The Effectiveness of The Effectiveness of generic Highly Active generic Highly Active

Antiretroviral Therapy for Antiretroviral Therapy for the treatment of HIV the treatment of HIV

infected Ugandan childreninfected Ugandan childrenPresenter: Linda Barlow-Mosha Presenter: Linda Barlow-Mosha

MD, MPH, FAAPMD, MPH, FAAP

Makerere University- Johns Hopkins University Makerere University- Johns Hopkins University Research CollaborationResearch Collaboration

3rd IAS Conference3rd IAS Conference

July 27, 2005July 27, 2005

BackgroundBackground 90% of the 2.1million HIV infected children are 90% of the 2.1million HIV infected children are

in sub-Saharan Africa in sub-Saharan Africa (UNAIDS, 2004)(UNAIDS, 2004)

Uganda has approximately 143,000 children Uganda has approximately 143,000 children living with HIV and 20,000 children are infected living with HIV and 20,000 children are infected each year through mother to child transmission each year through mother to child transmission (MTCT) (MTCT) (MOH, 2001)(MOH, 2001)

MU-JHU Research Collaboration has taken care MU-JHU Research Collaboration has taken care of over 3000 HIV infected children since 1988of over 3000 HIV infected children since 1988 Death occurred in 30%,66%, 75% of the children at 1, Death occurred in 30%,66%, 75% of the children at 1,

3, and 5 years respectively 3, and 5 years respectively (Marum et al. July 1996)(Marum et al. July 1996)

BackgroundBackground

Benefits of HAART have not yet been fully Benefits of HAART have not yet been fully realized in resource limited countries due realized in resource limited countries due to:to: High cost of drugsHigh cost of drugs Limited infrastructure to monitor patientsLimited infrastructure to monitor patients

Access has recently been increased for Access has recently been increased for patients in the developing world through:patients in the developing world through: Global funds Global funds World Bank funds-MAPWorld Bank funds-MAP PEPFAR (President Bush’s Initiative)PEPFAR (President Bush’s Initiative)

HAART in UgandaHAART in Uganda

Approximately 64,000 individuals on Approximately 64,000 individuals on HAART HAART (Ministry of Health,2005)(Ministry of Health,2005)

< 4000 are children under 15 years of age < 4000 are children under 15 years of age (Ministry of Health,2005)(Ministry of Health,2005)

Majority of the children on HAART are in Majority of the children on HAART are in a few clinicsa few clinics

Children are often left out because of :Children are often left out because of : Lack of infant HIV diagnostic testsLack of infant HIV diagnostic tests Limited appropriate drug formulationLimited appropriate drug formulation Inadequate knowledge on ARV use in childrenInadequate knowledge on ARV use in children

TriomuneTriomune Fixed dose combination (d4T+3TC+NVP) - Fixed dose combination (d4T+3TC+NVP) -

CIPLACIPLA Reduced cost has made HAART more Reduced cost has made HAART more

accessibleaccessible Clinical experience has documented Clinical experience has documented

satisfactory response satisfactory response (Laurent et al, 2004)(Laurent et al, 2004) In Uganda a study in adults documented a In Uganda a study in adults documented a

decline in viral load and increase in CD4 count decline in viral load and increase in CD4 count at 12 weeks into therapy at 12 weeks into therapy (Oyugi et al, Bangkok 2004)(Oyugi et al, Bangkok 2004)

Most of the fixed dose combinations available Most of the fixed dose combinations available are in tablet or capsule form and not in are in tablet or capsule form and not in formulations appropriate for young childrenformulations appropriate for young children

ObjectivesObjectives

Primary ObjectivePrimary Objective To determine the feasibility and To determine the feasibility and

effectiveness of a generic fixed dose effectiveness of a generic fixed dose combination tablet (Triomune) in HIV combination tablet (Triomune) in HIV infected childreninfected children

Secondary ObjectivesSecondary Objectives To assess adherence to Triomune To assess adherence to Triomune

among HIV infected childrenamong HIV infected children To document mortality rate of the To document mortality rate of the

children on therapychildren on therapy

MethodsMethods

ScreeningScreening HIV infected children from perinatal HIV infected children from perinatal

trials at MU-JHU Research trials at MU-JHU Research Collaboration and PIDC Mulago Collaboration and PIDC Mulago Hospital were screened using WHO Hospital were screened using WHO criteria for antiretroviral therapy in criteria for antiretroviral therapy in resource limited settings and CD4 resource limited settings and CD4 count/percentcount/percent

