What are the clinically recommended antiviral medications for common viral infections, including influenza, herpes simplex virus (HSV), varicella-zoster virus (VZV), hepatitis B, hepatitis C, human immunodeficiency virus (HIV), and SARS-CoV-2?

Clinically Recommended Antiviral Medications for Common Viral Infections

For common viral infections requiring antiviral therapy, the primary agents are: oseltamivir/zanamivir for influenza, acyclovir/valacyclovir for HSV/VZV, tenofovir-based regimens for hepatitis B, direct-acting antivirals for hepatitis C, nirmatrelvir/ritonavir for SARS-CoV-2, and combination antiretroviral therapy for HIV. 1

Influenza

Treatment must be initiated within 48 hours of symptom onset for maximum benefit. 1

• Oseltamivir (oral): First-line agent, approved for use even in newborns, effective against both influenza A and B 1
• Zanamivir (inhaled): Alternative agent, effective against influenza A and B, but carries risk of life-threatening bronchospasm 1, 2
• Baloxavir: Newer option evaluated in clinical trials 1
• Amantadine/rimantadine: No longer recommended due to widespread resistance 3, 2

Common pitfall: Do not use antivirals for uncomplicated influenza with symptoms >48 hours duration, as efficacy is not established 1

Herpes Simplex Virus (HSV) and Varicella-Zoster Virus (VZV)

Acyclovir or valacyclovir should be used for prophylaxis in all immunocompromised patients and maintained throughout treatment. 1

• Acyclovir:

  • IV formulation for severe infections including pneumonia 1
  • Oral for prophylaxis and mild-moderate infections 1
  • Mechanism: Competitive substrate for viral DNA polymerase 4, 3

• Valacyclovir:

  • Preferred oral agent due to better bioavailability 1
  • First-line for VZV reactivation 1
  • Prophylaxis should continue throughout malignancy treatment 1

No monitoring is required during prophylactic use. 1

Hepatitis B Virus (HBV)

Tenofovir disoproxil is the preferred first-line agent for chronic hepatitis B in patients ≥12 years of age. 1, 5

• Tenofovir disoproxil: 300 mg daily, no dose adjustment needed for hepatic impairment 1, 5
• Entecavir: Alternative nucleoside analogue, approved from age 2 years 1
• Lamivudine: Available as generic, higher resistance rates 1

Critical warning: All nucleoside analogues for HBV possess anti-HIV activity; screen for HIV before initiating therapy 5. Never stop nucleoside antivirals abruptly during concurrent illness (e.g., COVID-19) to avoid HBV reactivation 6.

Dose adjustments required for renal impairment but not hepatic dysfunction. 1

Hepatitis C Virus (HCV)

Direct-acting antivirals (DAAs) have replaced interferon-based regimens, with 8 agents currently approved representing 38% of all non-HIV antivirals. 1

• Sofosbuvir/velpatasvir: Pan-genotypic regimen, approved from age 12 years 1
• Elbasvir/grazoprevir: Alternative regimen, approved from age 12 years 1
• Glecaprevir/pibrentasvir: Additional pan-genotypic option 1

Most HCV drugs are contraindicated in advanced liver impairment (Child-Pugh C). 1

Significant drug-drug interactions exist due to CYP450 enzyme involvement; always check interactions before prescribing. 1

SARS-CoV-2 (COVID-19)

Nirmatrelvir/ritonavir is the first-line antiviral for non-severe COVID-19 in high-risk patients, demonstrating 39% reduction in hospitalization and 61% reduction in mortality. 6

Treatment Algorithm by Risk and Availability:

First-line: Nirmatrelvir/ritonavir (Paxlovid)

• Dosing: 300 mg nirmatrelvir/100 mg ritonavir orally twice daily for 5 days 6
• Must initiate within 5 days of symptom onset 6
• Mandatory drug interaction screening using Liverpool COVID-19 tool before prescribing 6
• Now has full EMA approval (initially conditional) 1

