Summary I: TB, Opportunistic Infections HCV/HBV …...La Pedrera, Barcelona February 21st 2017 Dr....

La Pedrera, BarcelonaFebruary 21st 2017

Dr. José M. MiróInfectious Diseases Service Hospital Clinic - IDIBAPS University of Barcelona

Barcelona (Spain)

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

E-mail address: [email protected]

Accepted, 1001 (52%)- Oral, 96 (5%)- Poster, 905 (47%) Hepatitis (mainly HCV), 123 (12%) Tuberculosis, 62 (6%) Cryptococcal meningitis + OIs 89 (9%) Cancer, 117 (12%)

Abstracts - CROI 2017

At last !!! All posters availablesince the first day of CROI 2017

OIs, HCV Coinfection & Tumors

Tuberculosis Cryptococcal meningitis Other infections Hepatitis – DAA Rx - LT Cancer

N= 2076 (519/arm)

Temprano

IPT

No IPT

Groups of analysis

9

Post-Temprano

6‐month IPT reduces mortality independently of ART in African adults with high CD4

# 78 IPT

6‐month IPT ↓ 37% mortality at 6 yr.

# 78 IPT

6‐month IPT reduces mortality independently of ART in African adults with high CD4

Shah NS, MDR TB and Transmission, Symposium CROI 2017

Duration of MDR/XDR Regimen: 8 months of intensive phase using 5 or more drugs, followed by 12 months of 3 drugs depending on response = 20 months

2017 EACS Guidelines of Rx MDR/XDR TB in HIV-infected Patients in Europe

Miro JM & Kirk O. Chairs OI Working Group. EACS Web Site, v.8.2 January 2017.

2017 EACS Guidelines of Rx MDR/XDR TB in HIV-infected Patients in Europe

Miro JM & Kirk O. Chairs OI Working Group. EACS Web Site, v.8.2 January 2017.

TB regimen• In persons with MDR/XDR TB, a regimen

with at least five effective TB medicines during the intensive phase is recommended, including pyrazinamide and four core second-line TB medicines - one chosen from group A, one from group B, and at least two from group C.

• If the minimum of effective TB medicines cannot be composed as above, an agent from group D2 and other agents from D3 may be added to bring the total to five.

The beginning of an authentic revolution in XDR-TB Treatment: The Nix-TB Trial

# 80LB Nix‐TB Trial

Mechanisms of action of new TB drugsZumla AI et al. Lancet Infect Dis 2014; 14: 327–40

Mechanisms of action of new TB drugsZumla AI et al. Lancet Infect Dis 2014; 14: 327–40


The Nix-TB Trial: Results



51% HIV+65% XDR

Paradoxical TB-IRIS• Recurrent, new or worsening inflammatory featuresof TB occurring during early ART

• Meta‐analysis of cohort studies 1

‐ Incidence 18% among HIV‐TB patients initiating ART‐ Hospitalization in 25%‐ TB‐IRIS attributable mortality in 2%‐Major risk factors include low CD4 count and early ART

• In patients with low CD4 count: ART initiation around 2 weeks on TB treatment reduces mortality, but increases TB‐IRIS incidence by > 2‐fold 2

1. Namale Future Microbiol 2015;10:10772. Uthman Ann Intern Med 2015;163:32

Integrase Inhibitor-Based ART regimens are an Independent Risk Factor for IRIS

Dutch cohort*French cohort**

OR (95%CI)

3.25 (1.83 - 5.80)1.99 (1.09 - 3.47)

*# 731 (ATHENA) & **# 732 (Dat’AIDS Study Group)

Inflammasomes* Play a Major Role in TB-IRIS Pathogenesis

# 733 *The inflammasomes are innate immune system receptors and sensors that regulate the activation of caspase-1 and induce inflammation in response to infectious microbes and molecules derived from host proteins

Corticosteroids in TB-IRIS

• Prednisone treatment of TB‐IRIS reduces duration of symptoms and hospitalisation 1

• Steroids have been associated with increased risk of infections and Kaposi’s sarcoma in HIV‐infected patients 2‐4

