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Session B: HIV Antiretrovirals Pre-departure Orientation 23 January 2007 Royce C. Lin, MD Assistant Clinical Professor of Medicine University of California, San Francisco Director, AIDS Consult Service Deputy Director, ASPIRE Positive Health Program. HIV/AIDS Division San Francisco General Hospital GOALS Review Kenyan ART guidelines Discuss WHO 2006 guidelines Review individual ARV agents Review principles of therapy switch Toxicity Side effects Monitoring considerations For side effects For adverse events Case Studies Available ANTIRETROVIRALS: U.S. NRTI (nucleoside analogs) Protease Inhibitor • • • • • • • • • • • • • • • • • Abacavir Didanosine Emtricitabine Lamivudine Stavudine Zidovudine Zalcitabine Tenofovir ABC DDI FTC 3TC D4T ZDV DDC TDF Amprenavir Atazanavir Fosamprenavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Darunavir NNRTI (non-nucleosides) Fusion Inhibitor • • • Integrase Inhibitors Delavirdine Efavirenz Nevirapine DLV EFV NVP • Enfuvirtide APV ATV FPV IDV LPV NFV RTV SQV TMC-114 T-20 Selecting HAART regimen: US Full access to all antiretroviral agents Which specific combo depends on Existing comorbidities, lab abnormalities Genotype (transmitted resistance) Patient preferences Once-daily dosing; pill burden considerations Wide variation in combos prescribed Benefits: tailor-fit; option to switch Selecting HAART regimen: RLS Limited access to all antiretroviral agents Generally, one-size-fits all: Cheap generics make ART ‘roll-out’ possible Algothrithmic approach enable rapid scale-up But this results in limited options, essentially…. Triomune for all, unless: Contraindication to any component Treatment of active TB Pregnancy considerations Treatment-limiting SAE/toxicity Constructing an Antiretroviral Regimen for Initial Therapy: a US-based approach Royce C. Lin, MD Assistant Clinical Professor Constructing a HIV Antiretroviral regimen Key principle: 3 active drugs 2 NRTI + NNRTI or PI “Nuc” backbone + either PI or NNRTI AKA: Two scoops rice + chicken or beef Choosing a regimen Step 1: Decide: NNRTI or PI Step 2: Pick a NRTI ”backbone” Choose components based on toxicity Take into account side effect, pill burden, patient preference, and cost Summary: DHHS Guidelines 2006 Chicken Beef Two Scoops Guidelines for the Use of Antiretrovirals in HIV-1 infected Adults and Adolescents 10 October 2006, Department of Health and Human Services, USA WHO 2006 Guidelines: Summary Table Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-limited Settings: Toward Universal Access. World Health Organisation 2006 Revision. WHO 2006 Guidelines: Summary Table Majority: D4T + 3TC + NVP in FDC Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-limited Settings: Toward Universal Access. World Health Organisation 2006 Revision. Recommended first-line regimens in TZ d4T+3TC+NVP, (All in one tablet: Fixed Dose Combination (FDC): I Triomune 40 twice daily (> 60 kg body weight). Triomune 30 twice daily (< 60 kg body weight). NB: For new patients use Nevirapine only once a day (half dose) for first 2 weeks by giving 1triomune in the evening and d4t and 3TC separate tablets in the morning II AZT+3TC+NVP Zidovudine and Lamivudine and Nevirapine, each twice daily NB: For new patients use Nevirapine only once a day (half dose) for first 2 weeks Recommended first-line regimens in TZ, continued III d4T+3TC+EFV Stavudine and Lamivudine twice daily and Efavirenz 600 mg once daily at night IV AZT+3TC+EFV Zidovudine and Lamivudine twice daily and Efavirenz once daily at night. Indications to change antiretroviral therapy within first line regime are to be determined by prescribing doctor: (see next slide) Recommended second-line regimens in Kenya ABC + ddI + LPV/r Abacavir and Lopinavir/ritonavir two times a day and Didanosine once a day on empty stomach ABC + TDF + LPV/r Learning ARVs for Kenya Goals Monitoring for SAFETY ARVs have many toxicities Toxicity depend on ARV class Some ARVs have fatal toxicities Switching therapy Some clients cannot tolerate their ART regimen Side effects Toxicity