Home CPD HIV management in Australia – Part 1

HIV management in Australia – Part 1

January 12, 2022

Case scenario

Marcus usually purchases his salbutamol inhaler from your pharmacy. Today he brings in a new prescription for Seretide (fluticasone + salmeterol) from his GP. You are aware that Marcus is prescribed Symtuza (darunavir + cobicistat + emtricitabine + tenofovir) by a different prescriber who is s100-accredited. You check for potential interactions and determine that co-administration of fluticasone with darunavir/ cobicistat may increase the risk of systemic corticosteroid effects, including iatrogenic Cushing’s syndrome.^9,14,24

Learning objectives

After successful completion of this CPD activity, pharmacists should be able to:

Discuss initial treatment options for people living with HIV in Australia
Describe potential interactions with antiretroviral medicines
Explain the pharmacist’s role in supporting a patient taking an antiretroviral medicine.

Competency Standards addressed (2016): 1.1, 1.4, 1.5, 2.2, 3.1, 3.5

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Introduction

Human immunodeficiency virus (HIV) has become a chronic treatable condition in Australia. It is managed with antiretroviral therapy (ART) prescribed by s100-accredited prescribers and available to be dispensed in community pharmacies. Treatment with ART can now be as simple as a single tablet each day; however, the wide variety of ART available, the ageing population, comorbidities and possible polypharmacy mean a pharmacist’s input is valuable in close monitoring of treatment regimens for potential interactions and side effects. Pharmacists are able to identify potential interactions, minimise polypharmacy and assist with the management of comorbidities. Pharmacists are also able to identify people living with HIV who would benefit from immunisation and to provide certain immunisations in line with state and territory legislation.

Australian epidemiology

Between 2014 and 2019 there was a 12% decline in HIV diagnoses in Australia, largely driven by a 20% decline in diagnoses among gay and bisexual men.¹ In 2019 there were 901 new diagnoses and a total of 28,918 people living with HIV (PLHIV) in Australia.¹ Though numbers of new diagnoses fluctuate, Aboriginal and Torres Strait Islander people continue to be diagnosed with HIV at a higher rate than Australian-born non-Indigenous Australians.¹

Management with antiretroviral therapies

ART is recommended for all diagnosed PLHIV, irrespective of clinical stage, viral load or CD4 count.² ART not only provides a clinical benefit to the HIV-infected individual, it also prevents transmission if the individual has achieved sustained virological suppression.²

There are currently five classes of antiretrovirals available:

1. Nucleoside and nucleotide reverse transcriptase inhibitors (NRTI and NtRTI)

NRTIs and NtRTIs cause premature DNA chain termination and inhibit viral replication. Nucleoside analogues include abacavir, lamivudine and emtricitabine. Tenofovir is a nucleotide analogue. These medicines are often used as a 2-drug ‘backbone’ in an ART regimen. They are found in single tablet regimens, helping to reduce pill burden for patients. Tenofovir, lamivudine and emtricitabine also have activity against hepatitis B virus.²

2. Non-nucleoside reverse transcriptase inhibitors (NNRTI)

NNRTIs disrupt reverse transcriptase, reducing enzyme activity and viral replication. The class includes nevirapine, efavirenz, rilpivirine, etravirine and doravirine (not yet available in Australia). They have a low genetic barrier to resistance.²

The older NNRTIs nevirapine and efavirenz are associated with significant side effects and are no longer recommended as initial therapy; however, some patients who have been on them long term continue to take them.

Rilpivirine is contained in several single tablet regimens. It is also included in a novel intramuscular ART preparation Cabenuva (rilpivirine-cabotegravir), which is approved by the Therapeutic Goods Administration (TGA) for use in adults with HIV type 1 who are virologically suppressed and have no resistance (or suspected resistance) to either medicine.

3. Protease inhibitors (PI)

PIs inhibit HIV protease, resulting in an immature, non-infectious virus. They have a higher barrier to resistance than a number of other antiretrovirals.³

The most common PIs are atazanavir and darunavir. PIs are taken with a pharmacokinetic enhancer (ritonavir or cobicistat), which inhibit cytochrome P450 3A4.⁴ This boosts the PI level, enabling less frequent dosing.⁴ The use of the ‘boosting’ agent means that interactions with PIs must always be considered.

