Coinfezione HIV-HCV e HIV- HBV Quando trattare?infecto.it/2005/slide/BOFFA.pdf · 2014. 12. 6. · Coinfezione HIV-HCV e HIV- HBV Quando trattare? Nicola Boffa Salerno 1stst INFECTIVOLOGY

Coinfezione HIVCoinfezione HIV--HCV HCV e e

HIVHIV-- HBVHBVQuando trattare?Quando trattare?

Nicola BoffaNicola BoffaSalernoSalerno

11stst INFECTIVOLOGY TODAYINFECTIVOLOGY TODAYPAESTUM 13PAESTUM 13--1414--15 MAGGIO 200415 MAGGIO 2004

P-2

ViralViralReplicationReplication

ImmuneImmuneResponseResponse

Necroinflammatory Necroinflammatory activityactivity

FibrosisFibrosis

1010--40 yrs40 yrs

ChronicChronicHepatitis B Hepatitis B

EXPOSURE TOEXPOSURE TOHBVHBV

AsymptAsympt. Cirrhosis. Cirrhosis

33 --6%

6%

x

yr.

x yr

.

InsertionalInsertional mutagenesismutagenesisepigenetic alterationsepigenetic alterations

↑↑Cell proliferationCell proliferation↓↓ApoptosisApoptosis

..2-

15 y

rs

HCCHCC

ESLDESLD

DeathDeath

ALTALT

HBeAg/HBeAbHBeAg/HBeAbHBcAbIgMHBcAbIgM

HBVHBVDNADNA

Histology:Histology:NecoinflammatoryNecoinflammatory activityactivityFibrosisFibrosis

HBcAbOccultHBcAbHBcAbOccultOccult

P-3

HCV and HIV InfectionHCV and HIV Infection

HCV and HIV have emerged as important and HCV and HIV have emerged as important and prevalent viral infections worldwideprevalent viral infections worldwide

Estimated prevalence of HCV in HIV infected Estimated prevalence of HCV in HIV infected patientspatients

30 30 -- 40% of all HIV40% of all HIV--infectedinfected60 60 -- 85% of hemophiliac patients85% of hemophiliac patients52 52 -- 90% of IDU90% of IDU4 4 -- 8% of MSM8% of MSM

P-4

HCV/HIV CoHCV/HIV Co--infection:infection:Geographical VariationGeographical Variation

Prevalence of HCV Among Populations of Prevalence of HCV Among Populations of HIVHIV--infected Patients, Published or Presented 1990infected Patients, Published or Presented 1990--20012001

*All or a high proportion of the patients were intravenous drug *All or a high proportion of the patients were intravenous drug users (users (IDUsIDUs))

Switzerland: 49.8%*

EuroSIDA study: 33.5%

Greece: 13.8%Thailand: 13%

Singapore: 2.7%

India: 92%*

South Africa: 1%

Brazil: 14.8-54.7%

Argentina: 58.5%*

USA: 11.7-33%

Canada: 69% Germany: 13.8-52%

Spain: 95%*

France: 29.3%

Martinique: 18%Italy: 69%

P-5

Prevalence of HCV and HBV coPrevalence of HCV and HBV co--infection in Italian HIV+infection in Italian HIV+from cohort and observational databasesfrom cohort and observational databases

4652

3,2 4 3,3 4,8

0

10

20

30

40

50

60

HCVAb+ HBsAg+ HBsAg+/HCVAb+

I.Co. N.A. 3917 pz. MASTER DBASE 8183 pz. I C O

N A

ItalianCohort

NaiveAntiretroviral

BergamoBergamoBrescia1Brescia1--22BustoBustoCremonaCremonaFerraraFerraraFirenzeFirenzeLeccoLeccoPaviaPaviaP. P. LigureLigureVerbaniaVerbania

In In ItalyItaly::60.000 HIV/HCV 60.000 HIV/HCV coco--infectedinfected9600 HIV9600 HIV--HBV HBV coco--infectedinfected9000 HIV9000 HIV--HBVHBV--HCV coHCV co--infectedinfected

% o

f pat

ient

s

ICONA, Bari 12-13 giugno 2002

P-6

PrevalencePrevalence of of HepatitisHepatitis VVirusesiruses infectioninfectionin 1238 HIV+ and in 1870 HIVin 1238 HIV+ and in 1870 HIV--

Infectious Diseases Department .Infectious Diseases Department .-- University of University of BresciaBrescia

68

11 1212

96

1612 10 4

HIVAll (1238)IDU (837)Sexual Exposure (401)

General Population (1870)

100

80

Prev

alen

ce, %

60

3 1,5 0,15

40

20

0HCVAb+ HBsAg+ HDVAb+

P-7

MASTER observational DBASE:MASTER observational DBASE:% HIV+ with % HIV+ with hypertransaminasemiahypertransaminasemia stratified stratified

according to according to etiologyetiology

54,549,1

65,2

% with elevated ALTHCVAb+HBsAgHCVAb+/HBsAg+ 86

3,8 10

31

69ALT> VN ALT < VN

BergamoBergamoBrescia1Brescia1--22BustoBustoCremonaCremonaFerraraFerraraFirenzeFirenzeLeccoLeccoPaviaPaviaP. P. LigureLigureVerbaniaVerbania

8103 HIV+8103 HIV+

P-8

HIV/HCV CoHIV/HCV Co--infectioninfection

HIV infected patients have prolonged life HIV infected patients have prolonged life expectancy due to availability of highly active expectancy due to availability of highly active antiretroviral therapyantiretroviral therapy