Failure Knowing how a HIV regimen is put together allows you to make intelligent and safe changes. How to learn ARVS Divide individual ARVs into 3 classes NRTI NNRTI PI Learn the “class effects” Each class of ARVs have common toxicities If you can remember which class an ARV belongs to, you can remember which toxicities to watch for Learn individual drugs Learn any other unique properties of each drug. Knowing each drug well is one of the most important parts of being a good HIV care and treatment provider! NRTI Nucleoside/tide Reverse Transcriptase Inhibitors (mimics Adenosine, Thymidine, Guanine, or Cytosine) NRTI: class effects • All may cause: – Mitochondrial toxicity – Lactic acidosis – Pancreatitis – Peripheral Neuropathy – Lipodystrophy – Hepatotoxicity NRTI tips How to recognize a NRTI 3 letters or numbers Generic name usually end in “ine” AZT, 3TC, DDI, D4T, ABC, TDF Zidovudine, lamividine, didanosine, stavudine NRTI Exceptions: abacavir, tenofovir end in “vir” but are NRTIs NNRTI Exceptions: nevirapine, delavirdine are NNRTI but end in “ine” NRTI = “Backbone” of ART Foundation of most ART combinations “Two scoops of rice” plus chicken or beef Two NRTI (rice) PLUS Chicken (NNRTI) or Beef (PI) NRTIs DISADVANTAGES ADVANTAGES Essential part of any ART combination Less drug-drug interactions Individual drugs with unique side effects/toxicities Class effect: Availability in resourcelimited settings Lactic acidosis Mitochondrial toxicity Peripheral neuropathy Lipodystrophy Hepatotoxicity 3TC (lamivudine/Epivir) • Toxicity – Few – Hepatitis B exacerbation • Side Effects – Few; class effect • Dosing – 150mg bid or – 300mg qd – Renal dosing available • Special Considerations – Hepatitis B D4T (stavudine/Zerit) • Toxicity – Lipoatrophy – Peripheral neuropathy – Pancreatitis – Lactic acidosis • Side Effects – Gen well-tolerated • Dosing – 40mg bid (if >60kg) – 30mg bid (if <60kg) Malar Wasting of Lipoatrophy AZT (zidovudine/Retrovir) • Toxicity – Anemia – Neutropenia – Thrombocytopenia – Myopathy • Side Effects – Nausea/vomiting – Headache – Dizziness • Dosing – 300mg bid DDI (didanosine/Videx) • Toxicity – Lactic acidosis – Peripheral neuropathy – Pancreatitis – Lipodystrophy • Side Effects – GI • Dosing – If EC, 400mg QD (<60kg: 250mg qd) – If reg tabs, 200mg bid (<60kg:125 bid/250qd) – Empty stomach ABC (abacavir/Ziagen) • Toxicity – FATAL hypersensitivity • Rash • Fever • GI (nausea/vomiting) • Respiratory (SOB) • Hypotension • Death on re-challenge – Class effect • Side Effects – Nausea, other GI • Dosing – 300mg bid or 600mg qd – Co-formulated with 3TC as Epzicom TDF (tenofovir/Viread) • Toxicity – Renal failure • Renal Tubular Necrosis • Hypophosphatemia – Hepatitis B exacerbation • Side Effects – Gen well-tolerated • Dosing – 300mg QD – Avoid in borderline renal dysfunction – Fanconi’s syndrome (rare) – Renal dosing necessary • Special Considerations – Hepatitis B NNRTI NON-nucleoside Reverse Transcriptase Inhibitors (blocks RT directly, NOT a nucleoside-analogue) NNRTI: class effects • All may cause: – Rash – Hepatotoxicity NNRTIs DISADVANTAGES ADVANTAGES Ease (low pill burden) Tolerability Less metabolic effects fat maldistribution, dyslipidemia Availability in resourcelimited settings Prone to resistance single mutation Cross resistance among NNRTIs Rash; hepatotoxicity Potential drug interactions (CYP450) NVP (nevirapine/Viramune) • Toxicity – Hepatotoxicity (can be fatal) • Cases of fulminant hepatitis death • Usually within 6 wks • Not in PMTCT • Increased risk in women – 12-fold risk: women, CD4>250 – 4-fold risk: men, CD4>400 – Rash (can be fatal) • • • Stevens-Johnson (erythema multiforme major) • Toxic epidermal necrolysis • Mild rash COMMON Side Effects • Well-tolerated Dosing • Lead-in dosing: 200mg daily x 2 weeks, then 200mg bd EFV (efavirenz/Sustiva) • Toxicity – Rash – Hepatitis – Teratogenic • Not for use in women of childbearing potential • Side Effects – CNS • Insomnia/Somnolence • Vivid dreams • “Spacey”, poor concentration • Gen. ↓ after 1-2 wks • Dosing – 600 mg qd PI Protease Inhibitors (binds/disables viral