HPI (2006) Question: Douglas T. Dieterich, MD. What is the risk of mother-to-child transmission in HCV for this woman?

Transcription

1 Case Presentation Douglas T. Dieterich, MD Professor of Medicine Mount Sinai School of Medicine HPI (2006) Slide #2 HPI: 30 yo white woman, G0P0. HCV+. PMH & FH: H/o multiple HCV treatments in the past. Possibly acquired perinatally - born to HCV+ mother. SH: Sexually active with HCV neg male partner. Quit smoking x 19 mo ago. No EtOH. No h/o IDU or transfusions. Question: Slide #3 What is the risk of mother-to-child transmission in HCV for this woman? 1

2 HCV and Pregnancy Slide #4 Mother-to-child transmission rate of 3-5% High rate of spontaneous clearance (25-50%) Factors known to the risk of perinatal transmission: HIV coinfection and higher maternal HCV RNA Elective C-section and withholding breastfeeding have NOT been demonstrated to reduce transmission PEG IFN and RBV are contraindicated in pregnancy and infancy Newer agents - a chance in the future for treatment in these patients? Arshad et al. HCV infection during pregnancy and the newborn period-- are they opportunities for treatment? J Viral Hepatology Apr;18(4): Labs on 3/4/2006 GLUCOSE 75 SODIUM 139 POTASSIUM 4.2 UREA NITROGEN 12 CREATININE 0.6 PROTEIN TOTAL 6.9 PLATELETS 305 ALBUMIN 4.3 CALCIUM 9.7 ALK.PHOSPHATASE 71 ALT(SGPT) AST (SGOT) 76 (H) 52 (H) GAMMA GT 26 BILIRUBIN TOTAL 0.5 Hepatitis C Genotype HCV RNA 1B 7 million Slide #5 What would you do now? Slide #6 1. Treat now 2. Hold treatment until later. 3. Order more tests. 2

3 Liver biopsy Slide #7 Stage 2/4 fibrosis (Stage 2/4 fibrosis) Slide #8 Slide #9 Patient was enrolled into PROVE3 study (telaprevir phase II study) 3

4 T24P24 trial Slide #10 Slide #11 Enrolled in a Study of Telaprevir Rx: Telaprevir 750 mg PO TID + PEG IFN No RBV on this trial arm Achieved undetectable HCV RNA at 5 weeks D/C after 8 weeks due to viral breakthrough. HCV RNA = 161,000 IU/ml Repeated to confirm = 338,000 IU/ml Response rate by group Slide #12 4

5 Slide #13 Probability of Resistant Variant by Subtype Probability median Probability of a patient being WT 1 Time 1a 1b (months) 0 16% 46% 3 22% 66% 6 32% 87% 12 60% 98% 16 94% 100% Based on Kaplan-Meier estimation using population sequencing; hash marks in plot Time after failure (months) indicate censored observations Significant difference (p<0.0001) between subtypes for the time to become WT by population sequencing (median, 95% CI) 1a: 10 months (9,11) 1b: 0.8 months (0,2) Presented at The International Liver Congress March 31, 2011 Probability Slide #14 Loss of Resistance by NS3 Position T54A V36M R155K Common 1a variants Common 1b variants median A156S/T V36A Time After Treatment Failure (months) Hash marks indicate censored observations V36M R155K V36A T54A A156S/T Median mos. to loss (95% CI) 9 (8,11) 10 (9,11) 4 (3,4) 3 (2,4) 4 (3,6) Presented at The International Liver Congress March 31, 2011 Slide #15 89% of Patients No Longer Have Detectable Resistant Variants Percent of samples from patients with no detectable variants n/n = 50/56 34/37 12/12 29/33 5/5 22/26 patients Overall variants 85 Population Sequencing Variants at HCV NS3 position Median follow-up time from end of prior study of 25 months (range 7-36) Variant categories are not mutually exclusive 5

