Complications Where do we go from here

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ComplicationsWhere do we go from here

• Sharon Nachman
• Chair, Complications Committee
• IMPAACT

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Recent/Past Endeavors

• OI prevention
• 254, 1008
• Vaccines
• 292, 1024, 1008, 1061s, 1057, others
• Metabolic
• 1045
• Psychiatric
• 1055

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Next steps

• New sites
• Domestic
• 13 NIAID, ?NICHD
• International
• 22 NIAID, ?NICHD
• New ideas
• Not so new diseases
• New pathogens to target
• New toxicities

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From the RFA

• TB
• PKs, treatment
• Diarrhea
• Rotavirus
• Malaria
• HPV
• Hypercholesterolemia and other metabolic issues
• Bacterial prophylaxis
• Psychiatric diagnoses and therapies

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Long term follow up

• What are the scientific questions?
• Focus on new therapies
• Do we focus on ARTs or include others?
• Enroll from clinical care and PT protocols
• Stand alone study
• Not duplicate SMART or AMP
• How to develop international studies for new
  adverse events?

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CCG

• Follow up into adulthood
• Delayed complications
• Effects of long term treatments
• How adolescents cope emotionally and physically
• Mental health
• Learning disabilities, neurocognitive issues,
  behavioral issues
• Treatment and prevention of malnutrition
• Enhancing response to TB, malaria medications

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CCG other issues

• Bone
• Cardiac
• Lipoatrophy and lipodystrophy
• Comparison of long term effects between domestic
  and international cohorts

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What is open or opening soon?

• 1041
• INH prophylaxis
• International
• 1047 CLOSED!!
• HPV IN HIV youth
• Domestic
• 1065
• Menactra vaccine in HIV youth
• Domestic
• 1063
• Atorvastatin
• Domestic
• 1055
• Psychiatric disorders
• Domestic

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New ideas

• 10 capsules submitted
• TB
• Treatment (2)
• Observational trial
• TB diagnosis
• Psychosis (treatment)
• Growth hormone for truncal adiposity (treatment)
• Bone remineralization (treatment)
• Cardiac risk diagnosis
• HIV nephropathy (prevalence, pathogenesis)
• Rotavirus vaccine

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Moving up from capsule

• CS 4060 Safety and immunogenicity of a live,
  attenuated, rotavirus vaccine (RotaTeqTM) in
  children born to HIV-infected mothers
• CAP 182C Impact of Oral Alendronate Therapy on
  Bone Mineral Density in HIV-Infected Children and
  Adolescents
• CAP 187C Open labeled study examining the safety
  and 36 week clinical and virological outcome of
  HIV infected children with pulmonary tuberculosis
  (PTB) treated with TB drug regimen including
  rifampicin and who are also managed with an
  anti-retroviral regimen (ARV) including either
  lopinavir-ritonavir (LPV/r) added ritonavir
  (RTV) or efavirenz (EFV) or nevirapine (NVP).
• CAP 192C Use of an interferon gamma based
  immunoassay for the diagnosis of latent
  tuberculosis in HIV infected children

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Use of an Interferon Gamma Based Immunoassay for
the Diagnosis of Latent Tuberculosis (LTBI) in
HIV Infected Children.

• Marc Foca, MD, Philip LaRussa, MD,
• Anne Gershon, MD
• Columbia University Medical Center

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Background

• The WHOs Stop TB strategy calls for isoniazid
  (INH) prophylaxis in HIV infected patients in
  whom active TB has been excluded in order to
  reduce the burden of active disease and spread in
  these patients.
• Pediatric burden of worldwide TB cases is
  estimated at 15
• Prevalence of LTBI in the pediatric population is
  unknown
• PPD impractical in many areas
• Refrigeration
• Patient must return in 48-72 hours for reading
• New assays based on gamma interferon production
  from TB specific lymphocytes could alleviate
  these difficulties without overburdening
  infrastructure

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Hypothesis

• An interferon gamma based immunoassay will have
  improved sensitivity and specificity compared to
  PPD placement for the diagnosis of latent
  tuberculosis (LTBI) in an HIV infected population
  of children1.
• Minimal laboratory infrastructure centrifuge,
  incubator, hemocytometer. Assay takes less than
  24 hours to perform with a short training period.
• 1. Liebeschuetz et al The Lancet 2004
  3642196-2203

