27 puoti.ppt [compatibiliteitsmodus]regist2.virology-education.com/2011/9eu/docs/27_puoti.pdf ·...

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus

HIV-HBV co-infections

Massimo Puoti

Dept. of Infectious Diseases

AO Ospedale Niguarda Cà Granda


HIV –HBV coinfection - Outline

• Rationale for treatment• How to use anti HBV tools in HIV+• When to start• How to treat• Open issues



• Rationale for treatment• How to use anti HBV tools in HIV• When to start• How to treat• Open issues


The global geographic distribution and annual mortality of chronic hepatitis B virus infection

and HIV infection.

Alter MJ J Hepatology 2006Centers for Disease Control and Prevention. Hepatitis B slide set. Available at: ttp://www.cdc.gov/ncidod/diseases/hepatitis/slideset/index.htm. 5. UNAIDS/WHO. HIV prevalence in adults, end 2006. Available at: http://data.unaids.org/Topics/Epidemiology/Slides02/AdultPrevJuly04Global_en.ppt#1.

350 million6%

40 million1%

2 - 4 million0.05 - 0.1%

Persons infected: n % of world population

Deaths in 2008 n % of infected

600.0000.2%

3 million7.5%

HBV HIV


Prevalence of HBV Co-infection in persons living with HIV in EuroSIDA cohort

• Among 9803 subjects in the EuroSIDA Cohort:

– 5883 had a HBsAgtest available attime of enrollment

• 530 (9%) were positive

North:HBsAg +:9.7 %

Central HBs Ag+ 9.2%

South HBsAg+ 9.1%

East HBsAg+: 6%

Argentina

HBV+: 17.8%

Konopnicki D et al.; AIDS. 2005.


HBV prevalence stable over 11 years in HOPS

Spradling et al JVH epub Feb 2010


Liver disease remains 2nd leading cause of death in later HAART era in HIV-infected

persons in D:A:D

• 33,308 participants from 1999-2008– 15.3% with HCV (Ab or RNA+)– 11.5% HBV (prior/active)

• 2482 deaths– 29.9% AIDS-related– 13.7% liver-related– 11.6% CVD-related

• Liver-related deaths declined over time– 2.67/1000 PYs (99-00) to 1.45/1000 PYs (07-08)

• Rates highest in CD4<100 cells/mm3

D:A:D study, AIDS Jun 2010 24 (10)


Factors associated with liver-related death in D:A:D

Factor Adjusted RR 95% CIAge, per 5 years older 1.16 1.09-1.24IDU (MSM reference) 5.02 3.56-7.08HTN 2.34 1.83-2.99Diabetes 2.37 1.68-3.35HCV 1.67 1.21-2.31HBV 2.37 1.74-3.22CD4 count per 50 cell/uL increase

0.82 0.79-0.85

HIV RNA >5 log cp/ml 1.68 1.01-2.80

D:A:D study, AIDS Jun 2010 24(10)


Impact of HBV on HIVART Reinitiation and HBV Rebound among HIV/HBV-co-infected Patients following ART Interruption in the Strategies for the Management of ART

(SMART) Study

Table 3. Predictors of antiretroviral therapy re-initiation in the SMART drug conservation arm. Multivariate model.

0.00031.13 (1.06 – 1.20)<0.00011.15 (1.08-1.22)Age (/10 years)

0.891.01 (0.88 – 1.16)0.610.97 (0.84-1.11)Female

<0.00011.19 (1.11 – 1.28)<0.00011.34 (1.25-1.44)Highest HIV RNA (Log10)

0.0121.19 (1.04 – 1.37)0.0111.18 (1.04-1.34)Baseline HIV RNA ≤400 copies/ml

<0.00011.14 (1.11 – 1.18)<0.00011.20 (1.16-1.23)Baseline CD4 count (/100 cells lower)

<0.00011.50 (1.42 – 1.58)<0.00011.67 (1.60-1.75)Nadir CD4 count (/100 cells lower)

<0.00011.41 (1.24 – 1.61)<0.00012.17 (1.91-2.45)Prior AIDS

0.661.04 (0.88 – 1.22)0.871.01 (0.87-1.18)HCV

0.00051.71 (1.27 – 2.31)<0.00011.95 (1.45-2.63)HBV

PMultivariateHazard ratio

PUnivariateHazard ratio

SMART study randomized HIV patients with a CD4 count above 350 cells/µL to a drug conservation (interrupt ART until CD4 <250 cells/µL) versus viral suppression (continued use of ART) group120 HBV coinfected from SMART study Frequent HBV DNA rebound following ART interruption accelerated immune deficiency.

