Injectable PrEP

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Introduction

On the 8th of August 2022 the Australian Therapeutic Goods Administration (TGA) approved the use of long-acting injections of cabotegravir (CAB-LA) as HIV pre-exposure prophylaxis (PrEP) for adults and adolescents with HIV acquisition risk (for those at least 12 years of age and weighing at least 35 kg). During their September 2023 meeting, the Pharmaceutical Benefits Advisory Committee (PBAC) recommended that CAB-LA be listed on the general schedule (with streamlined authority) for use as PrEP with further details to follow regarding patient suitability criteria for CAB_LA.

This ASHM guideline is intended to provide clinicians with relevant information on CAB-LA PrEP, to enable safe and evidence-based provision of this HIV prevention technology.

 

Evidence for effectiveness

The HIV Prevention Trials Network (HPTN) assessed the effectiveness of CAB-LA for the prevention of HIV infection in two multisite randomised controlled trials (RCTs), namely HPTN-083 and HPTN-084.[1, 2] With a similar design, these trials assessed effectiveness in different populations: HPTN-083 enrolled 4,566 cisgender men who have sex with men (MSM), and transgender women (12.5% of participants) who have sex with men, across 43 trial sites in the United States, Latin America, Africa, and Asia; whereas HPTN-084 enrolled 3,224 cisgender women across seven countries in sub-Saharan Africa.

In both trials, CAB-LA PrEP injections commenced after an oral lead-in phase, and participants were randomised (1:1) to receive either 8-weekly CAB-LA injections and daily oral placebo pills, or 8-weekly placebo injections and daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC). TDF/FTC is no longer available in Australia, having been replaced with several therapeutically equivalent generic versions of tenofovir, hereafter referred to as TD*/FTC.

Participants were followed for 153 weeks, with the primary endpoint being incident HIV infections.

Among MSM and transgender women, HPTN-083 estimated a 66% reduction in HIV risk (hazard ratio 0.34; 95% confidence interval (CI) 0.18 to 0.62) with CAB-LA compared with oral TDF/FTC. This superiority finding of CAB-LA versus oral TDF/FTC may not be translatable to the Australian context, due to very low HIV diagnosis rates among Australian PrEP users.[3, 4] In HPTN-083 and its subsequent open label extension, 34 HIV infections occurred in the CAB-LA group, of which six occurred in participants with appropriately timed CAB-LA doses and adequate plasma cabotegravir concentrations.[5]

Among cisgender women, HPTN-084 estimated an 88% reduction in HIV risk (hazard ratio 0.12; 95% CI 0.05 to 0.31) with CAB-LA compared with oral TDF/FTC. Four HIV infections occurred in the CAB-LA group, of which one infection occurred during the CAB-LA injection phase (rather than during the oral lead-in phase), and that participant had delayed injection visits and suboptimal plasma cabotegravir levels.

Pharmacokinetic studies have shown that three days after a single IM injection of CAB-LA 600mg, all participants had plasma cabotegravir concentrations that were four times the in vitro protein-adjusted 90% maximal inhibitory concentration (PA-IC90), and concentrations in rectal fluid peaked by day eight, indicating a rapid onset of action of CAB-LA.[6]

 

Safety and Adverse Events

Cessation due to adverse effects

Permanent discontinuation of PrEP due to adverse effects was uncommon in both HPTN-083 and HPTN-084, at 3.8% and 1.2% of participants respectively. In both trials, the discontinuation rate due to adverse effects was similar in the active CAB-LA and TDF/FTC arms.

Safety and systemic adverse effects

Adverse events rated grade 2 or higher were common in both HPTN-083 and HPTN-084, occurring in 92.5% and 92.2% of participants respectively, and similar between the active CAB-LA and TDF/FTC arms, apart from injection site reactions (ISRs) being more common in the active CAB-LA arms (discussed below). Adverse events rated grade 3 or higher included increased serum creatinine, increased lipase, and increased liver enzymes, all affecting <5% of participants across trials and were similar between the CAB-LA and TDF/FTC arms.

