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

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

Acknowledgements

Marco Vitoria

Meg Doherty

Andrew Hill

Kimberley Bonner

Teri Roberts