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WHO training, Pretoria, SA

WHO training, Pretoria, SA. Jens D. Lundgren, MD, DMSc Director, Copenhagen HIV Programme (044) Hvidovre University Hospital, 2650 Hvidovre, Denmark www.cphiv.dk ; e-mail: jdl@cphiv.dk. Copenhagen HIV Programme.

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WHO training, Pretoria, SA

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  1. WHO training, Pretoria, SA Jens D. Lundgren, MD, DMSc Director, Copenhagen HIV Programme (044) Hvidovre University Hospital, 2650 Hvidovre, Denmark www.cphiv.dk; e-mail: jdl@cphiv.dk

  2. Copenhagen HIV Programme • Research unit at University of Copenhagen (located at Hvidovre University Hospital) • Coordinating centre for: • Randomized controlled trials (RCT’s) • COLATE, MaxCmin 1&2 • NIH-sponsored: ESPRIT, SILCAAT, SMART • Network: +300 clinics on 5 continents • Cohort studies • EuroSIDA (since 1994) • Data collection of Adverse events of anti-HIV drugs (D:A:D) • Network: +200 clinics on 3 continents

  3. Agenda for 3 sessions • ADR from ART – examples • The risk:benefit ratio of ART • Methods to identify and understand AE’s in addition to spontanous reporting • Networking nationally and internationally • Terminology • ART=antiretroviral treatment • ARV’s=antiretroviral’s (i.e. drug’s used as part of ART)

  4. Global effort to collect ADRs of ART WHO course, Pretoria, SA September 2004

  5. Anti-HIV agents: 2004 Fusion inhibitors: T-20 (’03) Integrase inhibitors: ? (’03)

  6. Italian Cohort Main reasons of discontinuation of first HAART regimen within1st year: ICONA I C O N A Naive Antiretroviral Monforte et al. AIDS 1999

  7. Side effects of anti-HIV drugs • Early onset • Varies by drug: GI, renal, CNS, rash, liver • Late onset • peripheral neuropathy • osteopenia • liver toxicity • altered fat distribution • elevated lactic acid levels • diabetes mellitus • lipid changes in blood • (cardiovascular disease)

  8. (AZT-nonAZT) difference (and 95% CI) of one-year change in haemoglobin Oz-1 (n=105) Oz-2 (n=61) START I & II (n=301) BMS-148 (n=705) BMS-152 (n=491) Combined (n=1663) Differences in Haemoglobin (g/dl) at 1 year Moyle et al, 4th IWADRL, 2002

  9. Abacavir hypersensitivity reaction (HSR) • Symptoms: Fever, rash, malaise • Risk: From 1-8 (10) weeks from start. If HSR, exposure is associated with immediate death • Presence of HSR and HLA-B*5701 status Mallal et al, Lancet 2002): • B*5701 pos: 14/18 (78%) • B*5701 neg: 4/167 (2%) • Reduction of prevalence of HSR by denying patients with HLA-B*5701, HLA-DR7, HLA-DQ3 abacavir: • 9% to 2.5%

  10. Adverseevents 1.00 Saquinavir/r 0.75 Indinavir/r 0.50 0.25 0.00 0 4 12 24 36 48 Time (weeks) Time to initial grade 3 or 4 AE Proportion of subjects without a grade 3/4 AE P = 0.0002 (log rank test) MaxCmin1: Dragsted et al, JID, 2003

  11. Retinoid syndrome • Nails deformation, hair loss, dry lips or skin, itchy skin, eczema or ulcers • Assessment using a LDCD Study type questionnaire, i.e. both worsening and improvement of symptoms • At Week 24 and 48 • Patient’s and physician’s assessment of improvements and worsening • Cases defined at least moderate symptoms of retinoid worsening at one or more sites

  12. Retinoid status at Week 48

  13. The BEST Study: Treatment Arms TID group. Continue with: Indinavir 800 mg TID in combination with same 2 NRTIs BID group. Switch to: Indinavir 800 mg BID + Ritonavir 100 mg BID (liquid formulation) in combination with same 2 NRTIs Arnaiz et al, AIDS, 2003

  14. Nephrolithiasis/haematuria: time to development

  15. Abnormal fat distribution Lipoatrophy in face Lipoatrophy on arms Lipoatrophy on legs Lipoatrophy on arms Lipoatrophy on legs Increased abdominal fat (visceral) Mammae hypertrophy Lipoatrophy in face ”Buffalo hump”

  16. Both increased fasting and 2-hour insulin levels are evidence of insulin resistance in lipodystrophy P<0.05 mIU/mL P<0.05 Hadigan et al, CID; 32:130

