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Hepatitis and HIV Coinfection

Disclosure of Financial Relationships This speaker has the following significant financial relationships with commercial entities to disclose:. Speaker Tibotec, Merck, BIPI, Gilead, BMSResearch Support ViiV, Tobira Pharmaceuticals, Vertex, PfizerConsultant ViiV, Tibotec, Gilead. This slide

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Hepatitis and HIV Coinfection

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    2. Disclosure of Financial Relationships This speaker has the following significant financial relationships with commercial entities to disclose: Speaker – Tibotec, Merck, BIPI, Gilead, BMS Research Support – ViiV, Tobira Pharmaceuticals, Vertex, Pfizer Consultant – ViiV, Tibotec, Gilead

    3. Slide set adapted from Hepatitis and HIV Coinfection Presented by: Jeffrey A. Beal, MD At the 18th Annual Conference of the Florida/Caribbean AETC

    4. Session Objectives Review treatment options for coinfected patients including initiation of treatment, selection of treatment regimens, management of complications and follow up of treatmentfailure patients. Discuss novel therapeutic options for treatment. Review transplant criteria.

    5. HCV Sources of Infection Blood exposure/perinatal/sexual HCV 10 X more infectious than HIV 2? blood HCV sexual transmission inefficient Mother to infant in 2-5% of deliveries MMWR, Vol 58 (early release) March 24, 2009 Blood exposure – IDU and shared paraphernalia such as straws More sexual transmission heterosexual and MSM if HIV postitive/ traumatic sex Blood exposure – IDU and shared paraphernalia such as straws More sexual transmission heterosexual and MSM if HIV postitive/ traumatic sex

    6. Hepatitis C In U.S., 4 million HCV+ ? 85% chronic If chronic ? 20% cirrhotic @ 20 years Once cirrhotic ? 25% hepatocellular carcinoma (HCC) (0.5% of total HCV+) Alcohol (>20-50 g/d) & HIV worsen prognosis Usually no symptoms sometimes fatigue, RUQ ache, difficulty concentrating or isolated ? ALT/AST Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. MMWR; April 10, 2009, Vol. 58, No. RR-4 Also increased risk of liver ds. At older age when infected, male sex, and CD4 < 200. Less than 20% of patients have symptoms which Acute Hep C infection. The current recommendations for moderate alcohol intake are 1 drink per day for women and 2 drinks per day for men. One drink is described as 12 ounces of beer, 5 ounces of wine or 1 1/2 ounces of distilled liquor. 12 ounces beer = 153 calories and 13.9 grams alcohol 12 ounces lite beer = 103 calories and 11 grams alcohol 5 ounces wine (red) = 125 calories and 15.6 grams alcohol 5 ounces wine (white) = 121 calories and 15.1 grams alcohol 3 ounces sake = 117 calories and 14.1 grams alcohol 1 1/2 ounces liquor (80 proof or 40% alcohol) = 97 calories and 14 grams alcohol Also increased risk of liver ds. At older age when infected, male sex, and CD4 < 200. Less than 20% of patients have symptoms which Acute Hep C infection. The current recommendations for moderate alcohol intake are 1 drink per day for women and 2 drinks per day for men. One drink is described as 12 ounces of beer, 5 ounces of wine or 1 1/2 ounces of distilled liquor. 12 ounces beer = 153 calories and 13.9 grams alcohol 12 ounces lite beer = 103 calories and 11 grams alcohol 5 ounces wine (red) = 125 calories and 15.6 grams alcohol 5 ounces wine (white) = 121 calories and 15.1 grams alcohol 3 ounces sake = 117 calories and 14.1 grams alcohol 1 1/2 ounces liquor (80 proof or 40% alcohol) = 97 calories and 14 grams alcohol

    7. Hepatitis C 6 Genotypes Genotypes 1-3 are commonest in US, W. Europe: 75% are 1 (accounts for 90% of AfAm cases) 25% are “Non-1” Most are 2 & 3 4-6 Middle East/Africa/Spain African Americans less likely to achieve sustained virologic response (SVR) to treatment 28% AA 52% Cauc In us, 90% of african american cases are Genotype 1.In us, 90% of african american cases are Genotype 1.

    8. HIV and HCV Meta analysis 37 studies showed prior to HAART, HCV liver disease did not significantly increase mortality. Post HAART, HCV liver disease increases mortality and has become the most common cause of non-AIDS related death among HIV patients Liver related deaths in persons infected with HIV: the D:A:D study. Archives of Internal Medicine 166 (15): 1632-1641

    9. HIV/HCV Co-Infection is Clearly Associated with More Rapid Progression to Cirrhosis Soto, et al. J Hepat 1997 Compared 547 HIV- with 116 HIV+ All with chronic hepatitis C Incidence of cirrhosis HIV- 2.6% (mean HCV duration 23.2 years) HIV+ 14.9% (mean HCV duration 6.9 years)

