Summary I: Opportunistic Infections HCV/HBV Co-Infections ... · Other opportunistic infections ! IRIS ! Hepatitis co-infections OIs, Hepatitis Coinfections & Tumors 10.00 h Presentación

La Pedrera, Barcelona March 11th 2013

Dr. José M. Miró Infectious Diseases Service - ICMiD

Hospital Clinic - IDIBAPS University of Barcelona

Barcelona (Spain)

Summary I: Opportunistic Infections HCV/HBV Co-Infections & Tumors

E-mail address: [email protected]

10.00 h Presentación de la jornada Dr Bonaventura Clotet

10.15 h Resumen I: Infecciones oportunistas, tumores y VHB/C. Comorbilidad Dr Josep Ma Miró

10.45 h Resumen II: Nuevos enfoques terapéuticos y preventivos Dr Daniel Podzamczer

11.15 h Resumen III: Nuevos fármacos Dr Pere Domingo

11.45 h Resumen IV: Vacunas Dr Felipe García

12.15 h Coffee-Break

12.45 h Resumen V: Complicaciones del tratamiento y de la propia infección Dra Eugènia Negredo

13.15 h Resumen VI: Avances en investigación básica. Resistencias. Erradicación Dr Javier Martínez-Picado.

13.45 h Resumen VII: Interacciones farmacológicas y farmacocinética Dr Esteve Ribera

14.15 h “Los top 10 del CROI” Dr Josep M Llibre

14.45 h Discusión conjunta

15.00 h Clausura de la jornada Dr Josep M Gatell

15.15 h Almuerzo

UPDATE. 20 th CONFERENCE ON RETROVIRUSES AND OPPORTUNISTIC INFECTIONS

Barcelona, 11 de marzo 2013Auditori de La Pedrera Passeig de Gràcia, 92

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Con la colaboración:

§  Tuberculosis §  Cryptococcosis §  Other opportunistic infections §  IRIS §  Hepatitis co-infections

OIs, Hepatitis Coinfections & Tumors













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Comparative Performance of Rapid Urinary Lipoarabinomannan Assays and Xpert MTB/RIF

in HIV+ TB Patients in Uganda

Shah #146













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Shah #146













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Shah #146













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Shah #146













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Shah #146













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Shah #146













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Shah #146













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RCT Thrice-weekly Compared to Daily Anti-TB Treatment among HIV+ TB Patients in India

Patients with culture positive, rifampicin-sensitive pulmonary TB were randomized to receive daily (2EHRZ7/4HR7), part-daily (2EHRZ7/4HR3), or fully intermittent (2EHRZ3/4HR3) regimens under supervision followed by ART initiation (AZT/D4Twith 3TC/EFV) within 6 weeks of ATT

Gopalan 857

Daily (N=68)

Intermittent (N=37)

Sputum conversion -  Negative smear -  Negative culture

70% 97%

55% 76%

P-value

0.60 0.003













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What is the best cART regimen in TB-HIV coinfected patients – RCT at CROI 2013

855 – Matteelli Nevirapine- vs. Efavirenz-based ART in TB/HIV Patients in Burkina Faso (N=69) Rifampin-based anti-TB treatment. EFAVIRENZ > NEVIRAPINE 854 – Matteelli RIFART Study in Italy (N=121). EFAVIREZ (with rifampin) = LOPINAVIR/ritonavir (with rifabutin)

853 – Grinsztejn ANRS 12 180 Reflate TB Trial in Brazil and France (N=153). Rifampin-based anti-TB treatment. EFAVIREZ = RALTEGRAVIR 400 BID = RALTEGRAVIR 800 BID













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ANRS 12 180 Reflate TB Trial (N=153). Rifampin-based anti-TB treatment.

