Optimization of ART Regimen

NAHCC
11th September 2017
 Outline
• Learning objectives
• Overview of national guidelines in the context of
optimized ARVs
• Use of Dolutegravir
• Use of TLE400
• Immune Reconstitution Inflammatory Syndrome
• Use of LPV/r
 Learning objectives
• To describe the indications of optimized ARVs in the context of the current national guidelines

• To discuss the use of optimized ARV regimen with emphasis on the use of dolutegravir,
efavirenz 400mg and LPV/r formulations

• To describe Immune Reconstitution Inflammatory Syndrome (IRIS)

• To understand future optimization plans

 Why ARV optimization?
Optimization refers to making the best or most effective use of a resource

ARV Drug Optimization: Key Principles

• Reduce toxicity

• Improve palatability/pill burden

• Increase resistance barrier

• Reduce drug interactions

• Safe use across different age groups and populations (“Harmonization”)

• Reduce cost

•
 Section 1:
Overview of National Guidelines in the
Context of Optimized ARVs
National ART Guidelines 2016
• Ministry of Health made provision to
optimize ARVs once available in the
national guidelines
• The following formulations are currently
available:
• Dolutegravir (DTG) 50 mg
• TDF/3TC/EFV (300mg/300mg/400mg)
(TLE400)
• LPV/r pellets and 100/25 mg tablets
• ABC/3TC (120/60mg)
 National ART Guidelines 2016
• 1st line therapy:
• Use DTG as an alternative ARVs in first-line for PLHIV > 15yr on EFV
and unable to tolerate EFV
• Use of lower dose of EFV as TLE400 as preferred ART for initiation
• Use of pediatric friendly formulations of LPV/r (100/25 mg tablets and
40/10mg pellets)

• 3rd line therapy:

• DTG to be used following consultation with the Regional or National
Clinical HIV TWG (ulizanascop@gmail.com)
 HIV Life Cycle & ARV Action Sites
NRTI & NNRTI Integrase Inhibitor
Fusion Inhibitor
Protease Inhibitor

CCR5 Antagonist
Section 2:
Dolutegravir
 Dolutegravir: Outline
• Case reviews
• DTG evidence review
• DTG in clinical practice
• MoH guidance on indications for DTG use (MoH June 2017 circular on DTG)
• Adverse drug reactions and adverse events
• Dosing recommendations
• Case reviews
 Case 1
• A 48 year old female, newly diagnosed HIV, initiated on TDF/3TC/EFV.
Presents 4 weeks later with yellowness of the eyes and excessive fatigue.
On exam found to be jaundiced with mild RUQ abdominal tenderness
• What are the next steps:
A. Order LFTS
B. Order abdominal ultrasound
C. Order HAV IgM
D. Order HBsAG
E. Order HCV Ab
F. Stop all ART immediately
 Case 1 continued
• Laboratory tests return and ALT is 670 IU/ml, AST 430 IU/ml, mild
elevations in GGT and ALT:
• What will be your next step
A. Stop all ART until LFTs are normal
B. Continue current ART and only stop if the patient worsens
C. Change to TDF/3TC + ATV/r
D. Change to TDF/3TC + DTG
 Case 2
• 28 year old man known to have bipolar disorder, brought to your facility
with HIV, decision made to start ART.

• What regimen will you choose?

A. TDF/3TC/EFV
B. TDF/3TC + NVP
C. AZT/3TC/NVP
D. TDF/3TC + DTG
 Case 3
• 32 year old male, on Medication Assisted Therapy (MAT) has been on
ART for 2 years, and is currently on TDF/3TC + ATV/r. He has been on
MAT for 1 year, is compliant with therapy and is virologically suppressed

• What of the options below are appropriate for his continuing care?
A. Continue current regimen
B. Switch to TDF/3TC/EFV
C. Switch to TDF/3TC + DTG
 Case 4
• A truck driver with a drug habit falls ill while on transit. He was diagnosed to be
HIV-infected 2 months prior and was initiated on TDF/3TC + DTG 50mg. As he
complains of cough, and night sweats, he is investigated for TB – GeneXpert
results MTB positive / Rif sensitive. How will you proceed with his ARV
treatment?
A. Change to TDF/3TC/EFV600
B. Change to TDF/3TC/EFV400
C. Increase the dose of DTG from 50mg OD to 50mg BD
D. None of the above
 Case 5
• 24 year old non-pregnant woman accompanied to your facility by her mother
after being newly diagnosed with HIV. A decision is made to start ART but it is
established that she has a history of being treated for depression
• What regimen will you select for her?
A. TDF/3TC/EFV
B. TDF/3TC + NVP
C. AZT/3TC/NVP
D. TDF/3TC + DTG
• On her sixth month on ART she is noted to 8 weeks pregnant. How will
you manage her? Explain your decision.
Evidence Review
 DTG use in 1st Line: Head-to-Head Studies
Key findings:

