who recommendations for arv treatment in infants and … · who recommendations for arv treatment...

WHO recommendations for ARV treatment in infants and children

Dr Siobhan CrowleyPaediatric & Family HIV Care

Department of HIV/AIDSE-mail: [email protected]

http://www.who.int/hiv/paediatric/en/index.html


HIV in children is likely to be an on going problem

20042005 2006

2007

% Infant ARV

% maternal ARV/ART0102030405060708090

100

% receiving ARV intervention

ARV or ART exposure in tested women and their infants

% Infant ARV

% maternal ARV/ART

• Poor coverage of ANC HIV testing –

in 2004 10% up to 18% in 2008(ie. 82 % of women DO not get tested)

• Very few of those identified with HIV get ARVs-

34%

Required for universal access by 2010

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 Africa

Progress has been made in treating children

Estimated need as of 2006

No of children on ART

0

100000

200000

300000

400000

500000

600000

700000

2005 2006 2007

200520062007

Estimated need in 2006

ART outcomes -

good news across the globe

National programmes reporting good outcomes

1 year survival estimated as 93-95%

2 year survival 91%

Children everywhere are Starting Treatment LateBaseline

Median AgeBaseline

Median CD4

Janssens/Cambodia

2007

N=212

6.0 yrs 6%

George/Haiti2007 N=100

6.3 yrs 12%

Wamawala/Kenya 2007 N=67

4.4 yrs 6%

Reddi/S Africa 2007 N=151

5.7 yrs 8%

Puthanakit/Thailand 2007 N=107

7.7 yrs 5%

Kamya/Uganda 2007 N=250

9.2 yrs 8.6%

Rouet/Cote d’Ivoire

2006

N=786.5 yr 8%

Meta-analysis 1,195 children from 8 African

clinical trials53% >5 years of age, 70%

severe immune deficiency, 12% aged < 12 months

(KIDS-ART-LINC) Arrive 2008

Starting late 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

In 2007:

• only 8% of HIV exposed infants were tested in 1st

2 months of life

• only 4 % started on co-trimoxazole

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

47

17

76

23

78

30

01020304050607080

2005 2006 2007

No countrieswith PITCpolicy inchildren No countriesusing DBS

Presenter

Presentation Notes

We can only diagnose HIV in the first months of life using virological tests (HIV DNA PCR, HIV RNA PCR or bDNa or NASBA or ultrasenstive p24 antigen) As it takes some time to develop HIV infection and for HIV to start replicating, testing immediately at birth will not detect all those infants who HAVE HIV. HIV DNA PCR is the usual testing method that can be performed using DBS specimens and is therefore most used in context of PMTCT follow up. HIV RNA methods are reliable and can be done on plasma and whole blood specimens and are well suited to inpatient or sick infants where specimens using DBS are not essential. For ALL methods robust QA is required. Estimation of proportion of truly infected infants detected by testing at certain ages if all infants are breastfed would produce numbers as below for South Africa , base don performance of HIV DNA testing E.G. South AfricaTot infected (BF) % missed diagnosis at time of testing of total if BF Birth 59527 70 1st week 6001250 2nd week 6049730 3rd week 60980 20 4th week 6146311 6th week 619445 2nd month 624254 3rd month 644455 4th month 664505 5th month 684385 6th month 704105 The ongoing missed diagnosis reflects those who have recently acquired HIV through breastfeeding and are in the window period. Estimated numbers do not adjust for those who would have died. WHO therefore recommends to perform testing at or around 4-6 weeks for PMTCT follow up and whenever sick or HIV is suspected in infants known to be exposed.

85% infants meet criteria to start ART within 6 months

Prendergast AIDS. 2008 Jul 11;22(11):1333-43.

Presenter

Presentation Notes

Observatioanl study in SA HIV-infected infants received randomised immediate or deferred (once CD4<20%) 4-drug ART (zidovudine, lamivudine, nelfinavir and nevirapine) in a dedicated study clinic, with free outpatient and inpatient treatment of illness. All 63 HIV-infected infants were exposed to sd-NVP. 20/51 (39%) infants with baseline genotyping results had NNRTI resistance (most frequently Y181C; 20%). Median pre-ART viral load was 952,000 copies/mL. Infants starting immediate compared to deferred ART had fewer illness episodes (median 7 vs 12 illness episodes per infant; P=0.003), but no significant difference in mortality, virological suppression or CD4 repletion.

