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The SAINT Study

The SAINT Study. Jonathan Levin. 1. Results of HIVNET 012 2. Design of SAINT 3. Results of Petra 4. Results of SAINT 5. Conclusions from SAINT 6. A possible new study. 1. Results of HIVNET 012. Lancet 354 No 9181 1999 pp 795-802 Kampala, Uganda Treatments: Test: (n=310)

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The SAINT Study

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  1. The SAINT Study Jonathan Levin

  2. 1. Results of HIVNET 012 2. Design of SAINT 3. Results of Petra 4. Results of SAINT 5. Conclusions from SAINT 6. A possible new study

  3. 1. Results of HIVNET 012 • Lancet 354 No 9181 1999 pp 795-802 Kampala, Uganda • Treatments: Test: (n=310) 200mg oral nvp to mothers at onset of labour + 2mg/kg to babies within 72 hours of birth • Reference: (n=308) 600mg oral azt to mother at onset of labour, 300mg every 3h until delivery + 4mg/kg to babies bid for 7 days

  4. Results - HIV transmission rates • 6-8 weeks nvp 11.9% azt 21.3% absolute decrease in risk: 9.4% (p=0.003) relative decrease: 44% • 14-16 weeks 12 months nvp 13.1% nvp 15.7% azt 25.1% AZT 24.1% abs decrease: 12% 8.4% rel decrease: 47% 35% • The absolute decrease is maintained (biologically plausible) • The reference is of unproven efficacy - but since nvp is superior, its effectiveness is demonstrated

  5. 2. Design of SAINT • Multicentre South African Study - 11 sites • Treatments: Test: (n=655) nvp: 200mg oral in labour to mother, followed by second dose 24-48 hrs post delivery + 6mg oral to infant at 24-48 hrs • Referene: (n=662) Petra B Mother: ZDV 600mg then 300mg every 3hrs; 3TC 150mg bid; plus ZDV 300mg bid for 7 days; 3TC 150mg bid for 7 days; + infant ZDV 12mg bid for 7 days; 3TC 6mg bid for 7 days

  6. Rationale: Evaluate safety and effectiveness of arv regimen in late presenters • Primary Objective: • “… evaluate efficacy of nvp versus AZT + 3TC … in reducing MTCT of HIV”

  7. Sample size calculation: • Assume: (a) With no treatment transmission at 8 weeks is 25% (b) Petra B will reduce this to 16% • Then sample size of 655 per group will give 90% power to detect as significant a reduction by nvp to 11.5% • I.e. Assumption was that study would show nvp superior to Petra B

  8. 3. Results of Petra • HIV transmission at 6 weeks Petra A 5.7% (n=354) Petra B 8.9% (n=354) Petra C 14.2% (n=353) Placebo 15.3% (n=339) • So SAINT protocol overestimated transmission in placebo group • Estimated benefit of Petra B over placebo is 6.4% • (Relative decrease is 42%)

  9. HIV transmission at 18 months Petra A 14.9% Petra B 18.1% Petra C 20.0% Placebo 22.2% • Estimated benefit of Petra B over placebo is 4.1% • (Relative decrease is 18%)

  10. 4. Results of SAINT • Overall HIV transmission at 8 weeks NVP 12.3% (n=643) Petra B 9.3% (n=646) • Estimated benefit of Petra B over nvp is 3% • no follow up to 18 months

  11. Maternal NVP resistance • At 4 weeks after delivery 68% (74/109) of mothers had resistant virus • Follow up specimens were collected 6-18 months. 11.8% of isolates were still resistant • Resistance in SAINT more serious than in HIVNET 012 • Perhaps due to 2 doses of nvp to the mother

  12. 5. Conclusions from SAINT • Researchers “Considerable overlap of confidence intervals and reduced transmission rate (compared to hypothesized placebo rate of 25%) confirm that both treatments are effective” • N.B. Altman and Bland “Absence of evidence is not evidence of absence”

  13. Correct Statistical conclusion “There is insufficient evidence to conclude that Petra B is superior to nvp” • SAINT is inconclusive it does not show that nvp is effective it does not show that nvp is not effective

  14. HIVNET 012 and SAINT do not give consistent results • Possibilities • Results of SAINT unduly pessimistic (? Effect of using late presenters) • Results of HIVNET 012 unduly optimistic • True results are not consistent over the two sites (RSA versus Uganda) (? Subtype C versus subtype A) • We do not have enough information to make a conclusion on above

  15. 6. Possible Alternative Study • Was SAINT an equivalence study? No because it was not designed as an equivalence study. • For an equivalence study we must pre-specify equivalence limits • e.g. since in Petra, Petra B was better than placebo by 6.4% could choose limits of 3.2%

  16. If we had done this, confidence interval for difference between Petra B and nvp must lie between (-3.2%; 3.2%). • The actual confidence interval for the difference is (-0.4%; 6.4%) • So even if it were designed as equivalence study it would not have shown equivalence

  17. Possible study - non inferiority of nvp versus Petra A or nvp versus Thai AZT regime (Botswana) • Specify non inferiority margin of 5% • (So this says that nvp would lead to at most 5% more transmissions than Petra A/AZT Thai)

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