En Afrique, chez les patients infectés par le VIH, dans Temprano

6. Conséquences de facteurs de risque cardiovasculaire chez les patients VIH

6.3. En Afrique, chez les patients infectés par le VIH, dans Temprano

Ces données sur les causes de mortalité au Sud et au Nord nous invitent à considérer la place éminente de la tuberculose dans les causes de décès. En effet, même si les facteurs de risque cardiovasculaires augmentent dans les pays du Sud et que leur effet peuvent être potentialisé par l’effet propre du virus par le biais de l’inflammation chez les personnes vivant avec le VIH, il reste que le poids de la Tuberculose est tout à fait dominant dans les personnes infectées par le virus, et « masque » en quelque sorte les effets des facteurs cardiovasculaire. C’est pourquoi nous nous sommes intéressés à la mortalité dans Temprano « Suivi Prolongé »(TSP), sur l’effet propre des antirétroviraux et de l’INH dans la réduction de ce risque.

Dans la suite de l’essai Temprano tel que décrit plus haut, nous avons suivi tous les patients jusqu’à Janvier 2015, c’est-à-dire jusqu’à M30 du dernier patient inclus. Durant ce suivi, les patients qui acceptaient ce suivi prolongé venaient tous les 3 mois et avaient leur transport remboursé et les médicaments ARV donnés dans le cadre du programme national. Nous n’avions pas les moyens de faire un recueil de morbidité aussi poussé que dans la durée de l’essai proprement dit, mais nous avons notifiés les décès et cherché activement les perdus de vues de la même manière que pendant

P a g e 125 | 183

la période de suivi « normal ». L’objectif de notre analyse était de regarder la mortalité prolongée dans Temprano, en intention de traiter selon les bras INH ou sans INH, à l’aide d’un modèle de Cox. Voici nos résultats en résumé. 2,056 patients (CD4 moyen à 477/mm3) ont été suivis pendant 9,404 patient-années (Temprano 4,755; TSP 4,649). Un total de 86 décès a été observé (Temprano 47; TSP 39), 34 chez les patients randomisés dans les bras INH (probabilité de décès à 6 mois de 4.1%, IC95%2.9 à 5.7) et 52 chez les patients randomisés sans INH (probabilité de décès à 6 mois 6.9%, IC95%5.1 à 9.2). Le hazard ratio de décès pour la stratégie INH comparée à non INH était de 0.63 (IC95%, 0.41 à 0.97) après ajustement sur la stratégie ARV (Précoces vs. Différé) et de 0.64 (IC95%0.41 à 0.98) après ajustement sur la stratégie ARV et les CD4 à l’inclusion. En conclusion, chez ces patients africains infectés par le VIH avec des CD4 élevés, 6 mois d’INH conduit à une réduction de 37% de la mortalité indépendamment des ARV précoces et du niveau de CD4 à l’inclusion.

