Presentation on theme: "Management of HIV/TB Co-infection"— Presentation transcript:
1Management of HIV/TB Co-infection Dr.G.ManoharanMedical Director,International Training and Education Center for Health IndiaClinical Associate Professor, DGH,UW.
2Topics to be discussedWhen to start ART in HIV associated TuberculosisDuration of TB treatmentIntermittent Vs Daily TB treatmentDrugs used in the TB TreatmentRecurrent TB/Relapse/Re-infectionRole of steroids
3Case study 35 yrs. male HIV +VE Hospitalized for weight loss, fever, and cough with expectorationDiagnosed as sputum negative pulmonary TB, oral candidiasis and HIV wasting.CD4 cell count- 70 cells & 18.3%Chest x-ray : 29th May, 04.
4Case study OI s managed appropriately Managed with ATT ( 2HREZ and 4RH), ART ( ddI,3TC and EFV) along with CTZ and VitaminsFollowed up regularly for almost an year
7TB therapy in patients with HIV-TB Co-infection Aims of TB therapy are toAchieve cure and prevent deathPrevent relapseRender patients non-infectious as rapidly as possiblePrevent the emergence of drug resistance.
8TB therapy in patients with HIV-TB Co-infection So to achieve our aim, we need tokill the actively metabolizing TB bacilli (Isoniazid)destroy less actively replicating bacilli in the acidic and anoxic closed lesions(Pyrazinamide)kill near-dormant bacilli that might otherwise cause a relapse of the disease (Rifampin)
9TB therapy in patients with HIV-TB Co-infection So the Anti TB drugs are given asInitial Intensive phasefollowed by aContinuous Phase
10TB therapy in patients with HIV-TB Co-infection 1. When will you start ART in patients with HIV-TB Co infection?2. Do you give 6 months therapy or 9 months therapy?3.Do you treat with intermittent regimen or daily Regimen?4. What drugs do you use? Rifampin throughout the therapy?5.What to do after the completion of ATT?
111 .When to Start Antiretroviral Therapy in HIV- TB co-infection Early ARTIRISDrug ToxicityDrug interactionsHigh pill burdenDelayed ARTAIDS related IllnessMortality
12Studies: Early Vs Late initiation of ART The Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPIT) trialThe AIDS Clinical Trials Group Study A5221The Cambodian Early versus Late Introduction of Antiretrovirals (CAMELIA) studyN Engl J Med 365;16 october 20, 2011
13SAPiT Trial: Main Findings Integrated therapy associated with 56% reduction in risk of death Vs sequential therapyOutcomeIntegrated Therapy (n = 429)Sequential Therapy (n = 213)HR (95% CI)P ValueAll patientsDeath rate per 100 person-yrsDeaths, n5.42512.1270.44 ( ).003CD4+ cell count ≤ 200 cells/mm38.22315.3210.54 ( ).04CD4+ cell count > 200 cells/mm31.127.060.16 ( ).02Integrated therapy independently associated with reduced risk of death (HR: 0.43; 95% CI: ; P = .004)
14SAPiT: Increased survival with concurrent HIV and TB treatment Abdool Karim SS, et al. CROI Abstract 36a.0.700.750.800.850.900.951.00SurvivalMonths Postrandomization123456789101112131415161718192021222324Intensive phase of TB treatmentPost-TB treatmentContinuation phase of TB treatmentEarly ARTSequential ART
16At wk 50, the median gain in the CD4 count was 118 in the earlier-ART group and 112 in the later-ART group (P = 0.22).whereas Viral load was undetectable in 96.5% of pts, with no difference between the two study groups (P = 0.82),
17CAMELIA trial : Early initiation of ART (2 weeks after the start of tuberculosis therapy) significantly increases survival among HIV infected adults with newly diagnosed tuberculosis and CD4+ T-cell counts of 200 per cubic millimeter or lower.This is of particular relevance in resource-limited settings where tuberculosis is the leading cause of death in HIV-infected patients
18Duration of TB treatment 2. TB therapy in patients with HIV-TB Co infectionDuration of TB treatment6 Months Vs 9 Months or longer…..