    10. Liver Disease: A Major Cause of Death ART has slowed the progression of HIV disease and decreased the rate of HIV-associated mortality. With increased longevity, other comorbidities, such as chronic liver disease, have assumed greater importance. HCV and HIV share routes of transmission, so coinfection with is common, especially in injection drug users and hemophiliacs [2–6]. HCV-infected patients have a 20% risk of developing cirrhosis within 20 years; it leads to chronic hepatitis in 85% of patient]. HIV disease may modify chronic HCV infection’s natural history, accelerating progression from chronic active hepatitis to cirrhosis, end-stage liver disease, and death. Enhanced risk of liver toxicity using antiretroviral agents in the presence of underlying chronic hepatitis C is a serious consideration. In injection drug users, rates of coinfection with HIV and HCV range from 52% to 93%. Strategies to prevent infection by hepatitis viruses (hepatitis B vaccine) and specific treatment (interferon plus ribavirin for hepatitis C virus) should be encouraged among HIV-infected persons. ART has slowed the progression of HIV disease and decreased the rate of HIV-associated mortality. With increased longevity, other comorbidities, such as chronic liver disease, have assumed greater importance. HCV and HIV share routes of transmission, so coinfection with is common, especially in injection drug users and hemophiliacs [2–6]. HCV-infected patients have a 20% risk of developing cirrhosis within 20 years; it leads to chronic hepatitis in 85% of patient]. HIV disease may modify chronic HCV infection’s natural history, accelerating progression from chronic active hepatitis to cirrhosis, end-stage liver disease, and death. Enhanced risk of liver toxicity using antiretroviral agents in the presence of underlying chronic hepatitis C is a serious consideration. In injection drug users, rates of coinfection with HIV and HCV range from 52% to 93%. Strategies to prevent infection by hepatitis viruses (hepatitis B vaccine) and specific treatment (interferon plus ribavirin for hepatitis C virus) should be encouraged among HIV-infected persons.

    11. Other Possible Interactions Between Hepatitis C & HIV HCV does not appear to consistently affect progression of HIV disease Chronic HCV does not appear to consistently affect CD4 response to combination ART (cART) Cirrhosis suppresses immunity—may affect CD4 May be associated with changes in psychiatric fxn., ? QOL, ? prevalence DM

    12. Viral Hepatitis in HIV+ Patients Acute viral hepatitis may be severe or fatal Acute viral hepatitis may add to liver damage already present from other causes e.g. - Acute hepatitis A on chronic hepatitis C may be deadly Vaccinate if not Immune Assess response to vaccination Best response when CD4 >350 Consider double dose Hep B vaccine Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. MMWR; April 10, 2009, Vol. 58, No. RR-4 Vaccinate if immune to A or B. Best response when CD4>200. For the Hep C infected patient vaccinate regardless of CD4 and if immune reconstitution occurs with CD4 rise to above 250, consider revaccination. Vaccinate if immune to A or B. Best response when CD4>200. For the Hep C infected patient vaccinate regardless of CD4 and if immune reconstitution occurs with CD4 rise to above 250, consider revaccination.

    13. HCV Testing Algorithm Regarding negative HCV RNA, retesting at 6 months can be considered as “a single positive qualitative assay for HCV RNA confirms active HCV replication, but a single negative assay does not exclude viremia and may reflect only a transient decline in viral level below the level of detection of the assay.” Reference NIH Consensus Conference Statement 2002.HCV Testing Algorithm Regarding negative HCV RNA, retesting at 6 months can be considered as “a single positive qualitative assay for HCV RNA confirms active HCV replication, but a single negative assay does not exclude viremia and may reflect only a transient decline in viral level below the level of detection of the assay.” ReferenceNIH Consensus Conference Statement 2002.

    15. HCV Screening Genotyping & Hep C VL are helpful in predicting response to therapy 1 ( & 4) is more refractory to treatment If VL <4-500,000 IU/mL Geno 1 easier to treat 2 & 3 are very responsive HIV should be controlled and ARV stable Attempt to get CD4>200 with cART\ Pts with CD4% >25 are more likely to have SVR PHQ-9 Depression Screen – hx of suicidal ideation – MH referral Use of contraception mandatory if treating.Use of contraception mandatory if treating.

    16. HCV Screening Preg. test (unless hysterectomy or tubal ligation) & must be willing to use Birth control CBC, Platelet – Hgb must be >10.5 g/dL, ANC >1000/µL, and Platelets > 50k. Use of hematopoietic growth factor OK. LFT, PT, PTT, INR – if coagulopathy, ?bili, encephalopathy, ascites refer to transplant center. Cr. Cl. > 50cc/min. Newly on ART, be sure stabilized for a few months before starting treatment. Mild depression should be treated. Some prophylax all with anti-depressants due to strong correlation of depression with IFN. With CrCl < 50cc/min can consider IFN therapy aloneNewly on ART, be sure stabilized for a few months before starting treatment. Mild depression should be treated. Some prophylax all with anti-depressants due to strong correlation of depression with IFN. With CrCl < 50cc/min can consider IFN therapy alone

    17. HCV Screening TSH (autoimmune thyroiditis potential complication of therapy) Uncontrolled cancer or cardiopulmonary disease is contraindication Baseline ECG if hx. pre-existing cardiac ds. or = 50 y/o Ophthalmology Exam –IFN retinitis IFN exacerbates sarcoidosis Uncontrolled autoimmune diseases will be exacerbated by IFN.IFN exacerbates sarcoidosis Uncontrolled autoimmune diseases will be exacerbated by IFN.

    18. Treatment of Disease Benefit > Risk If no contraindication to Peg-IFN/RBV HCV genotype 2 or 3 HCV genotype 1 with HCV RNA <800,000 IU/ml Sig. hepatic fibrosis (bridging or cirrhosis) Stable HIV not requiring ART Acute HCV (< 6 mo. duration) Cryoglobulinemic vasculitis or membranoproliferative glomerulonephritis Patient motivated for treatment Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. MMWR; April 10, 2009, Vol. 58, No. RR-4

