ART in CHILDREN

1
ART in CHILDREN

• Dr Leon J. Levin

Antiretroviral Therapy
2
HAART
Since late 1995 ADULTS CHILDREN
3
AIDS 2002- Impact of HAART on Morbidity and
Mortality
USA 81 children 1994-2000
XIV International AIDS conference- July 7-12 2002
Abstract ThPeB7230
4
Goals of Antiretroviral Therapy

• Restoration or preservation of immunological
  function
• Improvement in clinical symptoms
• Reduction in morbidity and mortality
• Maximal and durable suppression of Viral Load

Southern African Journal of HIV Medicine Nov
2000, pp 19-30
5
The relationship between Viral Load and CD4 counts
DISASTER
6
The relationship between Viral Load and CD4 counts
Viral Load Speed of Train
CD4 count length of track
DISASTER
7
Monitoring HIV Infection and Therapy - CD4 counts
HIV Paediatric Classification System Immune
categories based on Age specific CD4 lymphocyte
count and
CDC 1994 Revised Classification system for
human immunodeficiency virus infection in
children less than 13 years of age. MMWR 199443
(no.RR12)1-10.
8
Viral Load in Adults
9
Viral load in Infants
10
Viral Load and disease Progression
11
HIV RNA levels(Viral Load)
Normal variability(adults) 3 X (0.5
log10) Children - spontaneous
decline Significant change gt 3 X ( 0.5
log10) gt 2 years gt 5 X (0.7 log10) lt 2
years
12
PACTG 338
Proportion of Children with undetectable HIV
RNA Levels categorized by Baseline HIV RNA
Ritonavir containing arms
S. A. Nachman et al JAMA 2000283492-498
13
Monitoring for Antiretroviral Therapy

• Aims
• 10 fold drop(1 log10) in Viral load after 8-12
  weeks
• Viral load undetectable at 4-6 months
• Viral load lt 10 000 copies/ml
• Frequency of testing
• After 1 month -Viral Load
• After 3 months - Viral Load and CD4 count
• 3-6 monthly - Viral Load and CD4 count
• Intercurrent infections and Vaccinations may
  transiently affect Viral Load and CD4 count

14
BASIC HIV LIFECYCLE
CD4 Cell
HIV in plasma
Protease Inhibitors act here
HIV enters cell
CD4 RECEPTOR
Nucleus
RNA
DNA
ASSEMBLY
Reverse Transcriptase
Protease
Release of daughter viruses
DNA
NRTIs and NNRTIs act here
15
ANTIRETROVIRAL DRUGS
Available in Paediatric Formulation
16
CHOOSING a REGIMEN
Protease Inhibitor(PI)

NRTI Backbone (2 NRTIs)
OR
NNRTI
17
Proposed Recommended ARV regimens

• 2 NRTIs 1 PI (I II IV)
• 2 NRTIs 1 NNRTI (I II III)
• 1 NRTI 1 NNRTI 1 PI (I or IIIIIIV)
• ABCZDV3TC

Preferred Regimen Only in Special
Circumstances
18
Nucleoside Reverse Transcriptase Inhibitors
(NRTI's)
Zidovudine ZDV AZT Didanosine ddI
Zalcitabine ddC Stavudine d4T 3TC
Abacavir ABC

• Backbone of any Therapy
• Usually combine 1 Thymidine 1 non-Thymidine
  analogue
• 3TC develops rapid resistance (M184V)
• ddI needs to be taken on an empty stomach
• ddI needs to be separated from the PI by 1-2 hrs
• Mitochondrial side-effects
• Lactic Acidosis
• AZT bone marrow suppression
• d4T peripheral neuropathy
• ddI pancreatitis, peripheral neuropathy
• ddC peripheral neuropathy, mouth ulcers
• ABC hypersensitivity reaction
• Avoid using d4T and ddI together

19
Non Nucleoside Reverse Transcriptase Inhibitors
(NNRTI's)
Nevirapine NVP Vira-mune Efavirenz EFV
Stocrin Delavirdine DLV Rescriptor

• Powerful Antiviral effect
• Rapid development of resistance
• Major Adverse effects
• NVP skin rash, hepatitis
• EFV CNS effects, skin rash
• Drug interactions Pis, Rifampicin others
• EFV no data in children lt 3 years

