Training on the Use of Dolutegravir (DTG) for

the Management of HIV/AIDS

 Session Objectives

Review of updates in the 2016 Adult ART Guidelines

Rationale for introduction of DTG in first line

adult and third line ART in Nigeria

Understand Guidance for DTG Substitution

2
Review of updates in the 2016 Adult ART
Guidelines

3
Initiation criteria

TEST AND TREAT!

• Everyone is eligible for ART irrespective of CD4 count, age or clinical staging

• It is desirable to initiate ART as soon as possible after diagnosis

• The 2016 guidelines recommends retesting prior to commencing ART

• Before starting ART, adequate counseling to ensure client readiness should be

done

<<Refer to page 29, Section 3.3.2 of the 2016 ART Guidelines>>

First Line ART for Adults
Patient Category Recommended first Alternative first line regimen
line Regimen
Adults TDF + 3TC(or FTC) + TDF + 3TC (or FTC) + DTG
EFV
Adolescents (10- TDF + 3TC(or FTC) + TDF + 3TC (or FTC) + *DTG
19years) EFV AZT + 3TC + EFV
TDF + 3TC (or FTC) +EFV400
AZT+3TC+NVP
TDF + 3TC (or FTC) + NVP
ABC +3TC +EFV
*DTG can only be given over age 12 and 40 kg
Recommended Schedule for Monitoring Adults on ART:
Clinical Assessments
Pre-
Every 12 Every 24 Every Clinic
Treatment Week 4 Week 8 Week 12
Weeks Weeks Visit
(Baseline)

Physical Exam X X X X X

Adherence
X X X X X
Counselling

Clinical Screening for

X X X X X X X
TB

Clinical Screening for

Chronic Care &
Positive Health X X X X X X X
Dignity & Prevention
Services (PHDP)
Recommended Schedule for Monitoring Adults on ART:
Laboratory Tests
Pre- Every 12
Every 6
Treatment Month 1 Month 3 Month 6 Month 12 Months
Months
(Baseline) (Annual)
HIV-1 RNA (viral load
‡ X‡ X‡ ‡ X
estimation)
CD4+ X X X X
Hb/PCV X X1 X X
WBC, Platelets X As clinically indicated
ALT X As clinically indicated
Creatinine (Estimated
X X
CrCl)
HbsAg and HCV X
Urinalysis X X3 X3
Syphilis test X
VIA*/Pap Smear X Annually thereafter

AST, ALP, FBS,

Amylase, Preg test,
Lipid profile, U/E, As clinically indicated
GeneXpert, Chest X-
Ray

X Essential
1 For patients on AZT; 2 Patients on NVP; 3 patients on TDF

‡ Desirable: Baseline viral load can be performed especially for those with prior exposure to ARVs but is not routinely recommended
X‡. It is recommended that all clients initiating ART should have viral load determined at 6 and 12 months following initiation of therapy and 12 monthly thereafter to
determine the efficacy and suitability of the regimen for the individual client. In suspected cases of virologic failure viral load testing should be repeated 3 months after an
intense regime of reinforced adherence counselling and support. A viral load test result of >1000cp/ml following reinforced adherence counselling and support is indicative
of virologic failure. Clients with persistent virologic failure despite adherence interventions should have their drug regimen switched to second line ART regimen.
* Visual inspection with acetic acid.
Algorithm for treatment failure Management
After at least 6 months of ART initiation

Clinical Failure:
Adults: CD4 count falls to the baseline or persistently below 100/mm3
Children: WHO clinical staging stage
3 and 4 with exception of TB)
Adults: WHO Clinical Stage 4
And some stage 3 (Pulmonary TB
New severe bacterial infections)
Immunological Failure:
Virological Failure:
50% decline from on-therapy CD4 peak level
Viral Load>1000 copies/ml
Children< 5yrs with CD4 persistently below 200/mm3
(1st test)
Or CD4% below 10%
Children> 5yrs with CD4 persistently below 100/mm3

Routine/ Targeted Viral Load Testing

Viral Load>1000 copies/ml (1st VL test)