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Outcomes

• Groups I (PPD/CXR-) and III (PPD/CXR) would
  allow an estimate of the sensitivity and
  specificity of the IFN assay compared to PPD
• Group II (PPD-/CXR-) would provide interesting
  data on development of disease if PPD and CXR
  negative subjects with a positive IFN assay go on
  to develop active disease.
• Group IV (PPD-/CXR) would be treated initially
  for an alternative diagnosis, but follow-up would
  indicate how many went on to a diagnosis of TB

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Endpoints

• Primary
• To compare the sensitivity, specificity, and
  positive/negative predictive value of an
  interferon gamma based assay to standard PPD
  placement for the diagnosis of LTBI.
• Secondary
• To provide data on the prevalence of LTBI in this
  patient population
• To inform prophylaxis recommendations
• Prevalence high enough to recommend blanket
  prophylaxis
• Prevalence low enough to offer targeted
  prophylaxis

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CAP 182C Phase I/II Trial of Oral Alendronate
for HIV Infected Youth with Low Bone Mineral
Density (BMD)

• George K Siberry, MD, MPH
• Bret J Rudy,MD

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Background Rationale

• Low BMD associated with fractures
• Low BMD in childhood -gt adult osteoporosis
• Most lifetime bone mass laid down in adolescence
• Bisphosponates (alendronate) effective in
  reducing BMD loss in adults with osteoporosis
• Higher rates of low BMD in HIV adults and
  children (Amorosa review 2006 Obrien2001
  P1045)
• Additional factors TDF, PI, Depoprovera,
  Nutritional status, steroids, anticonvulsants

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Background Rationale

• Alendronate (ALEN) in HIV adults with low BMD
  safe and improved spine BMD (Mondy 2005)
• Limited data for safety and BMD improvement in
  non-HIV children with osteoporosis treated with
  ALEN (Unal 2006)
• No ARV interactions expected with ALEN
• Increase jaw osteonecrosis with (intravenous)
  bisphosphonates (Capsoni 2006 Woo 2006)
• DEXA established norms for children
• Quantitative ultrasound no radiation but very
  limited data Rosso 2005

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Primary Objectives

• Compare BMD in the lumbar spine at 6, 12 and 24
  months to baseline.
• Estimate rates of adverse effects at 6, 12 and 24
  months of alendronate use.
• Compare performance of radiation-free
  quantitative ultrasound to gold-standard DEXA for
  measurement of BMD

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Population Study Design

• Phase I/II, 2-year trial
• Population 12-24 year old HIV
• Inclusion HIV acquired in infancy/childhood
  Spinal BMD Z-score lt-2.0
• Exclusion Systemic steroids anticonvulsants
  GH deficiency, 1 hyperparathyroidism, renal
  failure Cushing syndrome. Active dental
  infection. Significant dental/periodontal
  disease.
• N30 (N15 to detect 3 change in BMD)

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Study Outline

• Visits screening, entry, 6, 12, 24 months
• Treatment
• Calcium dose 1000 mg daily
• Vit D Dose 400 I.U. po daily
• Alendronate
• gt30kg 10mg daily
• 30kg 5mg daily
• Assessments (0, 6, 12, 24 months)
• DEXA Quantitative ultrasound
• Dental exams (safety)
• Blood and urine markers of bone formation and
  absorption and of vitamin D status

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Clinical and virological outcome of HIV infected
children with pulmonary tuberculosis (PTB)
treated with a rifampicin-containing TB drug
regimen and anti-retroviral regimens (ARV)
including either lopinavir-ritonavir (LPV/r)
added ritonavir (RTV), or efavirenz (EFV) or
nevirapine (NVP)

• Shabir A Madhi
• Mark Cotton

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Background and Rationale

• Rifampicin, key anti-TB bactericidal drug, shares
  drug-interactions with PIs (except ritonavir)
  and NNRTIs through induction of cytochrome p-450.
• Treatment of HIV infected children on ARV for TB
  frequently requires the substitution of PIs and
  NNRTIs
• HIV infected children with TB not treated with
  ARV 3.5 fold higher mortality than children on
  dual TB-ARV treatment (i.e. started on ARV within
  2-8 weeks of starting TB treatment)
• Current 1st line ARV regimen in South Africa
• lt 3 years d4T, 3TC lopinavir/r
• 3 years d4T, 3TC, Efavirenz
• TB regimen H/R/Z x 2 months H/R x 4 (?7
  months)

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Hypothesis

• Potential ARV (PI and NNRTI)-TB (rifampicin) drug
  interactions may be dealt with through dose
  modification of the relevant ARVs without
  adversely affecting the safety, clinical
  response, virological (HIV viral load) and/or
  immunological outcomes (CD4 count) of dually
  (TB-HIV) treated HIV infected children.

