1. Antiretroviral Treatment in the Context of TB/HIV Co-infection Major Aspects of Background Document 2 Marco Vitoria HIV/AIDS Department WHO Geneva Feb 2005

2. ART for HIV+ with TB Possible Strategies currently recommended: –Delay ART (and treat TB with RMP based regimens) –Use any ART regimen + anti-TB regimens without RMP –Use a RMP-compatible ART regimen 2 NRTI + NNRTI (EFV or NVP) -1 st line 2 NRTI + PI/r (SQV/r or LPV/r + RTV) -2 nd line 3 NRTI ( with ABC) – Alternative 1 st line

3. Important Concepts to be consider in TB/HIV treatemnt Rifampin and CYP 450 (3A4, 2B6, 3A5) CYP and Host Genetics("Farmacogenomics") ART pK and Safety (hepatic) in patients with TB/HIV co-infection under dual treatment (ART & RMP)

4. Objectives Review of the Literature (Pub Med) Overview of concomitant use of NNRTI and PI with antituberculous drugs (emphasis in safety and efficacy of NNRTI and PI when used concomitantly with RMP) What we need to know ? List of major ongoing & planned studies on ART in TB/HIV patients What to do in the meantime?

5. Major Questions Nevirapine versus Efavirenz –Efficacy in TB/HIV Nevirapine and Rifampin –Resistance & Efficacy (pK interactions) –Toxicity Risk Efavirenz and Rifampin –Safest Dose (efficacy vs adverse effects) PI and Rifampin –Efficacy and safety (hepatic)

6. NVP vs EFV: What is the better drug in HIV Treatment ? Current WHO Guidelines NVP: 1 st line regimens in RPS, available as FDC (adherence, cost, operational aspects). Good tolerance, favourable lipid profile (reducing coronary risk). Led in dose. Hepatotoxicity and Rash. EFV: 1 st line regimen - Preferential drug in TB/HIV, contraindicated in pregnancy and psychiatric disorders. Once daily drug. CNS symptoms, hypercolesterolemia and ginecomastia.

7. NVP vs EFV: What is the better drug in HIV Treatment ? Metanalysis: Equivalent virologic suppression and short term efficacy at 24 and 48 weeks One non controlled study showed limited virologic and immunologic advantage of EFV in the first 12 months, but no relevant efficacy difference throughout 18 months comparison

8. NVP vs EFV: What is the better drug in HIV Treatment ? Pharmacokinetics: NVP and EFV partially metabolized by CYP 3A4 and CYP 2B6 and mild inducers of this enzyme system RMP pK don't change significantly. Small pK studies show large interpatient variability

9. NVP vs EFV: What is the better drug in HIV Treatment ? Different side effect profile: –Hypersensitivity syndrome & skin rash NVP (7%) versus EFV (4%) –Hepatitis NVP (2%) versus EFV (0,3%) –CNS Symptoms EFV (40-50% in the first weeks of treatment. Suicidal attempting 1-3%) Clinical Practice: Drugs are equivalent options: choice should be based on safety profile and specific contraindications

10. NVP and RMP: Concerns about Resistance, Efficacy and Toxicity Drug Interaction and NVP Resistance/Faliure: –NVP: High Therapeutic Index –Reduction of NVP serum levels (31-58%) but generally above the viral inhibitory concentration –Good immunological and virological response in small studies (non controlled) –No dose adjustment recommended by majority of experts –Large intervariability independently of RMP concomitant use (further investigation required)

11. Rifampin – NVP case serie from HIVNAT pK Lab (n=60) David Burger; 2005 BKK Symp HIV Med, data provided by Saskia Autar 85% of NVP levels in therapeutic range

12. NVP and RMP: Concerns about Resistance, Efficacy and Toxicity General NVP Toxicity Profile Concern about RMP-NVP use (lack of solid data about concomitant use) Mechanisms: Direct and immune mediated hepatic & skin involvement –Stratified & comparative risk of any hepatic reaction with NVP use in HIV+ patients (studies without TB): NVP versus other ARV (10x) NVP in with CD4 > 400/mm3 (3x) NVP in with CD4 > 250/mm3 (12x) –Presence of liver disease HBV and HCV co-infection Histological stage and fibrosis pK of NNRTI not significantly modified NVP accelerating hepatic fibrosis ? No data on additive risk of hepatotoxicity of TB drugs in HIV-HBV or HIV-HCV co- infection –Elevated plasma levels (hepatic disease or slower clearance- CYP2B6) –NVP plasma levels > 6 mg/l (92% of liver toxicity) –NVP levels > 5.3 mg/l in 1 st 90 days (2.5 x for rash) –However other studies (observational cohorts) didn't find any correlation

