1. Optimising ART sub-Saharan Africa
Presented by Prof R.P.H. Peters
Prof Venter is acknowledged for provision of some of the slides
Pretoria, Saturday 17th February 2018

2. Outline of talk Outline of talk Optimising ART in sub-Saharan Africa
HIV epidemic and scale of the ART programme
Positive and negative effects of ART
How to provide life long ART
Optimising first-line ART
Optimising second-line ART
Conclusion
HIV epidemic and scale of the ART programme
Positive and negative effects of ART
How to provide life long ART
Optimising first-line ART
Optimising second-line ART
Conclusion

3. HIV epidemic in sub-Saharan Africa

4. HIV epidemic in South Africa
HIV and South Africa
HIV epidemic in South Africa
UNAIDS country progress report

5. ART programme evolution
HIV and South Africa
ART programme evolution
2004
2010
2016
2013
ART in public sector
CD4 count <200 cells/mm3
CD4 count <350 cells/mm
CD4 count <500 cells/mm
CD4 count any
cells/mm
Pregnant women
WHO stages & specific conditions

6. Importance of ART: for population (1)
Early (At diagnosis, but cells/mm3 as inclusion) vs. Delayed (CD4 <250 cells/mm3 or AIDS-related symptoms)
Cohen MS et al. NEJM 2011

7. HR = 0.37 or 96.3% reduction in transmission
Importance of ART: for population (2)
N=27
HR = 0.37 or 96.3% reduction in transmission %
N=1
Delayed
Immediate

8. Importance of ART: for population (3)
Approach to HIV epidemic control

9. Importance of ART: for individual
ART initiation
CD4 >500 cells/mm3
vs.
CD4 <350 cells/mm3
Clinical trial
START Study Group. NEJM 2013

10. Impact of ART programme
Reduction in mortality and morbidity
Prolonged lifespan
Reduction in (opportunistic) infections
Bor J et al. Science 2013
Hoogendoorn JC et al. Epidemiol Infect 2017

11. ART “normalizes” life-expectancy
Life-expectancy catching-up with HIV-negative individuals if on ART and virologically suppressed

12. Morbidity associated with ART
But how about long-term side-effects and accelerated ageing associated with lifelong ART?
ATHENA cohort

13. Morbidity and HIV in Zimbabwe
Hypertension
CKD
Cancer
Depression
Malignancy
Smit M et al. AIDS 2018

14. Morbidity associated with ART
Effects of (chronic) HIV and ART on the eye?
Conjunctival ‘sludging’
Anterior segment conditions
Accelerated ageing (cataract)
Poster segment conditions (HIV retinopathy)
Conjunctival sludging
Cataract
Cotton-Wool spots
Schaftenaar E et al. Epidemiol Infect 2017

15. How to provide lifelong ART?
Current cost ART in RSA: R 6 billion / annum

16. A quick recap… HIV life cycle
Current cost ART in RSA: R 6 billion / annum

17. Smits RL et al. Frontiers Genetics 2013
Current cost ART in RSA: R 6 billion / annum

18. How do we ensure lifelong ART with good treatment outcomes for 7 million people in South Africa?
Effective drugs: rapid and strong suppression

19. How do we ensure lifelong ART with good treatment outcomes for 7 million people in South Africa?
Effective drugs: rapid and strong suppression
Kanters S et al. Lancet HIV 2016

20. How do we ensure lifelong ART with good treatment outcomes for 7 million people in South Africa?
Effective drugs: rapid and strong suppression
Kanters S et al. Lancet HIV 2016

21. How do we ensure lifelong ART with good treatment outcomes for 7 million people in South Africa?
2) Well-tolerated drugs: limited side-effects
Kanters S et al. Lancet HIV 2016

22. How do we ensure lifelong ART with good treatment outcomes for 7 million people in South Africa?
Affordable drugs: cost of components, fixed dose combinations and adherence/resistance barrier of 1st-line drugs
*For example - if daily ART are would be R1 cheaper:
-This would save R30 per month
-This would save R 365 per patient per year
-This would save the programme (4 million people on ART) a total of R per annum (24%)

23. WHO Guidelines 1st line regimen

24. ART regimens in South Africa

25. Side effect (and size) driver, resistance weak link
First-line ART regimen in South Africa
TDF
XTC
EFV
Side effect (and size) driver, resistance weak link
Cost driver

26. Side effect (and size) driver, resistance weak link
First-line ART regimen in South Africa
TDF
XTC
EFV
Side effect (and size) driver, resistance weak link
Cost driver

27. High value of tenofovir
1st line recommendation by WHO
Well tolerated, daily
Hep B treatment for free
Renal, bone concerns
Replacing TDF for TAF
-Reduction in cost (300mg vs. 25mg)
-Same benefits but less side-effects

28. Side effect (and size) driver, resistance weak link
First-line ART regimen in South Africa
TDF
XTC
EFV
Side effect (and size) driver, resistance weak link
Cost driver

29. Pros and cons of efavirenz
Daily, cheap, co-formulated, huge experience base, TB (and most everything else)-friendly
EFV side effects predictable, treatable, substitutions relatively easy
Limited genetic resistance barrier
Increasing recognition of CNS side effects
Rash, hepatitis, gynaecomastia, lipids
Depression and serious and fatal rare CNS side effects recently recognised

