Benefits/Risks of initiating ART at CD4+ >500

2. Benefits/Risks of initiating ART at CD4+ >500 HIV - A NEW ERA Mark Boyd and Chris Bourne The Kirby Institute for infection and immunity in society Sydney Sexual Health Centre and UNSW 15th March 2014

3. Disclosures Mark Boyd AbbVie Boehringer-Ingelheim Bristol Myers Squibb Gilead Sciences Janssen-Cilag Merck Chris Bourne has no disclosures

4. Starting ART at CD4+ >350 Considerations • RCTs • Cohorts • Quality of evidence • Transmission risk

5. Starting ART at CD4+ >350 RCTs CIPRA HT001 • strong evidence of clinical benefits at CD4 <350 compared with CD4+ <200 SMART substudy • suggests starting ART CD4+ >350 better that CD4+ < 250 HPTN 052 • relatively small RCT designed to test whether ART can prevent transmission in HIV serodiscordant couples • suggested a benefit for starting at CD4+ >350 (median CD4 440) compared with starting at CD4+ <250 (median CD4 230) • strong evidence for T4P

6. RCTs: meta-analysis WHO assessment: ‘low quality’ evidence

7. RCTs: meta-analysis Observational cohorts NA-ACCORD, HIV-CAUSAL, When to start consortium, CASCADE - these have undergone meta-analysis along with 17 other cohort studies found on systematic review

8. Cohort studies: meta-analysis (death) WHO assessment: ‘moderate quality’ evidence

9. Cohort studies: meta-analysis (AIDS/death) WHO assessment: ‘moderate quality’ evidence

10. Starting ART at CD4+ >350 Evidence quality • Considerations • RCTs are the gold standard because all factors that underlie a decision to start (or not to start ART) are subjected to randomisation • Cohort studies are subject to bias for which adjustment is difficult • likely substantial biases in the cohort databases over the 15 years of follow-up • poor reporting of adverse events (AE, SAE and SNAE) meaning a poor understanding of risks and benefits of ART besides AIDS and death

11. Starting ART at CD4+ >350 Transmission risk • HPTN 052 provides strong evidence that treatment is prevention • in serodiscordant heterosexual couples • The degree of prevention in MSM is not known, but likely to be substantial • Considering transmission risk reduction now needs to be part of any decision about when to start

12. Starting ART at CD4+ >350 Other issues • Is HIV replication at any CD4+ level simply bad and should therefore be managed? • meaning that ART should be offered to all? • Does the (possibly quite minor) benefit of ART at CD4+ >500 outweigh the risks? • ART is safer (probably) but not completely • D:A:D has recently identified renal toxicity signals for TDF but also LPV/r and ATV/r, ABC still linked to AMI in D:A:D (CROI 2014) • dyslipidaemia, insulin resistance, fatty liver disease, neurotoxicity, musculo-skeletal adverse events, etc.

13. Starting ART at CD4+ >350 Other issues Are we forgetting the lessons of history only 15 years after the last time we thought it was obvious that we should ‘Hit Hard, Hit Early’?

14. ART at CD4+ >350: comparison guideline

15. When to start: summary of the status of the evidence • RCTs relatively uninformative for initiating at CD4+ >350 • Cohorts give ‘moderate’ quality evidence for treatment >350-500 • Cohorts give discordant evidence for treatment CD4+ >500 • Cohorts are relatively silent on adverse events and some potential benefits • Transmission risk reduction seems clear • Is ART as safe as many now believe? • TDF, b-LPV, b-ATV and renal function, ABC and AMI, bPIs and metabolic disturbance, ABC and AMI • Might benefits be more substantial than we realise?

16. When to start What can we advise? Reasonable to state that: • All people with HIV should consider commencing ART • All decisions to start ART should be made by the individual with HIV in consultation with their health care providers • HIV clinicians should discuss the current state of knowledge regarding when to start ART with all individuals with HIV who are not yet on treatment

17. When to start What can we advise? • ART has been shown to greatly reduce HIV transmission in heterosexual, serodiscordant couples • A substantial reduction in HIV transmission risk is highly likely in MSM • A decision to start ART should take into account personal health benefits and risks, plus reduction in transmission risk

18. When to start What can we advise? If CD4+ < 350 or HIV associated condition there is strong evidence from randomised trials that ART reduces morbidity and mortality • ART is strongly recommended for people in this group

19. When to start What can we advise? In people with a CD4 count >350-500 there is moderate evidence from observational studies that ART is associated with reduced morbidity and mortality • ART is recommended following discussion of the limitations of the current knowledge of benefits and risks between PLHIV and HCWs

20. When to start What can we advise? In people with a CD4 count >500 there is limited evidence about where the balance between the benefits and risks of ART lies. However, the benefits of ART potentially outweigh the risks and should be particularly considered in the following situations:

21. When to start in PLH with CD4+ >500: • Chronic viral hepatitis co-infection • HIVAN • Pregnancy • Concern about HIV transmission • Cardiovascular disease • Malignancies • Neurological diseases • Older age • T-cell activation/inflammation • Acute HIV-infection