Suspected Treatment Failure

3 months of reinforced adherence * Sites without VL capacity should be linked to

support/treat Opportunistic infections facilities with capacity for VL
testing
Reassess after 3 months of reinforced
adherence-
Improvement observed (for clinical, immunological and virological No Improvement but adherence
VL<1,000 U/L improvements) assured VL>1,000 U/L
Repeat VL test (2nd VL test)

Decide Treatment Failure

Continue current first Switch to 2nd line ART

line ART regimen
Second and Third Line ART for Adults
• Adults should only be switched to 2nd or 3rd Line ART after confirmed treatment
failure
• Confirm 2L failure (before switching to 3L) with resistance profiling if possible
• Switching should only be authorized by highly experienced clinicians
• Viral Load Monitoring is the preferred method for diagnosis of Treatment Failure
• Virological Failure = Viral Load >1000 copies/ml based on two consecutive viral
load measurements in 3 months, with adherence support following the first viral
load test
Patients Failing
Population Second-Line Regimens Third-Line Regimens*
First-Line Regimens
2 NRTIs + EFV 2 NRTI + ATV/r or LPV/r DRV/r** + DTG*** ± 1 – 2 NRTIs
Adults and adolescents (>10
years) 2 NRTI + ATV/r or LPV/r
2 NRTIs + DTG DRV/r + 2 NRTIs + NNRTI
Pregnant and breastfeeding DRV/r + DTG ± 1 – 2 NRTIs
2 NRTIs + EFV 2 NRTIs + ATV/r or LPV/r
women

**In PI-experienced patients, recommended DRV/r should be 600/100mg taken twice daily.

*** Safety and efficacy data on DTG use in adolescents younger than 12years and pregnant women are yet unavailable
 Rationale for introducing DTG 50mg for
alternative first line adult and third line ART in
Nigeria

10
Outline
• Dolutegravir (DTG) product profile
• DTG Clinical benefits
• DTG drug-drug interaction
• DTG side effects and IRIS
• Use in special populations
• Guidance for DTG substitution

11
 Integrase Inhibitors
A New Class of Antiretroviral Drug
Reverse Transcriptase Inhibitors
NRTIs NNRTIs
Zidovudine AZT Nevirapine NVP
virions Stavudine D4T Efavirenz EFV
Abacavir ABC Rilpivirine RIL
RNA Lamivudine 3TC Etravirine ETV
Didanosine DDI
Tenofovir TDF/TAF
DNA
assembly
protein Protease Inhibitors
Lopinavir LPV
Ritonavir RTV
Atazanavir ATZ
Fusion Inhibitors Darunavir DRV
Integrase Inhibitors
Enfurtivide T20
Raltegravir RAL
CCR5 receptor blockers
Elvitegravir EVG
Dolutegravir DTG
Dolutegravir Product Profile (DTG)

Drug class Integrase Strand Inhibitor (INSTI)

Current Manufacturers Aurobindo, Mylan (other suppliers developing
products including DTG)
Use Can be used for the 1L and 3L therapy
Form Single and Triple FDC with TDF+3TC (“TLD”);
administered once-daily
Single: Approved 2016
Availability TLD: Two suppliers received US FDA tentative
approval August 2017
Single Tablet: $44 per patient, per year

Price FDC: Generic production of TDF/3TC/DTG has

recently been priced at $75 per patient per year
for low income countries
Pack size 30 pills (one-month supply)

13
Dosing guide for DTG 50mg tablets
 DTG 50mg should be taken once daily in conjunction with other ARVs (TDF/3TC or ABC/3TC
depending on prescribed regimen), with or without food
 Patients should take ARVs at a convenient time daily to promote adherence; best to
take DTG containing ART in the morning to minimize insomnia.
 DTG should be taken with water and swallowed without being crushed or chewed
 If the patient misses a dose, it should be taken as soon as possible, providing the next
dose is not due within 4 hours. If the next dose is due within 4 hours, the patient
should not take the missed dose and simply resume the usual dosing schedule.
 DTG comes in a pack of 30 tablets which will last a patient approximately one month

