Small case series of 5 patients - Viral load at the end of HCV treatment may not always imply therapeutic failure

Correspondence
The American Journal of Gastroenterology - September 6, 2017

Case series of 5 patients with quantifiable viral loads at the end of treatment who subsequently achieved sustained virologic response (SVR)

Owing to the limitations of this small case series of 5 patients, definitive conclusions regarding the clinical usefulness of end-of-treatment viral loads cannot be made. Although further studies are needed to determine the significance of quantifiable viremia at the end of treatment, the results of this case series demonstrate that this phenomenon does not always imply therapeutic failure.

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Detectable Viremia at the End of Treatment With Direct-Acting Antivirals Can Be Associated With Subsequent Clinical Cure in Patients With Chronic Hepatitis C: A Case Series
Lindsey M. Childs-Kean University of Florida College of Pharmacy, Department of Infectious Diseases, Gainesville, Florida Joseph Hong Antimicrobial Stewardship Program, Bay Pines VA Healthcare System, Bay Pines, Florida

DOI: http://dx.doi.org/10.1053/j.gastro.2017.06.062

We report a case series of 5 patients with quantifiable viral loads at the end of treatment who subsequently achieved sustained virologic response (SVR) with recommended hepatitis C virus (HCV) direct-acting antiviral (DAA) regimens.

All 5 patients had HCV genotype 1a, were male, and none were coinfected with human immunodeficiency virus.

Their ages ranged from 56 to 67 years. All patients had a baseline viral load between 2,000,000 and 7,000,000 IU/mL (Table 1Table 1).

Three of the patients received 8 weeks of ledipasvir/sofosbuvir (LDV/SOF), one received 12 weeks of LDV/SOF, and one received 12 weeks of paritaprevir/ritonavir/ombitasvir/dasabuvir with ribavirin (PrOD+RBV). One patient who received 8 weeks of LDV/SOF and the patient who received PrOD+RBV were African American. One of the patients who received LDV/SOF had possible cirrhosis based on his elevated Fibrosis-4 scores; none of the other patients who received LDV/SOF seemed to have cirrhosis. The patient who received PrOD+RBV had compensated cirrhosis. All of the patients who received LDV/SOF were treatment naïve; the patient who received PrOD+RBV had previously received pegylated interferon monotherapy. Two patients receiving LDV/SOF received concomitant omeprazole therapy and were advised to take it at the same time as LDV/SOF. All patients reported complete adherence to the DAA regimen and tolerated treatment well. Viral loads were measured using the Abbott M2000 RealTime System (Abbott Laboratories, Lake Bluff, IL), which has a lower limit of quantification of 12 IU/mL, lower than that in published phase III trials.^{1, 2, 3}

Table 1 Virologic Trends During and After HCV Treatment

       

Patients	Units	Baseline	Week 2	Week 4	Week 6	Week 8	Week 10	Week 12	SVR4	SVR12
1	IU/mL	2,200,224	—	350	181	70	—	—	23	ND
	Log_HCV	6.34	—	2.54	2.26	1.85	—	—	1.36	ND
2	IU/mL	2,557,795	—	49	63	21	—	—	<12	ND
	Log_HCV	6.41	—	1.69	1.80	1.33	—	—	<1.08	ND
3	IU/mL	3,852,020	—	100	—	51	—	13	ND	ND
	Log_HCV	6.59	—	2	—	1.71	—	1.12	ND	ND
4	IU/mL	5,799,660	1564	486	286	107	—	—	<12	ND
	Log_HCV	6.76	3.19	2.69	2.46	2.03	—	—	<1.08	ND
5	IU/mL	6467,869	3008	780	441	248	56	25	<12	ND
	Log_HCV	6.81	3.48	2.89	2.64	2.39	1.75	1.40	<1.08	ND

HCV, hepatitis C virus; ND, not detected; SVR, sustained virologic response.

There are few data on the impact of end of treatment viremia on achieving SVR with DAAs. Sidharthan et al⁴ assessed the impact of viremia at the end of treatment in predicting SVR. Six patients were identified with quantifiable viremia at end of treatment, five who received 6 weeks of LDV/SOF + GS-9669 and one who received 6 weeks of LDV/SOF + GS-9451. All 6 patients achieved SVR.⁴ In the ION-2 trial (Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed-Dose Combination ± Ribavirin in Treatment-Experienced Subjects With Genotype 1 HCV Infection); 1 patient receiving 12 weeks of LDV/SOF had a viral load of 42 IU/mL at the end of treatment. Subsequent viral loads at weeks 4, 12, and 24 weeks after treatment were undetectable.⁵ To our knowledge, there are no additional published accounts describing the impact of quantifiable viral loads at the end of treatment in patients who have received recommended DAA regimens.

Sidharthan et al⁴ offered theories as to the mechanisms of ongoing viral clearance after completion of HCV treatment, namely, the ability of the patient’s innate immune system to eradicate the remaining residual virus after completing therapy. Another theory involves the detection of residual noninfectious viral particles by the HCV assay. A viral kinetic study by McGivern et al⁶ discovered the production of defective virions in the presence of DAAs, detectable by in vitro assays but incapable of assembly and release as infectious virus.

The patients in our case series were managed before updated treatment duration recommendations for 8-week LDV/SOF regimens based on subgroup analyses. Backus et al⁷ evaluated the real-world efficacy of LDV/SOF in treatment-naïve veterans with HCV genotype 1 infections. Independent factors reducing the likelihood of achieving SVR in patients receiving 8 weeks of treatment included those with quantifiable viral loads at week 4 and African Americans. The impact of race is consistent with findings from a study by Su et al,⁸ which evaluated the association between race and treatment failure rates in those receiving either an 8-week or 12-week treatment course of LDV/SOF monotherapy. Although 1 patient in this case series involved an African American man who achieved SVR after 8 weeks of LDV/SOF, the authors do not currently advocate this practice given the currently available literature. Similarly, 2 patients had quantifiable viremia at week 4 of treatment and, thus, should be given a treatment extension to 12 weeks. However, our case series may provide some assurance of SVR if a patient chooses to self-discontinue treatment after only 8 weeks of LDV/SOF.

Owing to the limitations of this small case series of 5 patients, definitive conclusions regarding the clinical usefulness of end-of-treatment viral loads cannot be made. Although further studies are needed to determine the significance of quantifiable viremia at the end of treatment, the results of this case series demonstrate that this phenomenon does not always imply therapeutic failure.

The American Journal of Gastroenterology - September 6, 2017