hiv treatment trials - virology...

HIV treatment trials

in ressouce limited settings

Xavier Anglaret & Serge Eholie

Programme PACCI/site ANRS de Côte d’Ivoire

HIV treatment trials

... in ressouce limited settings

Xavier Anglaret

Programme PACCI/site ANRS de Côte d’Ivoire

1. What it takes to run a trial2. Trials, cohorts or models... ?3. Current ART trials4. Discussion

Outline

1. Money ... Millions ($, €...)2. Time ... Years3. Facilities, capacities, expertise...

• Multi-disciplinary approach− Clinical− Biology− Methodology/statistics...

• Multi-site, multi-country...• Training, bulding experience and skills...

− In doctors, nurses, social workers... and patients

What it takes to run a trial

Ongoing HIV randomized trials in Africa, May 2013Source: clinicaltrials.gov website,

Key words : HIV & Phase 2, 3 & active(n=103)

http://www.clinicaltrials.gov

1. What it takes to run a trial2. Trials, cohorts or models... ?3. Current ART trials4. Discussion

Outline

• Cohorts & observational databasesReal-life description...Makes you think & raise hypotheses...

ModelsHelp address :Tricky questions, when no RCT can be done...Long-term issues...

Randomized trialsHighest level of proof...

Trials, cohorts or models ?

• Cohorts & observational databaseso Real-life description...Makes you think & raise hypotheses...




Boule AIDS 2010; 24: 563

• Cohorts & observational databaseso Real-life description...o Help think & raise hypotheses...




2nd-line with TDF 2nd-line without TDF

Wandeler JAIDS 2012; 61:41

Source: IeDEA West Africa Collaboration, Ekouevi D. personal communication

Baseline M6 M12 M18 M24NRTIs+PI n=247

177n=130

264n=96264

n=82306

n=65311

3 NRTIs n=14223

n=7294

n=5265

n=3254

n=3240

HIV-2 infected patients


• ModelsHelp address :Tricky questions, when no RCT can be done...Long-term issues...




• ModelsHelp address :o Tricky questions, when no RCT can be done...o Long-term issues...

Randomized trialsHigher level of proof...


EFV or NVP in women of childbearing age ?

Ouattara AIDS 2013; 26:625

1. What is the exact (extra)foetotoxicity of EFV, as compared to NVP ?

2. What are the long term consequences, for a childbearing age women, of starting ART with EFV, as compared to starting with NVP

= issues NEVER to be addressed by randomized controlled trials

EFV or NVP in women of childbearing age ?

Ouattara AIDS 2013; 26:625



Randomized trialsHigher level of proof...




• Randomized trialso Highest level of proof...




• Randomized trialso Highest level of proof...

Com

plmentarity


2006: WHO guidelines

1999: Randomized trials results

Trials and cohorts : Cotrimoxazole prophylaxis

2006: WHO guidelines

20042003

2005

2006

2005

2005

1999: Randomized trials results

Trials and cohorts : Cotrimoxazole prophylaxis

1. What it takes to run a trial2. Trials, cohorts, or models... ?3. Current ART trials4. Discusion

Outline

1. When to start...2. What to start with...3. How to monitor and manage... (ART toxicity,

IRIS, TB, other morbidity events, pregnancy, failure...)

4. What to switch with...• In second line...• In third line...

5. Specific populations• HIV-2• HBV-HCV

Current ART trials

When to start ART

Strategic Timing of Antiretroviral Treatment« START »

Follow-up : at least 3 years for each participantCurrently enrolled : 4027 (including 696 in sub-Saharan Africa)Primary endpoint : serious AIDS and non AIDS events

http://ClinicalTrials.gov/show/NCT00867048 http://insight.ccbr.umn.edu/report/start

34 countriesTrial 1st inclusion : April 2009 ; Trial close-up: 2016Sample size: 4600

NIAID/INSIGHT

START study

Enrollment by country

http://insight.ccbr.umn.edu/report/start/enroll_by_loc.html

START study

Enrollment by country

http://insight.ccbr.umn.edu/report/start/enroll_by_loc.html

Sub-Saharan Africa :

N=696

30 months Prolonged follow-up (up to Dec 2014)

Primary Outcome at 30 monthsDeath or severe morbidity (AIDS,

non-AIDS invasive bacterial diseases, non-AIDS malignancies)

Inclusion criteria:• CD4<800mm3 AND • no WHO criteria for starting ART

ANRS 12136 « Temprano »Côte d’IvoireTrial 1st inclusion : March 2008 ; Trial close-up: December 2014Sample size: 2077

http://ClinicalTrials.gov/show/ NCT00495651 http://mereva.net/temprano Anglaret Antivir Ther 2013; 18:45