Hepatitis C is a leading cause of morbidity Hepatitis C is a leading cause of morbidity and mortalityand mortality

Compared with HCV monoCompared with HCV mono--infectioninfectionHigher HCV RNA titersHigher HCV RNA titersMore rapid progression to cirrhosis and end stage More rapid progression to cirrhosis and end stage liver diseaseliver disease∴∴ more urgency to treatmore urgency to treat

P-9

Impact of HIV Coinfection Impact of HIV Coinfection HCVHCV--Related Clinical OutcomesRelated Clinical Outcomes

0

5

10

15

20

25

30

HIV/HCV HCVPL

D (%

)

Montreal hemophilia cohortMontreal hemophilia cohort154 patients (81 HIV+)154 patients (81 HIV+)

Risk PLDRisk PLDOdds ratio 7.4 Odds ratio 7.4 Mean duration between Mean duration between HCV and PLD: 17.2 yearsHCV and PLD: 17.2 years

Survival after PLD Survival after PLD Mean: 3.2 years Mean: 3.2 years 73% developed AIDS73% developed AIDS

HCV = hepatitis C virus; HIV = human immunodeficiency virus; PLD = progressive liver disease. Lesens et al. J Infect Dis. 1999;179:1254-1258.

P-10

Increasing Mortality From Increasing Mortality From ESLD in Patients With HIVESLD in Patients With HIV

One third of 1998 cohort One third of 1998 cohort had recent history of had recent history of discontinuing HAART discontinuing HAART secondary to secondary to hepatotoxicityhepatotoxicity

More than 1/2 who died More than 1/2 who died with ESLD had either with ESLD had either NDVL or CD4 >200/mmNDVL or CD4 >200/mm33 6 6 months prior to deathmonths prior to death

ESLD = end stage liver disease; NDVL = no detectable viral load.Bica et al. Clin Infect Dis. 2001;32:492-497.

ESLD

-Rel

ated

Dea

ths

(%)

1991

1996

1998

1114

5050

40

30

20

10

0

P-11

MortalitMortalitàà per AIDS ed insufficienza epatica (ESLD) per AIDS ed insufficienza epatica (ESLD) in una coorte di pazienti di Torino e Verona, 1987in una coorte di pazienti di Torino e Verona, 1987--20012001

0

20

40

60

80

100

120

87 88 89 90 91 92 93 94 95 96 97 98 99 00 01

Dead from AidsDead from liver failure

Di Perri G. et al., 2001

P-12

Trend dei tassi di mortalitTrend dei tassi di mortalitàà per ESLDper ESLD

2.352.35--6.636.633.93.926.626.6828828222220012001

1.931.93--5.985.983.43.422.822.8744744171720002000

1.391.39--5.055.052.72.717.817.8672672121219991999

1.611.61--5.275.272.92.919.619.6764764151519981998

1.091.09--3.983.982.12.114.114.1853853121219971997

1.161.16--4.044.042.12.114.614.6893893131319961996

--116.76.760946094414119871987--9595

95% CI95% CIRate Rate ratioratio

ESLD per ESLD per 1000 P1000 P--YYPP--YYESLDESLDAnnoAnno

Poisson regression analysis: p = 0.002 Di Perri G. et al., 2001

P-13

Update 2002Update 2002Morbidity/Mortality in HIV/HCVMorbidity/Mortality in HIV/HCV

80 -

70 -

60 -

50 -

40 -

30 -

20 -

10 -

0 -0 5 10 15 20 25 30

Per

cent

age

of C

irrho

sis

HIV Negative

HIV Positive

HCV Duration (years)P=.04.HCV = hepatitis C; HIV = human immunodeficiency virus.Di Martino et al. Hepatology. 2001;34:1193-1199.

P-14

Outcomes After HAART According to Outcomes After HAART According to HCV Status and IVDUHCV Status and IVDU

Aliv

e W

ithou

t Pro

gres

sion

(%)

Time Since HAART (months)

Swiss HIV CohortHCV+, IVDU+HCV+, IVDU-HCV-, IVDU-

1009590858075706560

0 7 14 21 28 35 42

HAART= highly active antiretroviral therapy; HCV = hepatitis C virus; IVDU = intravenous drug use. Greub et al. Lancet. 2000;356:1800-1805.

P-15

EffectEffect of HAART on of HAART on HepatitisHepatitis CC

HaartHaart isis associatedassociated withwith a a substanzialsubstanzialimprovementimprovement in in survivalsurvival and and thisthis inclutedincluted a a significantsignificant improvementimprovement in in liverliver--relatedrelated deathsdeathsattibuitedattibuited toto HCV HCV

QurishiQurishi N, N, KreuzbergKreuzberg C, C, LuchtersLuchters G, G, etet al.al. EffectEffect of of antiretroviralantiretroviral therapytherapy on on liverliver--relatedrelated mortalitymortality in in patientspatients withwith HIV and HIV and hepatitishepatitis C virus C virus coinfectioncoinfection. . LancetLancet. 2003;362:1708. 2003;362:1708--17131713

P-16

Why treat HCV infection in patients with HIV?Why treat HCV infection in patients with HIV?