30. Depression Efavirenz (6%) 2x higher risk for suicidality
Meta-analysis
n=5332, 4 RCT
Efavirenz (6%)
2x higher risk for suicidality
Rilpivirine (8%)
Elvitegravir/COBI (5%)
Raltegravir (6%)
Atazanavir/r (2%)
For composite endpoint
‘Only’ trend for completed/attempted suicide (17 events occured)
EFV
EFV-free
Lack of association between use of efavirenz and death from suicide: evidence from the D:A:D study #O315 Wednesday 5 November
C. Smith; L. Ryom; A. d’Arminio Monforte; P. Reiss; A. Mocroft; W. El-Sadr; R. Weber; M. Law; C. Sabin; J. Lundgren.
Cohen et al., Lancet 2011; Molina et al, Lancet 2011; Elion et al., JAIDS 2013; Mollan et al, Ann Intern Med, 2014

31. TDF XTC EFV First-line ART regimen in South Africa Efavirenz 400mg?
Dolutegravir?
Rilpivirine: TB, VL and food issues

32. Efavirenz 400mg.. Non-inferior to EFV 600mg but less side-effects
Studies currently underway – pregnancy and TB
Then, if mass switch to 400mg; cost saving ≈ 5-10%

33. Efavirenz 400mg..
Encore1 Study Group. Lancet Infect Dis 2015

34. Efavirenz 400mg..
Encore1 Study Group. Lancet Infect Dis 2015

35. Efavirenz 400mg..
“In countries with pre-treatment HIVDR to NNRTIs below 10%, and no availability of low-cost generic DTG in a fixed-dose combination, transition from EFV600 to EFV400 might have some financial advantages. However, this would introduce the potential for 2 transition events (from EFV600 to EFV400, then from EFV400 to DTG-based regimens). Countries with pre-treatment HIVDR to NNRTIs at or above 10% should avoid the use of EFV400-containing regimens, and move to DTG as the preferred first-line regimen”
TASP trial: 9% pre-treatment drug resistance; largely NNRTIs

36. Efavirenz 400mg..
“In countries with pre-treatment HIVDR to NNRTIs below 10%, and no availability of low-cost generic DTG in a fixed-dose combination, transition from EFV600 to EFV400 might have some financial advantages. However, this would introduce the potential for 2 transition events (from EFV600 to EFV400, then from EFV400 to DTG-based regimens). Countries with pre-treatment HIVDR to NNRTIs at or above 10% should avoid the use of EFV400-containing regimens, and move to DTG as the preferred first-line regimen”
Pre-therapy drug-resistance in the Cape Winelands
Van Zyl GU et al. AIDS 2017

37. Dolutegravir
Strong drug (high resistance barrier) with very good efficacy
50mg once-daily
Very good efficacy
Potential to be low cost and co-formulated: raltegravir and elvitegravir expensive
Increases metformin and reduces rifampicin levels
Minimal toxicity – but NEW data re CNS and IRIS..

38. Dolutegravir

39. The US and EU has long moved on from EFV-based treatment
Dolutegravir
Major parameters
EFV 600
DTG
Occurrence of SAEs
comparable
Better virologic suppression 
Better CD4 recovery
Less treatment discontinuation
Less occurrence of subjective side effects
Lower potential for drug–drug interactions
Efficacy in HIV-2 infection
Efficacy in TB coinfection
Efficacy and safety in pregnant/breastfeeding women
Availability as generic formulations
The US and EU has long moved on from EFV-based treatment

40. Summary of options for 1st line
Major outcomes
INSTI vs. EFV600
DTG vs. other INSTI
DTG vs. EFV600
DTG vs. EFV400
EFV400 vs. EFV600
Quality of evidence
Viral suppression
INSTI better
DTG better
comparable*
comparable
moderate
CD4 recovery
INSTI better
EFV400 better
Treatment discontinuation
Mortality
low
AIDS progression
SAE
*Estimated effects favored DTG, but statistical analysis not significant
WHO Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection – What’s New Policy Brief, November Available at

41. New combination: TAF/FTC/DTG
Almost unbreakable – people on first-line DTG, no resistance
DTG slightly cheaper than EFV, TAF much cheaper than TDF – generics: immediate 20% price reduction (CHAI: closer to 50%)
Possibility of harmony for >12 years (and possibly below)
WDF Venter et al. Curr Opinion HIV AIDS 2017

42. Optimisation of PIs: side-effect issues

43. Optimisation of PIs: safety issues
Use of PI in a different way
Non-inferiority study of DRV/r at lower dose vs. LPV/r
 Reduced pill burden
Better toxicity profile
Higher resistance profile
Prodrugs and new formulations of current PIs

44. Summary and conclusion (1)
ART programme in South Africa has evolved hugely
Benefit for the individual
Benefit for the population
Large population ageing on ART and ‘at risk’ for morbidity and resistance
Treatment optimisation important
Tolerability and treatment outcomes
Cost and affordability

45. Summary and conclusion (2)
First-line regimen likely to change in public sectors across sub-Saharan Africa in the coming years
EFV400mg, DTG and TAF valuable options

46. Thank you! Acknowledgements Unitaid
Southern African HIV Clinicians Society
Prof Francois Venter