Strong, moderate-quality evidence

Report
Country Experience Informing Feasibility
•
Option B+ (Malawi)
•
Tenofovir phase in 1st line( Zambia)
Implementing Option B+: Malawi
Accelerated global phasing out of d4T
•
d4T phase out in HIV programmes
•
Raising CD4 threshold to 350 cells (Ethiopia)
•
Viral Load roll out
(MSF and Kenya)
MSF UNITAID Funded Viral Load Project
(2013-2015)
The ART programme in Ethiopia
No of ART sites (2006-2012)
2013 ARV Guidelines: Highlights
OVER 50 NEW
RECOMMENDATIONS
TABLES,
CHECKLISTS
& ALGORITHMS
ICONS
ICONS
FOR
FOR
NEW
TARGET
RECOMMENDATIONS
POPULATIONS
ADDITIONAL
SUMMARY
BRIEFS
• Clinical
(15 PAGES)
• Operational and Service
Delivery
• HIV testing & counselling
6 CHAPTERS: ALONG THE CONTINUUM OF CARE
Key Themes of New Recommendations
•
•
•
•
•
Clinically relevant
Earlier initiation of ART (CD4 ≤ 500)
Immediate ART for children below 5
years
ART initiation for all pregnant and
breastfeeding women (Option B/B+) and
lifelong ART (Option B+)
Harmonization of ART across populations
(e.g., adults and pregnant women,
Option B/B+) and age groups
Simplified, fewer, and less toxic 1st-line
regimens (TDF/XTC/EFV)
Operationally relevant
•
•
Use of Fixed Dose Combinations as a
preferred approach
•
•
Recommend task shifting,
decentralization, and integration
Improved patient monitoring to support
better adherence and detect earlier
treatment failure (increased use of VL)
Community based testing to
complement broader HTC
1.
What are the components of Guidance for
Programme Managers?
Design an inclusive
and transparent
process
Discuss key data
needed for evidencebased decisions
Review tools for
costing and planning
Examine key
parameters for
decision making
Discuss
implementation
considerations
When to Start ART
Summary of Changes in Recommendations:
When to Start in Adults
TARGET
POPULATION
(ARV-NAIVE)
2010 ART GUIDELINES
HIV+ ASYMPTOMATIC
CD4 ≤350 cells/mm3
HIV+ SYMPTOMATIC
PREGNANT AND
BREASTFEEDING
WOMEN WITH HIV
HIV/TB CO-INFECTION
HIV/HBV COINFECTION
HIV+ PARTNERS IN
SERODISCORDANT
COUPLE
RELATIONSHIP(S)
WHO clinical stage 3 or 4
regardless of CD4 cell count
CD4 ≤350 cells/mm3
or
WHO clinical stage 3 or 4
2013 ART GUIDELINES
CD4 ≤500 cells/mm3 (CD4
≤ 350 cells/mm3 as a
priority)
No change
STRENGTH OF
RECOMMENDATION &
QUALITY OF EVIDENCE
Strong, moderate-quality
evidence
Strong, moderate-quality
evidence
Strong, moderate-quality
Regardless of CD4 cell count
evidence
or WHO clinical stage
Presence of active TB disease,
regardless of CD4 cell count
No change
Strong, low-quality evidence
Evidence of chronic active HBV
disease, regardless of CD4 cell
count
Evidence of severe chronic
Strong, low-quality evidence
HBV liver disease,
regardless of CD4 cell count
Regardless of CD4 cell
Strong, high-quality evidence
No recommendation established count or WHO clinical stage
Evidence Summary: When to Start in Adults
o Systematic Review of 24 studies (3 RCTs, 21 observational )
o Multiple countries throughout Europe, North America, Central &
South America, sub-Saharan Africa and Asia-Pacific
o 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 (RCTs)
Low quality evidence for lower risk of progression
to AIDS or death with early ART (2 RCTs)
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
10
% infected
8
6
Unknown (n=3)
4
Not from partner
(n=7)
From partner
(n=29)
2
0
Early ART
o
o
o
o
Late ART
RCT to examine efficacy of ART in preventing
HIV transmission between discordant
couples
HIV+ partner had CD4 ≥ 350-550 cells/µL and
was 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
o High to moderate quality evidence that
treatment prevents sexual transmission of
HIV (1 RCT and observational data)
Recommendations: CD4 Independent Conditions
INITIATE ART REGARDLESS OF CD4 COUNT OR CLINICAL STAGE
ADULTS WITH HIV…
CHILDREN < 5
YEARS OLD WITH
HIV
RECOMMENDATION
…and active TB disease
Strong, low-quality
evidence
…and HBV co-infection with severe liver
disease
Strong, low-quality
evidence
…who are pregnant or breastfeeding
Strong, moderate-quality
of evidence
…in a HIV serodiscordant partnership
Strong, high-quality
evidence
Infants diagnosed in the first year of life
Strong, moderate-quality
of evidence
Children infected with HIV between one
and below five years of age
Conditional, very-lowquality evidence
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
2013 ART GUIDELINES
STRENGTH &
QUALITY OF
EVIDENCE
HIV+ ARV-NAIVE AZT or TDF + 3TC (or
