Optimizing Care for the Optimizing Care for the HIV-Hepatitis Coinfected Patient Supported by an educational grant from Abbott Sponsored by The Academy

Optimizing Care for the Optimizing Care for the HIV-Hepatitis Coinfected PatientHIV-Hepatitis Coinfected Patient

Supported by an educational grant from Abbott

Sponsored by The Academy for Continued Healthcare Learning

Mark Holodniy, MDProfessor of Medicine

Stanford UniversityStanford, California

Intended Audience

This activity is intended for HIV specialists from a wide range of disciplines, including but not limited to internal medicine, family practice, and infectious disease physicians. Pharmacists, nurses and other healthcare professionals focusing on HIV care are also encouraged to attend.

In accordance with PhRMA guidelines, this program is intended for healthcare professionals only.

Activity Purpose

To update physicians, pharmacists, nurses and other health care professionals, on recent advances in HIV research and the management of HIV infectious disease.

Method of Participation

This activity will consist of a lecture meeting with collateral slides, syllabus, and interactive question and answer session.

Accreditation The Academy for Continued Healthcare Learning (ACHL) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide

continuing medical education for physicians.

Designation The Academy for Continued Healthcare Learning (ACHL) designates this educational activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The Academy for Continued Healthcare Learning (ACHL) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. In order to receive credit, pharmacists must

complete the activity requirements and evaluation at the conclusion of the program. This activity has been approved for a maximum of 0.1 CEU.

ACPE Universal Program Number (UPN): 396-000-06-013-L02 Initial Release Date: 01/20/06

The Academy for Continued Healthcare Learning (ACHL) has been reviewed and approved as an Authorized Provider by the International

Association of Continuing Education and Training (IACET). ACHL has awarded 0.1 CEU to participants who successfully complete this program. IACET CEU credit may be used toward nursing credits. Contact your local accrediting body for details.

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Mark Holodniy, MD, has no relevant affiliations or financial relationships to disclose.

The ACHL staff members and others involved with the planning, development, and review of the content for this activity have no relevant affiliations or financial relationships to disclose.

The content for this activity was developed independently of the commercial supporter. All materials are included with permission. The opinions expressed are those of the faculty and are not to be construed as those of the publisher or grantor.

This educational activity was planned and produced in accordance with the ACCME Essential Areas and Elements, Policies, and Standards for Commercial Support as well as the ACPE Criteria for Quality and Interpretive Guidelines. Recommendations involving clinical medicine in a continuing medical education (CME/CE) activity must be based on evidence that is accepted within the profession of medicine as adequate justification for their indications and contraindications in the care of patients. All scientific research referred to, reported or used in CME/CE in support or justification of a patient care recommendation must conform to the generally accepted standards of experimental design, data collection and analysis.

Participants are advised that one or more presentations in this CME/CE activity may contain references to unapproved or unlabeled uses of drugs or devices. Participants should note that the use of these agents outside current approved labeling is considered investigational and are advised to consult current prescribing information for these products.

Disclaimer

Housekeeping Information

• Please refer to the syllabus for complete CME/CE credit information

• Please return your completed enrollment/evaluation forms to the Meeting Host before you leave

• Please turn your cell phones to off or vibrate

Learning Objectives

Upon completion of this activity, participants should be able to

• Describe liver-related adverse events in HIV-Hepatitis coinfected patient

• Examine associated hepatotoxicity with different treatment modalities

• Review treatment options, taking into consideration hepatic safety

Liver-Related Adverse Events

• Liver-related adverse events are the most common grade 4 adverse events in HIV positive patients

• Hospitalizations for liver related events are more common than hospitalizations for opportunistic infections or for IDU related events

• Liver toxicity of ARV agents should be seriously considered before initiating therapy

Most Common Grade 4 Events:CPCRA Cohort

0

1

2

3

per

100

Per

son-

Yea

rs

Reisler RB, et al. JAIDS. 2003;34:379-386.

Liver2.6

Neutropenia1.5

Anemia1.1 CVD

0.9Pancreatitis

0.9 Psychiatric0.8 Renal

0.6

Incidence

N=2947; CPCRA=Terry Beirn CommunityPrograms for Clinical Research on AIDS.

