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The ART of Treating TB and HIV Co-Infection

The ART of Treating TB and HIV Co-Infection. Kelly Dooley, MD, PhD. Drug-Drug Interaction Satellite Workshop XIX International AIDS Conference Sunday 22 nd July 2012. Presented by: Kelly Dooley MD, PhD Johns Hopkins University School of Medicine. HIV and Tuberculosis Epidemiology.

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The ART of Treating TB and HIV Co-Infection

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  1. The ART of TreatingTB and HIV Co-Infection Kelly Dooley, MD, PhD Drug-Drug Interaction Satellite WorkshopXIX International AIDS ConferenceSunday 22nd July 2012 Presented by: Kelly Dooley MD, PhD Johns Hopkins University School of Medicine

  2. HIV and TuberculosisEpidemiology Global Burden of Tuberculosis, 2010 WHO Report 2011 Global Tuberculosis Control

  3. TB Incidence in Africa, 1990 and 2005 Chaisson and Martinson, N Engl J Med 2008;358:1089

  4. Objectives • Describe the epidemiology of TB/HIV co-infection • Discuss optimal timing of initiation of ART among patients with TB • Learn about therapeutic options for co-treatment of HIV and TB

  5. At what point after HIV seroconversion does a patient’s risk for TB increase compared with the general population? • Within the first year • After the CD4 decreases below 500 cells/mm3 • After the CD4 count decreases below 350 cells/mm3 • After the CD4 count decreases below 200 cells/mm3 • What, TB hasn’t been eradicated?

  6. At what point after HIV seroconversion does a patient’s risk for TB increase compared with the general population? • Within the first year • After the CD4 decreases below 500 cells/mm3 • After the CD4 count decreases below 350 cells/mm3 • After the CD4 count decreases below 200 cells/mm3 • What, TB hasn’t been eradicated?

  7. TB susceptibility among HIV-seropositive persons Study in 24,000 South African gold miners shows risk TB doubles in first year of HIV infection Sonnenberget al. (2005) JID 191: 150.

  8. What is the most effective strategy for prevention of TB disease among patients with HIV? • 6-9 months of isoniazid preventive therapy • Isoniazid preventive therapy, indefinitely • Combination ART • INH plus ART • Bed nets

  9. What is the most effective strategy for prevention of TB disease among patients with HIV? • 6-9 months of isoniazid preventive therapy • Isoniazid preventive therapy, indefinitely • Combination ART • INH plus ART • Bed nets

  10. TB Rates by ARV and INH Treatment Status in South African Adults with HIV * Adjusted for age, sex, CD4, prior history of TB, urban/rural Golub et al, AIDS 2009;23:631-6

  11. Now, to our case • LS is a 52 year old man from West Africa, living in the U.S. for 12 years • Diagnosed 1 year ago with HIV in setting of PCP pneumonia • Reports to clinic with 6 month history of weight loss, 1 month history of productive cough, fevers • CD4 count of 5 cells/mm3,sputum smear AFB+

  12. Chest radiograph

  13. What should be our overall plan for LS? • Start TB treatment, initiate ART after his 6-month TB treatment course is complete • Start TB treatment, initiate ART at the end of the intensive phase (after 2 months) • Start TB treatment, initiate ART 2-4 weeks later • Start TB and HIV treatment concurrently • Fluoroquinolone for community-acquired pneumonia

  14. What should be our overall plan for LS? • Start TB treatment, initiate ART after his 6-month TB treatment course is complete • Start TB treatment, initiate ART at the end of the intensive phase (after 2 months) • Start TB treatment, initiate ART 2-4 weeks later • Start TB and HIV treatment concurrently • Fluoroquinolone for community-acquired pneumonia

  15. Timing of Initiation of ART for Patients with TB and HIV SAPIT trial • Concurrent TB and HIV treatment reduces mortality • Improved survival in patients with high or low CD4 counts CAMELIA, STRIDE, and SAPIT trials • Starting ART within 2 weeks of TB treatment may reduce risk of mortality or AIDS-defining illnesses • Benefit seen among those with CD4<50 cells/mm3 AbdoolKarim S et al. (2010) NEJM 362: 697; NEJM (2011) 365 – Blanc et al., Havlir et al., AbdoolKarimet al.

  16. Effects of timing of ART on mortality, by baseline CD4 cell count: SAPIT trial 21/137 22/281 6/86 2/186 AbdoolKarimS et al. (2010) NEJM 362: 697.

  17. Effects of ART timing on outcomes in CAMELIA and patients with CD4 < 50 in STRIDE and SAPIT trials 42% ↓ p=0.02 68% ↓ p=0.06 34% ↓ p=0.004 AbdoolKarim S et al. (2010) NEJM 362: 697; NEJM (2011) 365 – Blanc et al., Havlir et al., AbdoolKarimet al.

