Your SlideShare is downloading. ×
0
Management of HCV in the Correctional Setting William M. Cassidy, MD LSU Health Science Center Baton Rouge, La
Hepatitis C Natural History <ul><li>Variable </li></ul><ul><li>Complications of HCV result from cirrhosis </li></ul>
Question <ul><li>Do all HCV patient develop cirrhosis </li></ul><ul><li>Can HCV be non-progressive </li></ul><ul><li>If so...
Natural History of HCV <ul><li>…chronic hepatitis C is a progressive fibrotic disease… </li></ul><ul><li>Progression from ...
Staging of Fibrosis on Liver Biopsy
Histologic Progression of HCV Normal Mild Chronic Hepatitis Moderate Chronic Hepatitis Cirrhosis II-8
Modeling of Liver Fibrosis  in Chronic Hepatitis C   n=1157 patients Rapid progressors Intermediate progressors Slow progr...
Fibrosis Index <ul><li>Stage of fibrosis seen on liver biopsy </li></ul><ul><li># years infected </li></ul>
Twelve-year Follow-up of 154 Patients with HCV Compensated Cirrhosis Sangiovanni et al. EASL Meeting, Madrid 18-21 April 2...
Ideally <ul><li>Treat first those with histologically aggressive HCV. </li></ul>Goal of Treating Prevent cirrhosis Not eli...
Approach to Treatment of Chronic Hepatitis C on the Basis of  Histologic Findings <ul><li>Young patients:  </li></ul><ul><...
Sources of Infection for Persons With Hepatitis C Sexual 15% Other * 1% Unknown 9% Injection drug use 60% * Nosocomial; ia...
Effect of Adherence on SVR Following PEG-IFN  and RBV Therapy in HCV Genotype 1 Patients Both Doses   80% RBV Dose <80%; ...
Adherence During First 12 Wks of PEG-IFN   -2b + RBV Therapy Affects Early Virologic Response Both Doses  80% RBV Dose <...
Adherence: Take-home Messages <ul><li>Adherence critical for SVR in patients with genotype 1, but role in genotype 2 and 3...
SVR and Weight in African Americans Slide courtesy of Jacobson adapted  from Jacobson IM et al.  Hepatology . 2004; 40 (su...
Shiffman ML et al, Hepatology 2005;42:217A PEG IFN + RBV 800-1400  PEG IFN +  RBV 800-1400 + Epo PEG IFN + RBV 1000-1600 +...
Optimizing Therapy <ul><li>RBV dose is important determinant of SVR </li></ul><ul><li>Higher doses have benefit in  “more ...
HCV: Tailoring Duration of Therapy
Patterns of  Virologic Response
PEG-IFNs Viral Load Decrease (log copies/mL) ETR SVR 0 72 Rapid Viral Response (RVR) 4 48 Viral RNA (–) 0 Wks of Therapy R...
PEG-IFNs ETR SVR 72 “ Complete” Early Viral Response (EVR) 4 48 Viral RNA (–) 0 12 Wks of Therapy Viral Load Decrease (log...
PEG-IFNs ETR SVR 72 4 48 Viral RNA (–) 0 12 24 ≥ 2 log drop but HCV RNA (+) Wks of Therapy “ Partial” Early Viral Response...
Rationale for Evaluating  HCV Antiviral Therapy Early <ul><li>Identify patients in whom therapy should be truncated </li><...
Patients With a Virologic Response (%) HCV RNA Status Week 4   Negative  ≥ 2 log     <2 log     ≥ 2 log      <2 log   ...
Shorter Treatment Duration for HCV-1 and Rapid Virologic Response (RVR) <ul><li>366 treatment naïve HCV-1 and HCV-4 pts re...
Rapid Virologic Response (RVR) of PEG-IFN alfa-2b/RBV Treatment Predicts SVR after 24 Weeks in Genotype 1 CHC Patients 24 ...
RVR of PEG-IFN α -2a /RBV  in Genotype 1 Patients  Patients (%) 17/18 32/33 29/40 51/55 n = 16/18 29/33 29/40 50/55 24-LD*...
RVR of PEG-IFN α -2a /RBV in Genotype 1 Patients EOT SVR *24 and 48 indicate treatment duration in wks; LD indicates 800 m...