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Study groups (N50 in each)
Notes 1ARV will be initiated in all children lt
12 months of age and based on presence of
severe/advanced immunosupression using 2006 WHO
recommended CD4 threshold levels in children 12
months of age and/or based on clinical
discretion of attending physician. 2Dose
adjustment at time of initiating TB
treatment 3Inclusion of children on a NVP regimen
or switching these children to LPV/rRTV would
require additional guidance from pharmacist
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Objectives of study

• Primary objectives
• Determine the 36 week virological and
  immunological outcome in HIV infected children
  with PTB dually treated
• To determine the safety of an ARV regimen with 2
  NRTIs and either LPV/r RTV, EFV (125 dosage)
  or NVP (130 dosage) in HIV infected children
  dually treated with a rifampicin-containing TB
  drug regimen.
• Secondary objectives
• To determine the 48 week virological and
  immunological outcome in HIV infected children
• Describe the pharmacokinetic profile of ARVs
  (LPV, RTV or EFV, or NVP) and rifampicin in HIV
  infected children during the dual treatment phase
  for TB-HIV.
• immune-reconstitution syndrome and outcome

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Study population..

• Multi-centered study involving any site using
  study ARV and TB regimen
• Children aged 6-14 months with clinical or
  microbiological diagnosis of PTB (exclude EPTB)
• Children been stable on ARV for at least three
  months or in whom ARV initiation is planned
  within 2-8 weeks of initiating TB treatment
• Study sample N50 per arm
• Timelines enrollment complete in 12-18 months.

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CS4060Safety and immnunogenicity of a
live,attenuated rotavirus vaccine in
HIV-infected and uninfected children born to
HIV-infected mothersMyron Levin
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Background

• Rotaviral diarrhea is a significant health burden
  in all countries, but is often especially
  threatening in resource poor settings
• This will be a significant problem at
  international sites and will complicate the care
  of children with neonatal HIV infection
• Licensed rotavirus vaccines are safe and
  efficacious in HIV-uninfected children
• Rotavirus vaccine should be made available to
  protect HIV-infected children

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Objectives

• Primary safety within 42 days after any dose in
  HIV-infected and uninfected infants
• Secondary
• Immunogenicity after the third dose (serum
  IgA-ELISA and neutralization assays)
• Shedding of vaccine strain virus
• Relationship of responses to CD4, HIV RNA, and
  ART

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Design

• Contact mothers -90 to 30 days of birth
• International sites
• Test at week 8-12 for CD4 and HIV RNA (VL)
• 3-doses of 5-valent vaccine or placebo
• OPV as per standard of care
• Blood sample pre-dose and after Dose 3 repeat
  CD4 and HIV RNA
• Stool samples after each dose
• Weekly clinic or home visits

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Design

• Monitoring
• Enroll 20 HIV-infected with 15 CD4 and assess
  before proceeding
• Then continue enrolling this stratum and observe
  the first 20 HIV-infected with lt 15 CD4 before
  proceeding
• Sample 240 each vaccine/placebo
• 80 in each group with HIV 160 uninfected
• Equal numbers with low and high CD4

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Issues

• Detects Grade 3 SAE of lt3.7 in HIV-infected
  lt1.9 in uninfected at 95 C
• Compare in the two groups
• SAEs - Detect 15-20 difference between vaccine
  and placebo recipients
• Antibody titers look for 3-folds rise in titer
• Shedding (measure of efficacy?) - exploratory
• Relate to immune status and viral load
  exploratory
• Accrual rate see P1041
• Design will detect infection acquired post-partum
• Copra-antibodies? (measure of mucosal immunity)

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