    19. Look for Complications of Chronic Hepatitis Alpha-fetoprotein alone not enough to screen out HCC Abd. US to r/o mass, lesion, ascites, organomegaly Liver biopsy? Gold standard in evaluating hepatitis and cirrhosis—how “close” to cirrhosis is your patient? Fibrosure™ & Fibroscan™ not validated in HIV yet, but non-invasive measures of fibrosis Cannot rule our concurrent diseases, over-diagnoses fibrosis Fibrosure™ may be affected by elevated bilirubin due to atazanavir or indinavir Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. MMWR; April 10, 2009, Vol. 58, No. RR-4 Surveillance for HCC from American Association for the Study of liver Diseases (AASLD) guidelines= For HCV infected patients with cirrhosis, Ultrasound liver every 6-12 months. If US not available, AFP testing is suggested. NOTE: only HCV-infected patients with cirrhosis or advanced fibrosis have an indication for screening because the risk of HCC is very low in patients without cirrhosis. (Current Hepatitis Report; Special Populations; Hepatitis C and Hepatocellular Carcinoma; Leach, et.al. ;page 88; Low grade liver fibrosis – option to observe and not treat (F0-F1) Non-invasive tests (transient elastography (TE, Fibroscan), the SHASTA score, or combination of both) can be used initially, and IF NEGATIVE for fibrosis, observation may be reasonable. Tx warranted if METAVIR fibrosis stage is greater than F2, reserving liver biopsy for indeterminate results. (Current Hepatitis Report; Special Populations; Viral Hepatitis in Patients with HIV Infection; Dieterich, et.al. ;page 108. Noninvasive testing strategies to evaluate liver fibrosis are an area of active research. Several tests are available that can reliably separate patients with minimal fibrosis from those with cirrhosis, but these tests fail to distinguish intermediate stages of fibrotic disease Surveillance for HCC from American Association for the Study of liver Diseases (AASLD) guidelines= For HCV infected patients with cirrhosis, Ultrasound liver every 6-12 months. If US not available, AFP testing is suggested. NOTE: only HCV-infected patients with cirrhosis or advanced fibrosis have an indication for screening because the risk of HCC is very low in patients without cirrhosis. (Current Hepatitis Report; Special Populations; Hepatitis C and Hepatocellular Carcinoma; Leach, et.al. ;page 88; Low grade liver fibrosis – option to observe and not treat (F0-F1) Non-invasive tests (transient elastography (TE, Fibroscan), the SHASTA score, or combination of both) can be used initially, and IF NEGATIVE for fibrosis, observation may be reasonable. Tx warranted if METAVIR fibrosis stage is greater than F2, reserving liver biopsy for indeterminate results. (Current Hepatitis Report; Special Populations; Viral Hepatitis in Patients with HIV Infection; Dieterich, et.al. ;page 108. Noninvasive testing strategies to evaluate liver fibrosis are an area of active research. Several tests are available that can reliably separate patients with minimal fibrosis from those with cirrhosis, but these tests fail to distinguish intermediate stages of fibrotic disease

    20. Comparison of Scoring Systems for Histological Stage

    21. Benefits & Goals of Treating Chronic Hepatitis C Viral eradication (“sustained viral remission”, SVR) Delay progression of fibrosis Prevent/delay bad clinical outcomes of cirrhosis Liver decompensation Hepatocellular carcinoma Death Improve tolerance and effectiveness of HAART Allows aggressive antiretroviral drug therapy Enhanced immune reconstitution? Increases survival SVR = HCV RNA negative 24 weeks after cessation of treatment.SVR = HCV RNA negative 24 weeks after cessation of treatment.

    22. Response Rates toTreatment Chronic Hepatitis C In studies, sustained viral remission w/ newer treatments: PEG ?IFN + ribavirin Genotype 1 & 4 (~ 30 -70 % SVR) Genotype 2 & 3 (>80% SVR) SVR with PEG ?IFN + ribavirin reduces cirrhosis, HCC, transplant, death by 9-fold HIV disease is not affected by ?IFN or ribavirin

    23. Hepatitis C Treatment Toxicities Pegylated aINF 2a or 2b Flu-like symptoms Depression/suicidal Fatigue, dizziness Anorexia, nausea/diarrhea Bone marrow suppression Serious infections Autoimmune disease Thyroid, diabetes Hair loss, oral ulcers Pulmonary fibrosis Stevens-Johnson, hypersensitivity Retinal hemorrhage, cotton wool spots Ribavirin Anemia/hemolysis dose dependent 2.5-3g ? within 4 weeks Erythopoietin Depression Embryocidal / Category X Teratogenic for up to 6 months after treatment FDA Ribavirin Pregnancy Registry Visual Toxicity associated with Peg IFN – retinopathy most commonly occurs without visual symptoms and manifests as retinal hemorrhages, cotton wool spots. Presumed pathology is IFN effects on the retinal microcirculation. Incidence 15-80%. Because disease most commonly occurs without symptoms and is reversible on IFN discontinuation routine required screen not recommended. Patients at increased risk (HTN and DM) should be screened before and during therapy. Visual Toxicity associated with Peg IFN – retinopathy most commonly occurs without visual symptoms and manifests as retinal hemorrhages, cotton wool spots. Presumed pathology is IFN effects on the retinal microcirculation. Incidence 15-80%. Because disease most commonly occurs without symptoms and is reversible on IFN discontinuation routine required screen not recommended. Patients at increased risk (HTN and DM) should be screened before and during therapy.

    24. Treatment of HCV coinfection PEG IFN a-2a (fixed 180 mcg) or a-2b (wt-based 1.5 mcg/kg)* subcutaneously every week + Ribavirin 1000 mg (wt. <75 kg)-1200mg mg (wt. >75 kg) all genotypes1. Duration all genotypes is 48 weeks.2 Pegasys = alpha 2a PegintronPegasys = alpha 2a Pegintron

    25. Ribavirin Interacts with cART

    26. Peginterferon and Ribavirin RVR = Rapid viral response (undetectable VL) at week 4 predicts SVR EVR = Early viral response, 12 week viral load is undetectable or decreased by 2 logs. ETR = End of treatment response, undetectable viral load at end of treatment. SVR = Sustained viral response, undetectable 6 or more months after therapy. RVR = Rapid viral response (undetectable VL) at week 4 predicts SVR EVR = Early viral response, 12 week viral load is undetectable or decreased by 2 logs. ETR = End of treatment response, undetectable viral load at end of treatment. SVR = Sustained viral response, undetectable 6 or more months after therapy.

