Antiretroviral Guidelines

US DHHS Guidelines with Australian commentary

Optimizing Antiretroviral Therapy in the Setting of Virologic Suppression

Last Updated: December 18, 2019; Last Reviewed: December 18, 2019

Panel's Recommendations for Optimizing Antiretroviral Therapy in the Setting of Virologic Suppression

Panel’s Recommendations

Advances in antiretroviral (ARV) treatment and a better understanding of HIV drug resistance make it possible to consider switching a person with HIV from an effective regimen to an alternative regimen in some situations.
The fundamental principle of regimen optimization is to maintain viral suppression without jeopardizing future treatment options.
Adverse events, drug-drug or drug-food interactions, pill burden, pregnancy, cost, or the desire to simplify a regimen may prompt a regimen switch.
It is critical to review a patient’s full ARV history, including virologic responses, past ARV-associated toxicities and intolerances, and cumulative resistance test results, before selecting a new antiretroviral therapy regimen (AI).
Monotherapy with either a boosted protease inhibitor or an integrase strand transfer inhibitor has been associated with unacceptable rates of virologic failure and the development of resistance; therefore, monotherapy as a switch strategy is not recommended (AI).
When switching an ARV regimen in a person with hepatitis B virus (HBV)/HIV coinfection, ARV drugs that are active against HBV infection should be continued (AII). Using 3TC or FTC as the only drug in a regimen with HBV activity is not recommended (AII), as HBV resistance to these drugs can emerge. Discontinuation of HBV drugs may lead to reactivation of HBV, which may result in serious hepatocellular damage.
Consultation with an HIV specialist is recommended when planning a regimen switch for a patient with a history of resistance to one or more drug classes (AIII).
Close monitoring to assess tolerability, viral suppression, adherence, and safety is recommended during the first 3 months after a regimen switch (AIII).

Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion

AU Comment: Long-Acting Injectable Cabotegravir and Rilpivirine in Persons Living with HIV

Injectable antiretroviral treatment with Cabenuva (Cabotegravir 600mg + Rilpivirine 900mg) is PBS approved in adults and adolescents 12 years and older (>35kg) who have previously received PBS-subsidised HIV therapy and must be the sole PBS-subsidised therapy prescribed.
This treatment involves two separate intramuscular injections (each 3mL) preferably delivered via a ventrogluteal injection technique, delivered by a healthcare provider every 2 months after two initial loading doses given 4 weeks apart. This approach combines cabotegravir (INSTI, a structural analogue of Dolutegravir) and Rilpivirine (NNRTI, also available in oral form and incorporated into Eviplera/Odefsey/Juluca formulations).

Current DHHS guidelines provide recommendations and practical advice around Cabenuva therapy. The overall recommendation is that ventrogluteal IM injections of CAB and RPV can be used to replace an existing oral ARV regimen in people with HIV with sustained viral suppression for 3 to 6 months (optimal duration is not defined) (AI). This treatment is non-inferior to existing oral antiretroviral therapy, leading to FDA approval in January 2022.

These recommendations are endorsed by ASHM, with relevant points highlighted here:

Long-acting injectable CAB plus RPV is indicated in individuals with sustained (3 to 6 months) virologic suppression (HIV-1 RNA <50 copies/mL) on a stable ARV regimen, with no history of treatment failure, and with no known or suspected resistance to either cabotegravir or rilpivirine.
This treatment is currently contraindicated in women who are pregnant or planning pregnancy, and in patients with active or occult Hepatitis B infection unless additional specific treatment for HBV infection is used (e.g. entecavir).
Cabenuva is contraindicated in the presence of ongoing anticonvulsant therapy (phenytoin, carbamazepine), TB and MAC therapy (rifampicin, rifabutin), dexamethasone, and St John’s wort.
Oral lead-in dosing for 4 weeks is available through PBS but is not required or recommended in clinical practice noting that clinical trials have found no differences in adverse events, tolerability, efficacy, or PKs between the direct-to-inject and oral lead-in extension arms.
Injection site pain is common with early injections (~80%) but reduce in severity with subsequent injections with ongoing rates of 10-30%. This is a rare cause of treatment discontinuation (<1%), and in clinical trials 98% of participants expressed a preference to continue with injectable Cabenuva therapy rather than return to oral treatment.

