Hypersensitivity to Abacavir

1. Hypersensitivity to Abacavir Holly Batterman, M.D. Senior Regional Medical Scientist N. California and Pacific Northwest

2. Characteristics of Idiosyncratic Drug Reactions Relatively infrequent or rare Usually 1 in 10,000 Not predicted by pre-clinical or phase I studies Relatively dose-independent Mechanism unknown

3. Possible Mechanisms of Drug Hypersensitivity Syndrome

4. Hapten Hypothesis Most drugs not chemically or immune reactive Drug is metabolized to a reactive intermediate Reactive intermediate covalently binds to proteins Metabolite-protein adduct activates immune cells Immune system activation leads to cytokine release and development of symptoms

6. Hypothesis for Drug Hypersensitivity Syndrome 

7. Description of Hypersensitivity Reactions to Abacavir Multiple organ systems involved Four most common symptoms: Fever, rash, GI, malaise/fatigue Less common symptoms: Edema, musculoskeletal, respiratory, mucous membrane, headache, paresthesia Resolves upon stopping ABC Reappears on rechallenge (DO NOT)

8. Time to Onset of ABC Hypersensitivity Reaction (n = 636)

9. Signs and Symptoms of Abacavir Hypersensitivity Reaction Reported With a Frequency of ?10% (n=636)

10. Combinations of Symptoms Reported with ABC Hypersensitivity (n=1306)

11. Comparison of Clinical Presentation of Selected Signs and Symptoms Initially and on Rechallenge (n=112) Symptom Initial Rechallenge Fever 58% 71% Rash 51% 64% GI 42% 45% Lethargy/malaise 31% 45% Respiratory 16% 21% Headache 9% 10% Hypotension 5% 24% Abnormal renal function 5% 12% Tachycardia 1% 11%

12. Respiratory Symptoms May be part of the initial presentation in conjunction with other symptoms 18% of reported hypersensitivity reactions had 1 or more respiratory symptoms No single respiratory symptom was reported in >6% of cases Most common: tachypnea, cough, pharyngitis Rarely reported: wheezing (small airway symptoms) Respiratory Symptoms Associated With ABC HSR Respiratory Group % of All Reactions Tachypnea 5.5 Cough 4.9 Pharyngitis 4.1 Parenchyma 2.7 Other 2.6 Para-nasal sinus 2.4 Respiratory distress 1.5 Large airway 0.9 Pleural space 0.6 Small airway 0.5 Respiratory Symptoms Associated With ABC HSR Respiratory Group % of All Reactions Tachypnea 5.5 Cough 4.9 Pharyngitis 4.1 Parenchyma 2.7 Other 2.6 Para-nasal sinus 2.4 Respiratory distress 1.5 Large airway 0.9 Pleural space 0.6 Small airway 0.5

13. Rash is More Distinct for What it is Not Not often the first symptom Not always present Not reason patient seeks medical attention Not always noticed by the patient Not often severe

14. Laboratory Abnormalities Observed During ABC Hypersensitivity Reaction Hematological: decreased total lymphocyte count Hepatic: elevation of AST, ALT Renal: increase serum creatinine Muscle: elevation creatine phosphokinase Laboratory values return to baseline values after discontinuation of ABC

15. Risk Factor Analysis for Hypersensitivity Reactions to Abacavir Introduction A Cutrell, M Edwards, H Steel, B Spreen, W Powell, S McGuirk, S Hetherington 1st IAS 2001 Buenos Aires, Argentina Poster 527

16. Objective Explore potential factors that may identify patients in different risk categories for hypersensitivity reactions to abacavir

17. Methods for Meta-Analysis 5,332 subjects from 25 protocols 5,135 without hypersensitivity 197 (3.7%) with hypersensitivity Cases identified by individual review except Expanded Access Program

18. Percentage of Patients Experiencing Hypersensitivity by Protocol

19. Statistical Models Model 1 All patients Clinical data only Model 2 Excluded Expanded Access patients Clinical and laboratory data Baseline laboratory data included Stepwise selection procedure

20. Results from Multivariable Model 1: Laboratory Parameters Excluded Step Predictor Odds 95% CI % Ratio 1 ART-experienced 0.58 (0.44, 0.78) 3.0% at ABC start 2 Of African descent 0.59 (0.38, 0.91) 2.5%

21. Results from Multivariate Model 2:Laboratory Parameters Included No laboratory parameters were identified as statistically significant in this model