Second-line: Remdesivir

• IV administration, faster recovery rates particularly in patients with low-flow oxygen requirements and <10 days of symptoms 7, 6
• Preferred for hospitalized patients 7

Third-line: Molnupiravir

• Oral agent showing 6.8% vs 9.7% hospitalization/death rate 7
• Inferior to nirmatrelvir/ritonavir in indirect comparisons 7, 6

Specialized populations: High-titer convalescent plasma or inhaled interferon beta-1a for immunocompromised patients with hematological malignancies when standard antivirals unavailable 7, 6

Treatments to AVOID: Hydroxychloroquine, lopinavir/ritonavir alone, ribavirin alone—no benefit demonstrated 6

Critical pitfall: The 5-day treatment window is narrow; emphasize early testing and rapid treatment initiation 6

Cytomegalovirus (CMV)

Valganciclovir is recommended for CMV reactivation in immunocompromised patients with preserved bone marrow function. 1

• Valganciclovir: Oral agent for treatment 1
• Ganciclovir: IV alternative 1
• Foscarnet: Alternative for resistant cases 1
• Letermovir: Approved specifically for CMV prophylaxis (not treatment), particularly post-allogeneic transplant 1
• Maribavir: Approved for CMV treatment 1

Baseline CMV IgG/IgM status should be collected before starting immunosuppressive therapy. 1

Respiratory Syncytial Virus (RSV)

Oral ribavirin should be strongly considered in moderately to severely immunocompromised patients, particularly HSCT recipients, solid organ transplant recipients, and those on active chemotherapy. 8

• Not recommended for immunocompetent adults (D-I recommendation) 1, 8
• Dosing for immunocompromised: 600-800 mg twice daily orally, or 2g aerosolized for 2 hours every 8 hours 8
• Combination with IVIG (500 mg/kg every other day) recommended for allogeneic HSCT patients with RSV pneumonia 8
• Monitor for hemolytic anemia, abnormal liver function, and declining renal function 8

Common pitfall: Do not use palivizumab for treatment—it has no therapeutic benefit and is only approved for prophylaxis 8

Human Immunodeficiency Virus (HIV)

While 43 HIV drugs exist and represent the majority of approved antivirals, specific HIV treatment regimens are beyond the scope of this general antiviral overview 1. All HIV patients require combination antiretroviral therapy (cART) with at least three agents from different classes. 5

Critical cross-consideration: Many HBV nucleoside analogues (tenofovir, lamivudine, entecavir) possess anti-HIV activity; always screen for HIV before initiating HBV therapy to avoid inadvertent HIV monotherapy and resistance development 5.

Epstein-Barr Virus (EBV)

Rituximab is the treatment option for EBV reactivation, with evidence supporting prophylactic use post-allogeneic HSCT. 1

• Routine EBV DNA monitoring not recommended unless persistent fever and fatigue suggest reactivation 1

Key Drug-Drug Interaction Considerations

Many antivirals are CYP450 substrates, inhibitors, or inducers, particularly those for HCV, CMV, SARS-CoV-2, and poxviruses. 1

• Nirmatrelvir/ritonavir has extensive interactions requiring mandatory screening 6
• HCV direct-acting antivirals require careful review of concomitant medications 1
• Tenofovir interacts with didanosine, atazanavir, darunavir, lopinavir/ritonavir, and HCV antivirals 5

Renal and Hepatic Dosing Adjustments

Most antivirals require dose adjustment for renal impairment, while HCV drugs are contraindicated in advanced liver disease. 1

• HBV drugs: No hepatic adjustment needed 1
• HCV drugs: Avoid in Child-Pugh C cirrhosis 1
• Tenofovir: Reduce frequency with CrCl <50 mL/min 5

Pediatric Considerations

Most HBV and HCV drugs are approved for children, with minimum ages ranging from 2-12 years depending on the agent. 1

• Oseltamivir: Approved in newborns 1
• Entecavir and tenofovir: From age 2 years 1
• CMV and hepatitis D drugs: Not approved for children 1