In patients infected with HIV, HCV clearly has In patients infected with HIV, HCV clearly has a worse prognosis a worse prognosis

Evidence is mounting that HCV worsens the Evidence is mounting that HCV worsens the prognosis of HIV (Swiss cohort study)prognosis of HIV (Swiss cohort study)

In patients infected with HIV, HCV may soon In patients infected with HIV, HCV may soon be the leading cause of death be the leading cause of death

HAART HAART hepatotoxicityhepatotoxicity may necessitate HCV may necessitate HCV treatment in order for patients to tolerate HIV treatment in order for patients to tolerate HIV medicationsmedications

P-17

Obstacles in the Treatment Obstacles in the Treatment of HIV/HCV Patientsof HIV/HCV Patients

Higher degrees of fibrosis at baselineHigher degrees of fibrosis at baseline

Higher baseline levels of HCV RNAHigher baseline levels of HCV RNA

PrePre--existing existing cytopeniascytopenias

Mental health and substance abuse issuesMental health and substance abuse issues

Drug interactionsDrug interactionsPotentiationPotentiation of drugof drug--induced toxicitiesinduced toxicitiesPotential negative impact on HIV controlPotential negative impact on HIV control

P-18

RIBAVIRINARIBAVIRINA

inibizione della fosforilazionedi timidina

in vitro

ZDV ddIddC3TCd4T

in vivo

• nessuna interazione con HAART• acidosi lattica (ddI ?)

P-19

PathwayPathway metabolico che conduce al potenziamentometabolico che conduce al potenziamentodi di didanosinadidanosina ((ddIddI) da parte di ) da parte di ribavirinaribavirina (RBV)(RBV)

RBV

Ribavirina-MP

IMP-DH IMP

Inositolo

Nucleosidi naturali

ddI

ddIMP

ddAMP

- +

ddIADP

ddIATP- -

DNA γ-polimerasiRT-HIV

P-20

Question about use of IFN/RBVQuestion about use of IFN/RBVin HIVin HIV--Infected PatientsInfected Patients

Will HIV control wane?Will HIV control wane?

Will CD4 counts decline?Will CD4 counts decline?

Will preWill pre--existing anemia be exacerbated by existing anemia be exacerbated by use of RBV?use of RBV?

Will DDIWill DDI--associated toxicities increase with associated toxicities increase with the use of RBV?the use of RBV?

Will treatment be safe and effective?Will treatment be safe and effective?

P-21

Treatment of HIV/HCV With PEGTreatment of HIV/HCV With PEG--IFN IFN αα--2b 2b + RBV+ RBV

68 patients na68 patients naïïve to IFNve to IFN

73% on ART; CD4 >30073% on ART; CD4 >300

HIV RNA <5,000 copies/mlHIV RNA <5,000 copies/ml

50% with high HCV RNA; 35% with genotype 350% with high HCV RNA; 35% with genotype 3

Only 17% with liver biopsyOnly 17% with liver biopsy

Duration of treatment dependent on genotypeDuration of treatment dependent on genotype

Perez-Olmeda, M. AIDS 2003;17(7):1023-28.

P-22

Treatment of HIV/HCV With PEGTreatment of HIV/HCV With PEG--IFN IFN αα--2b + RBV2b + RBV

ETR: 40%ETR: 40%

SVR: 28% (intention to treat)SVR: 28% (intention to treat)

30% relapsed off therapy30% relapsed off therapy

No adverse effect on HIV controlNo adverse effect on HIV control

Perez-Olmeda M. AIDS. 2003;17(7):1023-28.

P-23

Treatment of HIV/HCV With PEGTreatment of HIV/HCV With PEG--IFN IFN αα--2b + RBV2b + RBV

Predictors of Virological Response to HCV Therapy—Multivariate Analysis of SVR

Parameter OR P

HCV genotype 3 3.5 0.052HCV RNA <800,000 IU/mL 5.5 0.009

Perez-Olmeda M. AIDS 2003;17(7):1023-28

P-24

ACTG A5071: Study DesignACTG A5071: Study Design

21 centers:134 patients randomized

IFN α-2a + RBV 600 mg → 1 g/d

PEG-IFN α-2a 180 µg qw+ RBV 600 mg → 1 g/d

Biopsy Biopsy for virologic response

67

67

Follow-up

6 MIU tiw 3 MIU tiw

Biopsy for virologic nonresponse:Histologic response → continueHistologic nonresponse → D/C

0 12 24 48 72

Weeks

P-25

ACTGACTG--A5071A5071

BaselineIFN-RBV (n =

67)PEG-RBV (n =

66)CD4+ cell count, median

cells/mcL444 492

Genotype 1 78% 77%

Fibrosis (median) 2.0 2.0

Results SVR -- 72 weeks

All patients 8 (12%) 18 (27%)*

Genotype 1 3/52 (6%) 7/51 (14%)

Other genotypes 5/15 (33%) 11/15 (73%)

Premature discontinuation

For adverse reactions 8 (12%) 8 (12%)

*

PP </= </= .05.05

P-26

ACTG A5071: ACTG A5071: HistologicHistologic Response (HR) in Response (HR) in VirologicVirologic NonNon--responders (NR) (24 responders (NR) (24 settsett))

IFN + R PEG-IFN + Rn=67 n=66

NR 57 (85%) 37 (56%)

Wk 24 bx obtained 37 23

Histologic response 15 (40%) 6 (26%)

VR + HR 25 (37%) 35 (53%)

