2. The Objectives of this training are:
1. Bring HCWs up to speed on why we optimize regimen (Pediatric) using DTG-
10.
2. To Introduce DTG10mg
• Rational for use of DTG10 as preferred first line combination of ARV for CLHIV
• Advantages of DTG10 over LPV/r
• Preparation and Administration of DTG10
• Possible side effects
3. Train providers including Field officers and ICAP mentors on the
implementation/rollout plan for DTG10
• Discuss consideration for rollout of DTG10
• Agree on the rollout training of HCWs for prompt transition of children to DTG10 based
regimen
Objectives of this Training
3. • What is Regimen Optimization?
• ART Formulatory in South Sudan
o Current ART optimization Status among CLHIV in S. Sudan
• Current WHO Recommended First Line ART regimen in Pediatric Population
o ART sequencing options for pediatric population
• Comparing DTG and LPV/r
• pDTG: Weight-based dosing, Preparation and Administration
o Solving Challenges
• Special Consideration, Pharmacokinetics and Side-Effects
• Considerations for Rollout
• pDTG Implementation/Transition Plan for S. Sudan
• Case Studies and FAQ
Presentation Outline
4. • Optimization refers to making the best or most effective use of a resource
• Optimized ARVs are those that are:
o Potent and very effective
o Less toxic
o Well tolerated and easy to take
o Reduce the risk of treatment failure
o Have a high genetic barrier to resistance
o Less costly for the program
• Optimized ARVs should also be harmonized across populations but this is
not always possible
What is optimization?
5. Optimal ARVs for infants, children and
adolescents: What we want in ART
formulations
Optimal ARVs for infants, children and
adolescents: What we want in ART
formulations
6. What we have in ART formulations:
LPV/r for 1st line in < 3 years
• Requires cold chain
• Bitter taste
• Heavy to carry
• Hard to store
Kaletra syrup
Age group Preferred 1st Line
<3 years ABC or AZT + 3TC + LPV/r
7. Methods
All children <15year currently active on ART were included
Data collection strategy included a cross sectional design leveraging on the existing medical record
systems at the health facilities supported by ICAP.
Clinical, laboratory and treatment data were abstracted from the existing paper and electronic
medical records at the supported facilities.
ICAP’s staff abstracted the data using an excel based data abstraction tool
All children included are currently active on treatment.
The assessment was conducted to understand the reason/s for low VS despite ART optimization in
the country, which was high compared to other countries.
8. Methods
Analyses included;
Description of variables using frequency, mean, median and SD
Correlations using logistic regression models to estimate associations
between VS and all potentially related individual-level factors (such as
age, duration on ART, combination of ARVs, dosages and time to
develop viremia),
Comparison between groups to determine predictors.
12. Is ART Dosage appropriate for current weight?
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Frequency Percent
627 46.3
725 53.6
ART DOSE FOR WEIGHT
No Yes
14. Conclusion
VL coverage is low
Proportion of children on ART with High viral load among those who had the test ranges
from 36% - 38% using 1000copies/mL or 50copies/mL respectively.
Over 14% of children are currently on NNRTI based regimen, which seems to be a sub-
optimal regimen.
Viremia is not related with
• Current age
• Current weight
• Regimen used including the regimen class
• Adherence to treatment could be the key factor although not assessed in the
study.
15. NNRTI resistance is rising in young children
79%
72%
48%
23%
44%
22%
25%
13%
0%
20%
40%
60%
80%
100%
0-3
months
4-6
months
7-12
months
13-18
months
Source: WHO – 2011 HIV DR surveys in PCR positive infants
• In young infants HIVDR levels are
very high
• Most of this is NNRTI resistance
~40% Y181
• Even children who are “not
exposed” to PMTCT had high levels
16. Viral resistance in sexually active youth with HIV RNA>5000
copies/ml (n=38)
• 42% of 92 sexually active ≥1 VL >5000 copies/ml
• 81 % had resistance to ≥1 ARV class
• 24% had some resistance to drugs in all 3 classes
• 63% with resistance reported unprotected sex Tassiopoulos, CID, 2013.
Slide courtesy of Theodore Ruel
Viral resistance in sexually active youth with HIV RNA>5000
copies/ml (n=38)
17. Teasdale, Mutiti, Arpadi et al
12 month VS rates (95%CI)
<12 months: 37.2% (28.4-
46.0)
1-5 years: 61.8% (51.6-70.4)
6-12 years: 71.3% (61.7-78.9)
Compared to children <12
months, 1-5 year olds had 1.5
times more likely to have VS
<1000 copies (p=0.007) and 6-
12 year olds had 1.7 higher
hazards of VS<1000 copies
(p<0.001)
Viral suppression in ART naïve children starting treatment,
Eastern Cape South Africa
0
.2
.4
.6
.8
1
cumulative
incidence
0 6 12 18 24
Months since ART initiation
<12 months 1-5 years 6-12 years
Cumulative incidence of viral suppresion <1000copies/mL by age
VS with ART is particularly challenging in
infants
22. • 30% of the children on ART are on DTG50mg based regimen
• About 70% of CLHIV in South Sudan are on PI based (LPV/r) ART regimen
• Viral suppression among children on ART is around 61%
Current Situation of DTG Use among CLHIV in S. Sudan
23. What is the current WHO recommendation for pediatric First-Line
ART?