Dore JG et al AIDS 2010; 24: 857-65


Impact of HIV on HBV• Increased rate of chronicization (Bodsworth, JID 1989; Hadler, JID 1991)

• Decreased rate of HBeAg seroconversion (Krogsgaard, Hepatology 1987; Bodsworth, JID 1989; Gilson, AIDS 1997)

• Increased rate of reactivation in “occult infection” (Piroth J Hepatol 2002)

• Decreased necroinflammatory activity (Bodsworth, JID 1989; Mills, Gastroenterol 1990; Goldin, J Clin Pathol 1990; Gilson, AIDS 1997)

• Increased rate of HBV replication (Perillo, Ann Int Med 1986; McDonald, J Hepatol 1987; Colin, Hepatology 1999; Gilson, AIDS 1997)

• Increased evolution towards cirrhosis (Colin, Hepatol 1999; Di Martino, Gastroenterology 2002)

• Increased rate of cirrhosis decompensation if CD4 < 200 (Di Martino Gastroenterology 2002)

• Increased risk of HCC especially in immunosuppressed MSM (Kew et al JAIDS 2010 Clifford AIDS 2008)

• Increased Liver Related Mortality (Thio The Lancet 2002)

Case Control Cross sectionalCase control prospectiveCohort prospective

Puoti M et al. J Hepatology 2006 modified


Rationale for treatment of HBV in HIV +

2 - 4 million of persons co-infected6-9% persons with HIV are HBsAg+Stable prevalence of HBV coinfection in persons living with HIV HBV infection in HIV+: worse course and higher mortality it causes directly 3% of all deaths in HIV+ developed world

Puoti M et al J Hepatol 2006 modified


HIV‐HBV coinfection

• Strong rationale for treating HBV in persons living with HIV


Interferons

AntiviralsRT e DNApol inhibitorsLamivudine, AdefovirEntecavir ,TelbivudineTenofovir, Emtricitabine,

Active against HIV: only with ARTNot active against HIV

dNTP pool

HIV

B cell Anti HBsAnti HBe


Is Telbivudine active against HIV ?

HIV VIRAL LOAD OVER TIME

YESCase report45 years old man HBsAg+ HBeAg + 662,000,000 cp/mLCD4 613; HIVRNA 14,462 cp/mLHe opted for ADV+TBD vs. TDF based ART

NONo activity in several in vitro experiments:BH-10 and NL4-3 in cells treated for 3 to 7 days, PhenoSense™ HIV assay:drug sensitive ref. HIV-1 strain (CNDO), a multi-drug resistant strain (MDRC4), 8 different wild-type HIV-1 clinical isolates (A, B, BF, C, and D), 2 HIV multi-drug resistant strains

Avila C et al CROI 2009 Poster abstract 813bLow E et al AIDS 2009


Telbivudine In Vivo Direct Inhibitory Activity against HIV-1 RT?

Milazzo L, et al. Antivir Ther 2009; 14:869-872


HIV-HBV coinfection


• Indication to HAART strongly influence the choice of treatment strategy


Hepatitis Cirrhosis Decompensated cirrhosis

Fibrosis No Mild Moderate Severe

METAVIRIshak’s

F0S0

F1S 1-2

F2S3

F3S4

F4S5-6

HBVDNA : >2.000 UI/mL > 15 UI/mL

Consider treatment Treat

CD4 > 500From G. Carosi, M Rizzetto. Treatment of chronic hepatitis B: recommendations from an Italian Workshop.Dig Liv Dis 2011 i

Consider OLT


Hepatitis Cirrhosis Decompensated cirrhosis

Fibrosis No Mild Moderate Severe

METAVIRIshak’s

F0S0

F1S 1-2

F2S3

F3S4

F4S5-6

HBVDNA : > 2000 UI/mL > 15 UI/mL

Treat

Do not stop anti HBV drugsCD4 < 500

From G. Carosi, M Rizzetto. Treatment of chronic hepatitis B: recommendations from an Italian Workshop.Dig Liv Dis 2010 in pressConsider OLT


HIV-HBV coinfection


• Indication to HAART strongly influence the choice of treatment strategy

• Disease stage, HBVDNA and CD4 counts the main determinants of treatment initiation and maintenance


HBV/HIV coinfectioncontroversies across guidelines

Guideline EACS1 BHIVA 2 DHHS3 EASL4 AASLD5

CD4 CUT OFF FOR HAART

500 500 ANY ND ND

LIVER BIOPSY ONLY IF BORDERLINE

ALT &/OR HBVDNA < 2000

IU/mL

IF NO HAART( treat if F> 2)

Fibroscan 8 kPa equivalent?

