HIV and TB coinfection: Updates Awewura Kwara, MD, MPH &TM Associate Professor, Alpert Medical School of Brown University
Learning objectives Identify the optimal timing of antiretroviral therapy in patients with HIV/TB coinfection Recognize factors that influence the selection of optimal concurrent HAART regimens in HIV/TB coinfected patients Recognize and manage complications associated with concurrent treatment of HIV and TB
Case presentation 47-year old female presented with a 2-month history of abdominal pain, diarrhea, weight loss, cough, fever & night sweats. No significant past medical history No known TB exposure Born in Zimbabwe and moved to US 6 months prior to presentation Severe wasting, T - 102.4 o F,HR - 76, RR - 18, BP - 120/80.
Case presentation
Case presentation Sputum was AFB smear positive and eventually grew M. tuberculosis Rifampin, Isoniazid, Pyrazinamide and Ethambutol started and HIV test sent HIV test - positive, CD4-63 cells/µl (1.8%), HIV-1 RNA level 435,000 copies/ml. Bactrim DS one daily and fluconazole 100 mg daily added to therapy
Clinical management issues When should HAART be initiated after starting TB treatment? What antiretroviral regimens can be used concurrently with TB therapy? Toxicities concerns and how should patient be managed?
EPIDEMIOLOGY OF HIV/TB COINFECTION
HIV/TB: Profound Effect on Individuals The annual risk of TB in HIV infected approximates the lifetime risk of HIV uninfected Small and Fujiwara, N Eng J Med 343:189, 2001
Estimated TB incidence (per 100,000 population) 1000 800 600 400 200 0 TB incidence closely correlated with HIV prevalence in Africa 0 10 20 30 40 HIV prevalence, adults 15-49y WHO
RATIONALE FOR CONCURRENT THERAPY
TB death rates per HIV status, 2009 Numbers under bars indicate the number in each cohort, not evaluated outcomes not included 14 Collaborative TB/HIV activities, 2010
Effective TB treatment does not delay HIV disease progression 111 HIV-infected patients hospitalized with TB (12 died) HIV plasma load was high at baseline and remained high despite anti-tb therapy Anti-TB therapy had no significant influence on CD4+ cell count Morris L, et al. JID 2003;187:1967-71
HAART during TB treatment saves lives Concomitant HAART markedly improves survival in HIV-infected patients with HIV/TB coinfection. Manosuthi, W et al. JAIDS. 43(1):42-46
WHEN TO START ANTIRETROVIRAL THERAPY?
Integrated HIV and TB therapy is challenging Optimal timing of ART is unclear Immune restoration inflammatory syndrome (TB-IRIS) What regimens Overlapping drug toxicities Pharmacokinetic drug-drug interactions Implementation issues
Early versus delayed initiation of antiretroviral therapy during TB treatment Early ART (before 8 wks of TB treatment) Delayed ART (after 8 wks of TB treatment) Adherence demand Ability to determine the cause of adverse events Drug-drug interaction Severe immune reconstitution inflammatory events HIV disease progression (new OI or death Problematic with use of 4-drug for TB and multidrug therapy for HIV Complex because of the large number of medications started in a short time period and overlapping side effects profiles Problematic Risk may be increased Risk may be decreased Less problematic because fewer drugs necessary for TB treatment Simpler because the number of drugs for TB treatment is less and there has been more time to evaluate response to TB treatment Problematic Risk may be decreased Risk may be increased Burman WJ. Clin Chest Med 2005;26:283-294
SAPiT study: integrated antiretroviral TB therapy improves survival Abdool Karim SS, et al. NEJM 2010;362:697-706
Highlights of AIDS 2010 clinicaloptions.com/hiv CAMELIA: ART Initiation at Wk 2 vs Wk 8 of TB Therapy in HIV-Coinfected Patients WHO 2010 guidelines recommend to [1] Initiate HAART in all HIV-infected patients with TB, regardless of CD4+ cell count Initiate TB therapy before HAART, with HAART added as soon as possible and within 8 wks of TB therapy CAMELIA: randomized, open-label trial of HIV-infected patients with newly-diagnosed AFB-positive TB and CD4+ cell count 200 cells/mm 3 [2] Compared HAART initiation (d4t + 3TC + EFV) at Wk 2 (n = 332) vs Wk 8 (n = 329) of TB therapy All patients received standard TB therapy for 6 mos 1. WHO. Available at: http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf. 2. Blanc FX, et al. AIDS 2010. Abstract THLBB106.
