15.2 Antiviral drug resistance and combination therapies

Antiviral drug resistance is a major hurdle in fighting viral infections. It occurs when viruses mutate, allowing them to replicate despite medication. This leads to treatment failure, increased healthcare costs, and the spread of resistant strains.

Combination therapies are a powerful tool against resistance. By targeting multiple viral processes, they create a higher barrier to mutation. This approach enhances effectiveness, reduces viral rebound, and improves long-term suppression of infections like HIV and hepatitis C.

Antiviral drug resistance

Definition and implications

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• Antiviral drug resistance develops when viruses replicate despite the presence of inhibitory medications
• Genetic mutations in viral genomes alter drug targets or virus entry mechanisms into host cells
• Drug-resistant viruses continue replicating and progressing disease during antiviral therapy
• Resistant strains limit treatment options for patients and create public health challenges through transmission
• Healthcare costs increase due to more expensive or extended treatments for resistant infections
• Genetic testing monitors drug resistance to guide treatment decisions and develop new antiviral strategies

Clinical impact

• Treatment failure occurs when resistant viruses continue replicating despite ongoing therapy
• Physicians must switch to alternative, potentially less effective or more toxic drug regimens
• Patients may experience prolonged illness, increased complications, or treatment-related side effects
• Resistant strains can spread to others, leading to community-wide challenges in disease control
• Immunocompromised individuals face higher risks from drug-resistant viral infections
• Economic burden increases from extended hospitalizations, additional medications, and lost productivity

Mechanisms of resistance development

Genetic basis of resistance

• Viral replication errors introduce genetic mutations, especially in viruses with high mutation rates (HIV, influenza)
• Antiviral drugs create selection pressure favoring survival of resistant viral variants
• Resistance-conferring mutations alter viral enzymes, proteins, or surface structures
• Some viruses acquire resistance through genetic recombination between different strains
• Compensatory mutations restore viral fitness lost due to primary resistance mutations
• Genetic barrier to resistance varies among antivirals (single vs. multiple mutations required)

Specific resistance mechanisms

• Target site alterations reduce drug binding or efficacy (neuraminidase mutations in influenza)
• Changes in viral surface proteins prevent drug entry or binding (HIV gp120 mutations)
• Increased expression of drug target proteins overwhelms inhibitory effects
• Efflux pumps expel antiviral drugs from infected cells (herpesvirus resistance to acyclovir)
• Alternative metabolic pathways bypass drug-inhibited steps (HIV reverse transcriptase mutations)
• Viral genome segmentation facilitates rapid evolution and resistance (influenza reassortment)

Managing antiviral resistance

Prevention strategies

• Early initiation of potent antiviral therapy suppresses viral replication and mutation opportunities
• Regular viral load monitoring and resistance testing guide treatment decisions
• Combination therapies targeting different viral life cycle stages create higher genetic barriers to resistance
• Patient education and adherence support minimize suboptimal drug levels selecting for resistant variants
• Novel antiviral drug development combats existing resistant strains
• Restricted antiviral use in appropriate clinical scenarios reduces unnecessary selection pressure
• Public health measures prevent community spread of resistant viral strains

Treatment approaches

• Genotypic and phenotypic resistance testing informs drug selection
• Salvage therapy regimens combine multiple active agents for multi-drug resistant viruses
• Drug holidays allow wild-type virus to outcompete resistant strains in some cases
• Dose optimization maximizes drug efficacy while minimizing resistance development
• Cross-resistance patterns guide selection of alternative drug classes
• Therapeutic drug monitoring ensures adequate antiviral concentrations
• Novel delivery methods (long-acting injectables, implants) improve adherence and reduce resistance risk

Combination therapies for viral infections

Benefits of combination approach

• Higher genetic barrier to resistance requires multiple simultaneous mutations
• Synergistic drug effects enhance overall antiviral activity
• Broader coverage against diverse viral populations or quasispecies
• Reduced viral rebound and improved long-term suppression (HIV treatment)
• Potential for shorter treatment durations in some infections (hepatitis C)
• Targeting multiple viral life cycle stages increases effectiveness (influenza)

Challenges and considerations

• Increased risk of drug-drug interactions and adverse effects
• Higher treatment costs create access barriers in resource-limited settings
• Complex regimens potentially reduce patient adherence
• Difficulty in attributing side effects to specific drugs in combinations
• Potential for antagonistic drug interactions reducing overall efficacy
• Need for careful drug selection based on individual patient factors and viral genetics
• Ongoing research focuses on fixed-dose combinations and long-acting formulations to simplify regimens