NO IF NO HAART( treat if F> 2)

ONLY IF BORDERLINE

ALT &/OR HBVDNA < 2000

IU

TX FOR PTS NOT ON HAART

1)EARLIER HAART

2) PEGIFN IF FAVOURABLE PREDICTORS

1) PEGIFN2) ADF+TBD3) EARLIER

HAART

EARLIERHAART

1) ADEFOVIR + TBD

1) PEGIFN2) ADEFOVIR

TX FOR PTS ON HAART

TDF+XTC .TDF+XTCETV + FULL

HAART IF TDF CONTRAIND.

TDF+XTC; ETV /ADV /TBD +

FULL HAARTIF TDF

CONTRAIND

TDF + XTC TDF + XTCOR PEG IFN OR

ADF

1 EACS Guidelines for the clinical management and treatment of chronic hepatitis B and C co-infection in HIV-infected adults in press2 BHIVA guidelines for the management of coinfection with HIV-1 and chronic hepatitis B orC HIV Medicine 20103DHHS Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents MMWR 20114 EASL Clinical practice Guidelines Management of chronic hepatitis B J Hepatology 2009; 50: 212-2235 AASLD practice guidelines : HBV an update Hepatology 200), 50: 1-36


More controversies

• TDF withdrawal


HAART Containing Tenofovir (Viread) plus Emtricitabine (Emtriva) Is Effective for HIV-HBV

Coinfected Patients, but Treatment Should Not Be Interrupted

• 16 HIV-HBV Thai in the STACCATO trial (out of 362)• Continuous therapys vs. CD4 guided STI • HBV replication was suppressed below the level of

detection in 15 of 16 coinfected patients. • After treatment interruption,

– HBV DNA increased by a median 2.52 logs (range 0.49-4.70).– Transaminase increased in 5 of 6 patients (mostly

asymptomatic)– 1 individual experienced a severe hepatitis flare.

• All respond completely when emtricitabine/tenofovir-containing HAART was restarted.

• In the continuous therapy:– 1 anti HBe seroconversion– 1 anti HBs seroconversion

Nuesch R AIDS 2008


HBV/HIV coinfectioncontroversies across guidelines

Guideline BHIVA 2 DHHS3

NEED TO DISCONTINUE TENOFOVIRLAM NAIVES

Add Entecavir to new HAART regimen

ENTECAVIR + FULLY SUPPRESSIVE HAART

NEED TO DISCONTINUE TDF LAM EXPERIENCED

Entecavir 1 mg + Adefovir 10 mg + fully suppressive

HAART

ENTECAVIR 1 mg + FULLY SUPPRESSIVE HAART

ORADV + XTC /TBD* + FULLY

SUPPRESSIVE HAART OR

PEGIFN in NON CIRHOTICS*

* More data are needed

1 EACS Guidelines for the clinical management and treatment of chronic hepatitis B and C co-infection in HIV-infected adults in press2 BHIVA guidelines for the management of coinfection with HIV-1 and chronic hepatitis B orC HIV Medicine 20103DHHS Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents MMWR 20114 EASL Clinical practice Guidelines Management of chronic hepatitis B J Hepatology 2009; 50: 212-2235 AASLD practice guidelines : HBV an update Hepatology 200), 50: 1-36


HIV-HBV coinfection• Strong rationale for treating HBV in persons

living with HIV• Indication to HAART strongly influence the

choice of treatment strategy• Disease stage, HBVDNA and CD4 counts the

main determinants of treatment initiation and maintenance

• TDF + FTC dual therapy is the standard• Controversies on therapeutic choices in:

– Pts with no need or not willing to start HAART– Pts with contraindications to TDF


Open issues

• What about suboptimal response to TDF-XTC?


TENOFOVIR IN HIV/HBV COINFECTED PATIENTS WITH OR WITHOUT LAMIVUDINE-RESISTANCE PATIENTS:

A 4-YEAR STUDY

• 40 HIV/HBV coinfected patients treated with LAM:– 15 LAM-R ( HBVDNA 5-8 Log

cp/mL)• 3 rt M204I• 9 rtM204V/I + rtL180M• 3 rt V173L + rtM204V/I +

L180M– 25 HBVDNA undetectable– All 40 HBVDNA

undetectable after 3 to 6 yrs

* Not associated with virologic breakthrough or non responseQuiros Roldan et al Antiviral Therapy 2008


Virologic response & Resistance• 10/82 (12%) did not achieve virologic response

•13% (9/67) HBeAg+ • 7% (1/15) HBeAg-) • 3 compliant with HIVRNA undetectable added ETV undetectable HBVDNA after 12-27 mo • 4/10 LAM –R at baseline ¼ persistence

•4/82 (5%) breakthrough (3 without virologic response 1 HBVDNA undetectable at baseline)

•2 low adherence •2 HCC ( 1 with rtA181V, RT L180M, rt L80I, rt M204I)


Open issues• What about suboptimal response to TDF-XTC?