26. Tablets:
• Dispersible tablets for Oral suspension (Tivicay PD) 5mg, 10 mgs
Preferred formulation for pediatric patients < 20kg
• Film Coated Tablets (Tivicay) 10mg, 25mg, 50mg
Do not use film coated tablets in patients weighing <14 kg
Note:
• Approved for use in pediatric patients who are treatment-naïve or treatment-experienced but naïve to INSTI
• DTG film-coated tablets and DTG dispersible tablets are not bioequivalent and not interchangeable on a milligram-
per-milligram basis
Fixed Dose Tablets:
• (Dovato) Dolutegravir 50mg/Lamivudine 300mg
• (Triumeq) ABC 600mg/Dolutegravir 50mg/Lamivudine 300mg
for patients with weight
DTG Formulations
27. • Prescription and Dosing
• Preparation and Administration
• Solving Challenges
• Special Considerations
• Concerns
pDTG
30. • DTG may be taken without meals
• Fully disperse the dispersible tablet in 10 – 20mls of clean drinking water
• Ensure to give child to drink after full dispersion and within 30 minutes of
mixing .
• Rinse the dosing cup with small amount of water and give this additional
water to the child to ensure full dose is taken
• DTG should be taken 2 hours before or 6 hours after taking cation-containing
antacids or laxatives, sucralfate, oral iron supplements, oral calcium
supplements or buffer medications
Preparation and Administration of Dispersible Tablets
31.
32. 1. Vomiting
2. Refuses to take or spits out because of the taste
3. Child chews dispersible
4. Child unable to swallow all dispersible
5. Child holding dispersible in the mouth
Solving Challenges
33. • If child has swallowed dispersible and vomits within 20 minutes, re-
administer the full dose
• If more then 20 minutes have passed, no need to repeat the dose
• Try giving the dispersible before or after a meal and see which is easier for
the child to tolerate
• Give fewer dispersible at a time (one tab)
Child vomiting after taking suspension
34. • If child has swallowed dispersible and vomits within 20 minutes, re-
administer the full dose
• If more then 20 minutes have passed, no need to repeat the dose
• Try giving the dispersible before or after a meal and see which is easier for
the child to tolerate
• Give fewer dispersible at a time (one tab)
Child vomiting after taking suspension
35. • DTG10 has a strawberry like taste and usually should not be a challenge
• Add the tabs to safe drinking water just before administering
• Give a spoon of something sweet or sticky that coats the mouth such as
peanut butter before giving the suspension.
• If available give something cold/frozen to child to numb mouth before
giving the solution
• If the child enjoys the taste of the dispersible tablet or other medicine
they take (cotrim liquid or multivitamin liquid) give DTG10 before and let
the child swallow them with the other medicine.
Child refuses to take or spits out because
of the unfamiliar taste
36. • Give with water instead of directly on the tongue then quickly follow up
with water or milk
• Let the child practice swallowing the tab at a time without chewing, then
complete the dose gradually.
Child may swallow DTG 10 tabs (broken or whole)
37. Special Considerations: TB/HIV Coinfection
• The recommendation is to use DTG twice daily across age groups and weight bands
when treating TB/HIV co-infection:
3 – 19.9 kg
ABC/3TC
120 mg/60 mg
DTG 10mg
12
hours
Later
Repeat
DTG 10mg
20 – 30Kg
ABC/3TC
120 mg/60 mg
DTG 50mg
12
hours
Later
Repeat
DTG 50mg
For children weighing >30kg on fixed dose TLD, DTG50 should be repeated after 12 hours as described above>
38. Although the dose of Lamivudine (3TC) and dolutegravir (DTG) in TLD FDC is
safe for children <30kg, the 300mg tenofovir (TDF) in TLD FDC is not.
Concerns include:
• Prevents proper bone mineralization – in children <30kg before they reach
10 years of age, the foundation for bone growth is still being built. TDF
300mg can prevent this process, weaken a child’s bones and putting them at
increased risk of spontaneous fracture. A history of bone aches following
long term TDF use should give a high index of suspicion
• Kidney Toxicity – TDF is also associated with a risk of acute kidney injury and
reduced kidney function in children. Depending on the severity this could
lead to the loss of vital minerals and proteins
Concerns about Using TLD Fixed Dose Combination (FDC) in
Children <30kg
40. • Drugs that induce enzymes such as UGT1A1 and CYP3A substrate may
decrease the plasma concentration of DTG
E.g.
