ICASA IAS

Scaling up Treatment Delivery Programmes: Issues, Challenges & Best

Practices

Siobhan Crowley

HIV Department

WHO Geneva

% Pregnant women with HIV who received ARVs to reduce MTCT increased 2004-2007 - but 49% still received only single dose nevirapine

Distribution of ARV regimens, 2007

Percentage of pregnant women with HIV receiving ARVs for PMTCT in low- and middle-income countries

Towards Universal Access – Scaling up priority HIV/AIDS interventions in the health sector. WHO/UNAIDS/UNICEF, June 2008

More children are receiving ART

Increased from 75,000 in 2005 to almost 200,000 in 2007 19 of 20 countries with highest PMTCT burden are in sub-Saharan Africa90% of burden is in 20 countriesEast,S and SE Asia increase coverage from 18% to 25% in 2008

0

50,000

100,000

150,000

200,000

250,000

End 2005 End 2006 End 2007

Child

ren <1

5 rec

eiving

ART

East, South & South East Asia

Eastern Europe & Central Asia

Latin America & Caribbean

West and Central Africa

Eastern and Southern Africa

Total=75,000 Total=197,600Total=127,300

78% increase from 2005-2006

55% increase from 2006-2007

Towards Universal Access: Scaling up priority HIV/AIDS interventions in the health sector, WHO/UNAIDS/UNICEF 2008

Progress has been made

WHO - A Public Health Approach

Goal

Maximize survival with improved quality of life

Principles:

Population-based approach

Evidence-based standards of care

Simplified standardised treatment regimens & patient monitoring

Decentralised and integrated service delivery

Core elements of the a Public Health Approach

Comprehensive approach to HIV prevention, care and ART Provider-initiated Testing and Counselling Prevention for those who test negative Positive prevention for those who test positive Pre-ART care for those who do not need ART immediately Continuum of care Decentralised and integrated service delivery Treatment literacy, adherence and chronic care Simplified clinical monitoring & basic laboratory

Harmonised ART Policy Guidance

IMAI/IMCI Implementation tools

Audience for WHO guidelines

Primarily national planners and policy makers engaged in public sector ART and in target-setting Which ARVs to make available in public sector for

first and second-line regimens How to use: the four Ss of clinical management:

when to start, substitute, switch and stop

Care implementers - basic knowledge to use ARVs effectively according to national policy recommendations

Trainers, M&E experts – to design appropriate tools and materials to support national policy recommendations

When to start ART

Recommendations for initiating antiretroviral treatment in adults

WHO Clinical Staging

CD4 testing not available

CD4 testing available

1 Do not treat

Treat if CD4 cell count < 200/mm3

2 Do not treat

3 Treat

Consider ART if CD4 < 350/mm3, start

before it drops to < 200 /mm3

Recommend for all HIV+ pregnant

women if CD4 < 350 /mm

4 Treat Treat irrespective of CD4 cell count

Issues for -when to start

Earlier initiation of adult ART with CD4 350 – 500

Reduced non AIDS events from cohort data not RCTs, and in industrialised settings

May further reduce HIV transmission

? Feasibility of CD4 dependent strategy

No's - estimates for disease burden rise > 30%

Associated costs

Health systems demands – increase # providers/sites

Caution with NVP in women + CD4 > 250, men >400

Areas for 2008 review in criteria to start ART adults

CD4

Stage

< 200 200-349 350-499 >500

1 Treat ? Treat Do not treat Do not treat

2 Treat

? Treat

Do not treat Do not treat

3 Treat Treat ? Treat ? Treat

4 Treat Treat Treat Treat

When to start in pregnant women

Currently WHO recommends ART in all symptomatic women with CD4 < 350, Consider ART for all pregnant women with CD4 < 350 Prophylaxis (AZT + 3TC tail + Sd NVP ) for non ART

eligible

Being evaluated: ? combination prophylaxis for all pregnant women <350

or < 500 +/- combination prophylaxis for all women who are breast-feeding

? Treat all pregnant women irrespective of CD4 Extended infant prophylaxis if breastfeeding

Key issues ART & pregnancy

? Safety of stopping post-partum: SMART data Access to CD4 in ANC Feasibility in universal ART antenatal / MCH clinic

settings ? What to use – NVP contraindicated CD4 > 250,

Efavirenz – teratogenic, concerns re TDF, PIs and metabolic complications not

Complexity and health systems demands Equity: very different ART access for pregnant ? Adherence in well women ? adverse pregnancy outcomes

Children

Starting ART when severely immunodeficient increases mortality

Months from

ART start Probability of Death After Starting ART

Immune Deficient at Start ART Not Immune Deficient at Start

ART

6 months 7.8% 1.8%

12 months 8.2% 2.2%

6% excess mortality

73% median age > 5 years of age, > 50% start with severe immune deficiency, most deaths within 6 months of starting ART