Grinsztejn 853













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Grinsztejn 853













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Grinsztejn 853













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Grinsztejn 853













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Grinsztejn 853















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Western & Central Europe 500

North Africa & Middle East

6,500

Sub-Saharan Africa

720,000

Eastern Europe & Central Asia

27,200

South & South-East Asia

120,000 Oceania

100

North America 7,800

Caribbean 7,800

Latin America 54,400

East Asia 13,600

Global total: 957,900 cases (range: 371,700 – 1,544,000)

Estimated annual cases of HIV-associated cryptococcosis in the World

Park et al. AIDS 2009; 23: 525-30













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Western & Central Europe

45

North Africa & Middle East

3,600

Sub-Saharan Africa

504,000

Eastern Europe & Central Asia

15,000

South & South-East Asia

66,000 Oceania

10

North America 700 Caribbean

4,300 Latin America

29,900

East Asia 1,200

Global total: 624,700 deaths (range: 125,000 – 1,124,900)

Estimated annual deaths from HIV-associated cryptococcosis in the World

Park et al. AIDS 2009; 23: 525-30













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Immediate vs. Deferred cART in Fungal OIs (ACTG A5164) Zolopa AR, et al. PLoS ONE. 2009;4(5):e5575. Epub 2009.

Immediate cART is beneficial

in the ACTG trial !













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•  Early vs. Deferred (10 weeks) cART in Cryptococcal Meningitis (N=54) –  Rx: Fluconazole 800 mg daily and d4T/

3TC/NVP –  No use of amphotericin or management of

raised intracranial pressure •  Mortality: 87% early vs. 37%

delayed (P=0.002) –  Most deaths in immediate ART group

occurred within the first month, possibly due to IRIS

–  Fluconazole-NVP drug interaction postulated

HIV-associated Cryptococcal Meningitis (Uganda): Immediate vs. Deferred cART

Makadzange A, et al. Clin Infect Dis. 2010; 50(11):1532-8. Comparison of Kaplan-Meier Survival Estimates

by Treatment Group

1.00

0.

75

0.00

0.

25

0 200 400 600 800

Time to Death (in days)

0.50

Time to Death (days)

P=0.028 Deferred

Early Surv

ival













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ART Initiation within the First 2 Weeks of Cryptococcal Meningitis Is Associated with Higher Mortality Cryptococcal Optimal ART Timing (COAT) Trial

Randomization Stratified by Site and by Altered Mental Status

Primary end point: Survival at 26 weeks

Enrollment Started Nov 2010; halted April 27, 2012 by NIAID Africa DSMB

Boulware #144













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Medication and Dose 2 weeks ~ 3 weeks 8 weeks 46 weeks

Amphotericin (0.7-1.0 mg/kg/day)

Fluconazole 800mg daily Continue until CSF is sterile1

Fluconazole 400mg daily 1

Fluconazole 200mg daily

Continue for ≥12 months AND until CD4 > 200 cells/mL for ≥ 6 months

Treatment Phase Induction Consolidation Secondary Prophylaxis

1 Longer duration of consolidation therapy if CSF culture positive at 2-weeks. Therapeutic LPs at Diagnosis, Day 7, Day 14, and additional LPs as needed for pressure control

COAT Trial Treatment for Cryptococcal Meningitis

Boulware #144













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Early ART (n=88)

Deferred ART (n=89)

Age, median (IQR) 35 (28,40) 35 (30,40) Male Gender, n (%) 46 (52%) 47 (53%)

No Prior AIDS or TB, n (%) 57 (65%) 59 (66%) Prior/Current TB 22 (25%) 19 (21%) Prior AIDS illness and TB 9 (10%) 11 (12%)

Altered Mental Status, n (%) Glasgow Coma Scale <15 at study entry

12 (13.6%) 12 (13.5%)

CD4 cells/mL, median (IQR) 19 (9, 69) 28 (11, 76) CSF Opening Pressure, mm H2O 283 (+128) 287 (+148) CSF Quant. Culture log10 CFU/mL 5.2 (4.0, 5.6) 4.8 (3.7, 5.5) CSF WBC <5 cells/mL 45% 32%

