Co-infection in Thailand. Chiangrai Thailand

Transcription

1 Treatment of TB-HIV Co-infection in Thailand Dr.Pacharee Kantipong M.D. 26 September 2008 Chiangrai Regional Hospital Chiangrai Thailand Presentation Outlines Situation of HIV, TB, TB/HIV; global, Thailand, Chiangrai province Review of natural course of TB and HIV Impact of HIV in TB patients Benefits of ART in TB/HIV Management of TB-HIV coinfection -When to start ART -What to start -Drug interaction -IRIS -Adverse drug reaction TB/HIV collaborative activities in Chiangrai Hospital 1

2 Chiangrai, Thailand China Vietnam Chiangrai Areas 11,678 sq..kms., 18 Districts, 1,698 Villages, 1 City Municipal, 51 Municipal communities Bangkok Cambodia Population 1.2 millions (hill tribe 13 %) Chiangrai Regional Hospital 2

3 Koch's Famous Lecture On the evening of March 24, 1882 Robert Koch, a German physician and scientist, presented his discovery of Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB). He began by reminding the audience of terrifying statistics: Global Impact of TB One-third of the world s population is infected with TB bacteria Approximately nine million new cases of TB occur each year Between two and three million people die each year with TB TB is the leading cause of death in HIV- infected individuals More than 100, children die from TB every year 3

4 Estimated TB incidence rate, 2006 Estimated new TB cases (all forms) per population No estimate or more The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. WHO All rights reserved 4

5 Global Impact of HIV Almost 40 million adults and children worldwide were living with HIV in 2006 Between 2004 and 2006, the number of people living with HIV increased in every region of the world PLHIV increased by 2.6 million worldwide between 2004 and 2006 Adults and children estimated to be living with HIV, 2007 Western & Eastern Europe Central Europe & Central Asia million [ million] [ million] East Asia Middle East & North [ million] Africa South & South-East [ ] Asia Sub-Saharan Africa 4.2 million Latin America 22.0 million [3.5 Oceania 5.3 million] 1.7 million [ million] [ million] [ ] North America 1.2 million [ million] Caribbean [ ] Total: 33 million (30 36 million) 5

6 Global Impact of TB/HIV In many regions of the world, TB is the most common opportunistic infection in people living with HIV TB accounts for an estimated 15% %to60 60% of AIDS- related deaths worldwide TB accelerates the progression of HIV disease HIV accelerates the progression from TB infection to TB disease Due to their weakened immune systems, HIV-infected individuals are at increased risk for re-infection with TB, and subsequent recurrent active TB Estimated HIV prevalence in new TB cases, 2006 HIV prevalence in TB cases, (%) No estimate or more The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. WHO All rights reserved 6

7 Facts Every day worldwide: > 6000 people die from HIV although HIV is now treatable 5000 people die from TB although TB is curable Facts TB is among the leading killers of people living with HIV (PLHIV) causes % of total deaths 7

8 Thailand information Population with 63.4 millions One of 22 high TB burden countries. An estimated 90,000 all TB patients An estimated 556,848 PLHIV in % of HIV infection in pregnant women ART is available at district level HIV epidemic in Thailand and deaths due to AIDS (Case) AIDS Deaths due to AIDS Source :Bureau of Epidemiology, Department of Disease Control, MOPH, Thailand 8

9 70,000 60, ,000 40,000 30,000 20,000 10,000-49,758 TB patients in Thailand, ,948 59,138 58,907 59,281 58,433 56,229 54,793 30,607 30,670 30,437 29,919 29,081 28, ( 2001) 2545 (2002) 2546 (2003) 2547 (2004) 2548 (2005) 2549 (2006) 2550 (2007) ผ ป วยท งหมด (All Types) ผ ป วยใหม เสมหะพบเช อ (New M+) slide 16 Source: Boreal of Tuberculosis (Report TB07), MOPH, Thailand Burden of HIV in TB Patients About 24% of TB patients in Thailand were HIV-infected in % in Ubon-rachathani 34% in Chiang Rai 25-50% of HIV-infected TB patients in Thailand were diagnosed with TB before learning about their HIV status. *Data from Thai TB-Net 9