Risk factors for death:• low CD4• < 18 months age• WHO stage 3/4 • viral load greater than 6·0 log• severe malnutrition

Arrive E et al. 14th CROI, Los Angeles, CA, 2007 Abs. 727

Sutcliffe et al. Lancet Infect Dis 2008;8: 477–89

CD4% Increase in Children on cART in SSA

Sutdiffe CG et al. Lancet Infect Dis 2008;8:447-89

0.0

00

.20

0.4

00

.60

0.8

01

.00

0 3 6 9 12Time to Death (months)

Failu

re P

rob

ab

ilit

y

Deferred

Immediate

CHER STUDY : 76% Reduction in the Risk of Death with Immediate Compared to Deferred ART

Patients at risk

5299145213252Immediate

224472104125Deferred

Month 12Month 9Month 6Month 3Month 0

P = 0.0002

Most deaths occurred within first 6 months (i.e., before age 10 months)

immediate

deferred

16%

4%

Revised WHO Guidelines 2008 : When to Start Antiretroviral Therapy in HIV-Infected Children

< 12 months

HIV Confirmed

< 12 months

Presumptive Severe

HIV*

1- 4 yrs > 5yrs

All regardless of

CD4/clinical

All regardless of

CD4/clinical

Clinical or

immune

criteria

Clinical or immune

criteria

<20%

or

12-35 mos: <750/uL

36-59 mos: <350/uL

<15%

or

<200/uL

( or as adults)

*If Viral test is not possible, use presumptive diagnosis of severe HIV (thrush, severe pneumonia or sepsis) in infants with +ve HIV antibody test and with clinical symptoms of severe HIV – confirm infection status as soon as possible.

What to use

Adults & children (1 year or over)

Clinical and/or immunological criteria

to start ART

Standard first line regimen

NNRTI + 2NRTI

< 3 years NVP + AZT

+ 3TC

> 3 years EFV + AZT

+ 3TC

Standard second line regimen

PI + 2 new NRTI

What ART to Start in infants –2008 revision

No infant or maternal

ARV exposure

MTCT ARV Exposure

Sd NVP or NNRTI containing ART

No NNRTI exposure

Unknown infantmaternal MTCT

Exposure

NVP triple ARTPI triple ART#

NVP triple ART

NVP triple ART

# If no PI is available use NVP triple ART

Mum 34%Baby 18%

Revised simplified dosing infants & children

1 ADULT FDC AM & PM

1 BABY FDC AM & 1 PM

1 ADULT FDC AM & 0.5 PM

2 BABY FDC AM & PM

2 BABY FDC AM & 1 PM

0.5 ADULT FDC AM + PM

WHO FDC ARV tablet regimen superimposed

Same dosingirrespective of FDC, or

same dosing for all three single ARV agents

Most dose adjustments done in 1st

year Adapted from T. NUNN

Percentage of adults and children on 1st and 2nd line regimens (2007)

97% 97%

3% 3%

0%10%20%30%40%50%60%70%80%90%

100%

Adult Children

1st Line 2nd Line

0

200

400

600

800

1000

1200

1400

1600

1800

2004

2005

2006

2007

2008

Median transaction prices for one years treatment

Transaction prices for ARVs Summary Report form GPRM Oct 2008

First line failure – when to switch

WHO Definitions of Treatment Failure for Patients on a First-Line Antiretroviral Regimen

Clinical failure a Occurrence of new or recurrent WHO stage 4 condition

CD4 cell failure Fall of CD4 count to pre-therapy baseline (or below) or

50% fall from the on-treatment peak value (if known) or

Persistent CD4 levels < 100 cells/mm3

Virological failure Plasma viral load >10,000 copies/ml

a. Any clinical event must be differentiated from the immune reconstitution inflammatory

syndrome (IRIS)

Virologic ClinicalImmunologic

Viral load

CD4 count

"Early Switch" "Late Switch"

Failure / When to Switch

Clinicalcriteria

WHO ART Failure Meeting: Major Conclusions

Time on ART :Clinical: WHO Stage 3 or 4 after at least 1 year on ART CD4: confirmed CD4 < 100-200 after at least 1 year on ART

(check/reinforce adherence before switching decision)

HIV RNA threshold : Maintain 10,000 as a switch point (little immediate immune damage). Action when VL> 1,000 (adherence, toxicity, drug interaction assessment) and start to consider switching

More efficient use of VL (targeted strategy)Confirm immunologic/clinical failure (?discordance)Pregnant women Adherence monitoring

