HIV HCV Co Infection Case: The Agnostic Radiologist

Transcription

1 HIV HCV Co Infection Case: The Agnostic Radiologist Douglas T. Dieterich, M.D Professor of Medicine Division of Liver Diseases, Gastroenterology and Infectious Diseases Department of Medicine Mount Sinai School of Medicine New York, New York

2 HPI: 43 y/o male radiologist with 3 young children, has hemophilia VIII, HIV/HCV cirrhosis presents to the office for the first time with his father, an internist, in September 2010 Surgical History: Lap cholecystectomy 2 yrs ago with liver biopsy Social History: no drugs, tobacco or alcohol. Allergies : ASA and Bactrim

3 Meds: TDF/FTC, ritonavir, atazanavir, Factor VIII Long history of taking ddi and d4t in the past Physical Exam : BMI 34, Extreme facial wasting, hepatosplenomegaly without ascites or edema MRI Liver: September 2010 cirrhotic liver, splenomegaly. Spontaneous splenorenal shunt, 3x2.6 cm liver nodule with uptake in 3 phases no washout most likely inflammatory, HCC less likely.(pt does not believe it is HCC)

4 Which factor best predicts a 1. Pt is a physician poor prognosis? 2. Pt has 3 young children 3. Pt accompanied by his father,a physician 4. Pt has had biopsy-confirmed cirrhosis for 2 years before seeking a liver opinion 5. Pt has a long history of ddi and d4t use 6. Pt has grade 1 varices 7. He comes from the ID doc who treated all the hemophiliacs with ddi and d4t.

5 Liver Bx:2009 during Cholecystectomy mild portal chronic inflammation, moderate interface hepatitis and mild lobular activity. Trichrome stain shows cirrhosis. Grade 3/4 Stage 4/4 EGD: 2009 grade 1 varices Fibroscan Score=48kpa (c/w cirrhosis) 2010 What is the significance of that score?

6 Treatment History HCV Rx Hx: tried PEG/RBV x 2 weeks and stopped due to multiple side effects, in 2007

7 Laboratory Values CBC: WBC 4.5, Hb 13.1, Plt 58 PT 17.7, INR (OH) Vitamin D 12 Alb 3.6, TB 5.2, Cr 1, ALT 227, AST 193, ALKP 186, HOMA score 3.8 AFP 20.4 CD4 215 (26%), HIV VL <50 c/ml HCV RNA 177,000 IU/ml, HCV GT 1a Is this low viral load a good or a bad prognostic sign?

8 September 2010 Would you do an IL 28 b test? If so would you make a recommendation based on the results? What would that recommendation be? If CC If CT, TT

9 SVR in HIV HCV Pts According to IL28b Pineda,J;Cruz,W; Camarcho,E et. al.

10 Factors Associated with SVR in HIV HCV Treated Pts.

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12 Viral Kinetics by IL28b Allele

13 Likelihood of SVR

14 Does IL-28b GT Predict SVR in Coinfected Patients? Retrospectively looked at IL-28b status and IP-10 levels of 72 HIV/HCV coinfected patients Age, sex, BMI, liver stiffness, baseline HCV and HIV levels, CD4+ cell count were similar in CCs and non-ccs Payer BA et Al., EASL 2011, Abstract 1337

15 Results: SVR CC = 81%, SVR non-cc = 51% (p = 0.008) SVR IP-10 < 400 = 78%, SVR IP-10 > 400 = 13% (p< )

16 Laboratory Values CBC: WBC 4.5, Hb 13.1, Plt 58 PT 17.7, INR (OH) Vitamin D 12 CMP: Alb 3.6, TB 5.2, Cr 1, ALT 227, AST 193, AP 186, HOMA score 3.8 AFP 20.4 CD4 215 (26%), HIV VL <50 c/ml HCV VL 177K, HCV GT 1a Is this low viral load a good or a bad prognostic sign?

17 Any other issues that need to be addressed before treatment? Platelets 58,000 INR OH Vitamin D 12 HOMA score 3.8 AFP 20.4 CD4 215 (26%), HIV VL <50 c/ml

18 Insulin Resistance Influences Response to Treatment with PegIFN/RBV in HIV/HCV Co- Infected Patients Ryan P. et al. JAIDS 2010.

19 Insulin Resistance Influences Response to Re-Treatment with PegIFN/RBV in HIV/HCV Co- Infected Patients 35% 14% 7% 6/17 5/36 3/41 Vachon, ML. et al. J hepatol 2011.

20 Insulin Resistance Predicts Non-Response to Re-Treatment with pegifn/rbv in HIV/HCV Co-Infected Patients HOMA- IR < 2 1 Multi-variable Analysis Outcome = SVR AOR (95%CI) p-value > ( ) Log ( ) 0.04 HCV RNA Vachon, ML. et al. J Hepatol 2011.