10 New New TB TB cases cases by HIV by HIV status status in Chiang in Rai Chiangrai Province, Province fiscal year HIV-positive HIV-positve HIV-negative HIV-unknown % 29.0 % TB/HIV Research Project (RIT RIT-JATA JATA) Excluded T-in duplicate Burden of TB in HIV Patients No population-based TB prevalence survey of HIV-infected persons has been done in Thailand Estimate that 2.7% of all HIV infected persons develop TB annually in Thailand 10

11 One Life Two diseases One Response Natural History of Tuberculosis 70% NON INFECTED PEOPLE Exposure 10-30% Infectious Disease 50% of smear positive Death Infection 10% HIV 40-50% 90% NO DISEASE 5% IN 2 YEA 5% Reactivation TB 11

12 Natural Course of HIV Infection and Common Complications nt CD4+ cell Coun Acute HIV infection syndrome CD4+ T cells Asymptomatic TB VL Relative level of Plasma HIV-RNA TB HZV OHL PPE OC CMV, MAC PCP CM Months Years After HIV Infection Correlation between CD4 counts and Clinical Manifestation of Tuberculosis Pulmonary TB CD4 counts Lymphatic, serous TB TB Meningitis Disseminated TB Duration of HIV Infection (yrs) 12

13 Spectrum of CD4 in HIV- TB Patients a cohort in NE-Thailand CD4 <100 CD CD4 >250 18% 12% CD4 <100 70% Thus, extra-pulm TB is the most common findings Distribution of CD4 among AFB+ TB cases with HIV infection 13.90% % 13.90% % This information is from index cases of the household contact study, CD4 is available for 144 cases out of the 217 AFB+ index cases in three hospitals, Chiang Rai. TB/HIV Research Project (RIT RIT-JATA JATA) 13

14 High/Earlier Mortality among HIV-Infected Infected TB Patients 29% of HIV-infected TB patients t died d during TB treatment (Data collected from four provinces and the national infectious diseases hospital in Thailand in 2005 ) *Data from Thai TB-Net Month of death for 334 HIV-infected TB patients that died during TB treatment from four provinces and the national infectious diseases hospital in Thailand, October 2004-September 2005* 100 Proportion dead Month of TB Treatment *Cumulative Mortality Rate Sanguanwongse et al., J Acquir Immune Defic Syndr.2008 Jun1;48(2):

15 Underutilization of ART among HIV-infected TB patients Thailand reported that only 32% of HIV- infected TB patients received ART in 2006* *Thailand s 2008 report to UNAIDS 15

16 Benefits of ART in HIV-infected TB patients Reduction in death rate during TB Rx Improved survival Declining prevalence of drug-resistant resistant TB Reduction in death rate during TB Rx Population-based study in Ubon- ratchathani, Thailand: * Death during TB treatment occurred 7% % of HIV-infected TB patients who received ART 43% of those who did not receive ART. *Akksilp et al., Emerging Infectious Diseases,

17 Mortality among HIV-infected TB patients that were bacteriologic (n=126) or culture confirmed (n=96) and initiated ART during TB treatment days to wait for ART = chance of death 12.0 Ha azard ratio for mortality *Only statistically significant at 120 days Days until antiretroviral therapy was initiated bacteriologic-confirmed Expon. (bacteriologic-confirmed) *TB/HIV Observational Study, TB treatment outcome of NEW pulmonary AFB positive by HIV status in Chiang Rai province, Fiscal year % 30.4% 32.3% 32.4% 35.9% 38.1% 48.6% 51.6% 58.3% 62.6% 12.6% 9.6% 3.8% 4.9% 64.5% 4.9% 7.5% 5.5% 5.4% 51.4% 56.7% 53.1% 5.3% 51.9% 51.4% 2.3% 48.1% 4.7% 38.4% 35.7% 33.1% 26.7% 25.2% 1.8% 3.2% 1.4% 1.7% 2.9% 2.1% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 2.7% 2.3% 3.1% 1.9% 1.3% % 17.1% 12.6% 2.4% Success Default Died Failure Transfer out TB/HIV Research Project (RIT-JATA) % 16.7% 10.7% 3.0% % 5.2% 16.9% 5.0% % 7.3% 17.3% 3.1% % 7.9% 11.9% 3.7% % 9.1% 9.7% 2.9% % 9.0% 10.3% 4.8% % 5.4% 9.8% 3.7% % 8.1% 11.3% 3.4% % 5.6% 12.9% 4.1% % 7.4% 14.1% 2.9% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 17