Baseline Characteristics by Arm

Boulware #144













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P=0.03

70%

55%

Causes of death Early vs. Deferred - Cryptococcosis (21 vs. 10) - Septicemia (8 vs. 5) - TB (2 vs. 2) - IRIS-related (1 vs. 2)

Boulware #144













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Apriori Subgroups

Boulware #144













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IRIS Incidence Subjects with IRIS Events - By Treatment Group (Adjudicated)

Early ART Deferred ART P-value 1

Subjects with at least one event Definite/Probable CM-IRIS 5 (5.7%) 5 (5.6%) 0.999 Possible CM-IRIS 9 (10.2%) 2 (2.2%) No CM-IRIS 74 (81.8%) 62 (69.6%) Died before ART 2 (2.3%) 20 (22.4%)

Overall 88 (100.0%) 89 (100.0%)

Definite/Probable/Possible CM-IRIS of those receiving cART

14 (16.2%) 7 (10.1%) 0.347

1 Fisher's exact p-value

Odds Ratio = 1.7 (95% CI: 0.65 to 4.54) for IRIS with early ART Boulware

#144













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Recommendations •  No benefit for starting ART during cryptococcal

induction therapy 1.  Treat Cryptococcus first, optimally 2.  Counsel for HIV & ART while hospitalized

–  Link/register for outpatient care 3.  Verify 2-week CSF culture is sterile before starting ART or

↓fluconazole to 400mg

4.  Aim to start ART at ~4 weeks 5.  In Whom to Delay ART initiation (~5-6 weeks) - Paucity of CSF inflammation (<5 WBCs/mL CSF)

- Altered Mental Status / Sepsis Boulware

#144

Chang 2012 #955













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Chang 2012 #955













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No Benefit of Mitarzapine Add-on to cART in HIV+ Patients with PML in France (INSERM)

Canestri #399

0.72 [0.60 – 0.81]

0.50 [0.21 – 0.74]; 0.58 [0.40 – 0.73]













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Acyclovir Prophylaxis Reduces the Incidence of Herpes Zoster among HIV+ Individuals

Barnabas #868

Acyclovir prophylaxis reduced HZ incidence by 65% (HR = 0.35, 95% CI 0.20‐0.63, p<0.001

§  Randomized, double‐blind, placebo‐controlled trial of acyclovir (400 mg twice daily), among HIV-infected women and men from 7 African countries.

§  At baseline, none of the participants were receiving antiretroviral therapy and all had CD4 counts >250 cells/µL.













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RCT - Crofelemer (Fulizak®)125 mg for Treating Non-infectious Diarrhea in HIV+ Individuals

MacArthur #787

Crofelemer is an oligomeric proanthocyanidin extracted from the stem bark latex of the Croton lechleri tree. It inhibits chloride ion (Cl-) secretion and accompanying high volume water loss in secretory diarrhea via dual inhibition of cystic fibrosis trans-membrane conductance regulator (CFTR) and calcium-activated Cl- channels (CaCC) in the intestinal epithelium.













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RCT - Crofelemer 125 mg for Treating Non-infectious Diarrhea in HIV+ Individuals

MacArthur #787

Inclusion criteria: HIV, CD4+ cell counts ≥100 cells/mm3, and a history of diarrhea (persistently loose stools despite regular antidiarrheal medication use [RCT or open-label study] or ≥1 watery bowel movement per day without

regular antidiarrheal medication use [RCT only]), occurring for ≥4 weeks.













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PI- vs. NNRTI-based ART in 16 HIV+ Patients with Hodgkin Lymphoma Receiving Adriamycin + Bleomycin +

Vinblastine + Dacarbazine Chemotherapy

Ibrahim #744















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Maraviroc does not Prevent IRIS in High Risk Subjects Initiating ART (CADIRIS Trial)

Sierra-Madero JG et al. Abstract 182LB

Hypothesis: CCR5 blockade with Maraviroc would block the post‐ART distribution of effector T cells from blood to tissues thereby decreasing the risk of clinical IRIS.













