1. Medicine
  2. Microbiology and Infectious Disease

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

  1. Barnaby Flower  Is a corresponding author
  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
  1. Oxford University Clinical Research Unit, Vietnam
  2. Department of Infectious Disease, Imperial College London, United Kingdom
  3. Hospital for Tropical Diseases, Vietnam
  4. MRC Clinical Trials Unit at UCL, University College London, United Kingdom
  5. Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, United Kingdom
  6. Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Faculty of Tropical Medicine, Thailand
  7. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, United Kingdom
  8. MRC Centre for Global Infectious Disease Analysis, School of Public Health, Imperial College London, United Kingdom
  9. Nuffield Department of Medicine, University of Oxford, United Kingdom
  10. The National Institute for Health Research, Oxford Biomedical Research Centre, University of Oxford, United Kingdom
https://doi.org/10.7554/eLife.81801
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Cite this article
  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
(2023)
Efficacy of ultra-short, response-guided sofosbuvir and daclatasvir therapy for hepatitis C in a single-arm mechanistic pilot study
eLife 12:e81801.
https://doi.org/10.7554/eLife.81801
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16 figures, 6 tables and 2 additional files

Figures

Figure 1
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Study design.

*HCV RNA on days 0, 1, 2, 7, 10, 14, 17, 21, 24, 28, (42, 56), EOT +3, EOT +7, EOT +10, EOT +14, EOT +17, EOT +21, EOT +24, EOT +28s, EOT +56, EOT +84.

Figure 2
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Screening and enrolment.
Figure 3
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Primary outcome, with HCV subtypes (n=51).

All 13 individuals who experience treatment failure with 4-week SOF/DCV were cured with 12-week SOF/DCV retreatment.

Figure 4
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Sofosbuvir RAS and Daclatasvir RAS at baseline, treatment failure, and at start of retreatment in all participants who failed first-line treatment.
Appendix 1—figure 1
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Mean (95% CI) HCV RNA by visit day.
Appendix 1—figure 2
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HCV RNA kinetics in participants treated with 4 weeks SOF/DCV.
Appendix 1—figure 3
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Median HCV RNA (log10), by PCR assay, at different time points in participants treated with 4 weeks SOF/DCV A = Abbott Architect (LLOQ = 12 IU/ml).

C=COBAS AmpliPrep/COBAS TaqMan HCV Quantitative Test, version 2.0 (Roche Molecular Systems, LLOQ = 15 IU/ml)

Appendix 1—figure 4
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Time to viral suppression <LLOQ and eventual treatment outcome.

*No treatment failures in 8 week arm. D28 is the EOT visit for those who received 4 weeks. D56 visit is the EOT visit for those who received 8 weeks.

Appendix 1—figure 5
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Timing of treatment failure (confirmed HCV VL >2000 IU/mL) (n=13).

*Note twice weekly sampling in first 4 weeks after EOT, monthly thereafter.

Appendix 1—figure 6
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All sofosbuvir resistance-associated substitutions at baseline (with treatment outcome).
Appendix 1—figure 7
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Proportion of each subtype with sofosbuvir resistance-associated substitutions at baseline (with treatment outcome).
Appendix 1—figure 8
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All daclatasvir resistance-associated substitutions at baseline (with treatment outcome).
Appendix 1—figure 9
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Proportion of each subtype with daclatasvir resistance-associated substitutions at baseline (with treatment outcome).
Appendix 1—figure 10
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SOF-RAS at baseline (D0), time of virological rebound (R) and start of retreatment (RT_W0) Grey boxes represent missing data.
Appendix 1—figure 11
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DCV-RAS at baseline (D0), time of virological rebound (R) and start of retreatment (RT_W0)Grey boxes represent missing data.
Author response image 1
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Tables