0.00

0.20

0.40

0.60

0.80

1.00

0 3 6 9 12Time to Death (months)

Failu

re P

roba

bilit

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%

Violari A,et

al. N Engl

J Med2008 Nov 20;359(21):2233-44.

Presenter

Presentation Notes

CHER: Trial recruited and enrolled 377 infants with confirmed HIV infection without advanced immune suppression between 6 and 12 weeks of age who had CD4 cell percentages equal to or greater than 25 percent. Eligible infants were randomly enrolled in one of three groups immediate antiretroviral therapy (Zidovudine (AZT) + Lamivudine (3TC) + Lopinavir/Ritonavir (LPV/r) for 40 weeks, immediate antiretroviral therapy for 96 weeks, control group: ART was only initiated after doctors observed signs of clinical or immunological progression (e.g. CD4 cell percentage decline) Deferring the start of ART until an infant has clinical or immunologic decline was the standard of care in South Africa; however, the specific immunologic and clinical criteria for starting therapy in this study were slightly different from South African or World Health Organization (WHO) guidelines, and were changed over time to reflect revised WHO recommendations. In this study, ART is started or restarted when %CD4 dropped below 20 % for infants greater than one-year old or %25 for infants less than one-year old or if symptomatic and severe disease occurs as defined by (CDC) criteria. All participants followed a schedule of regular clinical visits for a minimum of 3.5 years, with the clinical team available 24 hours a day for consultation, referrals and advice. All children received Co-trimoxazole and Pneumococcal vaccine Inclusion: HIV DNA PCR confirmed HIV infection CD4 >25% ART naïve except for pMTCT Age <12 weeks ART Regimen: ART: ZDV + 3TC + LPV/r On June 20, 2007, the DSMB reviewed the interim data and found a significant increase in survival among infants who received immediate ARV therapy (96 percent) compared to infants who received therapy later (84 percent) based on declining immune function linked to a defined CD4+ T-cell count and/or clinical progression. Based on this finding, the DSMB recommended that no additional infants be placed in the deferred-treatment arm of the study and infants in this arm be evaluated for potential initiation of ARV therapy. The DSMB also recommended that all infants enrolled in the study be followed for the planned duration of approximately 3.5 years. 20% breast fed Endpoints: Primary: Death OR failure of 1st line ART regimen Secondary, including: Cumulative rate of disease progression and hospitalisation Grade 3 & 4 adverse events Development of ART Resistance Death rate per 100 person-years (Arm 2&3 vs 1) 3 months 10 vs 41 3 to 6 months 4 vs 23 6 to 12 months 3 vs 9 Conclusions: Starting ART before 12 weeks of age in HIV infected infants without sign of severe or advance immunodeficiency reduces early mortality by 75%

Nevirapine

resistance

Meta analysis:

Arrive et al Int

J Epidemiol.

2007 Oct;36(5):1009-21. 2007

SD NVP SD NVP +

post partumARV

mother

baby0

10

20

30

40

50

60

% NVP resistance detected

Prevalence of NVP resistance

mother baby

Response to Antiretroviral Therapy after a Single, Response to Antiretroviral Therapy after a Single, PeripartumPeripartum

Dose of Dose of NevirapineNevirapine

Lockman S, et al. NEJM 2007;356:135-47

Analysis after 6 months of HAART: 10/13 in SD NVP group and 1/12 placebo group

had HIV RNA >400 copies/mL

Median ageat start HAART

8.5 months

Single dose of NVP

Placebo

% w

ith R

NA

>40

0 c/

mL

Presenter

Presentation Notes

Of the 60 women who started nevirapine-based ART within six months of giving birth, 24 had received a single dose of nevirapine during labor, while 36 had received a placebo. (All of the women in the study were given zidovudine from 34 weeks into their pregnancies through delivery; similar to nevirapine, zidovudine reduces HIV transmission from mother to child.) Of the women in this group who received a single dose of nevirapine during labor, 41.7 percent subsequently experienced treatment failure, or "virologic failure," within a half a year of starting ART -- compared to zero percent among the women in this group who had received placebo during delivery. Similar differences were found at follow-up visits one and two years after ART had started. Treatment response was also measured among 30 infants in the study who received nevirapine-based ART. More than three-quarters of the 15 infants who were exposed to single dose nevirapine as newborns did not respond adequately to the triple-drug treatment (compared with 9.1 percent of the 15 infants without prior nevirapine exposure). While these results raise concerns regarding the use of nevirapine-based ART for infants following single-dose nevirapine exposure, no of infants studied was small, and additional data among infants is needed.