• DTG superior to EFV, ATV/r, and DRV/r

• Virological failure rates similar, but fewer adverse events with DTG
• DTG had faster time to virological suppression
• No patients who failed DTG developed new INSTI mutations

• DTG superior to RAL for patients with high baseline viral load
(>100,000)
Walmsley, NEJM 2013; Walmsley, JAIDS 2015; Orrell, AIDS Conf 2016; Clotet, Lancet 2014; Molina, Lancet HIV 2015;
Raffi, Lancet 2013; Raffi, Lancet ID 2013
 DTG use in 1st Line: Switch Study
Study ARV History Current regimen Switch Results
(HIV RNA <50)

STRIIVING Virally Stable patients on DTG / ABC / 3TC vs. No difference in

suppressed • PI/r, Continue current ART efficacy
patients on 1st • NNRTI, or
line ART • INSTI-based No virological
regimen failures in either
arm
NEAT 022 Virally Stable patients on Switching to a Maintained viral
(switch suppressed • PI/r, dolutegravir regimen suppression and
from PI/r to patients on PI/r from a boosted improved lipid
DTG) protease inhibitor fractions in
regimen patients with
high CVD risk
1. Lake, Antiviral Therapy 2017
2. . Gatell JM, Assoumou L, Moyle G, et al. Program and abstracts of the 9th IAS Conference on HIV Science; July 23-26,
2017; Paris, France. Abstract TUAB0102.
 DTG use in 2nd and 3rd Line
• DTG superior to RAL and LPV/r for treatment-experienced patients

• DTG still effective after patients fail RAL, but requires increased dosing
(50 mg BD instead of once-daily)
Study ARV History Comparison Results
(HIV RNA <50)

SAILING > 2-Class ARV Dolutegravir QD vs. Raltegravir Dolutegravir superior

resistance (71% vs. 64%)

VIKING-3 Integrase Single-arm, Dolutegravir BID Virological

resistance suppression (69%)
DAWNING NNRTI-based 1st Dolutegravir QD vs. LPV/r Dolutegravir superior
line failure
(82% vs. 69%)
1. Cahn, Lancet 2013; Castagna, JID 2014; Akil, Antiviral Ther 2015
2. Castagna A et al. J Infect Dis. 2014 Aug 1; 210(3): 354–362.
3. DAWNING: 24-week interim data
 Tsepamo: Birth Outcomes When Initiating
First-line DTG vs EFV in Pregnancy
• Prospective cohort study in HIV-infected women in Botswana initiating ART with EFV/FTC/TDF vs
DTG/FTC/TDF while pregnant (N = 5438)

Adverse Birth Outcomes, DTG EFV aRR*  Few first-trimester ART

n (%) (n = 845) (n = 4593) (95% CI) exposures (DTG, n = 116;
Any 291 (34.4) 1606 (35.0) 1.0 (0.9-1.1) EFV, n = 396); most second/third
 Severe 92 (10.9) 519 (11.3) 1.0 (0.8-1.2) trimester
Stillbirth 18 (2.1) 105 (2.3) 0.9 (0.6-1.5)
Neonatal death (< 28 d) 11 (1.3) 60 (1.3) 1.0 (0.5-1.9)  Only 1 major congenital
Preterm birth (< 37 wks) 149 (17.8) 844 (18.5) 1.0 (0.8-1.1)
abnormality observed (skeletal
 Very preterm (< 32 wks) 35 (4.2) 160 (3.5) 1.2 (0.8-1.7) dysplasia in EFV-exposed group)
SGA (< 10th percentile 156 (18.7) 838 (18.5) 1.0 (0.9-1.2)
weight)  ABO risks similar when initiating
 Very SGA (< 3rd 51 (6.1) 302 (6.7) 0.9 (0.7-1.2) first-line DTG vs EFV in
percentile weight) pregnancy
*For DTG vs EFV; adjusted for maternal age, education, gravida.