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Virion assembly

Translation and polyprotein processing

RNA replication

Receptor binding and endocytosis

Fusion and uncoating

(+) RNA

Transport and release

Treatment Targets against HCV

NS3/4A Protease Inhibitors

Boceprevir

Telaprevir













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Faldaprevir/Simeprevir

HCV GT-1 SVR Rates Over Time According to the Type of anti-HCV Therapies

IFN IFN + RBV Peg-IFN + RBV Peg-IFN+ RBV + Boceprevir/Telaprevir

15-20% 35-40% 45-50% 70-75%

- -

17-35%

61-74%

1990 1998 2001 2011

HCV HCV/HIV













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Definitions of failure on prior Peg-IFN/RBV therapy

Detection limit

Relapse Null response

Breakthrough Partial response

Treatment

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72

HC

V R

NA

leve

l

Weeks

2 log10 drop N

on-response

Adapted from Shiffman M. Curr Gastroenterol Rep 2006 Neumann A, et al. Science 1998; De Bruijne J, et al. Neth J Med 2008













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Efficacy of Telaprevir and Boceprevir in HCV/HIV Coinfected Patients – ANRS Trials

36 – Cotte ANRS HC26 TelapreVIH Study (N=69) HIV+ patients treated with ART, who had previously failed ≥12 weeks pegIFN-RBV for HCV genotype 1 co-infection. Null-responders with cirrhosis were excluded. EVR16 = 88% (95% CI 81-96%)

37 – Poizot-Martin ANRS-HC27 BocepreVIH Study (N=52) HIV+ patients treated with ART, who had previously failed ≥12 weeks pegIFN-RBV for HCV genotype 1 co-infection. Null-responders with cirrhosis were excluded. EVR16 = 63% (95% CI 51-75%)













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Efficacy of Faldeprevir/Peg-INF/RBV in HCV/HIV Coinfected Patients

40LB – Dieterich STARTVerso 4 (N=308) - Faldaprevir (FDV; BI 201335) is an hepatitis C virus (HCV) NS3/4A protease inhibitor (PI) in late-stage clinical development for the treatment of HCV genotype 1 (GT1) infection. - HCV/HIV patients who were HCV treatment-naïve or relapsed after previous HCV therapy were randomized to receive FDV 120 or 240 mg once daily (QD) for 12 or 24 weeks, in combination with pegIFN (180 µg once weekly) and weight-based RBV for 24 or 48 weeks (response guided). Week 12 <LLoQ TND -  Treatment naïve = 82% -  Relapsers = 91%













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Efficacy of Simeprevir/Peg-INF/RBV in HCV/HIV Coinfected Patients

154LB – Dieterich TMC435-C212 Study (N=106) - Simeprevir (TMC435) is a potent, oral, once-daily (QD), investigational hepatitis C virus (HCV) NS3/4A protease inhibitor with efficacy against HCV genotype 1 mono-infection - Patients who were treatment-naïve and non-cirrhotic (n = 50) or prior relapsers (n = 14) received a response-guided treatment (RGT) regimen of simeprevir (150 mg once daily) for 12 weeks plus PR for 24 or 48 weeks. Prior partial (n = 10) or null (n = 28) responders and patients with cirrhosis (3 treatment-naïve patients and 1 relapser) received treatment for 48 weeks. SVR 12 = 77% RVR - Naïve = 71% - Relapsers = 93% - Partial responders = 80%

Potential targets for anti-HCV therapy

Protease-‐ Inhibitors

NS5B-‐Polymerase Inhibitors (NI, NNI)