20
Protease Inhibitors
Ritonavir (RTV) Norvir Abbott Solution /
capsules Nelfinavir(NFV) Viracept
Roche Tablets / powder for
solution Indinavir(IDV) Crixivan Merck Capsu
les Saquinavir(SQV) Invirase Roche Hard
gel capsule Fortovase Roche Soft gel
capsule Lopinavir/ritonavir Kaletra
Abbott Solution / capsules (LPV/RTV)

• Powerful antiretroviral effects
• Need a few successive mutations for high level
  resistance
• Adherence
• Drug interactions incl. Rifampicin and
  antihistamines
• Major S/E Diarrhoea (NFV),Renal calculi(IDV)
  Lipodystrophy, Diabetes Mellitus, osteoporosis
• Highly protein bound, thus do not cross BBB

21
Lopinavir/ritonavir (Kaletra)

• Combination of 2 Protease Inhibitors
• Lopinavir (active medication)
• Ritonavir booster
• Powerful PI
• Works against some PI resistant virus
• Solution tolerated well

22
BROAD STROKES
23
1994 Revised HIV Paediatric classification
system-clinical categories
Category N Not Symptomatic. Children who have
no signs or symptoms considered to be the result
of HIV infection or who have only one of the
conditions listed in category A.

CDC. 1994 Revised classification system for human
immunodeficiency virus infection in children less
than 13 years of age. MMWR 1994 43 (No. RR-12)
1-10.
24
1994 Revised HIV Paediatric classification
system-clinical categories
Category A Mildly Symptomatic Children with two
or more of the following conditions but none of
the conditions listed in categories B and C
Lymphadenopathy (gt0.5 cm at more than two sites
bilateral one site) Hepatomegaly
Splenomegaly Dermatitis Parotitis Recurrent
or persistent upper respiratory infection,
sinusitis, or otitis media
CDC. 1994 Revised classification system for human
immunodeficiency virus infection in children less
than 13 years of age. MMWR 1994 43 (No. RR-12)
1-10.
25
1994 Revised HIV Paediatric classification
system-clinical categories

• Category B Moderately Symptomatic
• Children who have symptomatic conditions other
  than those listed for category A or category C
  that are attributed to HIV infection. Examples of
  conditions in clinical category B include but are
  not limited to the following
• Anemia (lt 8 gm/dL), neutropenia (lt1,000/mm3), or
  thrombocytopenia (lt100,000/mm3 ) persisting gt30
  days
• Bacterial meningitis, pneumonia, or sepsis
  (single episode)
• Candidiasis, oropharyngeal (i.e., thrush)
  persisting for gt2 months in children aged gt6
  months
• Cardiomyopathy
• Cytomegalovirus infection with onset before age
  1 month
• Diarrhea, recurrent or chronic
• Hepatitis

CDC. 1994 Revised classification system for human
immunodeficiency virus infection in children less
than 13 years of age. MMWR 1994 43 (No. RR-12)
1-10.
26
1994 Revised HIV Paediatric classification system
- clinical categories
Category B Moderately Symptomatic -
Continued Herpes simplex virus (HSV) stomatitis,
recurrent (i.e., more than two episodes within 1
year) HSV bronchitis, pneumonitis, or
esophagitis with onset before age 1 month
Herpes zoster (i.e., shingles) involving at least
two distinct episodes or more than one
dermatome Leiomyosarcoma Lymphoid
interstitial pneumonia (LIP) or pulmonary
lymphoid hyperplasia complex Nephropathy
Nocardiosis Fever lasting gt1 month
Toxoplasmosis with onset before age 1 month
Varicella, disseminated (i.e., complicated
chickenpox)
CDC. 1994 Revised classification system for human
immunodeficiency virus infection in children less
than 13 years of age. MMWR 1994 43 (No. RR-12)
1-10.
27
1994 Revised HIV Paediatric classification system
- clinical categories
Category C Severely Symptomatic Children who
have any condition listed in the 1987
surveillance case definition for acquired
immunodeficiency syndrome (AIDS), with the
exception of LIP (which is a category B
condition).
CDC. 1994 Revised classification system for human
immunodeficiency virus infection in children less
than 13 years of age. MMWR 1994 43 (No. RR-12)
1-10.
28
1994 Revised HIV Paediatric classification system
- clinical categories
Category C Severely Symptomatic