Zash R, et al. IAS 2017. Abstract MOAX0202LB. Slide credit: clinicaloptions.com

 DTG: Pregnancy and
Children/Adolescents
• Pregnancy
• Results from 845 women in Botswana
• No increased risk of adverse outcomes when DTG is started during
pregnancy (compared to EFV) or even exposed in 1st trimester
• Children/Adolescents
• FDA approved DTG for 6 years and older and weighing 30-40 kg (35 mg dose)
• Approved for ≥ 40 kg using adult dose (50 mg)
• Studies in progress for ≥ 4 weeks of age
• Peds formulations likely to be available within next 1-2 years

Antiviral preg register; Zash, IAS Conf 2017 (abstract)

 DTG in Clinical Practice
and
Current MoH Circular Indications of DTG
 MoH Circular: DTG Use in 1st Line
• Alternative 1st line for patients who cannot use EFV (instead of ATV/r)
Contraindication to EFV are:
• Psychiatric history,
• Adverse events with EFV: CNS side effects that are severe or do not improve with
continued use for 1 month, Moderate or severe rash/ hypersensitivity reaction,
dyslipidemia, Gynaecomastia
• Preferred 1st line for initiation in PWID (instead of ATV/r)
• Substitution for patients who are virally-suppressed on PI/r-based 1st line
(PWID)
 MoH Circular: Use Beyond 1st Line

• Patients failing PI/r-based regimen

• Guidelines recommend DRT to determine regimen after failing PI/r

• DRT is approved through Regional or National Clinical HIV TWG

• Regional/National TWG will review DRT results and determine if DTG should
be used as part of next regimen
 DTG use in Pregnancy
The circular does not recommend initiating DTG in pregnant, or who are intending to
become pregnant

If a patient is already on DTG and is determined to be pregnant:

It is reasonable to continue DTG rather than switching to another ARV

DTG is expected to be classified as safe in pregnancy soon and

pregnancy restriction will probably be removed in 2017/2018
 DTG use in TB
The circular does not recommend initiating DTG in patients who are on TB treatment

Patient already on DTG at the time of TB diagnosis:

Use standard rifampicin-based anti-TB treatment; Continue DTG and increase the
dose to 50 mg BD for the duration of TB treatment; Adjust the DTG dose after
competing TB treatment to 50mg OD

Patients with 2nd line PI/r based ART and develops TB

Substitute PI/r to DTG 50 mg BD and initiate Rifampicin based TB treatment ( to
reduce pill burden due to single TB drugs with ART, better adherence); Continue
DTG based ART; Adjust the DTG dose after competing TB treatment to 50mg OD
 ARV regimens for CALHIV
2016 GL Preferred 1st line ART
Children < 3 years ABC/3TC +LPV/r
For <2 weeks age: AZT/3TC/NVP is preferred as per the current 2016 guidelines
Children 3 years to < 10 years ABC/3TC + EFV

NEW Recommendations for immediate implementation

Age/weight Preferred First line regimen Remarks
<2weeks AZT/3TC/NVP As per 2016 revised guidelines
>2 weeks and < 25 kg ABC/3TC+LPV/r All children on NVP change to LPV/r
All children on AZT change to ABC
25 kg up to < 35 kg ABC/3TC+ATV/r All children on NVP change to ATV/r
All children on AZT change to ABC
< 35 kg ABC/3TC+EFV Children currently on this regimen and virally suppressed
Do not change
< 15 years and >35 kg ABC/3TC+DTG New initiations

> 15 years and >35 kg TDF/3TC+DTG For all adolescents (New and current if virally
suppressed and no contraindication on use of the
regimen
 TB HIV CO-INFECTION in CALHIV
• Children on LPV/r – continue with boosted ritonavir.