• Mainly in patients not on ART

• Rifampicin increases clearance of prednisone by 45% 5

• Hypothesis: Prednisone safely prevents TB‐IRIS1. Meintjes AIDS 2010;24:23812. Elliott QJM 1992;85:8553. Elliott JID 2004;190:8694. Mayosi NEJM 2014;371:11215. McAllister BMJ 1983;286:923

# 81LB

240 participant

s

Informed consentRandomised 1:1

Start ART+

4 weeks prednisone

Start ART+

4 weeks placebo

Follow-up for 12 weeks(Visits at weeks 1,2,4,8 and 12)

Follow-up for 12 weeks(Visits at weeks 1,2,4,8 and 12)

TB TREATMENT

ARTART started within 30 days of TB treatment

Recruitment at 4 public sector HIV-TB clinics in Khayelitsha, Cape Town, South Africa August 2013 – February 2016

Additional 28 week visit and 1 year phone call added to ascertain HIV‐related cancers (DSMB recommendation after IMPI trial)

Trial design: 1:1 randomized, double-blind, placebo-controlled trial

Prednisone or identical placebo• 40 mg/day for 2 weeks then 20 mg/day for 2 weeks (total 4 weeks)• Started with ART in patients at high risk of TB-IRIS

# 81LB

Consort diagram

# 81LB

Primary endpoint: Paradoxical TB-IRIS

# 81LB

Time to TB-IRIS event

Median time to TB‐IRIS restricted to those who developed TB‐IRIS:Placebo arm = 8 days (IQR 3‐12)Prednisone arm = 10 days (IQR 5‐13)

# 81LB

Open-label corticosteroids for TB-IRIS treatment

# 81LB

33 events in 29 patients:Cryptococcal meningitis (n=3)Oesophageal candida (n=10)Sepsis (n=7)Pneumonia (n=7)Pyelonephritis (n=1)Clostridium difficile (n=3)Dysentry (n=2)

1 Kaposi’s sarcoma case at week 28 in a participant in placebo armwho discontinued ART at week 20

(ascertainment to 1 year incomplete)

New AIDS-defining & invasive bacterial infections

# 81LB

CD4 count and HIV viral load at week 12

# 81LB

ConclusionsIn patients at high risk of paradoxical TB‐IRIS and improving on TB treatment, prednisone during the first 4 weeks of ART

‐ Reduced the incidence of TB‐IRIS by 30%

‐ Reduced requirement for corticosteroids to treat TB‐IRIS by 53%

‐Was well‐tolerated with no excess risk of infection or malignancy

# 81LB

Combination Antifungal Therapy for Cryptococcal Meningitis in AIDS Patients

Combination Antifungal Therapy for Cryptococcal Meningitis in AIDS Patients

Day JN et al. N Engl J Med 2013;368:1291-302.Day JN et al. N Engl J Med 2013;368:1291-302.

P=0.04

P=0.1369%67%

56%

Combination Antifungal Therapy for Cryptococcal Meningitis

Combination Antifungal Therapy for Cryptococcal Meningitis

Day JN et al. N Engl J Med 2013;368:1291-302.Day JN et al. N Engl J Med 2013;368:1291-302. P<0.001P<0.001

−0.31 log10 CFU/d −0.42 log10 CFU/d −0.32 log10 CFU/dClearance = 53% Clearance = 74% Clearance = 64%

Antifungal treatment of Cryptococcal MeningitisAntifungal treatment of Cryptococcal Meningitis

2017 CDC/NIH/IDSA Recommendationshttp://aidsinfo.nih.gov/guidelines2017 CDC/NIH/IDSA Recommendationshttp://aidsinfo.nih.gov/guidelines

0 wk 2 wk 10 wk Lifelong or until cART-induced IRAcute phase Maintenance therapy

Amphotericin B+ FlucytosineAmphotericin B+ Flucytosine

Fluconazole400 mg/d

Fluconazole400 mg/d

Fluconazole200 mg/d

Fluconazole200 mg/d

• Efficacy of an Abbreviated Induction Regimen of Amphotericin B Deoxycholate for Cryptococcal Meningoencephalitis: 3 Days of Therapy Is = to 14 Days

(Experimental cryptococcal meningoencephalitis in rabbits)

• Abbreviated Amphotericin B Deoxycholateregimens have been tested in humans in therecently completed ACTA randomizedcontrolled trial

Toxicity of abbreviated regimes is significantly less than withstandard 14‐day regimens

Bicanic et al. AAC 2015

Livermore J et al. MBio 2014; 5(1):e00725‐13.