• Serious bacterial infections, 2 cultureve
  episodes in 3y period) - septicaemia, pneumonia,
  meningitis, bone / joint, abscess internal organ
  or body cavity
• Candidiasis (oesophageal or pulmonary)
• Coccidioidomycosis, Cryptococcosis,
  Histoplasmosis (disseminated)
• CMV disease at agegt 1 m (excl LN, spleen, liver)
• Encephalopathy
• HSV mucocutaneous ulcer gt 1m, or bronchitis,
  oesophagitis, pneumonitis if gt 1 month
• Kaposi sarcoma
• Lymphoma
• Mycobacterium tuberculosis (disseminated or extra
  pulmonary)

CDC. 1994 Revised classification system for human
immunodeficiency virus infection in children less
than 13 years of age. MMWR 1994 43 (No. RR-12)
1-10.
29
1994 Revised HIV Paediatric classification system
- clinical categories
Category C Severely Symptomatic continued

• Mycobacterium avium or kansasii (disseminated)
• PCP
• Progressive multifocal leukoencephalopathy
• Salmonella septicaemia (recurrent)
• Cerebral toxoplasmosis onsetgt 1 m of age
• Wasting in the absence of other illness to
  explain
• persistent weight loss gt10 of baseline
• or downward crossing of 2 of the following
  percentiles (95th, 50th, 25th, 5th) in a child gt
  1 y
• or lt 5th centile weight for height on 2
  consecutive measurements gt 30 d apart
• (1) chronic diarrhoea (gt 2 loose stools per day gt
  30 days) or
• (2) documented fever gt 30 days intermittent or
  constant

CDC. 1994 Revised classification system for human
immunodeficiency virus infection in children less
than 13 years of age. MMWR 1994 43 (No. RR-12)
1-10.
30
Monitoring HIV Infection and Therapy - CD4 counts
HIV Paediatric Classification System Immune
categories based on Age specific CD4 lymphocyte
count and
CDC 1994 Revised Classification system for
human immunodeficiency virus infection in
children less than 13 years of age. MMWR 199443
(no.RR12)1-10.
31
WHO staging system for children

• CLINICAL STAGE I
• Asymptomatic
• Generalised lymphadenopathy
• CLINICAL STAGE II
• Unexplained chronic diarrhoea
• Severe persistent or recurrent candidiasis
  outside neonatal period
• Weight loss or failure to thrive
• Persistent fever
• Recurrent severe bacterial infections
• CLINICAL STAGE III
• AIDS-defining opportunistic infections
• Severe failure to thrive
• Progressive encephalopathy
• Malignancy
• Recurrent septicaemia or meningitis

32
SA Antiretroviral Roll Out in Children Staging
System

• Stage I
• AsymptomaticGeneralized lymphadenopathy
• Hepatomegaly
• Splenomegaly
• Parotomegaly
• Chronic suppurative OM
• Eczema/ Seborrhoeic Dermatitis
•  

33
SA Antiretroviral Roll Out in Children Staging
System
Stage II

•          Unexplained chronic diarrhoea (? 2
  weeks)
•          Failure to thrive
• o       60 - 80 expected body weight
• o       Not responding to nutritional
  rehabilitation or anti-TB therapy (if clinically
  indicated). Other correctable causes excluded
•          Recurrent or severe bacterial infection
  (? 2 episodes pneumonia or 1 episode meningitis)
•          Oral candidiasis beyond neonatal period
  
• o       Severe persistent or recurrent, not
  responding to topical therapy
•          Haematological
• o       Thrombocytopoenia (platelet count lt 40
  000 X 109/l) not responding to prednisone
  2mg/kg/day after 2 weeks
• o       Neutropaenia (neutrophil count lt 500 X
  109/l) not responding to switch from
  cotrimoxazole to dapsone
•          Severe lymphoid interstitial
  pneumonitis
• Persistent hypoxia lt 90 in the absence of acute
  infection
• Persistent tachypnoea in the absence of acute
  infection
• Easy fatiguability on exertion
• Evidence of bronchiectasis
• Cor pulmonale
•          2 episodes Zoster or severe herpetic
  disease