P-27

48 Wk

Screening

IFN α-2b 3 MIU TIW + RBV 800 mg/d

PEG-IFN α-2b 1.5 mcg/kg/wk +RBV 800 mg/d

n = 158

n = 157

RIBAVIC (ANRS HCO2): RIBAVIC (ANRS HCO2): PEGPEG--IFN IFN αα--2b/RBV2b/RBV

(N = 416) n = 206

n = 210

Pol et al. J Hepatology 2003;38:92A

P-28

RIBAVIC:RIBAVIC:Patient DemographicsPatient Demographics

80% on HAART80% on HAART

Mean CD4 = 515Mean CD4 = 515

60% HIV <200, Mean HIV RNA = 3.48 log60% HIV <200, Mean HIV RNA = 3.48 log1010

F3F3--4 = 39%, normal ALT = 16%4 = 39%, normal ALT = 16%


P-29

RIBAVIC: SVR RIBAVIC: SVR (412 Patients) (412 Patients) –– ITT analysisITT analysis

27

15

0

20

40

60

ITT

% U

ndet

ecta

ble

PEG-IFN α-2b/RBV

IFN α-2b/RBV

P-30

RIBAVIC: SVR RIBAVIC: SVR for those who completed therapyfor those who completed therapy

38

26

0

20

40

60

on treatment

% U

ndet

ecta

ble

PEG-IFN α-2b/RBV

IFN α-2b/RBV

P-31

RIBAVIC: RIBAVIC: ETR in Genotype 1/4ETR in Genotype 1/4

9

26

0

5

10

15

20

25

30

Genotype

IFN + RBVPEG - IFN +RBV

Patie

nts

With

EVR

(%)


P-32

RIBAVIC: RIBAVIC: Safety and TolerabilitySafety and Tolerability

High rate of High rate of SAEsSAEs, resulting in therapy , resulting in therapy discontinuations (34% PEG; 36% std IFN)discontinuations (34% PEG; 36% std IFN)

Psychiatric, 21 eventsPsychiatric, 21 eventsInfections, 12Infections, 12HematologicHematologic, 9, 9Liver failure, 10Liver failure, 10HyperlactatemiaHyperlactatemia, 8, 8

•• Association with Association with ddIddI (OR ~ 23)(OR ~ 23)


P-33

APRICOT Study DesignAPRICOT Study Design

FollowFollow--upupIFN alfa-2a (3 MIU, tiw) plus RBV (800 mg daily)

FollowFollow--upupPEG-IFN alfa-2a (180 µg, qw) plus RBV placebo

FollowFollow--upupPEG-IFN alfa-2a (180 µg, qw) plus RBV (800 mg daily)

Study WeeksStudy Weeks00 48482424 7272

P-34

Key Inclusion CriteriaKey Inclusion CriteriaHCV criteriaHCV criteria

1.1. Liver biopsy (Liver biopsy (≤≤15 months) consistent with 15 months) consistent with 2.HCV infection, If cirrhotic Child2.HCV infection, If cirrhotic Child--Pugh GradePugh Grade AA

HIV criteria HIV criteria 1.HIV antibody or quantifiable HIV RNA1.HIV antibody or quantifiable HIV RNA2.CD42.CD4++ cell count cell count

•• ≥≥200/200/µµL L oror•• ≥≥100/100/µµL to L to <<200/200/µµL with L with <<5000 copies/5000 copies/mmLL

HIV RNAHIV RNA3.HIV disease stable with or without anti3.HIV disease stable with or without anti--retroviral retroviral treatmenttreatment

P-35

Baseline Characteristics: HCVBaseline Characteristics: HCVIFN alfaIFN alfa--2a 2a PEGPEG--IFN alfaIFN alfa--2a2a PEGPEG--IFN alfaIFN alfa--2a2a

+ RBV+ RBV + Placebo+ Placebo + RBV+ RBV(N = 285)(N = 285) (N = 286)(N = 286) (N = 289)(N = 289)

HCV RNA (IU/HCV RNA (IU/mLmL x 10x 106 6 ))MeanMean 5.25.2 6.36.3 5.65.6MedianMedian 3.63.6 4.64.6 3.53.5RangeRange 0.006 0.006 -- 4444 0.006 0.006 -- 3030 0.006 0.006 -- 4444

HCV Genotype (%)HCV Genotype (%)Type 1Type 1 6060 6161 6161Type nonType non--11 4040 3838 383822 55 66 4433 2626 2626 282844 88 77 66OtherOther <<11 <1<1 <1<1

P-36

Baseline Characteristics: HIVBaseline Characteristics: HIVIFN alfaIFN alfa--2a 2a PEGPEG--IFN alfaIFN alfa--2a2a PEGPEG--IFN alfaIFN alfa--2a2a

+ RBV+ RBV + Placebo+ Placebo + RBV+ RBV(N = 285)(N = 285) (N = 286)(N = 286) (N = 289)(N = 289)

ART* (%)ART* (%) 8484 8585 8484

HIV RNAHIV RNAMedianMedian <<5050 <<5050 <<5050RangeRange <<50 50 -- 640,622640,622 <<50 50 -- 490,625490,625 <<50 50 -- 580,679580,679

CD4CD4++ CountsCounts(cells/(cells/µµL)L)

MeanMean 542542 530530 520520<<200 (%)200 (%) 77 55 66

*Any treatment used as antiretroviral therapy*Any treatment used as antiretroviral therapy