4. Integrase inhibitors (INSTIs)

INSTIs prevent the integration of HIV DNA into the nucleus of the host cell. They are recommended in all starting ART regimens.³ They have high virologic efficacy, favourable tolerability and toxicity profiles, and are easy to use.³

Dolutegravir and bictegravir are the most common INSTIs and are both available in single tablet regimens. Cabotegravir is available in tablet form and, as mentioned previously, has recently been approved as a long-acting intramuscular formulation with rilpivirine. INSTIs have recently been associated with weight gain,⁵ an area which needs further research.⁶

5. Entry inhibitors

Entry inhibitors include enfuvirtide (a fusion inhibitor) and maraviroc (a CCR5-receptor antagonist). These drugs are limited to management of more complex patients. Fostemsavir was recently TGA approved; it has been very helpful for those with limited options in clinical trials.⁷

Table 1 – Key practice points for commonly used antiretrovirals

ANTIRETROVIRAL	WHEN DOSE REDUCTION IS REQUIRED	KEY SIDE EFFECTS	PRACTICE POINTS
Abacavir	Hepatic impairment8	Nausea Increased cardiovascular events10	Contraindicated in patients with HLA-B*5701 allele; patients are tested for this before prescribing8
Lamivudine	Renal impairment8	Rash8	Activity against hepatitis B virus
Emtricitabine	Renal impairment9	Rash8	Activity against hepatitis B virus8 Only available as a combination product
Tenofovir alafenamide (AF)	Combined with p-glycoprotein inhibitor8 See individual product recommendations for renal impairment 8	Association with weight gain9 Osteopenia8,9	Activity against hepatitis B virus8 Only available as combination product
Rilpivirine	Avoid in severe hepatic impairment8	Insomnia8 Abnormal dreams8	Must be taken with food8 Only start if viral load <100,000 copies/mL8
Dolutegravir	Avoid in severe hepatic impairment8	Association with weight gain9
Bictegravir	Avoid in severe hepatic impairment9	Possible association with weight gain9	Available as a combination product only
Elvitegravir	Alter based on other single tablet regimen components	Possible association with weight gain9	Available as a combination product only Number of drug interactions due to combination with cobicistat
Atazanavir	Avoid in severe hepatic impairment8	Nausea8 Diarrhoea8 Raised lipids8 Raised bilirubin8 Nephrolithiasis8	Take with food8 Available on its own and combined with cobicistat
Darunavir	Avoid in severe hepatic impairment8	Nausea8 Diarrhoea8 Raised lipids8 Rash (sulphonamide moiety)8	Available on its own and combined with cobicistat

References: Rossi,⁸ Panel on Antiretroviral Guidelines for Adults and Adolescents,⁹ Currier¹⁰

Novel antiretroviral agents

There are currently several antiretroviral agents in development, and novel methods of administration are under investigation.

Key practice points for commonly used antiretrovirals are outlined in Table 1. This list is not exhaustive, and pharmacists should always check tertiary references for information on doses, side effects and other important prescribing considerations.

ARTs are provided to patients at a subsidised cost through the section 100 Highly Specialised Drugs Program. In addition to infectious disease physicians, general practitioners and nurse practitioners are able to prescribe these medicines if they become a HIV s100-accredited prescriber.

A list of accredited GPs is available on the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) website (www.ashm.org.au/PrescriberListing).

First-line treatment options

Guidelines for HIV management are published by organisations worldwide.^9,11,12 Australia follows the United States Department of Health and Human Services guidelines. ASHM provides Australian commentary on the US guidelines.³

Initial ART for treatment-naive patients normally features two NRTIs combined with a third antiretroviral such as an INSTI, NNRTI or a boosted PI.³ Therapy should be individualised after considering HIV viral load, childbearing potential, potential adverse effects, dosing frequency, adherence issues, comorbidities, interactions and resistance mutations.

