ANTIRETROVIRAL TOXICITY Strategies for prevention and treatment

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1 ANTIRETROVIRAL TOXICITY Strategies for prevention and treatment Francisco Antunes Professor da Faculdade de Medicina da Universidade de Lisboa e Director do Serviço de Doenças Infecciosas do Hospital de Santa Maria CHLN, EPE Lisboa, Portugal

2 Guidelines 2009: when to start therapy? symptomatic HIV disease ARV recommended for all patients asymptomatic HIV disease decision based on CD4 cell count CD4 count (cells/µl) ARV recommendation <350 ARV recommended >350 <500 ARV generally deferred >500 ARV generally not recommended DHSS, IAS-USA, BHIVA guidelines 2009

3 DHHS guidelines 2009 The panel recommends initiating antiretroviral therapy in treatment naïve patients with 1 of the following 3 types of regimen NNRTI + 2 NRTI PI (preferably boosted with ritonavir) + 2 NRTI INSTI + 2 NRTI

4 DHHS guidelines 2009: preferred regimens for treatment naïve patients efavirenz + tenofovir + emtricitabine (AI) ritonavir-boosted atazanavir + tenofovir + emtricitabine (AI) ritonavir-boosted darunavir + tenofovir + emtricitabine (AI) raltegravir + tenofovir + emtricitabine (AI) selection of a regimen should be individualised based on virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance testing results, and comorbid conditions based on individual patient characteristics and needs, in some instances, an alternative regimen may actually be a preferred regimen for a patient

5 Toxicity Is a Major Reason for Discontinuation of First-Line HAART ICONA Study Group Median follow-up: 45 weeks Study population: 862 ARV-naive patients 84.3% receiving unboosted PI + NRTIs Discontinuations: n = 312 (36%) Cause of discontinuation: Toxicity Nonadherence Failure Other 20% 14% 8% 58% d Arminio Monforte A, et al. AIDS. 2000;14:

6 Categorizing Antiretroviral Toxicities Immediately life threatening Potentially fatal Acute or short term Occur within first few months of beginning therapy Can affect adherence Chronic or long term Can occur at any time Anticipate in patients on long-term therapy

7 Immediately Life-Threatening Toxicities ABC hypersensitivity Pancreatitis Lactic acidosis Hepatitis Stevens-Johnson syndrome

8 Common Early Toxicities of HAART Gastrointestinal intolerance Anemia Sleep disturbances Hyperbilirubinemia

9 ZDV-Related Anemia ZDV associated with increased risk of anemia in developed world settings Retrospective analysis of 54 clinical trials: ZDV in regimen associated with a 2.27 odds ratio for developing anemia [1] GS 934: 6% of discontinuations due to anemia with ZDV/3TC + EFV vs 0% with FTC + TDF + EFV at 48 wks [2] CNA30024: 4% of discontinuations due to anemia with ZDV/3TC + EFV vs 0% with ABC + 3TC + EFV at 48 wks [3] In DART substudy, incidence of grade 4 anemia appeared higher still in resource-limited settings (6.6%) [4] Potential reasons: comorbidities, malnutrition, malaria 1. Edwards M, et al. IAS Abstract TuFo Gallant JE, et al. N Engl J Med. 2006;354: DeJesus E, et al. Clin Infect Dis. 2004;39: Ssali F, et al. CROI Abstract 24.

10 Central Nervous System Effects Clinical presentation Wide range of symptoms Time frame Headache, dizziness, vivid dreams, sleep/mood alteration (depression), psychosis (rare) Occurs early and often, subsides with continued therapy Incidence with EFV: Range: 26% to 58% 2% to 7% discontinuation rate of EFV due to CNS effects EFV neurologic symptoms typically resolve within first 4 weeks No difference in incidence of depressive episodes or long-term depression among NNRTInaive patients switching to EFV vs continued PI Occasionally associated with other ARVs (eg, ZDV insomnia)

11 Hyperbilirubinemia and PIs Gilbert syndrome caused by mutated UDPglucuronosyltransferase 1A1 gene (UGT1A1*28) Occurs in 3% to 10% of general population; associated with unconjugated hyperbilirubinemia ATV, IDV use also associated with unconjugated hyperbilirubinemia Genotyping for UGT1A1*28 can identify patients at risk for hyperbilirubinemia In Swiss Cohort study, > 50% of UGT1A1*28 homozygous patients receiving ATV or IDV had 2 episodes of hyperbilirubinemia in jaundice range Rotger M, et al. J Infect Dis. 2005;192:

12 Long-term Complications Associated With ART Peripheral nervous system Neuropathy, myopathy Metabolic Glucose disorders Insulin resistance Impaired glucose tolerance Hyperglycemia/diabetes Dyslipidemia HDL triglycerides cholesterol Cardiovascular Cardiac disease Morphologic Fat accumulation Abdominal obesity Buffalo hump Gynecomastia Fat loss

13 NRTI-Associated Distal Symmetric Polyneuropathy Associated with several NRTIs; dose related ddc > ddi > d4t > ZDV In vitro studies suggest mitochondrial toxicity as the cause Frequently misdiagnosed Higher risk with Advanced HIV or AIDS History of peripheral neuropathy Concomitant use of > 1 potentially neurotoxic drug Patients Without Peripheral Neuropathy (%) Log-rank P value <.001 AZT/3TC d4t + ddl Week Robbins GR, et al. XIV IAC, Abstract LbOr20A/B.

