INTRODUCTION

The National Department of Health (NDoH) has provided for more comprehensive, standardised, simplified and less toxic drug combinations for the HIV programme in South Africa. The standardised first- and second-line regimens are based on efficacy, safety and tolerability. However, there are predictable resistance mutations that develop after first-line failure and it is therefore believed that the second-line therapy selected should achieve viral suppression. When second line anti-retroviral (ART) stops working, there is a process to follow to perform resistance testing and then apply to the Third Line ART (TLART) Peer Review Committees (PRCs) for third-line treatment, due to the complexity and expense of TLART. Right to Care has been involved in assisting the TLART Committee since its inception in September 2013, by providing two clinicians on the Paediatric TLART Committee, as well as, providing administrative support. Below we provide some useful information and assistance to facilitate the process of applying for TLART.

BACKGROUND

There is a growing need for TLART across South Africa with the number of applications for TLART access increasing rapidly. The NDoH has constituted the Adult and Paediatric TLART Peer Review Committees with the mandate of making recommendations for TLART for those patients who have failed first and second-line ART as prescribed in the Standard Treatment Guidelines (STGs) and Essential Medicines List (EML). In order to access TLART, patients must have resistance to protease inhibitors (PI), identified through HIV resistance testing, and are experiencing virological failure. These patients can access TLART following authorisation from the NDoH through consultation with the TLART Committee. The procurement of TLART medicines has been decentralised to provinces where the treating facility orders and manages TLART medicines.

TLART medicines include the following:

Darunavir (DRV)

Tablets: 75mg; 150mg; 400mg; 600mg

Oral suspension: 100mg/ml (not available in South Africa, available on compassionate use access from manufacturer with the South African Health Products Regulatory Authority (SAHPRA) Section 21 approval)

Dolutegravir (DTG)

Tablets: 50mg

This is now available as part of first line therapy, but is still used in TLART

Raltegravir (RAL)

Tablets: 25mg (chewable); 100mg (chewable, scored, divisible), 400mg (film-coated)

Low barrier of resistance, DTG is preferred

Etravirine (ETR)

Tablets: 25mg, 100mg

INDICATIONS FOR RESISTANCE TESTING

Adults and Adolescents

Any patient failing a PI-based regimen and who meets the definition of confirmed virological failure, i.e., a viral load (VL) > 1000 c/ml on at least three occasions over two years.

Resistance testing for adults and adolescents failing a DTG-based second-line regimen and who meet the definition of confirmed virological failure may be authorised by an expert on a case-by-case basis. Resistance testing for clients failing a DTG-containing first-line regimen is not indicated

Any adult with an elevated VL on a PI or DTG-based regimen (irrespective of time on the regimen) who received concurrent rifampicin-containing TB treatment and unboosted ART.

Any newly diagnosed patient who has received pre-exposure prophylaxis (PrEP) in the last six months.

Infants and Children

Any child failing a PI or DTG-based regimen and who meet the definition of confirmed virological failure, i.e., a VL > 1000 c/ml on at least three occasions over two years.

Any child with an elevated VL on a PI or DTG-based regimen (irrespective of time on the regimen) who received concurrent rifampicin-containing Tuberculosis (TB) treatment and unboosted ART.

Any newly diagnosed child <2 years of age whose mother was receiving PI-based ART during pregnancy and/or during breastfeeding.

HOW TO DO RESISTANCE TESTING

Genotypic resistance testing will only be accurate if the patient is fully adherent for some time before doing the test. Since patients are often non-adherent when failing a regimen and don’t always admit to being non-adherent, it doesn’t make sense to do a resistance test straight away. Rather explain to the patient that you are about to do a very expensive test to see which of their antiretrovirals (ARVs) are not working. But the test will not be accurate unless they take every dose for a full month. So let the patient rather make sure they take every dose for the next month and then do the resistance test. That way you are more likely to have an accurate test.

