Preventing recurrent TB in high HIV-prevalent areas What are the options for TB Control Programmes?

DEFINITION OF RECURRENT TB TB which re-occurs after a patient has been previously diagnosed with TB and completed a full course of treatment Bacteriologically confirmed or based on clinical criteria Due to reactivation or reinfection

EXTENT OF RECURENT TB: RESULTS OF STUDIES (1) Systematic review assessing the influence of HIV and rifampicin therapy 47 studies world wide 17 studies from sub-Saharan Africa (Korenromp, Scano, Williams, Dye, Nunn. Clin Inf Dis)

EXTENT OF RECURENT TB: RESULTS OF STUDIES (2) Recurrent TB (rate/pa) HIV-negative 1.9% HIV-positive 4.5% 7 months or > Rifampicin 1.4% 5-6 months Rifampicin 2.0% 2-3 months Rifampicin 4.0% [level of background TB is important]

EXTENT OF RECURRENT TB: REPORTS FROM NTPs AND WHO Problems NTP annual notifications to WHO include “Relapse”, “Failure” and “Rx after DF” WHO does not include “Failure” or “Rx after DF” in Global TB Reports NTPs do not notify WHO about recurrent smear-negative TB or EPTB

Case History: Malawi High HIV-prevalence country In 2000, 77% of TB patients HIV+ve 1990 - 1999 2- 4% all cases were relapse sm+ve PTB Almost no cases of recurrent sm-ve PTB / EPTB Operational research 1999 12% sm-PTB /EPTB registered as “new” cases had been previously treated for TB

From 1999, Malawi improved its registration of patients in terms of new and previously treated cases, especially with smear-ve PTB and EPTB

Malawi Case Notifications Year Total TB New Recurrent 1998 22674 22069 605 (3%) 1999 24396 23728 668 (3%) 2000 24846 22789 2057 (8%) 2001 27672 25217 2455 (9%) 2002 26532 23724 2808 (11%) recurrent TB = relapse, failures, treatment after default plus recurrent sm-ve PTB and EPTB

Why the need to reduce recurrent TB? Recurrent TB cases:- consume resources have a more difficult regimen increase TB transmission in the community cause additional morbidity and mortality erode faith in NTP amongst patients, staff, and community

Options to reduce risk of recurrence Use RH in continuation phase (CP) Extend duration of CP in HIV+ patients Give post-treatment isoniazid to HIV+ve patients who complete anti-TB treatment Treat HIV+ve TB patients with HAART

For each option: Evidence of effectiveness Current practice Operational considerations [consider especially for sub-Saharan Africa]

RH in Continuation Phase (CP) evidence of effectiveness Systematic review by Korenromp, Scano et al (Clin Inf Dis) IUATLD Clinical Trial A, RH throughout has lower recurrence than EH in CP [done mainly in HIV-negative patients]

RH in the CP: current practice in Africa All programmes use RH in IP Many programmes use EH in CP (6mo)

Option: Replace EH with RH in CP for all patients The dangers: RH needs distribution to all Rx outlets RH must be given by DOT Possible irrational use of RH If H resistance high, then R as “monotherapy” Risk of creating MDR-TB May increase difficulties with use of HAART

Extend duration of CP: evidence of effectiveness In HIV+ve patients: 2RHZE/4RH, then 6RH recurrent TB = 1.9% 2RHZE/4RH, then placebo recurrent TB = 9.0% (Perriens et al, NEJM 1995)

Extend duration of CP: current practice in Africa Not used by any TB programme in Africa

Option: Extend duration of CP for HIV+ve patients Need knowledge of HIV-status and therefore need links with VCT Evidence only for RH (although may work for EH) Different lengths of Rx for HIV+ve and HIV-ve patients, and may cause confusion Long use of RH may delay start of HAART

Provide IPT to HIV+ve patients who complete treatment: evidence of effectiveness Study in Haiti HIV+ve patients: 2RHZ/4RH, then 12H recurrent TB = 1.4% 2RHZ/4RH, then placebo recurrent TB = 7.8% (Fitzgerald et al, Lancet 2000)

Post-treatment isoniazid: current practice in Africa Not used by any TB programme in Africa

Option: IPT to HIV+ve patients who complete Rx Need knowledge of HIV-status and therefore need links with VCT Adherence may be better than with 1o IPT What is the optimal length of 2o IPT ? Who administers and monitors 2o IPT ? Will HAART obviate the need for 2o IPT?

Treat HIV+ TB patients with HAART: evidence of effectiveness In West, HAART reduces risk of TB in HIV-positive persons In South Africa HAART reduces risk of TB in HIV-positive persons (2.4% vs 9.7% pa) [Risk reduction most in the immunocompromised] No studies showing effect for recurrent TB

HAART to HIV+ve TB patients: current practice in Africa Not used by any TB programme in Africa

Option: HAART to HIV+ve patients with TB Need knowledge of HIV-status and therefore need links with VCT Need significant increased funding Need a structure for safe and secure supply and delivery of HAART

WAYS FORWARD Country TB programmes to determine true burden of recurrent TB If burden is high, then determine which of the four options is most cost-effective, feasible and least dangerous to do - Clinical studies / operational research / philosophy of “learn as we do”