2008 revisions (April + November)

For infants expert panel reviewed:•

When to perform virological

testing

•

Which tests to use when

•

When to start ART

•

What ARVS to start in infants with HIV

•

ARV dosing for infants

WHO -

new recommendations for starting ART in infants

All infants under 12 months of age with confirmed HIV infection should be started on antiretroviral therapy, irrespective of clinical or immunological stage.

GRADE Evidence profile = Moderate

Strength of Recommendation =

STRONG

http://www.who.int/hiv/pub/paediatric/WHO_Paediatric_ART_guideline_rev_mreport_2008.pdf


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 immunecriteria

Clinical or immune criteria

<20% or

12-35 mos: <750/uL36-59 mos: <350/uL

<15% or

<200/uL(as in 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 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 ART

PI triple ART#

NVP triple ART

NVP triple ART

# If no PI is available use NVP triple ART

Mum 34%Baby 18%

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

Distribution of first line regimens in children

42%

29%

11% 9%

91%

0%

20%

40%

60%

80%

100%

D4T + 3TC +NVP

ZDV + 3TC +NVP

ZDV + 3TC +EFV

D4T + 3TC +EFV

total

Source: WHO AMD Survey 2007

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 #


Children 3 or over EFV + AZT #


# if anaemia

use alternative ABC or d4T

WHO recommendations for infant ARV prophylaxis

Clinical scenario Recommendations Maternal extended pAZT Sd

NVP + 7 days AZT

Maternal cART AZT x 7 days

Less than 4 weeks maternal cART

or

AZT

Sd

NVP + 4 wks AZT

Mother presents in labour Sd

NVP + 4 wks AZT

Infant seen in < 72 hrs after birth no maternal ARVs given

Sd

NVP + 4 wks AZT

No infant combination or short course ARV possible

Sd

NVP

Ped ARV working group General Criteria for dosing recommendations

•

Maximum number of tablets at any one dose should be no more than three.

•

Minimum dose is one half tablet of products that are scored

•

Limit the number of dosing forms for each single ARV or FDC required for prevention and treatment of HIV in adults and children.

•

Harmonize dosing schedules and weight-based dose switching points for all products wherever possible –

Facilitate FDC switches

Ped ARV working group (2)

•

Attempted to avoid dosing any single ARV component below 90% of intended delivered dose and not more than 25 % above intended dose. Better to give a bit too much than too little.

•

For nevirapine, the group sought to avoid dosing below (150mg/m2).

•

Each individual drug considered was assessed for a range of tablet strengths using the same tool and principles.

•

Focused on most critical agent (narrow therapeutic range) and linked dosing for other agents

Challenges•

Various drug clearance and distribution pathways have different age dependency –

ideal

dosing changes vary by age and drug

•

Consequences –

Expected to result in non approved doses.

–

FDCs

not limited to same ratio as adult formulation

–

While aimed a achieving a target dose done with consideration that are actually shooting for a target exposure (labeled doses are not always optimal)

–

Some compromise needed

Predicted Nevirapine

Exposure in Infants < 12 Months

0 60 120 180 240 300 360

Age (days)

0

2

4

6

8

10

12

NV

P C

min

(mcg

/mL)

Cmin

95%

75%

50%

25%

5%

Target

0 60 120 180 240 300 360

Age (days)

0

20

40

60

80

100

120

140

NV

P A

UC

(mcg

*h/m

L)

AUC

95%

75%

50%

25%

5%

Target

0 60 120 180 240 300 360

Age (days)

0

2

4

6

8

10

12

NV

P C

min

(mcg

/mL)

Cmin

95%

75%

50%

25%

5%

Target

0 60 120 180 240 300 360

Age (days)