There is a special form that needs to be completed to do a resistance test. Please fill in the form as fully as possible to avoid it being rejected. Here is the link to the form to request a resistance test  http://tiny.cc/gg87qz

HOW TO APPLY FOR THIRD LINE ART

The following blood tests need to be done if recent tests are not available (within 3 months):

Full blood count (FBC)

Creatinine

Alanine aminotransferase (ALT)

Hepatitis B Surface Antigen

Viral Load (VL)

CD4 count

To apply for third line antiretrovirals, the following documents are required:

  1. Third Line Application Form (to be completed by the applicant). The Applicant is the senior clinician at facility level who is applying for TLART access for the patient). The form is called Application for third line antiretrovirals_092017_1 and can be found by clicking on this link Application for Third Line Antiretroviral Therapy
  2. HIV drug resistance test result (available from the laboratory).

Applications are then sent to the Committee at: TLART@health.gov.za
Please send one patient’s application per email. If more than 1 application is sent in the same email, the other applications are sometimes missed and are not processed.

Application form processing:

Once the complete application form and drug resistance test has been received, the patient is assigned a unique reference number that they will keep for life. This reference number should always be quoted/indicated with subsequent communication with the TLART Committee regarding the patient. A Stanford resistance score is calculated according to the drug resistance test (online at https://hivdb.stanford.edu/hivdb/by-mutations/) and a regimen is recommended by the TLART Committee, according to the relevant algorithm (available online at: www.health.gov.za/index.php/affordable-medicines/category/524-third-line-antiretrovirals), and the clinical presentation of the patient.

The recommended regimen is then sent to the relevant Provincial Medical Depot and the applicant, who writes a prescription and sends it to the pharmacy so that they can order the medicines for the patient.

Common reasons for a delayed response to TLART applications:

a) Incomplete application forms can delay the processing of the application forms.
In particular:

  • Illegible handwriting;
  • No contact details for the doctor and pharmacist on the application form (Recommendations from the Committee are only sent to the applicant’s email address as per the application form);
  • Missing laboratory results (such as renal function, haemoglobin, etc…)

b) Emails with a missing drug resistance test.
c) Application form not attached on the email.
d) Emails with more than 1 patient’s application attached.
e) No clear indication of enhanced adherence counselling done for the patients failing second line ART.

Right to Care has been working with the TLART Committee to decrease the number of incomplete submissions of TLART applications by developing a guidance document to act as a reference for clinicians at facility level on processes to be followed. This will also reduce the processing time of TLART applications by the secretariat.

FURTHER RESOURCES

  • WEBSITES:

    • HIVInSite
      • Comprehensive, up-to-date information on HIV/AIDS treatment and prevention from the University of California, San Francisco
      • ucsf.edu/InSite?page=Treatment
    • HIV Drug Interactions

    SMARTPHONE APPLICATIONS:

    • Epocrates (free to download and use)
    • Liverpool HIV iChart (through the University of Liverpool) (free to download and use)
  • WEBSITES:

    SMARTPHONE APPLICATIONS:

    • EMGuidance (free to download and use)
      • South Africa’s STGS and EML for all levels of care (Primary Health Care; Hospital -paediatrics and adults; Tertiary and Quaternary)

QUESTION AND ANSWERS

Concomitant tuberculosis infection

The use of rifampicin is contraindicated with the use of darunavir, and rifabutin should be used instead:

  • Rifabutin, oral, 150mg daily (Adult Hospital Level STGs and EML: 2019);
  • Patients must be monitored for uveitis (by an ophthalmologist) and for anaemia and neutropenia;
  • As of 1 July 2020, rifabutin is not available on the Master Procurement Catalogue (for procurement in the public sector); it is however available for procurement through Pfizer. Contact your pharmaceutical depot and Pfizer for details on how to order.

Taking rifampicin and lopinavir/ritonavir (LPV/r)

Adults

  • LPV/r dose should be doubled.

Paediatrics

  • If on LPV/r tablets, then the LPV/r dose should be doubled.
  • If on LPV/r solution then this must be super boosted with additional ritonavir, to ensure a 1:1 ratio of lopinavir and ritonavir. See the STGs and EML for Paediatrics (Hospital Level, 2017), available from health.gov.za/index.pho/standard-treatment-guidelines-and-essential-medicines-list). See table 1 below for dosing.
  • Ritonavir oral powder 100mg is available on the Master Procurement Catalogue for procurement (see the circular – NDoH Circular notice-ritonavir powder – available at health.gov.za/index.php/circulars, for further information).