Daily Abbr

#82 AMBITION‐CM

The pharmacokinetics of liposomal amphotericin B in murineplasma (red) and cerebrum (black) in cohorts of mice infectedwith Cryptococcus neoformans receiving LAmB 20 mg/kg SINGLEDOSE i.v.

The terminal half‐life in theplasma and cerebrum iscirca 133 hours = 5,5 days.

Lestner JM et al. Submitted to AAC 2017.

#82 AMBITION‐CM

RCT: Ambition in Cryptococcal Meningitis

#82 AMBITION‐CM

AMBITION‐cmIntermittent High Dose AMBISOME on a High Dose FluconazoleBackbone for Cryptococcal Meningitis Induction Therapy in sub‐Saharan Africa: An Adaptive Randomised Controlled Non‐inferiority Trial

Study HypothesisShort‐course high‐dose Ambisome given with high dosefluconazole will be non‐inferior to 2 weeks daily‐dosedAmphotericin based induction therapy for the treatment of HIV‐associated cryptococcal meningitis.

Primary Objective:To determine the Early Fungicidal Activity (EFA) of threealternative schedules of intermittent high doseAmbisome in comparison with standard daily Ambisomefor induction therapy for HIV‐associated cryptococcalmeningitis.

Secondary Objectives:1. Determine PK parameters and PK/PD associations2. Determine the clinical efficacy and safety3. Model the cost‐effectiveness of alternative schedulesof intermittent high dose Ambisome

Primary Endpoint:EFA of alternative Ambisome schedules.

Secondary Endpoints:1. Mortality at 2 and 10 weeks.2. Proportions of patients in each arm suffering clinicaland laboratory‐defined grade III/IV adverse events;median % change from baseline in laboratory definedparameters, by treatment arm.


#82 AMBITION‐CM

Step 1 of the study was stopped by the DMC at thepre‐planned interim analysis as the primary endpointhad been reached with the recommendation that thetrial proceed onto Step 2.

*No patients lost to follow‐up during initial two‐week follow‐up. One patient lost to follow‐up following discharge from hospital at week 2.

54 patients excluded‐ 11 Previous episodes of cryptococcal meningitis‐ 1 Confused and unable to obtain consent from relatives‐ 9 Died prior to enrolment‐ 10 Refused consent‐ 19 On antifungals >48hrs‐ 2 Less than 18years old‐ 2 Other (poor baseline renal and or liver function)

Single dose (n=18)

Two doses (n=20)

Three doses (n=21)

Control (n=21)

1 Patient excluded (prior episode of CM)

20 patients analysed

21 patients analysed*



134 Patients screened

80 Patients randomized


#82 AMBITION‐CM

Primary Endpoint: EFA


#82 AMBITION‐CM Day JN et al. NEJM; 2013.

Primary Endpoint: EFA

All 3 short course Liposomal Amphotericin B treatment arms were non‐inferior to control


#82 AMBITION‐CM

MortalityAll Control Single Dose Two Doses Three Doses P‐value

2 weeks 15% (12) 10% (2) 11% (2) 15% (3) 25% (5) 0.52

10 weeks 29% (23) 29% (6) 22% (4) 15% (3) 50% (10) 0.09


#82 AMBITION‐CM

MortalityAll Control Single Dose Two Doses Three Doses P‐value

2 weeks 15% (12) 10% (2) 11% (2) 15% (3) 25% (5) 0.52

10 weeks 29% (23) 29% (6) 22% (4) 15% (3) 50% (10) 0.09

All Control Single Dose Two Doses Three Doses P‐value

All AEs 88 19 29 14 26 0.50

Grade 3 AEs 45 7 18 9 11 ‐

Grade 4/5 AEs 43 12 11 5 15 ‐

L‐AmB related Grade 3*

11 4 2 2 3 ‐

L‐AmB related* Grade 4

3 3 0 0 0 ‐

Adverse Events

*Related includes all AEs classified as possibly, probably, or definitely related to study drug.


