Should hepatitis C (HCV) genotype be identified prior to initiation of treatment with sofosbuvir (Sovaldi)?

Hepatitis C Genotype Testing Before Sofosbuvir Treatment

Treatment with pangenotypic regimens, including sofosbuvir/velpatasvir, can be initiated without knowledge of the genotype and subtype with a high probability of success, though genotype determination remains useful in certain clinical scenarios.

Current Recommendations on HCV Genotyping

The European Association for the Study of Liver Disease (EASL) provides clear guidance on HCV genotyping before treatment with sofosbuvir-containing regimens:

• Pangenotypic HCV drug regimens, including sofosbuvir/velpatasvir and glecaprevir/pibrentasvir, can be used to treat individuals without identifying their HCV genotype and subtype, simplifying therapy 1
• However, identifying certain genotypes before starting first-line therapy remains useful and may be required where:
  • Drug procurement or pricing dictates genotype-specific treatment
  • Treatment regimens need optimization 1

Clinical Scenarios Where Genotyping Remains Important

1. Patients with Suspected Resistant Subtypes

• Some HCV subtypes (e.g., 1l, 4r, 3b, 3g, 6u, 6v) harbor natural polymorphisms that confer inherent resistance to NS5A inhibitors 1, 2
• Migrants from regions where these resistant subtypes are prevalent would benefit from genotype and subtype determination 1
• In geographical areas where these resistant subtypes are present, HCV genotype and subtype should be determined whenever possible 1

2. Patients with Cirrhosis

• For patients with genotype 3a and compensated cirrhosis, treatment with sofosbuvir/velpatasvir requires modification:
  • Either 12 weeks of sofosbuvir/velpatasvir plus ribavirin
  • Or 12 weeks of sofosbuvir/velpatasvir/voxilaprevir 1
• Real-world data shows lower SVR rates (95%) in genotype 3 patients with cirrhosis compared to other genotypes 3

3. Treatment Duration Optimization

• For certain genotype-specific regimens like ledipasvir/sofosbuvir, treatment duration can be optimized based on genotype:
  • For genotype 1, treatment duration and efficacy vary by subtype (1a vs 1b) 4
  • For genotypes 4,5, and 6, specific treatment recommendations exist 4

Methods for HCV Genotyping

When genotyping is performed, the following methods are recommended:

• Genotyping/subtyping should use an assay that accurately discriminates subtype 1a from 1b 1
• The most reliable method is sequence analysis of the NS5B or another coding region followed by phylogenetic analysis 1, 2
• Reverse hybridization with line probe assay accurately identifies genotypes 1-6 and subtypes 1a and 1b, but may misclassify uncommon subtypes 1, 2

Practical Approach to HCV Treatment with Sofosbuvir

1. For most patients in resource-rich settings with access to pangenotypic regimens:

   • Treatment can be initiated without genotype determination using sofosbuvir/velpatasvir for 12 weeks 1
   • This approach yields high SVR rates (>95%) across all genotypes 3, 5

2. For patients with suspected or known cirrhosis:

   • Determine genotype before treatment, especially to identify genotype 3
   • For genotype 3 with cirrhosis, consider modified regimens 1, 3

3. For patients from regions with high prevalence of resistant subtypes:

   • Perform genotype and subtype determination when possible 1
   • Consider alternative regimens if resistant subtypes are identified

Potential Pitfalls to Avoid

• Misclassification of subtypes: Using assays based only on 5'-UTR region may not accurately discriminate between subtypes 2
• Overlooking cirrhosis status: Cirrhosis must be identified as some treatment regimens must be adjusted accordingly 1
• Ignoring regional variations: Not considering the possibility of uncommon subtypes in patients from certain geographical regions 1, 2
• Unnecessary testing: Performing genotype testing when using pangenotypic regimens in settings where testing limits access to care 1

In summary, while pangenotypic sofosbuvir-containing regimens can be used without genotype determination in many cases, genotyping remains valuable for optimizing treatment in specific patient populations, particularly those with cirrhosis or from regions with high prevalence of resistant subtypes.