who 2013 arv guidelines launch

Critical issues for Adults with HIV: Presentation of Systematic reviews and Main recommendations

WHO 2013 ARV Guidelines Launch

Dr. Meg Doherty, WHO, GenevaCoordinator Treatment and Care

Objectives of Presentation

• Overview of Evidence Base and Rationale for Recommendations for Adults:

• When to Start ART• What ART to Start (First-Line)• What ART to Switch to (Second-Line)• How to Monitor ART

When to Start ART

Summary of Changes in RecommendationsWhen to Start in Adults

TARGET POPULATION(ARV-NAIVE) 2010 ART GUIDELINES 2013 ART GUIDELINES

STRENGTH OF RECOMMENDATION

& QUALITY OF EVIDENCE

HIV+ ASYMPTOMATIC CD4 ≤350 cells/mm3

CD4 ≤500 cells/mm3 (CD4 ≤ 350 cells/mm3 as a priority)

Strong, moderate-quality evidence

HIV+ SYMPTOMATIC WHO clinical stage 3 or 4

regardless of CD4 cell count No change Strong, moderate-quality evidence

PREGNANT AND BREASTFEEDING WOMEN WITH HIV

CD4 ≤350 cells/mm3 orWHO clinical stage 3 or 4

Regardless of CD4 cell count or WHO clinical stage


HIV/TB CO-INFECTION

Presence of active TB disease, regardless of CD4 cell count

No changeStrong, low-quality evidence

HIV/HBV CO-INFECTION

Evidence of chronic active HBV disease, regardless of CD4 cell count

Evidence of severe chronic HBV liver disease, regardless of CD4 cell count

Strong, low-quality evidence

HIV+ PARTNERS IN SD COUPLE No recommendation

establishedRegardless of CD4 cell count or WHO clinical stage

Strong, high-quality evidence

Evidence Summary: When to Start in Adults

• Systematic Review of 24 studies (3 RCTs, 21 observational )

• Multiple countries throughout Europe, North America, Central & South America, sub-Saharan Africa and Asia-Pacific

• Outcomes reported:

mortality

progression to AIDS

progression to AIDS or death

non-AIDS defining cancer

serious non-AIDS events

CD4 increase

viral suppression, failure, rebound

SAE and grade 3 or 4 lab

abnormalities

Evidence Summary:Risk of Death and/or Progression to AIDS

Clinical Trials (2 RCTs)Low quality evidence for lower risk of progression to AIDS or death with early ART Observational studies Moderate quality evidence for lower risk of death (13 studies) or progression to AIDS (9 studies) with early ART

Observational dataRCTs – SMART / HPTN 052

Risk of Death or Progression to AIDS

Risk of Death

Risk of Progression

to AIDS

Evidence Summary:Risk of HIV Sexual Transmission

Early ART Late ART0

2

4

6

8

10

Unknown (n=3)Not from partner (n=7)From partner (n=29)

% in

fect

ed

• RCT on efficacy of ART to prevent HIV transmission between discordant couples

• HIV+ partner with CD4 ≥ 350-550 cells/µL randomized to early vs. delayed ART

• Significant HIV prevention benefit – a 96% reduction in transmission.

• 1 genetically linked infection in early ART arm versus 29 infections in delayed arm.

Observational dataClinical Trial - HPTN 052

Early ART Late ART

RCT and Observational data• High to moderate quality evidence that

treatment prevents sexual transmission of HIV (1 RCT and observational data)

Populations With No Specific Recommendations

Insufficient evidence and/or favorable risk-benefit profile for ART initiation at CD4 > 500 cells/mm3 (or regardless of CD4 count) in the following situations:

Individuals with HIV who are 50 years of age and older

Individuals co-infected with HIV and HCV

Individuals with HIV-2

Key populations with a high risk of HIV transmission (e.g.: MSM, sex workers, IDU)

These populations should follow the same principles and recommendations as for other adults with HIV

WHAT ART REGIMEN TO START

FIRST-LINE REGIMENS (PREFERRED ARV REGIMENS)

TARGET POPULATION 2010 ART GUIDELINES 2013 ART GUIDELINES

STRENGTH & QUALITY OF EVIDENCE

HIV+ ADULTS AZT or TDF + 3TC (or FTC) + EFV or NVP

TDF + 3TC (or FTC) + EFV(as fixed dose combination)