#82 AMBITION‐CM

All Control Single Dose Two Doses Three Doses P‐value

Grade 3 AEs

Anaemia 6% (5) 0% (0) 11% (2) 15% (3) 0% (0) 0.11

Renal impairment 5% (4) 0% (0) 6% (1) 0% (0) 15% (3) 0.10

Hypokalemia 1% (1) 0% (0) 0% (0) 5% (1) 0% (0) 0.39

Grade 4 AEs

Anaemia 1% (1) 5% (1) 0% (0) 0% (0) 0% (0) 0.42

Renal impairment 1% (1) 0% (0) 0% (0) 0% (0) 5% (1) 0.39

Hypokalemia 1% (1) 5% (1) 0% (0) 0% (0) 0% (0) 0.42

Adverse Events*

*During induction therapy

%

% increase in creatinine over 2‐week induction therapy

drop in hemoglobin over 2‐week induction therapy

Bicanic et al. AAC 2015

0.9g/dL

2.3g/dL

73%

14%

L‐Am

B

AmB‐d


#82 AMBITION‐CM

AMBITION Phase-III study – clinical endpoint non-inferiority trialL‐AmB 10 mg/kg day 1 (single dose)vsAmphotericin B deoxycholate 1.0 mg/kg/d 14 days(“control arm”)

All patients will receive fluconazole 1200 mg/d for first 2 weeks, then 800 mg/d until 10weeks and 200 mg/d thereafter. ART will be initiated 4‐6 weeks post initiation ofantifungal therapy

Endpoints:Primary: All‐cause mortality within the first 10 weeks

Secondary: Early Fungicidal Activity (EFA); 2‐week mortality; tolerability and adverseevents; cost‐effectiveness

850 patients total (425 per arm) (10% NI margin)

#82 AMBITION‐CM

Sertraline* and High-dose Fluconazole Treatment of Cryptococcal Meningitis in Tanzania

#744

- 0.25 - 0.44Survival

at 10 wk = 21%Survival

at 10 wk = 21%

*400 mg/d during 2 weeks and 200 mg/d for 12 weeks

Day JN et al. NEJM; 2013.

HIV-associated Talaromyces marneffei Infection

#83

International treatment guidelines

• Amphotericin B deoxycholate x 2 weeks, itraconazole400mg/day x 10 weeks, then 200mg/day until CD4 counts >100 cells/mm3 for 6 months1‐3

• Based on a Chiang Mai study: 74 patients. There was only one death, and treatment response was 97%4

1. IDSA and CDC guidelines 2009 2. British HIV guidelines 2013 3. Vietnam MoH 2013 4. Sirisanthana T et al. Clinical Infectious Diseases 1998


#83

Rationales for IVAP

• Amphotericin is not widely available in Asia, has significant side effects, requires hospitalization and prolonged infusion

• Itraconazole is better tolerated, is widely available, and costs a fraction (1/7) the price

• Itraconazole is used more frequently in large case series from Thailand, India, China, and Vietnam, and is similar to amphotericin in rates of mortality and clinical outcomes1‐5

1. Supparatpinyo et al. AAC 1993 2. Ranjana, J Infect 2002 3. Hu, Mycopathologica 2013 4. Le, CID 2011 5. Ha, AIDS Res and Therapy, 2012


#83

Research question

Is itraconazole non‐inferior to amphotericin, with the advantages of reduced toxicity and costs, allowing outpatient administration and wider access to treatment?


#83

573 patients were screened

133 Were excluded 95 Failed screening :

5 Were pregnant9 Had CNS involvement17 Had AST/ALT >400 U/L8 Had creatinine clearance <30 mL/min3 Had ANC <500 cells/µL30 Were on rifampicin28 Were on AmB or itraconazole >48h7 Declined to participate

38 Died, were discharged, or could not be contacted

Lost to follow‐up (n=9)3 Withdrew before day 14 6 Lost to follow‐up before week 24

219 amphotericin B

Lost to follow‐up (n=3)3 Lost to follow‐up before week 24

221 itraconazole

440 randomized (n=440)


#83

Cumulative incidence of the absolute risk of death until 24 weeks


#83

+10%

Summary of primary and secondary endpoints

Outcome Amphotericin B (N=217)

Itraconazole(N=218)