34
SA Antiretroviral Roll Out in Children Staging
System

• Stage III
•          Severe failure to thrive
• o       lt 60 expected body weight
• o       Not responding to nutritional
  rehabilitation or TB therapy if clinically
  indicated
•          Progressive encephalopathy
•          Recurrent septicaemia (? 2 episodes)
•          Bronchiectasis
•          Cardiomyopathy
•          Progressive nephroppathy
•          Candidiasis (oesophageal or pulmonary).
•          Disseminated fungal infection
  (Coccidioidomycosis, Cryptococcosis,
  Histoplasmosis)
• Disseminated mycobacterial infection (M
  tuberculosis, BCG, avium-intracellulare,
  Kansasii)

35
SA Antiretroviral Roll Out in Children Staging
System

• Stage III continued
•   CMV disease with onset at age gt 1 month (at
  site other than lymph nodes, spleen, liver).
•      HSV causing mucocutaneous ulcer persisting
  gt 1 month, or oesophagitis, pneumonitis,
  oesophagitis in a child older gt 1 month.
•      Pneumocystis carinii Pneumonia (PCP)
•      Progressive multifocal leukoencephalopathy.
•      Cerebral toxoplasmosis with onset gt 1 month
  of age
•     Recurrent/persistent Salmonella ESBL
•     Malignancies

36
Monitoring for Antiretroviral Therapy

• Aims
• 10 fold drop(1 log10) in Viral load after 8-12
  weeks
• Viral load undetectable at 4-6 months
• Viral load lt 10 000 copies/ml
• Frequency of testing
• After 1 month -Viral Load
• After 3 months - Viral Load and CD4 count
• 3-6 monthly - Viral Load and CD4 count
• Intercurrent infections and Vaccinations may
  transiently affect Viral Load and CD4 count

37
Efficacy of HAART

• Adults
• 43 - 75 undetectable Viral Loads
• Children
• 25 - 40 undetectable Viral Loads

38
Why?

• Higher Initial Viral loads in Children
• Problems with Adherence
• Incorrect choice of ARV drugs
• Inadequate plasma levels of ARV drugs
• Not enough ARV drugs

39
Efficacy of HAART

• Adults
• 43 - 75 undetectable Viral Loads
• Children
• 25 - 40 undetectable Viral Loads

40
Why?

• More potent ARVs
• Better tolerated ARVs
• More attention to Adherence
• Correct dosing of ARV drugs

41
Adherence

• Simplicity of Regimen
• Twice or once daily dosing
• No food restrictions
• Medication all taken together
• Volumes of liquids easy to measure
• Choose a regimen that is forgiving of poor
  adherence
• Education
• Dont start HAART on first visit
• Educate whoever is giving the medication
• Taste issues
• Follow up
• Pharmacy Records
• Bring Meds to each visit
• Treatment chart

42
Immune Reconstitution

• The initial increase in memory CD4 cells does not
  occur in children
• Children have a more rapid increase in Naïve CD4
  cells than adults
• Immune Reconstitution is age independent
• Immune Reconstitution is Immune Suppression
  independent
• Immune Reconstitution is often independent of
  virological response.

43
Balancing the Risks
Limiting future options
Progressive Resistance
Continuing a failing Regimen
Changing ART regimen too quickly
44
Finer Details
45
Probability of death within 12 months
XIV International AIDS conference- July 7-12 2002
Abstract TuPeC4849
46
PENTA GUIDELINES-2004
RECOMMENDATIONS ON WHEN TO START ART

Infants lt 12 months of age

• 1. Clinical
• Start all infants with CDC stage B or C (AIDS)
  disease.
• 2. Surrogate marker
• Start all infants with CD4 lt3035.
• Strongly consider starting with a VL gt1 million
  copies/mL.
• Many experts treat all asymptomatic infants.

www.ctu.mrc.ac.uk/PENTA/
47
PENTA GUIDELINES-2004
RECOMMENDATIONS ON WHEN TO START ART
Children aged 13 years of age

• 1. Clinical
• Start all children with stage C disease.
• 2. Surrogate marker
• Start all children with a CD4 lt20.
• Strongly consider starting with a VL gt 250 000
  copies/mL.