– Delayed HBVDNA negativization without resistance in small series but more data are needed

• What aboute late presenters with cirrhosis ?


TDF + XTC in HIV/HBV with advanced liver disease

• 9 cases of marked laboratory and clinical improvement maintained at > 3 years ( Gutierrez CID 2008;Lehmann C Infection 2006)

• One case of ALT flare with LF ( Baker JV AIDS 2007)


Hepatitis Flares in HIV-HBV coinfected patients starting anti HBV active HAART

(TICO trial substudy)

• TICO Trial substudy: • 36 antiretroviral naïve HIV/HBV in Thailand

randomized to receive:– TDF vs LAM vs TDF + LAM as part of an Efavirenz based

HAART– 8 (22%) cases with Hepatic Flares ( ALT > 5 x VN or > 200

within 12 weeks) 1 died for LF (3%)– Predictors of flares:

• High HBVDNA• High ALT• Low CD4

– Pathogenesis of flares: Immune Restoration Diseases by cytokines substudy:

• T cell and NK activation markers in cases IP-10 and sCD30 & • markers of IFN induction (IL-18) and activity (MCP-1)

Crane et al Hepatology 2009 JID 2009



– Delayed HBVDNA negativization without resistance in most series ETV add on poorly efective

• What aboute late presenters with cirrhosis ?• Pre emptive ADF+ TBD for 8 weeks no urgent HAART needed• stop HAART if flare up then immediate switch ADF+TBD





• Does dual therapy modify natural history of HBV/HIV coinfection?


Liver Related Mortality (LRM) in HBsAg + persons living with HIV in the HAART era

Ref Setting N of HBsAg

LRM x 1000 ppyy

Hoffmann et al, AIDS 2009; 23(14):1881

MACs Cohort HBsAg +

45 17

Lee et al, HIV Clin Trials 2009 10(3) 153-9

Clinic setting 72 10.5

Sellier et al, J Clin Virol 2010 47:13

HIV.HBV clinic cohort from Paris Hospitals

107 10.5

De Vries-Sluijs Gastroenterology 2010

HBVDNA+ from ATHENA cohort

82 10.6

Martin Carbonero L AIDS 2011

Carlos III Madrid 92 22

Factors associated with LRM : occurrence of HCC, HDV and HCV coinfection


Impact of 3TC on the risk of liver‐related death in HBs‐Ag/HIV+ individuals

Study of impact of ART with 3TC on the risk of liver‐related death

Inter‐cohort analysis (12 Europe, 1 Canada)

Results2041 patients, 758 (37%) IVDUsMedian follow‐up of 48 months

(range 2–91)217 died; 57 liver related

ConclusionsUse of 3TC associated with a 23%

decreased risk of liver‐related death over 4 years

Lamivudine withdrawal associated with an increased risk of LR death AOR 11.59 (95% CI:6.17‐21.75, p=0.0001) vs continuous Tx

Puoti M, Antiviral Therapy 2006

Association with other NRTI studied as ‘control group’33

3 p=0.003

p=0.0001

p=0.0001

p=0.004p=0.97

p=0.84

0.1

1

10

100

3TC-HAARTyear+

DLD Pre-

HAART

CD4+ per 100+cells

Age per 10+years

ddI-HAARTyear+

d4T-HAARTyear+

Factors independently associated with the risk of liver-related death from fitting a Poisson

regression model


Liver‐related mortality in human immunodeficiency virus‐infected patients between 1995 and 2003 in the

French GERMIVIC cohort study

ESLD related death % of total death ESLD related death: % of HBsAg+

Rosenthal E et al J Viral Hep 2007


Tenofovir may improve liver disease in HIV/HBV

• 7 HIV/HBV with cirrhosis (4 with biopsy) on tenofovir for 28 months

• All with prior lamivudine (6 continued when TDF added)• 1 with hepatic decompensation 6 weeks after starting TDF but

improved subsequently• Limitations: small, no repeat biopsy, short f/u

Pre-TDF Post-TDF P*ALT, IU/ml 63 37 0.06*Albumin, g/l 39 44 0.03*PT, seconds 17.5 15 0.02Child-Pugh stage 4A, 2B, 1C 7A*HBV DNA 6.23 x 107 35 0.02

Matthews et al, AVT 2007; 12:119*median


10% 10%45% 25%

worseningimprovement





• Does dual therapy modify natural history of HBV/HIV coinfection?

• Yes but Liver Related Mortality is still high HCC screening and reatment of HCV/HDV coinfections

27 puoti.ppt [compatibiliteitsmodus]regist2.virology-education.com/2011/9eu/docs/27_puoti.pdf ·...

Documents