HIV+ PREGNANT WOMEN

AZT + 3TC + NVP or EFV

HIV/TBCO-INFECTION

AZT or TDF + 3TC (or FTC) + EFV

HIV/HBV CO-INFECTION

TDF + 3TC (or FTC) + EFV

Summary of Changes in Recommendations: What to Start in Adults

Evidence Summary: What to Start

• Systematic review (10 RCTs): TDF+3TC (or FTC)+EFV superior vs. other EFV containing regimens and vs. TDF/3TC+ PI/r on major outcomes - occurrence of SAEs, virologic and immunologic response (high to moderate quality of evidence)

• Systematic review (7 RCTs, 27 observational): NVP > 2 fold more likely to be discontinued due any adverse effect compared to EFV (moderate to low quality of evidence)

• Systematic review of preclinical data (5 studies): support pharmacological equivalence interchangeability of 3TC and FTC (low quality evidence)

Immunologic Response (48 weeks)

Virological response (48 weeks)

Severe adverse events (48 weeks)

Comparative efficacy 3TC and FTC

Discontinuation NVP vs. EFV

WHAT ART TO SWITCH TO

TARGET POPULATION

WHAT TO SWITCH IN ADULTS (PREFERRED REGIMENS)

2010 ART GUIDELINES 2013 ART GUIDELINES

STRENGTH & QUALITY OF EVIDENCE

HIV+ ADULTS AND

ADOLESCENTS

If d4T or AZT used infirst-line

TDF + 3TC (or FTC) + ATV/r or LPV/r

No change strong, moderate-quality evidence

If TDF used in first-line

AZT + 3TC + ATV/r or LPV/r


HIV+ PREGNANT

WOMENSame regimens recommended for adults


HIV/TBCO-INFECTION

If rifabutin available Same regimens as recommended for adults


If rifabutin not available

NRTI backbone plus LPV/r or SQV/r with adjusted dose of RTV (i.e., LPV/r 400mg/400mg BID or SQV/r 400mg/400mg BID)


HIV/HBV CO-INFECTION AZT + TDF + 3TC (or FTC) + (ATV/r or LPV/r)


Summary of changes to recommendations: What ART to Switch to

Rationale: Comparative Analysis of ATV/r, LPV/r and DRV/r

Major parameters ATV/r LPV/r DRV/rConsistency with pediatric regimens no yes noNumber of pills per day (standard dose as FDC) 1 4 2-4

Convenience (once vs twice daily regimen)once daily twice daily Once or twice

dailySafety in pregnancy yes yes yesGI intolerance (diarrhea) Not frequent common Not frequentAvailability of heat stable FDCs yes yes noUse with TB treatment regimen that contains rifampin no yes no

Hyperbilirrubinemia + - -Dyslipidemia ± + ±Reduction cost potential low low highAccessibility in countries (registration status)

low high low

Availability of generic formulations yes yes no

HOW TO MONITOR AND WHEN TO SWITCH

RECOMMENDATION STRENGTHViral 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

Recommendations: Monitoring for ART Response

6 studies (4 RCTs and 2 observational studies)1. Clinical+Immunological versus Clinical+Immunological+Virological: (1 RCT + 1 obs

study ): no difference in terms of mortality and new AIDS-defining 2. Clinical+Immunological versus Clinical+Virological: (1 RCT): no difference in clinical

failure , switch to second line regimens , and resistance mutations . Children (Arrow 2013): mortality and disease progression are comparable between clinical and laboratory monitoring

Rationale: for VL

• Earlier capture of treatment failure & reducing HIVDR

• Help discriminate between treatment failure & non-adherence

• Lack of viral load or CD4 capacity should not prevent starting ART

• If VL availability limited, phase in use of targeted approach (or CD4/clinical monitoring)

• Same for adults & children

Targeted viral load monitoring (suspected clinical

or immunological failure)

Routine viral load monitoring (early detection of virological failure)

Switch to second-line therapy

Maintain first-line therapy

Viral load ≤1000 copies/ml

Viral load >1000 copies/ml

Repeat viral load testing after 3–6 months

Evaluate for adherence concerns

Viral load >1000copies/ml

Test viral load

Predictive value of WHO immunological and clinical criteria

Population Viral load Number of studies

Number of patients Sensitivity Specificity

Positive predictive

value

Negative predictive

value

Adults>5000

copies/mL 3 2288 68.9% 92.1% 27.0% 98.6%

Adults50-4999

copies/mL 12 15581 55.6% 74.5% 29.8% 89.6%

Adults>10000

copies/mL 2 3142 16.8% 95.5% 15.0% 96.0%

Children>5000

copies/mL 3 4100 4.5% 99.3% 54.9% 85.5%

Children>400

copies/mL 1 2256 6.3% 97.7% 20.0% 91.8%

Summary of Adult GuidelinesTopic 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

1 preferred option & 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 monitoring

who 2013 arv guidelines launch

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