Rifampicin
Rifabutin
Phenytoin
Phenobarbital
Oxcarbazepine
Carbamazepine
Multivitamin
• Drugs that inhibit these enzymes may increase DTG plasma concentration
E.g. Prednisolone
• DTG increases the plasma concentration of metformin leading to metformin
side effects
• It is important for clinicians to carefully review a patients medication
profile for potential drug interactions
DTG Metabolism
Ethinyl Estradiol/Norgestimate
Ferrous Fumarate
Isoniazid
Antacids
Calcium Carbonate
Dofetilide
41. Drug –drug interaction summary
Condition Drug interaction Effect Management plan
Psychosis/convulsion Phenobarbitone ,phenytoin
Carbamazepine with DGT
Reduced efficacy Use alternative drugs like
valproate
Only CZM can be used but
double the DTG dose
PUD Aluminium containing antacids and
DTG
Reduced absorption and
efficacy
Administer separately 2hours
before or after.
Active TB Rifampin and DTG
Reduced efficacy
Double the dose of DTG
Erectile dysfunction Sildenafil with DTG No change No adjustment required
Fungal infection Ketoconazole , Itraconazole with
DTG
No change No adjustment required
Oral contraception Oestrogen and progesterone
containing with DTG.
No change No adjustment required
42. More common
• Insomnia
• Headache
• Weight gain
Less common
• hypersensitivity reaction characterized by .
Rash
Constitutional symptoms
Organ dysfunction
• Neuropsychiatric symptoms
depression and/or suicidal thoughts or actions (especially in patients with a history of
psychiatric illness)
IRIS
• Severe cases appears to be more common in patients presenting with AHD
and initiated treatment with DTG
DTG Side Effects
45. DTG for ALL Children
In case of inadequate supply, the following group of children should be
prioritized
1. Those starting ART
2. Children on NNRTI-based regimens
3. Children who need to start Rifampicin-based TB treatment
4. Children on LPV/r liquid and solid formulations, particularly where those
continue to present challenges in administration and/or challenges with
attaining VL suppression
Prioritization may become important depending on Country
Context/circumstance
CONSIDERATIONS For Rollout of pDTG-10
46. Viral Load Status
• VL monitoring remains a good practice to deliver appropriate care to CLHIV
• However, VL status should not be considered a precondition to undertaking
a programmatic or individual transition
• CLHIV should not have their transition delayed due to lack of documented
VL (or unsuppressed VL)
• However, VL test be done three to six months post transition
CONSIDERATIONS For Rollout of pDTG-10
47. DSD - MMD
• Children who received MMD prior to transition to pDTG should remain
eligible for MMD after transitioning to pDTG
provided the CLHIV has optimal VL suppression.
VL testing every 6 month should be the standard for all CLHIV
• Anticipatory guidance should be provided to caregivers regarding any side
effects and what to do if there are any questions or concerns
Program to develop IEC materials on dosage/weight.
Preparation and administration
• Programs are encouraged to continue providing MMD and may consider
providing virtual/face to face follow-up 2 – 4 weeks after a child has
transitioned to pDTG.
HCW (mentor mothers) should be trained on DTG10 preparation and administration to
support caregivers of children transitioning to DTG10.
CONSIDERATIONS For Rollout of pDTG-10
48. Q: Should DTG10 Transition happen even if it results in
wastage of LPV/r
A: Yes
• It is in the best interest of the child and the program to promptly transition
all CLHIV (with weight 3kg – 19.9kg) to pDTG
• Transition should be timely and straight forward
• Phased transition should NOT be used to mitigate LPV/r wastages
CONSIDERATIONS For Rollout of pDTG-10
51. IMPLEMENTATION PLAN – Phase 1
S/N Activity
Timeline
Key
Responsible
Status Update
July
1 Notify/Sensitize Key Stakeholder
• Build consensus around implementation/rollout plan
ICAP/CDC Scheduled for Week of 11th July
2
Develop problem-based training materials/Job Aids
• With input from stakeholders ICAP Ongoing
3 Develop/Update M&E tools required to track transition
process
ICAP
4
Generate Line list of All CLHIV (≥ 3 years) showing
• Current age, weight at last visit, current regimen,
date of last visit, date of next visit, VL status
CDC-IPs
5 Quantify DTG10 Required for South Sudan Program PSM TWG
Done
(90 x 13,833)
50% in Sept. 50% in Dec
Procurement initiated
52. IMPLEMENTATION PLAN – Phase 2
S/N Activity Aug Sep Oct Nov Assumptions
(Comment)
Key Responsible
1 Stock Analysis What do we do with LPV/r
pellets in country?