Table 1: Dosing ritonavir oral powder according to weight (extract from the STGs and EML for Paediatrics (Hospital Level, 2017))

        Addition of ritonavir to Lopinavir/ritonavir when on Rifampicin

              (And for 2 weeks after stopping Rifampicin)

Target dose LPV/r standard dose + super-boosting with

Ritonavir (RTV) powder

TWICE daily

(≥0.75 x LPV dose twice daily)

Available

formulations

Ritonavir oral powder

100 mg / sachet

Weight (kg)
3-4.9  

100 mg (1 sachet) twice daily

5-5.9
6-9.9
10-13.9
14-19.9 200 mg (2 sachets) twice daily
20-24.9
25-29.9 300 mg (3 sachets) twice daily
30-34.9 400 mg (4 sachets) twice daily

The instructions on how to administer ritonavir oral powder are as follows:

  • Using the dosing chart above, determine how many sachets to use (please note full sachets must be used).
  • These sachets can be mixed with soft food or liquid.
  • Use only a small amount of food, to ensure child can consume all (never keep food mixed with ritonavir for more than 2 hours).

RESOURCES FOR CLINICAL MANAGEMENT AND DRUG INTERACTIONS

National HIV & TB Health Care Worker Hotline:

• Tel: 0800 212 506
• Email: pha-mic@uct.ac.za
• SMS/please call me/WhatsApp: (071) 840-1572

Right to Care Paediatric and Adolescent HIV Helpline:

Tel: (082) 352-6642
http://tiny.cc/8j87qz

Right to Care Adult HIV Helpline:

• Tel: (082) 957-6698
• Both Right to Care Helplines can be contacted via call/ SMS/please call me/WhatsApp

KZN Paediatric Hotline:

Tel: 0800 006 603

PAEDIATRIC DOSES OF THIRD LINE DRUGS

Document (Paed 3rd line cART dosing_23052019) available online at
www.health.gov.za/index.php/affordable-medicines/category/524-third-line-antiretrovirals

  • Both DRV and RTV should be taken with food as this increases absorption.

    Dosing:

    • Children <3 years of age OR <10 kg: DRV is not recommended.
    • Children ≥3 – <18 years of age AND ≥10 kg:

     

    Weight band

    (kg)

    Dose of darunavir and ritonavir:

    administer doses in table below twice daily with food

    10 – <11 DRV 200 mg (2.0 ml) + RTV oral solution 32 mg (0.4 ml) or RTV oral powder 100 mg (1 packet)
    11 – <12 DRV 220 mg (2.2 ml) + RTV oral solution 32 mg (0.4 ml) or RTV oral powder 100 mg (1 packet)
    12 – <13 DRV 240 mg (2.4 ml) + RTV oral solution 40 mg (0.5 ml) or RTV oral powder 100 mg (1 packet)
    13 – <14 DRV 260 mg (2.6 ml) + RTV oral solution 40 mg (0.5 ml) or RTV oral powder 100 mg (1 packet)
    14 – <15 DRV 280 mg (2.8 ml) + RTV oral solution 48 mg (0.6 ml) or RTV oral powder 100 mg (1 packet)
    15 – <30 DRV 400 mg (1 x 400 mg tablet or 4 ml)

    + RTV oral solution 48 mg (0.6 ml) or or RTV oral powder 100 mg (1 packet) or 100 mg tablet if able to swallow whole

    30 – <40 DRV 475 mg (1 x 400 mg + 1 x 75 mg tablets or 4.7 ml)

    + RTV 100 mg tablet (or RTV oral solution 1.25 ml or RTV oral powder 100 mg (1 packet) if unable to swallow whole RTV tablet)

    ≥40 DRV 600 mg (1 x 600 mg or 4 x 150 mg tablets or 6 ml)

    + RTV 100 mg capsule (or RTV oral solution 1.25 ml or RTV oral powder 100 mg (1 packet) if unable to swallow whole RTV tablet)

  • Dosing:

    • ³20 kg: 50 mg once daily
    • Children ³35 kg and ³10 years old, who have been recommended TDF, FTC/3TC and DTG, can take the TLD FDC tablet if available and renal function criteria are met (see table 1 below).

