Transcript Document

Rationale: 2nd Line Regimens in Adults
o Simplifying second-line ART
•
•
•
Limiting number of preferred options, and harmonisation across populations
Availability of more convenient heat stable bPI formulations
Daily dosing, FDC with reduced pill burden
o Management of co-morbidities in the context of 2nd line ART
•
•
o
TB (use of rifampicin and PIs)
HBV (use of ARV with anti-HBV activity)
Evidence summary – systematic review
•
•
(6 RCTs) - comparison of major PIs used for second-line ART (ATV/r, LPV/r and DRV/r)
—ATV/r comparable to LPV/r in ART-experienced individuals but better
virological response and better retention in care among ART-naive
—DRV/r better virological response and retention in care than LPV/r, both in
treatment-naive and experienced people
No good quality evidence to support changing the recommendation established in
the 2010 guidelines
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
Once or twice
daily
yes
Not frequent
yes
yes
common
yes
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
Viral load is recommended as the preferred
monitoring approach to diagnose and
confirm ARV treatment failure
STRENGTH
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
Rationale: VL Monitoring
o
o
o
o
o
o
Targeted viral load monitoring
(suspected clinical or
immunological failure)
To provide an early and more accurate indication of
treatment failure, reducing the accumulation of
HIVDR mutations and improving clinical outcomes.
Can also help to discriminate between treatment
failure and non-adherence
Can serve as a proxy for the risk of transmission at
the population level
Harmonized monitoring approaches between
adults and children
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)
Routine viral load monitoring
(early detection of
virological failure)
Test viral load
Viral load >1000
copies/ml
Evaluate for adherence
concerns
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
Evidence Summary: Virological vs. CD4 + Clinical Monitoring
6 studies (4 RCTs and 2 observational studies)
Main Findings:
1. Clinical+Immunological versus Clinical+Immunological+Virological: (1 RCT + 1
observational study ): no difference in terms of mortality (moderate-quality evidence) and
new AIDS-defining illness (moderate-quality evidence).
2.
Clinical+Immunological versus Clinical+Virological: (1 RCT): no difference in terms of
clinical failure (low), switch to second line regimens (low), and resistance mutations (low).
Children (Arrow 2013): mortality and disease progression are comparable between clinical
and laboratory monitoring
Limitations: limited duration of follow up and sample size
Viral load threshold:
o Children: 1 RCT: No difference in clinical or virological outcomes, but less drug resistance if
ART switched at a viral threshold of 1000 copies/mL compared to 30,000 copies/mL
(medium quality of evidence). (PENPACT1)
o viral blips (50–1000 copies/ml) during effective treatment not been associated with an
increased risk of treatment failure unless low-level viraemia is sustained
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%
Critical issues in
Children infected
with HIV
Key issues for Treatment and Care
Programmatic Challenges
– EID coverage remains poor
– ART coverage only 34% (in 22 priority countries)
– Limited availability of pediatric formulations and
difficulties in harmonizing regimens with adults
– Poor retention of children on ART and in care
Technical Challenges
– Provide the most effective regimen to deal with high VL
and rapid disease progression
– Optimization of ART treatment sequencing
When to start ART
AGE
GROUP
2010 RECOMMENDATIONS
AGE
GROUP
2013 RECOMMENDATIONS
<1 YEARS
Treat ALL
Strong recommendation,
moderate-quality evidence
< 1 YEAR
Treat ALL
Strong recommendation, moderate-quality
evidence
1-2 YEARS
Treat ALL
Conditional recommendation,
very-low-quality evidence
1-5 YEARS
2-5 YEARS
Initiate ART with CD4 count ≤750
cells/mm3 or <25%, irrespective
of WHO clinical stage
Treat ALL
Conditional recommendation, very-lowquality evidence
Priority: children < 2 years or WHO stage 3-4
or CD4 count ≤ 750 cells/mm3 or < 25%
≥5 YEARS
Initiate ART with CD4 count ≤350 ≥5 YEARS
cells/mm3 (As in adults),
irrespective of WHO clinical stage
AND
WHO clinical stage 3 or 4
CD4 ≤ 500 cells/mm3
Conditional recommendation, very-lowquality evidence
CD4 ≤350 cells/mm³ as a priority (As in
Adults)
Strong recommendation, moderate-quality
evidence
Rationale: ART Initiation in Children <5yrs
o Strong operational and programmatic advantages
• Simplification of criteria for ART initiation and harmonizing with adults
• Reduce barrier to ART initiation and facilitate expansion of coverage
• Reduces morbidity and improves immunological response
• May facilitate treatment of other preventable causes of under five mortality
• Acceptability: Earlier ART may facilitate family-based care, improve
retention in care and adherence.