protease enzyme) PI: class effects • All may cause: – Hyperlipidemia – Hyperglycemia – Fat redistribution – CYP 3A4 inhibitors – multiple drug-drug interactions Protease Inhibitors ADVANTAGES High potency Longest prospective data (durability) Esp. in advanced AIDS Less susceptible to resistance from virus “Salvage” therapy when NNRTI fails DISADVANTAGES Metabolic complications fat maldistribution, dyslipidemia, insulin resistance Drug interactions (CYP3A4) High cost Limited availability Ritonavir (RIT/Norvir) • Toxicity • Hepatotoxicity • Hyperlipidemia • Hyperglycemia/ insulin resistance • Drug-drug interactions! • Potent inhibition CYP3A4 • Increases levels of other PIs • Must check interactions • Side Effects – GI • Nausea/vomiting • Diarrhea • Abdominal pain • Dosing • “boosting” 100-200mg qd KAL (lopinavir+rit/Kaletra) • Toxicity • Hyperlipidemia • Hyperglycemia/ insulin resistance • Drug-drug interactions • Side Effects – GI • Nausea/vomiting • Diarrhea • Abdominal pain • Dosing • 3 tabs bid (400/100mg) • Other • Most potent ARV • Hard to develop resistance (>5 major PI-associated mutations ↓ efficacy) Constructing a HIV Antiretroviral regimen 2 NRTI + NNRTI or PI Exception: 3 NRTI in special circumstances only Choose components based on toxicity Take into account side effect, pill burden, patient preference, and cost Always need 3 active drugs! AZT 3TC(or FTC) + D4T (or DDI) ABC NRTI Backbone TDF AVOID D4T AZT + Competitive Inhibition Levels ↓ ddI + Excessive toxicity D4T ddC Putting it all together Cases in Treatment with ART Algorithm for selecting first line treatment 1st line regimen I. d4T + 3TC + NVP Replace d4T with AZT due to: • Peripheral neuropathy and NO anaemia Replace NVP with EFV due to: • Hepatoxicity • NVP intolerance • TB patient on rifampicin II. AZT + 3TC + NVP III. d4T + 3TC + EFV Modified 1st line regimen Replace d4T with AZT due to: • Peripheral neuropathy and NO anaemia Replace NVP with EFV due to: • Hepatoxicity • NVP intolerance • TB patient IV. AZT + 3TC + EFV Case 1: Switching for complications 34 yo Kenyan woman WHO IV, CD4 45 HIV wasting, chronic diarrhea Exam: cachexia, conjunctival pallor Labs: HgB 7 WBC 1.2 (40% PMN, 59% lymph, 1% eos) Plt 140k Remaining normal OK to start Kenyan first-line therapy? What if you are in South Africa? First-line is efavirenz/3TC/AZT Case 2: Switching for Complications 45 yo man WHO III, CD4 170 Prurigo, onychomycosis, and oral hairy leukoplakia and treated thrush Pre-ART labs: all normal Started on Triomune 4-months later, hospitalized for severe abdominal pain, nausea, vomiting, dehydration, inability to tolerate oral solids/liquids Differential diagnosis? What is your work-up? Case 2 Hospital labs: Clinical course: CBC, chemistry, LFT nl Lipase 600 ART stopped Hydration, electrolyte support Discharged 3 days later When the patient returns, would you resume ART? If so, with what combination? Case 3 45 yo Ugandan woman In 2002 ago was WHO III Social: administrative assistant Weight loss (75kg 66kg) Recurrent thrush, vaginal candidiasis Zoster with post-herpetic neuralgia Limited income, can spend up to 25,000 TSH on medications Advised to purchase generic Triomune Started Triomune October 2002 4 months later, weight 66kg 70kg 8 months later, no more recurrence of thrush 1 yr later, weight 74kg 3 yrs later, weight 74 kg Complains “I am starting to like a man….I think I look strange in the face” Fat loss in thighs and face. Otherwise feels well. Case 7: Switching for complications 33 yo Tanzanian woman Spouse also HIV+ WHO Stage III, CD4 180 Sexually active, cannot afford condoms Complains of chronic cough for 2 months Exam: thrush Labs: all within normal parameters CXR: “clear” OK to start Triomune? Case 7 Started on Triomune Tolerated well, no problems 3 weeks later Differential diagnosis? Exam: Cough increased Fever Weight loss Rales in RLL and LUL CXR: R apical infiltrate and LLL diffuse opacity, hilar lymphadenopathy not seen on prior CXR Labs: WNL Course of Action? Case 7 Diagnostics Sputum for AFB Given Amoxicillin AFB smear+ What should you do now? No improvement