Download - Country Experience I nforming F easibility
Country Experience Informing Feasibility
• Option B+ (Malawi)
• Tenofovir phase in 1st line( Zambia)
• d4T phase out in HIV programmes
• Raising CD4 threshold to 350 cells (Ethiopia)
• Viral Load roll out (MSF and Kenya)
Accelerated global phasing out of d4T
Implementing Option B+: Malawi
The ART programme in EthiopiaNo of ART sites (2006-2012)MSF UNITAID Funded Viral Load Project
(2013-2015)
2013 ARV Guidelines: Highlights
ADDITIONAL SUMMARY BRIEFS(15 PAGES)
ICONS FOR TARGET POPULATIONS ICONS FOR NEW RECOMMENDATIONS
6 CHAPTERS: ALONG THE CONTINUUM OF CARE
OVER 50 NEW RECOMMENDATIONS
• Clinical• Operational and Service
Delivery• HIV testing & counselling
TABLES, CHECKLISTS & ALGORITHMS
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)
Key Themes of New Recommendations
Operationally relevant• Use of Fixed Dose Combinations as a
preferred approach
• Improved patient monitoring to support better adherence and detect earlier treatment failure (increased use of VL)
• Recommend task shifting, decentralization, and integration
• Community based testing to complement broader HTC
1. What are the components of Guidance for Programme Managers?
Review tools for costing and planning
Discuss key data needed for evidence-
based decisions
Discuss implementation considerations
Examine key parameters for
decision making
Design an inclusive and transparent
process
When to Start ART
Summary of Changes in Recommendations: When to Start in Adults
TARGET POPULATION(ARV-NAIVE)
2010 ART GUIDELINES 2013 ART GUIDELINESSTRENGTH OF
RECOMMENDATION & QUALITY OF EVIDENCE
HIV+ ASYMPTOMATICCD4 ≤350 cells/mm3
CD4 ≤500 cells/mm3 (CD4 ≤ 350 cells/mm3 as a priority)
Strong, moderate-quality evidence
HIV+ SYMPTOMATICWHO 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
Strong, moderate-quality evidence
HIV/TB CO-INFECTIONPresence of active TB disease, regardless of CD4 cell count No change Strong, 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 SERODISCORDANT COUPLE RELATIONSHIP(S)
No recommendation establishedRegardless of CD4 cell count or WHO clinical stage
Strong, high-quality evidence
Evidence Summary: When to Start in Adults
o Systematic Review of 24 studies (3 RCTs, 21 observational )
oMultiple countries throughout Europe, North America, Central & South America, sub-Saharan Africa and Asia-Pacific
o 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 (RCTs)Low quality evidence for lower risk of progression to AIDS or death with early ART (2 RCTs)
Observational studiesModerate 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 ART0123456789
10
Unknown (n=3)Not from partner (n=7)From partner (n=29)
% in
fect
ed
o RCT to examine efficacy of ART in preventing HIV transmission between discordant couples
o HIV+ partner had CD4 ≥ 350-550 cells/µL and was randomized to early vs. delayed ART
o Significant HIV prevention benefit – a 96% reduction in transmission.
o 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 datao 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 RECOMMENDATION
ADULTS WITH HIV…
…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
CHILDREN < 5 YEARS OLD WITH HIV
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-low-quality 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
FIRST-LINE REGIMENS (PREFERRED ARV REGIMENS)
TARGET POPULATION 2010 ART GUIDELINES 2013 ART GUIDELINES
STRENGTH & QUALITY OF EVIDENCE
HIV+ ARV-NAIVE ADULTS
AZT or TDF + 3TC (or FTC) + EFV or NVP
TDF + 3TC (or FTC) + EFV(as fixed dose combination)
Strong, moderate-quality evidence
HIV+ ARV-NAIVE 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
Rationale: One Regimen For All
o Simplicity: regimen is very effective, well tolerated and available as a single, once-daily FDC and therefore easy to prescribe and easy to take for patients – facilitates adherence
o Harmonizes regimens across range of populations (Adults, Pregnant Women (1st trimester), Children >3 years, TB and Hepatitis B,)
o Simplifies drug procurement and supply chain by reducing number of preferred regimens (phasing out d4T)
o Safety in pregnancyo Efficacy against HBVo 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) o Affordability (cost declined significantly since 2010)
Preferred 1st line regimen: TDF + 3TC (or FTC) + EFV
Evidence Summary: What to Start
o 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)
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)
o 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
No increased risk of birth defects with EFV when compared with other ARVs
Evidence Summary: Safety of EFV and TDF in Pregnancy
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
o Excludes > 3 fold increased risk in overall birth defects
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/enNightingale 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
EFV
o Potential concerns include renal toxicity, adverse birth outcomes and effects on bone density
o 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)
o Limited studies showed no difference in fetal growth between exposed/unexposed
o No studies of TDF among lactating women, who normally have bone loss during breastfeeding
o Current data reassuringo More extensive studies ongoing
TDF
H I V / A I D S
DEPARTMENT
2013 Consolidated ARV Guidelines
Treatment Recommendations for Pregnant and
Breastfeeding Women: Critical Issues
Evolution of WHO PMTCT ARV Recommendations
2001 2006 20102004 Launch July 2013
PMTCT
4 weeks AZT; AZT+ 3TC, or SD NVP
AZT from 28 wks + SD NVP
AZT from 28wks + sdNVP +AZT/3TC 7days
Option A (AZT +infant NVP)Option B (triple ARVs)
Option B or B+Moving to ART for all PW/BF
ART
No recommendation
CD4 <200 CD4 <200 CD4 <350 CD4 <500
Move towards: more effective ARV drugs, extending coverage throughout MTCT risk period, and ART for the mother’s health
Rationaleo Limited coverage and implementation of PMTCT
and ART for pregnant women in many high burden countries• ~ 1.4 million HIV+ pregnant women• 65% PMTCT ARV coverage • Limited ART in those eligible for treatment• High loss to follow-up along PMTCT cascade• Low ARV coverage during breastfeeding
o Complexity of Option A
• Different treatment and prophylaxis regimens through pregnancy and breastfeeding
• Difficulty of long-term NVP dosing for infants
• Requirement for CD4 to determine eligibility
• Follow up along the PMTCT cascade is very low
o Current approach needs to be optimized to achieve universal access and elimination
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
New child HIV infections, low and middle income countries (thousands)
0
100
200
300
400
500
600
• 2009: ~430,000 infant infections• 2012: ~290,000 infant infections• 2015: Global Plan target <40,000
Steady progress reducing infant infections
“Option B+” “Option B”
For programmatic and operational reasons, particularly in generalized epidemics, all pregnant and breastfeeding women infected with HIV should initiate ART as lifelong treatment.
(conditional recommendation, low-quality evidence)
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)
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, low-quality evidence)
Recommendations
Rationale: Shift from Option A to B+ or B
Major issue now is not “when to start” or “what to start” but “whether to stop”
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
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
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
No change strong, moderate-quality evidence
HIV+ PREGNANT
WOMENSame regimens recommended for adults
No change strong, moderate-quality evidence
HIV/TBCO-INFECTION
If rifabutin available Same regimens as recommended for adults
No change strong, moderate-quality evidence
If rifabutin not available
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)
No change strong, moderate-quality evidence
HIV/HBV CO-INFECTION AZT + TDF + 3TC (or FTC) + (ATV/r or LPV/r)
No change strong, moderate-quality evidence
Summary of changes to recommendations: What ART to Switch to