Hazard Ratio For Death by Grade 4 Event (95% CI)

3.49(2.38-5.12)

P=.0001

1.02(0.61-1.72)

P=.93

1.76(0.99-3.09)

P=.051

7.08(4.15-12.05)

P=.0001

3.40(1.82-6.33)

P=.0001

1.91(0.79-4.63)

P=.15

4.60(2.45-8.66)

P=.0001

Prevalence of HIV/HCV Coinfection

• Johns Hopkins HIV clinic– Urban setting– Prospective, longitudinal

database – HCV-coinfection clinic

established in 1997

• 1742 HIV-infected patients screened for HCV infection (1997-2000)– HCV+: 798 patients

84%

14%10%

45%

0

20

40

60

80

100

Pre

vale

nce

of A

ntib

ody

HC

V+

, %

IDU Hetero- Homo- Entire sexual sexual Cohort Sex Sex

Sulkowski MS, et al. Hepatology. 2000;32. Abstract 204.

HIV/HCV CoinfectionPrevalence by Risk Factor

Impact of HIV Infection onHBV and HCV Disease Progression

• Impact of HIV infection– Accelerates the course

of HBV and HCV infection

• Liver disease associated with HBV or HCV infection– A leading cause of

morbidity and mortality among HIV-infected patients

HBV or HCV Disease Course

Chronic

HCCESLD

SlowlyProgressive

Cirrhosis

Recovery

Stable

HBV or HCV Infection

HCC=hepatocellular carcinoma.ESLD=end-stage liver disease.

Thomas DL, et al. JAMA. 2000;284:450-456. Benhamou Y, et al. Hepatology. 1999;30:1054-1058.Graham CS, et al. Clin Infect Dis. 2001;33:562-569.

Bodsworth NJ, et al. J Infect Dis. 1991;163:1138-1140.Gilson RJ, et al. AIDS. 1997;11:597-606.

15% 85%

68% 17%

4%13%

Rapid Progression of Liver Disease in HIV/HCV Coinfected Patients

• Prospective study of fibrosis progression in 67 coinfected patients • 2 biopsies, median time between biopsies was 2.84 years

8%

52%

14% 12%6%

2% 4% 2%

0

10

20

30

40

50

60

-1 NoChange

1 2 3 4 5 6

Pat

ient

s, %

Change in Ishak Score From First to Second Biopsy

>25% of patients with mild fibrosis on initial biopsy had ≥2 stage progression in fibrosis score

Patients With Mild Fibrosis (≤F1) on First Biopsy

Sulkowski M, et al. 12th CROI. Boston. 2005. Oral abstract 121.

Survival of Patients Coinfected WithHIV and Hepatitis B or C Virus

• Cohort study– 472 HIV patients followed

for 8343 patient-months• HIV alone (n=126) • HIV/HBV (n=72)• HIV/HCV (n=256)• HIV/HBV/HCV (n=18)

• Variables associated with liver death in the cohort coinfected with HCV, HBV, or both (n=346)– 0 to 2 antiretroviral drugs– CD4 <200 cells/µL

25%

18%17%

22%

6%

15%

13%

28%

0

10

20

30HIV Mortality

Liver Mortality

Mor

talit

y, %

HIV HIV/HBV HIV/HCV HIV HBV/HCV

Bonacini M, et al. AIDS. 2004;18:2039-2045.

HIV or Liver Mortality

Association Between CD4 Cell Count and Liver-Related Death

• D:A:D Study– Prospective study with 23 441 people with HIV– 1248 deaths between 2000-February 2004

• Leading causes of death: – AIDS, 30%– Liver-related death 14% (79% associated with chronic hepatitis)– Heart disease 9%– Non-AIDS malignancies, 8%

• Relative risk of death for persons with CD4 <50 cells/mm3 as compared with persons with CD4 >500 cells/mm3

Category RR 95% CI P

AIDS 96.4 61.6-150.7 <.0001

Liver-Related 26.6 12.9-54.7 <.0001

Non-AIDS Malignancies 23.5 9.4-58.7 <.0001

Weber, R, et al. 12th CROI. Boston. 2005. Abstract 595.