MoH/USG
partners
2 ToT – for clinicians and pharmacists
Aim is to do this just before
facilities start DTG10 starts
hitting the facilities
USG - IPs
3
Decentralize Training to all HCW
involved in management of PLHIV
• Preparation and administration
• Data Clerks
Regional Team
Leads
4
Quantify DTG10 requirement per
region and per facilities PSM/USG-IPs
5 Receive and Distribute DTG10
6 Track rate of transition per facility USG-IPs
7 Monitor clinical outcomes post
transition to DTG10
Quarterly USG-IPs
53. What needs to be done?
• How many children are in care per region per facility
• Current age/Weight?
• What is the current regimen each child is taking?
• What is the appropriate optimized regimen for each child?
Quantification for Kick-off, Forecast
• What is the current stock of optimized regimen/ARV in each facility?
• Incorporate/include in ARV commodity management templates
• Make Requisition
Practical steps
54. Get the list of all children by facility
S# UAN Date ART start
Age (ART
start)
Weight on
most
recent visit
Weight on last
visit
Current
regimen
Optimized
regimen
Next appointment
date
55. Daily/Weekly
• # of pediatric visits today (newly identified and already on ART)
# of children already in care who visited today and already on DTG-based regimen
# of children already in care who visited today who were not on DTG-based regimen and
transitioned to DTG-based regimen today
# of newly diagnosed children who commenced ART today with DTG-based regimen
Monthly
• # of children on transitioned to DTG-based regimen
• % of children on DTG-based regimen
By facility
By region
ICAP S.Sudan
Monitoring transition
57. • A 2 weeks old child can be started on DTG based regimen?
Note:
• DTG is not approved for use in neonate
• DTG can be used in infants from 4 weeks of age and from 3kg body weight
True or False
False
58. • A 20 Kg child can be started on a daily dose of 30 to 50 mg DTG
True or False
True
59. • The efficacy of DTG 50 mg twice daily is reduced in patients with certain
combinations of INSTI-resistance mutations.
True or False
True
60. • Dose adjustment of DTG is necessary in patients with mild or moderate
hepatic impairment.
True or False
False
61. The dispersible tablet cannot be directly compared to those using the film-coated tablets.
Note:
• DTG film-coated tablets and DTG dispersible tablets are not bioequivalent and are not
interchangeable on a milligram-per-milligram basis
• Each formulation has different doses
True or False
True
62. A child with type two diabetes and HIV to be treated with metformin and DTG
10?
Do you combine ?
No ; childern normally have type 1 DM
but can be considered rarely with
dose adjustment needed for metformin
63. A patient with treatment failure requiring a combination of boosted Darunavir
and DTG-10
Do you combine ?
Yes ; DTG blood level will increase
but is safe.
64. A patient with grandmal seizure and CD4 count of 450/mm³ ; started on DTG10
containing regimen and phenobarbital
Do you combine ?
No; reduced efficacy
65. • A patient with chronic gastritis and CD4 count of 380/mm³ started on
ABC/3TC/DTG10 plus antiacids, vitamins and iron.
Note:
• DTG should be taken 2 hours before or 6 hours after taking cation-containing
antacids or laxatives, sucralfate, oral iron supplements, oral calcium
supplements or buffered medications
Do you combine ?
Yes; administer separately
66. A patient with TB and a CD4 count of 450/mm³ started on Rifampicin and TLD ?
Do you combine ?
Yes ; and double the dose of DTG
67. A child on optimized ART using LPV/r is transitioned to DTG10 without recent
VL. When should a VL test be done?
When is VL testing recommended ?
3 to 6 months post transition;
I want to say a brief word about VS during infancy. As many of you are aware efforts are being made to promptly initiate infants on ART as an important means of reducing early mortality. However what we are learning is that achieving VS can particulary challenging during this period. These are results from prospective observational study conducted in 4 public health facilities in the Eastern Cape of South Africa in which 300 children enrolled in routine clinical care services who were initiating ART in which VL was obtained at 6 month intervals in which we can see t(POINT) hat at least for the 1st 2 years on treatment children starting ART below of year have lower rates of VS compared to those starting at older ages.For those starting at less than 12 month of age VS rate was 37.2% which was considerable lower than children starting at older ages. This may be due to the often very levels of viremia (upward to more than 1 million copies as well as the difficulties of administering poorly palatable formulations particlarly ritonavir boosted LPV. NEXT slide
Even lower initial VS are reported among infants on Prospectively collected cohort data from routine ART in infants from 11 cohorts in IDEA Southern Africa. ART naïve started on ART <13 mo between 2004-12. N=4945 probability of viral suppression at 6 months was <30% and by 12 months it was 56%
