December 2019
ADDENDUM TO THE 2016 GUIDELINES FOR ANTIRETROVIRAL THERAPY FOR
THE PREVENTION AND TREATMENT OF HIV IN ZIMBABWE
Issue Number 2: December 2019
The National Medicines and Therapeutics Policy Advisory Committee (NMTPAC) and AIDS and
TB Directorate of the Ministry of Health and Child Care has conducted a rapid review of the
addendum to the 2016 ARV Guidelines following the release of the WHO July 2019 update on
recommendations on first line and second line antiretroviral regimens. Studies have
demonstrated a reduced risk of neural tube defects among women of child- bearing potential
using Dolutegravir (DTG) at peri-conception period since initial reports released in 2018. The
risk-benefits models suggest that the benefits of DTG for ART naïve women of child- bearing
potential include greater maternal viral suppression, fewer maternal deaths, fewer sexual
transmissions, and less mother-to child transmission of HIV.
The main changes from the previous March, 2019 version of the addendum are as follows:
•
•
Dolutegravir (DTG) is now the preferred antiretroviral medicine for first and second line
regimens for everyone living with HIV including adults, pregnant women, women and
adolescent girls of childbearing potential, children and people co-infected with TB.
Efavirenz (EFV) 400mg is safe for use among pregnant women. Pharmacokinetic and
pharmacodynamics studies suggest that the drug concentrations decline slightly during
pregnancy; however remain within therapeutic range and unlikely to reduce the drug efficacy.
Efavirenz 400 mg can be co-administered with rifampicin containing anti-TB treatment; is well
tolerated and plasma concentrations were maintained above the levels considered to be
effective.
When available, tenofovir alafenamide (TAF) may be considered for elderly patients above 50
years; patients with impaired kidney function, established osteoporosis and among HBV coinfected patients.
•
•
This Addendum is organized in the following main sections:
I.
II.
III.
IV.
V.
First- Line, Second- Line and Third-Line ARV Regimens for Adults and Adolescents;
First- Line, Second- Line and Third-Line ARV Regimens for Children;
Dolutegravir Use in HIV Post-Exposure Prophylaxis,
Drug-drug interactions
Management of Latent TB Infections.
1
December 2019
Each section provides guidance to the management recommendations followed by main
considerations for adopting the recommendations in Zimbabwe.
I.
First- Line, Second- Line and Third-Line ARV Regimens for Adults and Adolescents
First Line ARV Regimens for Adults and Adolescents
1st line ART
Preferred 1st line Regimens
Adults and adolescents including women
of child- bearing potential
TDF + 3TC + DTG (once
daily FDC)* (TLD1)
Alternative 1st line
Regimens
TDF (or TAF∞) +3TC (or
FTC) + EFV 400mg
TDF (or TAF) + FTC (or
3TC) + ATV/r
ABCµ+3TC+DTG*
⃰ TB patients on Rifampicin to receive DTG 50mg twice a day
µ
ABC/3TC/DTG 50mg can be administered to patients weighing at least 20 kg
TAF can be used as a substitute for TDF as part of preferred or alternate 1st line regimens
AZT/3TC backbone may be used in special circumstances (for example where TDF is contraindicated,
and TAF is not available)
∞
Main Considerations
• Dolutegravir (DTG) is a safe and efficacious drug with a rapid viral suppression, low
potential for drug-drug interactions and a high genetic barrier to developing ARV drug
resistance. It should be given as a preferred first line regimen for all populations unless
where contraindicated.
• Exposure to DTG at the time of conception may be associated with an increased risk of
neural tube defects (NTDs) among infants although NTD risk has been further reduced
compared to when first reported.
• DTG use has been associated with weight gain especially when co-administered with
TAF/3TC. Prior to initiating DTG; clinicians should advise patients on this potential side
effect and advise on the importance of adopting healthy life-styles including exercising,
taking healthy diets and avoidance of smoking.
• Effective contraception should be offered to adult women and adolescent girls of
childbearing age or potential.
• DTG can be prescribed for adult women and adolescent girls of childbearing age or
potential who wish to become pregnant or who are not otherwise using or accessing
consistent and effective contraception if they have been fully informed of the potential
increase in the risk of neural tube defects (at conception and until the end of the first
trimester).
2
December 2019
•
•
•
•
•
•
Pregnancy screening should be done at health facilities to ascertain pregnancy status among
women in order to support patient management. If pregnancy is identified, the client should
be fully informed of the risk of neural tube defects before initiation or continuation with
DTG-based regimens.