HAART and the Impact of HIV RNA, CD4, or Both on Liver Fibrosis

0

0.04

0.08

0.12

0.16

0.2

HIV RNA(copies/mL)

0.122

Isha

k F

ibro

sis

Uni

ts/Y

ear

Brau N, et al. 39th EASL. Berlin, 2004. Abstract 99.

0.145

0.196

0.121

0.155

0.123

0.162P=.04

P=.005

P=.005 P=.005

<400 400-99K ≥100K ≥350 <350 <400 ≥400

CD4(cells/mm3)

HIV RNA (copies/mL) +<500 CD4 cells/mm3

HAART and Liver Fibrosis in HIV/HCV Coinfected Patients

• HAART may slow fibrosis progression – HIV/HCV coinfection versus HCV monoinfection post-HAART: No

difference in:• Fibrosis progression rate (P=.29)

• Fibrosis stage (P=.87)

• Necroinflammatory grade (P=.89)

• Fibrosis progression rate (FPR) in Coinfected patients:- Strongly correlated with HIV RNA levels

- Coinfected patients with any HIV RNA >400 copies/mL had a faster FPR than coinfected patients with HIV RNA <400 copies/mL (P=.004)

- Coinfected patients with HIV RNA <400 copies/mL had a similar FPR to HCV monoinfected patients (P=.253)

- Increased with CD4 cell counts <500 cells/mm3 combined with HIV RNA >400 copies/mL (P=.005)

Brau N, et al. 39th EASL. Berlin, 2004. Abstract 99.

Impact of HAART and ART on Mortalityin HIV/HCV Coinfected Patients

• Bonn cohort (1990-2002)– 285 HIV/HCV coinfected

patients• Liver-related mortality

rates per 100 person-years– HAART: 0.45– ART: 0.69– No therapy: 1.70

• Predictors for liver-related mortality– No HAART– Low CD4 cell count– Increasing age

Qurishi N, et al. Lancet. 2003;362:1708-1713.

0.2

0.4

0.6

0.8

1

Days

Liver-Related Mortality

Cum

ula

tive

Su

rviv

al

0 1000 2000 3000 4000 5000 6000

HAART*ART

No therapy

*P=.018

0.2

0.4

0.6

0.8

1

Days

Overall Mortality

Cum

ula

tive

Su

rviv

al

0 1000 2000 3000 4000 5000 6000

ART

HAART*

No therapy*P<.001

Summary: Clinical Implications of Liver Damage and Benefits of HAART in Coinfected Patients

• Liver damage in HIV-infected patients causes significant morbidity and mortality

• HIV infection accelerates the course of viral hepatitis

• Patients with low CD4 cell counts have an increased risk of liver-related death

• HAART– Can be tolerated by coinfected patients– Controls HIV– May slow the progression of fibrosis, especially PIs – Improves immune status – Improves survival

Balancing HAART and Hepatic Safety

NRTIs

NRTI-Related Hepatotoxicity

• Syndrome of mitochondrial toxicity– Mitochondria have their own DNA (mtDNA) that

encodes 13% of mitochondrial proteins– NRTIs inhibit mitochondrial DNA synthesis, causing

mitochondrial dysfunction and cellular toxicity

• High-risk drugs– Stavudine, didanosine, zalcitabine

• Low-risk drugs– Abacavir, zidovudine, lamivudine

Fleischer R, et al. Clin Infect Dis. 2004;38:e79-e80.

Association of Dideoxynucleoside Analogues With Hepatic Steatosis

• Retrospective chart review of 179 HIV/HCV coinfected patients

• Univariate analysis

– Factors associated with steatosis; Dideoxynucleosides (P=.029) and the

number of nucleoside analogues (P=.042)

– Use of protease inhibitors was not associated with steatosis

• Multivariate analysis

McGovern B, et al. 12th CROI. Boston. 2005. Abstract 950.

Odds Ratio 95% CI P

Dideoxynucleosides 6.0 (1.9-18.9) .002

Other nucleoside analogues 3.0 (1.05-8.4) .04

HCV genotype 3 3.7 (0.92-14.5) .065


NNRTIs

NNRTI-Related Hepatotoxicity

• Incidence of ALT or AST elevations in randomized trials– Grade 3 (>5 x ULN) and 4 (>10 x ULN): 8% to 16%

• Hepatitis coinfection increases the risk of hepatotoxicity

• Nevirapine– Fatal hepatic necrosis

• US FDA “warning”Sulkowski MS, et al. Hepatology. 2002;35:182-189.