196 months supervised intermittent TB therapy in patients with and without HIV- Haiti Short-course, thrice-weekly therapy highly efficacious in HIV positive and HIV negative patients427 Patients ; 177 HIV +VEOutcomeHIV PositiveHIV NegativeCure81%89%Relapse5.4%2.8%Death9%1%Ref: Chaisson RE, Clermont HC, Holt EA, Cantave M, Johnson MP, Atkinson J, Davis H, Boulos R, Quinn TC, Halsey NA. Six-month supervised intermittent tuberculosis therapy in Haitian patients with and without HIV. Am J Respir Crit Care Med 1996;154:1034–1038.
20Successful Treatment rate 34-100% 91-99% Ref: El-Sadr WM, Perlman DC, Denning E, et al. A review of efficacy studies of 6-month short-course therapy for tuberculosis among patients infected with human immunodeficiency virus: differences in study outcomes. Clin Infect Dis 2001; 32: 623–632.TB OutcomeHIV InfectedHIV Un infectedCure Rate59-97%62-88%Successful Treatment rate34-100%91-99%Relapse Rates0-10%0-3%
21Outcome of 6 Vs 9 Months anti-TB treatment in HIV-associated tuberculosis (without ART) Antiretroviral treatment–naïve, HIV-Positive patients with TB, a 9-month regimen resulted in a similar outcome at the end of treatment but a significantly lower bacteriological recurrence rate compared with a 6-month thrice-weekly regimen. ARR was high with these intermittent regimens and neither mortality nor ARR was altered by lengthening TB treatment.ARR > Acquired Rifamycin ResistanceReference: Am J Respir Crit Care Med Vol 181. pp 743–751, 2010
22(2EHRZ3/4RH3) Vs (2EHRZ3/7RH3) Sputum culture negativity in months
23Kaplan-Meier plot showing time to death for patients in the 6-month regimen(blue line) and in the 9-month regimen (green line); P = 0.17 (not significant)..
24Time to bacteriological recurrence up to 36 months for patients in the 6-month and 9-month regimen 9 Months RegimenP = 0.036 Months Regimen
256 Months Vs 9 Months Therapy A retrospective review from the US showed no treatment failures in HIV-1 infected patients administered a 6 month standard rifampicin-based regimen but relapse rates were four-times higher in those treated for 6 months compared to those treated for longer.Nahid P, Gonzalez LC, Rudoy I, et al. Treatment outcomes ofpatients with HIV and tuberculosis. Am J Respir Crit Care Med2007; 175: 1199–1206.
26Duration of TB therapyOverall most studies concur that standard TB treatment should be given to HIV-1 infected patients whenever possible .A 6-month treatment regimen that includes rifampicin and INH throughout should be given for drug-sensitive TB (outside of the central nervous system). This is usually a regimen of four drugs for 2 months, followed by INH and rifampicin for a further 4 months..
27Duration of ATTCurrent recommendations: Standard 6-month regimens and the extension of therapy to 9 months for patients with extra pulmonary disease or a delayed response.NACO guideline: Recommended to follow RNTCP guideline.Guidelines for Prevention and Management of Common Opportunistic Infections/Malignancies among HIV-Infected Adult and Adolescent, May 2007; NACO.The Journal of Infectious Diseases 2007; 196 : S35-45 ; BHIVA treatment guidelines for TB/HIV infection, February 2005.
28Intermittent Dosing /Therapy Vs 3. TB therapy in patients with HIV-TB Co infectionIntermittent Dosing /Therapy VsContinuous therapy
29Contraindicated Once weekly INH and Rifapentine Twice weekly Rifampin- or Rifabutin- based regimens
30Pooled estimates of outcomes stratified by schedule of treatment administration during the initial intensive phase ( first 8 weeks)OutcomeTreatment ScheduleNo of events/subjectsPooled event rate(95% C1), %FailureDaily74/25312.5( )3 Times weekly12/1635.3( )Relapse142/12416.7( )18/6528.1(0-69.5)Death during Treatment430/295711.9( )31/19414.3( )
31Intermittent Dosing ( ATT) Current recommendations: In patients who have advanced immunodeficiency daily or three times weekly treatment for at least the first two months of intensive therapy.NACO guideline: Recommend intermittent ( three times weekly ) regimen( as per RNTCP guideline) for all patientsThe Journal of Infectious Diseases 2007; 196 : S35-45
32What drugs do you use? Rifampin throughout the therapy? 4. TB therapy in patients with HIV-TB Co infectionWhat drugs?What drugs do you use? Rifampin throughout the therapy?