22. Concurrent NNRTI Use Univariate analysis 873 nevirapine users: rate = 3% 669 efavirenz users: rate = 2% Multivariate model Apparent association with NNRTI use in Model 2 driven by a single study (CNA2007) No evidence of effect

23. Conclusions Incidence of hypersensitivity reactions to ABC in this risk factor analysis was 3.7% Only characteristics significantly associated with the probability of a hypersensitivity reaction were: Previous ART treatment (lower risk) African descent (lower risk) Concurrent use of NNRTIs did not consistently affect the frequency of hypersensitivity reactions

24. Making a Diagnosis Hypersensitivity to ABC is a clinical diagnosis Do not rely on laboratory tests Timing How soon after starting ABC did symptoms begin? Do symptoms appear or increase with each dose? Is there a succession of symptoms? Multi-system illness Single organ system manifestation is not sufficient to make the diagnosis

25. Making a Diagnosis Diagnosis of a hypersensitivity reaction should be based on the demonstration of a clinically compatible syndrome and should not be discounted by the possibility of an alternative diagnosis, such as: Gastroenteritis Acute onset respiratory diseases Reactions to other medications, even when demonstrated by rechallenge Communication with patient is key

27. Management of the Acute Reaction Discontinue ABC Patient should return unused medication Assess the severity: vital signs Supportive therapy as indicated Hospitalization may be appropriate in some cases IV fluids, support with pressor agents for hypotension Role of steroids or antihistamines not known

28. Ongoing Initiatives Continue to educate health care providers and patients Continue to promote careful monitoring of patients who receive ABC-containing therapy Continued vigilance with new ABC-containing products Continued research into mechanisms, including clinical, immunological, metabolic, and genetic factors

29. Backup Slides

30. Abacavir (ABC) Combined with 3TC and ZDV is Highly Effective and Durable Through 48 Weeks in HIV-1 Infected, Antiretroviral Therapy-Naïve Subjects (CNA3003) -pivotal trial for ABC approval -pivotal trial for ABC approval

31. Most Common Adverse Events with ABC/3TC/ZDV Most Common AEs 0-16 & 16-48 weeks - This slide compares the original triple therapy ITT group before & after 16 weeks -Note that the number of events considered G3/4 were small - The decreased number of events reported after 16 weeks could reflect that pts are acclimating to the regimen; Most Common AEs 0-16 & 16-48 weeks - This slide compares the original triple therapy ITT group before & after 16 weeks -Note that the number of events considered G3/4 were small - The decreased number of events reported after 16 weeks could reflect that pts are acclimating to the regimen;

32. Selected Clinical Adverse Events for COM and TZV in Therapy-Naïve Adults Over 16 Weeks

33. Interruptions in Abacavir Dosing Are Not Associated With Increased Risk of Hypersensitivity in the HEART Study  (NZT4006)

34. Background Therapy with abacavir is associated with hypersensitivity reaction in 3-5% of patients Hypersensitivity reactions occur rapidly and with greater severity in patients that are rechallenged with ABC after having an initial reaction Concern has been raised regarding association of hypersensitivity with interruptions of therapy, particularly in patients with less than optimal adherence

35. Objectives Evaluate the frequency and duration of therapy interruptions in 24-week study of COM and ABC Evaluate relationship between interruptions in therapy and incidence of hypersensitivity NZT4006 study was a randomized, open-label trial of COM/ABC in under-represented populations. The study compared patients that received routine counseling with those that received routine counseling with four modules of and educational course. Results of the trial and the adherence data from the study were presented in Durban at the International AIDS meeting. Data for this presentation was derived from an examination of the MEMS trackcap data from the study.NZT4006 study was a randomized, open-label trial of COM/ABC in under-represented populations. The study compared patients that received routine counseling with those that received routine counseling with four modules of and educational course. Results of the trial and the adherence data from the study were presented in Durban at the International AIDS meeting. Data for this presentation was derived from an examination of the MEMS trackcap data from the study.

36. Methods 195 therapy-naïve adults (ITT population) HIV-1 RNA >40 c/mL and <100,000 c/mL, CD4 ?50 cells/mm3 Subjects randomized to receive education intervention plus counseling or counseling alone All subjects received COM and ABC BID for 24 weeks in bottles with MEMS trackcaps MEMS data (n=161) evaluated for interruptions of therapy 205 patients were enrolled but only 195 patients took drug. MEMS data was only available from 161 patients.205 patients were enrolled but only 195 patients took drug. MEMS data was only available from 161 patients.