Reisler R, et al. 1st IAS Conference. Buenos Aires, 2001. Abstract 43.Stern J, et al. JAIDS. 2003;34(suppl 1):S21-S33.

Wit FW, et al. J Infect Dis. 2002;186:23-31.van Leth F, et al. Lancet. 2004;363:1253-1263.

Gallant JE, et al. JAMA. 2004;29:191-201.

Risk Factors for Severe, Life-Threatening Hepatotoxicity With Nevirapine

• Women with CD4 cell counts >250 cells/mm3

– Have a 12-fold higher risk versus women with <250 cells/mm3

– Can be fatal• Greatest risk of severe and potentially fatal

hepatic events often associated with rash– Occurs in first 6 weeks of nevirapine therapy– Close monitoring recommended. In some cases,

hepatic injury progresses despite discontinuation of treatment

• Nevirapine should not be used for chronic therapy among women with CD4 >250 cells/mm3 when other options exist

Viramune [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2005.

Meta-Analysis of AACTG Studies:Odds Ratio of Severe Hepatotoxicity

• Retrospective analysis of 21

AACTG studies

– 9003 patients

• Single and double NRTIs

• Triple regimens including NRTIs,

NNRTIs, and PI

• Overall incidence

– Severe hepatotoxicity: 10%

• 23% discontinued due to severe

hepatotoxicity

– Liver-related mortality: 0.3%

• NRTI-based regimen: 0.46%

• NNRTI or PI-based regimen: 0.13%

Reisler R, et al. 1st IAS Conference. Buenos Aires. 2001. Abstract 43.

Incidence of Severe

Hepatotoxicity(95% CI)

Efavirenz (n=65) 10.8(3.3-18.3)

Nevirapine (n=594) 8.9(6.6-11.2)

Delavirdine (n=137) 3.6(0.5-6.7)

Total NNRTI (n=796) 8.2(6.3-10.1)

Grade 3 or 4 elevations (>5 x ULN).

2NN Study: Severe Hepatotoxicity in Patients Receiving NNRTI-Based Regimens

• Treatment-naïve patients– 1216 enrolled– HBV coinfected: 5.2%– HCV coinfected: 9.5%

• NNRTI + d4T + 3TC – Nevirapine qd (400 mg)– Nevirapine bid (200 mg)– Efavirenz qd (600 mg)– Nevirapine + efavirenz qd

(400 + 800 mg)• 2 nevirapine-attributed deaths

– Fulminant hepatitis, pancreatitis, renal failure

– Stevens-Johnson syndrome (recovered)

• Later developed septicemia due to a methicillin-resistant Staphylococcus aureus infection

van Leth F, et al. Lancet. 2004;363:1253-1263.

0

5

10

1513.6%

8.3%9.1%

4.5%

Grade 3/4 Hepatotoxicity

Pat

ient

s, %

Nevirapine

QD BID Efavirenz Efavirenz + (n=220) (n=387) (n=400) Nevirapine (n=209)

ALT and AST >5 Times ULN

0

5

10

15

20

25

Pat

ient

s (%

)

ALT AST

13%

7%

• Seropositive for hepatitis B and C at study entry– 137 patients treated with

efavirenz-containing regimens

– 84 patients treated with indinavir + 2 NRTIs

• Discontinuations due to liver or biliary system disorders were similar (2% to 3%)

Sustiva [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2003.

7%

20%

Efavirenz-containing regimens Indinavir + 2 NRTIs

Study 006: Patients WithHepatitis C and/or Hep B Coinfection

Summary of NNRTIs and Hepatic Safety

• There appears to be a modest class effect of NNRTIs on abnormal liver enzyme levels

• Rate of serious clinical (symptomatic) hepatotoxicity, ALT and/or AST levels >5 times ULN is relatively low– May be significantly higher in patients coinfected with

HBV or HCV

• Unique hepatic event associated with nevirapine– Immune-mediated – Associated with rash– Occurs almost exclusively within the first 6 weeks of

nevirapine treatment


PIs

PI-Related Hepatotoxicity

• Incidence of ALT and/or AST elevations in registration trials– Grade 3 (>5 x ULN) and 4 (>10 x ULN): 1% to 9%

• Full-dose ritonavir– Only PI identified as an independent risk factor for

severe hepatic injury

• Boosting doses of ritonavir (≤200 mg/d)– Not associated with significantly higher incidence of

severe hepatotoxicity versus other PIs

• Less data on newer PIs– Atazanavir or fosamprenavir

Sulkowski MS, et al. Clin Infect Dis. 2004:38(suppl 2):S90-S97.