• Program to source for ritonavir powder for pediatric patients

• RAL – for those unable to tolerate super boosted LPVr

• Disadvantage of using RAL – low resistance barrier but better option than
triple nukes. Need for doubling dose of RAL

• DTG – dose needs to be doubled for those who are TB HIV co-infected
 Assessing Contraindication to EFV
• ART naïve PLHIV:
• Mental status evaluation to assess for presence of mental illness
• Screening for depression using the PHQ-9 form
• Determine if currently on treatment for any mental illness
• If mental illness is present, initiate DTG as alternative to EFV
• PLHIV on EFV based ART:
• At every clinic visit:
• Screen for EFV related AEs and assess severity
• Screen patient for mental illness, depression or treatment for mental illness
• If AEs persistent for over 4 weeks, substitute EFV with DTG
Do not ignore patient’s concerns about persistent complaints
 DTG: Adverse Events (AEs)
• Generally well tolerated

• Most common AEs are insomnia, headache, nausea, diarrhea

• CNS AEs are common in older age (> 60 years), co-administration

with ABC, and higher plasma drug levels

• Insomnia may improve if administered with low-fat meal or on an

empty stomach (theoretical)
Note: Advise patient to take DTG in the morning and preferably with low fat diet to
minimize the AEs

Fettiplace, JAIDS 2017; Sabranski, HIV Glasgow Conf 2016; De Boer, AIDS 2016; Yagura, CROI 2017
 DTG: Immune Reconstitution Inflammatory
Syndrome (IRIS)
• Compared to PI/r or NNRTI; use of INSTI is associated with
• Much faster rate of virological suppression and CD4 recovery

• Risk of IRIS may be double with INSTI for patients at high risk due to an inflammatory
response to residual opportunistic infections (e.g. TB, MAC, CMV and PCP) in patients
with:
• Low baseline CD4
• High baseline viral load
• Advanced clinical stage
• Diagnosed opportunistic infection
• Requires further evaluation and treatment. Consult a senior clinician or the National
HIV Clinical Support Center in case of any concerns
Dutertre, JAIDS 2017; Wijting, CROI 2017
 DTG Formulation and Dosing
• Dolutegravir, is currently available as a single 50 mg tablet

• Adults (any weight), and adolescents > 15 years & ≥ 35 kg: 50 mg

once take with or without food

Please note: TLD FDC will be available soon!

 DTG Formulation and Dosing

Missed Dose take the missed dose as soon as possible unless

it is within 4 hours of the next scheduled dose.
Do not double the next dose if a dose is skipped

Mild or moderate hepatic No dose adjustment is necessary

impairment:
Severe hepatic Not recommended because - lack of data
impairment:
Mild or moderate renal No dose adjustment required
impairment:
 Drug interactions
• Significant drug interactions
• Rifampin: use DTG 50 mg BD
• Rifabutin: no dose adjustment required
• Antacids and multivitamins/minerals: use 2 hrs before or 6 hrs after DTG dose
(Does not apply to PPIs)
• Metformin: use lower dose of metformin and monitor glycemic control
• Anti-seizure medications: consult, may need alternative anticonvulsants
• Contraindications
• Hypersensitivity to DTG
• End-stage renal disease; end-stage liver disease (not studied)
Case Reviews
 Case 1
A 48 year old female, newly diagnosed HIV, initiated on TDF/3TC/EFV.
Presents 4 weeks later with yellowness of the eyes and excessive fatigue. On
exam found to be jaundiced with mild RUQ abdominal tenderness
• What are the next steps:
A. Order LFTS
B. Order abdominal ultrasound
C. Order HAV IgM
D. Order HBsAG
E. Order HCV Ab
F. Stop all ART immediately
 Case 1 continued
Laboratory tests return and ALT is 670 IU/ml, AST 430 IU/ml, mild
elevations in GGT and ALT:
• What will be your next step
A. Stop all ART until LFTs are normal
B. Continue current ART and only stop if the patient worsens
C. Change to TDF/3TC + ATV/r
D. Change to TDF/3TC + DTG
 Case 2
28 year old man known to have bipolar disorder, brought to your facility
with HIV, decision made to start ART.

• What regimen will you choose?