o Limited evidence
• PREDICT trial: AIDS-free survival did not differ between deferred and early
•
treatment group in older children (median age 6.4 years).
IeDEA Southern African Causal Modeling Analyses:
—in children 2-5 years no difference in mortality between early ART vs. starting
ART later. 75% of children with CD4 >25% (or 750 cells) become eligible within 3
years of enrolment
o Most feasible in settings with high burden of HIV disease and low ART coverage,
and limited access to immunological testing.
What ART to start: age < 3 years
Age group
<12 months
Prior exposure to
PMTCT ARV’s
Exposed
2010
recommendations
LPV/r + 2 NRTIs
Not Exposed
Exposure unknown
12 to <36
months
Regardless of exposure
NVP + 2 NRTIs
• AZT + 3TC
• ABC + 3TC
• d4T + 3TC
2013
recommendations
LPV/r plus 2 NRTIs
If LPV/r not available,
NVP-based
Plus
NRTI backbone:
• AZT or ABC + 3TC
• (d4T+3TC*)
• When HIV RNA monitoring is available, consider to substitute LPV/r with
NNRTI after virological suppression is sustained (conditional, low quality)
Rationale
LPV-based Regimen in Children < 3 years
o
o
o
o
Importance of a potent first line regimen in young
children in context of high viral load and rapid
disease progression
Evidence of superiority of LPV regimen regardless
of PMTCT exposure
• Systematic review of two RCTS: reduced risk of
discontinuing treatment and virological failure
or death
Low failure rate and good resistance profile at
treatment failure with limited selection of
resistance to NRTIs (Violari et al. Glasgow 2012)
Reduction of malaria incidence by 41% (Achan et al
2012)
o
Desirability to have one preferred regimen for
children <3 years
o
Anticipating the availability of new formulations
(LPV containing sprinkles and sachets)
LPV superior to NVP
Treatment Discontinuation
Virological failure or death
Implementation Considerations: LPV Use in Children <3yrs





Cold chain requirements
Low adherence due to poor palatability
Lack of FDC available
Lack of second line options in RLS
Interaction with TB drugs
 Sprinkles soon available and “4in1”FDC are under development
 Simplification by switching to NVP once virological suppression is achieved
is safe in children without baseline resistance to NNRTI (Coovadia et al 2010,
Kuhn et al 2012)
 Dropping LPV/r and adding ABC can be an option for children who get TB
while on ART (Arrow trial 2013)
What to start in > 3 years
Age group
2010
recommendations
2013
recommendations
Age group
3-10 years
NNRTI
NVP or EFV
plus
3-19 years
2 NRTIs
in preferential order:
AZT + 3TC
ABC + 3TC
d4T + 3TC
TDF + FTC + EFV to be
used as preferred
regimen if HIV/HBV
coinfection and >12
years and > 35 Kg
(Including > 10 yrs
who weighing <35kg) 2NRTIs
EFV is preferred
NVP as alternative
In preferential order:
ABC + 3TC
AZT or TDF + 3TC or FTC
10-19 years
(weighing ≥35 kg)
(align with adults)
NNRTI
EFV is preferred
NVP as alternative
2NRTIs
In preferential order:
TDF + FTC or 3TC
ABC + 3TC
AZT + 3TC
Rationale: What to start in children ≥3 years
o Opportunity for harmonization with adults – improve children’s access to ART
o Convenience of once daily regimens and FDC where available
o Better sequencing of therapy (ABC and TDF) as first line and thymidine
o
analogues (AZT) as second line.