Appearance  Available as single film coated pill 50mg formulation

Packaging  Individual package contains 30 tablets

Storage Conditions  DTG does not require refrigeration

Clinical Benefits: DTG leads to faster viral suppression
SINGLE Study*

88% suppressed
at 48 weeks (vs
81% for EFV)

* Walmsley S. NEJM 2013;369:1807-18 1

 Clinical Benefits: DTG is more tolerable
SINGLE Study*

Favors DTG Favors EFV

10% of EFV patients

discontinued
treatment due to
adverse effects (vs.
2% with DTG)

*Walmsley S. NEJM 2013;369:1807-18 16

Clinical Benefits: DTG more efficacious compared to other
INSTI
RAL versus DTG in Treatment Experienced Adults SAILING Study*

* Cahn P. Lancet 2013;382:700-08 17

Clinical Benefits: Convenient

• Smaller pill size

– Substantial programmatic cost savings

– Potential for improved adherence

18
Clinical Benefits: Higher genetic barrier to resistance

• Compared to NNRTI and older integrase inhibitors, DTG

has a higher genetic barrier to resistance
– Requires multiple (usually at least 3) mutations for full
resistance
– Low-level Integrase resistance can be overcome with twice
daily dosing1
– Active against RAL-resistant virus as shown in the VIKING
trial2

1. Costagna A et al. J Infect Dis. 2014 Aug 1;210(3):354-62

2. Eron JJ et al. J Infect Dis. 2013 Mar 1;207(5):740-8
DTG Clinical Summary:
Research studies have shown non-inferiority or superiority and better tolerability of
DTG when compared with leading ARV treatment options

DTG
Clinical Trial Compared Key Conclusions
to
 DTG non-inferior/superior (88% vs. 81%) at 48-weeks
 Fewer discontinuations due to adverse effects with DTG (2%) vs. EFV (10%)
SINGLE (1) EFV  DTG patients reached virologic suppression faster (median time to suppression = 28-days vs.
84-days)

SPRING (2)  DTG non-inferior at 48-weeks (88% vs. 85%)

RAL  DTG-based regimens superior with treatment-experienced patients
SAILING (3)
 DTG superior to DRV/r-based therapy at 48-weeks in ART naïve patients
FLAMINGO (4) DRV/r  DTG superior in patients with VL > 100,000 copies/ml (82% vs. 52%)

DRV/r,  DTG is associated with low rates of psychiatric or other side effects (DTG: 3% -8% vs. DRV/r,
EFV, RAL: 3% - 7%)
Pooled analysis (5) EFV, RAL,  Despite higher baseline rates of psychiatric symptoms, DTG was generally associated with
ATV/r lower rates of new diagnoses compared to all other study groups

Pooled Analysis of  Analysis looked at outcomes based on baseline VL, CD4, combination with ABC/3TC or
RAL, EFV, TDF/FTC, age, gender or race
SPRING2, SINGLE  In no case was the comparator seen to be clearly better than DTG, and in most cases DTG
DRV/r
and FLAMINGO (6) was associated with better virologic response

(1) Walmsley SL et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. NEJM 2013;369:1807-18.
(2) Raffi F et al. Once-daily DTG versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet 2013,381:735-43.
(3) Cahn P et al. DTG versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet
2013,381:735-43.
(4) Molina, J.M., et al. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study.
(5) Fettiplace A et al. Psychiatric symptoms in patients receiving dolutegravir. J Acquir Immune Defic Syndr. 2016. 20
(6) Raffi F et al. Dolutegravir efficacy at 48 weeks in key subgroups of treatment-naïve HIV-infected individuals in three randomized trials. AIDS 2015;29:167-74
DTG: Fewer drug-drug interactions

• Co-administration with metformin increases metformin levels, with

unclear significance

• Contraindicated with dofetilide

• Co-administration with etravirine lowers DTG levels

– reversed with simultaneous administration with LPV/r or DRV/r or ATV/r.