ADULTS
FTC) + EFV or NVP
HIV+ ARV-NAIVE
PREGNANT
AZT + 3TC + NVP or EFV
WOMEN
HIV/TB
CO-INFECTION
AZT or TDF + 3TC (or
FTC) + EFV
HIV/HBV
CO-INFECTION
TDF + 3TC (or FTC) + EFV
TDF + 3TC (or FTC) + EFV
(as fixed dose
combination)
Strong,
moderate-quality
evidence
Rationale: One Regimen For All
Preferred 1st line regimen:
TDF + 3TC (or FTC) + EFV
o
o
o
o
o
o
o
Simplicity: regimen is very effective, well tolerated and available as a single, oncedaily FDC and therefore easy to prescribe and easy to take for patients – facilitates
adherence
Harmonizes regimens across range of populations (Adults, Pregnant Women (1st
trimester), Children >3 years, TB and Hepatitis B,)
Simplifies drug procurement and supply chain by reducing number of preferred
regimens (phasing out d4T)
Safety in pregnancy
Efficacy against HBV
EFV is preferred NNRTI for people with HIV and TB (pharmacological compatibility
with TB drugs) and HIV and HBV coinfection (less risk of hepatic toxicity)
Affordability (cost declined significantly since 2010)
Evidence Summary: What to Start
o
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)
Virological response (48 weeks)
Severe adverse events (48 weeks)
o
o
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)
Discontinuation NVP vs. EFV
Comparative efficacy 3TC and FTC
Evidence Summary: Safety of EFV and TDF
in Pregnancy
EFV
No increased risk of birth defects with
EFV when compared with other ARVs
TDF
o
o
o
o
o
Systematic review (including Antiretroviral
Pregnancy Registry), reported outcomes
for 1502 live births to women receiving
EFV in the first trimester and found no
increase in overall birth defects
Excludes > 3 fold increased risk in overall
birth defects
o
o
o
Potential concerns include renal toxicity,
adverse birth outcomes and effects on
bone density
Systematic review assessed the toxicity of
fetal exposure to TDF in pregnancy
• In Antiretroviral Pregnancy Registry,
prevalence of all birth defects with
TDF exposure in 1st trimester was
2.4% (same as background)
Limited studies showed no difference in
fetal growth between exposed/unexposed
No studies of TDF among lactating
women, who normally have bone loss
during breastfeeding
Current data reassuring
More extensive studies ongoing
Source: Ford N et al. AIDS, 2011. Ford N et al. AIDS, 2013. Ekouevi DK et al.J AIDS, 2011. WHO, Geneva Use of EFV during pregnancy. 2012.
http://www.who.int/hiv/pub/treatment2/efavirenz/en
Nightingale SL. JAMA, 1998. British HIV Association. Guidelines for the management of HIV infection in pregnant women. HIV Medicine. 2012. De Santis M et al. Arch of Int
Medicine, 2002.
Source: Antiretroviral Pregnancy Registry Steering Committee http://www.APRegistry.com Siberry GK et al. AIDS, 2012
2013 Consolidated ARV Guidelines
HIV/AIDS
DEPARTMENT
Treatment Recommendations
for Pregnant and
Breastfeeding Women:
Critical Issues
Evolution of WHO PMTCT ARV
Recommendations
2006
2010
Launch
July 2013
PMTCT
2004
4 weeks AZT;
AZT+ 3TC, or
SD NVP
AZT from 28
wks + SD NVP
AZT from 28wks Option A
Option B or B+
+ sdNVP
(AZT +infant NVP) Moving to ART
+AZT/3TC 7days Option B
for all PW/BF
(triple ARVs)
ART
2001
No
recommendation
CD4 <200
CD4 <200
CD4 <350
Move towards: more effective ARV drugs, extending coverage
throughout MTCT risk period, and ART for the mother’s health
CD4 <500
Rationale
o
Limited coverage and implementation of PMTCT
and ART for pregnant women in many high
burden countries
Steady progress reducing infant infections
• ~ 1.4 million HIV+ pregnant women
New child HIV infections, low and middle
income countries (thousands)
• 65% PMTCT ARV coverage
600
• Limited ART in those eligible for treatment 500
• High loss to follow-up along PMTCT cascade 400
• Low ARV coverage during breastfeeding
300
o
Complexity of Option A
•
•
•
•
o
Different treatment and prophylaxis regimens
through pregnancy and breastfeeding
200
100
Difficulty of long-term NVP dosing for infants
Requirement for CD4 to determine eligibility
Follow up along the PMTCT cascade is very low
Current approach needs to be optimized to achieve
universal access and elimination
0
2000
2005
2010
•2009: ~430,000 infant infections
•2012: ~290,000 infant infections
•2015: Global Plan target <40,000
2015
Recommendations
“Option B+”
“Option B”
All pregnant and breastfeeding women infected with HIV should initiate triple ARVs (ART),
which should be maintained at least for the duration of mother-to-child transmission risk.
