Mina Hosseinipour, M.D., M.P.H Lilongwe Malawi

Transcription

1 Mina Hosseinipour, M.D., M.P.H Lilongwe Malawi

2 Overview of Early Mortality in ART programs in Resource Poor Settings Predictors of Mortality Causes of Mortality Cohort studies Autopsy studies The role of TB in mortality

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4 27 clinics in Africa, South America, and Asia >40,000 patients on HAART Principal Investigators François Dabis Matthias Egger Mauro Schechter Funding: ANRS & NIH

5 6.4% ( ) 1.8% ( ) Braitstein et al; Lancet 2006.

6 Mortality in the first year of HAART (ART-LINC) 16 8 Hazard ratio (95% CI) Months from starting HAART HR unadjusted HR adjusted *Adjusted for cohort, sex, age, baseline CD4, HAART regimen, stage of disease Braitstein et al. Lancet 2006; 367:

7 Mortality by baseline CD4 cell count (ART-LINC and ART-CC) Cumulative mortality (%) Sub-Saharan Africa Europe & North America < 25 cells/µl cells/µl cells/µl cells/µl > 200 cells/µl Months after starting ART

8 Survival proportion over 21 months among patients (n=1235) from the time of entering a community-based antiretroviral treatment programme in South Africa. Lawn AIDS 2008

9 910 patients: 10% deaths at 12 months - 85% deaths in the first 6 months Severe P et al New Eng. J. Med :

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11 Vast majority of 1st-year deaths occur early after HAART initiation Many in the first months Most by 6 months Vast majority of 1st-year deaths occur among those with advanced disease Lower CD4 counts associated with increased risk of death Bisson et al, PLoS ONE Stringer, J. S. A. et al. JAMA 2006;296: Braitstein et al. Lancet 2006; 367:

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13 Many Government Programs do not have active follow-up of clients Loss to follow-up rates in scale up programs range from 1 to 30% What is the status of LTFU patients?

14 Outcomes in the Antiretroviral Therapy Program, Lusaka, Zambia (April 2004-November 2005) Stringer, J. S. A. et al. JAMA 2006;296: % dead 21% lost Copyright restrictions may apply.

15 High Rates of Death Among those Lost to Follow-up A. Initial Outcomes as Determined by Passive Follow-up Infectious Disease Care Clinic (n=410) 1 Kaplan Meier Survival On HAART (76%) Dead (7%) Lost (17%).9 Survival.85 B. Definitive Outcomes as Determined by Active Follow-up Infectious Disease Care Clinic (n=410) days Active Follow-up Passive Follow-up % of those lost to follow-up had died On HAART (78%) Dead (17%) Lost (5%) Bisson et al. PLoS ONE 2008.

16 Hochgesang M, et al XVI International AIDS Conference. Abstract TUPE0119

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18 Mortality by baseline CD4 cell count (ART-LINC and ART-CC) Cumulative mortality (%) Sub-Saharan Africa Europe & North America < 25 cells/µl cells/µl cells/µl cells/µl > 200 cells/µl Months after starting ART

19 Cohort 3 month Mortality (%) BMI Total lymphocyte count Risk Factors CD4 count WHO stage III/IV HB Ethiopia 16.7 <18.5 <750/ml NA IV <10.0g % Senegal?? 18.5 <1200/ml <200 NA NA Tanzania 19.2 <16 NA NA NA <8.0g % Dream 16.3 <18 NA <200 III/IV <10.4 g%

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21 Causes of Death Less Consistently reported Loss to Follow-up issues Reported Causes of Death often Non-specific Few Autopsy Studies to confirm causes of Death

22 6 Cohort Studies (5 SSA, 1 Haiti) TB was among the leading cause of death in 5/6 cohorts TB likely under-reported due to difficulty in making diagnosis and LTFU rates Lawn CID 2006:43: , Etard AIDS 2006:20: , Zachariah 2006: 20: , Moore CROI 2007 Abs 34, Kambugu IAS 2007 WEPEBO55; Severe, NEJM 2005