P-37

12%

20%

40%

0%

10%

20%

30%

40%

50%

60%

IFN alfa-2a + RBV PEG-IFN alfa-2a +Placebo

PEG-IFN alfa-2a +RBV

Sustained Sustained VirologicVirologic ResponseResponse%

of P

atie

nts

% o

f Pat

ient

s

N = 285 N = 286 N = 289

P = 0.0078P = 0.0078

P = P = <<0.00010.0001P = P = <<0.00010.0001

P-38

7%

20%14%

36%29%

62%

0%

10%

20%

30%

40%

50%

60%

70%

Genotype 1 Genotype 2, 3

IFN alfa-2a + RBV PEG-IFN alfa-2a + Placebo PEG-IFN alfa-2a + RBV

Sustained Sustained VirologicVirologic ResponseResponseby Genotypeby Genotype

N = 171 N = 175 N = 176 N = 89 N = 90 N = 95

% o

f Pat

ient

s%

of P

atie

nts

P-39

Withdrawal from TreatmentWithdrawal from Treatment

5%3%

14%12% 12%

24%

15%

10%

<.1%0%

5%

10%

15%

20%

25%

30%

IFN alfa-2a + RBV PEG-IFN alfa-2a +Placebo

PEG-IFN alfa-2a +RBV

Laboratory abnormality Adverse event Non-safety

% o

f Pat

ient

s%

of P

atie

nts

P-40

Adverse Events Adverse Events ≥≥20%20%

IFN alfaIFN alfa--2a 2a PEGPEG--IFN alfaIFN alfa--2a2a PEGPEG--IFN alfaIFN alfa--2a2a+ RBV+ RBV + Placebo+ Placebo + RBV+ RBV

(N = 285)(N = 285) (N = 286)(N = 286) (N = 288)(N = 288)

FatigueFatigue 40%40% 41%41% 44%44%PyrexiaPyrexia 35%35% 43%43% 44%44%HeadacheHeadache 41%41% 38%38% 39%39%MyalgiaMyalgia 29%29% 33%33% 36%36%NauseaNausea 25%25% 27%27% 30%30%DiarrheaDiarrhea 24%24% 26%26% 28%28%InsomniaInsomnia 29%29% 21%21% 26%26%AstheniaAsthenia 24%24% 22%22% 28%28%DepressionDepression 22%22% 20%20% 26%26%ArthralgiaArthralgia 18%18% 20%20% 20%20%Weight decreasedWeight decreased 14%14% 18%18% 20%20%

P-41

Incidence of Laboratory and Clinical Incidence of Laboratory and Clinical Events Associated with HCV TreatmentEvents Associated with HCV Treatment


(N = 285)(N = 285) (N = 286)(N = 286) (N = 289)(N = 289)N (%)N (%) N (%)N (%) N (%)N (%)

ANC <0.5 x10ANC <0.5 x1099/L/L 11 ((<<1)1) 3737 (13)(13) 3131 (11)(11)

Platelets <20 x10Platelets <20 x1099/L/L 00 (0)(0) 11 ((<<1)1) 11 ((<<1)1)

Hemoglobin Hemoglobin 44 (1)(1) 1010 (3)(3) 1111 (4)(4)<8.5 <8.5 g/dLg/dL

Triglycerides Triglycerides 1010 (4)(4) 1616 (6)(6) 1616 (6)(6)>1200 mg/>1200 mg/dLdL

Weight decrease Weight decrease 7575 (26)(26) 7070 (25)(25) 7272 (25)(25)of >10%of >10%

Serious depressionSerious depression 22 ((<<1)1) 44 ((<<1)1) 33 ((<<1)1)

P-42

Impact of HCV Treatment on Absolute Impact of HCV Treatment on Absolute CD4CD4++ Count and CD4Count and CD4++%*%*


Baseline**Baseline**CD4CD4++ cells/cells/µµLL 512512 481481 476476CDCD44++%% 2626 2525 2525

Change fromChange frombaseline at baseline at week 48**week 48**

CD4CD4++ cells/cells/µµLL --9999 --115115 --140140CD4CD4++%% +2.3+2.3 +2.1+2.1 +3.9+3.9

** Patients who completed 48 weeks of treatment Patients who completed 48 weeks of treatment **** MedianMedian

P-43

Impact of HCV Treatment on HIVImpact of HCV Treatment on HIV--1 RNA1 RNAMedian LogMedian Log1010 HIV RNA (copies/HIV RNA (copies/mLmL))

∆∆ from Baselinefrom Baseline ∆∆ from Baselinefrom Baselineat Endat End 4 Weeks after4 Weeks after

BaselineBaseline of Treatmentof Treatment End of TreatmentEnd of Treatment

Patients receiving ARTPatients receiving ARTat baselineat baseline

IFNIFN alfaalfa--2a + RBV2a + RBV 1.6991.699 0.0000.000 0.0000.000PEGPEG--IFNIFN alfaalfa--2a + Placebo2a + Placebo 1.6991.699 0.0000.000 0.0000.000PEGPEG--IFNIFN alfaalfa--2a + RBV2a + RBV 1.6991.699 0.0000.000 0.0000.000

Patients Patients notnot receiving ARTreceiving ARTat baselineat baseline

IFNIFN alfaalfa--2a + RBV2a + RBV 3.8523.852 0.0000.000 0.4140.414PEGPEG--IFNIFN alfaalfa--2a + Placebo2a + Placebo 4.0614.061 --0.9830.983 0.0550.055PEGPEG--IFNIFN alfaalfa--2a + RBV2a + RBV 3.9473.947 --0.8940.894 0.0560.056

P-44

PEGPEG--IFN SVR: All Genotypes and Genotype 1IFN SVR: All Genotypes and Genotype 1(ACTG 5071 vs RIBAVIC vs APRICOT)(ACTG 5071 vs RIBAVIC vs APRICOT)