Women meeting treatment eligibility criteria should continue lifelong ART .
(strong recommendation, moderate-quality evidence)
For programmatic and operational
reasons, particularly in generalized
epidemics, all pregnant and
breastfeeding women infected with
HIV should initiate ART as lifelong
treatment.
In some countries, for women who
are not eligible for ART for their own
health, consideration can be given to
stopping the ARV regimen after the
period of mother-to-child
transmission risk has ceased.
(conditional recommendation, lowquality evidence)
(conditional recommendation, lowquality evidence)
Rationale: Shift from Option A to B+ or B
BENEFITS FOR MOTHER AND CHILD
BENEFITS FOR PROGRAM DELIVERY &
PUBLIC HEALTH
Ensures all ART eligible women initiate
treatment
Reduction in number of steps along PMTCT
cascade
Prevents MTCT in future pregnancies
Same regimen for all adults (including
pregnant women)
Potential health benefits of early ART for
non-eligible women
Simplification of services for all adults
Reduces potential risks from treatment
interruption
Simplification of messaging
Improves adherence with once daily, single
pill regimen
Protects against transmission in discordant
couples
Reduces sexual transmission of HIV
Cost effective
Major issue now is not “when to start” or “what to start” but “whether to stop”
Programmatic considerations for B+
• Initiate all HIV+ pregnant and breastfeeding women on ART
• Operational and programmatic advantages to lifelong ART for
pregnant and breastfeeding women (“B+”), particularly in settings
with:
–
–
–
–
–
Generalized epidemics
High fertility (though need to strengthen FP)
Long duration of breastfeeding
Limited access to CD4 to determine ART eligibility
High partner serodiscordance rates
• National programmes need to decide B or B+
ARVs and breastfeeding
2013 (no change from 2010)
National agencies should decide between promoting mothers with HIV to either
breastfeed and receive ARV interventions or to avoid all breastfeeding
Where the national choice is to promote BF, mothers whose infants are HIV
uninfected or of unknown HIV status should:
• exclusively breastfeed their infants for the first six months of life
• introduce appropriate complementary foods thereafter, and continue
breastfeeding for the first 12 months of life
• breastfeeding should then only stop once a nutritionally adequate and safe diet
without breast-milk can be provided
(strong recommendation, high-quality evidence for the first 6 months;
low-quality evidence for the recommendation of 12 months)
Implementation Issues
• Adequate planning for changes in guidelines
• Expansion and integration of ART into PMTCT sites
— Supply chain for ARVs (avoidance of stock-outs)
— Task-shifting for ART initiation
— Adherence, retention, follow up, linkages with chronic ART
— All MNCH sites become ART sites
• Access to ART monitoring
Major challenge for PMTCT and MNCH settings:
• How to expand access to VL monitoring?
• How to utilize CD4 data, especially for women with high baseline CD4?
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
HIV/HBV
CO-INFECTION
STRENGTH & QUALITY
OF EVIDENCE
strong, moderatequality evidence
If d4T or AZT used in
first-line
TDF + 3TC (or FTC) +
ATV/r or LPV/r
No change
If TDF used in first-line
AZT + 3TC +
ATV/r or LPV/r
No change
strong, moderatequality evidence
No change
strong, moderatequality evidence
No change
strong, moderatequality evidence
No change
strong, moderatequality evidence
No change
strong, moderatequality evidence
Same regimens recommended for adults
If rifabutin available
HIV/TB
CO-INFECTION
2013 ART
GUIDELINES
If rifabutin not
available
Same regimens as
recommended for adults
Same NRTI backbones
recommended for adults plus
LPV/r or SQV/r with adjusted
dose of RTV (i.e., LPV/r
400mg/400mg BID or SQV/r
400mg/400mg BID)
AZT + TDF + 3TC (or FTC) + (ATV/r or LPV/r)

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