Incidence and Risk Factors of HAART-Associated Hepatotoxicity

• Retrospective cohort analysis (n=560)• Risk factors for grade 4 liver enzyme elevations (HR

[95% CI])– Female sex: 2.8 [1.3-5.8]– Baseline ALT levels (per 10 U/L increase): 1.05 [1.01-1.11]– Chronic HCV infection: 5.0 [2.3-10.7]– Chronic HBV infection: 9.2 [4.1-20.6]– Recent discontinuation of lamivudine: 6.8 [2.1-22.7]– Recent start of nevirapine:* 9.6 [3.2-28.3]– Recent start of full-dose ritonavir:* 4.9 [2.0-12.1]– No increased risk if ritonavir dose ≤200 mg bid

*12-week period after start of drug.†Patients without NRTIs experience using first-line ARV versus subsequent regimens.

Wit FW, et al. J Infect Dis. 2002;186:23-31.

Hepatotoxicity Associated with PI-Based Regimens ± Low-Dose Ritonavir: Design

• Prospective study (n=1161)

– Evaluate grade 3/4 AST/ALT elevations of PIs

– Median follow-up: 211−365 days

• Baseline characteristics

– Age*: 37 years

– Male: 73%

– African American: 77%

– HCV+: 46%

– HbsAg+: 10%

– ALT*: 30 IU/L

– CD4*: 168 cells/mm3

– HIV RNA*: 4.7 log10 copies/mL

*median

24%

51%8%

9%

8%

NelfinavirSaquinavir/r

Indinavir/r

Lopinavir/r

1st PI-Containing Regimen

Sulkowski MS, et al. Hepatology. 2003;38:698A.Sulkowski MS, et al. AIDS. 2004;18:2277-2284.

Indinavir

Relative Risk of Severe

Hepatotoxicity(95% CI)

HCV+ 1.73 (1.14-2.63)

CD4 >50 cells/mm3 0.51 (0.33-0.79)

HIV RNA >10,000 copies/mL

2.59 (1.08-6.18)

Indinavir 2.30 (1.06-4.98)

Indinavir/RTV 2.73 (1.33-5.63)

Saquinavir/RTV 2.39 (1.47-3.89)

Risk Factors for PI-AssociatedDrug-Induced Liver Injury

• No increased risk observed with lopinavir/r and nelfinavir– Results consistent with

data from the randomized control trial by Walmsley (Study 863)

• HIV/HCV-coinfected patients– 84% had no drug-induced

liver injury

Sulkowski MS, et al. Hepatology. 2003;38:698A.Sulkowski MS, et al. AIDS. 2004;18:2277-2284.

Multivariate analysis

Study 863: 60-Week Safety of Lopinavir/r and Nelfinavir by Hepatitis Status

• Hepatitis B/C-positive patients– Patients with ALT/AST >3x ULN were excluded at screening

regardless of hepatitis status• Lopinavir/r patients (n=57) tended to have a lower

incidence of grade 3/4 AST and ALT elevations compared with nelfinavir-treated patients (n=68) – AST: lopinavir/r 4% versus nelfinavir 13%– ALT: lopinavir/r 12% versus nelfinavir 17%

• Similar incidence of discontinuations due to hepatic adverse events in both groups (4%)

• No discontinuations due to elevated liver enzymes in either group

• No hepatic-related events resulted in death

Bernstein B, et al. 1st IAS Conference. Buenos Aires. 2001. Abstract 525.

