La Pedrera, BarcelonaMarch 1st 2016

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

Barcelona (Spain)

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

E-mail address: jmmiro@ub.edu

Accepted, 951 (49%)- Oral, 114- Poster, 884 Hepatitis (mainly HCV), 97 Tuberculosis, 31 Other OIs and Cancer, 45

Abstracts - CROI 2016

OIs, HCV Coinfection & Tumors

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

START

Effect of Immediate-initiation ART on risk of severe bacterial infections (SBI) in HIV positive

people with CD4 count > 500/mm3

Jemma O’Connor, Fred Gordin, Andrew Phillips, Brian Angus, David Cooper, Beatriz Grinsztejn, Gustavo Lopardo, Satyajit Das, Aimee Wilkin, Elbushra Herieka, David Jilich, Hartwig Klinker, Pacharee Kantipong, Karin Klingman,

Jens Lundgren for the INSIGHT START study group

CROI 2016 #474

NEJM 2015

START

Results - endpoint summary• 94 people experienced at least one Severe Bacterial

Infection [SBI] (immediate-initiation group n=28, deferred-initiation group n=66) during 13,890 person-years at risk (incidence of 0.68 per 100 person-years of follow-up (PYFU), 95% CI 0.54–0.81).

• Of the 94 people who developed an SBI, 50 experienced a bacterial infectious disease [BID] (immediate-initiation group n=14, deferred-initiation group n=36) and 48developed bacterial pneumonia (immediate-initiation group n=14, deferred-initiation group n=34).

BID = grade 4 severity, requiring unscheduled hospitalisations or causing death

CROI 2016 #474

START

Results - Change in BiomarkersCROI 2016 #474

START

Results SBI - Cox model CROI 2016 #474

CROI 2016 #160

CROI 2016 #160

CROI 2016 #160

CROI 2016 #160

CROI 2016 #160

CROI 2016 #160

CROI 2016 #160

CROI 2016 #160

#708

Hospitalizations with AIDS and Chronic End‐Organ Conditions in the HIV Outpatient Study (HOPS) 

#708

Hospitalizations with AIDS and Chronic End‐Organ Conditions in the HIV Outpatient Study (HOPS) 

#708

Hospitalizations with AIDS and Chronic End‐Organ Conditions in the HIV Outpatient Study (HOPS) 

Hospitalizations occurred increasingly among patients who were older, had higher CD4 cell counts and lower HIV viral loads.

OIs, HCV Coinfection & Tumors

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

#155

#155RCT designed for nurses in rural primary care clinicsObjectives: Rapid diagnosis and Rx to TB in HIV and early ART in order to reduce mortality. 

#155

‐ 83% culture positive TB started TB treatment within 7 days‐ The TB Fast Track algorithm enable nurses to identify people at highest risk of TB and increased % starting TB treatmentSupports existing WHO policy on empirical TB treatment!

#155

#155

The TB Fast Track algorithm did not reduce mortality

#155

The TB Fast Track algorithm did not reduce time to start ART

Treatment Outcomes for HIV/MDR‐TB Co‐infection in the Era of ART in Botswana

#755

Treatment Outcomes for HIV/MDR‐TB Co‐infection in the Era of ART in Botswana

#755

TB Outcomes with ATV/r and Rifabutin‐containing TB Regimen in HIV/TB Co‐Infected Patients in South India 

#753

ATV/r‐ART NNRTI‐ART

#158LB

#158LB *High intrinsic resistance against MTB BlaC

*

#158LB

MeropenemAmx‐Clv

FaropenemAmx‐Clv HRZE

751

Association of Tuberculosis With CD4 Recovery and HIV RNA Decline on ART in Europe 

OIs, HCV Coinfection & Tumors

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

Pre-ART Cryptococcal Antigen Titer Associated with Preemptive

Fluconazole FailureBozena M Morawski 1, David R Boulware 1, Elizabeth

Nalintya 2, Agnes Kiragga 2, Francis Kakooza 2, Radha Rajasingham 1, Benjamin J Park 3, Yukari