18 Death rate and percentage of TB with HIV positive receiving ARV during TB treatment in Chiang Rai province Fiscal year , Thai only ARV of TB patients (%) Death during TB treatment (%) Fiscal year Comparison of survival rate among TB/HIV patients with/without ART Retrospective study : 01/ / patients, mean CD4 =49(19-129) cells/mm3 surv vival rate p< Manosuthi W et al J AIDS 2006; 43: year 2 year 5 year ARV without ARV The mortality rate was reduced for 80% 18

19 Survival rate between HIV-infected TB patients who received and did not receive ART October 2004-March On ART No ART Days to Treatment Outcome No ART On ART Sanguanwongse et al., J Acquir Immune Defic Syndr.2008 Jun1;48(2): Declining prevalence of drug- resistant TB Retrospective e study in BND infectious hosp. HIV/TB patients receiving ART increasing from % Prevalence of MDR decreasing from 48% to 7.9% Sangkanuparph S, et al J Med Assoc Thai May;90(5):

20 Diagnosis of TB Microscopy-AFB Chest radiography Culture PCR in Medical school Ultrasound CT scan Treatment of TB in HIV+ Same as in HIV-negative Standard TB Rx : 2 IRZE + 4 IR Induction - 2 months Isoniazid Rifampicin Pyrazinamide Ethambutol Consolidation -IR 4 months (7mo in some pt) Consolidation -IR 10 months in TB meningitis Every effort should be made to use a rifamycin-based regimen for the entire course of therapy 20

21 Challenging in Treatment TB-HIV Simultaneous ART and TB therapy can be complicated by: High pill burden Adherence Overlapping drug toxicities Drug-drug interactions Immune reconstitution inflammatory syndrome (IRIS) When to start ART in active TB? First priority is to initiate standard anti-tb treatment Optimal time to initiate ART is not known 2wk 4wk 8wk 6mo Anti-TB While waiting the results of current research, decision should be individualized 21

22 WHO 2006 CD4 cells/mm 3 ART Timing after TB Rx <200 Recommend 2-8 wks Recommend After 8 wks >350 Defer Re-evaluateevaluate at 8wks and at the end of TB Rx Not available Recommend 2-8 wks BHIVA guidelines Feb.2005 CD4 cells/mm 3 start ART <100 ASAP After 2 m of TB Rx >200 After completing 6 m of TB Rx 22

23 Thai TB/HIV National Guidelines for treatment of HIV-Infected Infected TB patients ( ) CD4 count < > 250 TB/ART treatment 1) Start TB treatment 2) Start ART as soon as TB treatment is tolerated (usually after 2 weeks of TB treatment) 1) Start TB treatment 2) After 2 weeks to 2 months of TB treatment, start ART 1) Start TB treatment 2) F/U CD4 every 3-6 months 3) If CD4<250, start ART Significance of Starting Patients on ART In Thailand > 50% of TB-HIV patients have CD4<100,these patients should be started on ART as soon as possible. In most hospitals in Thailand, this is not happening right now. *Data from Thai TB-Net 23

24 What is the appropriate ART regimen for HIV-infected TB patients? D. Havlir

25 Thai TB/HIV National Guidelines First line: 2NRTIs+EFV (d4t+ T+3TC) TC) or (AZT + 3TC) If EFV is not available: GPO-VIRZ (AZT+3TC+NVP) TC+NVP) GPO-VIRs (d4t+ T+3TC+NVP) TC+NVP) Drug Interaction 25