www.ctu.mrc.ac.uk/PENTA/
48
PENTA GUIDELINES-2004
RECOMMENDATIONS ON WHEN TO START ART

• Children aged 412 years
• 1. Clinical
• Start all children with stage C disease.
• 2. Surrogate marker data
• Start all children with CD4 lt15 ( less urgency
  in the 9-12 year old child.)
• Strongly consider starting with a
• VL gt250 000 copies/mL.

www.ctu.mrc.ac.uk/PENTA
49
PENTA GUIDELINES-2004
RECOMMENDATIONS ON WHEN TO START ART

• Adolescents aged 1317 years
• 1. Clinical
• Start all adolescents with stage C disease.
• 2. Surrogate marker data
• Start all adolescents with a CD4 absolute count
  between 200 and 350 cells mm3

www.ctu.mrc.ac.uk/PENTA
50
When to start?(WHO guidelines)

• Children less than 18 months if
• Symptomatic (Stage III)
• CD4 lt 20
• Children older than 18 months if
• Symptomatic (Stage III)
• CD4 lt 15

51
Indications for Initiation of Antiretroviral
Therapy-USA
Children lt12 Months
www.aidsinfo.nih.gov
52
Indications for Initiation of Antiretroviral
Therapy-USA
Children gt 12 Months
www.aidsinfo.nih.gov
53
Eligibility for Antiretroviral Therapy for SA
Antiretroviral Roll Out in Children

• Clinical Criteria  
• Recurrent (gt 2 admissions per year)
  hospitalisations for HIV complications OR a
  prolonged hospitalisation for HIV(gt 4 weeks) OR
• The patient satisfies the modified WHO Stage II
  or III disease OR 
• For relatively asymptomatic patients, one can
  consider CD4 percentage lt20 if lt 18 months or
  lt15 if gt 18 months.
•  Social criteria
• At least one identifiable caregiver who is able
  to supervise child or administer medication
• Disclosure to another adult living in the same
  house is encouraged so that there is someone else
  who can assist with the childs ART
•  

54
Indications for Antiretroviral Therapy SA HIV
Clinicians Society Guidelines 2005

Infants lt 12 months of age

• Start all infants with CDC stage B or C
• (AIDS) disease.
• Start all infants with CD4 lt3035.

55
Indications for Antiretroviral Therapy SA HIV
Clinicians Society Guidelines 2005
Children aged 13 years of age

• Start all children with Selected Category B
  diseases or stage C disease.
• Start all children with a CD4 lt20.

56
Indications for Antiretroviral Therapy SA HIV
Clinicians Society Guidelines 2005
Children aged 412 years

• Start all children with Selected Category B
  diseases or stage C disease
• Start all children with CD4 lt15-20

57
Indications for Antiretroviral Therapy HIV
Clinicians Society Guidelines 2005

• Adolescents aged 1317 years
• Follow adult guidelines

58
Selected Category B diseases

• Persistent Candida infection (gt 2 months in
  children gt 6 months old)
• Cardiomyopathy
• Chronic Diarrhoea
• Disseminated Herpes Simplex Virus
• Leiomyosarcoma
• Lymphoid interstitial pneumonitis (LIP) or
  pulmonary lymphoid hyperplasia complex
• Nephropathy
• Disseminated Varicella

59
Recommended Antiretroviral Regimens - USA

• Protease Inhibitor Based Regimens
• Strongly Recommended 2 NRTI's LPV/RTV or NFV
  or RTV
• Alternative Recommendation 2 NRTI's APV(gt 4
  years) or IDV
• Non-Nucleoside Reverse Transcriptase Inhibitor
  Based Regimens
• Strongly Recommended gt 3years 2 NRTI's EFV (
  NFV)
• lt
  3years 2 NRTI's NVP
• Alternative Recommendation 2 NRTI's NVP (gt
  3years )
• Nucleoside Analogue Based Regimens
• Strongly Recommended None
• Alternative Recommendation AZT 3TC ABC
• Use in Special Circumstances 2 NRTI's
• Not Recommended
• Monotherapy
• ddC ddI, d4T or 3TC
• AZT d4T
• 2 NRTI's SQV (SGC or HGC) as single PI