<ul><li>Extended  Treatment Duration  in HCV Patients  with Genotype 1 </li></ul>
48 vs 72 Wks of PEG-IFN α -2a  & RBV Tx Sanchez-Tapias JM et al.  Hepatology  2004;40:218A (Abstract # 126). n=165 n=162 P...
48 vs 72 Wks of PEG-IFN and RBV Tx n=231 n=225 27% Relapse 18% Relapse HCV RNA Negative (%) PEG-IFN   -2a 180   g/wk + R...
Prolonging Therapy May Decrease  Relapse in Late Responders 81% N = 456 G1 patients PEG-IFN   -2a + RBV 800 mg/day 48 vs ...
Extended Duration of Treatment for HCV-1 <ul><li>There are reduced relapse rates with prolonged duration of treatment for ...
Genotypes 2 and 3 Is 12-16 Wks  of Therapy Adequate?
Shorter Treatment for HCV Genotypes 2 & 3? N = 122 Peg-IFN   -2b 1.5   g/kg/wk  + Riba 800-1400 mg/d PCR(-) at 4 & 8 wee...
Peg-IFN   -2a (180   g/wk) + Ribavirin 800-1200 mg/day Untreated Genotype 2 or 3  (N=153) *HCV RNA was assessed after 4 ...
Shorter Treatment for HCV Genotypes 2 & 3? N = 213 Peg-IFN   -2b 1   g/kg/wk  + Riba 1,000-1,200 mg/d PCR(-) at 4   week...
HCV Genotype 2 and 3 With High Viral Load: Higher Relapse Rate? Zeuzem S et al.  Hepatology  2004;40:993-999.   Genotype 2...
Viral Factors in Hepatic Steatosis <ul><li>Chronic Hepatitis C: N=755 </li></ul><ul><li>Steatosis: 41.7% </li></ul><ul><li...
Host Factors and Hepatic Steatosis Obese Patients (  30 kg/m 2 ;  n=37) Non-obese Patients (<30 kg/m 2 ; n=78) Present No...
HCV and Steatosis:  Impact on Fibrosis  (cont) Adinolfi et al.  Hepatology  2001 0.00 0.05 0.10 0.15 0.20 0.25 Rate of Pro...
Obese Patients (  30 kg/m 2 ; n=40) Non-obese Patients (<30 kg/m 2 ; n=88) Moderate to Severe None to Mild Cesario K et a...
The Impact of Superimposed Steatosis or  Its Risk Factors on HCV Treatment <ul><li>Obesity may increase the volume of dist...
The Impact of Superimposed Steatosis or  Its Risk Factors on HCV induced liver disease <ul><li>Hepatitis C and steatosis (...
Upcoming SlideShare
Loading in...5
×

4 IDCR NCCHC Cassidy HCV 2006.ppt

242

Published on

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
242
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
9
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide
  • Slide II-10 Staging of Chronic Hepatitis A numeric grading system, the histologic activity index or Knodell’s score, has been developed in an effort to standardize the evaluation of liver biopsies. This provides an index of the extent of disease ranging from zero to 22, calculated as the sum of scores for each category. However, the extent of fibrosis is likely to be the most important finding in patients with chronic hepatitis C. In an alternative system, separate scores are given for the inflammatory and fibrotic components of the disease. Thomas DL, Lemon SM, Infectious Diseases and Their Etiologic Agents, Chapter 143, Hepatitis C Slide by Eliot Godofsky, MD
  • Slide II-8 Histologic Progression of HCV This slide illustrates the histologic progression of chronic HCV infection from a disease-free state, through mild and moderate chronic hepatitis, and ultimately cirrhosis. Slide Courtesy of W. Bennett, MD.
  • Slide III-38 Approach to Treatment of Chronic Hepatitis C on the Basis of Histologic Findings Relatively young patients who have aggressive disease that is confirmed histologically are most likely to benefit from therapy, since progression to cirrhosis is very likely. In addition, young patients who have only mild or moderate disease should be encouraged to undergo treatment because they will likely experience progression of the disease during their lifetime as well. The response to therapy is likely to be best when disease is histologically mild, rather than waiting until the disease becomes more severe. In contrast, older patients who have a shorter remaining life span may die with chronic hepatitis C rather than from chronic hepatitis C; as a consequence, in these patients, treatment may not be indicated. Management of Hepatitis C. NIH Consensus Statement 1997 March 24-26; 15 (3).