Probability of Survival Highlights of AIDS 2010 clinicaloptions.com/hiv CAMELIA: Survival With Early vs Late Therapy in TB-Coinfected Patients Wk 50 Survival Probability, Early vs Late Therapy 1.00 Early arm 0.90 Late arm 0.80 0.70 Log rank P =.0042 0.60 0 50 100 150 200 250 Wks From TB Treatment Initiation 100 150 Survival Probability, % (95% CI) Early Arm 86.1 (81.8-89.4) 82.6 (78.0-86.4) 82.0 (77.2-85.9) Late Arm 80.7 (76.0-84.6) 73.0 (67.7-77.6) 70.2 (64.5-75.2) Blanc FX, et al. AIDS 2010. Abstract THLBB206. Graphic used with permission.. P.07.006.002 Factors Independently Associated With Mortality Factor Multivariate Adjusted HR (95% CI) Late therapy 1.52 (1.12-2.05).007 BMI 16 1.68 (1.07-2.63).01 Karnofsky score 40 Pulmonary + extrapulmonary TB Significantly higher incidence of IRIS with early vs late HAART 4.03 vs 1.44 per 100 person-mos, respectively (P <.0001) P 4.96 (2.42-10.16) <.001` 2.26 (1.62-3.16) <.001 NTM 2.84 (1.13-7.13) <.001 MDR-TB 8.02 (4.00-16.07) <.001
The STRIDE study: ACTG5221 Results: Proportion with AIDS/Death Immed. N=405 Early N=401 All 12.9% 16.1% 0.45 CD4<50 15.5% 26.6% 0.02 CD4>50 11.5% 10.3% 0.67 Nearly 70% enrolled from African sites Patients received Efavirenz + TDF/FTC Median (IQR) CD4 77 (36 145) P Randomized strategy trial of immediate (within 2 weeks) and early (8-12 weeks) PVL < 400 copies/ml was 74% and no diff between groups MTB IRIS was 11% in immediate and 5% in early group (P =0.002) Havlir D, et al. CROI 2011, Boston. Abstract # 38.
SAPiT Trial: Analysis of the integrated arm Results: Risk of AIDS or Death IRR (95% CI) All 0.89 (0.44 1.79) 0.73 CD4<50 0.32 (0.07 1.13) 0.06 CD4>50 1.51 (0.61 5.95) 0.34 Done in South Africa All patients received Efavirenz + ddi/3tc Median (IQR) CD4 150 (77 254) Early (N=214); late (N=215) P Randomized study of early (within 4 weeks) and early (8-12 weeks) Over 90% achieved viral suppression after 18 months IRR (early vs. Late) for MTB IRIS was 4.7 and 2.2 for CD4< and >50, resp. Abdool Karim Q, et al. CROI 2011, Boston. Abstract # 39LB.
Challenges of immediate ART (within 2 weeks) in sub-saharan Africa Rapid HIV and TB diagnosis Rapid staging of HIV disease by CD4 count or by clinical criteria Integration of HIV and TB program to ensure availability of ART at site of diagnosis Prevention, early recognition and treatment of MTB IRIS Implementation issues with scale-up of intervention
WHAT ART REGIMEN?
INH, rifampin, PZA, and ethambutol (4 drugs, 10 pills once a day) Burman WJ. CFAR Symposium 2005, Boston
INH, rifampin, PZA, ethambutol, cotrimoxazole, AZT, 3TC, efavirenz (8 drugs, 14-16 pills, 2-3 doses per day) Are you sure that I won t, like, blow up if I take all of these pills? Burman WJ. CFAR Symposium 2005, Boston
Rifampicin is an essential (crucial) component short-course chemotherapy Jindani A, et al. Lancet 2004; 364:1244-1251
Rifampicin is a potent inducer of cytochrome P450 enzymes Niemi M, et al. Clin Pharmacokinet 2003;42:819-850 Rifampicin effect is variable Rifabutin has less induction effect on CYP3A4 Rifampicin is the only rifamycin readily available in TB endemic areas
DRUG DRUG P-gp * + DRUG * Portal blood + * * DRUG metabolite Enterocyte Systemic metabolite Hepatocyte *Rifamycins induces CYP systems and P-gp leading to increased metabolism and efflux of the PIs or NNRTIs. Rifampin >>> Rifabutin > rifapentine
Wilkinson GR. NEJM 2005;2211-2221 A. Mechanism of induction of CYP3A4- mediated metabolism of drug substrate B. The resulting reduced plasma drug concentration PXR Pregnane X receptor; RXR retinoid X receptor
Geiner B, et al. J Clin Invest 1999;104:147-153 a) Duodenal biopsy immunostained for P-gp before administration of rifampin b) biopsy after 9 days administration of rifampin 600mg daily
100 Decrease in serum concentrations (AUC) of HIV-1 protease inhibitors with rifampin or rifabutin With 100 mg RTV 80 60 40 * * 20 0 ND 0 0 SQV RTV IDV NLV AMP LPV ATV Clin Infect Dis 1999; 28: 419-30 Rifampin Rifabutin 12 th CROI, abstract 657