A. TDF/3TC/EFV
B. TDF/3TC + NVP
C. AZT/3TC/NVP
D. TDF/3TC + DTG
 Case 3
32 year old male, on Medication Assisted Therapy (MAT) has been on ART
for 2 years, and is currently on TDF/3TC + ATV/r. He has been on MAT for 1
year, is compliant with therapy and is virologically suppressed

• What of the options below are appropriate for his continuing care?
A. Continue current regimen
B. Switch to TDF/3TC/EFV
C. Switch to TDF/3TC + DTG
 Case 4
A track driver with a drug habit falls ill while on transit. He was diagnosed to be
HIV-infected 2 months prior and was initiated on TDF/3TC + DTG 50mg. As he
complains of cough, and night sweats, he is investigated for TB – GeneXpert
results MTB positive / Rif sensitive. How will you proceed with his ARV
treatment?
A. Change to TDF/3TC/EFV600
B. Change to TDF/3TC/EFV400
C. Increase the dose of DTG from 50mg OD to 50 mg BD
D. None of the above
 Case 5
24 year old non-pregnant woman accompanied to your facility by her mother
after being newly diagnosed with HIV. A decision is made to start ART but it is
established that she has a history of being treated for depression
• What regimen will you select for her?
A. TDF/3TC/EFV
B. TDF/3TC + NVP
C. AZT/3TC/NVP
D. TDF/3TC + DTG
• On her sixth month on ART she is noted to 8 weeks pregnant. How will
you manage her? Explain your decision.
Section 3:
TLE400
 Guidance
Current stocks of TLE400 will be utilized in Nairobi county by June
2018

No new procurement of TLE400 as TLD as FDC will be available soon

Where TLE400 is not availed and if patient transfers in with TLE400,

change it to TLE600
 Formulation
• TLE400 is available as fixed dose combination and co-formulated as
TDF/3TC/EFV (300/300/400mg)

• TLE600 is available as fixed dose combination and co-formulated as

TDF/3TC/EFV (300/300/400mg)

• TLE400 is recommended for use in adults

• Since there is no sufficient data on safety and efficacy for the use of EFV400 in
PLHIV with TB and during pregnancy, these populations should not
receiveTLE400
 TLE400
• Case reviews

• TLE400 evidence review

• TLE400 in clinical use

• Adverse drug reactions and adverse events

• Dosing recommendations
• Case reviews
 Case 1
• A 24 year old woman newly diagnosed with HIV is ready to start
ART

• Which regimen will you put her on?

A. TDF/3TC/EFV600mg
B. AZT/3TC+EFV600mg

C. AZT/3TC+EFV400mg
D. TDF/3TC/EFV400mg
TLE400 Evidence Review
 TLE 400 use in 1st Line: Head-to-Head Studies
Study ARV History Comparison Results
(HIV RNA <200)
ENCORE-1 TDF 300 mg/ FTC 200 Efavirenz 400 vs Efavirenz Non-inferior
mg + EFV 400 mg daily 600mg once daily (90.0% vs. 90.6%)
or EFV 600 mg daily
• Comparable • Better

• Viral suppression • CD4 cell count recovery

• Mortality • Discontinuations due to AEs (adverse events)

• AIDS-defining illnesses • Toxicity

• Emergent SAEs (severe adverse events) • Cost

• Pill size
• Data not yet available on EFV400 plasma concentrations during pregnancy and when co-administered
with rifampicin-containing TB treatment
• Lower doses of first-line treatment components, when possible, would lead to savings, which could be
used to treat more PLHIV
TLE400 use in Clinical Practice
 Populations Targeted for TLE 400
• ART Naïve PLHIV adults :
• TLE400 will be the preferred 1st line regimen except in PLHIV with TB /
presumptive TB or pregnant.

• Do not initiate TLE400 to women of reproductive age unless on effective

contraception
 Assessing contraindication to TLE 400
• TB / Presumptive TB:
• Screen patient for TB using the TB ICF card
• Determine if patient is currently on treatment for tuberculosis
• If TB / Presumptive TB is established, initiate TLE600 and maintain patient on
TLE600 after TB treatment
• Pregnancy:
• Conduct a pregnancy intention assessment at ART initiation and at every visit
• If pregnancy determined or patient is planning to have a child, initiate and
maintain patient on TLE600 after pregnancy and breastfeeding period
 TLE400 use in Pregnancy and TB
Pregnancy:
• If a woman becomes pregnant while on TLE400, assess for TF before
substituting TLE400 for TLE600. After pregnancy and breast feeding period,
continue with TLE600

TB:
• If TB is diagnosed while on TLE400, assess for treatment failure and if no TF,
change from TLE400 to TLE 600. After TB treatment, continue with TLE600.
 EFV 400: Adverse Events (AEs)
• Same AEs as TLE600 but less frequent and less severe
• Most common adverse events are dizziness and rash
 Formulation and Dosing
No sufficient data available to determine whether the reduced dose of EFV in
TLE400 will modify the known drug interactions attributed to EFV 600mg
 Case 1
• A 24 year old woman newly diagnosed with HIV is ready to start
ART

• Which regimen will you put her on?