MethodsMethods Data collectionData collection

BaselineBaseline CBC, CD4%/CD4 abs,Viral LoadCBC, CD4%/CD4 abs,Viral Load Liver function test and Renal function testLiver function test and Renal function test

Follow up 2 yearsFollow up 2 years CBC, CD4%/CD4 abs, and viral load – every 12 wksCBC, CD4%/CD4 abs, and viral load – every 12 wks Adherence assessment by self report and pill counts Adherence assessment by self report and pill counts

– at all routine visits– at all routine visits Plasma storage for later NVP resistance testingPlasma storage for later NVP resistance testing Sub-study for NVP pharmacokinetic (n=20)Sub-study for NVP pharmacokinetic (n=20)

Preliminary data after 48 weeks on therapy Preliminary data after 48 weeks on therapy will be presentedwill be presented

ResultsResults

Total number screened – 164 HIV infected Total number screened – 164 HIV infected childrenchildren 90 enrolled 90 enrolled 81 given Triomune (d4T/3TC/NVP) as 181 given Triomune (d4T/3TC/NVP) as 1stst line line

regimeregime 72 remain on Triomune 72 remain on Triomune 14 are on alternative regimens14 are on alternative regimens

8 due to weight <13kg8 due to weight <13kg 4 due to hypersensitivity to NVP4 due to hypersensitivity to NVP 1 hepatitis1 hepatitis 1 virologic failure1 virologic failure

4 deaths4 deaths

ResultsResults

At EnrollmentAt Enrollment Median age – 5yrs (1-14yrs)Median age – 5yrs (1-14yrs)

48% female48% female 96% < 396% < 3rdrd percentile expected weight for percentile expected weight for

age age 67% < 567% < 5thth percentile expected height for percentile expected height for

age age 60% WHO stage II and 16% WHO stage III60% WHO stage II and 16% WHO stage III 26% with CD4 percent < 5%26% with CD4 percent < 5% 67% with CD4 percent between 5-15%67% with CD4 percent between 5-15%

ResultsResultsBaselinBaselinee

n= 90n= 90

12 12 wkswks

n= n= 7878

24 24 wkswks

n= n= 5252

36 36 wkswks

n=25n=25

48 48 wkswks

n=23n=23

Median Median CD4%CD4%

9%9%(0.2-22)(0.2-22)

17%17%(1-41)(1-41)p<0.0001p<0.0001

23%23%(7-44)(7-44)p<0.000p<0.00011

27%27%(8-58)(8-58)p<0.0001p<0.0001

32%32%(10-76)(10-76)p<0.0001p<0.0001

Median Median Viral Viral Load Load (copies/mL(copies/mL))

Non-detectable Non-detectable <400copies/ml<400copies/ml

284,39284,3911

(150-(150->750,000)>750,000)

121121

(0-(0->750,000>750,000))

p<0.0001p<0.0001

141141

(0-(0-133,469)133,469)

p<0.000p<0.00011

190190

(0-(0-140,418)140,418)

p<0.0001p<0.0001

190190

(0-(0-416,941)416,941)

p<0.0001p<0.0001

Results Results

0

5

10

15

20

25

30

35

Me

dia

n C

D4

%

Baseline WK12 WK24 WK36 WK48

Time

Distribution Of Medain CD4 percent Over Time

n=90

n=78

n=52n=25

n=23

t t est s1

0

200000

400000

600000R

N

A

P

C

R

1 2 3 4 5

vi s i t

Baseline

12wks24wks 36wks

48wks

ResultsResultsViral Load vs Baseline, 12, 24,36, Viral Load vs Baseline, 12, 24,36,

