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WHO Guidelines and future perspectives for treatment
monitoring
Nathan FordDept of HIV/AIDS
World Health Organization
WHO ART guidelines evolution
Topic 2002 2003 2006 2010 2013
When to start
CD4 ≤200 CD4 ≤ 200 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
1st 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
2nd 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
3rd Line None None None DRV/r, RAL, ETV DRV/r, RAL, ETV
Viral LoadTesting
No No (Desirable)
Yes(Tertiary centers)
Yes(Phase in)
Yes(preferred)
Vitoria M, et al, Current Opinions HIV/AIDS, 2013
WHO ART guidelines evolution
Topic 2002 2003 2006 2010 2013
When to start
CD4 ≤200 CD4 ≤ 200 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
1st 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
2nd 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
3rd Line None None None DRV/r, RAL, ETV DRV/r, RAL, ETV
Viral LoadTesting
No 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 monitoringVitoria M, et al, Current Opinions HIV/AIDS, 2013
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
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.
Pop Viral load Sensitivity Specificity PPV NPV
Adults >5000 68.9% 92.1% 27.0% 98.6%
Adults 50-4,999 55.6% 74.5% 29.8% 89.6%
Adults >10,000 16.8% 95.5% 15.0% 96.0%
Children >5,000 4.5% 99.3% 54.9% 85.5%
Children >400 6.3% 97.7% 20.0% 91.8%
Immunological and clinical criteria
Rutherford et al, IAS 2014
Pop Viral load Sensitivity Specificity PPV NPV
Adults >5000 68.9% 92.1% 27.0% 98.6%
Adults 50-4,999 55.6% 74.5% 29.8% 89.6%
Adults >10,000 16.8% 95.5% 15.0% 96.0%
Children >5,000 4.5% 99.3% 54.9% 85.5%
Children >400 6.3% 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
Loutfy et al, PLoS ONE, 2013
Transmission
Loutfy et al, PLoS ONE, 2013
Viral load to reinforce adherence and confirm treatment failure
Repeat viral load after 3-6months
Evaluate foradherence concerns
Viral load > 1,000copies/mL
Test viral load
Routine viral loadmonitoring (early detection
of virologic failure)
Targeted viral loadmonitoring (suspected clinical
or immunological failure)
Viral load > 1,000copies/mL
Viral load < 1,000copies/mL
Maintain first-linetherapy
Switch tosecond-line therapy
Proportion resuppressing after adherence intervention
Bonner et al, JAIDS 2013
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.
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)
Future of CD4 for monitoring?
Hill A, IAS 2013; Gale et al CID 2013
If VL <200 copies/mL and CD4 >300 cells/uL, 97% probability
of CD4 > 200 cells/uL for 4 years
AcknowledgementsMarco Vitoria
Meg Doherty
Andrew Hill
Kimberley Bonner
Teri Roberts