Manabe 2,4, Jonathan E Kaplan 3, David B Meya 1,2

1 University of Minnesota; 2 Infectious Diseases Institute, Uganda; 3 U.S. Centers for Disease Control and Prevention; 4 Johns Hopkins University

#159

CrAg Prevalence

#159

Protocol for CrAg+ Persons• Enrolled shortly after CD4 draw & CrAg result• Initiated preemptive fluconazole at enrollment

– 800mg/day for 2 weeks, then 400mg/day for 8 weeks

– No secondary prophylaxis• Fluconazole intervention exclusion criteria:

Suspected meningitis, history of cryptococcalmeningitis, known cirrhosis or jaundice, allergy or pregnancy

• ART initiated ~2 weeks after fluconazole• Participants followed for 6 months

#159

Population Characteristics

CharacteristicTiters <1:160n=92 (61%)

Titers ≥1:160n=59 (39%) P-value

Age, years 32 [28, 39] 34 [26, 40] 0.69BMI, kgs/m2 19.3 [17.4, 21.1] 19.3 [17.3, 21.2] 0.70Women, percent 39 (42.4%) 29 (49.2%) 0.42Time to enrollment 8 [3.5, 13.5] 8 [3, 13] 0.86Receiving rifampicin 15 (16.3%) 5 (8.5%) 0.17WHO stage III or IV 54 (58.7%) 39 (66.1%) 0.36

#159

Risk of Cryptococcal Meningitis

10-week risk 6-month riskCrAg Titer Cutoff

Hazard Ratio (95%CI)

P-value Hazard Ratio (95%CI)

P-value

>1:160 4.55 (0.97, 21.32) 0.06 9.20 (2.14, 39.58) <0.01

>1:320 5.25 (1.10, 24.95) 0.04 6.33 (1.76, 22.82) <0.01

>1:640 10.07 (2.25, 45.0) <0.01 12.10 (3.38, 43.37) <0.001

*Competing risks regression. Results present the sub-Hazard Ratio adjusted for CD4 cells/L and participant age

#159

Mortality Risk among CrAg+#159

≈10%

≈30%

CrAg+ Risk of Meningitis or Death #159

≈15%

≈40%

Immunologic Discrimination of CryptococcalIRIS from Culture‐positive Relapse

• Prospective cryptococcal meningitis cohorts in Uganda, 2006-2012

• Profiled CD4, viral loads, and CSF cytokines between paradoxical IRIS (n=62) vs. culture-positive relapse (n=12)

• CD4 Change on ART, neither necessary nor predictive:– paradoxical-IRIS events did not consistently have substantial

reconstitution of CD4+ cells (61% increased by >25 cells/L) – In culture positive relapse 50% increased >25 cells/µL.

• Viral Loads– All IRIS events had appropriate virologic responses– 50% of culture-positive relapses had virologic failure. #762

CSF Profiles

Y-axis ValuesWBC in cells/LProtein in mg/dLCytokines in pg/mL

Th2Th1

#762

OIs, HCV Coinfection & Tumors

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

824

Safety of stopping primary T. gondii prophylaxis with suppressed viremia and CD4>100/mm3

#765

Viral loadCD4

Prophylaxis

N Engl J Med 2016;374:636‐46.

N Engl J Med 2016;374:636‐46.

Survival = 81.5% (22/27)

#77LB

#77LB

#77LB

‐ RCT 1:1 to receive either: 3 infusions of 50 mg/kg ZMappTM 3 days apart plus oSOC (combination arm) or oSOC alone (control arm).‐ Early closure of the RCT due to the extinction of the Ebola outbreak in 2016.

OIs, HCV Coinfection & Tumors

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

HCV Cure in HCV/HIV coinfected patients: Are we there?

LTAcute

Hepatitis

Ledipasvir/Sofosbuvir FDC

FDC, fixed‐dose combination. 54

• Ledipasvir– Once‐daily, oral, 90‐mg 

NS5A inhibitor

• Sofosbuvir‒ Once‐daily, oral, 400‐mg 

NS5B inhibitor

• Ledipasvir/Sofosbuvir FDC–Once‐daily, oral, fixed‐dose (90/400 mg) combination tablet

–Single‐tablet regimen for hepatitis C

SOF nucleotide

polymerase inhibitor

LDVNS5A

inhibitor

SOF nucleotide

polymerase inhibitor

SOF nucleotide

polymerase inhibitor

LDVNS5A inhibitor

SOF nucleotide polymerase inhibitor

LDVNS5A inhibitor

SOF nucleotide polymerase inhibitor

55

Ledipasvir/Sofosbuvir for 6 Weeks in HIV-Infected Patients with Acute HCV Infection

Patients with chronic HIV and acute HCV infection – HCV GT 1 or 4– ART consistent with LDV/SOF co-administration with HIV <200 copies/mL

or not receiving ART with no plans to start

Acute HCV infection with detectable HCV RNA (Roche COBAS® AmpliPrep/COBAS® TaqMan® version 2.0, LLOQ=15 IU/mL) for <24 weeks, defined by

– HCV RNA-positive and negative anti-HCV antibody/HCV RNA test within last 6 months or

– Elevated ALT/AST >2.5 x ULN in past 6 months with normal LFTs in past year, and other causes excluded

5 sites in Germany and UKART, antiretroviral therapy

Week 0 6 18

LDV/SOF FDCN=26SVR12

#154LB

56

Results: SVR4 and SVR12 (ITT)

*3 patients relapsed, 1 was reinfected (GT 1a at baseline, 4d in post-treatment).Error bars represent 95% confidence intervals.

85% 77%

0

20

40

60

80

100

Pat

ient

s, %

20/2622/26

SVR4

4 Virologicfailures*

4 Virologic failures*2 Lost to follow-up

SVR12

#154LB

57

Results: Baseline HCV RNA and Treatment Outcome (SVR)

0

1

2

3

4

5

6

7

8

SVR12 RelapseSVR4H

CV

RN

A (lo

g 10

IU/m

L)Reinfection

The 3 relapses had BL VL >7 log10 IU/mL: GT 1a (2) and 4 (1). No new NS5A or NS5B RAVs were observed #154LB

LT

HCV Cure in HCV/HIV coinfected patients: Are we there?

IFN-free DAA Regimens

A New Predictive Index Predicts Outcomes in Compensated Cirrhosis in HCV/HIV

#529

LS≥21 predicts variceal bleeding (#530)  

#582

Response to DAA‐based regimens in HIV‐HCV co‐infected patients in real‐life, France 

Sofosbuvir‐based regimens: with daclatasvir, ledipasvir or simeprevirwith/without ribavirin for HCV GT 1 (61%), GT 3 (14%) and GT 4 (21%)

≈90%

#584

Response to DAA‐based regimens in HIV‐HCV co‐infected patients in real‐life, Germany 

#584

Response to SOF‐LDV for 8 weeks in HIV‐HCV co‐infected patients in real‐life, Germany 

#538 LB

High Efficacy of HCV Treatment by Primary Care Providers: The ASCEND Study 

Specialists = SVR 92%‐ Primary care = SVR 97%‐ Nurses = SVR 95%

HBVLT

HBV Cure in HBV/HIV coinfected patients: Are we there?

Liver transplantation in HIV/HBV coinfected patients: a cohort study

Five-year patient survival Five-year graft survival

#571

OIs, HCV Coinfection & Tumors

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

#630

Risk Factors for Hodgkin (HL) and Non‐Hodgkin Lymphoma (NHL) in Europe

#617

Global Burden of Cervical Cancer in HIV‐Positive Women on Antiretroviral Therapy

#162

Is Intensive Cervical Cancer ScreeningJustified in Immunosuppressed Women?

#161

#161

#161

#161

#161No influence on persistent oral HPV, or single detection at last visit (HR [95%CI] 0.68 [0.26, 1.80])

A.H. BorgesD.R. BoulwareK. Buchacz R.T. DaveyA.H. DiaconA. PhillipsH. FurrerA. GrantJ. D. Jenks

Acknowledgements

http://www.croiconference.org

J. LundgrenC. ManzardoS. MaussA. MocroftJ.A. PinedaJ.K. RockstrohI. WakedL. WittkopT. Wilkin