21 Does Vitamin D Play a Role? Vitamin D is an immune modulator HCV-infected patients have a high prevalence of 25(OH)D deficiency 1,2 Among HCV mono-infected patients, 25(OH)D deficiency is related to severe liver fibrosis and low response to HCV treatment with pegifn and RBV 1,2 Vitamin D supplementation can improve SVR 3 25(OH)D deficiency is prevalent in HIV-infected patients 4,5 The impact of vitamin D deficiency and supplementation before or after HCV treatment in HIV/HCV co-infected patients is unknown 1. Petta S. et al. Hepatology 2010; 2. Lange CM. et al. J Hepatol 2011; 3. Mouch SA. et al. (abstract) J Hepatol 2011; 4. Mueller NJ. Et al. AIDS 2010; Childs KE. et al. AIDS Res Hum Retroviruses 2010.

22 The patient decides, despite IL 28b CC genotype in September to wait a little longer for treatment Then in April 2011 sends an Have you heard of the telaprevir study in HIV patients presented by Sulkowski? I replied Did you notice who the second author was? And by the way, Sulkowski is sitting next to me and he agrees that you need to be treated now!

23 Interim Analysis of a Phase 2a Double-Blind Study of Telaprevir in Combination with Peginterferon Alfa-2a and Ribavirin in HIV/HCV Coinfected Patients Part A: no ART T/PR TVR + PR PR Follow-up SVR PR48 (control) Pbo + PR PR Follow-up SVR Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC) T/PR TVR + PR PR Follow-up SVR PR48 (control) Pbo + PR PR Follow-up SVR Weeks (EFV)=efavirenz; (TDF)=tenofovir; (FTC)=emtricitabine; (ATV/r)=ritonavir-boosted atazanavir; (3TC)=lamivudine; (T) TVR=telaprevir 750 mg q8h or 1125 mg q8h (with EFV); Pbo=Placebo; (P) Peg-IFN=pegylated interferon alfa-2a (40 kd) 180 µg/wk; (R) RBV=ribavirin 800 mg/day or weight-based (1000 mg/day if weight <75 kg, 1200 mg/day for if weight 75 kg; France, Germany) Roche COBAS TaqMan HCV test v2.0, LLOQ of 25 IU/mL (pts with values below 25IU/mL were reported as <25 detectable or undetectable)

24 Percent of patients with HCV RNA Undetectable Undetectable HCV RNA at Week 12 (ITT) n/n = No ART EFV/TDF/FTC ATV/r+TDF+FTC/3TC PR Total Total /7 12/16 8/14 25/37 1/6 1/8 1/8 3/22 Telaprevir + PR PR

25 % of pts with SVR. ADVANCE, Naïve G1 Pts SVR by IL28B Genotype in Pts with Available IL28B Data SOC T12PR T8PR 100% 80% 60% 64.0% 90.0% 87.0% 71.0% 73.0% 58.0% 59.0% 40% 20% 25.0% 23.0% 0% 35/55 45/50 39/45 20/80 48/68 44/76 6/26 16/22 19/32 Jacobson et al, EASL 2011, late-breaker poster (1369) CC CT TT

26 SPRINT-2: IL-28B CC Polymorphism as a Predictor of SVR (Multiple Stepwise Logistic Regression Model) Genotype: 1b/Other vs 1a P <0.001 Odds Ratio (95% CI) Age 40 vs >40 P = IL28B Genotype: CC vs. Non-CC P < BOC/RGT vs PR48 P < BOC/PR48 vs PR48 P < Baseline HCV-RNA: 400,000 vs. >400,000 P < Only 7-9% of patients had VL 400, Only covariates remaining significant at α=0.05 after adjustment for the other variables were retained in the model as shown in the figure. Factors entered but not retained in the model were, region, race, gender, weight, BMI, steatosis, platelets, ALT, statin use, and fibrosis

27 Patients with HCV RNA <15 IU/mL (%) INFORM-1: effect of IL28B genotype on early viral kinetics with IFN-free treatment CC non-cc CT TT * /12 9/33 10/12 9/33 11/12 21/33 Study day 14 Week 4 of PR Week 12 of PR * Difference in the response rate between CC and non-cc is statistically significant Chu T, et al. EASL 2011, poster (1323)

28 Meanwhile back in Radiology April 2011 MRI Abdomen Impression: 1. Liver cirrhosis and portal hypertension (splenomegaly and varices), with areas of confluent fibrosis. 2. Increase in size of periportal infiltrative lesion in segment 6/7 measuring 2.7 x 4.0 CM. Although this may still represent an area of perivascular confluent fibrosis, HCC or cholangiocarcinoma should be excluded. Furthermore, followup HCC surveillance should be performed with Magnevist in the future.

29 . April 2011 CT Abdomen IMPRESSION: 1. LIVER CIRRHOSIS, WITH EVIDENCE OF PORTAL HYPERTENSION. 2. ILL-DEFINED LOW DENSITY ABNORMALITY IN THE RIGHT POSTERIOR HEPATIC LOBE, CORRESPONDING TO AN ABNORMALITY PRESENT ON THE MRI. CLINICAL ASPECTS OF THE CASE WILL DICTATE WHETHER THIS REGION IS APPROPRIATE FOR PERCUTANEOUS BIOPSY. 3. MILD NEPHROLITHIASIS. 4. STATUS POST CHOLECYSTECTOMY

30 What do you do now? Biopsy lesion Repeat MRI with Magnevist in 3 months Start teleprevir Peg RBV, then get MRI Start Vit D, treatment of HOMA score and thrombopoietin All of the above Consult the patient s father Refer to Sulkowski in Baltimore