Patients (%)

Lopinavir/rHBV/HCV+

(n=57)

Lopinavir/rHBV/HCV–

(n=269)

NelfinavirHBV/HCV+

(n=68)

NelfinavirHBV/HCV–

(n=259)

Glucose (250 mg/dL) 2 2 3 1

AST (>5 x ULN) 4 3 13 2†

ALT (>5 x ULN) 12 3* 17 <1†

Total cholesterol(>300)

10 11 8 6

Triglycerides(>750 mg/dL)

10 11 0 3

Amylase(>2 x ULN)

4 3 3 2

Study 863: Selected Adverse Events and Laboratory Abnormalities

*P<.05 and †P<.001 vs hepatitis positive

Bernstein B, et al. 1st IAS Conference. Buenos Aires. 2001. Abstract 525.

Study 863: Demographics of HIV/HCV Coinfected Patients

Lopinavir/r(n=29)

Nelfinavir(n=41)

HIV RNA (log10 copies/mL)

Median (range) 5.12 (3.02-6.28) 5.02 (2.98-6.72)

CD4 (cells/mm3)

Median (range) 205 (2.5-868) 186 (15-818)

HCV RNA (log10 IU/mL)

Median (range) 6.28 (1.70-7.32)(n=22)

6.45 (2.95-7.36)(n=35)

ALT (IU/L)

Median (range) 44 (16-265) 39 (14-100)

All patients received lamivudine + stavudine.All patients received lamivudine + stavudine.HCV Genotype 1: 71% of patients.HCV Genotype 1: 71% of patients.

Sherman KE, et al. 11th CROI. San Francisco. 2004. Abstract 811.

Study 863 HIV/HCV-Coinfected Patients: CD4 Cell Counts Through 48 Weeks

0

50

100

150

200

250

CD

4 C

hang

e F

rom

Bas

elin

e(c

ells

/mm

3 )

0 8 16 24 32 40 48

LPV/r (n=29) (n=23) (n=20)Nelfinavir (n=41) (n=34) (n=35)

Weeks

234

184

On-Treatment

Lopinavir/r + d4T + 3TCNelfinavir + d4T + 3TC

P=0.247


0

20

40

60

80

100

0 6 12 18 24 30 36 42 48

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48

Study 863 HIV/HCV-Coinfected Patients: Time to HIV RNA <400 and <50 Copies/mL

All patients received lamivudine + stavudine.

HIV RNA<400 Copies/mL

Pat

ient

s, %

Weeks

100%

87%

HIV RNA<50 Copies/mL

Weeks

100%

73%

Lopinavir/r (n=29)Nelfinavir (n=41)

Lopinavir/r (n=29)Nelfinavir (n=41)

First evaluatedat 24 weeksP=.274 P=.308


Pat

ient

s, %

Study 863 HIV/HCV-Coinfected Patients:Mean ALT Through 48 Weeks

0

10

20

30

40

50

60

70

80

90

Mea

n A

LT,

IU/L

0 8 16 24 32 40 48

LPV/r (n=29) (n=24) (n=21)Nelfinavir (n=41) (n=37) (n=35)

Weeks

63

44

On-Treatment

**PP<.05 and <.05 and ††PP<.01 vs LPV/r.<.01 vs LPV/r.

Lopinavir/r + d4T + 3TCNelfinavir + d4T + 3TC


*

*

†

Meta-Analysis of Lopinavir/Ritonavir Efficacy in HIV/HCV Coinfected Patients

• 48-week exposure data from 8 clinical trials– 819 adult HIV-infected patients

• Hepatitis positive: 132 patients with HCV and/or HBV coinfection

• Hepatitis negative: 687 patients

• 5-year exposure data from Study M97-720• Lopinavir/ritonavir

– At least as safe as nelfinavir– 6.9% to 12.8% experienced grade 3+ ALT elevations– Overall coinfected patients did have 3 to 4 fold higher

risk of ALT and AST elevations versus those without hepatitis

da Silva, et al. 15th IAC. Bangkok, 2004. Abstract MoPeB3285.

