Efficacy of ultra-short, response-guided sofosbuvir and daclatasvir therapy for hepatitis C in a single-arm mechanistic pilot study

  1. Barnaby Flower
  2. Le Manh Hung
  3. Leanne Mccabe
  4. M Azim Ansari
  5. Chau Le Ngoc
  6. Thu Vo Thi
  7. Hang Vu Thi Kim
  8. Phuong Nguyen Thi Ngoc
  9. Le Thanh Phuong
  10. Vo Minh Quang
  11. Thuan Dang Trong
  12. Thao Le Thi
  13. Tran Nguyen Bao
  14. Cherry Kingsley
  15. David Smith
  16. Richard M Hoglund
  17. Joel Tarning
  18. Evelyne Kestelyn
  19. Sarah L Pett
  20. Rogier van Doorn
  21. Jennifer Ilo Van Nuil
  22. Hugo Turner
  23. Guy E Thwaites
  24. Eleanor Barnes
  25. Motiur Rahman
  26. Ann Sarah Walker
  27. Jeremy N Day
  28. Nguyen VV Chau
  29. Graham S Cooke

  • Curated by eLife

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    eLife assessment

    This work provides valuable knowledge to the ongoing research to establish an algorithm to shorten the duration of hepatitis C therapy with direct-acting antivirals. This is an important study that is a nice addition to previous reports evaluating the utility of response-guided therapy for shortening the duration of HCV treatment. Given the disease burden and the high costs of treatment, especially in low-income countries, this is a major goal that was also advocated by the WHO. Although the main objective (shortening therapy to 4 weeks) was not adequately achieved (<90% success rate), the study's results may suggest that re-treatment in case of failure is safe and efficient, although further studies with a larger number of patients are needed for confirmation.

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Abstract

World Health Organization has called for research into predictive factors for selecting persons who could be successfully treated with shorter durations of direct-acting antiviral (DAA) therapy for hepatitis C. We evaluated early virological response as a means of shortening treatment and explored host, viral and pharmacokinetic contributors to treatment outcome.

Methods:

Duration of sofosbuvir and daclatasvir (SOF/DCV) was determined according to day 2 (D2) virologic response for HCV genotype (gt) 1- or 6-infected adults in Vietnam with mild liver disease. Participants received 4- or 8-week treatment according to whether D2 HCV RNA was above or below 500 IU/ml (standard duration is 12 weeks). Primary endpoint was sustained virological response (SVR12). Those failing therapy were retreated with 12 weeks SOF/DCV. Host IFNL4 genotype and viral sequencing was performed at baseline, with repeat viral sequencing if virological rebound was observed. Levels of SOF, its inactive metabolite GS-331007 and DCV were measured on days 0 and 28.

Results:

Of 52 adults enrolled, 34 received 4 weeks SOF/DCV, 17 got 8 weeks and 1 withdrew. SVR12 was achieved in 21/34 (62%) treated for 4 weeks, and 17/17 (100%) treated for 8 weeks. Overall, 38/51 (75%) were cured with first-line treatment (mean duration 37 days). Despite a high prevalence of putative NS5A-inhibitor resistance-associated substitutions (RASs), all first-line treatment failures cured after retreatment (13/13). We found no evidence treatment failure was associated with host IFNL4 genotype, viral subtype, baseline RAS, SOF or DCV levels.

Conclusions:

Shortened SOF/DCV therapy, with retreatment if needed, reduces DAA use in patients with mild liver disease, while maintaining high cure rates. D2 virologic response alone does not adequately predict SVR12 with 4-week treatment.

Funding:

Funded by the Medical Research Council (Grant MR/P025064/1) and The Global Challenges Research 70 Fund (Wellcome Trust Grant 206/296/Z/17/Z).

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  1. Version published to 10.7554/elife.81801 on eLife
  2. eLife

    Author Response

    Reviewer #2 (Public Review):

    This clinical trial is conducted to pursue short course DAA therapy. For an ultra-short course to work, it has to be simple, equally efficacious to established treatments, and requires no additional workup (like genotyping, IL28B, HCV VL determination, etc after initiation of therapy as shown in Liu et al.). This is because our aim is to simplify therapy to treat most people, especially those who are not engaged in care. This work struggles to achieve these goals, as the to the SVR for short-course therapy is unacceptably low. The authors' conclusion that treat short first and then you can treat those who fail again does not appear to achieve these goals, as realistically,it is difficult to re-engage marginalized population from an elimination perspective. The ideal is to treat them in one attempt.

    We would like to clarify that we do not propose treating with 4 weeks and then retreating, because we acknowledge an unacceptable first line cure rate with this approach. We suggest 8 weeks may achieve cure rate of greater than 90% in mild liver disease (18/18 participants with slow virological response were cured with 8 weeks SOF/DCV in this study). Since retreatment with the same drug combination is effective, there is arguably less jeopardy in a regimen with 90% cure rate than previously perceived.

