When to start, when to switch ART and monitoring of ARV side effects

Transcription

1 When to start, when to switch ART and monitoring of ARV side effects Thanomsak Anekthananon, MD Faculty of Medicine Siriraj Hospital September 4, 2009

2 Recommended Websites Free e-book: HIV Medicine 2007 hivmedicine.com Free e-book: Guidelines: Best links: Resistance Websites

3 Baseline evaluation and Laboratory Body weight, BP CBC, CD4, SGOT, SGPT, Chol, TG, HDL, LDL, Cr Urine examination VDRL, HBsAg, (Anti-HCV for IVDU, elevated transaminases) Chest x-ray

4 CD4+ cell count Most recent CD4 cell count is strongest predictor of disease progression and survival Significant change defined as ~30% change of absolute count and 3 % change in CD4%. HIV RNA load Surrogate marker for treatment response may be useful in predicting clinical progression. DHHS Guidelines Oct 10, 2006

5 Goals of Therapy Maximal and durable suppression of viral load. Restoration or preservation of immunologic function. Improvement in quality of life. Reduction of HIV-related morbidity and mortality.

6 Major Targets of Antiretroviral Agents RT Inhibitors NRTI: AZT, ddi, d4t, 3TC, ABC, FTC NNRTI: NVP, DLV, EFV, ETV NTRTI: TDF Protease Inhibitors SQV,RTV, IDV, NFV, ATV, APV, fapv, LPV/rtv, TPV, DRV ds DNA Integrase inhibitor RAL HIV DNA RT vpr Integrase Proviral DNA Genomic RNA Protease RNA Transcription mrna Entry Inhibitors CXCR4 CCR5: MVC Fusion gp41: T-20 Spliced mrna Polyprotein Protein

7 Timeline of ARV Development DLV ZDV ddi ddc d4t NVP 3TC ABC EFV TDF FTC ETV NRTI NNRTI PI SQV RTV NFV APV LPV/r ATV FPV TPV DRV Entry inhibitor IDV T-20 MVC Integrase inhibitor RAL

8 Current Antiretroviral Medications NRTI Abacavir ABC Didanosine DDI Emtricitabine FTC Lamivudine 3TC Stavudine D4T Zidovudine AZT Tenofovir TDF NNRTI Efavirenz EFV Nevirapine NVP Etravirine ETV Integrase inhibitor Raltegravir RAL PI Atazanavir ATV Darunavir DRV Fosamprenavir FPV Indinavir IDV Lopinavir/rtv LPV/rtv Nelfinavir NFV Ritonavir RTV Saquinavir SQV Tipranavir TPV Fusion Inhibitor Enfuvirtide T-20 CCR 5 antagonist Maraviroc

9 DHHS Guidelines: Indications for initiating ART Clinical condition and/or CD4 History of AIDS-defining illness CD4 count <200 cells/mm 3 Recommendations ART should be initiated. CD4 count cells/mm 3 Pregnant women* HIV-associated nephropathy coinfected with HBV, when HBV treatment is indicated Patients with CD4 >350 cells/mm 3 who do not meet any of the specific conditions listed above Optimal time to initiate therapy in asymptomatic patients with CD4 >350 cells/mm 3 is not well defined. Patient scenarios and comorbidities should be taken into consideration. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Nov 3,

10 When to treat WHO Guidelines Anteretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach 2006 Revision.

11 SMART: Subgroup Analysis in Patients Not Receiving ART at Study Entry HIV-infected patients with CD4+ cell count > 350 cells/mm 3 (N = 5472) Deferred Arm Intermittent ART (n = 2720; 228 not receiving ART at trial start) Immediate Arm Continuous ART (n = 2752; 249 not receiving ART at trial start) Study halted prematurely; mean follow-up: 18 mos Treatment definitions for subanalysis Deferred: ART initiated when CD4+ cell count < 250 cells/mm 3, CD4+ cell percentage < 15%, or HIV symptoms Immediate: ART initiated immediately after randomization Primary endpoints OD or death from any cause Fatal or nonfatal OD Serious non-aids events Fatal and nonfatal OD plus serious non-aids events Emery S, et al. J Infect Dis. 2008;197:

12 SMART: Immediate Therapy Reduces Risk of OD, Serious Non-AIDS Events Immediate group experienced substantially fewer events compared with deferred group Excess risk associated with deferring therapy: 5.4 events/100 person-yrs Event, n Deferred Immediat HR (Rate per 100 Arm e Arm (DC/VS Person-Yrs) (n = 228) (n = 249) ) 95% CI P Value OD/death 15 (4.8) 5 (1.3) OD only 11 (3.5) 4 (1.1) Serious non- AIDS events 12 (3.9) 2 (0.5) Composite 21 (7.0) 6 (1.6) Emery S, et al. J Infect Dis. 2008;197:

13 Incidence of Multiple Comorbidities Increases With Age in HIV-Infected Pts Cohort of HIV-infected patients attending a metabolic clinic; 30 years (n = 38), years (n = 551), years (n = 1216), years (n = 253), and > 60 years (n = 69) Comorbid conditions: diabetes, obesity, cardiovascular disease, hypertension, hepatic disease, kidney disease, osteoporosis, and hypothyroidism Patients (%) No comorbidity 1 comorbidity 2 comorbidities 3 comorbidities 4 comorbidities 5 comorbidities > 60 Age (Years) Guaraldi G, et al. Glasgow Abstract P300. Reproduced with permission.

14 Thai AIDS Society (TAS) Guidelines for ART 2008 J Med Assoc Thai 2008;91:

15 What to Start: Initial Combination Regimens for ARV-Naïve Patient?

16 DHHS recommended regimens for treatment-naïve patients Recommendation NNRTI PI NRTI Preferred EFV* ATV/rtv OD TDF/FTC DRV/rtv OD FVP/rtv bid LPV/rtv OD or bid Alternative NVP ATV # OD ABC ξ /3TC FPV/rtv OD FPV bid SQV/rtv bid ddi+3tc AZT/3TC *Except during first trimester of pregnancy or in women with high pregnancy potential. or lamivudine. Only in women with CD4<250 or in men with CD4 <400. ξ Use only if HLA-B*5701 negative. Use with caution in patients with cardiovascular risk or HIV RNA >100,000 copies/ml. # RTV 100 mg /d must be given when TDF or EFV is used with ATV Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. November 3, 2008; Available at

17 Antiretroviral Medications: Should not be offered at any time Antiretroviral components not recommended: ddi+d4t d4t+azt FTC+3TC Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. January 29,

18 First-line ARV drugs for adults and adolescents (WHO) WHO Antiretroviral therapy for HIV infection in adults and adolescents in resource-limited settings: Towards universal access.

19 Thai AIDS Society (TAS) Guidelines for ART 2008 J Med Assoc Thai 2008;91:

20 Recommended Doses (1) Antiretroviral Form Dose recommended AZT (Azidothymidine) 100, 250, 300 mg capsule mg q 12 h ddi (didanosine) - Chewable buffered tablet (125, 200 mg) - Enteric coated (EC) capsule (250, 400 mg) <60 kg: 250 mg OD ac >60 kg: 400 mg ODac d4t (Stavudine) Capsule:15, 20, 30 mg 30 mg q 12 h 3TC (Lamivudine) 150, 300 mg tablet 150 mg q 12 h or 300 mg q 24 h ABC* (Abacavir) 300 mg tablet 300 mg q 12 h or 600 mg q 24 h TDF (Tenofovir) 300 mg tablet 300 mg OD *No need for dosage adjustment for renal insufficiency

21 Recommended Doses (2) Antiretroviral Form Recommended Nevirapine (NVP) 200 mg tablet 200 mg OD x 14 days then 200 mg q 12 h Efavirenz (EFV) 600 mg tablet 600 mg hs

22 Recommended Doses (3) Antiretroviral Form Dose recommended GPO VIR TM (d4t/3tc/nvp) GPOVIR (S30): d4t 30mg + 3TC 150 mg + NVP 200 mg GPOVIR (S30) 1 tab q 12 h* AZT/3TC combination GPO VIR Z-250 (AZT/3TC/NVP) AZT 300 mg/3tc 150 mg tablets AZT 250 mg/3tc 150 mg/ NVP 200 mg 1 tab q 12 h 1 tab q 12 h* * NVP 200 mg OD for the first 14 days