ASHM recommends the following initial regimens for most people with HIV³:

bictegravir/tenofovir alafenamide/ emtricitabine
dolutegravir/abacavir/lamivudine – only if patient is HLA-B*5701 negative and doesn’t have chronic hepatitis B virus (HBV) coinfection
dolutegravir plus (emtricitabine or lamivudine) plus (tenofovir alafenamide or tenofovir disoproxil)
raltegravir plus (emtricitabine or lamivudine) plus (tenofovir alafenamide or tenofovir disoproxil)
dolutegravir/lamivudine – except for individuals with HIV RNA >500,000 copies/mL, HBV coinfection, or when ART is started before resistance or HBV testing are available.

Table 2 – Single tablet regimens

BRAND	COMPONENTS
Biktarvy	Bictegravir 50 mg, tenofovir AF 25 mg, emtricitabine 200 mg
Triumeq	Dolutegravir 50 mg, abacavir 600 mg, lamivudine 300 mg
Genvoya	Elvitegravir 150 mg, cobicistat 150 mg, tenofovir AF 10 mg, emtricitabine 200 mg
Odefsey	Rilpivirine 25 mg, tenofovir AF 25 mg, emtricitabine 200 mg
Dovato	Dolutegravir 50 mg, lamivudine 300 mg
Juluca	Dolutegravir 50 mg, rilpivirine 25 mg
Symtuza	Darunavir 800 mg, cobicistat 150 mg, tenofovir AF 10 mg, emtricitabine 200 mg

References: Rossi⁸

A switch in ART may be required due to treatment failure, pregnancy, adherence issues, interactions, antiretroviral toxicity, simplification or comorbidities. Principles of switching ART will be covered in ‘HIV management in Australia: complex cases’, in the February edition of Australian Pharmacist.

Single tablet regimens

To reduce the pill burden and aid treatment adherence, a number of single tablet regimens are available. These are listed in Table 2. The only single tablet regimens recommended by ASHM as initial regimens for most PLHIV are Biktarvy and Triumeq.³ In certain circumstances, some of the other single tablet regimens are appropriate as initial treatment.

Drug interactions

Antiretroviral medicines are implicated in many interactions. When dispensing a new medicine or switching antiretroviral regimen, potential interactions should always be considered. In addition, undertaking a regular review of all medicines, including non-prescription and complementary medicines, will help to identify potential interactions. The University of Liverpool’s HIV Drug Interactions checker (www.hiv-druginteractions.org/checker) is a useful online resource for checking interactions. There is limited information on interactions with complementary medicines. The Natural Medicines Database (https://naturalmedicines.therapeuticresearch.com) is a useful resource.

ART interactions may result in reduced absorption or altered metabolism or excretion.¹³ Interactions resulting from cytochrome P450 enzyme induction or inhibition are significant.¹³ The boosting agents ritonavir and cobicistat are strong 3A4 inhibitors.¹³ Ritonavir also has a complex interaction profile due to its effects on other CYP450 enzymes (such as CYP2D6, CYP2C9 and CYP2C19) and UGT1A1, as well as being an inhibitor of various membrane transporters (e.g. P-glycoprotein).¹³ Due to the number of potential interactions with ritonavir containing ART, extra care is required when dispensing this medicine.

Table 3 lists some of the common interactions. This list is not exhaustive, and pharmacists should be vigilant when dispensing these medicines and always check tertiary references for potential interactions.