    27. Defining Success RVR = Rapid viral response (undetectable VL) at week 4 predicts SVR EVR = Early viral response, 12 week viral load is undetectable or decreased by 2 logs. ETR = End of treatment response, undetectable viral load at end of treatment. SVR = Sustained viral response, undetectable 6 or more months after therapy.

    28. Defining Response in HIV/HCV Lack of Early Virologic Response (<2 log10 IU/mL ? HCV VL from baseline or undetectable) at wk 12 is predicts virologic failure. (<3% chance SVR) Current guideline: discontinue treatment if EVR not seen If HCV undetectable @ 12 weeks (EVR)? continue If HCV undetectable @ end of tx (ETR)? repeat @ 72 weeks If still undetectable ?SVR!! < 2% will have SVR< 2% will have SVR

    29. Managing Adverse Effects Avoid dose reductions where feasible Moderate depression ?PEG IFN a-2a to 135 mcg and further ? to 90 mcg may be needed ? PEG IFN a-2b by 50% Supportive counseling/antidepressant medication therapy Severe depression or suicidal – D/C Treatment!

    30. Managing Adverse Effects

    31. The 'Correction of Hemoglobin and Outcomes in Renal Insufficiency' (CHOIR) study, published November 16, 2006 in the New England Journal of Medicine, reports the adverse cardiovascular complications as a composite of the occurrence of one of the following events: death, myocardial infarction [MI], hospitalization for congestive heart failure, or stroke. The CHOIR study findings underscore the importance of following the currently approved prescribing information for Procrit, Epogen, and Aranesp [darbepoetin alfa], including the dosing recommendation that the target hemoglobin not exceed 12 g/dL. The 'Correction of Hemoglobin and Outcomes in Renal Insufficiency' (CHOIR) study, published November 16, 2006 in the New England Journal of Medicine, reports the adverse cardiovascular complications as a composite of the occurrence of one of the following events: death, myocardial infarction [MI], hospitalization for congestive heart failure, or stroke. The CHOIR study findings underscore the importance of following the currently approved prescribing information for Procrit, Epogen, and Aranesp [darbepoetin alfa], including the dosing recommendation that the target hemoglobin not exceed 12 g/dL.

    32. Managing Adverse Effects Nausea: Dronabinol (Marinol®) 2.5-10 mg po bid for RBV induced nausea Or Premedicate with 12.5-25 mg promethazine (Phenergan®) or 5-10 mg prochlorperazine (Compazine®)

    33. What if ESLD develops? Liver transplantation may be a viable option in selected HIV+ individuals Experimental, outcomes similar to HIV-/HCV+ Need good HIV control, adherence HCV recurrence is common in new liver Re-treatment x 3 months after transplant 5-year survival is 51% (vs.81% in HIV-/HCV+) In recent years, several research teams have found that outcomes of liver transplantation in HIV positive patients are nearly as good as those in HIV negative people. However, in HIV positive and negative individuals alike, HCV infection typically recurs in the new liver following the procedure. In recent years, several research teams have found that outcomes of liver transplantation in HIV positive patients are nearly as good as those in HIV negative people. However, in HIV positive and negative individuals alike, HCV infection typically recurs in the new liver following the procedure.

    34. HCV Lifecycle and STAT-C Targets HCV, hepatitis C virus; ER, endoplasmic reticulum; LD, luminal domain; STAT-C, specifically targeted antiviral therapy for HCV.   The HCV lifecycle and the mechanism of actions of various STAT-C agents are shown on this slide. The virus binds to specific cell surface receptors, is endocytosed, fuses with the hepatocyte membrane, and becomes uncoated before creating a replication membranous web where the virus is replicated, proteins are translated, new variants are assembled and are transported again to the membrane and released into the circulation. The NS3/4a protease inhibitors’ mechanisms of action are to inhibit the cleavage of the viral polyprotein into various independent HCV proteins. NS5B polymerase inhibitors interfere with the RNA replication process of the virus, and there is an interesting new molecule class, the NS5A inhibitors, that probably interfere with various stages of creation of this membranous replication web, but their role has not been well defined in the HCV lifecycle.HCV, hepatitis C virus; ER, endoplasmic reticulum; LD, luminal domain; STAT-C, specifically targeted antiviral therapy for HCV.   The HCV lifecycle and the mechanism of actions of various STAT-C agents are shown on this slide. The virus binds to specific cell surface receptors, is endocytosed, fuses with the hepatocyte membrane, and becomes uncoated before creating a replication membranous web where the virus is replicated, proteins are translated, new variants are assembled and are transported again to the membrane and released into the circulation. The NS3/4a protease inhibitors’ mechanisms of action are to inhibit the cleavage of the viral polyprotein into various independent HCV proteins. NS5B polymerase inhibitors interfere with the RNA replication process of the virus, and there is an interesting new molecule class, the NS5A inhibitors, that probably interfere with various stages of creation of this membranous replication web, but their role has not been well defined in the HCV lifecycle.

    36. New HCV Agents – Boceprevir and Telaprevir Boceprevir and Telaprevir, the 2 new oral HCV protease inhibitors has phase 3 data Telaprevir (plus peg/rbv) 75% of patients achieved SVR . Telaprevir is taken only for 12 weeks, peg/RBV is taken during the entire 48 weeks In mono infection with HCV68% of patients in studies had undetectable HCV viral load at 4 weeks and 58% at weeks 4 and 12 (212/363).

    37. New HCV Agents Telaprevir, Relapse rates were low, 9%. On-treatment virologic failure rates were only 3%. Patients with no, mild or portal fibrosis had a 78% SVR . Patients with cirrhosis with a 62% SVR, and for African A. the SVR was 62% Rash 56% with 6% a severe rash, on average hemoglobin went down from 12.3 g/dL approx to 11 by week 8. It's expected that FDA will approve this month

    38. Pharmacokinetic Interactions Between ARVs and Telaprevir Background:  Atazanavir/ritonavir (ATV/r), darunavir/r (DRV/r), fosamprenavir/r (FPV/r), and lopinavir/r (LPV/r) are substrates and inhibitors of CYP3A. Efavirenz (EFV) is an inducer of CYP3A. Telaprevir (TVR) is a substrate and inhibitor of CYP3A. In previous trials with TVR 750 mg every 8 hours, TVR Cmin was reduced by 47% by EFV and tenofovir AUC24h was increased by 30% by TVR. Interactions between TVR and antiretroviral (ARV) agents were evaluated to guide studies of TVR in HIV/hepatitis C virus (HCV) co-infected patients. Methods:  Three separate open-label, randomized cross-over trials were conducted in HIV/HCV– healthy volunteers. In 2 studies, volunteers received 2 treatments; TVR 750 mg every 8 hours for 10 days, followed by a washout and ATV/r 300/100 mg once daily, DRV/r 600/100 mg twice daily, FPV/r 700/100 mg twice daily, or LPV/r 400/100 mg twice daily (n = 20 each) for 20 days with co-administration of TVR 750 mg every 8 hours from day 11 onwards, or vice versa. All compounds were taken with food. In another study, 20 volunteers started TVR 750 mg every 8 hours for 7 days followed by EFV/tenofovir disoproxil fumarate (TDF) 600/300 mg once daily for 7 days after a washout. Subsequently, volunteers received TVR 1125 mg every 8 hours and EFV/TDF 600/300 mg once daily for 7 days or TVR 1500 mg every 12 hours and EFV/TDF 600/300 mg once daily for 7 days in a randomized order without a washout. TVR was taken with food and EFV/TDF was taken on an empty stomach in the morning. Least square means (LSMeans) and 90%CI of treatment ratios (test/reference) were calculated for the log-transformed AUCtau and Cmin Background:  Atazanavir/ritonavir (ATV/r), darunavir/r (DRV/r), fosamprenavir/r (FPV/r), and lopinavir/r (LPV/r) are substrates and inhibitors of CYP3A. Efavirenz (EFV) is an inducer of CYP3A. Telaprevir (TVR) is a substrate and inhibitor of CYP3A. In previous trials with TVR 750 mg every 8 hours, TVR Cmin was reduced by 47% by EFV and tenofovir AUC24h was increased by 30% by TVR. Interactions between TVR and antiretroviral (ARV) agents were evaluated to guide studies of TVR in HIV/hepatitis C virus (HCV) co-infected patients. Methods:  Three separate open-label, randomized cross-over trials were conducted in HIV/HCV– healthy volunteers. In 2 studies, volunteers received 2 treatments; TVR 750 mg every 8 hours for 10 days, followed by a washout and ATV/r 300/100 mg once daily, DRV/r 600/100 mg twice daily, FPV/r 700/100 mg twice daily, or LPV/r 400/100 mg twice daily (n = 20 each) for 20 days with co-administration of TVR 750 mg every 8 hours from day 11 onwards, or vice versa. All compounds were taken with food. In another study, 20 volunteers started TVR 750 mg every 8 hours for 7 days followed by EFV/tenofovir disoproxil fumarate (TDF) 600/300 mg once daily for 7 days after a washout. Subsequently, volunteers received TVR 1125 mg every 8 hours and EFV/TDF 600/300 mg once daily for 7 days or TVR 1500 mg every 12 hours and EFV/TDF 600/300 mg once daily for 7 days in a randomized order without a washout. TVR was taken with food and EFV/TDF was taken on an empty stomach in the morning. Least square means (LSMeans) and 90%CI of treatment ratios (test/reference) were calculated for the log-transformed AUCtau and Cmin

    39. New HCV Agents - Boceprevir Patients received a 4-week lead in with peg/rbv before starting boceprevir, hence, this will likely be used this way. Patients with a 1 log or more decline in viral load after the 4-week lead-in, 82% achieved SVR. Patients with undetectable viral load at week 8, 90% achieved SVR. 49% had anemia, 1% discontinued, 13% dose reduced due to anemia, 24% used EPO for treatment of anemia.

    40. New HCV Agents - Boceprevir RESPOND 2 study - The SVR were significantly higher in patients randomized to receive boceprevir (56-75%) compared to those who got peginterferon alfa-2b plus ribavirin alone (40 %). Week 4 lead-in response predicted SVR: if a patient had 1 log or more decline in viral load at week 4, 73-79% achieved SVR. The boceprevir treatment arm, was associated with an incremental risk of significant anemia compared to peginterferon/ribavirin, and epoetin alfa was more frequently used.

    41. Key Points about HCV/HIV

    42. What is true among the statements given below? HCV Genotype one has a poor response to treatment HCV Genotype one has more rapid progression to cirrhosis In HCV/HIV coinfection, if the HCV VL is low the development of cirrhosis is less In HCV/HIV coinfection, the dose of ribarvirin has no relationship to treatment response

    43. Hepatitis B Hepatitis B sex, perinatal, IDU, blood 350 million CAH-B worldwide 1.25 million CAH-B patients in U.S. Carriers increased risk of developing Cirrhosis, hepatic decompensation, and HCC 15-40% of carriers will develop serious sequelae in their lifetime Estimated 350 million worldwide are chronically infected with HBV; 1.25 million in US. CAH-B defined as HBsAg positive for greater than 6 months. Over 1 million have chronic HBV in US Relative risk of HBV from needle stick in HCW is 30%, vs. HIV 3% Most of children are asymptomatic but much more likely to have chronic disease. Estimated 350 million worldwide are chronically infected with HBV; 1.25 million in US. CAH-B defined as HBsAg positive for greater than 6 months. Over 1 million have chronic HBV in US Relative risk of HBV from needle stick in HCW is 30%, vs. HIV 3% Most of children are asymptomatic but much more likely to have chronic disease.

    44. Hepatitis B & HIV Acute HBV may be more severe Only 25% symptomatic: acute jaundice, elevated liver enzymes, fatigue, NVD 10% become chronic ? cirrhosis/CA in 20-30 yrs Ethanol, HIV, other hepatitis viruses ~10% of HIV+ have CAH-B HIV/HBV 19x > liver deaths than HBV alone 8x > liver deaths than HIV alone heavy use of alcohol (20 g/d in women and 30 g/d in men) may be a risk factor for the development of cirrhosis.heavy use of alcohol (20 g/d in women and 30 g/d in men) may be a risk factor for the development of cirrhosis.

    45. Hepatitis B & HIV 8 genotypes (A?H) Genotype A Most common in HIV/HBV in U.S.– 75% may respond best to pegIFN-a Genotype G Least common in HIV/HBV in U.S. – 25% Marker of rapid fibrosis Chronic hepatitis B does not change mortality All genotypes present in the US. At least A to G. Not sure on H Genotype A is widely distributed in Northwest Europe, North America and Central Africa, while genotypes B and C are present in Asia only; genotype D has been found worldwide with its highest prevalence in the Mediterranean area(16, 21) the Middle East and South Asia, particularly in India. Genotype E is found in sub-Saharan Africa and genotype F in South and Central America. Genotype G has been found in France and in USA, but recent data point to a Central America or Mexican origin, while the newly discovered genotype H, seems so far to be restricted to the northern part of Latin America Arq. Gastroenterol. vol.44 no.1 São Paulo Jan./Mar. 2007 Prevalence of HBV-genotypes in immigrants affected by HBV-related chronic active hepatitis Chronic hepatitis B does not change mortality All genotypes present in the US. At least A to G. Not sure on H Genotype A is widely distributed in Northwest Europe, North America and Central Africa, while genotypes B and C are present in Asia only; genotype D has been found worldwide with its highest prevalence in the Mediterranean area(16, 21) the Middle East and South Asia, particularly in India. Genotype E is found in sub-Saharan Africa and genotype F in South and Central America. Genotype G has been found in France and in USA, but recent data point to a Central America or Mexican origin, while the newly discovered genotype H, seems so far to be restricted to the northern part of Latin America Arq. Gastroenterol. vol.44 no.1 São Paulo Jan./Mar. 2007 Prevalence of HBV-genotypes in immigrants affected by HBV-related chronic active hepatitis

    46. Hepatitis B & HIV “Studies of nucleos(t)ide analogue therapies have not shown any relation between HBV genotypes and response” Additional data needed before HBV genotype determination in clinical practice is recommended. AASLD Practice Guidelines; Hepatology, Vol.50, No. 3, SEP 2009

    47. Serology of Chronic HBV HBsAg HBsAb HBeAg HBV DNA + - +/-* + *Pre-core protein/core promoter mutation Do not express HBeAg Lower HVB DNA than eAg+ Severe inflammation?cirrhosis Longer duration of disease?older More resistant to therapy Non-A genotypes, Asia/Europe Mutations prevents expression of eAg, poorer immune control/greater inflammatory response Moderate or high levels of persistent HBV replication or reactivation of HBV replication following a period of quiescence after HBeAg seroconversion leads to HBeAgnegative chronic hepatitis B, which is characterized by HBV DNA levels2,000 IU/ml and continued necroinflammation in the liver.78Most patients with HBeAg-negative chronic hepatitis B harbor HBV variants in the precore or core promoter region.Mutations prevents expression of eAg, poorer immune control/greater inflammatory response Moderate or high levels of persistent HBV replication or reactivation of HBV replication following a period of quiescence after HBeAg seroconversion leads to HBeAgnegative chronic hepatitis B, which is characterized by HBV DNA levels2,000 IU/ml and continued necroinflammation in the liver.78Most patients with HBeAg-negative chronic hepatitis B harbor HBV variants in the precore or core promoter region.

    48. Hepatitis B & HIV: “Occult” HBV Isolated HBcAb IgG HBsAg HBsAb HBcAg HBV DNA - - - + More common in HIV+ and HCV Diagnosed by HBV DNA positive If HBV DNA negative, vaccinate If HBV DNA neg, consider false pos. HBcAb vs check HBcAb-IGM to rule out acute infection window phase. Patients with HIV infection can have high levels of HBV DNA and hepatic necroinflammation with anti- HBc but not HBsAg, so called “occult HBV”.115 Therefore it is prudent to test all HIV infected persons for both HBsAg and anti-HBc and if either is positive, to test for HBV DNA. Persons who are negative for all HBV seromarkers should receive hepatitis B vaccine. If feasible, hepatitis B vaccine should be given when CD4 cell counts are 200/uL as response to vaccine is poor below this level. Persons with CD4 counts below 200 should receive HAART first and HBV vaccine when CD4 counts rise above 200/uL.115,116 HEP Sep 2009 It is unclear whether hepatitis B vaccine should be administered to patients with “isolated” anti-HBc because, in addition to a false-positive result, this pattern may signify exposure in the distant past with subsequent loss of anti-HBs or more rarely, occult HBV [1007]. One approach in this setting is to administer one dose of hepatitis B vaccine followed in 2 weeks by anti-HBs testing to determine if an anamnestic response occurs, although the overall response rate described in previous studies is low (16%) [973, 1008, 1009]. Larger studies in HIV-seronegative individuals with isolated anti-HBc demonstrate that most individuals mount a slow, or primary, rather than a rapid, or anamnestic, response after vaccination [1007]. The majority of HIV-infected patients with isolated anti-HBc are not immune to HBV infection and should be vaccinated with a complete primary series of hepatitis B vaccine (BII) [973, 1009]. Some experts would test for HBV DNA to rule out occult chronic HBV infection before administering a complete primary series of hepatitis B vaccine. If HBV DNA neg, consider false pos. HBcAb vs check HBcAb-IGM to rule out acute infection window phase. Patients with HIV infection can have high levels of HBV DNA and hepatic necroinflammation with anti- HBc but not HBsAg, so called “occult HBV”.115 Therefore it is prudent to test all HIV infected persons for both HBsAg and anti-HBc and if either is positive, to test for HBV DNA. Persons who are negative for all HBV seromarkers should receive hepatitis B vaccine. If feasible, hepatitis B vaccine should be given when CD4 cell counts are 200/uL as response to vaccine is poor below this level. Persons with CD4 counts below 200 should receive HAART first and HBV vaccine when CD4 counts rise above 200/uL.115,116 HEP Sep 2009 It is unclear whether hepatitis B vaccine should be administered to patients with “isolated” anti-HBc because, in addition to a false-positive result, this pattern may signify exposure in the distant past with subsequent loss of anti-HBs or more rarely, occult HBV [1007]. One approach in this setting is to administer one dose of hepatitis B vaccine followed in 2 weeks by anti-HBs testing to determine if an anamnestic response occurs, although the overall response rate described in previous studies is low (16%) [973, 1008, 1009]. Larger studies in HIV-seronegative individuals with isolated anti-HBc demonstrate that most individuals mount a slow, or primary, rather than a rapid, or anamnestic, response after vaccination [1007]. The majority of HIV-infected patients with isolated anti-HBc are not immune to HBV infection and should be vaccinated with a complete primary series of hepatitis B vaccine (BII) [973, 1009]. Some experts would test for HBV DNA to rule out occult chronic HBV infection before administering a complete primary series of hepatitis B vaccine.

    49. Counseling HBsAg Positive Sexual and household contacts need vaccination Newborn HBIG & HB Vaccine at delivery Abstinence or limited ETOH Prevention Barrier protection Cover cuts and scratches No sharing toothbrushes or razors No donating blood, organs, or sperm Clean blood spills with bleach or detergent AASLD Practice Guidelines; Hepatology, Vol.50, No. 3, SEP 2009

    50. Initial Evaluation H&P, FH of liver disease or HCC CBC, platelet, PT,PTT, CMP Urinalysis – if abnormal 24 hour urine for protein and creatinine HBeAg, HBeAb, HBV DNA HCV Ab., HDV Ab (if from endemic country or IDU) Liver US, Liver Biopsy AASLD Practice Guidelines; Hepatology, Vol.50, No. 3, SEP 2009 HDV Mediterranean areas and parts of south AfricaHDV Mediterranean areas and parts of south Africa

    51. HDV Mediterranean area, and parts of South Africa Occurs in two forms: Coinfection of HBV and HDV resulting in more severe acute hepatitis with higher mortality than acute HBV alone. Superinfection of HDV in a HPV carrier causing severe acute hepatitis and results in chronic infection with both viruses Increases risk of cirrhosis, decompensation, and HCC AASLD Practice Guidelines; Hepatology, Vol.50, No. 3, SEP 2009 A satellite virus dependant on HBV for production of envelope proteins.A satellite virus dependant on HBV for production of envelope proteins.

    52. Liver Biopsy Most useful in persons not meeting clear cut guidelines to treat HBV infected with LFT close to ULN (30 U/L for men; 19 U/L for women) especially if > 40 y/o may have abnormal histology and be at increased risk of mortality AASLD Practice Guidelines; Hepatology, Vol.50, No. 3, SEP 2009

    53. Risk Factors for Cirrhosis in CAH-B HBV DNA > 104 copies/mL [HR, 2.7) 105 [HR, 8.9-10.7] Male [HR, 3.0] Advanced age [HR, 3.6-8.3] Habitual alcohol consumption [HR, 2.6] HBV genotype C Coinfection with HCV or HDV or HIV Clinical Gastroenterology & Hepatology 2008; 6:1315-1341. AASLD Practice Guidelines; Hepatology, Vol.50, No. 3, SEP 2009 Previously established ULN in Male was 40 IU/mL and for Female was 30 IU/mLPreviously established ULN in Male was 40 IU/mL and for Female was 30 IU/mL

    54. HCC Screening Recommendations Asian men > 40, Asian women > 50, persons with cirrhosis, those with FH of HCC, Africans > 20, and any carrier > 40 y/o with persistent or intermittent ALT elevation and/or high HBV DNA >2,000 IU/mL needs US examination every 6-12 months AFP if US not available AASLD Practice Guidelines; Hepatology, Vol.50, No. 3, SEP 2009

    55. Risk Factors for HCC in CAH-B Cigarette smoking Older age Reversions from HBeAb+ to HBeAg+ Presence of cirrhosis 30-50% HCC occur in absence of cirrhosis HBV genotype C Core promoter mutation HCV coinfection Male gender FH of HCC AASLD Practice Guidelines; Hepatology, Vol.50, No. 3, SEP 2009

    56. Who to Treat? All patients with HBV/HIV need to be treated However, in HBV mono infection,- Anti-HBV treatment indicated if ? ALT and HBV DNA level > 20,000 IU/mL if HBeAg-positive 2,000 IU/mL if HBeAg-negative Some experts treat any level of HBV DNA especially if ALT is ? or if significant inflammation &/or fibrosis on biopsy

    57. When to Treat & With What (lamivudine or emtricitabine) + tenofovir backbone + ART drug Indefinite tx FLARES with stopping meds or onset of YMDD resistance — USE CAUTION 3TC resistant – entecavir or peg-IFN added Telbivudine – no data yet in HIV. Not effective against lamivudine resistant HBV Famciclovir -modest to good HBV DNA suppression -improvement in ALT/histology is more significant -may achieve HBeAg - in 40% -better in combo w/ lamivudine -possible consideration in future Telbivudine – no data yet in HIV. Not effective against lamivudine resistant HBV Famciclovir -modest to good HBV DNA suppression -improvement in ALT/histology is more significant -may achieve HBeAg - in 40% -better in combo w/ lamivudine -possible consideration in future

    58. One study suggested 24 month needed for HBeAg negative patients treated with Standard IFN alpha. Efficacy of PegIFN similar to or slightly better than IFN alpha. IFN treatment is accompanied by a flare in ALT in 30-40% of patients, such flares indicate a positive response but can lead to hepatic decompensation. Lamivudine is well tolerated in decompensated cirrhosis and can stabilize or improve liver function.One study suggested 24 month needed for HBeAg negative patients treated with Standard IFN alpha. Efficacy of PegIFN similar to or slightly better than IFN alpha. IFN treatment is accompanied by a flare in ALT in 30-40% of patients, such flares indicate a positive response but can lead to hepatic decompensation. Lamivudine is well tolerated in decompensated cirrhosis and can stabilize or improve liver function.

    59. Monitoring Nucleos(t)ide LFT q 3 months HBV DNA q 3-6 months HBeAg and HBeAb at end of 1 yr treatment and every 3-6 months therafter Virologic Breakthrough - Defined as > 1 log10 increase in HBV DNA from nadir during treatment AASLD Practice Guidelines; Hepatology, Vol.50, No. 3, SEP 2009 The durability of response after cessation of treatment is expected to be 70% to 90%. Viral relapse and exacerbations of hepatitis may occur after discontinuation of lamivudine therapy,201 including patients who have developed HBeAg seroconversion, and may be delayed up to 1 year after cessation of treatment. Thus, all patients should be closely monitored after treatment is discontinued (every 1-3 months for the first 6 months, and every 3-6 months thereafter). The end point of treatment for HBeAg-negative chronic hepatitis B is unknown. Post-treatment relapse can occur even in patients with persistently undetectable serum HBV DNA by PCR assay.The durability of response after cessation of treatment is expected to be 70% to 90%. Viral relapse and exacerbations of hepatitis may occur after discontinuation of lamivudine therapy,201 including patients who have developed HBeAg seroconversion, and may be delayed up to 1 year after cessation of treatment. Thus, all patients should be closely monitored after treatment is discontinued (every 1-3 months for the first 6 months, and every 3-6 months thereafter). The end point of treatment for HBeAg-negative chronic hepatitis B is unknown. Post-treatment relapse can occur even in patients with persistently undetectable serum HBV DNA by PCR assay.

    60. Remember If altering ARV regimen do not discontinue HBV medications without substituting other HBV therapy unless HBeAg seroconversion has occurred If stop HBV treatment, monitor closely for relapse AASLD Practice Guidelines; Hepatology, Vol.50, No. 3, SEP 2009 Seroconversion is the loss of HBeAg and presence of HBeAb in a person who was previously HBeAg positive and HBeAb negative.Seroconversion is the loss of HBeAg and presence of HBeAb in a person who was previously HBeAg positive and HBeAb negative.

    61. Genetic Barrier Figure 3. Antiviral activity and genetic barrier for resistance of current anti-HBV agents. ADV = adefovir; ETV = entecavir; FTC = emtricitabine; IFN = interferon; LAM = lamivudine; LdT = telbivudineFigure 3. Antiviral activity and genetic barrier for resistance of current anti-HBV agents. ADV = adefovir; ETV = entecavir; FTC = emtricitabine; IFN = interferon; LAM = lamivudine; LdT = telbivudine

    62. Defining Treatment Response Virologic response is HBV DNA <2,000 IU/mL at 24 weeks if on IFN Undetectable within 48 weeks on NUC Non-response is < 1 log10 IU/mL decrease from baseline at 3 months Breakthrough is > 1 log10 IU/mL increase compared to nadir

    63. What is true among the statements given below? Entecavir has no activity against HIV Peg-interferon has activity against HCV but not HBV In treating HBV/HIV co infection a liver biopsy will be very useful In treating HCV in coinfection a liver biopsy may be very useful When using direct acting antiviral we can avoid peg-interferon.

    64. Key Points about HCV/HIV

    66. Thank You Dushyantha Jayaweera, M.D., M.R.C.O.G., F.A.C.P. Professor in Clinical Medicine Division of Infectious Diseases University of Miami Miller School of Medicine

    67. Disclosure of Financial Relationships This speaker has the following significant financial relationships with commercial entities to disclose: Speaker – Tibotec, Merck, BIPI, Gilead, BMS Research Support – ViiV, Tobira Pharmaceuticals, Vertex, Pfizer Consultant – ViiV, Tibotec, Gilead

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