WHO 2013 ARV Guidelines Launch
Critical issues for Adults
with HIV: Presentation of
Systematic reviews and
Main recommendations
Dr. Meg Doherty, WHO, Geneva
Coordinator 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 Recommendations
When to Start in Adults
TARGET
POPULATION
(ARV-NAIVE)
2010 ART GUIDELINES
2013 ART GUIDELINES
CD4 ≤500 cells/mm3 (CD4
≤ 350 cells/mm3
as a priority)
HIV+
ASYMPTOMATIC
CD4 ≤350
HIV+
SYMPTOMATIC
WHO clinical stage 3 or 4
No change
regardless of CD4 cell count
PREGNANT AND
BREASTFEEDING
WOMEN WITH HIV
HIV/TB COINFECTION
HIV/HBV COINFECTION
cells/mm3
CD4 ≤350 cells/mm3
or
WHO clinical stage 3 or 4
Presence of active TB
disease, regardless of CD4
cell count
Evidence of chronic active
HBV disease, regardless of
CD4 cell count
HIV+ PARTNERS IN No recommendation
SD COUPLE
established
Regardless of CD4 cell
count or WHO clinical
stage
No change
Evidence of severe chronic
HBV liver disease,
regardless of CD4 cell
count
Regardless of CD4 cell
count or WHO clinical
stage
STRENGTH OF
RECOMMENDATION
& QUALITY OF
EVIDENCE
Strong, moderatequality evidence
Strong, moderatequality evidence
Strong, moderatequality evidence
Strong, low-quality
evidence
Strong, low-quality
evidence
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
 CD4 increase
 progression to AIDS
 viral suppression, failure, rebound
 progression to AIDS or death  SAE and grade 3 or 4 lab
 non-AIDS defining cancer
 serious non-AIDS events
abnormalities
Evidence Summary:
Risk of Death and/or Progression to AIDS
RCTs – SMART / HPTN 052
Observational data
Risk of Death or Progression to AIDS
Risk of Death
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
Risk of
Progression
to AIDS
Evidence Summary:
Risk of HIV Sexual Transmission
Clinical Trial - HPTN 052
Observational data
% infected
10
8
Unknown (n=3)
6
Not from
partner (n=7)
From partner
(n=29)
4
2
0
Early ART
•
•
•
•
Late ART
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.
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
Summary of Changes in Recommendations:
What to Start in Adults
FIRST-LINE REGIMENS (PREFERRED ARV REGIMENS)
TARGET
POPULATION
2010 ART GUIDELINES
HIV+ ADULTS
AZT or TDF + 3TC (or
FTC) + EFV or NVP
HIV+
PREGNANT
WOMEN
AZT + 3TC + NVP or
EFV
HIV/TB
AZT or TDF + 3TC (or
CO-INFECTION FTC) + EFV
HIV/HBV
TDF + 3TC (or FTC) +
CO-INFECTION EFV
2013 ART GUIDELINES
STRENGTH &
QUALITY OF
EVIDENCE
TDF + 3TC (or FTC) + EFV Strong,
(as fixed dose
moderatecombination)
quality
evidence
Evidence Summary: What to Start
•
•
•
Immunologic Response (48 weeks)
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)
Virological response (48 weeks)
Severe adverse events (48 weeks)
Discontinuation NVP vs. EFV
Comparative efficacy 3TC and FTC
WHAT ART TO SWITCH TO
Summary of changes to recommendations:
What ART to Switch to
TARGET
POPULATION
HIV+ ADULTS
AND
ADOLESCENTS
HIV+
PREGNANT
WOMEN
WHAT TO SWITCH IN ADULTS (PREFERRED REGIMENS)
2010 ART GUIDELINES
If d4T or AZT used in
first-line
TDF + 3TC (or FTC) +
ATV/r or LPV/r
If TDF used in firstline
AZT + 3TC +
ATV/r or LPV/r
HIV/HBV
CO-INFECTION
No change
strong, moderatequality evidence
No change
strong, moderatequality evidence