27% 27%

40%

14% 14%

29%

0%

10%

20%

30%

40%

50%

ACTG 5071 RIBAVIC APRICOT

All Genotypes Genotype 1

% S

VR%

SVR

Comparison of MonoComparison of Mono--infection infection Results (NV15942 and NR16071) Results (NV15942 and NR16071)

with Key Cowith Key Co--infection Results infection Results (NR15961)(NR15961)

PegPeg--ifnifn alfa2a alfa2a 180 180 µµg + g + RBV 800 mg, 48 weeksRBV 800 mg, 48 weeks

P-46

52% 52%

40%

0%

10%

20%

30%

40%

50%

60%NV15942 NR16071 NR15961

Sustained Sustained VirologicalVirological Response Response –– All All GenotypesGenotypes

((PegPeg--ifnifn alfaalfa--2a 2a 180 180 µµg + RBV 800 mg)g + RBV 800 mg)%

SVR

% S

VR

P-47

41%

76%

40%

78%

29%

62%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Genotype 1 Genotype 2, 3

NV15942 NR16071 NR15961

Sustained Sustained VirologicalVirological Response Response –– By GenotypeBy Genotype((PegPeg--ifnifn alfaalfa--2a 2a 180 180 µµg + RBV 800 mg)g + RBV 800 mg)

% S

VR%

SVR

N = 250 N = 141 N = 176 N = 99 N = 58 N = 95

P-48

ACTG-A5071,RIBAVIC, APRICOTpermit the following conclusions for HIV/HCV coinfection

1. The combination of PEG and ribavirin x 48 weeks in patients with virologic response at week 12 appears to be the standard.

2. The rates of SVR reported were 27% to 40% for all patients and 14% to 29% for genotype 1.

3. These rates are significantly lower than those reported for patients with HCV monoinfection.

4. HCV RNA virologic response with < 2 log10 IU/mL at 12 weeks predicts SVR but not necessarily histologic response.

5. The treatment is generally well tolerated and has no significant impact on HIV, although CD4+ cell counts decrease temporarily during therapy with PEG.

6. PEG may have significant anti-HIV activity in those with HIV viremia at baseline

P-49

Chronic hepatitis B in patients co-infectedwith HIV

HBsAg seropositivityHBsAg seropositivity : 10%: 10%

Higher prevalence of cirrhosis than HIV negative Higher prevalence of cirrhosis than HIV negative HBVHBV--infected patientsinfected patients

Decrease survival of HIVDecrease survival of HIV--HBV coHBV co--infected infected individualsindividuals compared compared to HIV monoto HIV mono--infectedinfected

Rustgi VK et al. Ann Intern Med. 1984;101:795-7.Colin JF et al. Hepatology. 1999;29:1306-10.

Gilson RJC et al. AIDS. 1997;11:597-606.

P-50

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 years

% o

fcirr

hosi

s

VIH negative

VIH positive

p=0.005

HIV/HBV co-infection: Natural history

Adapted from Di Martino V et al. Gastroenterology 2002; 123: 1812-1822

P-51

HIV/HBV coHIV/HBV co--infection: infection: Natural history Natural history (MACS)(MACS)

LiverLiver--related mortalityrelated mortality, in a , in a cohort cohort of 5293 patients, 1984 /1987 of 5293 patients, 1984 /1987 -- 20002000

N Viral N Viral status status LiverLiver--related related Liver Liver death death ppHIV HIV HBsAg mortalityHBsAg mortality (n) (1000 pers/(n) (1000 pers/yryr))

30933093 -- -- 0 0.0 0 0.0 139 139 -- + 1 0.8 + 1 0.8 0.040.042346 + 2346 + -- 35 1.7 <035 1.7 <0.0001.0001213 + + 26 213 + + 26 14.2 <0.0001 14.2 <0.0001 5293 62 5293 62 1.1 1.1

Liver related mortalityX 19 HBV/HIV vs HBV (RR18; 73,1-766,1 - p<0,001)

Thio CL et al. Lancet 2002; 360: 1921-1926.

P-52

Treatment of HBV in HIV co-infected patients

• Interferon

• Lamivudine

• Adefovir dipivoxil

• Tenofovir fumarate disoproxil

• FTC (Emtriva)

P-53

Treatment of HBV in HIV coTreatment of HBV in HIV co--infected patients: infected patients: IFN IFN αα2a2a

HBeAg and HBV DNA negativation (<5 pg/mL) inpatients treated with IFN α2a

MIU/TIWMIU/TIW HIV+HIV+ HIVHIV--

2.52.5 0/ 50/ 5 1/ 41/ 4

55 0/ 40/ 4 1/ 51/ 5

1010 0/ 50/ 5 4/ 94/ 9

ControlControl 0/ 30/ 3 0/ 60/ 6

Mac Donald et al. Hepatology. 1987;7:719-23.

P-54

Treatment of HBV in HIV coTreatment of HBV in HIV co--infected patients: infected patients: IFN IFN αα22

HBeAg and HBV DNA negativation (<5 pg/mL) in homosexualmen treated with IFN α2a

HIV+HIV+

(n=25)(n=25)

HIVHIV--

(n=25)(n=25)

10 MIU/TIW10 MIU/TIW

12 12 weeksweeks

1/12 (8.3%)1/12 (8.3%) 5/13 (38.5%)5/13 (38.5%)

ControlControl 0/13 (0%)0/13 (0%) 1/12 (8.3%)1/12 (8.3%)

Wong DK et al. Gastroenterology. 1995;108:165-71.