23 Lower-than-therapeutic doses of RTV is used as a pharmacokinetic enhancer to increase trough concentration (C min ) and prolong t 1/2 of active PIs The higher C min, the greater Cmin:IC 50 ratio, reducing chance of drug resistance Longer t 1/2 allows for less frequent dosing. DHHS Guidelines 23 Mar 2004

24 Single Dose Pharmacokinetics of Kaletra in Humans 10 LPV in Kaletra LPV alone Drug concentration (µg/ml) Hours Hsu A et al. 9th CROI, 2002

25 Steady-state Pharmacokinetics of IDV and LPV/r in HIV-infected Patients LPV/r 400/100 mg BID IDV 800 mg TID, fasting Drug plasma concentration (µg/ml) Time (h)

26 Steady-state Pharmacokinetics of IDV/RTV and LPV/r in HIV-infected Patients LPV/r 400/100 mg BID IDV 400 mg + RTV 400 mg BID with food Drug plasma concentration (µg/ml) Time (h)

27 PI Boosting: Consider Efficacy and Toxicity PI toxicity threshold Drug concentration Boosted PI PI level required to overcome resistant virus PI PI level required to overcome wild-type virus Time

28 Recommended Doses (4) Antiretroviral Form Dose recommended Indinavir (IDV) 200, 400 mg capsules IDV/rtv mg mg bid Nelfinavir (NFV) 250 mg tablet 1250 mg bid Atazanavir (ATV) 300 mg capsule ATV/rtv 300 mg mg OD Saquinavir (SQV) 500 mg tablet SQV/rtv 1000 mg mg bid Lopinavir + rtv (LPV/rtv) mg LPV mg rtv cap or 200 mg LPV + 50 mg rtv tab 3 cap (400/100 mg) bid 4 cap (533/ mg) bid when combined with EFV or NVP Treatment-naive patients 2 tab (400/100 mg) bid irrespective of coadministration with EFV or NVP Treatment-experienced pts 3 tab (600/150 mg) bid when combined with EFV or NVP

29 Monitoring Antiretroviral Therapy Clinical monitoring - effectiveness - toxicity - adherence Adherence assurance/counseling Immunological monitoring: CD4 q 6 months Virological monitoring: VL q 6-12 months Drug resistance testing Therapeutic drug monitoring

30 Correlation Between Nonadherence and Virologic Failure 100 Proportion with virologic failure (%) p= , r= > <70 Adherence (%) Paterson DL et al. Ann Intern Med 2000

31 Adherence Convenience of regimen Fit with daily activities Fewer doses Lower number of pills No food restrictions No significant drug interactions Pts belief in efficacy of regimen No difference between twice daily and once daily regimen

32 Adverse Drug Reactions

33 Adverse Events Associated With Antiretroviral Therapies Serious or Potentially Life- Threatening Events Hepatic events Lactic acidosis Hepatic steatosis Pancreatitis Stevens-Johnson syndrome/toxic epidermal necrosis Hypersensitivity reaction Bleeding episodes Bone marrow suppression Nephrolithiasis Nephrotoxicity Skin rash Events With Potential Long-term Complications Cardiovascular events Hyperlipidemia Insulin resistance/diabetes mellitus Osteonecrosis Events That May Compromise Quality of Life Central nervous system events Fat maldistribution Gastrointestinal intolerance Peripheral neuropathy

34 NRTI Class Adverse Effects

35 AZT: anemia, leucopenia, headache, nausea, vomiting, myopathy d4t: peripheral neuropathy, pancreatitis, dyslipidemia, rapidly progressive ascending neuromuscular weakness (rare) ddi: peripheral neuropathy, diarrhea, pancreatitis 3TC: minimal toxicity ABC: hypersensitivity reaction ddc: peripheral neuropathy, stomatitis TDF: renal toxicity, Fanconi s syndrome

36 NRTI class adverse effects Mitochondrial toxicity NRTIs inhibit gamma DNA polymerase, the enzyme responsible for copying mitochondrial DNA. lactic acidosis/hepatic steatosis esp. d4t lipoatrophy

37 ART and Lipoatrophy

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40 NRTI Choice: The Major Factor Driving Lipoatrophy Risk Highest Risk Intermediate Risk Lowest Risk Unknown d4t ZDV 3TC ddi + 3TC d4t + ddi ABC FTC TDF