www.aidsinfo.nih.gov
60
Recommended Antiretroviral Regimens USA
continued

• Insufficient Data to recommend
• 2 NRTIs Delavirdine
• Dual PIs with the exception of LPV/RTV
• NRTI NNRTI PI with the exception of
  EFVNFV1-2 NRTIs
• Tenofovir containing regimens
• Enfuvirtide (T-20) containing regimens
• Emtricitabine (FTC) containing regimens
• Atazanavir containing regimens
• Dual NRTI backbone recommendations
• Strongly Recommended AZT ddI, AZT 3TC, d4T
  3TC
• Alternative Recommendation ABC AZT, ABC 3TC,
  ddI 3TC
• Use in Special Circumstances d4T ddI, ddC
  AZT
• Insufficient Data TDF or FTC containing regimens
• Not Recommended ddC ddI, ddC d4T, ddC 3TC,
  AZT d4T

61
Recommended ARV regimens

• 2 NRTIs 1 PI (I II IV)
• 2 NRTIs 1 NNRTI (I II III)
• 1 NRTI 1 NNRTI 1 PI (I or IIIIIIV)
• ABCZDV3TC

Preferred Regimen Only in Special
Circumstances
62
No of mutations needed to develop high level
Resistance

• NNRTIs 1 mutation
• Protease Inhibitors- up to 8 mutations
• i.e PIs are more forgiving than NNRTIs

63
ARV drugs needing 1mutation to develop high level
Resistance

• 3TC
• NNRTIs-NVP,EFV,DLV
• Therefore NNRTIs should ideally not be used with
  Viral Loads gt 100 000 copies/ml or where there is
  a doubt about adherence

64
Routine Monitoring for Drug Toxicities

• General
• FBC, LFT 3-6 monthly
• Special Cases
• ddI, 3TC - Amylase 3-6 monthly
• NVP - LFT twice monthly X 2 months then 3
  monthly
• Pis Glucose, Cholesterol, Triglycerides 6-12
  monthly

65
Practical Prescribing

• Increase dosages as child grows
• Neonatal dosages are for .. Neonates
• d4T capsules
• use 20mg caps for 16-22kg child
• use 30mg capsules for 23-60kg child
• Use 3TC 150mg tablets from 25kg
• Round up dosages

66
HIVNET 012
Resistance Mutations

• Of 111 women who received 200mg of Nevirapine at
  onset of labour and their infants received 2mg/kg
  at 72hrs
• 21 (19) had Nevirapine mutations at 6 weeks
• 11/24 (46) of infected infants had Nevirapine
  mutations

Eshleman et al. AIDS 2001, 151951-1957
67
PHPT2
Single dose NVP AZT. NNRTI mutations in 18
Undetectable
VL lt 400 cps/ml
VL lt 50 cps/ml
11th CROI,2004,Abs 41LB
68
HAART AFTER FAILED MTCT PROPHYLAXIS

• Where NVP was used as a single dose in MTCT
  prophylaxis, it may be prudent to avoid NVP and
  EFV as part of combination therapy in this
  situation
• If AZT monotherapy was used in MTCT prophylaxis -
  Data support the use of AZT as part of
  combination therapy in infected infants
• If AZT and 3TC were used as dual therapy for
  MTCT prophylaxis, avoid 3TC only if the mother
  had a prolonged course of treatment without
  adequate viral suppression.
• If the mother was on triple combination therapy
  - where possible avoid the drugs the mother was
  taking especially if the mother had a detectable
  viral load. If the mother had a undetectable
  viral load, then it is probably acceptable to use
  the same agents in her HIV-infected baby

69
Regimens in SA Antiretroviral Roll Out in Children
Children lt 6 months - refer Specialist Centre
70
TB Treatment and HAART
OPTIONS

• Delay initiation of ART till after course of TB
  treatment.
• If not possible then delay ART for at least 1
  month of TB treatment to prevent immune
  reconstitution disease.
• Standard TB treatment together with ARV's
  compatible with rifampicin-
• i.e. 2 NRTIs either RTV or EFV (children gt
  3yrs).
• If the child is on Kaletra generally substitute
  ritonavir for the Kaletra. In certain
  circumstances, additional ritonavir can be added
  to the Kaletra regimen but data in children is
  scanty. Consult an expert.
• Standard TB treatment with a triple NRTI
  regimen, e.g. ZDV/3TC/ABC.(only effective
  with low viral loads) 
• Use rifabutin instead of rifampicin (difficult to
  obtain and very expensive) Ritonavir should not
  be used with rifabutin