0

20

40

60

80

100

120

140

NV

P A

UC

(mcg

*h/m

L)

AUC

95%

75%

50%

25%

5%

Target

Best fit Weight Best fit Weight Band dosingBand dosing

Simplified liquid = Simplified liquid = tablet Weight tablet Weight Band DosingBand Dosing

Source: Mark Mirochnick, MDEdmund Capparelli, PharmD

Predicted Exposure if WHO dosing vs FDA

C FDA0

20

40

60

80

100

Per

cent

age

of S

ubje

cts

Exc

eedi

ng T

hres

hold

Figure 4. Varying NVP Tablet Strength vs FDA Dosing (Liquid)

AUC > 48 Cmin > 3.0 AUC > 120

Proposed WHO unequal LPV Dosing in 10-14 kg weight band

LPV troughs typically maintained above equal 230mg/m2 dosing except at highest weight (14kg)

–

but still within 20% (similar to dosing ~2 hr late)

0 2 4 6 8 10 12 14 16 18 20 22 24

Time (hours)

0

2

4

6

8

10

12

14

Pre

dict

ed L

PV

Con

c (m

cg/m

L)

10kg Child

200mg am100mg pm

230mg/m2

am & pm

0 2 4 6 8 10 12 14 16 18 20 22 24

Time (hours)

0

2

4

6

8

10

12

14

Pre

dict

ed L

PV

Con

c (m

cg/m

L)

14kg Child

200mg am100mg pm

230mg/m2

am & pm

Edmund Capparelli, PharmD

Presenter

Presentation Notes

For 14kg child 18% lower trough = 1.82 hr delay in dosing

Revised simplified dosing

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

Other outcomes -on ART KIDS ART Linc•

Probability @ 1 year of death 6.0% or loss-to-follow-up 9.5% & at 2 yrs of 6.9% (95% CI 5.9–8.1) 19.2% (95% CI 17.4–21.1)

•

WHO review -

12 months, > 86% alive (72-95.7%) and on ART at 12 months.

D4T toxicity•

36M of ART-57% of children developed clinical lipodystrophy, requiring D4T substitution (AZT). Aurpibul

et al ThailandPatient Retention•

Kids ART Linc

-

risk of LTFU was 9.5%, higher in children with severe clinical status. –

6 M 2.6%–

12 M 4.9%–

24 M 9.9%•

18-24 months –

Thailand-

91% –

Kenya 86%Switch/Transition to second line-

Little data -

< 3% per annum-

Chris Duncombe

review ongoing ? Higher

Guideline issues still under review

•

d4T•

Clinical /CD4 algorithms for infant diagnosis •

Recommendations to support adherence •

Second line regimens for children ( preferred as FDC) •

Simple standard approaches to using viral load

Related:•

Infant post partum prophylaxis •

TB/HIV-

revised dosing for INH•

Malaria –just reviewed•

Immunisation –

measles and yellow fever reviews ongoing

Acknowledgments & resources:•

HIV Care Technical Reference group

•

Paediatric ARV dosing working group •

Infant Diagnosis Guideline Group

Meeting report summarising these recommendations http://www.who.int/hiv/pub/paediatric/WHO_Paediatric_ART_guideline_rev_mreport_20

08.pdfProceedings of the meeting http://www.who.int/hiv/pub/meetingreports/art_meeting_april2008/en/index.html2006 guidelines (being updated to reflect above) http://www.who.int/hiv/pub/guidelines/art/en/index.htmlTool to assist in developing dosing recommendationshttp://www.who.int/hiv/paediatric/generictool/en/index.htmlA programming guide –

how to scale up Paed

care and treatment: http://www.who.int/hiv/paediatric/Paeds_programming_framework2008.pdf

Paediatric HIV care landing page http://www.who.int/hiv/paediatric/en/index.html



http://www.who.int/hiv/pub/meetingreports/art_meeting_april2008/en/index.html

http://www.who.int/hiv/pub/guidelines/art/en/index.html

http://www.who.int/hiv/paediatric/generictool/en/index.html

http://www.who.int/hiv/paediatric/Paeds_programming_framework2008.pdf


who recommendations for arv treatment in infants and … · who recommendations for arv treatment...

Documents