ComparisonEstimate (95% CI); p‐value

Primary Outcome: Risk of death at 2 weeks –events (% risk)‐ Intention‐to‐treat population (ITT)‐Modified ITT ‐ Per protocol population

14/217 (6.51)11/211 (5.22)11/205 (5.37)

16/218 (7.37)16/216 (7.41)15/214 (7.01)

Absolute risk difference [%]:

0.86(‐3.94 to 5.65); Pnoninf<0.00012.18 (‐2.42 to 6.79); Pnoninf =0.00041.64(‐2.96 to 6.25); Pnoninf=0.0002

Overall survival until 24 weeks – events (risk)‐ Intention‐to‐treat population (ITT)‐Modified ITT‐ Per protocol population

24/217 (11.26)21/211 (10.03)21/205 (10.27)

45/218 (20.98)45/216 (21.02)43/214 (20.28)

Hazard ratio:1.88(1.15 to 3.09); P=0.0122.15(1.28 to 3.61); p=0.0042.02(1.20 to 3.40); P=0.008


#83

Outcome Amphotericin B (N=217)

Itraconazole(N=218)

ComparisonEstimate (95% CI); p‐value

Time to treatment success ‐ ITT‐ Patients with treatment success ‐ events (%)‐Median time [days]

199/217 (93.4)8 (6 to 11)

196/218 (90.7)9.00 (6 to 12)

Ratio of subdistributionhazards:

0.83(0.69 to 1.00); P=0.049

Relapse, IRIS, or death until 24 weeks – events (%)‐ Relapse ‐ IRIS

3/217 (1.5)0/217 (0.0)

15/218 (7.0) 14/218 (6.6)

Absolute risk difference [%]:5.45(1.63 to 9.27); P=0.0056.56(3.24 to 9.88); P=0.0001

Survival until 24 weeks by death cause – events (%)

‐ Deaths related to T. m‐ Deaths related to other causes‐ Deaths with insufficient information to assess cause

15/217 (7.0)7/217 (3.3)2/217 (0.9)

25/218 (11.6)14/218 (6.6)6/218 (2.8)

Ratio of subdistributionhazards:

1.66(0.87 to 3.14); P=0.121.97(0.80 to 4.89); P=0.14

2.95(0.60 to 14.63); P=0.18

Decrease in blood fungal count during first 14d‐Median [log10 CFU/mL per day]

‐0.95(‐1.29 to ‐0.53)

‐0.36(‐0.70 to ‐0.19)

Difference in change:0.52 (0.41 to 0.63); P<0.0001

Summary of secondary endpoints


#83

Conclusions• Although the risk of death was similar at 2 weeks, mortality

was two times higher in patients receiving itraconazole at 6 months

• Incidence of relapse, IRIS, and poor treatment response were significantly higher in patients receiving itraconazole

• Rate of fungal clearance was 4 fold slower in patients receiving itraconazole, providing the biological basis for the observed higher mortality and complications

• Amphotericin B should be made widely available for talaromycosis patients in Asia


#83

CNS Toxoplasmosis in AIDS Patients

Stopping Secondary TE Prophylaxis in Suppressed Patients with CD4 100‐200 is not Safe

#751 COHERE

0.5 [0.3,0.8]1.9 [0.7,3.8]

4.4 [1.6,9.5]

LT

Natural History HCV/HIV coinfected patients

Epi

Modeling HIV‐HCV epidemiology in the DAA era: the road to eradication

Victor Virlogeux, Laurent Cotte, Pascal Pugliese, Isabelle Poizot‐Martin, Marc‐Antoine Valantin, Lise Cuzin, Jacques Reynes, Eric Billaud, Thomas Huleux for

the DatAIDS study Group

#751 COHERE

HIV‐HCV epidemiology in France

0%10%20%30%40%50%

2012 2013 2014 2015

Naive Previously treated

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

2012 2013 2014 2015 End 2015

Spontaneous cure Naive SVR Failure

*

* SVR 95,2%

Poster 550, CROI 2017

#135

Projected HCV prevalence over the next 10 years in the overall population

HIV‐HC

V coinfected

patie

nts

2016 2018 2020 2022 2024 20260

1000

2000

3000

4000

5000

6000

7000

8000

Undiagnosed HCV/HIV patients

30% coverage50% coverage70% coverage90% coverage

#135

Projected HCV prevalence over the next 10 years in different risk group

Heterosexual HIV−HCV males

2016 2021 20260

400

800

1200 30% coverage50% coverage70% coverage90% coverage

Undiagnosed population

Heterosexual HIV−HCV females

2016 2021 20260

400

800

1200

IVDU HIV−HCV males

2016 2021 20260

500

1000

1500

2000

2500

2016 2021 20260

500

1000

1500

2000

2500

Other HIV−HCV females

2016 2021 20260

100

200

300

400

2016 2021 20260

100

200

300

400

Heterosexual males

Heterosexual females

IVDU males

IVDU females

Others males

Others females

#135

Projected HCV prevalence over the next 10 years in MSM

2016 2021 20260

400

800

1200 30% coverage50% coverage70% coverage90% coverage

Undiagnosed population

2016 2021 20260

400

800

1200

Low‐risk MSM High‐risk MSM

HIV‐HC

V coinfected

patie

nts

#135

Treatment as Prevention (TasP)* PoC= The Dutch Model

#137LB

2014 (Acute HCV)11.2/1000 PYFU (95% CI 9‐14)1.1% per year

IRR (95% CI) = 0.49 (0.34 – 0.69)Jan‐Dec 2014 11.2/1000Jan‐Jun 2016 6.9/1000 July‐Dec 2016 4.0/1000

2016 (Acute HCV)5.5/1000 PYFU (95% CI 4–7)0,55% per year

*Universal DAA therapy for chronic HCV in 2015

What about Syphilis in MSM at public health STD clinics:First six months of 2015:N=446 syphilis infections diagnosed

First 6 months of 2016:N=629 syphilis infections diagnosed = ↑41% in MSM)

Syphilis in HIV+MSM LGV in MSM

http://www.rivm.nl Thermometer sexuele gezondheid nov2016

§

63

LT

Natural History HCV/HIV coinfected patients

Effectiveness of DAAs In HIV/HCV-coinfectedPatients with Decompensated Cirrhosis

2,662 HIV/HCV-coinfected patients initiated DAA-based Rx in Madrid-Core

from Nov 2014 to May 2016

1,953 patients scheduled to finish treatment on May 31, 2016

146 patients with decompensated cirrhosis included in this analysis

709 patients were on treatment on May 31, 2016

1066 patients without cirrhosis736 patients with compensated cirrhosis5 unknown liver fibrosis stage

# 534

Variable N = 146Age years – median (IQR) 51 (48 – 54) Male – n (%) 102 (69.9)Prior IDU – n (%)* 85/97 (87.6)CDC category C – n (%)* 33/97 (34.0)CD4+ T cells/µL – median (IQR)* 474 (247 – 687)cART – n (%) 125 (85.6) Child-Pugh-Turcotte score – n (%)

CPT A 75 (51.4)CPT B 62 (42.5)CPT C 9 (6.2)

MELD score – median (IQR) 10 (8 – 12)History of hepatocellular carcinoma – n (%) 15 (10.3)Liver transplantation – n (%) 1 (0.7)Liver transplantation waiting list – n (%) 7 (4.8)Anti-HCV – naïve – n (%) 88 (60.3)

Patient characteristics

*Based on 97 patients with available data

# 534

Genotypes and HCV-RNA

Log10 HCV-RNAMedian = 5.98IQR = 5.47 – 6.43

*

* Non-subtyped G1, G2, mixed, undeterminedTotal=146

G1a N=49G1b N=32G4 N=30G3 N=22Other N=13

33.56%

21.92%

8.90%

15.07%

20.55%

# 534

0 20 40 60

SOF/LDV

SOF+DCV

SOF+SMV

SOF+RBV

PrOD

SMV+DCV

Number of Patients

N = 73

N = 36

N = 26

N = 7

N = 3

N = 1

DAA-based regimens

Ribavirin No. (%)Yes 69 (47.3)No 77 (52.7)

# 534

No-C Co-C De-C0

50

100

SVR

12 %

No.SVR ITTSVR (95% CI)RelapseBreakthroughDC due to AEDC other Death

93.5 91.2 80.8

1066997 (93.5)

(91.9 - 94.9)36 (3.4)3 (0.3)7 (0.7)21 (2.0)2 (0.2)

736671 (91.2)

(88.9 - 93.1)36 (4.9)1 (0.1)5 (0.7)11 (1.5)12 (1.6)

146118 (80.8)

(73.5 - 86.9)17 (11.6)1 (0.7)2 (1.4)3 (2.0)5 (3.4)

P<0.001

P<0.001P=0.067

Treatment outcomes by severity of liver-diseasePatients w & w/o cirrhosis in Madrid-CoRe scheduled to finish treatment on May 31, 2016

No-C = No cirrhosisCo-C = Compensated cirrhosisDe-C = Decompensated cirrhosis

# 534

G1a G1b G3 G4Other

CPT ACPT BCPT C

MELD<10

MELD≥10

Naïve

Pretrea

ted

0

20

40

60

80

100SV

R12

%

77.5

(38/49)

87.5

(28/32)

77.3

(17/22)

80.0

(24/30)

86.7

(65/75)

79.0

(49/62)

81.8

(72/88)

79.3

(46/58)

87.5

(63/72)

74.0

(54/73)

84.6

(11/13)

44.4

(4/9)

NS NSP = .043

NS

P = .005

Treatment outcomes by subgroups

# 534

Factors associated with treatment failure by logistic regression analysis

Covariate Odds Ratio 95% CI PSex- Male- Female

10.291 0.090 – 0.947 0.040

Child-Turcotte-Pugh score- CTP A- CTP B- CTP C

11.7239.425

0.689 – 4.3122.011 – 44.167

0.2450.004

Univariate logistic regression analysis was performed to assess the de association of the following baseline variables with treatment failure: age, sex, prior IDU, CDC category, CD4+ cells, concurrent ART, HCV genotype, HCV-RNA, CTP score, MELD score, history of HCC, liver transplantation (LT), LT waiting list, prior anti-HCV therapy, DAA regimen, and RBV use.

The final multivariate logistic regression model included baseline variables with a P value < 0.1 in the univariate analysis (sex and Child-Turcotte-Pugh score)

# 534

Conclusions

• The SVR12 rate with all-oral DAAs in coinfected patients with decompensated cirrhosis was 81%; significantly lower than in patients without cirrhosis and than in patients with compensated cirrhosis

• Male sex and Child-Turcotte-Pugh stage C were the only variables associated with treatment failure patients with decompensated cirrhosis

• The long-term impact of all-oral DAA therapy in HIV/HCV-coinfected patients with decompensated cirrhosis remains to be determined.

Effectiveness of DAAs In HIV/HCV-coinfected Patients with Decompensated Cirrhosis. CROI 2017. Abstract #: 1051

# 534

Influence of HIV on Changes in Liver Function in Cirrhosis after Anti-HCV Treatment (SVR)

#536

Low baseline serum albumin levels were associated with the risk of liver function worsening at the date of RVS12 to DAA.

Frequency of HCC diagnosis after SVR in HIV/HCV‐coinfected patients with cirrhosis

6,66

11,72

1,68 0,88

0

5

10

15

IFN PEG‐IFN + RBV DAA + PR DAA IFN free

%

HCC after SVR 1 17 4 8No. with SVR 15 145 238 907

19 centers from the GEHEP‐002 cohort reported data of the number of HIV/HCV‐coinfected patients with cirrhosis who achieved SVR in each period.

n=1305 HIV/HCV cirrhotics with SVR before January 2017

#139

HCC recurrence after therapy against HCV

0

20

40

60

80

100

IFN‐based DAA IFN‐free

n=19

%

n=8

4 (21)1 (12.5)

39 patients with HCC received therapy against HCV after HCC diagnosis• n=8 IFN‐based. All of them after HCC curative therapies.• n=31 DAA IFN‐free.

• n=19 with previous curative therapies against HCC and ultrasoundevidence of lack of nodules prior to HCV therapy.

HCC recurrence after potentially curative treatments among those undergoing HCV therapy

p = 0.9

#139

IFN-Free Rx is Effective and Safe for Treating HCV recurrence in HCV/HIV LT Recipients

#540 FIPSE

SVR 93% HIV+ SVR 95% HIV-

2-22xRisk of invasive

cervical cancer3

11xRisk of

persistent infection2

2xBurden of

HPV1

HIV & Cervical Cancer Burden

78

HIV-infected women are disproportionately affected by cervical cancer.