Injection-site reactions

ISRs were common in both HPTN trials. In HPTN-083, 81.4% of participants in the active CAB-LA arm complained of ISRs, compared with 31.3% in the TDF/FTC (placebo injection) arm. In HPTN-083, permanent discontinuation was strongly associated with higher-severity ISR from CAB-LA injections, and in total 2.4% of participants in the CAB-LA arm discontinued due to ISRs. In HPTN-084, 38.0% of participants in the CAB-LA arm complained of ISRs, compared with 10.8% in the TDF/FTC (placebo injection) arm, but no participants discontinued due to ISRs.

ISRs were usually rated as mild-to-moderate and typically lasted only a few days. Patients should be warned about these ISRs, but also reassured that ISRs usually improve after the initial 2-3 injections. The following advice can help to reduce the severity of ISRs:

  • Pro-actively take simple analgesia or NSAIDS a couple of hours prior to the scheduled CAB-LA injection and continue taking these if required for one or two days after.
  • Apply a warm compress to the injection site for 15-20 minutes after the injection.

Weight gain

In HPTN-083, participants in the CAB-LA arm gained 1.23 kg per year (95% CI 1.05 to 1.42) and those in the TDF/FTC arm gained 0.37 kg per year (95% CI 0.18 to 0.55). Similarly, in HPTN-084, participants in the CAB-LA group gained slightly more weight than those in the TDF/FTC group.

HIV acquisition during CAB-LA use: Drug resistance mutations and delayed diagnosis.

In HPTN-084, no major integrase strand transfer inhibitor (INSTI) resistance mutations were detected in any of the four HIV infections observed in the CAB-LA group.

In HPTN-083 and its open label extension, INSTI resistance mutations were detected in ten of the 18 cases who had at least one CAB-LA injection in the six-month period prior to their first positive HIV test.[5] Participants who acquired HIV had delayed diagnoses due to suppression of viral load and attenuation of the HIV antibody response, and this delayed detection contributed to the development of INSTI resistance mutations.[5, 7, 8] If HIV RNA tests had been used for screening, rather than standard 4th generation HIV Ag-Ab serology, the majority of infections would have been detected earlier. Retrospective analysis of HPTN-083 and its open label extension suggests that HIV RNA screening would have detected these infections before participants developed INSTI resistance in 75% (6 of 8) cases.[8] In response, the United States PrEP guidelines now recommend the use of HIV RNA tests to screen for HIV infection in people who are using PrEP (oral or injectable).[9] However, The impact of this HIV RNA screening strategy on time to diagnosis and prevention of INSTI resistance has not been prospectively studied. In Australia, the use of HIV RNA tests is strictly regulated and no HIV RNA tests have been approved for HIV screening in the setting of HIV PrEP use. HIV RNA alone is not a diagnostic test for HIV in adults and a negative test does not rule out HIV. In addition, HIV RNA tests are not Medicare-rebated for HIV screening. The World Health Organization recommends that in-country guidelines should use the national HIV testing algorithm for HIV screening in people using CAB-LA PrEP,[10] and we have adopted this approach in these guidelines.

 

Suitability for CAB-LA PrEP

When the TGA approved the use of CAB-LA in at-risk adults and adolescents (at least 12 years of age and weighing at least 35 kg) for the prevention of sexually transmitted HIV infection, it stipulated that patients must have a documented negative HIV test prior to initiation of CAB-LA for PrEP. Patients have the option of a one-month oral cabotegravir lead-in phase prior to the first CAB-LA injection, or patients may opt to initiate directly onto CAB-LA injections without an oral lead-in.

Any registered medical practitioner, or nurse practitioner, can prescribe oral TD*/FTC for PrEP in Australia. The October 2023 Pharmaceutical Benefits Advisory Committee (PBAC) listed CAB-LA on the general schedule with streamlined authority, which will permit broad prescribing of CAB-LA PrEP in Australia.

The ASHM PrEP guidelines committee advocates for informed patient decision making when selecting a PrEP regimen, including daily oral PrEP (TD*/FTC or TAF/FTC), on-demand oral PrEP, and CAB-LA injectable PrEP.

The suitability criteria listed below are designed to assist practitioners to determine the suitability of CAB-LA PrEP for individual patients. Note that the effectiveness of CAB-LA PrEP has been studied only among GBMSM and cisgender women, not among cisgender heterosexual men, nor among people whose main HIV risk is intravenous drug use. However, there is no known reason why CAB-LA PrEP should not be effective in these populations, and hence these guidelines recommend that CAB-LA PrEP should be considered as an option for anyone who is at risk of HIV.