41 Lactic Acidosis/Acidemia

42 Lactic acidosis and hyperlactataemia Definitions : - Hyperlactataemia: venous lactate > mmol/l - Lactic acidosis: arterial ph <7.35, venous lactate >5 mmol/l. BHIVA Guidelines Jul 2003

43 Severe lactic acidemia: fatigue, weight loss, nausea, vomiting, abdominal pain, dyspnea, and cardiac dysrhythmias Onset: acute or subacute (median of 4 months in 1 series). Common: tender hepatomegaly, peripheral edema, ascites, and encephalopathy. Jaundice is rare. Mildly AST/ALT common. BHIVA Guidelines Jul 2003

44 Diagnosis of nrti-associated lactic acidemia Lactate > 5 mmol/l + related new symptoms and signs, or > 10 mmol/l regardless of clinical presentation. Routine monitoring in absence of signs or symptoms not recommended. Schambelan M et al. JAIDS 2002

45 Treatment of lactic acidemia Stop ARV for patients with lactate >10 mmol/l or symptomatic with lactate >5 mmol/l Restart NNRTI and PI after lactate return to normal and symptoms resolve. If alternative nrtis are resumed, lactate levels should be monitored q 4 wks for at least 3 months. Schambelan M et al. JAIDS 2002

46 NNRTI Class Adverse Effects

47 NNRTI class adverse effects Rash Hepatotoxicity CNS side effects (EFV)

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57 Nevirapine Hepatotoxicity (8-18%); fulminant /cholestatic hepatitis/ hepatic failure may occur. Rash, SJS (0.3%), TEN, and hypersensitivity reactions. Increase risk in female; corticosteroid or antihistamine to prevent development of rash has not proven effective. monitored intensively during first wks of NVP therapy 14-day lead-in period with NVP 200 mg daily

58 Incidence of cross-hypersensitivity reactions between NNRTIs is unknown. Substitution of EFV for NVP appears safe NVP is not approved for post-exposure prophylaxis DHHS Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents Mar 23, 2004.

59 Efavirenz Major side effect is self-limited dysphoria. Incidence of SJS 0.1% hypercholesterolemia may be teratogenic BHIVA Guidelines Jul 2003

60 PI Class Adverse Effects

61 PI class adverse effects Hyperglycemia, insulin resistance Dyslipidemia Fat redistribution increase abdominal fat dorsocervical hump Increase bleeding episode in hemophilia GI intolerance (esp. RTV) Hepatitis Nephrolithiasis, hemolytic anemia (IDV) Indirect hyperbilirubinemia (IDV, ATV) Diarrhea (NFV) Osteonecrosis, Osteopenia, and Osteoporosis?

62 Hepatotoxicity can occur any time during treatment course more often with RTV- or RTV/SQV-containing regimens Potential risk factors: HCV/HBV co-infection, alcohol, baseline elevated liver enzymes, d4t use, and concomitant use of hepatotoxic agents. DHHS Guidelines 23 Mar 2004

63 Fat Maldistribution (Lipodystrophy) Fat wasting (lipoatrophy) Fat accumulation (hyperadiposity) Lipodystrophy syndrome = fat wasting and/or fat accumulation + metabolic abnormalities (e.g., insulin resistance, hyperlipidemia Lipodystrophy might be associated with lactic acidosis

64 Lipodystrophy: Definitions At least one of the following : Sunken cheeks in the face Prominent veins in the legs (not associated with heavy exercise) Loss of fat in the legs and arms Loss of shape in the buttocks Increase of fat around the gut (truncal obesity) Breast enlargement Fat pad on back of neck (buffalo hump) Lipoma

65 Treatment Failure

66 Why Does Treatment Fail? Baseline resistance or cross-resistance Use of less potent antiretroviral regimens Prior antiretroviral therapy Sequential monotherapy Adherence, side effects, toxicity Drug levels and drug interactions Tissue reservoir penetration Provider experience Other, unknown reasons

67 When to change therapy? Virologic failure incomplete virologic response (VL >400 c./ml by 24 wks or >50 c./ml by 48 weeks) virologic rebound (after suppression, recurrent viremia) Immunologic failure failure to increase CD4 cell count by over 1st year decrease to below baseline Clinical failure Occurrence/recurrence of HIV-related events (excluding immune reconstitution syndromes) DHHS Guidelines, May 2006