1. WHO Guidelines and future perspectives for treatment monitoring Nathan Ford Dept of HIV/AIDS World Health Organization

2. WHO ART guidelines evolution Topic20022003200620102013 When to start CD4 ≤200 - Consider 350 - CD4 ≤ 350 for TB CD4 ≤ 350 -Irrespective CD4 for TB and HBV CD4 ≤ 500 -Irrespective CD4 for TB, HBV, PW and SDC - CD4 ≤ 350 as priority 1 st Line 8 options - AZT preferred 4 options - AZT preferred 8 options - AZT or TDFpreferred - d4T dose reduction 6 options &FDCs - AZT or TDF preferred - d4T phase out 2 options & FDCs -TDF and EFV preferred across all populations 2 nd Line Boosted and non- boosted PIs Boosted PIs -IDV/r LPV/r, SQV/r Boosted PI - ATV/r, DRV/r, FPV/r LPV/r, SQV/r Boosted PI - Heat stable FDC: ATV/r, LPV/r Boosted PIs -Heat stable FDC: ATV/r, LPV/r 3 rd Line None DRV/r, RAL, ETV Viral Load Testing No (Desirable) Yes (Tertiary centers) Yes (Phase in) Yes (preferred) Vitoria M, et al, Current Opinions HIV/AIDS, 2013

3. WHO ART guidelines evolution Topic20022003200620102013 When to start CD4 ≤200 - Consider 350 - CD4 ≤ 350 for TB CD4 ≤ 350 -Irrespective CD4 for TB and HBV CD4 ≤ 500 -Irrespective CD4 for TB, HBV, PW and SDC - CD4 ≤ 350 as priority 1 st Line 8 options - AZT preferred 4 options - AZT preferred 8 options - AZT or TDFpreferred - d4T dose reduction 6 options &FDCs - AZT or TDF preferred - d4T phase out 2 options & FDCs -TDF and EFV preferred across all populations 2 nd Line Boosted and non- boosted PIs Boosted PIs -IDV/r LPV/r, SQV/r Boosted PI - ATV/r, DRV/r, FPV/r LPV/r, SQV/r Boosted PI - Heat stable FDC: ATV/r, LPV/r Boosted PIs -Heat stable FDC: ATV/r, LPV/r 3 rd Line None DRV/r, RAL, ETV Viral Load Testing No (Desirable) Yes (Tertiary centers) Yes (Phase in approach) Yes (preferred for monitoring, use of PoC, DBS) Earlier initiation Simpler treatment Less toxic, more robust regimens Better monitoring Vitoria M, et al, Current Opinions HIV/AIDS, 2013

4. Recommendations on ART Monitoring  Viral load is recommended as the preferred monitoring approach to diagnose and confirm ARV treatment failure ( strong recommendation, low-quality evidence )  If viral load is not routinely available, CD4 count and clinical monitoring should be used to diagnose treatment failure ( strong recommendation, moderate-quality evidence )  Definition of virological failure: plasma viral load above 1000 copies/ml based on two consecutive viral load measurements after 3 months, with adherence support (6 months post ART)  Higher threshold for DBS and point-of-care technologies

5. Mortality  Mortality (3 RCTs): adding viral load monitoring to immunological and/or clinical monitoring has not been associated with reduced mortality  Longer follow-up required to assess longer-term impact on survival, resistance profile and HIV transmission.

6. PopViral loadSensitivitySpecificityPPVNPV Adults>500068.9%92.1%27.0%98.6% Adults50-4,99955.6%74.5%29.8%89.6% Adults>10,00016.8%95.5%15.0%96.0% Children>5,0004.5%99.3%54.9%85.5% Children>4006.3%97.7%20.0%91.8% Immunological and clinical criteria Rutherford et al, IAS 2014

7. PopViral loadSensitivitySpecificityPPVNPV Adults>500068.9%92.1%27.0%98.6% Adults50-4,99955.6%74.5%29.8%89.6% Adults>10,00016.8%95.5%15.0%96.0% Children>5,0004.5%99.3%54.9%85.5% Children>4006.3%97.7%20.0%91.8% Rutherford et al, IAS 2014 Immunological and clinical monitoring have poor sensitivity and lower positive predictive value for identifying virologic failure Immunological and clinical criteria

8. Loutfy et al, PLoS ONE, 2013 Transmission Loutfy et al, PLoS ONE, 2013

9. Viral load to reinforce adherence and confirm treatment failure Proportion resuppressing after adherence intervention Bonner et al, JAIDS 2013

10. Implementation considerations ART access should be the first priority: Lack of laboratory tests for monitoring treatment response should not be a barrier to initiating ART Prioritization: If viral load availability is limited, it should be phased in using a targeted approach to confirm treatment failure. This may be particularly relevant in populations receiving ARVs to reduce HIV transmission, such as pregnant and breastfeeding women and in sero- discordant couples.

11. Implementation considerations Feasibility of phasing in VL capacity (DBS) PoC viral load on horizon Enables monitoring of treatment for prevention Equity Cost-effectiveness influenced by monitoring approach (frequency, additive or as replacement to CD4)

12. Future of CD4 for monitoring? Hill A, IAS 2013; Gale et al CID 2013 If VL 300 cells/uL, 97% probability of CD4 > 200 cells/uL for 4 years

13. Acknowledgements Marco Vitoria Meg Doherty Andrew Hill Kimberley Bonner Teri Roberts