Same regimens as
recommended for adults
No change
strong, moderatequality evidence
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)
No change
strong, moderatequality evidence
No change
strong, moderatequality evidence
Same regimens recommended for adults
If rifabutin available
HIV/TB
CO-INFECTION
2013 ART
STRENGTH & QUALITY
GUIDELINES
OF EVIDENCE
No change strong, moderatequality evidence
If rifabutin not
available
AZT + TDF + 3TC (or FTC) + (ATV/r or LPV/r)
Rationale: Comparative Analysis of
ATV/r, LPV/r and DRV/r
Major parameters
Consistency with pediatric regimens
Number of pills per day (standard dose as
FDC)
Convenience (once vs twice daily regimen)
Safety in pregnancy
GI intolerance (diarrhea)
Availability of heat stable FDCs
Use with TB treatment regimen that
contains rifampin
Hyperbilirrubinemia
Dyslipidemia
Reduction cost potential
Accessibility in countries (registration
status)
Availability of generic formulations
ATV/r
LPV/r
DRV/r
no
yes
no
1
4
2-4
once daily
twice daily
yes
Not frequent
yes
yes
common
yes
Once or twice
daily
yes
Not frequent
no
no
yes
no
+
±
low
+
low
±
high
low
high
low
yes
yes
no
HOW TO MONITOR
AND WHEN TO
SWITCH
Recommendations: Monitoring
for ART Response
RECOMMENDATION
STRENGTH
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
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
•
•
•
•
•
Targeted viral load
monitoring (suspected clinical
or immunological failure)
Earlier capture of treatment
failure & reducing HIVDR
Test viral load
Viral load >1000
copies/ml
Help discriminate between
treatment failure & nonadherence
Evaluate for adherence
concerns
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
Routine viral load monitoring
(early detection of
virological failure)
Repeat viral load testing
after 3–6 months
Viral load ≤1000
copies/ml
Viral load >1000
copies/ml
Maintain first-line
therapy
Switch to second-line
therapy
Predictive value of WHO immunological and
clinical criteria
Population
Viral load
Positive
Number Number of
Sensitivity Specificity predictive
of studies patients
value
Negative
predictive
value
Adults
>5000
copies/mL
3
2288
68.9%
92.1%
27.0%
98.6%
Adults
50-4999
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 Guidelines
Topic
2002
When to
start
CD4 ≤200
2003
CD4 ≤ 200
2006
2010
CD4 ≤ 200
CD4 ≤ 350
- Consider 350
- CD4 ≤ 350 for TB
-Irrespective CD4 for
TB and HBV
Earlier initiation
1st Line
8 options
4 options
8 options
6 options &FDCs
- AZT preferred
- AZT preferred
- AZT or
TDFpreferred
- d4T dose reduction
- AZT or TDF preferred
- d4T phase out
Simpler treatment
2nd Line
2013
CD4 ≤ 500
-Irrespective CD4 for
TB, HBV, PW and
SDC
- CD4 ≤ 350 as
priority
1 preferred option
& FDCs
- TDF and EFV
preferred across
all populations
Boosted and
non-boosted
PIs
Boosted PIs
Boosted PI
Boosted PI
-IDV/r LPV/r,
SQV/r
- ATV/r, DRV/r, FPV/r
LPV/r, SQV/r
- Heat stable FDC:
ATV/r, LPV/r
3rd Line
None
None
None
DRV/r, RAL, ETV
DRV/r, RAL, ETV
Viral Load
Testing
No
No
Yes
Yes
(Desirable)
(Tertiary centers)
(Phase in approach)
Yes
(preferred for
monitoring,
use of PoC, DBS)
Less toxic, more robust regimens
Better monitoring
Boosted PIs
- Heat stable FDC:
ATV/r, LPV/r