Efficacy of 6-month isoniazid preventive therapy in HIV-

infected adults

Writing Committee

Anani Badje

1,2

, Raoul Moh

1,2,3

, Delphine Gabillard

1,2

, Calixte Guéhi

1,4

, Mathieu

Kabran

2,5

, Jean-Baptiste Ntakpé

, Jérôme Le Carrou

1,2

, Gérard M. Kouame

, Eric

Ouattara

1,2

, Eugène Messou

1,2,6

, Amani Anzian

2,6

, Albert Minga

1,2,7

, Joachim Gnokoro

,

Patrice Gouesse

, Arlette Emieme

2,5

, Thomas-d’Aquin Toni

2,5

, Cyprien Rabe

, Baba

Sidibé

, Gustave Nzunetu

, Lambert Dohoun

2,7

, Abo Yao

2,7

, Synali Kamagate

, Solange

Amon

, Amadou-Barenson Kouame

, Aboli Koua

, Kouame-Barenson Amadou

,

Emmanuel Kouamé

, Marcelle Daligou

, Denise Hawerlander

, Simplice Ackoundzé

,

Serge Koule

, Jonas Séri

, Alex Ani

, Fassery Dembélé

, Fatoumata Koné

, Mykayila

Oyebi

, Nathalie Mbakop

, Olewole Makaila

, Carole Babatunde

, Nathanael

Babatounde

, Gisèle Bleoué

, Mireille Tchoutedjem

, Alain-Claude Kouadio

,

Ghislaine Sena

, Sahinou-Yediga Yededji

, Sophie Karcher

1,2

, Christine Rouzioux

,

Abo Kouame

, Rodrigue Assi

, Alima Bakayoko

, Serge K. Domoua

, Nina

Deschamps

, Kakou Aka

2,3

, Thérèse N’Dri-Yoman

2,16

, Roger Salamon

1,2

, Valérie

Journot

, Hughes Ahibo

2,5

, Timothée Ouassa

2,5

, Hervé Menan

2,5

, André Inwoley

2,5

,

Christine Danel

1,2*

, Serge P. Eholié

1,2,3*

, Xavier Anglaret

1,2*

, on behalf of the Temprano

ANRS 12136 study group.**

* Christine Danel, Serge P. Eholié and Xavier Anglaret contributed equally to this

manuscript

** A complete list of the Temprano ANRS 12136 Study Group members is provided in

the Supplementary Appendix

Authors affiliation:

Inserm U1219, University of Bordeaux, France

Programme PAC-CI, ANRS research site, Abidjan, Côte d’Ivoire

Service des Maladies Infectieuses et Tropicales, CHU de Treichville, Abidjan, Côte d’Ivoire

_{Unité de Soins Ambulatoire et de Conseil (USAC), Treichville, Abidjan, Côte d’Ivoire}

Centre de Diagnostic et de Recherches sur le SIDA (CeDReS), CHU de Treichville,

Abidjan, Côte d’Ivoire

Centre de Prise en Charge de Recherche et de Formation (CePReF), Yopougon, Abidjan,

Côte d’Ivoire

Centre Médical de Suivi des Donneurs de Sang (CMSDS), Treichville, Abidjan, Côte

d’Ivoire

_{Hôpital Général d’Abobo Nord, Abobo, Abidjan, Côte d’Ivoire}

_{Centre Intégré de Recherches Biocliniques d’Abidjan (CIRBA), Treichville, Abidjan, Côte}

d’Ivoire

_{Formation Sanitaire Urbaine Communautaire (FSU Com) d’Anonkoua Kouté, Abobo,}

Abidjan, Côte d’Ivoire

_{Hôpital El Rapha, Abobo, Abidjan, Côte d’Ivoire}

Laboratoire de virologie, CHU Necker, Paris, France

Programme National de Lutte contre le SIDA, Ministère de la Sante et de l'Hygiène

Publique, Abidjan, Côte d’Ivoire

_{Service de Pneumologie, CHU de Treichville, Abidjan, Côte d’Ivoire}

Service de Gastro-entéro-hépatologie, CHU de Yopougon, Abidjan, Côte d’Ivoire

Corresponding author:

Xavier Anglaret, MD, PhD

Centre INSERM 1219, Université de Bordeaux

146 rue Léo Saignat, 33076 Bordeaux Cedex

France

E-mail : Xavier.Anglaret@isped.u-bordeaux2.fr

Tel : +33 5 57 57 17 65 ; Fax : +33 5 57 57 45 28

Key words: Isoniazid preventive therapy, tuberculosis, antiretroviral treatment, sub-Saharan

Africa, randomized controlled trial

Abstract

Background: Temprano was a factorial 2x2 trial that assessed the benefits of early

antiretroviral therapy (ART) and 6-month isoniazid prophylaxis (IPT) among HIV-infected

adults in Côte d’Ivoire. Participants were randomly assigned to four groups (deferred-ART-

No-IPT, deferred-ART-plus-IPT, early-ART-No-IPT, early ART-IPT). Early ART and IPT

were shown to independently reduce the risk of severe morbidity at 30 months. Here we

present the efficacy of IPT in reducing mortality in the long term.

Methods: Participants who completed the trial follow up were invited to participate in a post

trial phase (PTP). The PTP endpoint was death in an intention-to-treat analysis. We used Cox

proportional models to compare mortality between the IPT and No-IPT strategies from

inclusion in Temprano to January 2015.

Results: 2,056 patients (mean baseline CD4 count 477/mm

) were followed for 9,404 patient-

years (Temprano 4,757; PTP 4,647). A total of 86 deaths were observed (Temprano 47; PTP

39), 34 in patients randomized to IPT (six-year probability 4.1%, 95% CI 2.9 to 5.7) and 52 in

those randomized to No-IPT (six-year probability 6.9%, 95% CI 5.1 to 9.2). The hazard ratio

of death for IPT compared to No-IPT was 0.63 (95% CI, 0.41 to 0.97) after adjusting for the

ART strategy (Early vs. Deferred), and 0.61 (95% CI, 0.39 to 0.94) after adjusting for the

ART strategy, baseline CD4 count and other key factors.

Conclusions: In these African HIV-infected adults with high CD4 counts, 6-month IPT led to

a 39% decrease in mortality, independently of ART initiation and baseline CD4 count.

Introduction

Based on repeated evidence that Isoniazid preventive therapy (IPT) decreases the risk of

tuberculosis in HIV-infected persons, the World Health Organization (WHO) has consistently

recommended since 1993 that persons living with HIV who are unlikely to have active

tuberculosis (TB) should receive at least 6 months of IPT. [1] However, 23 years later some

countries still have not adopted IPT, and in most of those who did the IPT coverage is low. [2-

3]

Among the barrier to adopting IPT at country level are the the lack of a common vision

between HIV and TB programs, and the fear that individuals who start IPT with unrecognized

active TB may develop drug resistant tuberculosis. [3-5] At the prescriber level, however,

there is also the feeling that IPT is a not a user-friendly entity, for several reasons.

First, clinical problems posed by IPT -- such as ruling out TB prior to prescribing ITP, or

dealing with symptoms suggesting drug intolerance or active TB in a patient taking IPT --

require different approaches among patients with low versus. high CD4 counts, those who

take ART vs. those who do not, or those who just started ART vs. those who have taken it for

years. Physicians already having to deal with major clinical problems in a context of limited

paraclinical facilities may legitimately fear that such heterogeneity complicates their practice.

[6]

Second, randomized controlled trials (RCT) have demonstrated the benefits of IPT in terms of

TB reduction, not of mortality. [7-9] Some studies have suggested that these benefits may

decrease after the treatment is stopped, leading to considerations of extending treatment from

6 months to 36 months or even to lifelong treatment in settings with a high prevalence of TB.

[10-13] In addition, IPT efficacy has been shown to be higher in patients with a positive

tuberculin skin test (TST), who represent a minority of HIV-infected individuals. [12] Some

physicians may thus feel discouraged from adopting a new intervention whose efficacy in

reducing mortality is unclear, and whose benefits may be limited to subgroups of patients and

decrease over time.

Finally, most RCTs of IPT have been performed in the pre-ART area and/or in patients with

low CD4 counts. [7-9,14] As successful ART also decreases the risk of TB [15-18], some

physicians may consider that the priority is to get people on ART and ensure immune

recovery through treatment success as early as possible, not to implement IPT.

Between 2008 and 2015, we did a randomized controlled factorial 2x2 trial to assess the

benefits of early ART, 6-month IPT, or both among HIV-infected adults with high CD4+ cell

counts in Ivory Coast. The trial endpoint was severe morbidity at 30-months. The final

analysis showed that immediate ART and 6 months of IPT independently led to lower rates of

severe morbidity than did deferred ART and no IPT, both overall and among patients with

CD4+ counts of at least 500/mm

. [16] After participants reached 30 months of follow-up in

the trial, it was proposed that they continue to be followed in a post trial phase (PTP). Here

we present the results of the analysis of the efficacy of IPT in reducing mortality at the end of

the PTP.

Methods

Temprano trial

Temprano was a randomized controlled, 2x2 factorial, superiority trial, conducted in nine

clinics in Côte d’Ivoire, West Africa. It started in March 2008 and ended in January 2015. The

trial design and main results have been previously reported. [16] In summary: The inclusion

criteria were HIV infection, 18 years of age or more, CD4 count below 800/mm

, and no

criteria for starting ART according to the most recent WHO guidelines. The latter included

the absence of active TB, as determined by using a

clinical algorithm. [1,19] No systematic Chest X-Ray was performed prior to inclusion.

A computer generated sequentially numbered

blocked randomization list, stratified by study clinics, was included in a software tool which

allowed access to the next available trial ID number and arm. Participants were randomized

into one of four arms: arm-1 (‘Deferred-ART’), in which ART was deferred until WHO

criteria for starting ART were met; arm-2 (‘Deferred-ART+IPT’), in which ART was deferred

until WHO criteria for starting ART were met and a six-month IPT was prescribed; arm-3

(‘Early-ART’), in which ART was started immediately; arm-4 (‘Early-ART+IPT’), in which

ART was started immediately and a six-month IPT was prescribed. After randomization, all

participants had a systematic Chest X-Ray and a series of blood tests including CD4 count,

plasma HIV-1 RNA and serum transaminases. The first 50% participants also had a

QuantiFERON

-TB Gold In-Tube [QFT-GIT] test (Celestis). Tuberculin skin tests were not

performed. IPT consisted of 300 mg of isoniazid daily, started at month 1 and stopped at

month 7. Patients randomized to receive IPT (arms 2 and 4) but who had images suggestive of

active tuberculosis on their baseline chest X-ray, had transaminases level above 2.5 times the

upper limit of normal, or developed clinical signs suggestive of tuberculosis during first

month were not prescribed IPT. All participants were followed 30 months. The primary

endpoint was severe morbidity, defined as a combination of all-cause deaths, AIDS diseases

(including TB), non-AIDS malignancies, and non-AIDS- invasive bacterial diseases

Post Trial Phase

As recruitment in Temprano started in March 2008, the first participant completed 30 months

of follow-up in September 2010. From this date on, all patients who reached their 30-months

visit were proposed to continue being followed in a post trial phase (PTP) until the last

included patient had been followed 30 months.

Temprano and the PTP had mostly similar procedures. In the PTP, as in Temprano: patients

had quarterly visits to their care center, and were asked to visit the medical team at the trial

clinic as soon as they had medical problems; CD4 count and plasma HIV-1 RNA were

measured every six months; consultations, CD4 count, viral load, and antiretroviral drugs

were free of charge; Patients who did not show up for a trial visit were traced by experienced

social workers, who used telephone calls and home visits to ascertain their vital status and

encouraged them to return to the clinic; Finally, the criteria for initiating ART in patients

randomized to deferred ART were the same in Temprano and in the PTP, meaning that

patients who completed Temprano follow-up without having started ART were proposed to

start ART in the PTP using the same criteria as if they were still followed in the trial.

There were two differences between Temprano and the PTP, however. First, in case of a

morbidity event in Temprano, transportation for unscheduled visits, investigations,

hospitalization and non-antiretroviral drugs were free of charge. In PTP, patients had to pay

for it, just as any other patient followed in routine condition in the same care center. Second,

the primary outcome was severe morbidity in Temprano whereas it was mortality in the PTP.

Statistics

All analyses were on intent-to-treat. We refer to trial ‘arms’ each time we show separate data

for each of the four arms, and trial ‘strategies’ whenever we show data combining patients

assigned to’ IPT’ (arm-2-and-4), ‘No-IPT’ (arm-1-and-3), ‘Early-ART’ (arm-3-and-4) and

‘Deferred-ART’ (arm-1-and-2).

In each arm and strategy we used the Kaplan-Meir method to estimate the cumulative

probability of event occurrence. We estimated rates by dividing the number of first events by

the cumulative time at risk. The time at risk started at randomization and ended on the date of

the last 30-month visit of the last Temprano participant (January 5, 2015), or at death.

Follow-up data were censored when participants were lost to follow-up before January 5,

2015. Patients were defined as lost-to-follow-up if they did not show up at their last quarterly

scheduled visit, and no further information on their vital status was available within the 6

months preceding the closing date of the database.

Cox proportional-hazards models were used to compare IPT strategies (IPT vs. no-IPT) with

respect to mortality. Because Temprano was a 2x2 factorial trial, we first only adjusted the

Hazard ratio for the other trial strategy (Early ART vs. Deferred ART) and for the trial center

(as a random effect). Subsequently, adjustment was also made for baseline CD4 count, to

explore the influence of the degree of immunosuppression on the results; and for variables

recognised as risk factors for mortality and/or TB (age, sex, HIV-1 viral load, hemoglobin,

and past history of TB), to explore potential confounding effects of these variables.

Finally, in ancillary analyses we successively: stratified by baseline CD4 count (<500 and

>500/mm

); considered death or loss-to-follow-up as the primary endpoint; restricted the

analyses to the sample of patients who had the QFT-GIT test performed at baseline, and

stratified the analysis for the result of the test (positive and negative or indeterminate).

Interaction between strategies was tested. The assumption of the proportional hazards was

examined. All reported p-values were two-sided and were not adjusted for multiple testing.

Statistical analyses were performed with SAS

9.3 software.

Funder, registration, and ethics

At the end of the 30-month follow-up in the trial, we asked patients for a new informed

consent for participating in the PTP. The Temprano trial protocol, which included the PTP,

was approved by the Côte d'Ivoire National Ethics Committee for Health Research. It was

registered at Clinical Trials.gov (NCT00495651). The sponsor had no role in the conduct of

the study and interpretation of the data..

Results

Baseline and follow-up characteristics

The first inclusion in Temprano occurred on March 18 2008, the last inclusion on July 16

2012, the first 30-month visit on August 13 2010 and the last 30-month visit on January 05

2015. Between March 2008 and July 2012, 2,076 patients were randomly assigned to

treatment groups; 20 (1%) were subsequently excluded and 2,056 (99%) were included in the

analyses (Figure-2 and Supplementary-Appendix-Figure-F1).

Baseline and follow-up characteristics of the 2,056 participants according to IPT strategies

(IPT and No-IPT) are shown in Table-1. Characteristics according to the four randomization

groups are shown in Appendix-Table-SA-T1. Between March 2008 and January 2015, the

2,056 participants were followed a total 9404 person-years, including 4757 during the trial

and 4647 during the PTP. The mean follow-up time was 4.6 years overall (SD 1.4), 4.6 years

(SD 1.4) in the IPT strategy and 4.5 years (SD 1.5) in the No-IPT strategy. Of the 1,030

patients assigned to the IPT strategy, 90% actually started isoniazid, and 94% of these

completed the 6-month treatment (Table-1).

Mortality

During follow-up, 86 deaths were recorded. The incidence of death was 0.7/100 person-years

in the IPT strategy (95% CI 0.5-0.9) and 1.1/100 person-years (95% CI 0.9-1.4) in the No-IPT

strategy; and ranged from 0.6/100 person-years (95%CI 0.3-1.0) in arm 4 (Immediate ART

plus IPT) to 1.3/100 person-years (95% CI 0.8-1.8) in arm 1 (Deferred ART, No-IPT). The

six-year probability of death was 4.1% (95% CI 2.9-5.7) in the IPT strategy and 6.9% (95%

CI 5.1-9.2) in the No-IPT strategy (Figure-3A); and ranged from 3.2% (95% CI 1.9-5.5) in

arm 4 (Immediate ART plus IPT) to 7.0% (95% CI 4.7-10.4) in arm 1 (Deferred ART, No-

IPT)(Figure-3B).

The hazard ratio of death for IPT compared to No-IPT was 0.63 (95% CI, 0.41 to 0.97) after

adjusting for the ART strategy (Early vs. Deferred) and the trial center; 0.64 (95% CI 0.41 to

0.98) after adjusting for the ART strategy, trial center and baseline CD4 count; and 0.61 (95%

CI 0.39-0.94) after adjusting for all variables shown in table 1. When restricting the analysis

to patients with baseline CD4 count >500/mm

, the hazard ratio was 0.41 (95% CI, 0.17 to

1.00). Other factors significantly associated with death were baseline CD4 count, Hemoglobin

and plasma HIV1 RNA (Table 2).

Mortality or loss to follow-up

During follow-up, 207 patients were lost-to follow-up (IPT: 97; No-IPT: 110), accounting for

an overall rate of loss to follow-up of 2.2/100 person-years (95% CI 1.9-2.5). The rate of loss

to follow-up was 1.2/100 person-years during the trial phase (95% CI 0.9-1.5), and 3.2/100

person-years during the PTP (95% CI 2.7-3.7); and 2.0/100 person-years in the IPT strategy

(95% CI 1.6-2.4) versus. 2.4/100 person-years in the No-IPT strategy (95% CI 1.9-2.8).

The six-year probability of death or loss to follow-up was 17.4% (95% CI 14.7-20.6) in the

IPT strategy and 21.3% (95% CI 18.3-24.7) in the No-IPT strategy (Supplementary-

Appendix-Figure-F2A); and ranged from 15.8% (95% CI 12.3-20.3) in arm 4 (Immediate

ART plus IPT) to 24.3% (95% CI 20.0-29.5) in arm 1 (Deferred ART, No-

IPT)(Supplementary-Appendix-Figure-F2B). The hazard ratio of death or loss to follow-up

for IPT compared to No-IPT was 0.77 (95% CI, 0.61 to 0.97) after adjusting for all variables

shown in table 1. Other factors significantly associated with death or loss to follow-up were

ART strategy, baseline hemoglobin and plasma HIV1 RNA (Table 2).

QuantiFERON-TB Gold In Tube test

Among the 967 patients who had a QTF-GIT test performed at baseline (IPT: 482; No-IPT:

485), the test was positive in 337 (IPT: 164; No-IPT: 173), negative in 597 (IPT: 306; No-

IPT: 291), and indeterminate in 33 (IPT: 12; No-IPT: 21) test. The number (%) of patients

with positive/negative/indeterminate tests was 269/480/27 (35%/62%/3%) among patients

with baseline CD4 <500/mm

vs. 68/117 /6 (36%/ 61%/ 3%) among those with baseline CD4

>500/mm

(p=0.95); and 30/50/6 (35%/58%/7%) among patients aged >50 years vs.

307/547/27 (35%/62%/3%) vs. among those aged <50 years (p=0.16).

After adjustment for the ART strategy (Early vs. Deferred), ITP strategy (ITP vs. No-ITP) and

trial center, the Hazard Ratio of death was 0.59 (95% CI 0.32 to 1.11, p=0.10) for patients

with a positive QTF-GIT test compared to those with a negative or indeterminate test at

baseline. The six-year probability of death was 3.1% (95% CI 1.3-7.3) in the IPT strategy vs.

5.2% (95% CI 2.6-10.4) in the no-IPT strategy among patients with positive QTF-GIT test

(Figure-3C); and 5.2% (95% CI 3.2-8.3) in the IPT strategy vs. 8.5% (95% CI 5.7-12.4) in

the No-IPT strategy among those with negative QTF-GIT test (Figure-3D).

There was no statistical interaction between the result of the QTF-GIT test at baseline and the

ITP strategy with regards to mortality (p=0.96). When stratifying the analysis by QTF-GIT

test results, the hazard ratio of death for IPT compared to No-IPT after adjustment for the

ART strategy and trial center was : 0.61 (95% CI 0.20-1.86) among patients with positive

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