Table 1
Baseline characteristics.
N/ median%/range
Total participants52
Age in years49.5(25.0, 67.0)
Female29(56%)
Body-mass index in kg/m223.3(18.7, 30.6)
Genotype 122(43%)
1a11
1b12 (1 withdrew)
Genotype 627(53%)
6a12
6e10
6h2
6l2
6u1
Genotype 2(m)1
Genotype 4(k)1
Baseline HCV viral load in IU/ml1,932,775(618, 11,200,000)
HCV viral load – log10 IU/ml (range)6.3(2.8, 7.0)
Past medical history:
Illicit drug use4(8%)
Alcohol dependence (historic; current excluded)4(8%)
Diabetes2(4%)
Hypertension7(13%)
Ischaemic heart disease1(2%)
Tuberculosis2(4%)
Current smoker18(35%)
Previous spontaneous clearance of HCV with re-infection2(4%)
Table 2
Treatment outcome.
N/median%/range
Detectable HCV viral load (HCV VL) at day 25096%
 Abbott39/4195%
 COBAS11/11100%
Median (IQR) HCV VL at day 2 in IU/ml269(104, 690)
 Abbott217(101, 690)
 COBAS459(209, 832)
Below threshold—for 4-week therapy34(65%)
 Abbott31(66%)
 COBAS3(60%)
Above threshold—for 8-week therapy18(35%)
 Abbott16(34%)
 COBAS2(40%)
Mean (SD) duration of first-line therapy received in days37(13.7)
Mean (SD) duration of all therapy received in days58(34.2)
Median weeks from enrolment to last visit (range)20(1, 42)
Primary outcome
Outcome available51
SVR12 by intention-to-treat analysis and per protocol analysis38(75% [95% CI 63, 86])
SVR12 by sensitivity analysis (i) [missing results = failure]38(73% [95% CI 61, 85])
SVR12 by post hoc analysis (ii) [G1 and G6 only]37(76% [95% CI 63, 88])
Secondary endpoints
Lack of initial virological response0(0% [97.5% CI 0, 7])
Serious adverse events0(0% [97.5% CI 0, 7])
Grade 3/4 clinical adverse events0(0% [97.5% CI 0, 7])
Non-serious adverse reactions18(35% [95% CI 22, 48])
Adverse events or reactions leading to change in study medication0(0% [97.5% CI 0, 7])

  1. Where not labelled, data presented as n (%; 97.5% confidence interval).

Table 3
Comparison of baseline factors, drugs levels and virological response in individuals failed to achieve SVR12 with 4-week therapy versus those who cured with 4- or 8-week therapy.
4-week cures (n=21)4-week failures (n=13)p8-week cures (n=17)
Host factors
Male (%)62%38%0.1829%
Mean age45480.2355
Mean BMI23230.4024
Median ALT54360.1031
Median AST34280.4433
IFNL4 delG/TT and TT/TT genotypes (rs368234815)71%58%0.4769%
Virus factors
Median D0 HCV VL916,0002,139,2580.204,982,889
 Abbott960,9131,972,8410.474,625,118
 COBAS916,0005,260,0000.404,605,000
D2 VL<LLOQ2/21 (10%)0/13 (0%)0.510%
 Abbott2/18 (11%)0/10 (0%)0.410/13 (0%)
 COBAS0/3 (0%)0/3 (0%)–0/5 (0%)
D7 VL<LLOQ9/21 (43%)1/12 (8%)*0.0540%
 Abbott8/18 (44%)1/9 (11%)0.090/13 (0%)
 COBAS1/3 (33%)0/3 (0%)1.000/5 (0%)
D10 VL<LLOQ9/21 (43%)9/13 (69%)0.176%
 Abbott8/17 (47%)8/10 (80%)0.121/10 (10%)
 COBAS1/4 (25%)1/3 (33%)1.000/6 (0%)
D14 VL<LLOQ14/21 (68%)9/13 (69%)1.0018%
 Abbott11/16 (69%)6/9 (67%)1.001/11 (18%)
 COBAS2/4 (50%)3/4 (75%)1.001/6 (17%)
HCV genotype 110/21 (48%)6/13 (46%)1.00
(vs Gt 6)		6/17 (35%)
1a4/21 (19%)5/13 (38%)0.15
(vs 1b)		2/17 (12%)
1b6/21 (24%)1/13 (8%)4/17 (24%)
HCV genotype 610/21 (48%)6/13 (46%)11/17 (65%)
6a6/21 (29%)2/13 (15%)0.58
(vs. 6e)		4/17 (24%)
6e†3/21 (14%)3/13 (23%)4/17 (24%)
Resistance-associated substitutions
Median (range) SOF-RAS0 (0–1)0 (0–2)0.760 (0–1)
Median (range) DCV-RAS2 (0–2)1 (0–2)0.172 (0–4)
Median (range) SOF- & DCV-RAS combined2 (0–3)2 (1–2)0.122 (0–4)
Drug exposure (n=37) §n=15n=8n=14
Median AUClast, SOF
(h×ng/ml) ‡		2360 (1120–4550)2220 (937–3910)0.9752120
(1430–2610)
Median AUClast GS-331007 (h×ng/ml) ‡11,700 (8420–14,100)15,100 (9240–19,700)0.02314,000
(10,200–17,400)
Median AUClast, DCV (h×ng/mL) ‡13,000 (6800–22,300)13,200 (6630–27,000)0.72814,200
(9210–17,000)

  1. Results presented as median (5th–95th percentile).

  2. *

    n=12, no HCV VL data for one participant’s day 7 visit.

