Ensuring ART for TB patients: experience from Thailand Praphan Phanuphak, M.D., Ph.D. The Thai Red Cross AIDS Research Centre

TB/HIV in Thailand 700,000 Thais are currently living with HIV/AIDS with 50,000 new AIDS cases/year 25% of Thai AIDS patients at any moment have TB 100,000 new TB in Thailand each year (42% are infectious cases), 20% of these occur in HIV patients 16% of Thai TB patients in 1996 were HIV-positive as compared to 5.6% in 1991 Positive PPD was found in 20% of Thai HIV patients in the MTCT-Plus program (N=500) 1ry INH resistance 6.2%, Rifam 2%, MDR 1%

Reducing drug-resistant tuberculosis among HIV-positive TB patients, Chiang Rai MDR-TB 1996-97 1998-99 2000-02 p primary 7.6% 4.1% 2.0% secondary 38.6% 22.8% 15.9% <0.001 Prevalence of primary MDR-TB was associated with -HIV positive status (OR 2.2, 95%CI 1.3-3.9) -being treated at provincial referral hospital in 1996-1998 (OR 2.6, 95%CI 1.5-4.6) Possible due to DOTS and control of nosocomial TB H. Yanai et al,:XV IAC: MoPeB3217

ART in Thailand A national commitment to treat 50,000 new patients in 2004 because of the World AIDS Conference, the cheaper generic ARV and the Global Fund Social security insurance scheme (for insured workers) provides ARV since July 2004 AZT, 3TC, AZT/3TC, d4T, ddI, NVP, d4T/3TC/NVP (GPO-vir), NFV are the available generic drugs 53 out of 76 provincial hospitals have CD4 facility in 2004, an increase from 19 Flow cytometer in 2002 Large scale training of doctors and nurses Thus, it looks like ART is not a problem in Thailand!

ARV budget 1992-2003 and expected to 2006, Thailand million baht

Healthcare infrastructure for ART in Thailand (2004) ARV sites expanded from 110 to 800 hospitals CD4 facility expanded from 19 to 53 hospitals with US$1.25M for reagents Viral load only in Bangkok, Chiang Mai, Khon Kaen and Udorn Thani Genotypic resistance only in 3 university hospitals in Bangkok TDM only at HIV-NAT (Bangkok) Accelerated training of ARV prescribers

Challenges of ART in TB/HIV co-infected patients at the policy level Although HIV, TB and STD are merged into the same bureau and although TB/HIV services are supposed to be integrated, it has not yet happened in real life. TB service has more manpower but personnel are older, less active and has much less budget. Thus, the HIV service has the control over the TB service. We have to make the TB service more dynamic and more powerful.

Challenges of HIV screening in TB patients TB doctors (GP, internist) have low awareness on HIV co-infection and on the perceived risk as well as have no skill of HIV counseling Regulation by Thai law that HIV testing needs consent and pre- and post-test counseling, i.e., additional effort and facility, thus, why to bother & low uptake! HIV testing is not free Thus, the existing VCT services should be more proactive & more accessible for TB patients

Challenges of CD4 testing in co-infected patients CD4 is rarely ordered by TB doctors and there is no national guideline for CD4 follow-up in HIV-infected patients, thus, frequently neglected Accessibility to CD4 service such as the combined VCT & CD4 services of the Thai Red Cross Anonymous Clinic CD4 testing is not free either, US$10

Challenges on ART in co-infected patients: Diverse guidelines When to start HAART? -2 weeks – 2 months vs. 6 months What ARV to be used? - 3NRTI vs. EFV (up dose?) vs. NVP Methods of delivery HAART? -DOTS like TB Rx? Docs are confused! Thus, single guideline for TB & HIV programs is needed.

Weerawat Manosuthi, Somnuek Sungkanuparph, Ammarin Thakkinstian, A Randomized Controlled Trial of Efavirenz 600 mg/day versus 800 mg/day in HIV-infected Patients with Tuberculosis Receiving Rifampicin Weerawat Manosuthi, Somnuek Sungkanuparph, Ammarin Thakkinstian, Asda Vibhagool, Sasisopin Kiertiburanakul, Wisit Prasithsirikul, Jongkol Sankote, Apicha Mahanontharit, Sasivimol Rattanasiri, Kiat Ruxrungtham Faculty of Medicine Ramathibodi Hospital, Mahidol University; HIV-NAT Research Collaboration, Thai Red Cross AIDS Research Center; Bamrasnaradura Institute, MOPH, Thailand: XV IAC: MoOrB1013

Baseline characteristics Parameter EFV 600 mg n = 42 M/F = 27/15 Age = 35.1 (6.9) BW = 50.6 (7.4) EFV 800 mg M/F = 35/7 Age = 35.1 (9.4) BW = 52.9 (9.4) p value CD4 count, median (range) %CD4, median (range) HIV RNA (copies/ml), median (range) HIV RNA log, 32 (1 - 279) 3.5% (0 - 20) 326,000 (7,360 - 750,000) 5.47 (3.87 - 5.87) 37.5 (0 - 384) 3% (0 - 17) 412,000 (10,900 - 750,000) 5.62 (4.04 - 5.87) 0.799 0.443 0.525 0.343

Distribution of plasma EFV levels between EFV 600 and 800 mg groups 3.02 (0.07-12.21)

Proportion of Patients with EFV level Number of patients 25 20 Plasma EFV level 15 p = 0.274 10 กราฟนี้ไม่แน่ใจ ถ้า wee จะใช้ ช่วย label ให้ด้วยนะ ว่าเป็น graph ของอะไร 5 p = 0.274 EFV 600 mg EFV 800 mg

Time to virologic success Probability of HIV RNA <50 copies/mL 1.00 p = 0.848 0.75 0.50 0.25 0.00 10 20 30 40 Weeks EFV = 600 EFV = 800

ARV therapy in advanced HIV-infected patients with active tuberculosis A retrospective study in CD4< 200 cells/mm3 with active TB at Ramathibodi Hosp. N= 23 CD4, cells/mm3 61.2 HIV RNA > 100,000 15 Median time in starting ART, weeks 8 (4-12) EFV 13(56.5%) NVP 10(43.5%) Clinical improved 23(100%) At 48 week HIV RNA < 400 19(83%) HIV RNA< 50 18(78%) Sungkanuparph S, et al,:XV IAC:MoOrB1015

Percentage of patients with undetectable HIV RNA after HAART <400 copies/mL 65.2% 78.3% 87.0% 82.6% <50 copies/mL 69.6%

CD4 response (mean) after HAART EFV group 77 103 166 212 196 NVP group 41 91 133 179 181 Total 61 100 157 190 185

HAART regimens in patients taking rifampicin Triple NRTI should be avoided. EFV containing regimen is preferred and up dosing of EFV is not needed. In resource-limited setting where only NVP-containing regimen is available, it still can be used. However, large pharmacokinetic and clinical outcome studies are urgently needed. Such firm guidelines should come out from CDC or WHO.

Challenges for ART in Thailand Weakness in management system Limited resources & continued political commitment How to improve adherence in view of limited laboratory monitoring? Drug resistance and higher cost of salvage regimens eg. what after GPO-Vir failure? VCT as entry point for care & ART NVP in PMTCT with 20% NVP resistance and with unavoidable future use of NVP-containing regimens Negative message for 1ry & 2ry prevention