/Ritonavir Treatment | Clinical Infectious Diseases | Oxford Academic (oup.com)
  3. Ranaganath N, O’Horo JC, Challner DW, et al. Rebound phenomenon after nirmatrelvir/ritonavir treatment of Coronavirus Disease-2019 in high-risk persons. Clin Infect Dis 2022 (June 14). https://doi.org/10.1093/cid/ciac481 Rebound Phenomenon after Nirmatrelvir/Ritonavir Treatment of Coronavirus Disease-2019 in High-Risk Persons | Clinical Infectious Diseases | Oxford Academic (oup.com)
  4. Wang L, Berger NA, David PB, et al. Covid-19 rebound after Paxlovid and Molnupiravir during January-June 2022. MedRxiv 2022. COVID-19 rebound after Paxlovid and Molnupiravir during January-June 2022 | medRxiv
  5. Deo R, Choudhary MC, Moser C, et al. Viral and symptom rebound in untreated Covid-19 infection. Medrxiv 2022. Viral and Symptom Rebound in Untreated COVID-19 Infection (medrxiv.org)
  6. Covid-19 rebound after Paxlovid treatment. May 24, 2022. HAN Archive – 00467 | Health Alert Network (HAN) (cdc.gov)

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

 

Why do some patients with Covid-19 develop a rebound after completing a course of Paxlovid (nirmatrelvir/ritonavir) and how common is it?

What existing drugs are currently being evaluated or repurposed for treatment of Coronavirus (Covid-19) infection?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Leave a comment

There are currently no drugs specifically approved for treatment of Covid-19 infections. However, there are legions of therapies that are being considered, tried, and/or evaluated in clinical trials. Many experts believe a combination of drugs may be necessary for optimal therapy. Here is my select list of potentially promising drugs from gleaning the literature and online resources to date.1-16

  • Remdisivir: A broad spectrum investigational nucleoside analogue, originally developed to treat a variety of viruses, including Ebola, SARS and MERS. Active in vitro against Covid-19. Favorable results have been reported in some cases, including the first reported patient in the U.S.
  • Chloroquine: An old drug used for its antimalarial activity as well as for its immune modulation and anti-inflammatory properties. Has also been found to be active in mice against a variety of viruses, including certain enteroviruses, Zika virus, influenza A H5N1.  Active in vitro against Covid-19, though hydroxychloroquine may be more effective. Evidence for its efficacy in treating acute viral infections in humans is currently lacking.
  • Lopinavir/ritonavir: Protease inhibitor combo used in HIV infection with possibly some benefit in the treatment of SARS. Recent study showed no significant efficacy in severe Covid-19 disease. 
  • Interferon-alpha: An antiviral cytokine used against hepatitis B and C viruses. May be more effective for prophylaxis than post-exposure, based on experimental animal studies involving SARS.
  • Ribavirin: Another nucleoside analogue approved for hepatitis C (in combination with other drugs) and respiratory syncytial virus (RSV) infections but also evaluated in SARS and MERS. Has been reported to be active in vitro against Covid-19.
  • Sofosbuvir: Inhibits RNA-dependent RNA polymerase. Approved for treatment of hepatitis C, but also with in vitro activity against Covid-19.
  • Tocilizumab: Anti-interleukin-6 monoclonal antibody used in rheumatoid and giant cell arthritis. Theoretically, may mitigate cytokine storm observed in some patients during the later stages of Covid-19 disease.

Of course, there are many more drugs some of which would not be expected to be effective against Covid-19, based on what we so far know this virus. These include darunavir/cobicistat, oseltamivir, immunoglobulins, arbidol (an antiviral used in Russia and China vs influenza), angiotensin receptor blockers, stem cell therapy, convalescent plasma, and traditional Chinese medicine.

Remember corticosteroids are currently not recommended in the absence of other indications for their use (see related PEARL).