  • 2005
  • CHECKED DATA IS CORRECT, COMING FROM FULL ARTICLE Ferenci P et al. J Hepatol . 2005;43:425
  • Transcript of "4 IDCR NCCHC Cassidy HCV 2006.ppt"

    1. 1. Management of HCV in the Correctional Setting William M. Cassidy, MD LSU Health Science Center Baton Rouge, La
    2. 2. Hepatitis C Natural History <ul><li>Variable </li></ul><ul><li>Complications of HCV result from cirrhosis </li></ul>
    3. 3. Question <ul><li>Do all HCV patient develop cirrhosis </li></ul><ul><li>Can HCV be non-progressive </li></ul><ul><li>If so, can liver histology differentiate progressive & non-progressive disease </li></ul><ul><li>Can Natural History impact treatment decisions </li></ul>
    4. 4. Natural History of HCV <ul><li>…chronic hepatitis C is a progressive fibrotic disease… </li></ul><ul><li>Progression from stage 1 to stage 4 was almost linear according to time. </li></ul><ul><li>Rate of fibrosis progression was not normally distributed. There are at least 3 major populations: slow, intermediate and rapid fibrosers. </li></ul>Poynard T, Bedossa P, Opolon. Natural History of liver fibrosis progression in patients with chronic hepatitis C. Lancet 1997;349:825-832
    5. 5. Staging of Fibrosis on Liver Biopsy
    6. 6. Histologic Progression of HCV Normal Mild Chronic Hepatitis Moderate Chronic Hepatitis Cirrhosis II-8
    7. 7. Modeling of Liver Fibrosis in Chronic Hepatitis C n=1157 patients Rapid progressors Intermediate progressors Slow progressors Poynard et al, Hepatology 1999
    8. 8. Fibrosis Index <ul><li>Stage of fibrosis seen on liver biopsy </li></ul><ul><li># years infected </li></ul>
    9. 9. Twelve-year Follow-up of 154 Patients with HCV Compensated Cirrhosis Sangiovanni et al. EASL Meeting, Madrid 18-21 April 2002 3.0% 44 (28%) Death 3.3% 48 (31%) Hepatocellular carcinoma 1.0% 15 (10%) GI bleeding 1.4% 21 (14%) Jaundice 2.7% 39 (25%) Ascites 3.7% 51 (33%) Clinical decompensation Mean Incidence Patients
    10. 10. Ideally <ul><li>Treat first those with histologically aggressive HCV. </li></ul>Goal of Treating Prevent cirrhosis Not elimination of infection per se.
    11. 11. Approach to Treatment of Chronic Hepatitis C on the Basis of Histologic Findings <ul><li>Young patients: </li></ul><ul><ul><li>aggressive disease - treatment indicated </li></ul></ul><ul><ul><li>mild-to-moderate disease - treatment encouraged </li></ul></ul><ul><li>Patients with stage 0 or stage 1 </li></ul><ul><ul><li>treatment can be safely deferred </li></ul></ul>III-38 Management of Hepatitis C. NIH Consensus Statement..