Decrease in serum concentrations (AUC) of nonnucleoside reverse-transcriptase inhibitors by rifampin or rifabutin 100 90 80 70 60 50 40 30 20 10 0 NVP DLV EFV 0 Rifampin Rifabutin Clin Infect Dis 1999; 28: 419-30
HAART and rifampin-based TB treatment 2 NRTI/NtRTIs plus NNRTI or PI Recommended dose of ARVs with rifampin Efavirenz (preferred) 600 mg or?800 mg daily (BW > 60 kg) Nevirapine 200 mg bid with no lead in (or 300mg bid*) Saquinavir/ritonovir 400/400 mg bid or 1000/100 mg bid* Lopinavir/ritonovir 400/400 mg bid* Maraviroc 600 mg twice-daily (increased dose) Raltegravir 400 mg twice daily (no change) *use with caution CDC treatment guidelines for HIV-TB, Dec 2007
Interactions between efavirenz and rifampincontaining TB treatment Rifampin caused a decrease in: mean Cmax by 24% Cmin by 25% AUC by 22% Although minimal effective efavirenz plasma concentration that assures virological success is not currently known, it is advisable to increase dosage of efavirenz to 800 mg/day when coadministered with rifampin Lopez-Cortes LF, et al. Clin Pharmacokinet 2002;41:681-690
Plasma EFV level (mg/l) EFV level in plasma (mg/l) Distribution of plasma EFV levels between EFV 600 and 800 mg groups (42 patients each) Figure 1a Efavirenz (EFV) level in plasma Figure 1b Plasma level of efavirenz (EFV) 25.0 22.5 20.0 17.5 15.0 12.5 p = 0.632 p = ns 25 20 15 10.0 7.5 5.0 2.5 0.0 3.02 EFV 600 mg EFV 800 mg Dose per day 3.39 (median) 3.02 (0.07-12.21) 10 p = ns 5 3.39 (1.03-21.31) p = 0.303 0 EFV 600 mg EFV 800 mg dose per day Manosuthi W, et al. XV IAC 2004, Bangkook, Thailand; Manosuthi W et al. AIDS 2005;19:1481-6
Early virologic response to efavirenz-based therapy is not influenced by TB cotreatment Lartey M, et al. CID 2011;52:547-50
Genetic factors appear to be the key determinant of EFV during TB treatment EFV PK with TB therapy is influence by and host genetics. Kwara at al. JCP 2008; Paradoxical effect of TB therapy in slow metabolizers. Kwara at al. AIDS 2011;25:388
HAART and rifabutin-based TB treatment 2 NRTI/NtRTIs plus 3 rd ARV PI LPV/r, ATV/r, fapv/r, SQV/r (standard doses) Atazanavir 400 mg qd Fosamprenavir 1400 mg bid Indinavir 1000 mg tid Nelfinavir 1000 mg tid Maraviroc or raltegravir (no change) Rifabutin dose 150 mg qod or 300 mg 3X/W* 150 mg qd or 300 mg 3XW 150 mg qd or 300 mg 3XW 150 mg qd or 300 mg 3XW 150 mg qd or 300 mg 3XW No change *associated with TB treatment failure and rifamycin resistance
HAART and rifabutin-based TB treatment 2 NRTI/NtRTIs plus NNRTI NNRTI Nevirapine 200 mg bid Efavirenz 600 mg qd Rifabutin dose 300 mg qd or 300 mg 3X/week 600 mg qd or qod
Special population: Pregnant women and children Efavirenz is contraindicated during at least the first trimester of pregnancy Higher risk of hepatotoxicity in women with CD4 >250 cell/µl with nevirapine No drug-drug interaction studies in pregnant women Efavirenz should not be used in children younger than 3 years old. Limited drug-drug interactions studies in children Triple nucleoside therapy may be the only viable option in some children or pregnant where rifabutin is not available
Immune restoration inflammatory syndrome (TB-IRIS) Paradoxical worsening of TB symptoms on TB and ART or incident TB (unmasked TB) soon after starting ART in HIV-infected patients Continue concurrent therapy or continue appropriate ART and initiate TB therapy Symptomatic therapy with NSAIDs or steroids may be necessary
Summary The HIV-associated TB is associated with increased morbidity and mortality The timing of concurrent ART should be started as soon as TB therapy is tolerated Optimal ART regimen will depend on whether rifampin or rifabutin is used
Acknowledgements USAID and Higher Education for Development for grant support Associate award # AID-641-LA-11-00001 Lifespan/Tufts CFAR grant # P30AI042853 from the National Institute of Allergy And Infectious Diseases Brown/Tufts AITRP Partner institutions, staff and faculty who have supported the partnership activities Medical knowledge FIESTA 2012 Organizers! THANK YOU FOR YOUR ATTENTION!