What is the current medical understanding on the use of Ivermectin, Hydroxychloroquine (Plaquenil), and Paxlovid (Nirmatrelvir/Ritonavir) in treating Covid-19?

Current Evidence on Ivermectin, Hydroxychloroquine, and Paxlovid for COVID-19 Treatment

Direct Answer

Do not use Ivermectin or Hydroxychloroquine for COVID-19 treatment in any setting—both are ineffective and Hydroxychloroquine may cause harm—while Paxlovid (nirmatrelvir/ritonavir) should be used for high-risk, unvaccinated outpatients with mild COVID-19 within 5 days of symptom onset.

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Hydroxychloroquine (Plaquenil)

Strong Recommendation Against Use

Hydroxychloroquine should be avoided for treating any stage of COVID-19 infection since it provides no additional benefit to standard care and could worsen prognosis, particularly when co-prescribed with azithromycin. 1

• The EULAR guidelines explicitly state that hydroxychloroquine should be avoided at all disease stages based on level 2 evidence 1
• In hospitalized patients, hydroxychloroquine was associated with increased mortality (OR 3.3,95%CI 1.1-9.6, p=0.03) in a Brazilian single-center study 2
• The combination of hydroxychloroquine and ivermectin resulted in the highest mortality rate (35.3%) compared to no treatment (13.6%) 2

Safety Concerns

• Risk of cardiac arrhythmias increases when combined with azithromycin 1
• May result in harmful effects particularly in more severe patients 1

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Ivermectin

Strong Recommendation Against Use

The IDSA recommends against ivermectin for ambulatory COVID-19 patients (strong recommendation, moderate certainty) and suggests against it for hospitalized patients (conditional recommendation, very low certainty). 1

Why Ivermectin Does Not Work

• In vitro activity against SARS-CoV-2 requires concentrations considerably higher than achievable in human plasma and lung tissue 1, 3
• The IC50 concentrations needed are not reached with standard human dosing 1
• Despite theoretical anti-inflammatory mechanisms, clinical trials showed no consistent benefit 3

Evidence from Clinical Trials

For hospitalized patients: 1

• No reduction in mortality (very low certainty evidence)
• No reduction in need for mechanical ventilation (very low certainty evidence)
• No improvement in clinical status (low certainty evidence)
• Only one study showed potential viral clearance benefit, but this was not replicated 1

For outpatient treatment: 1

• No reduction in mortality (very low certainty evidence)
• No reduction in need for mechanical ventilation (very low certainty evidence)
• No effect on symptom resolution (low certainty evidence)
• No reduction in hospital admissions 1

Systematic Review Findings

• A 2021 Cochrane review concluded that reliable evidence does not support ivermectin use for treatment or prevention of COVID-19 outside well-designed trials 4
• A 2024 systematic review of phase III RCTs found that ivermectin showed no treatment benefit despite mechanistic plausibility 5

Resource Considerations

• Using ivermectin diverts attention and resources away from proven effective treatments 1
• May contribute to drug shortages for helminth control programs where ivermectin is genuinely indicated 1
• In strongyloidiasis-endemic areas, presumptive ivermectin treatment may be appropriate for COVID-19 patients receiving corticosteroids (for helminth infection, not COVID-19) 1

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Paxlovid (Nirmatrelvir/Ritonavir)

FDA-Approved Indication

Paxlovid is FDA-approved for treatment of mild-to-moderate COVID-19 in adults at high risk for progression to severe disease, including hospitalization or death. 6

When to Use Paxlovid

Initiate treatment as soon as possible after COVID-19 diagnosis and within 5 days of symptom onset. 6

Dosing Regimen

Standard dose: 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet), all three tablets taken together twice daily for 5 days 6

Dose Adjustments for Renal Impairment 6

Moderate renal impairment (eGFR 30-59 mL/min):

• 150 mg nirmatrelvir + 100 mg ritonavir twice daily for 5 days

Severe renal impairment (eGFR <30 mL/min) including hemodialysis:

• Day 1: 300 mg nirmatrelvir + 100 mg ritonavir once
• Days 2-5: 150 mg nirmatrelvir + 100 mg ritonavir once daily
• Administer after hemodialysis on dialysis days

Severe hepatic impairment (Child-Pugh Class C): Not recommended 6

Efficacy Evidence

For unvaccinated, high-risk outpatients with mild COVID-19: 7

• May reduce all-cause mortality at 28 days (RR 0.04,95% CI 0.00-0.68; low-certainty evidence)
• May reduce hospital admission or death within 28 days (RR 0.13,95% CI 0.07-0.27; low-certainty evidence)
• Estimated absolute effect: 61 admissions or deaths per 1000 with placebo vs. 8 per 1000 with Paxlovid 7

Safety Profile 7

• May reduce serious adverse events (RR 0.24,95% CI 0.15-0.41; low-certainty evidence)
• Probably has little effect on treatment-emergent adverse events overall (moderate-certainty evidence)
• Probably increases treatment-related adverse events such as dysgeusia (altered taste) and diarrhea (RR 2.06; moderate-certainty evidence)
• Probably decreases discontinuation due to adverse events (RR 0.49; moderate-certainty evidence)

Critical Drug Interaction Warning 6

BOXED WARNING: Paxlovid includes ritonavir, a strong CYP3A inhibitor, which may lead to severe, life-threatening, or fatal drug interactions. 6

Before prescribing: 6

1. Review ALL patient medications to assess potential drug-drug interactions with strong CYP3A inhibitors
2. Determine if concomitant medications require dose adjustment, interruption, or additional monitoring
3. Consider benefit of reducing hospitalization/death versus risk of drug interactions for each individual patient

Contraindicated medications: 6

• Drugs highly dependent on CYP3A4 for clearance where elevated concentrations cause serious/life-threatening reactions
• Potent CYP3A inducers that may reduce nirmatrelvir/ritonavir concentrations and cause loss of virologic response

Limitations

• Not approved for pre-exposure or post-exposure prophylaxis 6
• Evidence limited to unvaccinated patients without previous SARS-CoV-2 infection 7
• No evidence available for hospitalized patients with moderate-to-severe disease 7
• Trial excluded patients on medications highly dependent on CYP3A4 7

Administration Details 6

• Take with or without food
• Administer at approximately the same time each day
• Nirmatrelvir must be co-administered with ritonavir (cannot use nirmatrelvir alone)

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Clinical Algorithm for COVID-19 Treatment Selection

Step 1: Assess patient setting and disease severity

• Outpatient with mild disease → Consider Paxlovid if high-risk
• Hospitalized requiring oxygen → Use corticosteroids (dexamethasone); consider tocilizumab or baricitinib 1
• Hospitalized without oxygen needs → No immunomodulatory therapy indicated 1

Step 2: If outpatient with mild disease, assess Paxlovid eligibility

• High risk for progression? (unvaccinated, comorbidities)
• Symptom onset ≤5 days?
• Review ALL medications for CYP3A4 interactions
• Check renal function (adjust dose if eGFR <60)
• Check hepatic function (avoid if Child-Pugh C)

Step 3: Never use

• Hydroxychloroquine (any setting, any severity) 1
• Ivermectin (any setting, any severity) 1