    12. 12. Sources of Infection for Persons With Hepatitis C Sexual 15% Other * 1% Unknown 9% Injection drug use 60% * Nosocomial; iatrogenic; Perinatal Adapted from Hepatitis Slide Kit http:// www.cdc.gov/ncidod/diseases/hepatitis/slideset . Accessed 07/21/05. Transfusion 10% (before screening) Occupational 4%
    13. 13. Effect of Adherence on SVR Following PEG-IFN and RBV Therapy in HCV Genotype 1 Patients Both Doses  80% RBV Dose <80%; PEG Dose  80% Both Doses <80% Treatment Factor PEG Dose <80%; RBV Dose  80% Ferenci P et al. J Hepatol . 2005;43:425-433. SVR (%) All Patients n=208 n=146 n=40 n=15 n=7 P =0.0143 P =0.0064 PEG-IFN  -2a 180  g qwk + RBV 1000-1200 mg/day
    14. 14. Adherence During First 12 Wks of PEG-IFN  -2b + RBV Therapy Affects Early Virologic Response Both Doses  80% RBV Dose <80%; PEG Dose  80% Both Doses <80% Treatment Factor PEG Dose <80%; RBV Dose  80% Davis GL et al. Hepatology 2003;38:645-652. 80% 70% 60% 33% <80%  80% 0% 50% 75% Chance of EVR (%) 25% 100% n=324 n=38 n=3 n=15 PEG-IFN  -2b Start Dose: 1.5  g/kg Each Wk RBV Start Dose: 800 mg/d
    15. 15. Adherence: Take-home Messages <ul><li>Adherence critical for SVR in patients with genotype 1, but role in genotype 2 and 3 less clear </li></ul><ul><ul><li>Discontinuations have major impact on SVR </li></ul></ul><ul><li>Adherence in first 12 wks of treatment affects EVR </li></ul><ul><ul><li>Data do not show a significant negative impact of late dose reductions (after 12-24 wks) </li></ul></ul><ul><li>Negative impact of drug reductions on EVR and SVR are based upon protocol-driven modifications </li></ul><ul><ul><li>Impact of smaller and/or temporary dose reductions on EVR/SVR not studied </li></ul></ul>
    16. 16. SVR and Weight in African Americans Slide courtesy of Jacobson adapted from Jacobson IM et al. Hepatology . 2004; 40 (suppl 1):217A. Abstract 125. Patients Achieving SVR (%) Overall SVR: 10% FD vs 21% WBD, P=0.004 9/77 7/81 2/30 8/62 18/80 10/32
    17. 17. Shiffman ML et al, Hepatology 2005;42:217A PEG IFN + RBV 800-1400 PEG IFN + RBV 800-1400 + Epo PEG IFN + RBV 1000-1600 + Epo Higher Than Conventional RBV Doses May Be More Effective <ul><li>Treatment naïve patients with genotype 1 </li></ul><ul><li>n=146 </li></ul><ul><li>PEG 2b 1.5 ug/kg + RBV + epo </li></ul>19% 49% 29% %SVR
    18. 18. Optimizing Therapy <ul><li>RBV dose is important determinant of SVR </li></ul><ul><li>Higher doses have benefit in “more difficult to treat” populations </li></ul><ul><ul><li>Genotype 1 </li></ul></ul><ul><ul><li>African-Americans </li></ul></ul><ul><ul><li>Overweight </li></ul></ul><ul><li>Dose-related anemia </li></ul><ul><ul><li>Growth factors use appear important in </li></ul></ul><ul><ul><li>higher dose protocols </li></ul></ul><ul><ul><li>Related to renal clearance </li></ul></ul>
    19. 19. HCV: Tailoring Duration of Therapy
    20. 20. Patterns of Virologic Response
    21. 21. PEG-IFNs Viral Load Decrease (log copies/mL) ETR SVR 0 72 Rapid Viral Response (RVR) 4 48 Viral RNA (–) 0 Wks of Therapy Rapid Viral Response (RVR) as a Predictor of SVR
    22. 22. PEG-IFNs ETR SVR 72 “ Complete” Early Viral Response (EVR) 4 48 Viral RNA (–) 0 12 Wks of Therapy Viral Load Decrease (log copies/mL) 0 “ Complete” Early Viral Response, (EVR) as a Predictor of SVR
    23. 23. PEG-IFNs ETR SVR 72 4 48 Viral RNA (–) 0 12 24 ≥ 2 log drop but HCV RNA (+) Wks of Therapy “ Partial” Early Viral Response (EVR) Viral Load Decrease (log copies/mL) 0 “ Partial” Early Viral Response, (EVR) as a Predictor of SVR
    24. 24. Rationale for Evaluating HCV Antiviral Therapy Early <ul><li>Identify patients in whom therapy should be truncated </li></ul><ul><li>Increase chance of SVR with prolongation of therapy in slow responders </li></ul><ul><li>Identify nonresponders and discontinue therapy: </li></ul><ul><ul><li>Avoids additional morbidity in those who will not respond </li></ul></ul><ul><ul><li>Reduces cost </li></ul></ul>Goal
    25. 25. Patients With a Virologic Response (%) HCV RNA Status Week 4 Negative ≥ 2 log  <2 log  ≥ 2 log  <2 log  Week 12 Negative Negative Negative ≥ 2 log  ≥ 2 log  Week 24 Negative Negative Negative Negative Negative Rates of Viral Clearance Predicts SVR PEG-IFN/RBV PEG-IFN  -2a 180  g + RBV 1000 – 1200 mg 91 72 60 48 43 0 20 40 60 80 100 Ferenci P et al. J Hepatol . 2005;43:425.