  17. D:A:D Baseline Risks for CVD % of total AIDS 2003; 17(8): 1179-94

  18. Lipid elevation and ART status at baseline in D:A:D % of all in stratum AIDS 2003; 17(8): 1179-94

  19. D:A:D Cholesterol elevation, ART, CD4 % with elevated total cholesterol ART status at baseline Baseline CD4 count AIDS 2003; 17(8): 1179-94

  20. Study 903Mean (95%CI) Change from Baseline in Triglycerides Wk 48, p < 0.001 110 • d4T+3TC+EFV 100 • TDF+3TC+EFV 90 80 70 74 mg/dL 60 50 Change from Baseline (mg/dL) 40 30 20 10 0 mg/dL 0 -10 -20 Week 44 40 32 48 36 16 20 28 24 4 2 12 BL 8 Staszewski et al, XIV IAC, LBOr17

  21. Metabolic and Physiognomic Changes in HIV Patients Receiving Antiretroviral Therapy • 1 syndrome or several? • 1 etiology or multifactorial? Dysregulation of glucose metabolism Lipid abnormalities Fat accumulation Fat atrophy

  22. Cardiovascular disease as a late - rather than early - onset side effect • Proposed mechanism for anti-HIV therapy induced increased risk is indirect • altered glucose metabolism • increase in cholesterol and triglycerid levels • altered fat distribution • Congitive dyslipidaemia - onset of clinical symptoms: 8-10 years • Emigration from low to high prevalence areas: 2-3 generations • Treatment of dyslipidaemia: effect after 2-4 years

  23. D:A:D MI by CARTexposure MIs per 1,000 PY (95% CI) Test for trend p<0.00001 Years on CART Total 126 36,199 No. MIs 3 9 14 22 31 47 No. PY 5,714 4,140 4,801 5,847 7,220 8,477 N Engl J Med. 2003;349 (21)

  24. D:A:D Adjusted RR 1.26 (95% CI: 1.12-1.41) CART per additional year Age per additional 5 years Male gender Previous CVD Ever smoking 5 Independent predictors of MI 0,5 Relative rate of myocardial infarction (95% CI) Multivariable Poisson model, also adjusted for family history, BMI, HIV transmission, cohort and race

  25. Mitochondria Mitochondrion • Energy power-houses • Have their own DNA • Mitochondrial DNA is replicated by a separate enzyme to nuclear DNA (DNA polymerase gamma) Cell

  26. ART naïve patients: Mean lactate values at 48 weeks (Δ from BL) † p=0.002 *p=0.003 † p<0.001 *p<0.001 mmol/L *p=0.006 Subgroup-female Subgroup-male Lactate overall * p-value as compared to ABC/COM † p-value as compared to COM/NFV Kumar P, et al. 9th CROI 2002; Abs 33

  27. Study 903Venous lactate sub-study at week 48* TDF+3TC+EFV d4T+3TC+EFVp-value (n=128) (n=129) Mean (mmol/L) 1.2 1.9 < 0.0001 *Samples collected per AACTG Lactic Acidosis guidelines 6/00 Gallant et al, 42nd ICAAC, 2002

  28. Risk of hyperlactatemia with different ART combinations - logistic regression Others ZDV+EFV (no PI or ddI) ZDV+PI (no ddI or EFV) ZDV (no PI, ddI or EFV) d4T &/or ddI + EFV + PI d4T &/or ddI + EFV, no PI d4T &/or ddI + PI, no EFV d4T &/or ddI, no EFV or PI Boubaker et al - Abstract 57, 7th CROI 2000

  29. Lactic acidemia Terminology • lactic acidosis venous lactate > 2 mmol/L + arterial ph <7.35 (rarely done) lactic acidemia venous lactate > 2 mmol/L • grade of lactate acidosis symptoms mortality acidemia (mmol/L) (%) severe >10 often always 80 moderate 5 -10 rare usual 0 mild 2 - 5 no sometimes 0 Risk & treatment 2-9 per 1,000 PY Stop ART – time to clinical recovery 1-3 weeks (risk of relapse higher if restarting same drug combination)

  30. Reversibility of symptomatic hyperlactatemia – other NRTI’s or NRTI sparing ? • Symptomatic hyperlactatemia in TARHELL (d4T, n=16 to ZDV(4) or ABC (12)1 • At wk 48 (med.): -0.80 mmol/L • Symptomatic hyperlactatemia at UCSD (d4T to ZDV or ABA, n=12)2 • At diagnosis: S-Lactate : 5.4 mM • 1 relapse of symptomatic hyperlactatemia • 2 discontinued due to unrelated reasons • 9 remained asymptomatic after median 27 months –S-lactate (med.) : 1.3 mM 1: Lonergan et al, 4th IWADRL, 2002. Abs 21 2: Lonergan et al, 42nd ICAAC, 2002. H-1080