Start anti-TB therapy? Continue Triomune? Stop Triomune? Replace Triomune? Drug interaction: Rifampin decrease NVP Use EFV+3TC+D4T Must provide birth control while on EFV Change in AUC: Interaction between RIF+ARV RIF levels ARV levels Nevirapine unchanged ↓ 58% Efavirenz unchanged ↓ 26% Ritonovir unchanged° ↓ 35% Saquinavir NR* ↓ 70%sgc 80%hgc Indinavir NR* ↓ 90% Nelfinavir NR* ↓ 82% Amprenavir NR* ↓ 81% AIDS Read 10(2):102-108, 2000. Adapted with permission from Burman WJ et al. Clin Infect Dis. 1999. Rifampicin + Efavirenz • YES. But optimal dosage unclear. • Rifampin decreases EFV 28% • Unclear if dose adjustment needed – Spanish study: ↑EFV from 600mg to 800mg overcomes PK1 – Descriptive studies supporting both 600 and 800 mg dose2,3 1. 2. 3. Lopez-Cortes L, Valderas R, Viciana P, et al. Pharmacokinetic interactions between efavirenz and rifampicin in HIV-infected patients with tuberculosis. Clinical Pharmacokinetics 2002; 41 (9):681-690. Lopez-Cortes L,et al. Efficacy, safety, and pharmaco-kinetics of efavirenz (EFV) 800 mg qd co-adminstrated with rifampin (R) in HIV-infected patients with tuberculosis, 2nd IAS Conference on HIV Pathogenesis and Treatment, Paris, France, July 1316, 2003. Vol. 8. Patel A, et al. To study the safety and antiretroviral efficacy of concomitant use of rifampicin and efavirenz in antiretroviralnaive tuberculosis co-infected HIV-1patients in India, 10th Conference on Retroviruses and Opportunistic Infections, Boston, Massachusetts, February 10-14, 2003. Rifampicin + Nevirapine • UNCLEAR. More data needed. • Rifampin decreases NVP 31% to 58% • Little clinical data – Small Spanish cohort (n=32): 74% with virologic suppression at 15 months1 • More studies needed – Esp. in resource-limited settings 1. Oliva J, Moreno S, Sanz J, et al. Co-administration of rifampin and nevirapine in HIV-infected patients with tuberculosis. Aids 2003; 17:637-8. Rifampicin + PI’s • NOT RECOMMENDED • Rifampicin decrease protease inhibitor levels 70-90% • Rifampicin induces hepatic enzyme cytochrome P450 3A4 • Results in MARKED INCREASE in metabolism of protease inhibitors • Few clinical studies on PI + rifampicin – Kaletra (lopinavir/ritonavir): variable Cmin. – Saquinavir/ritonavir tried PI’s in TB: Additive Toxicity – SQV/rit 1600/200 has been tried1 • High dose PI “boosted” with ritonavir – Ritonavir used to increase PI levels by inhibiting CYP3A4 • 3/20 with viral rebound, all with low Cmin – High hepatotoxicity with RIF + SAQ/RIT • Reported February 2005 in Dear Doctor letter • Phase I study: RIF 600mg + SAQ 1000mg + RIT 100mg • 11/28 (39.3%) developed hepatotoxicity – Transaminases up to 20x upper limit normal • Ritonavir + rifampin additive hepatotoxicity 1. Veldkamp AI, et al. Ritonavir enables combined therapy with rifampin and saquinavir. Clin Infect Dis 1999; 29:1586. Summary Points • HIV potentiates TB. TB accelerates HIV • Treating HIV-TB coinfection is complex – – – – Many clinical questions remain Rifampicin decreases levels of PI and NNRTI NRTI levels unchanged. Additive toxicity with some ARVs and TB therapy • ARV recommendation in TB therapy – EFV 600mg or 800mg is best option – NVP not well studied, levels decreased somewhat – PIs levels decreased significantly » Additive toxicity » Beware of hepatotoxicity, failure due to insufficient levels Algorithm for selecting first line treatment 1st line regimen I. d4T + 3TC + NVP Replace d4T with AZT due to: • Peripheral neuropathy and NO anaemia Replace NVP with EFV due to: • Hepatoxicity • NVP intolerance • TB patient on rifampicin II. AZT + 3TC + NVP III. d4T + 3TC + EFV Modified 1st line regimen Replace d4T with AZT due to: • Peripheral neuropathy and NO anaemia Replace NVP with EFV due to: • Hepatoxicity • NVP intolerance • TB patient IV. AZT + 3TC + EFV Summary Understand Toxicity of Individual ARV If symptoms develop, consider each individual ARV and what it can cause Also consider non-ART related causes Therapy switch For Toxicity of Complication of ART OK to switch within class • NVP EFV • D4T AZT or ABC • NVP should NOT be switched for D4T, AZT, DDI, ABC!