Isoniazid Prevention Therapy for HIV Positive Patients Increasing Tuberculosis Prevention for HIV-Patients in Ethiopia QuickTime and a decompressor are needed to see this picture. Ashok Reddy, MD University of Washington
Presentation TB risk among HIV+ patients TB/HIV data at Gondar University Isoniazid Preventive Therapy (IPT) in HIV+ patients Challenges
The Global Burden of TB New Cases Deaths Total TB Cases 9.4 million 1.3 million MDR TB Cases 511,000 150,000 XDR TB Cases 50,000 30,000 HIV related TB accounts for 1.4 million cases, approximately 15% of all TB cases Globally an estimated 2 billion people have latent TB WHO Global TB Report 2009
Burden of HIV Associated TB Tuberculosis is #1 cause of death in HIV patients Incidence of TB doubled in Africa between 1990-2005, approx 149 to 343 cases per 100,000 Autopsy study from Botswana reported that 30-40% of HIV-infected adults die from tuberculosis Ethiopia has 8th highest burden of TB
Where is Gondar? QuickTime and a decompressor are needed to see this picture. NOT the Fictional Kingdom in the Lord of the Rings
Where is Gondar? Gondar QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture.
Gondar University -- TB Clinic # of TB #HIV+ #HIV- #undocumented #ART Jan 08 61 21 8 32 12 Feb 88 36 18 34 14 March 62 20 8 34 3 April 81 31 7 43 8 May 55 25 8 22 11 June No data July 51 20 7 22 5 August 59 26 21 16 9 Sept 58 29 9 21 5 Oct 43 11 11 22 5 Nov 52 18 15 27 2 Dec 41 14 16 11 0 Total 651 251 128 284 74 % of new TB pts who are HIV pos (# is likely higher) : 251/367= 68.3% Most disturbing is that >43% of pts getting TB medications do not have a documented test
Gondar University -- ART Clinic Total Enrolled On TB Rx Started after HAART Started before HAART Jan 08 148 12 7 5 Feb 137 5 3 2 March 200 14 7 7 April 136 7 6 1 May 161 9 8 1 June 159 6 6 0 July 137 6 5 1 August 128 1 1 0 Sept 132 9 7 2 Oct 104 4 4 0 Nov 101 7 7 0 Dec 132 10 6 4 TOTAL 1675 90 67 23 Prevalence Rate (#cases/population): 5.3%
TB/HIV Co-Infection Havlir, D. V. et al. JAMA 2008;300:423-430.
Combating Epidemic of TB/HIV Co-Infection WHO/STOP TB commission (3 I s) Intensified TB Screening among HIV pts Provision of Isoniazid Preventive Therapy (IPT) TB infection Control The number of HIV infected persons reported to have been screened for TB was less than 1% while IPT was reported to have been provided to less than 0.1% of eligible persons in 2006.
Data on IPT in HIV+ Patients Figure 1. Efficacy of tuberculosis (TB [includes confirmed, probable, and possible active cases of TB]) preventive therapy (with any drug), compared with placebo, in reducing the incidence of active TB. Death denotes death due to all causes. CI, confidence interval; PPD, purified protein derivative; PPD unknown, unknown PPD status; +, positive;, negative. A relative risk of <1 favors treatment. Copyright Cochrane Collaboration; adapted with permission from [11]. Woldehanna and Volmink, Cochrane Review 2006
Durability of IPT in HIV pts Protection can be detected from 18 months to 4 yrs (Havlir JAMA 2008) Zambia study demonstrates that protection begins to wane after one year (Mwinga AIDS 1998) IPT strategies may not provide protection from re-infection in endemic areas
Effect of IPT + ART in Brazil Exposure category Person-Years TB cases IR (per 100 PYs) IRR Naïve 3,865 155 HAART only 11,627 221 IPT only 395 5 Both 1,253 10 TOTAL 17,142 391 3.98 (3.38-4.67) 1.91 (1.67-2.18) 1.27 (0.41-2.95) 0.80 (0.38-1.47) 2.28 (2.06-2.52) 1.0 0.48 (0.39-0.59) 0.32 (0.10-0.76) 0.20 (0.09-0.91) Golub et al., AIDS, 2007