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References

  1. US National Library of Medicine. https://clinicaltrials.gov/ct2/results?cond=2019nCoV&term=&cntry=&state=&city=&dist
  2. Li Guangdi, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nature Reviews Drug Discovery 2020; Feb 19, 2010. https://www.nature.com/articles/d41573-020-00016-0
  3. Harrison C. Coronavirus puts drug repurposing on the fast track. Nature Biotechnology 020, Feb 27. https://www.nature.com/articles/d41587-020-00003-1
  4. Velavan TP, Meyer CG. The COVID-19 epidemic. Tropical Medicine and International Health 2020;25:278-280. https://onlinelibrary.wiley.com/doi/full/10.1111/tmi.13383
  5. Elfiky AA. Anti-HCV, nucleotide inhibitors, repurposing against COVID-19. Life Sciences 2020;248. 11747. https://www.sciencedirect.com/science/article/pii/S0024320520302253
  6. Wang Y, Wang Y, Chen Y, et al. Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures. J Med Virol 2020;March 5. https://www.ncbi.nlm.nih.gov/pubmed/32134116
  7. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2029 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506. https://www.ncbi.nlm.nih.gov/pubmed/31986264
  8. Paules CI, Marston HD, Fauci AS. Coronavirus infections—More than just the common cold. JAMA 2020;323:707-78. https://jamanetwork.com/journals/jama/fullarticle/2759815
  9. Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Research 2020;177. 104762. https://www.sciencedirect.com/science/article/pii/S0166354220301145
  10. Gurwitz D. Angiotensin receptor blockers as tentavie SARS-CoV-2 therapeutics. https://www.ncbi.nlm.nih.gov/pubmed/32129518/
  11. Wang M, Cao R, Zhang L, et al. Remdesivir and chlorquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research 2020;30:269-71. https://www.nature.com/articles/s41422-020-0282-0
  12. Roques P, Thiberville SD, Dupuis-Maguirara L, et al. Paradoxical effect of chloroquine treatment in enhancing Chikungunya virus infection. Viruses 2018;10, 268. https://www.ncbi.nlm.nih.gov/pubmed/29772762
  13. Young BE, Ong SWX, Kalimuddin S, et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA 2020;March 3. https://jamanetwork.com/journals/jama/fullarticle/2762688
  14. Holshue ML, DeBolt C, Lindquist S, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020; March 5. https://www.nejm.org/doi/full/10.1056/NEJMoa2001191
  15. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020. March 9. https://www.ncbi.nlm.nih.gov/pubmed?term=32150618
  16. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl M Med 2020, March18. DOI:10.1056/NEJMoa2001282. https://www.nejm.org/doi/full/10.1056/NEJMoa2001282

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

What existing drugs are currently being evaluated or repurposed for treatment of Coronavirus (Covid-19) infection?

Catch these selected key clinical pearls on coronavirus disease (Covid-19)!

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , , , , , Leave a comment

Although the Covid-19 pandemic is continuing to evolve and our knowledge of its epidemiology and pathophysiology is still far from complete, you may find the following pearls based on published literature to date useful when discussing this disease with your colleagues or the public. 1-11