23 Cause of Death Dream N=260 Kenya N=15 Botswana N=24 Cameroon N=19 South Africa N=205 India N=155 Tuberculosis Cryptococcal Meningitis N.R Pneumonia N.R. 2 N.R Sepsis N.R. N.R. N.R 2 Wasting/GE Advanced HIV Poor Health/FUO Unknown Malaria 39 N.R. N.R. 1 N.R. N.R. Anemia 35 N.R. 1 N.R. N.R. N.R. KS N.R. 1 2 N.R. 11 N.R. Hepatotoxicity/ Drug Toxicity N.R. N.R. 3?1 6 N.R. Marazzi, AIDS Res Human Retrovirus 2008; Karcher TMIH 2007, Wester Epid & Social Science 2005, Mzileni 2008, Kamarasamy Int J Infect Dis 2009

24 Tuberculosis (16-51%) Invasive Bacterial Infections (8-49%) Wasting (13-43%) Cryptococcal Meningitis Kaposi s Sarcoma Unknown is the most common cause

25 Even in resource rich settings, Autopsies change the Cause of Death Primary diagnosis changed in 70% 36% of all opportunistic infections were missed. six of nine cytomegalovirus all tuberculosis 75% of Kaposi's sarcoma. Beadsworth Int J STD AIDS 20(2):

26 HIV wasting syndrome (93 patients) Disseminated TB was found in 41/93 (44%) Linear Trend between degree of wasting and prevalence of Tuberculosis. Lucas et al, BMJ 1994.

27 75 HIV-1 positive inpatient deaths in Kenya Tuberculosis, Pneumonia 96% of all deaths Tuberculosis >50%, Disseminated in 80% 104 HIV positive inpatient deaths in Botswana TB (40%), bacterial pneumonia (23%), Pneumocystis carinii pneumonia (11%), and Kaposi's sarcoma (11%) Rana, et al. JAIDS 2000, Ansari, et al Int J Tuberc Lung Dis 6(1):

28 Inpatient Pulmonary Unit in Cote d'ivoire 44% of deaths due to Tuberculosis High rates of disseminated TB South Africa HIV positive Gold Miners 35% of deaths due to TB 47% of all deaths had evidence of TB Clinical vs. Autopsy diagnosis for TB 43% Sensitivity and 67% Specificity Domoua, K. et al. (1995). Med Trop (Mars) 55(3): , Murray J. et al. (2007) AIDS: 21: S97-S104.

29 47 HIV-infected patients with premortem diagnosis of TB (none on ART) 79% Confirmed the diagnosis, 21% no TB 53% of patients the autopsy and clinical cause were concordant. Immediate or contributory causes of death were: extensive pulmonary tuberculosis, 32 (68%); disseminated tuberculosis, 28 (60%); bacterial pneumonia, 13 (26%); cytomegalovirus pneumonitis in seven (15%); Pneumocystis pneumonia was found in five cadavers (11%). Salmonella spp. was cultured from 11 splenic specimens. Martinson, AIDS 2007

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31 Do prevalent severe OIs increase risk of death early after HAART initiation? Stringer, J. S. A. et al. JAMA 2006;296:

32 Pulmonary TB ranged from 4.8/100 py in Cameroon to 17.7/100py in Kenya Of the TB cases, TB occurred within the first 3 months of ART 76.3% Cambodia 52.5% Thailand 51.9% Kenya 66.7% Malawi 80.0% Cameroon Bonnet,et al. AIDS 2006, 20:

33 Lawn Am J Respir Crit Care Med Vol 177. pp , 2008

34 Survival among patients with AIDS and TB and initiation of ART at GHESKIO-Haiti Koenig S, Fitzgerald JW, Pape JW CID 2009

35 High Early mortality in ART programs Risk Factors for Death well described Causes of death less well described TB is major player based on ART cohort,pre-art autopsy studies, and TB incidence trends Tuberculosis is a common incident infection post ART initiation associated with increased mortality

36 Do community deaths have a similar pattern to inpatients death? Do ART treated patients have the same spectrum of deaths? Could more aggressive screening for TB or empiric TB treatment in high risk patients modify mortality risk?