6 Patient Viral Populations Return to Pre-treatment State Slide #16 Clonal sequence analysis used to evaluate viral population from a representative 20 of 50 patients determined to be wild-type by population sequence On average, 78 ± 35 clones were sequenced at baseline and 88 ± 52 clones were sequenced at follow-up, per patient Each patient was tested to evaluate return to pre-statement state at NS3 positions 36, 54, 155 and 156 Variant Clonal Sequences at Baseline 1% (14/1567) Overall Frequency of Resistant Variants Variant Clonal Sequences during EXTEND Viral populations of every patient returned to their pre-treatment 1% state (16/1769) Slide #17 Patient Returns 2 yrs Later (2010) c/o intense of itching of feet & whole body. G1P0 F, 24 weeks pregnant. Partner tested serially (4 times) and remains seronegative. No other sxs. Pregnancy progressing normally otherwise. Labs done on 5/25/2010 ALPHA FETOPROTEIN 92.7 (H) ALT (SGPT) 20 AST (SGOT) 23 GAMMA GTP-BLD 26 TSH 1.62 PLATELET 278 BILIRUBIN DIRECT 0.1 BILIRUBIN TOTAL 0.2 ALBUMIN, BLD 3.5 CREATININE-SERUM 0.5 CHOLIC ACID 9.80 (H) 3.1 OR LESS DEOXYCHOLIC ACID OR LESS CHENODEOXYCHOLIC ACID OR LESS TOTAL BILE ACIDS (H) umol/l Slide #18 6

7 What to do? Slide #19 DDx? Rx? A/P: 24 weeks pregnant Slide #20 Labs: Bile acids non-confirmatory. DDx: Cholestasis? Rx: Ursodiol 500 mg PO BID. Counseling: 1. Preventing mother-to-child HCV transmission? 2. Elective C-section and prevention of other viral pathogens (HIV and HSV). 3. Procedures that predispose fetus to maternal blood? 4. Is HCV affecting the dx cholestasis? 5. Is there a role for early delivery as part of the accepted management of cholestasis of pregnancy? 6. Risks of delivery by C-section for failed inductions. IL28B Slide #21 Neither the mother's nor the child's IL28B status was associated with an increased likelihood of HCV vertical transmission. Children with CC are more likely to spontaneously clear HCV, as are those with non-genotypes A child having CC is the the only predictor of clearance of genotype 1 HCV. A Ruiz-Extremera et al. Genetic variation in IL28B with respect to vertical transmission of hepatitis C virus and spontaneous clearance in HCV infected children. Hepatology (abstract). March 16,

8 Slide #22 F/U visit 1 year later (6/6/2011) Gave birth 6 months ago to a healthy boy who will be screened at 1 year of age. States that her liver enzymes elevated into 2000s shortly following birth. Liver biopsy stage 1 (2002), stage 2 (2006). Transient elastography score 20. A/P? Stage II fibrosis at liver biopsy (2006). Transient Elastrography suggests higher fibrosis, but likely falsely elevated due to liver inflammation. Will do hepa-score today and IL28b. Will restart HCV retreatment at next visit in 6/2011. Visit on 6/16/2011 Slide #23 Today c/o RUQ pain. CT showed?varices. MRCP gallstones. Labs: HCV 7 million. IL28B CT, Hepascore F0. Ddx? Cholestasis of pregnancy with ALT of 2000 (???). A/P? Refer to surgery for cholecystectomy and liver biopsy to determine if pregnancy is OK before HCV retreatment. Slide #24 Surgical consult on 6/16/11 C/O recurrent RUQ, epigastric pain with dyspeptic symptoms. No H/O jaundice or pancreatitis. MRCP shows (+)stones with no evidence of obstruction. A/P: Patient to be scheduled for laparoscopic cholecystectomy, liver biopsy. Pre op work-up, labs, coags. Any other procedures? 8

9 Post-Op Plan Slide #25 Pt wants to conceive (2011) again Would you recommend she retreat Hep C first? What other issues might you be concerned about? If she agrees to treatment, what treatment will you recommend? Slide #26 Clinical Implications of Genetic Barrier to Resistance Subtype 1a V36M+R155K variant observed clinically R155K CGG - AAG Subtype 1b V36M+R155K variant not observed clinically R155 CGG - AGG 4 step R155K AGG - AAG V36M GTG - ATG 2 step V36M GTC - ATG V36 GTC -GTG McHutchison JG. New Engl J Med 2009;360;18: Hezode C. New Engl J Med 2009;360;18: