hiv and hepatitis c and b co- infection debika bhattacharya, md, ms ucla center for clinical aids...
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HIV and Hepatitis C and B Co-Infection
Debika Bhattacharya, MD, MS
UCLA Center for Clinical AIDS Research & Education
Assistant Clinical Professor of Medicine
David Geffen School of Medicine at UCLA
Overview
• Epidemiology• Natural history of HCV • Diagnosis• Treatment
J.B.’s story
• J.B was recently diagnosed with HIV and HCV.• He used to inject drugs and have unprotected
sex with men most of whom were HIV+, but hasn’t used injection drug in 2 years and is now in a monogamous relationship with a male HIV-negative partner over the last year.
• “What is hepatitis C and how did I get it ?”
What should you tell him?
• Hepatitis C is a virus and you probably contracted it by sharing needles but may have acquired it through sex.
• Hepatitis C is a flesh-eating bacteria and you contracted it by drinking contaminated water
• I don’t know—I fell asleep during those talks
What should you tell him?
• Hepatitis C is a virus and you probably contracted it by sharing needles but may have acquired it through sex.
• Hepatitis C is a flesh-eating bacteria and you contracted it by drinking contaminated water
• I don’t know—I fell asleep during those talks
United States >4 M
Americas>12 M
Africa >33 M
Australia>0.6 million
Western Europe
>10 million
>184 Million (M) Carriers WorldwideHepatitis C: A Global Health Problem
Eastern Europe
>10 million
Far East Asia>50 million
South/Southeast Asia>60 million
Mohd Hanafiah K et al. Hepatology. 2013;57(4):1333-42.
Prevalence of HCV Among Persons with HIV in the US
Thomas D. Hepatology. 2002;36:S201-S209. Courtesy Sylvestre
30%
70%
HCV/HIV Coinfected HIV monoinfected
HIV/HCV Overview
Epidemiology– Prevalence– Transmission
Prevention
– HCV genotypesNatural history of HCVDiagnosisTreatment
How do you get hepatitis C?
Source: Sentinel Counties, CDC
Sexual 15%
Other 1%*
Unknown 10%
Injecting drug use 60%
Transfusion 10%(before screening)
* Nosocomial; iatrogenic; perinatalSource: Centers for Disease Control and Prevention
Occupational 4%
Sexual Transmission
HETEROSEXUAL• Prevalence estimates of 2-10%• Monogamous couples in Italy1
– 3 infections• 0.37 per 1000 persons-years• Phylogenetic analysis:
discordant virus • HCV Partners Study (Northern
California)2
– HCV prevalence among partners of 4% (n=20), 11 discordant virus
– maximum incidence rate of HCV transmission by sex was 0.07% per year (95% CI 0.01-0.13)
HIV-INFECTED MSM Prevalence of 6-15.7% (East
Coast, Australia, SF, Europe)3-7
Estimated incidence rates of 0.83-0.87 per 100 person-years8,9
aOR of 4.5-5.7 for HCV infection compared to HIV-uninfected MSM8,10-11
1Vandelli C, et al. Am J Gastroenterol 2004, 2Terrault et al, Hepatology 2013, 3Garg et al, CID 2013, 4Wandeler et al, CID 2012, 5Raymond et al, Sex Transm Dis 2012, 6 Matser et al, PLoS One 2013, 7Matthews et al, CID 2011, 8Van de Laar et al, JID 2007, 9Ghosn Sex Transm Infect 2006, 10Richardson et al, JID 2008; 11Hammer Sex Transm Dis 2003
Risk Factors for Sexual Transmission
• Traumatic sexual practices (anal mucosal damage) – fisting, sex toys, bleeding
• Multiple partners, group sex• Non-injection drug use, particularly
stimulant use• Genital ulcer disease
Van de Laar et al, AIDS 2010Yaphe et al, Sex Transm Infect 2012
How can you prevent hepatitis C?
Do not reuse or share syringes, needles, water, or drugworks.
Do not share personal care items that might have blood
i.e. toothbrushes and razorsConsider health risks of tattoos and body-
piercingUse condoms
www.cdc.gov Hepatitis C Fact Sheet 2008
You will not get hepatitis C through:
• Breastfeeding • Sneezing • Hugging or kissing • Coughing • Sharing eating utensils or drinking glasses • Food or water • Casual contact
www.cdc.gov Hepatitis C Fact Sheet 2008
HIV/HCV Overview
Epidemiology– Prevalence– Transmission– HCV genotypes
Natural history of HCVDiagnosisTreatment
J.B’s story
• J.B.’s doctor also told him that he has genotype 3 disease
• “Why does it matter what type of hepatitis C I have?”
HCV genotypes:“Know your genotype”
HCV genotypes 1-6Genotypes 1-3 most common in USGeographic Distribution
HCV genotypes
Differ in Treatment ResponsesGenotype 3
– Lower likelihood of achieving cure– Even with newer antiviral agents
Genotypes 1,2– Higher likelihood of achieving cure– Genotype 1
Subtype matters; 1a vs 1b
HIV/HCV Overview
EpidemiologyNatural history of HCV
– How HIV impacts hepatitis CDisease Progression
DiagnosisTreatment
Acute Hepatitis C
Chronic Hepatitis 75%-85%
Cirrhosis 20%
10-20 years
Hoofnagle JH Hepatology. 1997;26 (suppl 1): 15S-20SDi Bisceglie, Hepatology, 2000
Natural History of Hepatitis C
Most patients with chronic HCV infection are asymptomatic
Sequelae of HCV Infection
• FibrosisCirrhosisLiver failure• Decompensated liver disease: ascites,
variceal bleeding, hepatic encephalopathy• Hepatocellular carcinoma (HCC)
• Death – increased mortality from both liver and non-liver diseases
HIV/HCV Overview
EpidemiologyNatural history of HCV
– How HIV impacts hepatitis CDisease Progression
DiagnosisTreatment
HIV accelerates natural history of HCV
• HIV accelerates rate of liver fibrosis progression– 2.9 times higher in HIV/HCV co-infection1
– Progression to cirrhosis occurs in • 15%-25% of HIV/HCV coinfected patients• 3%-6% of HCV mono-infected patients2-3
– Time to progression• 6 to 10 years in HIV/HCV coinfected individuals4
• 20 to 30 years in HCV mono-infected patients
1. CDC. MMWR. 2004;53(RR-15):49-53 2. Verucchi Infection. 2004;33:33-46. 3. Khalili M, Gastroenterol Clin N Am. 2004;33:479-496. 4. Chun S, Clin Liver Dis. 2005;9:525-533
Mortality by HCV status with AIDS Dx in cART era
Branch et al, CID 2012;55(1):137–44: Longitudinal Studies of the Ocular Complications of AIDS Cohort
In adjusted analysis: 50% increased risk of death with chronic HCV compared to HCV negative (RR 1.5, 95% CI 1.2-1.9)
20% = liver-related deaths
Proportion of deaths related to CVD, AIDS, non-AIDS cancers similar
Chronic
ClearedNo HCV
HIV/HCV Overview
EpidemiologyNatural history of HCVDiagnosisTreatment
HIV/HCV Overview
• Epidemiology• Clinical Course of HCV• Diagnosis
– Who should get tested?– HCV antibody and virologic testing– Liver biopsy– Noninvasive markers
• Treatment
Who should get tested for hepatitis C?CDC guidelines1
• Individuals with HIV• Individuals with hepatitis B• Individuals with a history of injection drug use• received a blood transfusion or solid organ transplant before July,
1992 • were a recipient of clotting factor(s) made before 1987 • have ever been on long-term kidney dialysis • have evidence of liver disease (e.g., persistently abnormal ALT levels)
Additional Recommendations2: 1945-1965 Birth Cohort • Prevalence of anti-HCV among persons born from 1945 to 1965 is
3.25%, 5x higher than among adults born in other years• Adults born during this time should receive one-time testing for HCV
regardless of prior HCV exposure risk
1. http://www.cdc.gov/hepatitis/hcv/guidelinesc.htm2. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6104a1.htm
HIV/HCV Overview
• Epidemiology• Clinical Course of HCV• Diagnosis
– Who should get tested?– Types of blood tests: antibody and virus– Liver biopsy– Noninvasive markers
• Treatment
Hepatitis C Diagnosis:Blood Tests to detect presence of HCV
• 1. Antibody• 2. Virus
Hepatitis C TestingAntibody Test
Antibody test (EIA)– Indicates past or active infection– Unlike hepatitis B, presence of antibodies
does not indicate immunity– Mean time to seroconversion: 10 weeks– 98% sensitive and specific
Special considerations for hepatitis C antibody testing in HIV infection
• Individuals who may not have HCV antibodies– CD4<200– Acute HCV
HCV Ab test less sensitive in HIV+ patients
• Up to 19% of HIV+ individuals with chronic hepatitis C have negative HCV Ab titers1
– CD4 count below 200 cells/mm3 (OR 2.80)2
• HCV RNA PCR (viral load) testing is indicated if chronic hepatitis C suspected– Unexplained transaminitis– History of IDU
1. George, et al. JAIDS 2002;31:154-1622. G Chamie, XVI International AIDS Conference. Toronto,
August 13-18, 2006. Abstract WEPE0046/13774.
Hepatitis C Testing:Virus Test
PCR
HCV RNA test (PCR)– Confirms active infection, infectivity to others– Quantitative or qualitative RNA tests exist; the
former is more often used because it provides a potentially useful viral load measurement
HIV/HCV Overview
• Epidemiology• Clinical Course of HCV• Diagnosis
– HCV Ab testing– Liver biopsy and noninvasive markers
• Treatment
How do we measure how much liver disease (fibrosis) a patient has?
• LIVER BIOPSY– Has been considered the gold standard– Subject to sampling error– Consider quality of biopsy specimen
• NON-INVASIVE MEASURES– Blood: perform well at extremes (minimal vs advanced fibrosis), not in mid ranges
• FIB-4: age, plt, ALT, AST; validated for HIV/HCV• FibroSURETM: alpha2 macroglobulin, alpha2 globulin, gamma globulin, apolipoprotein A1,
GGT, total bilirubin • APRI: AST-to-platelet ratio index; lower accuracy in HIV/HCV coinfection
– Transient elastography (FibroScan)
• LIVER ULTRASOUND – 88% sensitivity, 82-95% specificity for cirrhosis
Histologic Staging
No Fibrosis Portal Fibrosis Few septa
Stage 0 Stage 1 Stage 2
Numerous septa
Stage 3Cirrhosis
Stage 4
HIV/HCV Overview
• Epidemiology• Clinical Course of HCV• Diagnosis• Treatment
Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring, MD.
SV
R (
%)
IFN6 mos
PegIFN/ RBV
12 mos
IFN12 mos
IFN/RBV12 mos
PegIFN12 mos
2001
1998
2011
StandardIFN
RBV
PegIFN
1991
DAAs
PegIFN/RBV/DAA
IFN/RBV6 mos
6
16
3442 39
55
70+
0
20
40
60
80
100
DAA + RBV
± PegIFN
90+
2013
The Good News
HCV Life Cycle and DAA Targets
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
Receptor bindingand endocytosis
Fusion and
uncoating
Transportand release
(+) RNATranslation
andpolyprotein processing
RNA replication
Virionassembly
Membranousweb
ER lumen
LD
LDER lumen
LD
NS3/4 protease inhibitors
NS5B polymerase inhibitors
Nucleoside/nucleotide
Nonnucleoside
Block replication complex formation, assembly
NS5A inhibitors
RNA replication
Successful HCV treatment reduces risk of death and liver complications in HIV-
infected persons
Berenguer et al, CID 2012;55:728-36
Overall deaths Liver-related deaths
SVR = sustained virologic responseOverall deaths 9.2% non-SVR vs 1.3% SVRLiver-related deaths 5.7% vs 0.5%
Even
t –f
ree
surv
ival
J.B.’s StoryJ.B. wants to start treatment.
What can you tell him?
A. JB may clear the virus from his systemB. JB doesn’t need to worry about side
effects with his HIV medicationsC. There is no treatment for JBD. There may be newer, more effective
treatment for JB
J.B.’s StoryJ.B. wants to start treatment.
What can you tell him?
A. JB may clear the virus from his systemB. JB doesn’t need to worry about side
effects with his HIV medicationsC. There is no treatment for JBD. There may be newer, more effective
treatment for JB
HIV/HCV Overview
• Epidemiology• Natural history of HCV• Diagnosis• Treatment
Pegylated interferon and ribavirin (PR)
Has been the standard of care for HIV-infected patients (and until 2011, for HCV monoinfected patients)
Inadequate response rates in HIV– Genotype 1: 14-29% SVR– Genotype 2/3: 44-73% SVR
Chung RT et al, NEJM 2004; Torriani FJet al, NEJM 2004; Carrat F et al, JAMA 2004
Drug Classes
• Protease Inhibitors: --Previr– Simeprevir, Paritaprevir, Boceprevir, Telaprevir
• NS5B Inhibitors: --Buvir– Nucleotide Inhibitors
• Sofosbuvir
– Nonnucleotide Inhibitors• Dasabuvir
• NS5A Inhibitors: --Asvir– Ledipasvir, ombitasvir, daclatasvir
FDA-approved agents for HCV (as of August 2015)
• Interferon (pegylated, consensus, standard)• Ribavirin (with interferon)• HCV protease inhibitors:
– Boceprevir with PR – Telaprevir with PR– Simeprevir with PR
• HCV nucleotide polymerase inhibitor:– Sofosbuvir (with PR for GT1/4 and with RBV for GT 2/3)
• HCV NS5A inhibitor:– Daclatasvir
• Combination Regimens– Sofosbuvir/Ledipasvir– Paritaprevir/ritonavir/ombitasvir/dasabuvir
Phase III Studies of Sofosbuvir (Nuc) + Ledipasvir (NS5A) ± RBV in GT1 HCV
ION-1*: GT1 treatment-naive pts (16% cirrhotic): SOF/LDV
FDC ± RBV for 12 wks
Press release. These data are available in press release format only, have not been peer reviewed, may be incomplete, and we await presentation or publication in a peer-reviewed format before conclusions should be made from these data.
*24-wk arms not yet reported.
ION-3: GT1 treatment-naive pts: SOF/LDV FDC ± RBV
for 8 or 12 wks
SOF/LDV FDC SOF/LDV FDC + RBV
ION-2: GT1 treatment-experienced pts (20% cirrhotic): SOF/LDV FDC ±
RBV for 12 or 24 wks
8 Wks 12 Wks
202/215
206/216
201/216
12 Wks 24 Wks
102/109
107/111
108/109
110/111n/N =
209/214
211/217
SV
R12
(%
)
12 Wks
98 97100
80
60
40
20
0
94 93 95 94 96 99 99
ION-4: SOF/LDV for 12 Wks in GT 1/4 HIV/HCV Coinfection
• SOF/LDV for 12 weeks in HIV/HCV coinfected participants on ARV (n=335)– ART included TDF/FTC + EFV, RAL, or RPV– SVR12 96% overall but 10 relapses – all in black
patients– No patient with HIV virologic rebound– 4 patients had increase in creatinine >0.4 mg/dL
Naggie S, et al. CROI 2015. Abstract 152LB.
How to approach… genotype 3 patientsRegimen Cirrhosis TE Weeks Study SVR
Sofosbuvir + RBV No No 24 VALENCE 86/92 (93%)
Sofosbuvir + RBV Yes No 24 VALENCE 12/13 (92%)
Sofosbuvir + RBV No Yes 24 VALENCE 85/100 (85%)
Sofosbuvir + RBV Yes Yes 24 VALENCE 27/45 (60%)
Sofosbuvir + ledipasvir 12% No 12 ELECTRON-2 16/25(64%)
Sofosbuvir + ledipasvir + RBV 19% No 12 ELECTRON-2 26/26(100%)
Sofosbuvir + ledipasvir + RBV No Yes 12 ELECTRON-2 25/28(89%)
Sofosbuvir + ledipasvir + RBV Yes Yes 12 ELECTRON-2 16/22(73%)
PEG/RBV + Sofosbuvir No Yes 24 LONESTAR 10/12(83%)
PEG/RBV + Sofosbuvir Yes Yes 12 LONESTAR 10/12(83%
Sofosbuvir + PEG + RBV Yes Yes 12 BOSON (EASL 2015) 30/35 (86%)
Sofosbuvir + daclatasvir No No 12 ALLY-3 73/75(97%)
Sofosbuvir + daclatasvir No Yes 12 ALLY-3 32/34 (94%)
Sofosbuvir + daclatasvir Yes No 12 ALLY-3 11/19 (58%)
Sofosbuvir + daclatasvir Yes Yes 12 ALLY-3 9/13 (69%)
Sofosbuvir + daclatasvir ± RBV (20%RBV) 76% 73% 24 Hezode (EASL 2015) 52/59 (88%)
Sofosbuvir + daclatasvir + RBV Yes Unknown 12 Poordad (EASL 2015) 5/6 (83%)
Sofosbuvir + GS5816 No No 12 Everson (EASL 2014) 25/27 (93%)
Sofosbuvir + GS5816 + RBV No Yes 12 Pianko 53/54 (98%)
Sofosbuvir + GS5816 + RBV Yes Yes 12 Pianko 46/51 (90%)
Grazoprevir + elbasvir + Sofosbuvir Yes No 12 Poordad (EASL 2015) 10/11 (91%)
HCV treatment for HIV-infected persons
• HCV treatment should be considered in ALL HIV-infected persons
• In those with CD4<200 cells/cmm and not on ART, can consider delaying HCV therapy until CD4 improved on ART
• In those with CD4> 500 cells/cmm and HIV treatment naïve, can consider deferring ART until completion of HCV treatment (pill burden, drug interactions, toxicities)
DHHS Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents, March 28, 2012
HIV & HCV: Conclusions
• HIV accelerates the course of HCV disease
• Special considerations in HIV disease– Testing
• Antibody and Liver Biopsy– Treatment
• HCV treatment is indicated, beneficial, feasible
Overview
• Epidemiology• Natural history of HBV • Diagnosis• Treatment
Global Scope of HIV-HBV Co-infection
35-40 million 350-400
million
3-4 million
HIV CHB
HBsAg+
90% (36 million) of HIV-infected persons have HBV markers
Thio CL, AASLD, Boston, 2004
Epidemiology of HBV Infection in HIV Patients
• 65-90% of HIV patients having markers of current or prior HBV infection1,2
• 7-9% have chronic hepatitis B1-5
• MSM, IDU and immigrants from areas of high HBV endemicity most often affected
1. Shire NJ et al. JAIDS 2004;36:869-75. 2. Rodriguez-Mendez, et al. Am J Gastro 2000;95:1316-223. Kellerman SE, et al. J Infect Dis 2003;188:571-577 4. Thio, et al. Lancet 2002;360:1921-265. Ockenga J et al. J Hepatol 1997;27:18-24.
Hepatitis B Disease Progression
Acute Infection
Chronic Infection
Cirrhosis
Death
1 Torresi J, and Locarnini S, Gastroenterology 2000.2 Fattovich, G, Giustina, G, Schalm, SW, et al, Hepatology 1995.3 Moyer LA and Mast EE. Am J Prev Med. 1994.4 Perrillo R et al. Hepatology 2001.
5%-10% 1
Liver Failure (Decompensation)
30% 1
23% within 5 years 3
Liver Cancer (HCC)
CHB: 6th leading cause of liver transplantation in the US 4
Liver Transplantation
• MACS cohort, U.S.• 5293 MSM
– 48% (2559) HIV +• 8.3% (213/2559) HBSAg +
• Liver-related mortality:– 19 X in co-infected patients vs. HBV monoinfection (p<0.001)– 8 X in co-infected patients vs. HIV monoinfection (p<0.001)
Thio CL et al. Lancet 2002; 360: 1921-1926.
Serologic Screening for HBV in Co-infection
- - - Naïve (Immunize)
- + - Immune (vaccine induced)
- + + Resolved infection (immune)
- - + Latent or occult infection or
False +
+ - + Acute or chronic infection (assess duration)
HBsAg Anti-HBs Anti-HBc Interpretion
Prevention of HBV
¨ Behavioral counseling– safer sex practices– safer injection practices
¨ Immunization– all HIV+ with HBsAg-/HBs Ab- – unclear what to do with isolated HbcAb+– household members and sexual partners of chronic HBV
patients
Care of the HIV/HBV Co-infected Patient
¨ Behavioral counseling (reduce transmission)¨ Alcohol reduction¨ Screen for HAV immunity (immunize if negative)¨ Immunization of household members & sexual partners
for HBV¨ Serial monitoring of aminotransferases and tests of
hepatic synthetic function (INR, albumin)¨ Treatment of cirrhosis (if present)¨ Monitor for hepatocellular carcinoma¨ Drug therapy of HIV and HBV¨ Transplantation for decompensated cirrhosis
Treatment for HBV in HIV
¨ Treatment with antiretroviral therapy is recommended for all HBV/HIV coinfected, regardless of CD4 count or HBV disease stage
¨ Antiretroviral therapy regimen should include tenofovir and lamivudine (TDF and 3TC)
¨ Minimizes hepatitis B drug resistance
HIV/HCV resources for patients and educators
• CDC - HIV and Viral Hepatitis: http://www.cdc.gov/hiv/resources/factsheets/hepatitis.htm
• VA resources for the public: http://www.hepatitis.va.gov/patient/index.asp
http://www.hepatitis.va.gov/patient/diagnosis/ coinfection-index.asp• DHHS guidelines on HIV-1 treatment:
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf
• IDSA/AASLD/IAS-USA HCV Guidelines: www.hcvguidelines.org