A. TDF+3TC+EFV600mg
B. AZT+3TC+EFV600mg

C. AZT+3TC+EFV400mg
D. TDF+3TC+EFV400mg
 Section 4:
Immune Reconstitution
Inflammatory Syndrome (IRIS)
 Outline

•Definition
•Risk factors for developing IRIS
•IRIS case definition
•Diagnosis of IRIS
•Management of IRIS
 Definition of IRIS
IRIS refers to a paradoxical inflammatory reaction against a
foreign antigen (alive or dead) in patients who have started
antiretroviral therapy and who have undergone a
reconstitution of their immune responses against this antigen
 Immune Reconstitution Inflammatory Syndrome

• Paradoxical clinical worsening of preexisting infectious processes

• Caused by the host's regained capacity to mount an inflammatory response following the
initiation of ART
• Usually occurs in the first two months after starting ART in PLHIV with severe
immunodeficiency and quick immune recovery (rapid increase in CD4 counts and vial load
suppression)
• The clinical presentation can be of two types:
• Unmasked IRIS: Refers to the appearance of a previously undiagnosed disease
following ART initiation
• Paradoxical IRIS: Refers to the worsening of a previously diagnosed disease after ART
initiation
 Risk factors for developing IRIS
• Low baseline CD4 count (especially <50 cells/μl or <10%) with rapid
increase after initiation of ART
• A high viral load (>100,000 copies/mL)
• Disseminated or localized opportunistic infection
• Advanced clinical stage
• INSTI based ART for:
• ART- naïve patient
• ART re-initiation
• ART switch to a more effective ART regimen in patients failing to achieve
viral suppression
 IRIS
• Associated with increased risk of death (reported overall mortality rate of 4.5%).
Highest mortality rates (13% to 75%) reported among patients with IRIS
affecting the CNS
• Mortality rates depend on:
• Associated OI
• Access to treatment
• Diagnostic criteria
• Degree of immunosuppression
• Geography
 Presentation and Diagnosis of IRIS
• Common features of IRIS:
• Clinical deterioration after ART initiation
• Localized tissue inflammation, with or without a systemic inflammatory
response
• Majority of cases occur within 4 to 8 weeks after initiation / change
in ART
• Presentation varies depending on the underlying OI. Requires a high
index of suspicion
• Diagnosis is based largely on clinical judgment
 Presentation and Diagnosis of IRIS
• Detailed clinical history for patients suspected to have IRIS, including:
• History: Fever, cough or any specific symptoms including recently diagnosed
and past OIs;
• Treatment of OIs: date of initiation, duration of therapy, clinical response,
adherence, defaulter, resistance;
• ART initiation: date, regimen, adherence, prior history of ART, toxicity, any
drug interaction; CD4+ count and HIV viral load prior to ART initiation
• Assess the vital signs, including temperature, heart rate, blood pressure, and
respiratory rate
• Perform a careful and thorough physical examination. Include ophthalmologic
examination in all patients.
 Major Presentations of IRIS
Underlying OI IRIS Signs/Symptoms

Tuberculosis (TB) • Patients responding to TB treatment may have worsening of pulmonary symptoms
and X-ray findings, enlarging lymph nodes causing airway obstruction, or
meningeal symptoms
• Enlarging tuberculoma or pericardial effusions
• Hepatotoxicity, which may be difficult to distinguish from medication-induced
toxicity
• TB-IRIS may occur in patients with undiagnosed multidrug resistant TB
Cryptococcal Usually presents as worsening of meningitis symptoms, possible rapid hearing and/or
meningitis vision loss, ataxia, and/or elevated intracranial pressure
 Major Presentations of IRIS
Underlying OI IRIS Signs/Symptoms
Cytomegalovirus • Presents as retinitis, vitritis, or uveitis (variable timing, with median time to
(CMV) retinitis immune reconstitution vitritis 20 weeks after ART initiation in one study):
• Retinitis is inflammation that is usually at the site of previous CMV retinitis
lesions
• Uveitis and vitritis are the presence of inflammatory cells in the eye as a
result of IRIS and may help to distinguish IRIS from active CMV retinitis
• CMV-IRIS in the eye can cause rapid and permanent vision loss
Hepatitis B or C • Transient elevations in transaminases may occur after initiation of ART with
virus immune reconstitution and can be difficult to distinguish from drug-induced
hepatitis
• Hepatic flares are usually mild and self-limited but can result in decompensation
in someone with pre-existing cirrhosis
 Major Presentations of IRIS
Underlying OI IRIS Signs/Symptoms