  31. Risk factors for femoral osteonecrosis (MRI): % of HIV+ patients with osteonecrosis Prevalence: 15/339 (4.4%) in HIV+; 0/118 (0%) in HIV- (age, sex matched);p=0.02 Miller et al, AIM, 2002

  32. The balance when assessing appropriate use of a treatment intervention BAD Toxicity Effect GOOD

  33. AIDS ratesEuroSIDA 1994 -2003 36 2.5 Mocroft et al, Lancet 2003

  34. Changing population CD4 lymphocyte count in EuroSIDA CD4 count during period (/mm3) Mocroft et al, Lancet, 2003

  35. Risk of clinical disease progression by CD4 cell count at start of HAART Rate without AIDS or death 1.00 >350 0.95 200-349 0.90 100-199 0.85 0.80 0-99 0.75 0 1 2 3 Years from starting HAART Egger et al, ART Cohort Collaboration, Lancet, 2002

  36. But – this does NOT indicate that ART works less well in severely immunocompromised patients !!!

  37. Predictive ability of pre-therapy CD4 cell count on risk of disease progression in ART-naive patients starting HAART Rate % Pre-therapy CD4 count (cells/µL) # events 267 44 32 # w/CD4 count 237 29 23 N=2742 SHCS, Frankfurt, EuroSIDA Phillips et al, JAMA, 2001

  38. Relative hazard of viral load suppression < 500 c/mL within 32 weeks 2.0 1.5 1 0.67 0.5 >500 400- 300- 200- 100- < 100 499 399 299 199 Baseline CD4 count (per cubic millimeter) N=2742 SHCS, Frankfurt, EuroSIDA Phillips et al, JAMA, 2001

  39. Percent with viral load > 500 c/mL – baseline CD4 count N.S. CD4 count < 200 CD4 count > 350 CD4 count 200 - 349 Weeks from viral load < 500 copies per milliliter N=2346 SHCS, Frankfurt, EuroSIDA Phillips et al, JAMA, 2001

  40. Differential diagnosis of clinical events developing in severely immunodeficient patients recently started on ART • Further complications from pre-therapy impaired health status • Still susceptible to opportunistic infections also after initiation • Immune reconstitution syndrome • Adverse events

  41. Swiss HIV Cohort(*): Relative risk of different AIDS-defining events in 7/1997-6/1998 versus 1992-4 *: 6.636 patients followed for 18.498 person-years Ledergerber et al, BMJ 1999;319:23

  42. Systems complementary to spontaneous reporting

  43. Enthusiasm for an agent as a function of time since first introduced Enthusiasm ”CURE” ”DOG” REALISTIC Time since initiation of phase I trials (years) Textbook in Pharmacology, 1960’s

  44. Enthusiasm for HAART as a function of time since first introduced Enthusiasm 1996 “?” Time since initiation of phase I trials (years)

  45. Toxicity - ways of detection • Randomised trial: • randomised phase • open-label follow-up • Passive surveillance • Active survaillance: • cohort studies

  46. Why Randomization? • Conscious and unconscious bias eliminated from treatment assignment • Known and unknown confounders balanced on average Moderate treatment effects cannot be reliably established in the presence of moderate bias.

  47. Beta-carotene intake and cardiovascular mortality Male health workers USA Social insurance, men Finland Finland Social insurance, women Cohorts Male chemical workers Switzerland Hyperlipidaemic men USA USA Nursing home residents Male smokers Finland Skin cancer patients USA Trials (Ex)-smokers, asbestos workers USA Male physicians USA 0.1 0.5 0.75 1 1.25 1.5 1.75 Relative risk (95% CI) Egger et al. BMJ 1998

  48. ONLY RANDOMISED TRIALS CAN RELIABLE DEFINE THE RISK:BENEFIT RATIO OF ART IN A GIVEN SETTING BUT IT IS NOT ALWAYS FEASIBLE TO DO THEM, OR THEY DO NOT ANSWER THE QUESTION !

  49. Why are randomised trials not always able to provide the answers we are looking for ? • Stopped when there is significant differences • Ethically correct • But, durability ? (ART has to continue for life) • Use of laboratory endpoints (e.g. viral load) minimises duration and size of trial - result in rapid introduction of new drugs • Snap-short of the entire duration of ART • Not powered to detect differences in clinical meaningful outcomes related to benefit and risk from ART

  50. Pooled Analysis of Immediate vs. Deferred AZT No. AIDS/Death Events Year ofFollow-up 0- 209 0.52 (0.39 - 0.68) 1- 357 0.94 (0.76 - 1.16) 2- 440 1.05 (0.87 - 1.27) 3- 369 1.12 (0.91 - 1.38) 4- 307 0.98 (0.78 - 1.23) 5+ 226 1.10 (0.84 - 1.43) Hazard Ratio* *Immediate vs. deferred AZT

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