Table 3 – Examples of common ART interactions

MEDICINE / CLASS OF MEDICINE	MECHANISM	EXAMPLES	MANAGEMENT
Integrase inhibitors	Cationic chelation reduces absorption	Iron Calcium Zinc Magnesium aluminium	Dosing of integrase inhibitors and cations usually need to be separated. Timing depends on the specific medicines involved
Dolutegravir	Blocks organic cation transporter 2 (OCT2) in kidney	Metformin level increased	Consider monitoring glycaemic control and adjusting metformin dose when starting or stopping co-administration with dolutegravir. Some sources suggest a maximum dose of 1 gram metformin daily
Elvitegravir/cobicistat	P450 3A4 inhibition (cobicistat)	Increased levels of 3A4 substrates	Modify dose or avoid use of 3A4 substrate
Bictegravir	P450 3A4 substrate: levels lowered by inducers	Rifampicin Carbamazepine Phenytoin	Avoid strong inducers of 3A4
Tenofovir AF	P-glycoprotein substrate: absorption decreased by inducers	Rifampicin Carbamazepine St John’s wort	Avoid strong inducers of p-glycoprotein
Rilpivirine	Increased stomach pH reduces absorption	Antacids H2 antagonists Proton pump inhibitors	Take with a main meal Give antacids either 2 hours before or 4 hours after rilpivirine Give H2 antagonist at least 12 hours before or 4 hours after rilpivirine Avoid proton pump inhibitors
Older NNRTIs (efavirenz, nevirapine)	P450 3A4 inducers, reduce levels of other medicines	Methadone Statins Anticoagulants Antiplatelets	Recommendation differs for each individual medicine
Atazanavir	Increased stomach pH reduces absorption	Antacids H2 antagonists Proton pump inhibitors	Take with food Separate doses of antacids and atazanavir by at least 2 hours Refer to reference for H2 antagonist and proton pump inhibitor recommendations
Pharmacokinetic enhancers (cobicistat, ritonavir)	P450 3A4 inhibition	Warfarin Statins Anticoagulants Antiplatelets Corticosteroids Colchicine	Check every co-administered medicine when starting or stopping pharmacokinetic enhancer containing ART
Ritonavir	Inducer of: UGT1A1, CYP1A2, 2B6, 2C8, 2C9, 2C19 Inhibitor of: CYP3A4, 2D6, 2C9, 2C19, 2A6, 1A2, 2E1, p-glycoprotein	Levothyroxine Digoxin Lamotrigine Voriconazole Olanzapine Amphetamines	Check every co-administered medicine when starting or stopping ritonavir containing ART

References: Medland,² Rossi,⁸ Panel on Antiretroviral Guidelines for Adults and Adolescents,⁹ University of Liverpool¹⁴

HIV prevention

PLHIV taking ART daily who achieve an undetectable viral load and maintain a durable viral suppression (HIV RNA < 200 copies/mL) cannot sexually transmit HIV.^15–17 This is termed U=U or ‘undetectable equals untransmittable’. Since 2016, studies investigating ART effectiveness in preventing transmission have provided overwhelming evidence of U=U.^18–20 The U=U message has been life-changing for those living with HIV, reducing stigma and transmission-related anxiety.¹⁵

Condoms remain highly effective at preventing sexually transmitted infections (STIs). Pharmacists can provide evidence-based sexual health information, assisting patients to find a prevention strategy that works for them.

Other HIV prevention strategies include post-exposure prophylaxis (PEP) and pre-exposure prophylaxis (PrEP). For PEP, antiretrovirals need to be started within 72 hours of HIV exposure and taken for 28 days.²¹ A commonly used PEP regimen in Australia is tenofovir disoproxil plus emtricitabine.²¹ A third drug is added in certain cases.²¹ PrEP involves taking tenofovir disoproxil + emtricitabine once a day, ongoing.²² Daily PrEP is a highly effective HIV prevention strategy for men who have sex with men (MSM), heterosexual men and women, transgender people, and people who inject drugs who are at risk of HIV acquisition.²² The ASHM PrEP guidelines recommend PrEP for all people at risk of HIV.²² PrEP is subsidised through the Pharmaceutical Benefits Scheme (PBS).

A negative HIV test is required to prescribe PrEP, and it should be started within 7 days of the day the negative test was performed.²² Patients are then reviewed at least every 3 months when they return to their doctor for a prescription refill (or more frequently if required). This includes HIV and STI testing, as well as clinical review for signs of toxicity and to determine whether PrEP remains indicated.²²

On-demand or event-based PrEP has recently been recommended for cis-gender MSM only.²² This involves taking two tenofovir disoproxil + emtricitabine tablets at least 2 hours (up to 24 hours) before sex, followed by a single tablet 24 hours later, and another single tablet 24 hours after that.²²

Knowledge to practice

Pharmacists are integral in the multidisciplinary team caring for PLHIV. When supplying ART, pharmacists should speak with the patients to find out whether they are experiencing any possible side effects and if there have been any recent changes to their medicines, to identify any potential drug interactions. As PLHIV age, management of comorbidities (e.g. cardiovascular disease, renal impairment or diabetes) may result in complex medication regimens and polypharmacy.²³

A comprehensive medicine review can help to prevent interactions and reduce adverse clinical outcomes.