Meta-Analysis: Virologic Outcomes With Lopinavir/Ritonavir


0

20

40

60

80

100

0 8 16 24 32 40 48HIV

RN

A <

400

copi

es/m

L, %

Hepatitis positive(n=75)

Week

Treatment-NaïveHepatitis negative

(n=433)

P=0.2050

20

40

60

80

100

0 8 16 24 32 40 48HIV

RN

A <

400

copi

es/m

L %

Hepatitis positive(n=57)

Week

Treatment-Experienced

Hepatitis negative(n=254)

P=0.562


Meta-Analysis: Week 48 CD4 Cell Gain With Lopinavir/Ritonavir by Hepatitis Status


Treatment-Naïve

0

50

100

150

200

250

CD

4 C

hang

e, c

ells

/mm

3

HepatitisPositive(n=51)

HepatitisNegative(n=377)

211219

P=.69

Treatment-Experienced

0

25

50

75

100

125

150

175

200

225

CD

4 C

hang

e, c

ells

/mm

3

HepatitisPositive(n=39)

HepatitisNegative(n=181)

82

114

P=.17


Meta-Analysis Findings

• A higher percentage of HIV/HCV coinfected patients treated with lopinavir/ritonavir maintained HIV RNA levels <400 and <50 copies/mL compared with nelfinavir-treated patients

• Lopinavir/ritonavir appears at least as safe as nelfinavir in HIV/HCV coinfected patients– A minority of patients (6.9% to 12.8%) experienced

grade 3+ ALT elevations

• Lopinavir/ritonavir appears to be equally effective against HIV infection in HCV positive and negative patients


0

20

40

60

80

100

0 8 16 24 32 40 48Weeks

Pro

po

rtio

n w

ith

HIV

RN

A <

50 c

op

ies/

mL

QD - Hepatitis B/C negative (n=95)

QD - Hepatitis B/C positive (n=19)

BID - Hepatitis B/C negative (n=60)

BID - Hepatitis B/C positive (n=15)

Study 418: HIV RNA <50 Copies/mL Through Week

48 by Baseline Hepatitis Status (ITT NC=F)

Easterbrook P. et al. HIV7. Glasgow, UK. 2004. Abstract 164.

0

25

50

75

100

125

150

175

200

225

0 8 16 24 32 40 48Weeks

CD

4 co

un

t ch

ang

e fr

om

bas

elin

e, C

ells

/µL QD - Hepatitis B/C negative (n=95)

QD - Hepatitis B/C positive (n=19)

BID - Hepatitis B/C negative (n=60)

BID - Hepatitis B/C positive (n=15)

Study 418: CD4 Count Mean Change From Baseline by Baseline Hepatitis Status

Easterbrook P. et al. HIV7. Glasgow, UK. 2004. Abstract 164.

Patients eligible for resistance testing1

Genotypic results available

Lopinavir resistance2

Tenofovir resistance3

Emtricitabine resistance4

LPV/r 800/200 mg QD(n=115)

11

8/11

0/8

0/8

2/8

11

7/11

0/7

0/7

1/7

LPV/r 400/100 mg BID(n=75)

1HIV RNA >500 copies/mL any time during Weeks 12-24. All samples >500 copies/mLwere submitted for testing2LPV/r resistance: emergence of primary or active site mutation at protease positions8, 30, 32, 46, 47, 48, 50, 54, 82, 84, 90, with phenotypic LPV resistance FC > 2.5 vs WT 3TDF resistance: emergence of K65R or any TAM (41, 67, 70, 210, 215, 219) in RT4FTC resistance: emergence of M184V mutation in RT

Study 418 Incidence of Resistance Through Week 48

Molina JM, et al. XV IAC. Bangkok, Thailand. 2004. Abstract WePe5701.

Summary of PIs and Hepatic Safety

• Rate of serious clinical (symptomatic) hepatotoxicity, ALT and/or AST levels >5 times ULN is relatively low– Boosting doses of ritonavir not associated with

significantly higher incidence of severe hepatotoxicity versus other PIs

• Patients coinfected with HBV and/or HCV– Greater risk of hepatotoxicity– Lopinavir/ritonavir appears at least as safe as nelfinavir– Boosted PIs can help suppress resistance to other

ARV agents– More data for atazanavir and fosamprenavir are

needed in this patient population

Conclusions

Conclusions

• High prevalence of HIV-hepatitis coinfection

• HIV RNA and CD4 are correlated with fibrosis progression in coinfected patients

• Use of NNRTIs is associated with increased risk of hepatotoxicity

• For PI regimens, no increased risk if ritonavir dose <200 mg bid

Conclusions, cont.