  3. †

    h, l and u subtypes excluded from the table/analysis due to small numbers (≤2).

  4. ‡

    AUClast is the total exposure to the last time point (8 hr for SOF and 24 hr for GS-331007 and DCV).

  5. §

    Complete d0 and d28 data only available for 37 participants.

Appendix 1—table 1
Pharmacokinetic parameters from the naïve-pooled analysis.
SofosbuvirGS-331007Daclatasvir
Day 0Day 28Day 0Day 28Day 0Day 28
Cmax (ng/mL)1,3201,0709881,2301,1701,110
tmax (h)1.001.003.004.003.003.00
t1/2 (h)0.6700.6509.2012.47.318.18
AUClast (h×ng/mL)*1,5501,60010,50014,60011,40012,400
AUCINF (h×ng/mL)*1,5501,60012,70020,40012,80014,400

  1. Cmax is the maximum observed concentration, tmax is the time to reach the maximum concentration, t1/2 is the terminal elimination half-life (calculated using the 3–6 last concentration measurements, depending on drug and day), AUClast is the total exposure to the last time point (8 hours for SOF and 24 hours for GS-331007 and DCV), AUCinf is the total exposure extrapolated to infinity.

  2. *

    Extrapolation based on the last observed concentration measurement.

Appendix 1—table 2
Pharmacokinetic exposure from the individual analysis and pharmacodynamic parameters.
Pharmacokinetics
SofosbuvirGS-331007Daclatasvir
AUClast (h×ng/mL)1,140 (598-2,150)3,430 (2,200-4,720)9,770 (5,080-16,200)
Pharmacodynamics
AUC (days ×IU/mL)252,000 (19,200-1,370,000)
t1/2 (days)2.25 (0.986–5.22)
%ReductionEnrolment-Day199.9 (99.0–100)
%ReductionEnrolment-Day7100 (100–100)

  1. Data is presented as median (5th –95th percentile). AUClast is the total exposure to the last time point (8 hours for SOF and 24 hours for GS-331007 and DCV). AUC14 is the area under the viral load-time curve from enrolment (day 0) to day 14, t1/2 is the terminal viral half-life (estimated using at least three measurements), %ReductionEnrolment-Day1 is the reduction in viral load from enrolment to day 1, %ReductionEnrolment-Day7 is the reduction in viral load from enrolment to day 7.

  2. The half-life could not be determined for one participant due to only one sample above the lower limit of quantification.

Appendix 1—table 3
Pharmacokinetic-pharmacodynamic linear regression analysis.
Viral outcome measurement vs.Sofosbuvir AUClastGS-331007 AUClastDaclatasvir AUClast
Slope (95% CI)pSlope (95% CI)pSlope (95% CI)p-value
Area under the viral load-time curve–157
(−423–109)		0.23916.2
(−74.4–107)		0.719–14.2
(−67.1–38.6)		0.589
Viral elimination half-life1.55×10–4
(–8.70×10–4 - 5.60×10–4)		0.662–3.64×10–5
(–2.74×10–4 - 2.01×10–4)		0.7572.17×10–5
(–1.16×10–4 - 1.60×10–4)		0.751
Relative reduction in viral load at day 11.31×10–6
(–4.54×10–6 - 7.16×10–6)		0.6522.67×10–8
(–1.94×10–6 - 1.99×10–6)		0.9782.81×10–7
(–8.62×10–7 - 1.42×10–6)		0.621
Relative reduction in viral load at day 72.53×10–7
(–2.81×10–7 - 7.86×10–7)		0.3435.09×10–8
(–1.29×10–7 - 2.31×10–7)		0.5691.44*10–8
(–9.11×10–8 - 1.20×10–7)		0.783

  1. 95%CI is the 95% confidence interval around the slop.

Additional files

MDAR checklist
https://cdn.elifesciences.org/articles/81801/elife-81801-mdarchecklist1-v2.docx
Source data 1

Pseudo anonymised HCV RNA data for every participant.

https://cdn.elifesciences.org/articles/81801/elife-81801-data1-v2.xlsx

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  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
(2023)
Efficacy of ultra-short, response-guided sofosbuvir and daclatasvir therapy for hepatitis C in a single-arm mechanistic pilot study
eLife 12:e81801.
https://doi.org/10.7554/eLife.81801