13. NVP and RMP: Concerns about Resistance, Efficacy and Toxicity NVP Toxicity Profile (cont'd) Increase in liver enzymes are common but generally asymptomatic and in low/moderate grade (small and non controlled studies). Analysis of Clinical Trials with NVP (17 studies) –10% of NVP treated patients with elevated ALT (> 5x), but more than 2/3 asymptomatic (almost half of symptomatic with concomitant rash). Analysis of Observational Studies: NVP use not associated with significant increase in the risk of severe clinical hepatic events when compared with other ARV drugs. Small non controlled studies shown increase in ALT and clinical hepatitis when NVP used with RMP WHO recommendation: NVP and RMP should be use with caution only no alternative available and with close monitoring

14. EFV dose in TB/HIV co-infection treated with RMP (600 versus 800 mg) Similar pK phenomena observed with NVP and RMP interaction (reduction in EFV levels:13-33%). Safety profile: –Apparently is dose related –CNS adverse effects are frequent in the beginning of treatment (50%) but transitory (5-10% after 3 months). –Neuropsychiatry symptoms after 3 months in 25% of patients. –Sleep abnormalities associated with higher plasma levels (>4 mg/l). Small non controlled studies shown effective, pharmacological, clinical, immunological and virologic response with conventional 600 mg EFV dose pK studies accordingly body weight: EFV plasma concentration patients using RMP: – Patients with less than 50-60 Kg: similar to patients without TB (600 mg is adequate) –More than 50-60 kg : need better evaluation (small study shown EFV concentrations 50% lower) Large interpatient variability in small pK studies Clearance of EFV was higher in Caucasians than in Afro-Americans and Hispanics (impact on safety profile)

15. EFV and Rifampin : TDM and Efficacy Study Plasma EFV (C12) levels of EFV 600 vs. 800 mg group Appropriate EFV level 1-4 mg/L n = 38 n = 40 3.02 3.39 EFV 600 EFV 800 8% < 1mg/L 0% < 1mg/L TDM at Week 2 after treatment Weerawat Manosuthi et al. Bangkok AIDS Conf.2004 (TDM done at HIVNAT; study Supported by HSRI, Thailand); D. Burger, 2005 BKK Symp HIV Med 92% of patients with therapeutic levels

16. Protease Inhibitors and Rifampin: Safety and Clinical Efficacy Impact of RMP on PI levels: 80-90% reduction "Pharmacoenhancement" with low dose RTV can overcome RMP induction effect of some PIs: –SQV/r (1000/100 BID, 400/400 BID, 1600/200 MID) –LPV/r + RTV (400/100 + 300 BID) Pharmacological booster increase the side effect risk and can compromise adherence - Major side effect associated with boosted PIs: Hepatotoxicity –HBV & HCV co-infection associated with higher risk of elevation of liver enzymes (higher rates of grade 3 / 4 ALT elevations) –Comparative studies: No difference in ARV discontinuation, other hepatic events or death when compared without HBV & HCV co-infection –pK of PIs can be altered by hepatic disease but no change in doses are recommended for SQV/r and LPV/RTV (limited data) –Large majority of patients treated without side effects (low dose RTV didn't affect hepatic safety profile of PI based therapy)

17. Protease Inhibitors and Rifampin: Safety and Clinical Efficacy Retrospective and comparative study in patients using RMP - 3 NRTI, 2NRTI/NNRTI and 2NRTI/SQVr: well tolerated and safe but data is limited TB/HIV using RMP and SQV/r: –SQV/r 1600/200 (SQV AUC reduced by50% but still under therapeutic concentrations and clincial efficacy mantained) – SQV/r 1000/100 in HIV+: clinical efficacy and safety, but small Phase I study in HIV negative patients shown high rate of clinical hepatitis (AE less pronounced in HIV+?) –SQV/r 400/400, and LPV/RTV 400/400 – Apparently effective and safe but even more limited data

18. Conclusion: More studies are needed… Few published data (safety profile) Limited number of patients No controlled studies Mixed and conflicting results

19. What We Need to Know? ART & RMP: Studies on safety, efficacy, pK evaluation and pharmacovigilance (better define ART strategy in TB/HIV) Review the role of Triple Nukes in TB/HIV co-infection (DART Trial) Ongoing and planned studies on ART for HIV-infected TB patients (see database)

20. What to Do in the Mean Time? Need more clear recommendations and best informed practice in ART management of TB/HIV Better inform HCW about potential risks and benefits of ART & RMP and mixed/conflicting results in scientific literature EFV - Preferential drug (no dose adjustment for patients with less 50-60 kg) PI/r & NVP in patients using RMP– Use with caution Establish the potential role of some triple nukes regimens in TB/HIV treatment