NS5A Inhibitors

Cyclophilin Inhibitors

TLR-‐Agonists Therapeu6c Vaccine

Other IFNs PEG-‐IFN lambda

Entry-‐Inhibitors

Ribavirin

Class Potency Barrier to resistance

Toxicity and drug interactions

HCV genotype coverage

NS3 Protease inhibitors High Low Variable

Multiple DDI

1 Other

genotypes

NS5B Polymerase inhibitors

Nucleos(t)ide Moderate

High High

Mitochondrial toxicity PK interactions with

other N(t)s All

Non nucleoside Low

Moderate Very low Variable 1

NS5A Inhibitors Moderate

High Low Variable Variable

Cyclophilin Inhibitors Moderate High Low All

Comparison of direct antiviral agents

Modified from: Schaeffer and Chung, Gastroenterology 2012;142:1340-1350 Debes and Smith, Hepatology doi: 10.1002/hep.25696

Anti-HCV drugs in development

Launched

BMS-986094

GSK-2336805

Ledipasvir

ABT-267

VX-222

NS5B Non-Nucleosides

NS5A

Setrobuvir

Tegobuvir

BMS-791325 BI-207127

Cyclophilin

ABT-333

ABT-072

NS3 Protease

MK-5172

GS-9451

GS-9256

Danoprevir

ACH-1625

ABT-450

Faldaprevir

Vani- previr

Asuna- previr

Sime- previr

Alisporivir

Sofosbuvir

Dacla- tasvir

Telaprevir

Boceprevir

IDX-184

Mericitabine

NS5B Nucleosides

Phase III

Phase II













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IFN-free Regimens for Treating in HCV/HIV Coinfected Patients

41LB – Gane ELECTRON study (N=34 HCV GT1) Sofosbuvir (SOF) is a potent nucleotide analogue with a high barrier to resistance and excellent safety profile in clinical studies to date. Ledipasvir (LDV, formerly GS-5885) is a novel hepatitis C virus (HCV) NS5A inhibitor with picomolar potency against HCV GT1 and additive antiviral effect with SOF. SOF + LDV + RBV for 12 weeks. SVR -  Treatment naïve (N=25) = 100% -  Null responders (N=9) = 100%













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155LB – Lawitz COSMOS Study: Once-daily Regimen of Simeprevir + Sofosbuvir with or without Ribavirin. Hepatitis C Virus GT 1 Null Responders SVR 8 -  SMV + SOF + RBV = 26/27 (96%) -  SMV + SOF = 13/14 (93%)













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38 – Lawitz 12 Weeks of ABT-450/Ritonavir + ABT-072/333 + Ribavirin. ABT-450 = NS3 protease inhibitor, QD. ABT-333 and ABT-072 = Non-nucleoside NS5B polymerase inhibitors, QD. SVR 24 -  Treatment naïve = 86-95% -  Non-responders = 47%













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39 – King ABT-450/r + ABT-267 + ABT-333 + Ribavirin – Optimal Treatment Duration (8, 12 or 24 weeks) ABT-450 = NS3/4A protease inhibitor, QD ABT-267 = NS5A inhibitor, QD ABT-333 = Non-nucleoside NS5B polymerase inhibitor, BD. SVR 24 [12 weeks] -  Treatment naïve (N=237) = 89-99% -  Null-responders (N=90) = 89-93%













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IFN-free Regimens ABT-450/r + ABT-267 + ABT-333 + Ribavirin

King [39]

Liver Retransplantation (reLT) In HIV-Infected Patients: A Multinational Cohort (1997-2012)

Spain USA Italy Germany UK Argentina Portugal Switzerland Total

270 125 118 30 24 10 13 10

600

Number Primary LT

Number reLT (%)

14 (5) 9 (7) 5 (4)

4 (13) 2 (8) 1 (11) 1 (8)

1 (10) 37 (6)

Miro, 726

Patient survival rates according to HCV RNA status at reLT

P=0.008

80 (50,93)

42 (20,62)

Miro 726

J. Berenguer M. Cervantes P. Domingo

X. Forns

Acknowledgements

http://retroconference.org

JM Llibre JA Pineda J. Macias

JG Sierra-Madero













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Documents

Summary I: Opportunistic Infections HCV/HBV Co-Infections ... · Other opportunistic infections ! IRIS ! Hepatitis co-infections OIs, Hepatitis Coinfections & Tumors 10.00 h Presentación