26 Drug-drug interactions TB/HIV Absorption Rifampicin Metabolism CYP CYP3A4 Metabolism Antiretrovirals PIs NNRTIs Elimination Effect of Rifamycins on ARV drug levels Anti-TB SQV IDV NFV APV LPV NVP EFV Rifampin -84% -89% -82% -82% -75% -37% -25% Rifabutin -40% -32% -32% -15% 0-16% 0 Reverse transcriptase inhibitors -No effect Finch et al. Arch Intern Med 2002;162:

27 NNRTIs and RIF Do we need to adjust the NNRTI doses? A Randomized Controlled Trial of Efavirenz 600 mg/day versus 800 mg/day in HIV-infected Patients with Tuberculosis Receiving Rifampicin Probability of HIV RNA 1.00 <50 copies/ml Efavirenz (EFV) level in plasma p = Weeks EFV = 600 N=42 EFV = 800 N=42 Plasma EFV level (mg/l) EFV 600 mg p = ns 3.02 Dose per day EFV 800 mg 3.39 (median) Manosuthi W. AIDS 2005;19: Manosuthi W. AIDS 2006;20:

28 2NRTI + EFV: Studies with small numbers show efficacy and safety (Thailand, Brazil) 600 mg daily is probably sufficient for patients with mean body weight 50Kg (Thailand) EFV levels not significantly lowered 2 NRTIs + EFV with RF Concerns related to teratogenicity, EFV should not be used in -woman of childbearing potential without adequate contraception -woman who are in 1 st trimester of pregnancy 28

29 Notes When RF-containing regimen is completed and want to switch back from EFV to NVP (more convenient because of less pill count), no lead in dose is required apine concentration (mg/l) nevira NVP+RIF NVP time (hours) 148 samples collected : 74 on NVP+RIF, 74 GPOvir >85% samples on NVP+RIF level > 3.1 mg/l 29

30 NVP 400 mg/day ± Rifampicin NVP only n=70 70, NVP+RIF n=70 Mean plasma NVP levels at 8 and 12 weeks were lower in patients receiving rifampicin (p <.05) However, virological and immunological outcomes at 24 weeks were not different (p >.05) Manosuthi W et al. Clin Infect Dis. 2006; 43: Cmin of 24 cases receiving both NVP and RIF during TB treatment Recommended Cmin Cmin of NVP 10 Cmin (mg/ Case No Chiangrai Regional Hospital

31 Original article Pharmacokinetics and 48-week efficacy of nevirapine: 400 mg versus 600 mg per day in HIV-tuberculosis coinfection receiving rifampicin Anchalee Avihingsanon, Weerawat Manosuthi, Pacharee Kantipong, Charoen Chuchotaworn, Saiyud Moolphate, Waraporn Sakornjun, Meena Gorowara, Norio Yamada, Hideki Yanai, Satoshi Mitarai, Nobukatsu Ishikawa, David A cooper, Praphan Phanuphak, David Burger and Kiat Ruxrungtham Antiviral Therapy 2008;13:

32 CONCLUSIONS In NVP-RIF concomitantly treated patients, 200 mg NVP OD lead in led to a significant short- term suboptimal NVP level in the 400 mg arm, whereas NVP 600 mg/day was associated with a high rate of NVP hypersensitivity. At 48 wk efficacy (median CD4+ count rise and proportion with VL<50 copies/ml is comparable. Thus, NVP400 mg/day may be sufficient for Asian HIV-infected patients t receiving i RIF, but the NVP 200 mg lead-in should be avoided. In addition, AZT should also be avoided during the first 3 months of advanced HIV/TB 2 NRTIs + NVP with RF Recent studies in Thailand and South Africa showing -high therapeutic index of NVP -good outcomes in antiviral activity -few adverse events Standard NVP dosing is recommended Prefer to use because FDC is wildly available: less pill count and cheap 32

