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