Southern African Journal of HIV Medicine Oct
2002, pp 23-33
71
Switching to prevent and treat adverse effects

• 17 children 24-160/12 heavily pretreated
• All NNRTI naïve
• On 2-3 NRTIs and 1-2 PIs for median 21 months
  (range 5-50)
• All had VL lt400 copies /ml at switch for a
  median 13 months (range 4-55)
• PI switched to efavirenz (EFV) while NRTIs
  remained the same.

PEDIATRICS Vol. 111 No. 3 March 2003 e275
72
Switching to prevent and treat adverse effects

• At week 48 after the switch 16/17 had VL lt 50
  copies/ml. 1had VL of 61 copies/ml
• Mean CD4 increased from 35 to 38 at week 48
• Mean fasting Cholesterol dropped from 203mg/dL to
  105mg/dL at week 48
• Mean fasting triglycerides dropped from 126 mg/dL
  to 94 mg/dL at week 48

PEDIATRICS Vol. 111 No. 3 March 2003 e275
73
LIPODISTROPHY
DRUGS IMPLICATED IN LIPODISTROPHY d4T -
lipoatrophy Protease inhibitors visceral fat
accumulation
74
Switching to prevent and treat adverse effects
Switching from Stavudine to Abacavir to treat
Lipoatrophy

• Adult studies only
• Modest improvement in Lipoatrophy
• MITOX study
• 46 continued d4T- Limb fat 0.05kg
• 44 switched to ABC - Limb fat 0.46kg (p0.002)

Clin Infect Dis 2002, 35, 1219-1230
75
MITOX study- 104 week data
ZDV/d4T arm Limb fat increased by 0.49 1.38 kg
(13 P0.039) ABC arm Limb fat increased by
1.26 2.02 kg (35 P0.001)
AIDS 2004,18 1029 1036
76
Switching to prevent and treat adverse effects
Switching to NRTI sparing regimen to treat
lipodystrophy

• Adult study
• Advanced HIV- nadir CD4 200 cells/mm3 or HIV
  RNA 80,000 copies/mL)
• undetectable HIV RNA 200 copies/mL after at
  least 18 months of ART
• randomized to switch their initial successful
  antiretroviral regimen to open-label
  ritonavir-boosted Lopinavir (LPV/r) (533/133 mg
  twice daily) efavirenz (EFV) (600 mg once
  daily) vs EFV2 NRTI

12th CROI,2005,Abs 40
77
Switching to prevent and treat adverse effects
62 subjects Median baseline appendicular fat was
6 kg
Change in Appendicular Fat
12th CROI,2005,Abs 40
78
Treatment Failure
Reasons for changing therapy
Failure of current regimen with disease
progression - virologic -
immunologic - clinical Toxicity or
intolerance New data on more effective therapy
MMWR 199847(no.RR-4
79
Considerations for changing therapy
Treatment Failure

• Virologic considerations
• Triple therapy lt10 X (1 log10) ? from baseline
  VL at 8-12 weeks
• HIV RNA not undetectable at 4-6 months
• Repeated detection HIV RNA where previously
• undetectable
• A Reproducible increase in VL where previously
  a good response but low HIV RNA levels
• lt 2yrs gt 5 X (0.7log10) increase
• gt 2yrs gt 3 X (0.5log10) increase

www.aidsinfo.nih.gov
80
Treatment Failure
Considerations for changing therapy

• Immunologic considerations
• Change in immunologic classification. (e.g 2 to
  3)
• For children with CD4 T cell percentages of
  lt15 (i.e., those in immune category 3), a
  persistent decline of 5 percentiles or more in
  CD4 T cell percentage (i.e., from 15 to 10).
• A rapid and substantial decrease in absolute CD4
  T cell count (i.e., gt30 decline in lt6 months).

www.aidsinfo.nih.gov
81
Considerations for changing therapy
Treatment Failure

• Clinical considerations
• Progressive neuro-developmental deterioration
• Growth failure
• Disease progression e.g.. From clinical
  category A to B

www.aidsinfo.nih.gov
82
Failure of therapy

• Poor adherence
• Viral resistance
• Diminished efficacy of ARVs
• Decreased absorption of ARVs
• Inadequate dosages
• Increased metabolism
• Drug-drug interactions