& 48 Weeks& 48 Weeks

VIRAL LOAD

12wks

12wks

12 wks

Baseline

24 wks

36 wks

48 wks

ResultsResults

48 weeks after therapy48 weeks after therapy 96% 96% (22/23)(22/23) of children have CD4% > 15 of children have CD4% > 15 83% 83% (19/23) (19/23) of children have undetectable viral of children have undetectable viral

load (<400copies/ml) load (<400copies/ml) 42% (8/19) of the children with undetectable viral 42% (8/19) of the children with undetectable viral

loads were NVP exposed at birthloads were NVP exposed at birth Adherence rate – 95% in 90% of the childrenAdherence rate – 95% in 90% of the children Majority of children with poor adherence were Majority of children with poor adherence were

on syrupson syrups

Results- Toxicity and Results- Toxicity and MortalityMortality

Side EffectsSide Effects skin rash - 4% (4/90) skin rash - 4% (4/90) hepatitis - 1% (1/90) hepatitis - 1% (1/90)

Mortality rate is 4% (4/90)Mortality rate is 4% (4/90) 2/4 children had an initial CD4 count less than 2/4 children had an initial CD4 count less than

1%1% 3/4 children were severely immuno-3/4 children were severely immuno-

suppressed or WHO stage IIIsuppressed or WHO stage III Causes of death include toxoplasmosis, Causes of death include toxoplasmosis,

malaria, and pneumoniamalaria, and pneumonia

ResultsResults

Treatment FailureTreatment Failure Defined as viral load >400 Defined as viral load >400 copies/mlcopies/ml at 48 at 48

wks wks The 4 children with detectable viral The 4 children with detectable viral

loads loads history of poor/fair adherence to syrupshistory of poor/fair adherence to syrups exposure to single-dose Nevirapine at birthexposure to single-dose Nevirapine at birth baseline viral loads >750,000 baseline viral loads >750,000 copies/mlcopies/ml viral rebound effectviral rebound effect

Results- Treatment Results- Treatment FailureFailure

1/4 children with detectable viral loads has 1/4 children with detectable viral loads has also shown immunologic failure to therapyalso shown immunologic failure to therapy

BaselineBaseline

CD4%CD4%12wk12wk

CD4%CD4%24wk24wk

CD4%CD4%36wk36wk

CD4CD4%%

48wk48wk

CD4CD4%%

AA 11.111.1 31.831.8 27.427.4 32.132.1 32.532.5

BB 7.17.1 14.414.4 15.515.5 20.520.5 31.831.8

CC 2.22.2 7.87.8 12.412.4 14.514.5 9.99.9(4.5 at (4.5 at 60wk)60wk)

DD 13.213.2 21.121.1 30.630.6 34.834.8 39.239.2

ConclusionsConclusions The use of fixed dose combination in HIV The use of fixed dose combination in HIV

infected children is feasible and effectiveinfected children is feasible and effective Triomune led to a significant increase in Triomune led to a significant increase in

CD4 count and a decrease in viral load CD4 count and a decrease in viral load during the initial 48 weeks of therapyduring the initial 48 weeks of therapy

Adherence is better with a fixed dose Adherence is better with a fixed dose combination than syrupscombination than syrups

We are still monitoring the effect of We are still monitoring the effect of single-dose Nevirapine exposure on single-dose Nevirapine exposure on response to future NVP containing HAART response to future NVP containing HAART regimensregimens

AcknowledgmentsAcknowledgments Elizabeth Glaser Pediatric AIDS FoundationElizabeth Glaser Pediatric AIDS Foundation

International Leadership Award (ILA)International Leadership Award (ILA) Dr. Phillipa MusokeDr. Phillipa Musoke – Department of – Department of

Pediatrics, Makerere University Mulago / MU-Pediatrics, Makerere University Mulago / MU-JHU Research Collaboration, Recipient of ILAJHU Research Collaboration, Recipient of ILA

Program StaffProgram Staff – MU-JHU Research – MU-JHU Research CollaborationCollaboration P. Ajuna, M. Luttajumwa, B. Musoke, J. Walabyeki, P. Ajuna, M. Luttajumwa, B. Musoke, J. Walabyeki,

M. Owor, M. Mubiru, M.G. Nalubega, M. M. Owor, M. Mubiru, M.G. Nalubega, M. Namawejje, E. Babirekere Namawejje, E. Babirekere

MU-JHU Research CollaborationMU-JHU Research Collaboration Children and their caretakersChildren and their caretakers

Thank YouThank You