33Randomized controlled Trial of two 8-month regimens- a non inferiority study Ref: Results at 30 months of a randomized trial of two 8-month regimens for the treatment of tuberculosis: A.J. Nunn et al, Int J Tuberc Lung 15(6): , 2011
34Status at 30 months by treatment arm and HIV status Ref: Results at 30 months of a randomized trial of two 8-month regimens for the treatment of tuberculosis: A.J. Nunn et al, Int J Tuberc Lung 15(6): , 2011
35Treatment of Active Tuberculosis in HIV-TB Coinfected Patients: A systematic Review and Meta-Analysis.OutcomeDuration of RifamycinNo of events/subjectsPooled event rate(95% C1), %Failure2 Months27/8722.9 ( )6 Months45/13772.6 ( )>8 Months14/4411.9(0-4.0)Relapse40/25810.8(0-25.1)100/7309.8(0-19.8)20/3143.3(0-9.0)Death during Treatment205/107716.6( )196/157310.5( )60/50111.7( )
36Recurrence / relapse after the completion of Anti TB Therapy The role post treatment INH
375. TB therapy in patients with HIV-TB Co infection Recurrence / Re-infection In Brazil, TB recurrence rates were high in HIV-1 infected persons but if there was completion of initial TB therapy, use of ART and subsequent increases in CD4 cell counts then recurrence rates were low, suggesting re-infection may have been the reason for recurrence .Ref: Golub JE, Durovni B, King BS, et al. Recurrent tuberculosis in HIV-infected patients in Rio de Janeiro, Brazil. AIDS 2008; 22: 2527–2533.
38Recurrence of TB after completing Rx Rates of recurrence per 100 person – year of observationHIV+HIV-Zaire18.16Kenya16.70.5Zambia22Malawi18.21.7S. India15.03.0
40Strategies to Reduce Recurrence Rates 80% recurrences in HIV+: Re-infection90% recurrences in HIV-: ReactivationExtending treatment (RH2 up to 12 months ↓ recurrence to 1.9% compared to 9%.Post-treatment isoniazid prophylaxis for one year ↓ recurrence (1.4%/year) vs placebo (7.8%/ year)HAARTRef: Sonnenberg Lancet 2001; Penneris NEJM 1995;Fitzgerald DW Lancet 2000
41233 patients treated for TB Recurrence rate of TB in HIV+ and HIV- after therapy and Effect of Post-treatment Isoniazid233 patients treated for TBRandomizedHIV+ (142)HIV- (91)Placebo (74)Isoniazid(68)Placebo (40)Isoniazid (51)Recurrent TB1221Recurrence rateper 100 persons-years (95% CI)7.8 ( )1.4 ( )0.0 ( )0.7 ( )Ref: Fitzgerald D, Desvarieux M, Sévère P, Joseph P, Johnson WD Jr, Pape J.W. The Lancet :
45Am J Respir Crit Care Med Vol 167. pp 603–662, 2003
46Benefit of Cotrimoxazole therapy in HIV-TB co infected patients Studies in Coˆ te d’Ivoire & Malawi >> significant decrease in mortality and the number of hospital admissions & improved survivalIn a large study in Uganda >> The effect on mortality was seen only among patients with CD4 cell counts < 200 cells/mm3 or with WHO stage 3 or 4 HIV disease, but the reductions in morbidity were seen among all HIV-infected patientsIn a placebo-controlled study performed in Coˆ te d’Ivoire , 771 HIV-infected patients with TB were treated with daily cotrimoxazole, which resulted in a significant decrease in mortality and the number of hospital admissions.In a subsequent study performed in Malawi , among 717 patients with TB, the overall CFR fell from 37% to 29%—thatis, for every 12.5 patients with TB treated, 1 death was averted. CFRs were unchanged over a period of 2 years among HIVuninfected patients but fell among HIV-infected patients, from 43% to 24%. Improved survival became apparent after the first 2 months and was maintained beyond the end of treatment.In a large study in Uganda , an area with high rates