  18. How hard can it be?

  19. TB Treatment: Rifampin-- we love it, we hate it • Standard TB treatment: • Intensive phase: • isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) x 2 months • Continuation phase: • isoniazid and rifampin x 4 months

  20. RIF RIF RXR RXR PXR PXR RIFAMPIN: A promiscuous inducer of metabolizing enzymes Cytoplasm Phase II enzyme regulatory genes PGP regulatory gene CYP3A4 proximal promoter CYP 3A4 XRE MDR1 protein regulatory gene DNA mRNA Nucleus Dooley et al. (2008) JID 198: 948.

  21. How will you treat this patient?

  22. Co-treatment options

  23. “If Sustiva is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of Sustiva to 800 mg once daily is recommended.” Food and Drug Administration - January 6, 2012

  24. What is the right dose of EFV for people >50 kg taking RIF? Mean log EFV with RIF Mean log EFV alone Proportion with VL>400 copies similar in patients with and without TB Boulle et al. (2008) JAMA 300: 530 It may depend on your EFV CYP2B6 metabolizer genotype Ngaimisiet al. (2011) CPT 90: 406 See MOAB0301 and MOAB0302

  25. Nevirapine with RIF: skip the lead-in phase or avoid it altogether? TB+HIV HIV only ART-naïve patients – EFV vs. NVP (with lead-in): More virologic failure among those randomized to NVP Swaminathan et al. (2011) CID 53: 716 Patients already on NVP (200 BID): Similar proportion of patients with detectable VL comparing those with and without TB Boulleet al. (2008) JAMA 300: 530

  26. Raltegravir with rifampin: clinical significance of lower trough with BID dosing? Virologic suppression with RAL 800 QD vs. 400 mg BID (HIV patients without TB) With once-daily dosing, trough matters among patients with high viral loads Eron et al. (2010) Lancet ID 11: 907. 53% reduction in RAL trough with rifampin Wenninget al. (2009) AAC 53: 2852. See REFLATE trial: THLBB

  27. Boosted PIs with rifampin: balancing efficacy and toxicity • Boosted PI concentrations diminished >90% when given with rifampin • In healthy volunteers, increasing dose of PI results in high rates of hepatotoxicity • Strategies in patients with HIV/TB (LPV/r): • Double dose (adults): Gradual increase to double dose • Super-boosting (children): mg to mg parity of ritonavir and lopinavir Acosta 2007, Burger 2006, LaPorte 2004, Schmitt 2009, Haas 2009, Nijland 2008, L’homme 2009, Decloedt 2011, Reitz 2010, Ren 2008, Elsherbiny 2010, Frohoff 2011

  28. Rifabutin + Boosted PIs • Bidirectional drug interactions • RBT is metabolized by cytochrome P450 (CYP) 3A4, so you have to decrease the dose when you give it with CYP3A4 inhibitors, like ritonavir, to avoid toxicities • Expensive, not widely available, no pediatric formulation • Efficacy data is scanty • Clinical trials comparing RBT to RIF were largely conducted among patients not taking ARVs • Coordination of TB/HIV care is absolutely essential to ensure appropriate RBT dosing and prevent TB treatment failure HKCS/BMRC 1992; Gonzalez-Montaner 1994; McGregor 1996; Rowinska-Zakrzowska 1992; Schwander 1995

  29. What is the right dose of rifabutin to give to patients taking PI-based ART? Naiker et al., CROI 2011, abstract 650.

  30. Clinical course • You start your patient on TB treatment with HRZE • You decide you are going to change his rifampin to rifabutin and give him boosted darunavir plus TDF/FTC • Until the laboratory calls you…..

  31. Your patient has MAI, not TB! He is already taking a boosted protease inhibitor plus 2 NRTI. Now what do you do? • Treat MAI with clarithromycin, ethambutol, and rifabutin • Treat MAI with azithromycin, ethambutol, and rifabutin • Treat MAI with moxifloxacin, ethambutol, and rifabutin • Treat MAI with clarithromycin and ethambutol • Don’t treat it – it’s probably a contaminant

  32. Your patient has MAI, not TB! He is already taking a boosted protease inhibitor plus 2 NRTI. Now what do you do? • Treat MAI with clarithromycin, ethambutol, and rifabutin • Treat MAI with azithromycin, ethambutol, and rifabutin • Treat MAI with moxifloxacin, ethambutol, and rifabutin • Treat MAI with clarithromycin and ethambutol • Don’t treat it – it’s probably a contaminant

  33. Caution with clarithromycin • Metabolized by 3A4 • Inhibitor of 3A4 • Can cause QT prolongation with boosted PIs (risk for sudden death) • Concentrations can be reduced by NNRTI (and it can increase NNRTI concentrations and associated side effects) • If a macrolide is required for a patient taking ART for HIV, use azithromycin if it is available….

  34. Available guidance (2012 update coming soon….) http://www.cdc.gov/tb/publications/guidelines/TB_HIV_Drugs/PDF/tbhiv.pdf

  35. Recommendations

  36. Other alternatives

  37. Summary: the ART of treating patients with HIV and TB • Treating HIV and TB concurrently is life-saving, so drug interactions must be managed • Many knowledge gaps in dosing and expected frequency and severity of toxicities in patients • Much research in this arena, so new options are likely to be available soon

  38. Thank you for the opportunity to discuss this topic with you today.

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