14 Diabetes and Insulin Resistance Type 2 diabetes secondary to insulin resistance Usually asymptomatic Prevalence Type 2 diabetes By random glucose, 1% to 2% By OGTT, 6% to 10% Impaired glucose tolerance, extra 15% to 30% HIV-associated risk factors Lipoatrophy and fat accumulation, adiponectin, liver/muscle fat, inflammatory cytokines, low testosterone, oxidant stress, HCV coinfection, PI exposure Classical risk factors Abdominal obesity, physical inactivity, age, genetic factors, dyslipidemia

15 Metabolic Effects of Non-PIs Agent Lipids Glucose NRTIs TC + TG with d4t ± ddi insulin resistance with lipoatrophy EFV TC + HDL, TG No insulin sensitivity NVP* TC + HDL, TG? no *NVP ENFhas less of an effect on No lipids than EFV. No

16 Metabolic Effects of PIs Agent Lipids Glucose RTV TC/TG insulin resistance LPV TC/TG insulin resistance IDV TC/TG insulin resistance NFV LDL/TG, HDL No insulin sensitivity APV/FPV TC/TG No insulin sensitivity TPV TC/TG? SQV No No insulin sensitivity ATV No No insulin sensitivity DRV TC, TG??

17 HAART and the Risk of Myocardial Infarction: Updated Data From D:A:D Exposure to elements of HAART NNRTI: 6.3 years (range: ) PI: 3.0 years (range: ) NNRTI: 0.9 years (range: 0-3.2) Peak RR of MI in 2001; falling since Adjustment for lipids largely explains decline in MI PI exposure associated with similar increased risk as HAART exposure NNRTI exposure not associated with increased risk of MI Adjustment for NRTI exposure did not change risk Suggests that increased risk previously reported with HAART largely driven by PIs Friis-Møller N, et al. CROI Abstract 144. RR of MI RR of MI by ART Exposure ART PI* NNRTI *Adjusted for NNRTI exposure. Adjusted for PI exposure.

18 Studies of Treatment Interventions for Dyslipidemia Intervention Switch PI to ABC or EFV or NVP [1] Switch LPV/RTV to ATV [2] Lipid-lowering therapy [3,4] Outcome Decreases in TG Increase in HDL-C Decreases in TC, non-hdl-c, TG May be less effective in HIV-positive than HIV-negative populations May be more effective than switching ARVs 1. Fisac C, et al. IAC Abstract ThPe Gatell J, et al. IAC Abstract THPE Hollowell S, et al. ICAAC Abstract H Calza L, et al. AIDS. 2005;19:

19 Lipoatrophy: Risk Factors Almost certainly interrelated Therapy Thymidine analogue exposure (d4t > ZDV) PI use Host factors Age HIV disease factors Duration of illness Severity of illness: AIDS, low CD4+ cell count

20 Treatment Interventions for Lipoatrophy Intervention d4t or ZDV switch to ABC or TDF [1-6] Switch to NRTI-sparing regimen [7] Uridine (36 g TID) [8] Pravastatin (40 mg QD) [9] Rosiglitazone (4 trials) [10-13] Outcome Small but significant increases in peripheral fat May take 5-10 years to return to normal Increase in peripheral fat Efficacy in relation to HIV disease < HAART? ~ 1 kg increase in limb fat over 12 weeks Increase in total limb fat and subcutaneous fat Limb fat remained unchanged (3 trials) or increased (1 trial) 1. Carr A, et al. JAMA. 2002;288: Martin A, et al. AIDS. 2004;18: McComsey G, et al. Clin Infect Dis. 2004;38: Moyle G, et al. CROI Abstract 44LB. 5. Milinkovic A, et al. CROI Abstract Murphy R, et al. CROI Abstract 45LB. 7. Tebas P, et al. CROI Abstract Sutinen J, et al. 7th Lipo Workshop. Abstract. 9. Mallon P, et al. AIDS. In press. 10. Sutinen J, et al. Antiviral Ther. 2003;8: Carr A, et al. Lancet. 2004;363: Hadigen C, et al. Ann Intern Med. 2004;140: Cavalcanti R, et al. CROI Abstract 854.

21 Summary Antiretroviral therapy is lifelong treatment Should aim to select regimens with Good tolerability from the start to ensure adherence Adequate long-term safety profiles to preserve patients quality of life ARVs vary in type and degree of toxicities We still need to be alert for appearance or progression of long-term toxicities New ARVs have helped minimize the trade-off between efficacy and toxicity