• Avoid simultaneous administration with drugs containing divalent

cations (Ca++, Mg++ antacids and with iron)
– Can be taken at least 2 hours before of 6hrs after DTG

• Rifampin lowers levels by 50%

– dose increase to 50 mg twice daily (Not recommended in the 2016 guidelines)
21
DTG in TB patients on rifampicin
- Among healthy adults, double-dosing DTG (50mg BD) can overcome this drug-
drug interaction.1

- Additional pharmacokinetic and clinical outcome data from HIV/TB co-infected

will be available though the ING117175 study in 2019 2
22
1. Dooley KE et al. JAIDS 2013. 62; 21-7 2. https://clinicaltrials.gov/ct2/show/NCT02178592
DTG Side Effects

• Insomnia has consistently been observed with DTG at a

slightly higher frequency than the comparator in clinical trials

• Other side effects that have rarely been observed in clinical

trials include diarrhea, nausea, vomiting, upper respiratory
infection, cough, rash 1,2

1. Walmsley SL et al. NEJM 2013;369:1807-18 2. Cahn P. Lancet 2013;382:700-08

DTG side effects
SINGLE Study*

*Walmsley SL et al. NEJM 2013;369:1807-18 24

 Meta-analysis of AE
in DTG Clinical Trials
Hill A. EACS 2017 PE12/17
Cardiovascular AE
Trial DTG Arm Control Arm
(comparator)
Insomnia AE SINGLE 4/414 2/419 (EFV)
SAILING 1/357 2/362 (RAL)
FLAMINGO 4/242 1/242 (DRV/r)
SPRING-1 1/51 0/50 (EFV)
SPRING-2 1/411 0/411 (RAL)
ARIA 2/248 0/247 (ATV/r)
STRIVING 1/275 0/276 (CAR)
Total 14/1998 (0.7%) 5/2007 (0.2%)
Only 2 cardiovascular AE’s in DTG treated patients were considered drug-related and
subjects had multiple risk factors. Cardiovascular AE were broadly defined, including
arrhythmia, ischemia, congestive heart failure, myocarditis, cardiomyopathy, pericarditis.
 Higher rates of neuropsychiatric in cohort studies
than in clinical trials

de Boer MGJ. AIDS 2016;30:2831-4 26

DTG Adverse Events summary

• Slightly more neuropsychiatric side effects, particularly for

insomnia

• Interpreting cohort studies is complicated by bias, where

patients who suffer from neuropsychiatric side effects
might preferentially be treated with DTG rather than EFV

• DTG AE in clinical trials, rarely resulting in necessity to

discontinue DTG (1)

• Rare side effects will require ongoing pharmacovigilance to

identify and characterize

1. Fettiplace A et al. J Acquir Immune Defic Syndr. 2016 27

Immune Reconstitution Inflammatory Syndrome (IRIS)

• Several studies have found a greater risk of IRIS (roughly 2-3x higher)
associated with integrase inhibitors like DTG, but also RAL and EVG.

• This is not surprising given the speed at which integrase inhibitors

work to reverse HIV-associated immune suppression

28
 IRIS

29
Dutertre M. CROI 2017 Abstract 732
 IRIS

30
Wijting IEA. CROI 2017 Abstract 731
General risk factors for IRIS

• Risk factors for IRIS

– Low CD4+ cell count (≤200 cells/mm3) at ART initiation
– Disseminated opportunistic infections or tumors
– Shorter duration of therapy for opportunistic infections before
ART starts.

– IRIS is rarely fatal and can be managed

– With the exception of cryptococcal meningitis, outcomes are
improved with early ART in patients with OI
– this emphasizes the need to increase access to CrAg

31
Monitoring patients: Management and Prevention
of IRIS

• IRIS is generally self-limiting, and interruption of ART is rarely indicated.