P-55


• Interferon

• Lamivudine



• FTC (Emtriva)

P-56

Treatment of HBV in HIV co-infected patients: Lamivudine

One year of lam on HBV serological markers in HIV co-infected patients

HBV DNA >5 pg/mLn=27

HBV DNA <5 pg/mLn=10

0 (0%)

5 (18.5%)

0 (0%)

3 (11%)

26 (96.3%)

Loss of HBsAg

Loss of HBeAg

Seroconversion to anti-HBs

Seroconversion to anti-HBe

Loss of serum HBV DNA(MH- 1 000 000 copies/mL)Loss of serum HBV DNA(PCR – 1000 copies/mL)

23 (88.5%)

3 (30%)

⎯

2 (20%)

⎯

⎯

6 (100%)

Y Benhamou et al. Ann Intern Med. 1996;125:705-712.

P-57

Treatment of HBV in HIV co-infected patients: Lamivudine

Changes in ALT (UI/mL) during lamivudine therapy

0

50

100

150

200

250

300

Baseline 2 4 6 8 10 12

ALT

(UI/L

)

HBV DNA >5x105 copies/mL at baseline

HBV DNA <5x105 copies/mL at baseline

P<0.05

Lamivudine therapy duration (months)

Y Benhamou et al. Ann Intern Med. 1996;125:705-712.

P-58

Treatment of HBV in HIV coTreatment of HBV in HIV co--infected patients: infected patients: LamivudineLamivudine

-3,5

-3

-2,5

-2

-1,5

-1

-0,5

00 4 8 12 20 28 36 44 52

Time in Weeks

Med

ian

Cha

nge

in L

og H

BV

DN

A

Lamivudine Placebo

Median change in serum HBV DNA over 52 weeks

-2.7 log10 copies/mL

Dore GJ et al. J Infect Dis. 1999;180:607-13

P-59

Treatment of HBV in HIV co-infected patients: Lamivudine resistance

Cumulative risk for the development of HBV resistance to lamivudine

0.25

0.50

0.75

1

0 350 700 1050 1400

Days of lamivudine therapy

Prop

ortio

nof

pat

ient

s w

ith re

laps

e

N= 57

YMDD mutations were documented in all patients with resistance

of H

BV

repl

icat

ion

Number of patients 57 32 13 6 3under observation

Benhamou Y, et al. Hepatology 1999; 30:1302-06.

P-60


Interferon

Lamivudine

Adefovir dipivoxil

Tenofovir fumarate disoproxil

FTC (Emtriva)

P-61

Treatment of Treatment of LAMLAM--R R HBV in HIV coHBV in HIV co--infected patients: infected patients: AdefovirAdefovir

Baseline HBV characteristics Baseline HBV characteristics

Median HBV DNA (log10 copies/mL)

Median ALT (IU/L)

HBeAg positive

n=35

8.75

81

33

Liver Histology (METAVIR)

- Mean (±SEM) Activity

- Mean (±SEM) Fibrosis

- Cirrhosis

n=23

1.52 ± 0.15

2.04 ± 0.24

22%

HIV RNA (log10 copies/mL) Mean (±SEM) CD4 cell count (cells/mm3) Mean (±SEM)

2.88 ± 0.13

422 ± 34

Benhamou Y et al. Lancet. 2001. 358:718-23

Benhamou Y et al. AASLD 2003

P-62


Week 144 -5.5 log10 copies/mL

p<0.001

0.50

-0.50

-6.50

-5.50

-4.50

-3.50

-2.50

-1.50

0 4 8 12 16 20 24 28 32 36 40 44 48 60 72

Week 96 -4.8 log10 copies/mL

p<0.001

Week 48 -4 log10 copies/mL

P<0.001

N = 31 30 30 30 25 26 28 2884 96 108 120 132 144

Weeks on ADV

HB

V D

NA

(cop

ies/

mL)

35 35 33 32 33 33 31 30 30 30 31 31 31

Median change in serum HBV DNA

Benhamou Y et al. AASLD 2003Benhamou Y et al. Lancet. 2001. 358:718-23

P-63

Treatment of LAM-R HBV in HIV co-infected patients: Adefovir

Median Median cchangehange in in sserumerum ALTALT

200

N =

Week 14431 IU/L p<0.001

*: ULN of serum ALT levels is 37 IU/L

20

40

60

80

100

120

140

160

180

0 4 8 12 16 20 24 28 32 36 40 44 48 60 72 84 96 108 120 132 144

Weeks on ADV

Seru

m A

LT (I

U/L

)

* ULN

Week 9646 IU/L p<0.001

Week 4853 IU/L p<0.001

35 35 34 32 31 32 33 31 28 30 31 31 31 31 31 27 30 26 29 29 28

Benhamou Y et al. AASLD 2003Benhamou Y et al. Lancet. 2001. 358:718-23

P-64


0%3%

10%

19% 20%

37% 39%

64%

0%

10%

20%

30%

40%

50%

60%

70%

Baseline Week 48 Week 96 Week 144

Weeks on ADV

HBV DNA < 2.6 log10 copies/mL

ALT Normalization

Patie

nts

(%)

Benhamou et al. AASLD 2003

P-65


• Interferon

• Lamivudine



• FTC (Emtriva)

P-66

TDFTDF in HIV/HBVin HIV/HBV ccoo--iinfectednfected ppatientsatients

N Wild type/ LAM-R

Duration of TDF (weeks)

Change in HBV DNA (log10 copies/mL)