33 2 NRTIs + NVP with RF con t Close clinical and lab monitor of liver enzyme at wk 4,8,12 for pt. receiving i NVP+RIF NVP : risk of symptomatic or fatal hepatitis in woman with CD Triple NRTI + RF AZT + 3TC + ABC -safe with RIF -safe in pt with higher CD4 -safe in pregnant woman AZT + 3TC +TDF -efficacy data are limited with TB 33

34 TB occurs after ART Usually in the first three months Due to IRIS Missed TB at the time of start ART TB patients already receiving ART ART at the time TB occurs Options 2NRTIs + EFV 2NRTIs + NVP Triple NRTI Continue Substitute to EFV or continue Continue 34

35 TB patients already receiving ART con t ART at the time TB occurs PI based / boosted with rtv Options LPV/r but toxicity is an issue (400/400) SQV/r (1000/100) IDV/rtv (800/100) Other choice If the patients need PIs regimen, TB regimen without Rifampicin 35

36 Immune Reconstitution Inflammatory Syndrome (IRIS) Patients with HIV-related TB may experience a temporary worsening of symptoms, signs, or radiographic manifestations of TB after beginning ART Occurs as a result of the simultaneous administration of ART and anti-tb drugs TB/HIV: A Clinical Manual, World Health Organization, Paradoxical Reactions (Immune Restoration Syndromes) Common manifestations : (new or worsening) Adenopathy Pulmonary infiltrates Serositis Cutaneous or CNS lesions (spots) Prolong fever (> F) Median time : 6 weeks (4-80 days) Narita M, et al: Am J Respir Crit Care Med , 1998; McCormack JG, et al: CID , 1998; Hirsch HH, et al CID 38: , 2004; Avihingsanon A, et al. CROI

37 Risk Factors for IRIS Low baseline CD4 count (<50 50) High burden of pathogen (high viral load) HIV-Infected Infected TB Patients and IRIS HIV-Infected Infected TB Patients undergoing ART have symptoms consistent with IRIS, estimates ranging from 7-45% Rx: anti-inflammatory inflammatory drug or steroid Murdoch et al.,

38 Paradoxical Reaction or IRIS Active TB Worsening Radiograph After Anti-TB IRIS After HAART 38

39 Dx.Pulmonary Tuerculosis Before start Anti-TB drug 1 month after start Anti-TB ( Before start ARV ) 2 months after start ARV End of Anti-TB treatment Immune Reconstitution Inflammatory Syndrome (IRIS) Courtesy of Anton Pozniak 39

40 Overlapping toxicities of Anti-HIV with Anti-TB Adverse reaction Rash ART NVP, EFV R,H,Z TB Hepatitis NVP, EFV R,H,Z GI disturbance All Peripheral neuropathy d4t H CNS dysfunction EFV All H Anemia AZT R Summary of adverse events 40

41 Overlap toxicities: rash and hepatitis MDR and XDR in Thailand 41

42 3 rd Surveillance of Drug resistance in Tuberculosis: THAILAND 2006 Previously Treated All cases of resistance New Cases Cases ITEMS N % N % N % Total tested % % % Fully sensitive (HRZE) % % % Any resistance % % % H+R resistance (MDR-TB) % % % Any H resistance % % % Any R resistance % % % Mono-resistance % % % Two drugs resistance % % % Three drugs resistance % % % National Tuberculosis Reference Laboratory Center, TBC, BATS,DDC.MOPH Extensively Drug resistant Tuberculosis (XDR-TB) in Thailand, 2007 During 2004 to 2007 (April), 2194 multi- drug resistant t tuberculosis isolates were performed the drug susceptibility test to the second line drugs; Ofloxacin and Kanamycin, at the NTRL of Bureau of Tuberculosis, 0.96% were XDR-TB. 42