• Patients treated with boosted PIs tend to have a lower incidence of grade 3/4 AST and ALT elevations than patients treated with nelfinavir

• Boosted PIs tend to suppress HIV RNA better than nelfinavir in HIV/HCV coinfected patients

• Boosted PIs can help suppress resistance to other ARV agents (eg, tenofovir DF)

Recommended Regimens forTreatment-Naïve Patients: DHHS 2006

Preferred RegimensPreferred Regimens

Available at: http://aidsinfo.nih.gov/Default.aspx.

*Not recommended for use in 1st trimester, or in women with high pregnancy potential.†Ritonavir 100 mg/day recommended when tenofovir DF is used with atazanavir .‡ Low-dose: 100 to 400 mg/day as a pharmacologic booster.§Adult females and males with CD4 cell counts <250 and <400 cells/mm3, respectively.¶Soft-gel or hard gel capsules, or tablets.

PI-BasedAtazanavir†, fosamprenavir, ritonavir‡-boostedfosamprenavir, ritonavir‡-boosted indinavir, nelfinavir, or ritonavir‡-boosted saquinavir¶:

All used in conjunction with(3TC or FTC) + (ZDV or d4T or ABC or TDF or ddI)

Lopinavir/ritonavir + (3TC or FTC) +(d4T or ABC or TDF or ddI)

NNRTI-BasedEfavirenz* + (3TC or FTC) + (ABC or ddI or d4T)Nevirapine§ + (3TC or FTC) + (ZDV or d4T or ddI

or ABC or TDF)

Triple NRTI

Abacavir + 3TC + ZDV(only when a preferred or an alternative NNRTI-

or PI-based regimen cannot or should not be used)

Alternative RegimensAlternative Regimens

Lopinavir/ritonavir (400/100 mg [2 tablets] bid or800/200 mg [4 tablets] qd) +ZDV + (3TC or FTC)

Efavirenz* +(ZDV or TDF) + (3TC or FTC)

Post PresentationCME/CE Information

• Please return the completed enrollment/evaluation forms to the Meeting Host before you leave

• Certificate will be mailed to you within ~6 weeks• Please refer to the syllabus for complete

accreditation information• Inquiries/concerns may be directed to the CME

Administrator at (773) 308-7950, ext. 114

Thank You!

Case 1- HCV Diagnosis in HIV Infected Patient

• 43 y/o WM, unemployed, h/o IDU, found to be HIV positive last year. No f/u until today when he presents to clinic for evaluation

• You obtain labs and determine that his CD4 count is 227 (14%), HIV VL 84,000, Hemoglobin 13, ALT 51 and HCV Ab, HBV sAg are negative. No current meds.

• Given his HIV VL and CD4 count ARV Rx is recommended.

• In your consideration about ARV regimens in this patient, you discuss potential liver toxicity.

• Despite negative hepatitis serologies is any further or repeat testing warranted?

Case 2- HIV Treatment in the HIV/HCV Coinfected Patient

• 37 y/o AAF was diagnosed with HIV/HCV about 4 years ago. Remote h/o IDU and minimal ETOH intake. Has ongoing depression. Works as a medical assistant. Current meds are Zoloft and as needed ibuprofen.

• Current Labs today: HCV VL 7.1M genotype 1b, Chol 220 (LDL 131), ALT 51

• CD4 count has been in the 400s, HIV VL 12,000, but over the last couple of years has drifted down to 300 (17%) and the HIV VL is now 47,500.

• What type of ARV regimen would you consider using in this patient?

Case 3- HCV Treatment in the HIV/HCV Coinfected Patient

• 51 y/o HM with HIV/HCV for over 10 years. Intermittently employed as a house painter. H/o HTN, smoker, on ARV Rx (Sustiva, Truvada) with an undetectable HIV VL and CD4 count 451 (21%). His BMI is 29. Other labs include HCV VL 27.5M genotype 1a, ALT 67, Chol 247 (LDL 185), TG 97

• Liver biopsy 2 years ago showed grade 2 fibrosis and no cirrhosis.

• Although adherent to meds, he has missed a few appointments.

• Is this patient a candidate for HCV Treatment? What factors go into your decision?

Documents

Optimizing Care for the Optimizing Care for the HIV-Hepatitis Coinfected Patient Supported by an educational grant from Abbott Sponsored by The Academy