    Reviewer #3 (Public Review):

    This prospective study evaluated the utility of D2 VL determination for response-guided ultra-short (4w) sofosbuvir + daclatasvir treatment of chronic HCV patients (with mild disease) with G1+6. Shortening therapy duration reduces DAA use with a cure rate of 75% overall upon first-line treatment and 100% among retreated patients. In contrast to a previous report in G1b patients that showed a 100% success rate with D2-based 3-week triple therapy, the present study fails to show a good enough yield for a 4w sofosbuvir + daclatasvir regimen among G1+6 patients. Given the small number of patients, additional studies should determine whether a different time point and/or a different viral threshold could be more appropriate indicators to allow a 4-week duration of dual therapy (without a protease inhibitor).

    Strengths:

    A) An important study that is a nice addition to previous reports evaluating the utility of response-guided therapy for shortening the duration of HCV treatment. Given the disease burden and the high costs of treatment, especially in low-income countries, this is a major goal that was also advocated by the WHO.

    B) This study investigates an ultra-short protease-inhibitor-free regimen and therefore complements a previous (positive) RGT study of a 3-week triple regimen.

    C) This study is prospective with careful analyses of ample data, including the evaluation of RAS by gene sequencing. The follow-up was long enough and analyses of viral kinetics were performed. In addition, a detailed analysis of re-treatment outcomes and viral mutations in this population was performed

    D) Although the main objective (shortening therapy to 4 weeks) was not adequately achieved (<90% success rate), the study's results may suggest that re-treatment in case of failure is safe and efficient, although further studies with a higher number of patients are needed for confirmation.

    Limitations:

    A) Relatively small study cohort. Overall, only 34 patients were treated with a 4-week regimen. However, given the results, it seems that this number of patients who achieved only a 75% cure rate, is enough to exclude the use of a D2 RGUT, at least in G1+6 patients treated with sofosbuvir + daclatasvir. On the other hand, even 100% of success rate on 8-week treatment among 17 patients is not really enough to draw firm conclusions on the adequacy of this short regimen among this group of patients. A higher number of patients could better validate this positive result.

    Addressed in discussion. Firstly, it was powered to determine overall cure rate with 4- and 8- weeks treatment, rather than outcomes with each duration. It is possible that we would have seen patients failing 8 weeks therapy with a larger sample, and our cure estimates may therefore be imprecise.

    B) The values chosen for the RGT are arbitrary. The relatively small number of patients could not allow for a more detailed analysis of more appropriate time points and/or viral load thresholds to determine the adequacy of a 4-week of therapy in individual patients. The D2 500IU/ML threshold is based on a small previous phase 2 study on G1b patients treated with a triple-drug regimen, which does not necessarily imply dual therapy (w/o a protease inhibitor) involving patients with a different subtype of the virus. In this context, a control group treated with triple combination therapy (with a protease inhibitor) could be very helpful to the study.

    This was a mechanistic pilot study conducted in Vietnam, where antiviral options are limited. We therefore made a conscious decision to use licensed/available treatments (SOF/DCV) rather than Lau combination which is not WHO-approved.

    C) Is there a particular pattern of viral kinetics to 4w cured patients Vs. failures? Fig 1 (Appendix 1) only shows the means of viral load and the general kinetics for the whole population, but individual plots of viral kinetics are not presented although could potentially be useful. Also, according to the presented data, day 7 VL<LLOQ may be a better indicator for shortening treatment to 4w. A detailed graphical presentation of viral kinetics in these patients could be helpful.

    We have added appendix 1- figure 2 showing HCV RNA kinetics in participants treated with 4 weeks SOF/DCV, with cures (red lines) distinguished from treatment failures. In results section we comment on this that Even though the numbers are small, this helps illustrate that early on-treatment response alone may be of limited value in determining cure with ultra-short therapy.

    D) According to Table 3, no significant differences in the host or viral factors were detected between cured or failures of the 4w regimen. However, the low number of patients makes it very difficult to interpret these data and might miss potential differences between these two groups of patients, emphasizing again the difficulty in drawing firm conclusions from this study. In this context, I wonder whether a regression analysis would better define either viral (subtype, RAS) or host factors that are implicated in a 4w duration success.

    See above.

  3. eLife

    eLife assessment

    This work provides valuable knowledge to the ongoing research to establish an algorithm to shorten the duration of hepatitis C therapy with direct-acting antivirals. This is an important study that is a nice addition to previous reports evaluating the utility of response-guided therapy for shortening the duration of HCV treatment. Given the disease burden and the high costs of treatment, especially in low-income countries, this is a major goal that was also advocated by the WHO. Although the main objective (shortening therapy to 4 weeks) was not adequately achieved (<90% success rate), the study's results may suggest that re-treatment in case of failure is safe and efficient, although further studies with a larger number of patients are needed for confirmation.