Effect of IPT + ART in S. Africa Exposure Category TB cases Person-Years IR (95% CI) IRR Naive 200 2815 7.1 (6.2-8.2) 1.0 (Ref) HAART only 44 952 4.6 (3.4-6.2).65 (.46-91) IPT only 22 427 5.2 (3.4-7.8).73 (.44-1.13) IPT & HAART 1 93 1.1 (0.2-7.6) 0.15 (.004-.85) Golub et al., AIDS, 2009
Challenges of IPT Rule out Active Tuberculosis Resistance/Adherence Complicated and Costly Toxicity
Rule out Active Tuberculosis South Africa study screening of two or more symptoms (WL, Cough, NS, Fever) had 100% sen/88% spec (Mohammed, Int J Tuber Lung Dis 2003) Uganda study published a screening tool in 2009; (Were, Int J Tuber Lung Dis 2009) 1995 participants, the presence of any one of the following had a 99% sen/66% spec: Cough > 3 wks (OR 37.9; 21-67 95%CI) Fever > 1 month (OR 34.1; 20.2-57.6) Weight loss (OR 51.2; 28.5-92) Night Sweats (OR 21.9; 12-37) BMI <18 (OR 7.2; 4-12) Lymphadenopathy (OR 4.0; 2.4-6.6) Asymptomatic HIV-infected pts cxray, 1/563 was dx w/tb (Mosimaneotsile, Lancet 2003)
Resistance In a meta-analysis of 13 IPT trials, including both HIV infected and non-infected, there was low risk in the development of resistance (RR 1.45, CI 95% 0.85-2.47) (Balcell EID 2006) Standard treatment was effective in treating INHr TB (Nolan Int J Tuber Lung Dis 2002) Tanzania, 87% of pts eligible for IPT completed 9 month course (Munseri PJ, Int J Tuber Lung Dis 2008)
Complicated and Costly Preventing one case of TB is cheaper than treatment of active case TST testing in HIV+ pts in resource-limited setting (Swaminathan Int J Tuber Lung Dis 2008) Sens 74%, Spec 69% CD4 count < 100, TST fails to detect more than half Even pts CD4 > 500 decreased rate TST Operational research on TST Uganda 19% of pts did not return at appropriate time Thailand 86% of doctors LTBI tx did not perform TST testing
Toxicity INH-associated complications include anorexia, N/V, dark urine, icterus, fever, rash, and neuro Uganda RCT 3/1000 stopped with adverse event (Whalen NEJM 1997; 337:801) S. Africa, ART cohort, IPT was not associated with higher risk of hepatotoxicity (Hoffmann AIDS 2007) Monitor LTBI (baseline, 1 month)
Conclusion HIV has fueled the epidemic of tuberculosis; these diseases are so intertwined that prevention and care of one must be tied to the other IPT offers an effective strategy to decrease the burden of tuberculosis in HIV+ pts This intervention could be added into the framework of current Ethiopian ART clinics
Acknowledgements ITECH Clinical Team ITECH Gondar Data Team UW Dept of Medicine Dr. Scott Barnhart Dr. Judd Walson
Future TB Ward in Gondar
IPT in Children As of 2009, only one RCT of HIV-infected children and IPT Marked reduction of TB incidence 4% vs 10% in placebo No data on durability or long-term adverse events No information on IPT on children on ART
Balcells et al., EID 2006 Resistance
Effect of INH resistance on outcomes of treatment for active TB Failure Died Default/ transfer Success Drug-susceptible 2% 2% 11% 85% IHN-resistant (any) 4% 2% 12% 82% RIF-resistant (any) 11% 2% 13% 73% JAMA 2000;283:2537-45
CONTRAINDICATIONS OF IPT 1. Active tuberculosis. 2. Symptoms compatible with tuberculosis, even if the diagnosis of TB cannot be confirmed. 3. Abnormal chest x-ray. 4. Active hepatitis (chronic or acute). Known or reported high daily alcohol consumption. 5. Prior allergy or intolerance to Isoniazid. 6. Pregnancy.
Secondary Prevention of IPT 3 studies have shown a benefit of IPT following treatment of active TB in HIV+ patients Incidence Rate Ratios & 95% CI Reference Haller (1999) Fitzgerald (2000) Churchyard (2002) 0.3 0.18 0.45 1.0 Woldehanna and Volmink, Cochrane Review 2006