What to switch to……..second line

Patient group Preferred first line regimen

Preferred second line regimen

Infant not exposed to NVP NVP + AZT# + 3TC Boosted PI + 2 new NRTI

Infant exposed to NVP Lop/r + AZT # + 3TC NNRTI + 2 new NRTI

Infant Unknown NVP

exposure

NVP + AZT # + 3TC Boosted PI + 2 new NRTI

Children 3 or over EFV + AZT # + 3TC Boosted PI + 2 new NRTI

# if anaemia use alternative ABC or d4T

Summary of Regimen options - adults

ADULT OR ADOLESCENTS

Adult or adolescent NNRTI + 2 NRTI Boosted PI + 2 NRTI Woman starting ART in pregnancy

NVP + AZT + 3TC Doesn't apply

Women starting ART within 6 months of single dose NVP

NNRTI + 2 NRTI or 3 NRTI

Doesn't apply

CONCOMITANT CONDITIONS

Child, adolescent or adult with severe anaemia

NVP + 2NRTI (avoid AZT)

Boosted PI + 2NRTI (avoid AZT)

Child, adolescent or adult with TB

EFV + 2NRTI or 3NRTI

Boosted PI * + 2 NRTI

Adult or adolescent with Hepatitis B

TDF + 3TC + NNRTI Boosted PI + 2 NRTI**

Adult or adolescent with Hepatitis C

EFV + 2NRTI Boosted PI + 2 NRTI

IDU NNRTI + 2NRTI Boosted PI + 2 NRTI HIV-2 or dual infection 3NRTI Boosted PI + 2 NRTI

Options for adult second-line ART

1st Line NRTI Second line

NRTI Component PI Component

If AZT or d4T is used in 1st line

ABC + ddI or TDF+3TC (FTC)

ATV/r or

LPV/r

If TDF is used in 1st line AZT+3TC

If ABC is used in 1st line

AZT+3TC or TDF+3TC (FTC)

Managing co-infection with TB

Ethiopia3%

Kenya10%

Malawi5%

Mozambique4%Nigeria

6%

South Africa29%

Zambia3%

Zimbabwe4%

AFR*10%

DR Congo3%

Côte d'Ivoire2%

UR Tanzania3%

Swaziland1%

Uganda2%

Others15%

Brazil

AMR*

Russian Fed

EUR*

India

SEAR*

WPR

EMR

0

5

10

15

20

Geographical distribution of estimated HIV-positive TB cases, 2006

Opportunistic Illnesses

0

50

100

150

200

250

300

350

Screened for TB(44, 52%)

Diagnosed withTB (58, 58%)

Started on IPT(25, 38%)

0.96%

12%

0.08%

Number of people receiving the intervention as % of estimated PLHIV in reporting Countries

(Number of Countries reporting; % of total estimated HIV+ TB patients accounted for by those Countries)

Intensified TB case finding and IPT provision among people living with HIV, 2006

WHO the 3 'Is'

•Intensified case finding •Infection control for TB

•Isoniazid preventive therapy

Steering Committee

Time-Limited Subject Matter

Working Groups

WG

WG

WG

WG

WHO HIVResNet•Laboratory Network•Surveillance and Monitoring Network

WHO Secretariat

Modeling ofThe emergence and transmission of resistance

HIVDR database developmentand support

Public Health Assessment ToolFor evaluation of country HIVDR data

Global LaboratoryNetwork: Criteria,Protocols, Training,QA

The WHO HIVResNet is a global group of experts, laboratories, and organizations constituted to support HIVDR prevention, surveillance, and monitoring as antiretroviral treatment (ART) is rolled out worldwide.

Country HIVDR Committees

HIVDR monitoring & surveys

WGOperational Research

WGMutation lists forSurveillance and monitoring

Transmitted HIV drug resistance

Articles reporting results from HIVDR transmission surveys in 7 countries

all showed <5% DR in incident cases

Interface between prevention and care

Lancet, November 26, 2008

POSITIVE PREVENTION

Pre ART care – condoms safer sex

Disclosure & partner testing

MTCT prevention

OI & STI prevention

ART CARE

Reduce Viral load

Likely reduction transmission

PRIMARY PREVENTION

Prep and PEP

0.000

0.005

0.010

1980 2000 2020 20400.000

0.005

0.010

1980 2000 2020 2040

0.000

0.001

0.002

0.003

0.004

0.005

1980 2000 2020 20400.000

0.005

0.010

0.015

0.020

1980 2000 2020 2040

0.00

0.05

0.10

0.15

1980 2000 2020 20400.00

0.05

0.10

0.15

1980 2000 2020 2040

Year Year

Inci

den

ce/y

ea

r P

reva

lenc

e M

ort

alit

y/ye

ar

HIV ART

No ARTCurrent ARTProposed Universal ART

Acknowledgments:

Paediatric and adult Guideline groups

HIV DR team

HIV- dept staff

Paediatric ARV dosing working group

Charlie Gilks. Marco Vitoria, Lynne Mofenson, Ying-ru Lo,

HIV -AMD & GPRM

HIV- SIR Yves Soutyrandy

　

Thank you