3xRisk of

cervical pre-cancer1

1.95x95% CI: 1.20-

3.17Risk of death4

1. Jamieson DJ, et al. Characterization of genital human papillomavirus infection in women who have or who are at risk of having HIV infection. Am J Obs Gynecol 20022. Ellerbrock, TV, et al. Incidence of cervical squamous intraepithelial lesions in HIV-infected women. JAMA 20003. Denny LA, et al.. Human papillomavirus, human immunodeficiency virus and immunosuppression. Vaccine 20124. Dryden-Peterson S, et al. HIV Infection and Survival Among Women With Cervical Cancer. J Clin Oncol 2016.

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2014 WHO Guidelines

79

Single visit screen-and-treat using cryotherapy.

Loop electrosurgical excision procedure (LEEP) is an alterative for women not eligible for cryotherapy.

Conditional recommendations for the optimal treatment to prevent cancer.

1. Santesso N, et al. International Journal of Gynecology and Obstetrics World Health Organization Guidelines for treatment of cervical intraepithelial neoplasia 2 – 3 and screen-and-treat strategies to prevent cervical cancer the Guideline Support Group : Int J Gynecol Obstet 2016.

2014

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Cervical Cancer Screening and Diagnosis

80

1. Woodman CBJ, et al. The natural history of cervical HPV infection : unresolved issues. Nat Rev Cancer 2007.2. Khan MJ, et al. Treatment of cervical precancers: back to basics. Obstet Gynecol 2014.

Histology

Cytology(LSIL) (HSIL)

Degree of Risk

MildCytology Low

Grade SILHistology CIN 1

ModerateCytology High

Grade SILHistology CIN 2

SevereCytology High

Grade SIL+Histology CIN 3

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RCT to Treat CIN2/3 in HIV-Infected Women

Randomization

LEEPCryotherapyStudy Population

Eligible for Cryotherapy and LEEP

Clinical Measures Cytology Histology Plasma HIV-1 RNA HPV Swab

Statistical Analysis Intent to treat Chi-square tests Cox proportional

hazards regression

6 months

12 months

18 months

24 months

Baseline Study OutcomeTime to Recurrence

HSIL/CIN Grade 2

HSIL+/CIN Grade 3

Procedures

PAP smear

If indicated

Cervical biopsy

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400 Randomized

n=194 n=195

n=186

n=185 n=182

n=189

n=191

6 months

12 months

18 months

24 months

n=190

200 Cryotherapy 200 LEEP

82

1 Lost to Follow-up4 Deaths

1 Withdrawn


0 Withdrawn

1 Lost to Follow-up1 Death

0 Withdrawn


0 Withdrawn


0 Withdrawn


1 Withdrawn


0 Withdrawn


0 Withdrawn


14 Lost to Follow-up

4 DeathsStudy Retention = 92%

Consort flow-chart

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Log rank P=0.0191

27%Cryotherapy vs

18%LEEP

P=0.031

12-months

37%Cryotherapy vs

26%LEEP

P=0.018

24-months

Results: Higher Recurrence with Cryotherapy

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Higher Recurrence with Cryotherapy

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Most CIN 3 lesions are located within 5 mm of the surface but may extend further

Woodman CBJ, et al. The natural history of cervical HPV infection : unresolved issues. Nat Rev Cancer 2007.Khan MJ, et al. Treatment of cervical precancers: back to basics. Obstet Gynecol 2014.

CryotherapyDepth of tissue

destruction~5-7 mm

LEEPDepth of tissue

destruction~10-15 mm

Depth of CIN 5 mm

LEEP is a more expensive procedure but it is more cost-effective than treatment for cervical cancer

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J.R. ArribasX. AnglaretA. BadjeJ. BerenguerA. BoerekampsF. ConradieS. DormanA.H. DiaconS.A. Green

Acknowledgements

http://www.croiconference.org

J.N. JarvisT. LeE. LetangC. ManzardoG. MeintjesN. MerchanteJ.A. PinedaT. RodwellV. Virlogeux

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