  4. eLife

    Reviewer #1 (Public Review):

    Hepatitis C virus (HCV) infection continues to be an enormous global public health problem with over 70 million infected. The advent of all-oral direct-acting antivirals (DAAs) has transformed the landscape of HCV therapy and paved the path to the ambitious World Health Organization (WHO) goal of viral hepatitis elimination by 2030. Research to establish an algorithm to shorten DAA therapy duration while maintaining high cure rates would impact both treatment access and achieving HCV elimination. The current clinical study aimed to examine a response-guided therapy (RGT) algorithm to shorten the standard 12-week sofosbuvir and daclatasvir therapy based on measuring hepatitis C viral load level at day 2 of treatment. The authors managed to complete this study despite severe COVID-19-related restrictions. While the RGT algorithm failed to reach acceptable cure rates under the 4-week treatment arm, the study provides valuable kinetic data to test other RGT approaches. Also, this paper is novel since data on HCV RNA genotype 6 kinetics is lacking.

  5. eLife

    Reviewer #2 (Public Review):

    This clinical trial is conducted to pursue short course DAA therapy. For an ultra-short course to work, it has to be simple, equally efficacious to established treatments, and requires no additional workup (like genotyping, IL28B, HCV VL determination, etc after initiation of therapy as shown in Liu et al.). This is because our aim is to simplify therapy to treat most people, especially those who are not engaged in care.
    This work struggles to achieve these goals, as the to the SVR for short-course therapy is unacceptably low. The authors' conclusion that treat short first and then you can treat those who fail again does not appear to achieve these goals, as realistically, it is difficult to re-engage marginalized population from an elimination perspective. The ideal is to treat them in one attempt.

  6. eLife

    Reviewer #3 (Public Review):

    This prospective study evaluated the utility of D2 VL determination for response-guided ultra-short (4w) sofosbuvir + daclatasvir treatment of chronic HCV patients (with mild disease) with G1+6. Shortening therapy duration reduces DAA use with a cure rate of 75% overall upon first-line treatment and 100% among retreated patients. In contrast to a previous report in G1b patients that showed a 100% success rate with D2-based 3-week triple therapy, the present study fails to show a good enough yield for a 4w sofosbuvir + daclatasvir regimen among G1+6 patients. Given the small number of patients, additional studies should determine whether a different time point and/or a different viral threshold could be more appropriate indicators to allow a 4-week duration of dual therapy (without a protease inhibitor).

    Strengths:
    A. An important study that is a nice addition to previous reports evaluating the utility of response-guided therapy for shortening the duration of HCV treatment. Given the disease burden and the high costs of treatment, especially in low-income countries, this is a major goal that was also advocated by the WHO.
    B. This study investigates an ultra-short protease-inhibitor-free regimen and therefore complements a previous (positive) RGT study of a 3-week triple regimen.
    C. This study is prospective with careful analyses of ample data, including the evaluation of RAS by gene sequencing. The follow-up was long enough and analyses of viral kinetics were performed. In addition, a detailed analysis of re-treatment outcomes and viral mutations in this population was performed
    D. Although the main objective (shortening therapy to 4 weeks) was not adequately achieved (<90% success rate), the study's results may suggest that re-treatment in case of failure is safe and efficient, although further studies with a higher number of patients are needed for confirmation.

    Limitations:
    A. Relatively small study cohort. Overall, only 34 patients were treated with a 4-week regimen. However, given the results, it seems that this number of patients who achieved only a 75% cure rate, is enough to exclude the use of a D2 RGUT, at least in G1+6 patients treated with sofosbuvir + daclatasvir. On the other hand, even 100% of success rate on 8-week treatment among 17 patients is not really enough to draw firm conclusions on the adequacy of this short regimen among this group of patients. A higher number of patients could better validate this positive result.
    B. The values chosen for the RGT are arbitrary. The relatively small number of patients could not allow for a more detailed analysis of more appropriate time points and/or viral load thresholds to determine the adequacy of a 4-week of therapy in individual patients. The D2 500IU/ML threshold is based on a small previous phase 2 study on G1b patients treated with a triple-drug regimen, which does not necessarily imply dual therapy (w/o a protease inhibitor) involving patients with a different subtype of the virus. In this context, a control group treated with triple combination therapy (with a protease inhibitor) could be very helpful to the study.
    C. Is there a particular pattern of viral kinetics to 4w cured patients Vs. failures? Fig 1 (Appendix 1) only shows the means of viral load and the general kinetics for the whole population, but individual plots of viral kinetics are not presented although could potentially be useful. Also, according to the presented data, day 7 VL D. According to Table 3, no significant differences in the host or viral factors were detected between cured or failures of the 4w regimen. However, the low number of patients makes it very difficult to interpret these data and might miss potential differences between these two groups of patients, emphasizing again the difficulty in drawing firm conclusions from this study. In this context, I wonder whether a regression analysis would better define either viral (subtype, RAS) or host factors that are implicated in a 4w duration success.

  7. Version published to 10.1101/2022.08.15.22278752v1 on medRxiv