Kaposi’s • Presents as worsening of KS

sarcoma • Cutaneous lesions are the most common presentation; other signs include
(KS) lymphedema and oral, gastric, lung, genital, or conjunctival lesions
• Fatal cases of KS-IRIS have been reported

Cerebral • May present as cerebral abscess (also known as toxoplasmosis encephalitis) or,
toxoplasmosis rarely, diffuse encephalitis or chorioretinitis
 Minor Presentations of IRIS
Underlying OI IRIS Signs/Symptoms

Herpes simplex virus • HSV and VZV can reactivate after initiation of ART, even in patients without
(HSV) and varicella previously diagnosed disease
zoster virus (VZV)
• Presentations are usually similar to non-IRIS disease; however, IRIS may
worsen a patient’s symptoms

Nonspecific • A number of dermatologic manifestations, such as folliculitis and oral and

dermatologic genital warts, may appear or worsen during immune reconstitution
complications

For more details refer to https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3221202/

 Management of Mild and Severe IRIS
• Mild IRIS:
• Resolves over time in most patients

• Symptomatic treatment is often sufficient

• Severe IRIS may:

• Threatens a patient’s functional status

• Cause permanent disability
• Lead to death
 Management of Mild IRIS
• Provide standard therapy for underlying OI; if OI has already been treated then
don’t need to restart treatment, but should assess/consider treatment failure of
the OI
• Reassure patients that symptoms indicate immune reconstitution and not HIV
disease progression
• Provide additional support with the following to alleviate inflammation:
• NSAIDS for discomfort associated with mild inflammation / fevers
• Drain abscesses
• May have to excise inflamed and painful lymph nodes
• Inhaled steroids for bronchospasm or cough associated with mild pulmonary
inflammation
 Management of Severe IRIS
• Consider interruption of ART if IRIS is severe, in consultation with
the National HIV Clinical Support Centre and / or the Regional
TWGs
• If not caused by either cryptococcal meningitis or KS, give 1 to 2
mg/kg prednisone for 1 to 2 weeks, followed by a period of
individualized tapering of the dose
• Closely monitor patients receiving corticosteroids for development
of OIs, including TB disease and CMV retinitis
• Risks of corticosteroid therapy include:
• Hyperglycemia • Avascular necrosis
• Hypertension • Worsening of an existing infection
• Mental status changes • Predisposition to a new infection
 Section 5:
Introduction of LPV/r oral pellets and
other formulations
 Overview

• LPV/r recommendations in children

• LPV/r oral pellet introduction

• Acceptability of the LPV/r oral pellets

• Administration of LPV/r oral pellets

• Supply planning for LPV/r oral pellets

• FAQ’s
 ARV regimens for CALHIV
2016 GL Preferred 1st line ART
Children < 3 years ABC/3TC +LPV/r
For <2 weeks age: AZT/3TC/NVP is preferred as per the current 2016 guidelines
Children 3 years to < 10 years ABC/3TC + EFV

NEW Recommendations for immediate implementation

Age/weight Preferred First line regimen Remarks
<2weeks AZT/3TC/NVP As per 2016 revised guidelines
>2 weeks and < 25 kg ABC/3TC+LPV/r All children on NVP change to LPV/r
All children on AZT change to ABC
25 kg up to < 35 kg ABC/3TC+ATV/r All children on NVP change to ATV/r
All children on AZT change to ABC
< 35 kg ABC/3TC+EFV Children currently on this regimen and virally suppressed
Do not change
< 15 years and >35 kg ABC/3TC+DTG New initiations