Pharmacists must provide respectful care to all PLHIV, ensure health-related information is kept confidential, and adapt care to culturally and linguistically diverse populations.

Through regular dispensing of medication, pharmacists build a long-term relationship with their patients and play a pivotal role in adherence counselling and medication education.

Pharmacists may provide patients with links to patient support organisations, peer support workers or informal support organisations. These include:

The National Association of People with HIV Australia
The Institute of Many
The Australian Federation of AIDS Organisations.

Case scenario continued

With Marcus’s permission, you contact his GP and explain the potential risk associated with the concomitant administration of fluticasone and darunavir/cobicistat. You also explain that beclomethasone is a possible alternative, as it is not a substrate for CYP3A4.^9,14 The GP decides to review Marcus’s asthma management plan to avoid this potential interaction.

Conclusion

HIV has become a chronic treatable condition as a result of currently available antiretroviral therapies. These therapies often involve multiple antiretroviral medicines and sometimes complicated regimens; however, a number of single tablet regimens are available to help reduce the pill burden and aid adherence. In addition to managing HIV, antiretrovirals have an important role to play in post and pre-exposure prophylaxis to prevent HIV transmission. Antiretrovirals for both the management and prevention of HIV are available through community pharmacies, and pharmacists can assist patients and prescribers to manage these medicines as well as associated comorbidities.

Key points:

HIV treatment has evolved in recent times and many patients are now able to be managed on a single tablet regimen.
Antiretrovirals are implicated in many drug interactions. Potential drug interactions should always be considered when dispensing these medicines.
Pre-exposure prophylaxis (PrEP) with antiretrovirals is an important prevention strategy for patients at risk of contracting HIV.
People living with HIV who keep their viral load at an undetectable level by consistently taking their HIV medicines will not sexually transmit HIV. This is promoted through the ‘undetectable equals untransmittable’ message or U=U.

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References

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French M, Crock E, ed. HIV management in Australasia: a guide for clinical care. Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM), 2019. At: https://hivmanagement.ashm.org.au/about-hiv-management-in-australasia
What to start: initial combination regimens for the antiretroviral-naive patient. US DHHS guidelines with Australian commentary, 2019. At: https://arv.ashm.org.au/what-to-start-initial-combination-regimens-for-the-antiretroviral-naive-patient
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Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. 2021. At: https://clinicalinfo.hiv.gov/en/guidelines
Currier JS. Epidemiology of cardiovascular disease and risk factors in patients with HIV. In: UpToDate. Waltham: UpToDate; 2021. At: www.uptodate.com
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ALISON DUNCAN BPharm, GradDipClinPharm, MSHP is a Senior Clinical Pharmacist and Team Leader working at the Alfred Hospital and Melbourne Sexual Health Centre. She has a passionate interest in infectious diseases, particularly the treatment of opportunistic infections, HIV and antiretroviral therapy.

KATE MACKIE BPharm, GradDipClinPharm, MSHP, BCGP is a Senior Clinical Pharmacist at Alfred Health, Melbourne Health and Barwon Health. Conflict of interest: Alfred Health received funding from Gilead Sciences and ASHM (with support from ViiV Healthcare) to lead the PROM-GP study) Pharmacist review of medications for people living with HIV seen in general practice).

The authors would like to acknowledge Ivette Aguirre BPharm, MClinPharm, GradCertPharmPrac, BAppSc(MedLabSc), MSHP, Jenny Ly BPharm, GradCertPharmPrac, and Stav Mantas BPharm (Hons), MSHP, for their contributions to this paper.