Systematic review: EFV better short-term toxicity profile than NVP
Implementation Considerations
o Experience with TDF in children is limited. Long term impact is unknown
o No TDF-containing FDCs. Requires advocacy to bring to market
o Feasibility highly dependent on toxicity monitoring required and on the
o
availability of adequate formulations in the market.
Children stable on NVP do not need to substitute with EFV
Rationale: 2nd Line Regimens in Children
SECOND-LINE ART
PREFERRED REGIMENS
ADULTS AND ADOLESCENTS (>35 kg),
INCLUDING PREGNANT AND
BREASTFEEDING WOMEN
AZT + 3TC + LPV/r
AZT + 3TC + ATV/r
TDF + 3TC (or FTC) + ATV/r
TDF + 3TC (or FTC) + LPV/r
ABC + 3TC + LPV/r
ABC + 3TC + LPV/r
TDF + 3TC (or FTC) + LPV/r
<3 years
No change from first-line
regimen in use
AZT (or ABC) + 3TC + NVP
3-10 years
(< 35kg)
AZT (or ABC) + 3TC + EFV
TDF + 3TC + EFV
ABC (or TDF) + 3TC + NVP
If a NNRTI-based first-line
regimen was used
CHILDREN If a PI-based
first-line
regimen was
used
ALTERNATIVE REGIMENS
o Very few failures (Violari et al. Glasgow 2012)
o Good HIVDR profile once you fail on PI (selection of PI resistance
o
mutations rare, and limited NRTIs mutations (PENPACT1, CHER)
No PI cross-resistance: DRV can be used (CHIPS UK cohort 2011)
Summary Recommendations
Consolidation across:
- Continuum of HIV care
- Ages and populations
- Clinical, operational and programmatic guidance
- Existing and new recommendations
Key new recommendations:
- Earlier ART initiation ≤ CD4 500
- Single, preferred 1st line regimen (FDC)
- Lifelong ART for pregnant and breastfeeding women
- Immediate ART all children < 5 years
- Move to viral load monitoring
- Integration of ART into other services
- Decentralization and task-shifting
- Adherence support
Implications and impact (to 2015)
- Additional 3 million HIV-related deaths averted
- Additional 3.5 new HIV infections averted
- Cost - additional 10% on top of total resource needs
2010
Estimated impact on ART eligibility of
implementing the new recommendations
= 16.7
2013
CD4 <350*
on ART
= 25.9
CD4 <500*
<5y
**
**
Number of people eligible for ART in low- and middle-income countries in million per WHO
2010 and 2013 ARV guidelines, based on end of 2012 epidemic situation
* incl. co-infected with TB or HBV
** only CD4>500, others included in adults
Estimated impact on incidence and deaths of
implementing the new recommendations
WHO Global ART report, 2013
Strategic Use of ARVs (SUFA) for Treatment
and Prevention
Priorities for 14/15:
• ISS-SUFA 3
• Gaps in the current guidelines
• How gaps can be filled from
traditional and Implementation
Science Research
• Roadmap of guideline products
• Vision of moving to a Test &
Treat - Scenario 5 for 2015
Guidelines update
• How to get there?
• Setting the stage for the post2015 era
• Post 15x15 target
• New areas to consider
• Cure, linkage new flagship
(comorbidities, NCDs etc)
Jan 2014
CTX guidelines
Timeline new guidance and updates
Skin oral OI GL
Crypto GL
PEP
Jan 2015
CD4 monitoring
NCD & HIV
Infant testing
MH & HIV
HIVDR, Toxicity
Monitoring
Bey
ond
…
NTD & HIV
Tech update
Retention
Cure
July 2014
KP Consolidation
SI Consolidation
CoMorbidities
Hep Screening
HIV & nutrition
July 2015
ARV
Consolidation
Update
VL scale up
7/16/2015
Quality
22