83
Guidelines for Changing ARV regimens

• Assess Adherence
• Consider Resistance testing
• At least 2 new drugs
• Preferably 1 new drug class
• Dont add one drug to a failing regimen
• Consider Cross resistance ?
• Consider adding 3TC where M184V mutation present
  to maintain M184V mutation
• Quality of life in end stage disease
• Get advice from experienced clinicians

84
HAART and Adolescence

• Adherence
• Disclosing Diagnosis
• Dosages
• Tanner Stage I and II Paediatric dosages
• Tanner Stage III and IV Close Monitoring
• Tanner Stage V Adult Dosages

85
The child with End Stage AIDS
86
The child with End Stage AIDS
ISSUES

• May have slower response to ART
• May still develop OIs while on HAART
• Are at risk for IRIS
• Are at risk for adverse effects of HAART
• May need more potent HAART
• Require prophylaxis for Ois
• May be on numerous other medications

87
The child with end stage AIDS
APPROACH

• Exclude occult Opportunistic infections
• CXR
• TB Bactec for MAC and MTB bacteramia
• Prepare the parents for a Rocky ride initially
• Ongoing OIs due to low CD4 count
• IRIS
• ART toxicity

88
The child with end stage AIDS
APPROACH

• Delay non routine vaccinations as they will be
  ineffective
• Some children will do well without any problems

89
The child with End Stage AIDS
Prophylaxis for OIs

• PCP Prophylaxis
• MAC Prophylaxis

90
PCP Prophylaxis

• Start at age 4-6 weeks
• Continue till 4 months if 2 PCRs Negative
• Continue till 1 year if PCR positive or status
  uncertain
• If CD4lt15 continue prophylaxis
• If CD4gt15 stop prophylaxis but monitor CD4 count
  .
• Dosage of Co-trimoxazole 150mg/m2 Trimethoprim
  component daily or 3X a week
• (5mg/kg/dose of Trimethoprim component )
• Co-trimoxazole syrup40mg Trimethoprim and 200mg
  Sulfamethoxazole per 5ml
• Co-trimoxazole tablet80mg Trimethoprim and 400mg
  Sulfamethoxazole
• Alternative Dapsone 2mg/kg/dose daily

CDC.MMWR 199544(RR-4)1-11
91
Criteria for starting MAC prophylaxis

• lt 2 years- Immune category 3
• CD4 lt 15 or
• CD4 lt 750 cells /mm3 (lt12 months)
• CD4 lt 500 cells /mm3 (1-2 years)
• 2-6 years CD4lt 75 cells /mm3
• gt6 years CD4 lt 50 cells/mm3

MMWR 199746(RR-12)1-46
92
MAC prophylaxis

• 1st Line -Azithromycin or Clarithromycin
• 2nd Line - Rifabutin

93
MAC prophylaxis
DOSAGES

• Clarithromycin- 7.5mg/kg/dose bd (max 500mg bd)
• Azithromycin 20-25mg/kg/dose weekly (max
  1200mg/week)
• Rifabutin 5-6mg/kg/dose daily (max 300mg daily)

94

SA HIV CLINICIANS SOCIETY PAEDIATRIC DISCUSSION
GROUP(PDG)

• Email based case discussions
• Approximately 1 case per month
• Overseas opinions obtained once case fully
  discussed
• Fill in circulating forms

95
Practical Resources

• SA HIV Clinicians Society sahivsoc_at_gomail.co.za
• Dr Mark Cotton mcot_at_gerga.sun.ac.za
• Dr Glenda Gray gray_at_pixie.co.za
• Dr Leon Levin leonlevin_at_54.co.za
• Dr Avye Violari violari_at_mweb.co.za
• Dr Tammy Meyers meyerstm_at_paedshiv.wits.ac.za
• American Guidelines www.aidsinfo.nih.gov
• PENTA Guidelines   www.ctu.mrc.ac.uk/PENTA
• WHO Guidelines www.who.intDOH Guidelines
  http//www.doh.gov.za/docs/hiv-f.html