• Management involves:
– Treating any co-infections appropriately (refer to job aides of consolidated
guidelines for management protocols for major OIs)
– Reassuring the patient to prevent discontinuation of, or poor adherence to ART.
• Preventing IRIS
– Diagnose HIV early and initiate ART before CD4 declines to below 200 c/mm3.
– Screen for opportunistic infections
• TB for all patients (use intensified case finding protocol)
• Serum CRAG screen in ART-naïve adults followed by presumptive anti-fungal therapy can be
considered in patients with CD4+ <100c/mm3
– Initiate treatment of OIs before initiation of ART
• TB: Start ART 2 weeks after initiating TB treatment
• Cryptococcal Meningitis: Start ART 4-6 weeks after initiating CCM treatment
• Treatment for other OIs can be started concurrently with ART

***The timing of ART in people with opportunistic infections requires balancing a greater risk of IRIS after early initiation
against continuing high mortality if ART is delayed.
32
Is a CD4 count necessary prior to initiation of DTG?
• The current revised Nigeria guidelines recommends baseline CD4
count before initiation of any ARVs

– This will facilitate an early identification of those with low CD4 count who
are at higher risk of developing IRIS

• CD4 is not necessary to determine treatment eligibility but to

determine the need for prophylaxis and other services (more
adherence support and closer follow up).

• Important to screen for OI and aggressive treatment and/or

prophylaxis for major OIs particularly among those with advanced
HIV disease1
33
1. http://www.who.int/hiv/pub/guidelines/advanced-HIV-disease/en/
Special Populations

• Liver disease
– Discontinuation of TDF-based fixed dose combinations
have been associated with worsening of hepatitis B
– Drug interactions with hepatitis C DAA are minimal with
DTG
– Occasional increases in transaminases are seen at the start
of therapy, often considered to be associated with immune
reconstitution
– Increases in transaminases are more common among
patients co-infected with hepatitis B and C
– Rarely hypersensitivity reactions have been reported (<1%)
that are associated with increased transaminases
Special Populations

• Kidney disorders
– DTG decreases tubular secretion of creatinine without
decreasing glomerlular function, so increased serum
creatinine is seen
– DTG do not require dose adjustment in renal failure
Special Populations

• Pregnant women
– The current Nigeria guidelines does not recommended
DTG for pregnant women due to lack of sufficient data

– Additional data may be available soon. Other countries

(e.g. Botswana) are giving it to pregnant women.
Total and Severe Adverse Birth Outcomes

Zash R. 9th IAS Conference Abstract MOAX0202LB

34% 35%

Any adverse Note this includes

birth outcome
116 first trimester
exposures for DTG
Severe adverse 11%
birth outcome
11% and 396 for EFV

DTG/TDF/FTC EFV/TDF/FTC
(845) (N=4593)

Any Adverse
Birth Outcome 1.0 (0.9,1.1) ref
aRR* (95% CI)

Severe Birth Outcome

1.0 (0.8,1.2) ref
aRR* (95% CI)

*Models adjusted for maternal age, educational attainment and gravida

Guidance on DTG Substitution

38
Definition/Grading of Adverse Reactions

Adverse drug reaction (ADR) is defined by WHO as “a response to a drug which is noxious
and unintended, and which occurs at doses normally used in man for the prophylaxis,
diagnosis, or therapy of disease, or for the modification of physiological function.”

Category Definition
Mild Reaction (Grade 1)  Limited pain levels causing no interference with activity
 Pain levels cause greater than minimal interference with normal social or
Moderate Reaction
functional activities
(Grade 2)
 Patient’s daily activities are disrupted
 Pain levels result in inability to perform normal social or functional
Severe Reaction activities
(Grade 3)  Inability to perform daily activities
 Therapeutic intervention probable

 Any medical occurrence that at any dose results in:

 Life-threatening situation
Severe Life-Threatening
 Immediate patient hospitalization or prolongation of existing
Reaction (Grade 4)
hospitalization
 Persistent patient disability or incapacity
NNRTI intolerance: When do I substitute?
 Dermatological side effects of stage 3 or 4 or stage 1 or 2 side effects that persist
after 2-4 weeks on an NNRTI-based regimen
 Grade 3 or 4 neuropsychiatric side effects