43 Trend of MDR in Chiang Rai Province, (Exclude NTM cases) 30.00% 25.00% 23.5% MDR among Previously Treated Cases 20.00% 15.00% 12.6% 10.00% 5.00% 5.2% MDR among New Cases 1.3% 0.00% TB/HIV Research Project (RIT RIT-JATA JATA) Trend of MDR among new cases by HIV status Chiang Rai province, % 14.00% 12.00% HIV positive 10.00% 8.00% 6.00% 4.00% 5.1% 5.6% HIV negative 2.00% 0.00% 1.3% % TB/HIV Research Project (RIT RIT-JATA JATA) 43

44 Collaborative TB/HIV activities A. Establish mechanisms for collaboration 1. Set up coordinating bodies for TB/HIV activities at all levels 2. Conduct surveillance of HIV prevalence among tuberculosis patients 3. Carry out joint TB/HIV planning 4. Conduct monitoring and evaluation B. Decrease the burden of TB among people living with HIV/AIDS 1. Establish intensified TB case-finding 2. Introduce isoniazid preventive therapy 3. Ensure TB infection control in health care and congregate settings C. Decrease the burden of HIV among tuberculosis patients 1. Provide HIV testing and counselling 2. Introduce HIV prevention methods 3. Introduce co-trimoxazole preventive therapy 4. Ensure HIV/AIDS care and support 5. Introduce antiretroviral therapy 13 Integration of TB and HIV We formed CAT team (Collaboration AIDS and TB) CAT team includes every stakeholders that involves in HIV/TB care Develop guidelines how to integrate both diseases care together 44

45 Adult HIV patients Objective B: Education Counseling Early HIV Care CD 4 TB. Screening CD4 > 200 cells / cu.mm - F/U CD4 q 2, 4,6 mo. CD4 < 200 cells/ cu.mm OI prophylaxis, ARV Sputum AFB, CXR + VE VE TB. Rx. PPD + ve >5 mm ve < 5 mm Rx. TLTI ( INH 9 mo.) 45

46 TB cases among newly diagnosed HIV-positive in Chiang Rai Regional hospital, Number of screening TB Active TB % % % % % TOTAL % CD4 and TST CD4 TST < 5 TST > (N=761) 703 (92%) 58 (8%) (N=616) 517 (84%) 99 (16%) 501 (N=283) 216 (76%) 67 (24%) Total (N=1660) 1436 (87%) 224 (13%) 46

47 TB after HAART in 1 year 6.5% (78/1206) CD4 level N TB TB% % % % 36% Data from HIV patients receiving ARV in the year Integration of TB and HIV Objective C: Adult TB patients Rx TB OPD IPD Provider-initiated HIV testing HIV +VE HIV - VE CD4 Prevention Counseling CD4 > 200 cells / cu.mm - F/U CD4 q 2, 4,6 mo. CD4 < 200 cells/ cu.mm OI prophylaxis, ARV 47

48 Adult TB/HIV coinfection CD4 CD4 <100 CD CD4>200 Start ARV at 2 wk-2mo ASAP +Cotrimoxazole Start ARV After 2 mo Follow up CD4 After 6 mo BHIVA guidelines จ านวนผ ป วยว ณโรคท กประเภท TB all types in Chiangrai Regional ในโรงพยาบาล Hospital เช ยงรายประชาน เคราะห ป TB/HIV ResearchProject (RIT-JATA) 48

49 HIV status in TB patients ส ดส วนผ ป วยว ณโรคท กประเภทแบ งตามเอชไอว โรงพยาบาล เช ยงรายประชาน เคราะห ป % HIV-positive HIV-negative HIV-unknown 80% 60% 40% 20% 0% TB/HIV ResearchProject (RIT-JATA) % Admission and mortality rate ATC NAPHA Admission rate Mortality 49

50 Acknowledgements Dr. Kiat Ruxrungtham Associate Professor of Medicine,, Chulalongkorn University, and HIV-NAT, Thai Red Cross AIDS Research Centre;Bangkok, Thailand Dr. Anchalee Avihingsanon HIV-NAT, TRC-ARC, Bangkok, Thailand CAT team Chiangrai Regional Hospital Research Institute of Tuberculosis,Japan Patients participated in the studies 50