> 15 years and >35 kg TDF/3TC+DTG For all adolescents (New and current if virally
suppressed and no contraindication on use of the
regimen
LPV/r oral liquid and heat stable tablets
LPV/r oral liquid (80mg/20mg per
1mL)
• Can be used from 2 weeks of age onwards
• Toxic excipients- 42% ethanol; 15% propylene
glycol
• VERY unpleasant taste
• 2-80 C cold chain required until point of
dispensing
• Open bottle stable at 250C for 6 weeks

LPV/r heat stable tablet

(100mg/25mg)
• Can be used from 10kg onwards but ONLY in
children who are able to swallow whole tab
• 100/25mg tab = 15mm
• Cannot be crushed or chewed
 LPV/r 40mg/10mg oral pellets

• LPV/r oral pellets tentatively approved by USFDA in 2015

• Safety and acceptability established in infants ≥ 6 months,
limited evidence in infants 3-6 months of age
• Field evaluation is ongoing to determine if very young
infants are able swallow pellets
• LPV/r oral pellets may provide a better alternative to deliver
the preferred 1st line ART regimen for infants and young
children <3 years.
 National recommendations on use of LPV/r
formulations in different age groups

Formulation Age category Rationale

Liquid (80/20mg) 2 weeks - 9months of Easy to swallow for the infant

age
Pellets (40/10mg) 9 months -4 years of Easy to administer as they can
age take soft food like porridge
Tablets (100/25mg) 5 years and older Able to swallow the whole tablets
children Pellets are too many for this age

NB: This is a general guidance and there are no contraindication on use of liquid or pellets for
older children
 LPV/r Oral Pellet (40mg/10mg) per
capsule

Description:
 Tentative US FDA in May 2015
 Manufactured by Cipla
 Formerly referred to as sprinkles or mini-tabs
 Each capsule contains ~ 40 circular biconvex spheres
 Commercial pack size: 120 capsules/pack in HDPE bottles

10 TheUSFDA has approved the use of pellets in children ≥ 5kg, though the safety of dosing infants 3-4.9 kg has been demonstrated in a
small number of infants in CHAPAS-2. The pellets may be administered in this weight band if infants are developmentally able to swallow
them.
 Simplified Weight Band Dosing Schedule for LPV/r
Number of LPV/r oral Number of LPV/r
Weight Band LPV/r 80mg/20mg per ml 100mg/25mg
pellets
(Kg) oral liquid Oral tablets
40mg/10mg capsules
AM PM AM PM AM PM
3-4.9kg* 1 ml 1 ml 2 2 NR NR
5-5.9kg 1 ml 1 ml 2 2 NR NR
6-9.9kg 1.5 ml 1.5 ml 3 3 NR NR
10-13.9kg 2 ml 2 ml 4 4 2 2
14-19.9kg 2.5 ml 2.5 ml 5 5 2 2
20-24.9kg 3 ml 3 ml 6 6 2 2
25-29.9kg** NR NR 7 7 3 3
30-34.9kg** NR NR 8 8 3 3
≥35kg** NR NR 10 10 4 4
*The USFDA has approved the use of pellets in children > 5kg, though the safety of dosing in infants 3-4.9 kg has been demonstrated in a
small number of infants in CHAPAS-2 study;
** Substitute LPV/r to ATV/r to reduce pill burden
NR=Not Recommended
 Administration Tips
• Capsules must be opened to administer pellets. Capsules should NOT be swallowed

• Pellets should not be crushed or chewed as will develop a poor taste

• If mixing with soft food ensure pellets are swallowed whole and not chewed

• If mixing with liquid (water, milk etc..) add liquid immediately before administering pellets- if pellets are left in contact
with liquid will become sticky and will develop bad taste

• Do not give pellets with fruit juice or other acidic (sour) beverage/foods

• Give pellets with food/beverage that child prefers to take and will swallow without chewing. Examples of soft foods
that may be used: porridge, mashed potato, yogurt. Examples of beverages that may be used: water, milk.

• Administer 1 or 2 capsules of pellets at a time otherwise the amount of pellets may be too much for child to swallow at
once

• If child is resistant or vomiting pellets, try to administer with fewer pellets at a time

• Ensure no pellets remain in the mouth as the pellets will develop an unpleasant taste after about a minute of being
held in the mouth- provide additional soft food or beverage to child to ensure no pellets are retained in the mouth
 Thank you

For any queries and further clarifications, please contact

NASCOP hotline: 0726460000 National HIV Clinical Support Centre e-mail:
ulizanascop@gmail.com