Management of missed doses: Injectable HIV therapy requires regular attendance and maintenance of 8-weekly dosing schedules, and is recommended for individuals who have good adherence and engagement in care. The dosing window for Cabenuva therapy is up to 7 days before or after the scheduled date.

For planned missed doses (e.g. while travelling), bridging oral HIV therapy is recommended with the first dose taken two months after the last Cabenuva injection. Any fully suppressive oral antiretroviral regimen can be used, noting that daily oral Cabotegravir (30mg) + Rilpivirine (25mg) therapy – taken with food – can be prescribed for up to 2 months but is not recommended for longer bridging periods. (*Note that oral Rilpivirine therapy is contraindicated in the presence of PPI medications).
The recommended strategy for managing unplanned missed doses is outlined here: CABENUVA-PI-PIL-IFU2-IFU3.PDF (gskpro.com) (from Cabenuva Product Information).

AU comment: Delisting of Stribild and Eviplera

From 1 March 2020 the Single Tablet Regimen (STR) HIV treatments Eviplera® (tenofovir disoproxil fumarate, emtricitabine and rilpivirine) and Stribild® (cobicistat, elvitegravir, emtricitabine and tenofovir disoproxil fumarate) will no longer be available via the Pharmaceutical Benefits Scheme (PBS). This involves a decision on delisting taken by the Australian minister and department of health under advice from the PBAC.

Reducing the choices available has the potential to create confusion for patients and clinicians for whom these fixed dose combinations may be the preferable treatment in the future.

For any patients who have a medical need for these fixed dose combinations, cannot receive an alternative PBS reimbursed regimen and prefers the fixed dose combination to a multi-tablet regimen with the same agents, their treating physician can apply to Gilead for compassionate access.

For those individuals and/or groups particularly impacted by this change the optimal management is as follows:

Pregnant women and women wishing to conceive.

Women in this category require effective antiretroviral therapy that minimises any potential adverse effects for them or their baby. Data on adverse effects of antiretrovirals typically accrues post marketing from safety data about women becoming pregnant on newer antiretroviral regimens. Currently this data does not exist for newer agents such as tenofovir alafenamide, dolutegravir and bictegravir. In addition there may be an increased risk of neural tube defects in women who conceive while receiving dolutegravir. Therefore, current guidance for ARVs in pregnant women and those trying to conceive typically exclude these ARVs.¹ Eviplera® is therefore commonly prescribed in this group as it is well tolerated, a single tablet regimen and considered safe in pregnancy.

Options for women in this category:
- Apply for compassionate access to Eviplera®
- Change to a 2-tablet regimen of tenofovir disoproxil fumarate/emtricitabine and rilpivirine
- Consider another multi-tablet regimen containing a dual N(t)RTI backbone with either a: boosted protease inhibitor (Atazanavir/ritonavir or Darunavir/ritonavir) or raltegravir. All these regimens require 3 tablets per day (once daily); Raltegravir requires twice daily dosing

Individuals who are already tolerating Eviplera® without adverse effects, have virological suppression and wish to continue them.

Options for people in this category:
- Apply for compassionate access to Eviplera®
- Consider the following regimen changes after reviewing factors important when considering a switch of ART in the setting of virologic suppression:²
  - Change to a 2-tablet, once daily regimen of tenofovir disoproxil fumarate/emtricitabine and rilpivirine
  - Change to a single tablet fixed dose combination of tenofovir alefenamide/emtricitabine/rilpivirine
  - Change to other currently available fixed-dose combinations (FDCs) that require a switch to single tablet and include new drug classes such as integrase strand transfer inhibitors. These FDCs include
    - Dolutegravir/rilpivirine
    - Tenofovir alafenamide/emtricitabine/ bictegravir

Individuals who are tolerating Stribild®, have achieved virological suppression and wish to continue.

Options for people in this category:
- Apply for compassionate access to Stribild®
- Change to a single tablet regimen of tenofovir alefenamide/emtricitabine/elvitegravir/cobicistat
- Change to another single tablet FDC

References:

Situation-Specific Recommendations for Use of Antiretroviral Drugs in Pregnant Women and Nonpregnant Women Who Are Trying to Conceive. (Accessed 1/Oct/2019, at https://aidsinfo.nih.gov/guidelines/htmltables/3/6667.)
Optimizing Antiretroviral Therapy in the Setting of Virologic Suppression. (Accessed 1/Oct/2019, at https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/16/optimizing-antiretroviral-therapy-in-the-setting-of-virologic-suppression.)