  • Age group: Primarily an adult disease. Children (< 15-year-old) account for only a minority of symptomatic patients (<1%); ~50% of patients are between 15-49 years of age with 15% in the ≥ 65 year group. 1
  • Incubation period: A bit longer than seasonal flu. Median 4.0 days (IQR 2.0-7.0 days); an upper range up to 24 days has also been reported. In contrast, for seasonal flu the median incubation period is shorter (median 2.0 days, 1.0-7.0 days. 1,4,11
  • Transmission: Contact, droplet, and possibly airborne. On average each person may transmit Covid-19 virus to 2-3 other persons (vs <2 people for seasonal flu). Unlike SARS or MERS, but more akin to the seasonal flu, asymptomatic persons may also be able to transmit the disease. 4,5,11
  • Comorbid conditions (eg, diabetes, hypertension, COPD…): Present in about 1/3 of reported patients. 1
  • Symptoms 1,5
    • ~80% of patients may be either asymptomatic or have mild disease
    • Fever may be absent in ~50% of patients on presentation but will eventually develop in ~90% of hospitalized patients
    • Cough (2/3 dry) is present in majority (~80%) of cases
    • Rhinorrhea is uncommon (<10%), in contrast to the seasonal influenza
    • GI symptoms (nausea/vomiting/diarrhea) are uncommon by some reports(<10%), but not by others (>30.0%). 12
    • May take 9-12 days from onset of symptoms to severe disease
  • Labs 1
    • Lymphopenia is common (up to ~80%)
    • Abnormal liver function (AST and ALT) is found in about 1/3 of patients
    • C-reactive protein (CRP) is usually elevated (~80% of severe cases)
    • Procalcitonin is usually normal
  • Treatment: Supportive for now. Candidate drugs include remdesivir, lopinavir/ritonavir, chloroquine phosphate, ribavirin and several others.4
  • Mortality: Reported mortality among mostly symptomatic hospitalized cases is ~2.0% (0.9% without comorbidities, 5-10% in those with comorbidities, 50% among critically ill). Overall mortality rates will likely drop as more patients without symptoms or with mild disease are tested. In contrast, 2 other coronavirus diseases, SARS and MERS, have mortality rates of ~9.0% and 36.0%, respectively. 1,4,5

 

Bonus pearl: Did you know that, Covid-19-infected patients shed the virus in their nasopharyngeal secretions on the average for 12 days, some as long as 24 days?3

 

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References

  1. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of Coronavirus disease 2019 in China. N Engl J Med 2020. First published Feb 28, 220, last updated March 6, 2020. https://www.nejm.org/doi/10.1056/NEJMoa2002032
  2. Holshue ML, DeBolt C, Lindquist S, et al. First case of 2019 novel Coronavirus in the United States. N Engl J Med 2020; 382:929-36. https://www.nejm.org/doi/full/10.1056/NEJMoa2001191
  3. Young BE, Ong SWX, Kalimuddin S, et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA. Doi:10.1001/jama.2020.3204. Published online March 3, 2020. https://jamanetwork.com/journals/jama/fullarticle/2762688
  4. Wang Y, Wang Y, Chen Y, et al. Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures. J Med Virol 2020. Doi: 10.1002/jmv.25748. https://www.ncbi.nlm.nih.gov/pubmed/32134116
  5. Fauci AS, Lane HC, Redfield RR. Covid-19—Navigating the uncharted. N Eng J Med 2020. DOI:10.1056/NEJMe2002387. https://www.nejm.org/doi/full/10.1056/NEJMe2002387
  6. Del Rio C, Malani PN. 2019 novel coronavirus—important information for clinicians. JAMA 2020, Feb 5. https://www.ncbi.nlm.nih.gov/pubmed/32022836
  7. Lipsitch M, Swerdlow DL, Finelli L. Defining the epidemiology of Covid-19—studies needed. N Engl J Med 2020. Feb 19. DOI:10.1056/NEJMp2002125. https://www.ncbi.nlm.nih.gov/pubmed/32074416/
  8. Morens DM, Daszak P, Taubenberger JK. Escaping Pandora’s box—another novel coronavirus. N Eng J Med 2020. Feb 26. DOI:10.1056/NEJMp2002106. https://www.nejm.org/doi/full/10.1056/NEJMp2002106
  9. She J, Jiang J, Ye L, et al. 2019 novel coronavirus of pneumonia in Wuhan, China: merging attack and management strategies. Clin Trans Med 2020;9:19. https://clintransmed.springeropen.com/articles/10.1186/s40169-020-00271-z
  10. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497-506. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30183-5/fulltext
  11. Bai Y, Yao L, Wei T, et al. Presumed asymptomatic carrier transmission of COVID-19. JAMA 2020. Feb 21. https://jamanetwork.com/journals/jama/fullarticle/2762028
  12. Pan L, Mu M, Yang P, et al. Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study. Am j Gastroenterol 2020. https://journals.lww.com/ajg/Documents/COVID_Digestive_Symptoms_AJG_Preproof.pdf
Catch these selected key clinical pearls on coronavirus disease (Covid-19)!