Cooper D 12 5/7 24 -5±0.7*

Nelson M 20 9/11 52 4**

Ristig MB 6 0/6 24 4.3**

Benhamou Y 12 0/12 24 -3.83±0.38* * Mean. ** Median

Cooper D et al. CID. 2003: 124Nelson M et al. AIDS. 2003;17:F7-F10

Ristig MB et al. J Infect Dis. 2002;186:1844-7Benhamou Y et al. N Engl J Med. 2003;348:177-8

P-67

TDFTDF in HIV/HBVin HIV/HBV ccoo--iinfectednfected ppatientsatientsChange in HBV DNA during TDF therapy in HIV/HBV co-infected

HBV DNA (median; SD) (log10 copies/mL)

P

N

Median (range) of follow-up (months)

Baseline

End of follow up

Change from baseline

- Total

- HBeAg+

- HBeAg-

88

66

19

8.8 (1.0 – 21.0)

8.0 (1.0 – 21.0)

6.0 (1.0 – 17.0)

8.02 (1.97)

8.17 (1.55)

4.84 (2.15)

2.95 (1.54)

3.05 (1.67)

2.30 (2.15)

-3.82 (2.04)

-3.68 (2.00)

-2.54 (1.82)

< 0.001

< 0.001

< 0.001

Benhamou et al. For the TECOVIR Study Group. AASLD 2003

76% of the patients were receiving LAM at TDF initiation (presumed

LAM-R)

P-68


Time to DNA negativation (<2.3 copies/mL)


P-69


26.1

57.9

8.24.8

0

10

20

30

40

50

60

70

Patients with HBeAg+ at baseline (n=65) Patients with HBeAg- at baseline (n=19)

Prop

ortio

n of

pat

ient

s (%

)

HBV DNA negativation (<2.3 log10 copies/mL)

HBeAg negativation

HBeAg serconversion


P-70


• Interferon

• Lamivudine



• FTC (Emtricitabina)

P-71

FTCFTC in HIV/HBVin HIV/HBV ccoo--iinfectednfected ppatientsatients

-4

-3

-2

-1

0

0 12 24 36 48

FTC HBV+HIV d4T HBV+HIV FTC in Chronic HBV (FTCB-102)

Log 1

0H

BV

DN

A

24 22 20 20 1733 33 33 33 3310 10 10 7 7

FTC HBV+HIVFTC HBVd4T HBV+HIV

Median HBV DNA change from baseline

P-72

FTCFTC in HIV/HBVin HIV/HBV ccoo--iinfectednfected ppatientsatients

Resistance mutations in non HIV/HBV infected patientsResistance mutations in non HIV/HBV infected patients

1612

9

19

0

10

20

30

40

50

25 mg 100 mg 200 mg 200 mg

% 4848 WeeksWeeks 9696 WeeksWeeks

P-73

Cross Resistance Cross Resistance in vivoin vivo

M204VM204V

V173LV173L

A181VA181V

M250VM250V

L180ML180M

A184GA184G

S202IS202I

N236TN236T

M204IM204I

LAMLAM

ETVETV

LdTLdT

FTCFTC

ADV/ ADV/ TDFTDF

P-74

Treatment of Treatment of CCHB in HIV coHB in HIV co--infected patientsinfected patients

If ARV is indicated for HIVIf ARV is indicated for HIVHBV treatment has to be considered : TDF HBV treatment has to be considered : TDF –– FTC FTC –– LAM in LAM in ARV regimentARV regimentLAMLAM--R R patients : patients :

•• TDF or ADVTDF or ADV

If ARV is not indicated for HIVIf ARV is not indicated for HIVADVADV

PerspectivesPerspectives:: combinationscombinationsNRTsNRTs : Nucleotides (TDF : Nucleotides (TDF –– ADV) + Nucleosides (FTC ADV) + Nucleosides (FTC –– LAM)LAM)NRTIsNRTIs/PEG IFN/PEG IFN??

P-75

HAART Related HAART Related HepatotoxicityHepatotoxicity in HIV/HBV Coin HIV/HBV Co--infected Patientsinfected Patients

No.No. HAARTHAART HCV/HBVHCV/HBV IncidenceIncidence PredictorsPredictors

Sulkowski Sulkowski M.M. 211211 PIPI 51%51% 11%11% HCV, HCV, HBVHBV,, ↑↑CD4, CD4, RTVRTV

SavesSaves M.M. 748748 PIPI 41%41% 9%9% HCV, HCV, HBVHBV previous previous cytolysiscytolysis

NunezNunez M.M. 222222 PI, PI, NNRTINNRTI 40%40% 9%9% HCV, age, HCV, age, alcoholalcohol

Sulkowski Sulkowski M.M. 8787 2 NRTI2 NRTI 61%61% 6%6% HCV, HCV, HBVHBV, , ↑↑ CD4CD4

Saves Saves M.M. 12491249 2 NRTI2 NRTI 44%44% 6%6% HCV, HCV, HBVHBV previous previous cytolysiscytolysis

Sulkowski M et al. JAMA 283:74-80. Saves M et al. AIDS 1999;13:F115-F121.

Nunez M et al. JAIDS 2001;27:426-31.

P-76

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Coinfezione HIV-HCV e HIV- HBV Quando trattare?infecto.it/2005/slide/BOFFA.pdf · 2014. 12. 6. · Coinfezione HIV-HCV e HIV- HBV Quando trattare? Nicola Boffa Salerno 1stst INFECTIVOLOGY