First-line

Lubumbashi trial

Wk 48 LPV/r NVP pN=216 % N=209 %

VL>1000 cp/ml 3 1.4% 12 6% 0.03>1 resistance 1 0.5% 8 4% NS

VL<50 cp/ml 147 68% 144 69% NSDeath 19 8.8% 18 8.3% NSLoss to follow-up 10 4.6% 4 1.9% NS

Clumeck, CROI 2013, abstr. 559

République Démocratique du CongoTerminatedSample size: 425 patients

Inclusion criteria :• Adults, HIV-1, ART naïve

PI or NNRTI as First-line Treatment of HIV in West Africa - the PIONA Trial

Design :

Inclusion criteria • Adults, naive of ART

386patients randomized into two arms• LPV/r + 2 NRTIs (preferably : ZDV+3TC)• EFV or NVP + 2 NRTIs (preferably: ZDV+3TC)

Outcomes at 12 months• Primary : VL < 400 cps/ml• Secondary: resistance mutations, mortality, morbidity, CD4

evolution

Guinea BissauTrial 1st inclusion : May 2011 ; Trial close-up : Fev 2014Sample size: 386

Aarhus university, Denmark; Hospital Simão Mendes, Guinea Bissau

http://ClinicalTrials.gov/show/NCT01192035


ANRS 12115 – DAYANACameroon, SenegalTerminatedSample size: 120 patients Inclusion criteria :

• Adults, HIV-1, ART naïve

Second-line

Study of Options for 2nd-line Effective Combination Therapy(SELECT)

Primary outcome at Wk 24 Plasma HIV RNA < 400 copies/ml

Malawi, South AfricaTrial 1st inclusion: Jan 2012; Trial close-up: April 2015Sample size: 600; Follow-up: 96 wks

Inclusion criteria :• 1st-line NNRTI-based >6 months• Failure (plasma HIV RNA >1000 cps/ml x 2)

ACTG - NIAID

http://clinicaltrials.gov/show/NCT01641367

A Trial of 2 Options for 2nd-line Combination ART (SECOND-LINE)

Primary outcome at Wk 48 : Plasma HIV RNA < 200 copies/ml

Nigeria, South Africa & 16 non-African countriesTrial 1st inclusion : Sept 2009; Trial close-up: Aug 2013Sample size: 550; Follow-up: 48 wks

Inclusion criteria :• 1st-line NNRTI-based >6 months• Failure (plasma HIV RNA >500 cps/ml x 2)

Kirby Institute, Australia

http://clinicaltrials.gov/show/NCT00931463

1277 PATIENTS

RANDOMIZE

Boosted-PI + 2 NRTIs

(according to local standard of care)

Boosted-PI + RAL

Boosted PI + RAL(12wk induction)

Boosted-PI(Monotherapy)

FOLLOW-UP FOR 144 WEEKS

Primary Outcome –Good clinical HIV disease control – defined at wk 96 as : No new WHO Stage 4 events AND CD4 cell count > 250 cells/mm3 AND VL < 10,000 copies/ml OR VL >10,000 copies/ml with no PI resistance mutations

EDCTP - MRC Malawi, Uganda, Zimbabwe, Kenya, ZambiaTrial 1st inclusion: April 2010; Trial close-up: April 2013

http://earnest.cineca.org/ http://ClinicalTrials.gov/show/NCT00988039

Europe - Africa Research Network for Evaluation of Second-line Therapy (EARNEST)

Inclusion criteria :• 1st-line NNRTI-based AR >2 years,• Failure (modified WHO2006 criteria)

ANRS 12169 - 2LADY

Primary outcome at wk 48Plasma HIV RNA < 50 copies/ml

Cameroon, Senegal, Burkina FasoTrial 1st inclusion : 2009 ; Trial close-up: end 2013Sample size: 450

Inclusion criteria :• 1st-line NNRTI-based ART >2 years,• Failure (modified WHO2006 criteria)


ANRS - EDCTP

ANRS 12286 - MOBIDIP

ANRS 12169 2LADY

FTC + TDF + LPV/r

ABC + DDI + LPV/r

FTC + TDF + DRV/r

LPV/r

LPV/r + 3TC

DRV/r + 3TC

DRV/r

N=150

N=150

N=150

N = 82

N = 82

N = 50

N = 50

N = 454 (Réel)

ARM A

ARM B’

ARM B

ARM A’

Cameroon, Senegal, Burkina FasoTrial 1st inclusion : 2013 ; Trial close-up : 2016Sample size: 264

Primary outcome : at wk 96Plasma HIV RNA < 50 copies/ml

Inclusion criteria :• Patients from the 2LADY trial,• Plasma HIV RNA < 50 copies/ml

Third-line

ANRS 12286 - THILAO

Primary outcome at Month-12Plasma HIV RNA < 50 copies/ml

Côte d’Ivoire, Senegal, Burkina Faso, MaliTrial 1st inclusion : April 2013 ; Trial close-up: 2016Sample size: 200

Inclusion criteria :• 1st-line NNRTI-based; 2nd-line PI-based ART >6 months• Failure (plasma HIV RNA >1000 cps/ml)

Management Using Latest Technologies to Optimize Combination Therapy After Viral Failure

(MULTI-OCTAVE)

Primary outcome at Wk 48 Plasma HIV RNA < 200 copies/ml

South AfricaTrial 1st inclusion : Oct 2012; Trial close-up: April 2018Sample size: 500

Inclusion criteria :• 1st-line NNRTI-based; 2nd-line PI-based ART >6 months• Failure (plasma HIV RNA >1000 cps/ml x 2)

ACTG - NIAID

http://clinicaltrials.gov/show/NCT01641367 Lorenzana AIDS 2012; 26:1083

Randomization : standard vs reinforced adherence counselling

(Rando)

ANRS 12294 – FIT-2Côte d’Ivoire, Senegal, Burkina Faso, Guinée Bissau, TogoTrial 1st inclusion : January 2014 ; Trial close-up : 2017Sample size: 210

Primary outcome : at wk 96• Plasma HIV-2 RNA < 50 cps/ml

AND• CD4>100/mm3

AND • no ARV regimen definitively

jeopardized

Inclusion criteria :• HIV-2 positive• ART naïve • CD4 200-500/mm3

TDF-FTC-ZDV

TDF-FTC-LPV/r

TDF-FTC-RAL

N=150

N=150

N=150

N = 70

N = 70

N = 50

N = 50

N = 454 (Réel)

ARM A

ARM B’

ARM B

ARM A’

N = 70ARM C

Ran

dom

isat

ion

Intermediate outcome at wk 24:• CD4> 50/mm3

• And Plasma HIV-2 RNA <50 copies/Ml

(if <55% patients, stop the arm)

Tuberculosis

Should adults who start ART with low CD4 counts receive a systematic TB curative treatment ?

Exetasis PrOMPT REMEMBERSponsor ANRS AMC-UvA - EDCTP ACTG - NIAIDSettings Côte d’Ivoire

UgandaVietnam

GabonMozambiqueSouth AfricaUganda

Malawi, South Africa, Peru, Brazil, Kenya, India, Zambia, Zimbabwe, Haïti

Sample size 1050 334 839Start date End 2013 Aug 2011 Oct 2011End of study 2017 2016 May 2016Follow-up 48 wks 24 wks 96 wksCD4 count <100 <50 & BMI<18 <50ART TDF-FTC-EFV EFV-based TDF-FTC-EFVPrimary Outcome Survival with no

invasive bacterialinfection at 48 wks

Survival at 24 wks Survival at 24 wks

1. What it takes to run a trial2. Trials, cohorts, or models... ?3. Current ART trials4. Discusion

Outline

Discussion (1) : Current key issues

• Starting (much) earlier : from « when to start » to « when not to start » ?

• Protease inhibitors in 1st line ?• Place of drugs currently not recommended

by WHO in 1st, 2nd and 3rd line ? (integrase inhibitors, darunavir, next generation NNRTI) ?

• Avoid long term (and unecessary) NRTIs use ?

• Induction/maintenance

• Large... Multicountry... Trials• Increasing representativeness ?• A broad and integrated approach of the use

of drugs in 1st, 2nd, 3rd ... line Taking into account :− VL and genotype availability− High incidence of TB (low access to rifabutin...)− High rate of pregnancy/breastfeeding, low rate of

contraception/articifial feeding...− Low resources, limited care facilities... and

heterogeneity− Use of various other drugs (eg: antimalaria...)

Discussion (2) : Toward...

• Trials + cohorts + models reinforce one another, and will do so increasingly

• From ART research to other antivirals research (HBV, HCV...)...

Discussion (3) :

1. Results...2. Money... facilities, expertise...3. Daily practise improvement

« Clinical research is an integral part of good care practises, not a luxury »

Discussion (4) :What it gives to participate in

clinical studies

hiv treatment trials - virology...

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