     

    Table 1: Assessing renal function (2019 ART Clinical Guidelines for the management of HIV in adults, pregnancy, adolescents, children, infants and neonates, NDoH, 2019)

    Children on concomitant rifampicin-containing TB regimens:

    • ³20 kg: 50 mg 12 hourly
    • If on tenofovir/lamivudine/dolutegravir (TLD) fixed-dose combination (FDC): additional DTG 50 mg 12 hours after TLD dose
  • Dosing:

    • Neonatal dose (refer to Table below):
      • Birth – age 7 days:

    1.5 mg/kg/dose once daily.

    Note: If the mother has taken RAL 2-24 hours before delivery, the neonate’s first dose should be given between 24-48 hours after birth.

    • Aged 8-28 days:

    3 mg/kg/dose twice daily.

    Body Weight
    (kg)
    Dose of oral suspension
    Birth to 1 Week – Once daily dosing*
     2 – <3 kg  0.4 mL (4 mg) once daily
     3 – <4 kg  0.5 mL (5 mg) once daily
     4 – <5 kg  0.7 mL (7 mg) once daily
     1 to 4 Weeks – Twice daily dosing
     2 – <3 kg  0.8 mL (8 mg) twice daily
     3 – <4 kg  1 mL (10 mg) twice daily
     4 – <5 kg  1.5 mL (15 mg) twice daily
     *The dosing recommendations are based on approximately 1.5 mg/kg/dose.
     †The dosing recommendations are based on approximately 3 mg/kg/dose.

    No dosing information is available for preterm infants or infants weighing <2 kg.

    • Infants ≥4 weeks of age:

    6 mg/kg/dose twice daily (or dose according to Table below).

    • Children ≥4 weeks of age AND weighing ≥3 kg – <20 kg: dosing of oral suspension:
    Weight band

    (kg)

    Dose of oral suspension
    3 – <4 2.5 ml (25 mg) twice daily
    4 – <6 3 ml (30 mg) twice daily
    6 – <8 4 ml (40 mg) twice daily
    8 – <11 6 ml (60 mg) twice daily
    11 – <14 8 ml (80 mg) twice daily
    14 – <20 10 ml (100 mg) twice daily

     

    • Children with body weight 11-20 kg may be dosed with either oral suspension or chewable tablets.
    • Children ≥11 kg body weight:
      • If <25 kg: chewable tablets by weight-based dosing chart below to maximum of 300 mg twice daily.
      • If ≥25 kg body weight, 400 mg film-coated tablet twice daily OR chewable tablets twice daily.

    Dosing of chewable tablets:

    Weight band

    (kg)

    Dose Number of chewable tablets
    11 – <14 75 mg twice daily 3 x 25 mg twice daily
    14 – <20 100 mg twice daily 1 x 100 mg twice daily
    20 – <28 150 mg twice daily 1.5 x 100 mg twice daily
    28 – <40 200 mg twice daily 2 x 100 mg twice daily
    ≥40 300 mg twice daily 3 x 100 mg twice daily

     

    • Child / adolescent with body weight ≥25 kg and adult dose:

    400 mg film-coated tablet twice daily

    Children on concomitant rifampicin-containing TB regimens:

    • Clinician should engage with the Third Line Committee to review ART and TB treatment (dosing with twice the recommended paediatric dose of RAL during the period on rifampicin may be considered although data is limited and not available for all ages and RAL formulations).
    • Children <6 years of age: not recommended
    • Children ≥6 – <18 years of age AND ≥16 kg:

     

    Weight band

    (kg)

    Dose
    16 – <20 100 mg twice daily
    20 – <25 125 mg twice daily
    25 – <30 150 mg twice daily
    ≥30 200 mg twice daily

     

    • Adult dose:

    200 mg twice daily after food

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