ART experienced patients should be transitioned to a DTG-containing regimen after
confirming a suppressed HIV viral load of <1,000 copies/ml in the past twelve months:
o If VL is suppressed, substitute the NNRTI (Efavirenz and Nevirapine) with DTG
o If VL is unsuppressed, manage as treatment failure with 3 enhanced adherence
counselling (EAC) sessions over 3 months of good adherence followed by a repeat VL
test. If the patient remains unsuppressed, switch patients to a DTG-based second line
regimen.
In PLHIV with TB using rifampicin, the dose of DTG should be increased to 50 mg twice
daily.
Use of Nevirapine (NVP) and Efavirenz (EFV) 600mg in adults and adolescents is being
phased out and health providers are advised to limit its use. Due to high levels of
pretreatment HIV drug resistance in Zimbabwe (>10%), NNRTIs are less preferred
Tenofovir alafenamide (TAF) a derivative of TDF has less renal and bone toxicity
compared to TDF. TAF may be used as a substitute for TDF for adults and adolescents.
When available, TAF should be considered in elderly patients above 50 years, patients with
Creatinine Clearance of 30 – 60ml/min and HBV co-infected. However, TAF should NOT
be used in HIV/TB co-treatment; among HIV infected pregnant women and patients with
renal impairment with CrCl below 30.
In order to facilitate effective management of patients on ART; it is critical to make the
distinction between patients on first line versus those taking second line ART. The program
will use TLD1 to refer to patients taking first line DTG-based regimens while TLD2 will
refer to those on second line DTG-based regimens.
3
December 2019
Second Line ARV Regimens for Adults, Adolescents including Pregnant and Breastfeeding Women
Failing first-line
Regimens
Preferred second-line
Regimens
Alternate second-line Regimens
TDF (or TAF) + 3TC +
DTG or
ABC + 3TC + DTG
TDF (or TAF)+3TC(or
FTC)+ATV/r
AZT + 3TC+ ATV/r
AZT + 3TC + LPV/r
AZT + 3TC + DTG⃰⃰⃰⃰ ⃰⃰
AZT + 3TC + LPV/r
TDF (or TAF) + 3TC +
EFV
AZT + 3TC + EFV
TDF (or TAF) + 3TC + DTG⃰⃰ ⃰⃰
If TDF + 3TC or ABC + 3TC (or FTC) was used in the failing first-line regimen, AZT + 3TC should be used
in second-line ART and vice versa
⃰⃰ ⃰⃰ For HIV/TB coinfection on rifampicin based regimen, use LPV/R (super booster) instead of ATV/r and
DTG B.D instead of DTG O.D
Maintain TDF in the second line for patients with chronic HBV coinfection
Main Considerations:
•
•
Patients failing first line (ref to ART Guidelines) should be switched to an effective second
line regimen.
Precautions in the use of DTG also apply for second and third line ARV regimens
Third Line ARVs for Adults and Adolescents
In adolescents older than 12 years and adults; the preferred 3rd line ART can include Dolutegravir
(50mg), Darunavir (600mg)/Ritonavir (100mg) and 2NRTIs.
Main Considerations:
•
•
•
•
GENOTYPING TESTING IS RECOMMENDED PRIOR TO SWITCHING PATIENTS
FAILING SECOND LINE ART with clinicians required to actively rule out poor adherence
before genotypic testing.
In PI experienced patients; Darunavir (600mg)/Ritonavir (100mg) should be given twice daily
Third line patients with a history of integrase strand transfer inhibitor (INSTI) use, such as
Raltegravir, DTG should be given twice daily
Switching patients from second to third- line ARV regimens should be performed in
consultation with a specialist physician/paediatrician
4
December 2019
RECOMMENDATIONS FOR ART REGIMENS FOR CHILDREN
Dolutegravir in combination with two nucleoside reverse transcriptase inhibitors is recommended
as a first line ART regimen in infants and children with approved DTG dosing. As is usual dosing
guidance and formulations are available for adults and older adolescents, while paediatric dosing
and formulations are being developed. Zimbabwe is one of the countries conducting the
IMPAACT P1093 trial investigating use of DTG right down to 4 weeks, and it is anticipated that
the formulations and dosage recommendations will be available for use from 4 weeks of age.
N.B. Children weighing >20kgs can use the adult 50mg tablet of DTG.
Currently 10mg, 25 mg formulations as well as dispersible 5mg tablets are in the process of being
manufactured.
Recommendations for 1st line regimens for children
Preferred
Alternatives
NEONATES
AZT+3TC+RAL⃰⃰
AZT+3TC+NVP
CHILDREN
ABC+3TC+DTG⃰⃰⃰⃰ ⃰⃰
ABC+3TC+LPV/r
Special circumstances
AZT+3TC+LPV/r
ABC+3TC+EFVµ
AZT+3TC+LPV/r∞
⃰⃰For the shortest time possible (ideally for 2 weeks with transition to LPV/r syrup or granules). To allow for
convenience and to align with the EPI schedule, RAL in neonates can be given for the first 6 weeks of life
with substitution to LPV/r at 6 weeks of age until dosage formulations of DTG become available.