37. Demographics for Patients with MEMS Data (n=161) This study was designed to recruit patients from populations that are typically under-represented in clinical trials. This study was designed to recruit patients from populations that are typically under-represented in clinical trials.

38. Results Treated cohort (n=195), MEMS data (n=161) Mean percentage of doses taken was 71% 4/195 patients had a suspected hypersensitivity reaction to ABC 3 subjects with MEMS data had suspected hypersensitivity reactions on days 5, 9 and 46 of therapy; none had therapy interruptions 1 subject without MEMS data had a suspected hypersensitivity reaction on day 6; pill count data suggests patient did not miss any doses Four subjects in the trial were diagnosed with symptoms that were consistent with hypersensitivity to abacavir. MEMS data was available for three subjects, none of these subjects had interruptions in their therapy. The fourth subject did not have MEMS data available but pill count data was available. According to the study drug page in the case report form the subject started drug on 1/25/99 and stopped on 1/30/99. The hypersensitivity was reported on 1/30/99. Pill count log recorded 70 tablets of abacavir dispensed on 1/25/99. On 2/9/99 the subject returned 60 abacavir tablets. This suggests the subject did not have any therapy gaps in their abacavir before the reported hypersensitivity.Four subjects in the trial were diagnosed with symptoms that were consistent with hypersensitivity to abacavir. MEMS data was available for three subjects, none of these subjects had interruptions in their therapy. The fourth subject did not have MEMS data available but pill count data was available. According to the study drug page in the case report form the subject started drug on 1/25/99 and stopped on 1/30/99. The hypersensitivity was reported on 1/30/99. Pill count log recorded 70 tablets of abacavir dispensed on 1/25/99. On 2/9/99 the subject returned 60 abacavir tablets. This suggests the subject did not have any therapy gaps in their abacavir before the reported hypersensitivity.

39. Therapy Interruption >2 Days

40. Therapy Interruption >5 Days

41. Therapy InterruptionDuration and Number (n=161) Therapy interruptions were analyzed for gaps of >2 days and >5 days. For the 2 day time period days were analyzed for 0, 1-4 and >4 gaps. For the >5 day period gaps of 1 or >1 period were noted. None of the subjects with gaps in therapy during the 24 week study had hypersensitivity. Tables with this data are in the backup slides.Therapy interruptions were analyzed for gaps of >2 days and >5 days. For the 2 day time period days were analyzed for 0, 1-4 and >4 gaps. For the >5 day period gaps of 1 or >1 period were noted. None of the subjects with gaps in therapy during the 24 week study had hypersensitivity. Tables with this data are in the backup slides.

42. Data from Other Clinical Trials 1,021 patients in phase II and III trials 164 (16.1%) had at least 1 treatment interruption (NOT for hypersensitivity reaction) lasting ?24 hours 219 interruptions among these patients No patients developed a hypersensitivity reaction This data was obtained from reviewing case report forms from Phase II and III studies. One subject did have a dosing interruption and subsequent hypersensitivity. This appeared to be an initial reaction which occurred during the first 6 weeks of therapy. This was thought to be an initial reaction and not a rechallenge reaction. Therefore this patient is not included in this analysis since the concern was over rechallenge type reactions. Demographics for the populations were: males ~80% females ~20% White=67%, Black =19%, other =14% However, no consistent demographic parameter has been found that correlates with HSR, thus, the results of the NZT4006 study can probably be generalized to other populations. This data was obtained from reviewing case report forms from Phase II and III studies. One subject did have a dosing interruption and subsequent hypersensitivity. This appeared to be an initial reaction which occurred during the first 6 weeks of therapy. This was thought to be an initial reaction and not a rechallenge reaction. Therefore this patient is not included in this analysis since the concern was over rechallenge type reactions. Demographics for the populations were: males ~80% females ~20% White=67%, Black =19%, other =14% However, no consistent demographic parameter has been found that correlates with HSR, thus, the results of the NZT4006 study can probably be generalized to other populations.

43. Conclusions Interruptions of antiretroviral therapy are common in practice and in clinical trials Therapy interruptions of ?2 days occurred in >70% of the NZT4006 study population Interruptions of therapy with ABC do not appear to be associated with increased risk of hypersensitivity reaction