 Grade 2 neuropsychiatric side effects persisting for more than one month
 Grade 1 neuropsychiatric side effects that are worsening

 Hepatotoxicity of grade 3 or 4 (AST and/or ALT levels >10 times above the upper
limit of normal)
 Gynaecomastia of any grade

40
Management of ARV Side Effects/Toxicities
Category Definition
 Limited pain levels causing no interference
with activity
Mild Reaction
 Pain levels cause greater than minimal
interference with normal social or
Moderate
functional activities
Reaction
 Patient’s daily activities are disrupted
 Pain levels result in inability to perform
Severe normal social or functional activities
Reaction  Inability to perform daily activities
 Therapeutic intervention probable
Action
 Monitor for 1-month
 If side effects worsen, substitute
the offending drug in same ARV
class without stopping ART
 Monitor for 1-month
 If side effects worsen or continue,
substitute the offending drug in
same ARV class without stopping
ART
 Substitute the offending drug
without stopping ART

 Any medical occurrence that at any dose  Discontinue all ARV drugs and
results in: manage medical event; substitute
Severe Life-
 Life-threatening situation offending drug when patient is
Threatening
 Immediate patient hospitalization or stable
Reaction
prolongation of existing hospitalization
 Persistent patient disability or incapacity
Contraindications to NNRTIs
 History of psychiatric illness and seizures
 Patients concurrently taking benzodiazepines
 On-going complications of neurological disease that block the provider’s ability to
assess side effects of EFV
 Severe hepatic impairment
 Situations where the only available family planning method is hormonal
contraception containing levonorgestrel, ethinyl estradiol, or etonogestrel
EFV contra- DTG contra-
indicated indicated
History of psychiatric illness and seizures Yes No
Patient receiving benzodiazepines or carbamazepine Yes Yes
Ongoing complications of neurological disease that block ability to Yes No
assess side effects of EFV
Severe hepatic impairment Yes No
HIV/TB co-infected PLHIV No Yes*
Situations where the only FP method is hormonal contraception Yes No
containing levonorgestrel, ethinyl estradiol, or etonogestrel 42
Substituting DTG for EFV/NVP in a patient
 In assessing if an existing patient should be substituted to DTG from EFV/NVP,
follow the below guidance:

Time on ART HCW Substitution Guidance

 Not necessary to perform a viral load test

< 6 months
 Determine if substitution is necessary depending on ARV Side Effect/Severity Level
(see previous slide)

 If VL was done within last 3 months and is suppressed at 6-month mark post-ART
initiation, no VL test required before substitution due to Side Effects/Toxicity

 If VL not suppressed, repeat VL test 1-month after 3rd intensive adherence

> 6 months counseling session to determine if treatment is failing (in which case switch patient to
a 2L regimen and do not start DTG)

 If patient has been on ART for more than 6 months without any VL test, do VL load
test before proceeding with any substitutions.
43
Substituting a Patient off DTG
 In assessing if an existing patient should be substituted off DTG to a different
regimen, follow the below guidance:

Time on ART HCW Substitution Guidance

 Not necessary to perform a viral load test

< 6 months
 Determine if substitution is necessary depending on ARV Side Effect/Severity Level

 If VL was done within last 3 months and is suppressed at 6-month mark post-ART
initiation  no VL test required before switching due to Side Effects/Toxicity

 If VL not suppressed  repeat VL test 1-month after 3rd intensive adherence

> 6 months counselling session to determine if treatment is failing (in which case switch patient
to a 2L regimen)

 If patient has been on ART for more than 6 months without any VL test, do VL load
test before proceeding with any substitutions/switches.

44
Key Points

• DTG is available in a single tablet and soon in FDC at a cheaper price

• Is better tolerated, more efficacious, less resistance

• Expanded potency for first and third line

• Fewer drug interactions

• Dosing recommended in the morning to minimize insomnia

• Baseline CD4 count is not necessary to determine treatment eligibility

• No dose adjustment required in renal failure