⃰⃰ ⃰⃰ For age and weight groups with DTG approved dosing and where LPV/r is not available
µ
From 3 years of age
∞
In cases where no other alternatives are available
5
December 2019
First line, 2nd and 3rd line ART Regimens for Children
Failing First line
ABC+3TC+LPV/r
ABC+3TC+DTG
ABC+3TC+EFV
Second line
AZT+3TC+DTG
TDF+3TC+LPV/r
TDF+3TC+DTG
AZT+3TC+ATV/r or LPV/r
Third line
DRV/r+2NRTIs
DTG+DRV/r+2NRTIs
TDF+3TC+DTG
Where dosage guidelines and appropriate formulations are available, DTG is preferred as first
line in children
DTG can also be used in 1st, 2nd and 3rd line
EFV should not be used in children less than 3 years of age
DRV should not be used for children younger than 3 years of age.
DRV should be used with ritonavir boosting in those above 3 years of age
II.
Post-Exposure Prophylaxis (PEP)
Adults/Adolescents:
Preferred Regimen
TDF /3TC/ DTGa
OD
Alternative Regimen
TDF /3TC/ ATV/rb OD
a,b
Available at all health facilities from clinic upwards as starter pack and one-month
course.
•
Main
Considerations:
There should be no delay in starting the best available starter pack in situations where
resistance is suspected. Start the best available starter pack and then get expert advice on
way forward.
6
December 2019
III.
Important Drug-drug Interactions
Drug-drug interactions with DTG
Key drug interaction
Suggested management
Amodiaquine
Use an alternative antimalarial agent
Carbamazepine
Use DTG twice daily or substitute with an alternative
anticonvulsant agent
Phenytoin and phenobarbitone
Use an alternative anticonvulsant agent
Metformin
Limit daily dose of metformin to 1000mg when used
with DTG & monitor glycemic control
Polyvalent
cation
products
containing Al, Ca, Fe, Mg and Zn
(eg: antacids, multivitamins &
supplements)*
Use 2 hours before or 6 hours after DTG
Rifampicin
Use DTG twice daily or substitute with rifabutin
IV.
Management of Latent TB Infection (LTBI) among PLHIV (addendum to the HIV
guidelines)
The TB/HIV guidance in this addendum to the Zimbabwean 2016 National ART guidelines aims
to COMPLEMENT and NOT SUBSTITUTE efforts currently being implemented by the country
in managing latent TB infection in PLHIV and give further guidance to HCWs on WHAT TO DO
in settings where DTG based regimens are being rolled out.
7
December 2019
Treatment options for LTBI for children, adolescents and adults (including pregnant
women) living with HIV on First line regimens
On DTG based regimen
And EFV based
regimens*
On TAF, PIs and
NNRTIs excluding EFV
Regimen
Children below 2years
Preferred Regimens
Alternative
Rifapentine + Isoniazid (HP)
weekly for 3 months (3HP) [for
children >2years and adults]
Isoniazid daily for 6 months
Isoniazid daily for 6 months
Isoniazid daily for 6 months
Dosing Schedule for treatment of LTBI for children, adolescents and adults (including
pregnant women) living with HIV on First line regimens
Drug Regimen
Isoniazid alone
Rifapentine plus
isoniazid
Dose
Daily for 6 months
Adults: 5 mg/kg
Children: 10mg/kg)
Weekly for 3 months (12 doses) (3HP)
Isoniazid
Individuals aged ≥ 12 years: 15 mg/kg
Individuals aged 2–11 years: 25 mg/kg
Maximum dose
300 mg
Isoniazid,
900mg
Rifapentine,
900mg
Rifapentine*:
10.0–14.0 kg = 300 mg
14.1–25.0 kg = 450 mg
25.1–32.0 kg = 600 mg
32.1–50.0 kg = 750 mg
> 50 kg = 900 mg
Main Considerations:
• Patients receiving Tuberculosis Preventive Therapy (TPT) SHOULD BE REGULARLY
AND ACTIVELY MONITORED FOR ADVERSE DRUG EVENTS (ADRs) including
hepatoxicity [refer to 2016 national ART guidelines] at every clinic visit. Caution should
be taken on use of IPT on pregnant women where potential risk for ADRs is high
8
December 2019
•
•
REPEAT DOSING FOR 3HR or 3HP is NOT RECOMMENDED
PATIENTS ON INH OR 3HP or 3HR COURSE WILL REQUIRE CO-TREATMENT
WITH PYRIDOXINE to prevent peripheral neuropathy [refer to 2016 national ART
guidelines for dosing]
9