of bacterial resistance to cotrimoxazole, the effect of such prophylaxis on morbidity, mortality, CD4 cell count, and viral load was evaluated among people with HIV infection. Cotrimoxazole prophylaxis was associated with a 46% reduction in mortality (hazard ratio, 0.54 [95% CI, 0.35–0.84]; Pp.006) and the number of hospital admissions (hazard ratio, 0.69 [95% CI, 0.48–0.98]; Pp.04). The annual rate of decline in CD4 cell count was lower during prophylaxis than before prophylaxis (77 vs. 203 cells/mm3; P ! .0001), and the annual rate of increase in viral load was lower (0.08 vs log10 copies/mL; Pp .01). The effect on mortality was seen only among patients with CD4 cell counts !200 cells/mm3 or with WHO stage 3 or 4 HIV disease, but the reductions in morbidity were seen among all HIV-infected patients.Additional studies corroborated these findings and the feasibility of implementing cotrimoxazole therapy within a TB control program .(1) Wiktor SZ et al ; Lancet 1999; 353:1469–75. (2) Mwaungulu FB et al. Bull World Health Organ 2004; 82:354–63. (3) Mermin J, et al, Lancet 2004; 64:1428–34.
47Adjunctive TherapyImmunomodulators including corticosteroids, therapeutic vaccines, and other drugs and biologics—have the potential to shorten TB treatment by modulating the host response and helping the immune system to eliminate persistent organisms.(1) Imperiali FG et al ; Clin Exp Immunol; 2001; 123:435–42. (2) Ehlers S et al ; J Rheumatol Suppl 2005; 74:35–9. (3) Keane J et al ; Rheumatology 2005; 44:714–20. (4) Wallis RS et al ; J Infect Dis 1996; 174:727–33. (5) Wallis RS et al ; AIDS 2004; 18:257–64. (6) Bekker LG et al ; J Infect Dis 2000; 181:954–65. (7) Smego RA et al ; Int J Tuberc Lung Dis 2003; 7:208–13.
48Role of Steroids in the management of HIV-TB co infection In HIV-1-infected adults with pulmonary or pleural TB, corticosteroids do not improve survival or reduce TB recurrence [1-3].A sub study of HIV-1 infected persons within a randomised controlled trial of dexamethasone for TBM in Vietnam showed a trend towards increased survival in the dexamethasone arm .Most physicians, therefore, give steroids to patients with TB meningitis and use dexamethasone 12–16 mg?day-1 intravenously until the patient begins taking medicines orally.An alternative is prednisolone 1.5 mg?kg-1?day-1 for 3 weeks and tapered over the next 3 weeks .A randomised controlled trial of adjunctive prednisolone in HIV-1-infected patients with effusive tuberculous pericarditis demonstrated reduction in mortality among patients who received prednisolone despite the relatively small sample size (n558) .1 Mayanja-Kizza H, Jones-Lopez E, Okwera A, et al. Immunoadjuvant prednisolone therapy for HIV-associated tuberculosis: a phase 2 clinical trial in Uganda. J Infect Dis 2005; 191: 856–865.2 Elliott AM, Luzze H, Quigley MA, et al. A randomized, doubleblind, placebo-controlled trial of the use of prednisolone as an adjunct to treatment in HIV-1-associated pleural tuberculosis. J Infect Dis 2004; 190: 869–878.3 Hakim JG, Ternouth I, Mushangi E, et al. Double blind randomised placebo controlled trial of adjunctive prednisolone in the treatment of effusive tuberculous pericarditis in HIV seropositive patients. Heart 2000; 84: 183–188.4 Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004; 351: 1741–1751.5 Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev 2008; 1: CD
49Thank youITECH India/Arogyaan express our gratitude and thanks to Lucie Kroschel and Alex McGee for their logistic support.