    26. 26. Shorter Treatment Duration for HCV-1 and Rapid Virologic Response (RVR) <ul><li>366 treatment naïve HCV-1 and HCV-4 pts received standard PEG + RBV </li></ul><ul><li>79 (22%) W4 HCV RNA – patients received a total of 24 wks of therapy </li></ul>Ferenci et al. Hepatology 2005;42(suppl 1):218A. 24 wks may suffice for HCV-1 with LVL and early fibrosis if RVR PEG-IFN 180  g/wk plus RBV 1,000-1,200 mg/day
    27. 27. Rapid Virologic Response (RVR) of PEG-IFN alfa-2b/RBV Treatment Predicts SVR after 24 Weeks in Genotype 1 CHC Patients 24 Wks Tx Zeuzem S, et al. Journal of Hepatology . 2006; 44:97-103. Patients (%) Week at which patient was first RNA negative.
    28. 28. RVR of PEG-IFN α -2a /RBV in Genotype 1 Patients Patients (%) 17/18 32/33 29/40 51/55 n = 16/18 29/33 29/40 50/55 24-LD* 24-SD* 48-LD* 48-SD* EOT SVR *24 and 48 indicate treatment duration in wks; LD indicates 800 mg/day of RBV; SD indicates 1000-1200 mg/day of RBV. Jensen D et al. Hepatology 2006(in press). Patients With an RVR at Wk 4
    29. 29. RVR of PEG-IFN α -2a /RBV in Genotype 1 Patients EOT SVR *24 and 48 indicate treatment duration in wks; LD indicates 800 mg/day of RBV; SD indicates 1000-1200 mg/day of RBV. Jensen D et al. Hepatology 2006(in press). n = 116/208 133/210 13/81 19/84 72/208 92/210 59/84 51/81 Patients Without an RVR at Wk 4 Patients (%) 24-LD* 24-SD* 48-LD* 48-SD*
    30. 30. <ul><li>Extended Treatment Duration in HCV Patients with Genotype 1 </li></ul>
    31. 31. 48 vs 72 Wks of PEG-IFN α -2a & RBV Tx Sanchez-Tapias JM et al. Hepatology 2004;40:218A (Abstract # 126). n=165 n=162 P =0.0144 48% Relapse 13% Relapse HCV RNA Negative (%) 90% of Patients HCV-1
    32. 32. 48 vs 72 Wks of PEG-IFN and RBV Tx n=231 n=225 27% Relapse 18% Relapse HCV RNA Negative (%) PEG-IFN  -2a 180  g/wk + RBV 800 mg/day. Berg T et al. Hepatology 2004;40:238A (Abstract # 169). All Patients HCV-1
    33. 33. Prolonging Therapy May Decrease Relapse in Late Responders 81% N = 456 G1 patients PEG-IFN  -2a + RBV 800 mg/day 48 vs 72 wks Week 12 (+) 48 weeks Berg et al. Hepatology. 2004;40:238A. Abstract No. 169 . (+) HCV RNA positive % relapse 44% Week 12 (+) 72 weeks
    34. 34. Extended Duration of Treatment for HCV-1 <ul><li>There are reduced relapse rates with prolonged duration of treatment for patients with chronic HCV and HCV-1 </li></ul><ul><li>Sanchez-Tapias et al. used a low and fixed dose RBV </li></ul><ul><li>Berg et al. only found benefit in a subgroup of patients </li></ul><ul><li>Slow responders may respond to prolonged duration </li></ul>Conclusions
    35. 35. Genotypes 2 and 3 Is 12-16 Wks of Therapy Adequate?
    36. 36. Shorter Treatment for HCV Genotypes 2 & 3? N = 122 Peg-IFN  -2b 1.5  g/kg/wk + Riba 800-1400 mg/d PCR(-) at 4 & 8 weeks? 95 (78%) YES NO 27 (22%) Treated x 14 wk SVR 90% Treated x 24 wk SVR 56% h
    37. 37. Peg-IFN  -2a (180  g/wk) + Ribavirin 800-1200 mg/day Untreated Genotype 2 or 3 (N=153) *HCV RNA was assessed after 4 weeks with a lower limit of detection of 600 IU/mL. Von Wagner M et al. Gastroenterology 2005;129:522-527 16 vs 24 Weeks of Peg-IFN/RBV in Genotype 2 or 3 HCV Patients Wk 4 HCV RNA (-)* Wk 4 HCV RNA (+)* 16 wks (n=71) 24 wks (n=68) 24 wks (n=14) Randomize SVR 36% SVR 80% SVR 82%
    38. 38. Shorter Treatment for HCV Genotypes 2 & 3? N = 213 Peg-IFN  -2b 1  g/kg/wk + Riba 1,000-1,200 mg/d PCR(-) at 4 weeks ? 133 (62%) YES NO 80 (38%) Treated x 12 wk SVR 85% Treated x 24 wk SVR 64% *HCV RNA was assessed after 4 weeks with a lower limit of detection of 50 IU/mL. Mangia A et al. N Engl J Med 2005;352:2609-2617.
    39. 39. HCV Genotype 2 and 3 With High Viral Load: Higher Relapse Rate? Zeuzem S et al. Hepatology 2004;40:993-999. Genotype 2 Genotype 3 n=20 n=22 n=99 n=83 n=2 n=7 n=17 n=1 Peg-IFN  -2b 1.5  g/kg/wk + Ribavirin 800 – 1400 mg/day x 24 Weeks
    40. 40. Viral Factors in Hepatic Steatosis <ul><li>Chronic Hepatitis C: N=755 </li></ul><ul><li>Steatosis: 41.7% </li></ul><ul><li>Independent predictors of steatosis: </li></ul><ul><ul><li>HCV genotype 3, obesity (BMI), ETOH (current), and age </li></ul></ul>Rubbia-Brandt et al. GUT 2004 HCV genotype 3 is the most important viral factor associated with steatosis HCV Viral Factors Associated with Steatosis
    41. 41. Host Factors and Hepatic Steatosis Obese Patients (  30 kg/m 2 ; n=37) Non-obese Patients (<30 kg/m 2 ; n=78) Present None Cesario K et al. DDW 2005. Obesity and Steatosis
    42. 42. HCV and Steatosis: Impact on Fibrosis (cont) Adinolfi et al. Hepatology 2001 0.00 0.05 0.10 0.15 0.20 0.25 Rate of Progression Fibrosis Units/yr 0 1 2/3 Grade of Steatosis
    43. 43. Obese Patients (  30 kg/m 2 ; n=40) Non-obese Patients (<30 kg/m 2 ; n=88) Moderate to Severe None to Mild Cesario K et al. DDW 2005. HCV and Steatosis: Impact on Fibrosis (cont)
    44. 44. The Impact of Superimposed Steatosis or Its Risk Factors on HCV Treatment <ul><li>Obesity may increase the volume of distribution, resulting in lower serum antiviral drug concentrations </li></ul><ul><li>Steatosis may alter hepatic structure and function, decreasing the contact between antiviral drug & infected hepatocytes </li></ul><ul><li>Leptin resistance may alter the T-cell response, decreasing the potential for viral clearance </li></ul>Potential Mechanisms for Decreased Response to Antiviral Therapy The Exact Mechanism is Unknown
    45. 45. The Impact of Superimposed Steatosis or Its Risk Factors on HCV induced liver disease <ul><li>Hepatitis C and steatosis (N=19) </li></ul><ul><li>Three-month weight reduction program </li></ul><ul><ul><li>Weight loss 5.9±3.2 kg </li></ul></ul><ul><ul><li>Decrease in waist of 9.0±5.0 cm </li></ul></ul><ul><ul><li>Fasting insulin 16±7 to 11±4 mmol/l </li></ul></ul><ul><ul><li>ALT improved (16/19) </li></ul></ul><ul><ul><li>Patients with paired biopsy (N=10) </li></ul></ul><ul><ul><ul><li>9 pts showed reduction in steatosis, improvement in fibrosis (3:1), and activated stellate cells </li></ul></ul></ul>Hickman et al. GUT 2002
    1. A particular slide catching your eye?

      Clipping is a handy way to collect important slides you want to go back to later.

    ×