The following harm reduction strategies should additionally be offered to people who inject drugs:

  • Access to clean injecting equipment through “needle-and-syringe programmes”.
  • Access to take-home naloxone, which is available through pharmacies. This is relevant to anyone who uses opioids or anyone who is likely to witness opioid use, but also for people who inject other drugs that can be contaminated with opioids.

These first two suitability criteria are crucial for any patient considering CAB-LA PrEP:

  1. The patient is at risk of HIV if PrEP is not prescribed: See main PrEP guidelines for HIV risk guidance.
  2. The patient is currently HIV-negative: A recent negative HIV test result must be available prior to the first CAB-LA injection, ideally within the prior 7 days, or up to 4 weeks prior in a patient with no recent HIV risk (e.g. if they are adherent to oral PrEP, or not sexually active, in the past six weeks).

The following factors are relevant when assessing a patient’s suitability for CAB-LA PrEP:

  1. The patient has medical contraindications to oral TD*/FTC, such as renal impairment and/or low bone mineral density. Of note, most patients with these conditions will be able to safely use oral tenofovir alafenamide with emtricitabine (TAF/FTC), which is also approved by the TGA for daily oral PrEP, but not PBS-listed. TAF/FTC is expensive when purchased privately in Australian pharmacies, but can be imported affordably, under the TGA’s personal importation scheme (see main PrEP guideline section on TAF/FTC).
  2. For a PrEP-experienced patient, the clinician has documented prior and/or current difficulties adhering to oral PrEP.
  3. For a PrEP-naïve patient, the clinician anticipates that the patient will have difficulties adhering to oral PrEP due to medical, mental health and/or psychosocial factors.
  4. The patient reports potential barriers to adherence to oral PrEP. This may include difficulty remembering to take tablets, and concerns around privacy when needing to store PrEP tablets. The latter may be particularly relevant for people who live in shared accommodation, and who have not disclosed their sexual practices to their co-habitants, those who are experiencing homelessness, or those who may be at risk of intimate partner violence.
  5. The patient is willing to have an intramuscular injection every two months, recognising that these can be painful and associated with injection site reactions.
  6. The patient’s life circumstances can incorporate ongoing CAB-LA injection visits every two months. For example, it may be difficult to attend these visits for patients who travel frequently, or have limited financial resources or complex social/family dynamics. Importantly, planned missed visits can be bridged with oral cabotegravir tablets, but unplanned missed visits may result in HIV risk with the additional risk of cabotegravir resistance (see section on missed injection visits).
  7. The patient understands the concept of the long pharmacokinetic tail of CAB-LA, and once CAB-LA is ceased they will need to use some form of effective HIV prevention for at least twelve months after their final CAB-LA injection.

 

Contraindications to CAB-LA PrEP

Absolute contraindications to CAB-LA PrEP:

  1. HIV infection or unknown HIV status
  2. Insurmountable barriers that will likely prevent regular attendances for CAB-LA injection appointments
  3. Known hypersensitivity to cabotegravir or excipients in the tablets or injection formulation
  4. Drug-drug interactions. Cabotegravir is primarily metabolised by uridine diphosphate glucuronosyl transferase (UGT) 1A1, with some contribution from UGT1A9. Medications that are strong inducers of these enzymes will reduce efficacy of CAB-LA PrEP. For this reason, CAB-LA PrEP is contraindicated in people receiving rifampicin, rifapentine, phenytoin, phenobarbital, carbamazepine, or oxcarbazepine. CAB-LA PrEP users need to be informed of the risk of drug-drug interactions, and the need to inform other prescribers of their CAB-LA PrEP use prior to the initiation of any new medication. Further guidance is available from the HIV drug interaction checker from the University of Liverpool: https://www.hiv-druginteractions.org/checker

Other safety considerations:

  1. Renal impairment: Cabotegravir has a favourable renal safety profile, and no dosage adjustment is required for individuals with renal impairment who are not on dialysis.[11] Serum creatinine rises were observed in a small number of individuals receiving CAB-LA in HPTN-083 and HPTN-084, and hence these guidelines currently recommend monitoring of renal function (by serum creatinine and eGFR) during CAB-LA use, until more renal safety data are accumulated. In the event of a significant deterioration in renal function, prescribers are advised to seek advice from an experienced CAB-LA prescriber or a renal physician experienced with antiretrovirals.
  2. Hepatic impairment and toxicity: No dosage adjustment is required for individuals with mild to moderate hepatic impairment (Child-Pugh A or B). CAB-LA has not been studied in individuals with severe hepatic impairment (Child-Pugh C). These guidelines currently recommend monitoring of liver transaminase levels during CAB-LA use, until more liver safety data are accumulated. In the event of a significant deterioration in liver function, prescribers are advised to seek advice from an experienced CAB-LA prescriber or a hepatologist experienced with antiretrovirals.
  3. Hepatitis B virus (HBV) infection: Unlike some other HIV antivirals, CAB-LA has no activity against HBV. Hence, people who need both HBV treatment and HIV PrEP, should be recommended a HIV PrEP regimen that also treats HBV, such as daily oral TD*/FTC or daily TAF/FTC. Also, if people with HBV are switched to CAB-LA from daily oral TD*/FTC or TAF/FTC, this switch could result in a flare of their HBV infection. It is also important to consider that for people who have no immunity to HBV (i.e. who are HBsAb negative), CAB-LA will not offer protection against HBV infection, unlike TD*/FTC or TAF/FTC.[12] See the PrEP Guidelines section on HBV for further information.
  4. Hepatitis C virus (HCV) infection: CAB-LA has no activity against HCV. Every person diagnosed with HCV should be recommended to access HCV treatment using direct-acting antivirals (DAAs).
  5. Adolescents and children: The safety and efficacy of CAB-LA has not been established in children < 12 years of age or in people weighing less than 35kg.
  6. Elderly: No dosage adjustment is required in elderly individuals, but data are limited in individuals aged 65 years and over.
  7. Pregnancy: Category B1. Data on cabotegravir in pregnancy are limited, and the effect of CAB-LA on human pregnancy is unknown. Women and other people capable of childbearing should be provided with contraceptive advice prior to commencement of CAB-LA, and CAB-LA should only be used during pregnancy if the expected benefit justifies potential risks to the foetus. It should be noted that cabotegravir has been detected in systemic circulation for up to 12 months or longer after a CAB-LA injection.
  8. Hypersensitivity reactions: Rarely, use of other INSTIs has been associated with hypersensitivity reactions, which are characterised by skin rash and sometimes organ dysfunction, including liver injury. To date, no such reactions have been observed with CAB-LA.
  9. Patients with a history of buttock augmentation surgery will need to be assessed for the presence and location of implants to see if it is safe to commence CAB-LA. Injection of CAB-LA into an implant will render CAB-LA ineffective.
  10. HIV resistance mutations: If an individual initiates CAB-LA in the context of undiagnosed HIV, or if they acquire HIV during use of CAB-LA, then their HIV virus can develop resistance to cabotegravir, which may also confer resistance to other INSTI-based HIV treatments. See section titled “Managing HIV diagnoses during CAB-LA PrEP”.

 

Practicalities of delivering CAB-LA PrEP injections

Prior to administration of CAB-LA PrEP, clinicians should familiarise themselves with the administration instructions contained in the packaging.

Storage and transport of cabotegravir injections

CAB-LA vials can be stored at room temperature, and do not need to be refrigerated.

Self-administration

Self-administration of CAB-LA injections is currently not recommended.

 

Starting CAB-LA PrEP

ASHM recommends a two-appointment approach when initiating CAB-LA PrEP, but under certain circumstances it may be safe to initiate CAB-LA PrEP in a single appointment, as outlined below.

The two-appointment approach

Commencement appointment 1:

  1. Ascertain whether the patient would benefit from taking PrEP. See full ASHM PrEP guidelines for HIV risk guidance: https://prepguidelines.com.au/
  2. Assess suitability for CAB-LA PrEP, as described in the section “Suitability for CAB-LA PrEP”.
  3. If a patient wishes to commence CAB-LA PrEP, discuss the need to commit to having ongoing two-monthly injection visits and discuss how they might achieve this. For example, by setting recurring two-monthly phone reminders to make clinic appointments. Subsequent injections can be administered up to seven days before or after the scheduled injection date, and hence for some people it may be useful to set recurring reminders to occur seven days before the scheduled injection date, to provide a 14-day administration window.
  4. Assess for signs and symptoms of acute HIV infection (see https://prepguidelines.com.au/).
  5. Perform laboratory testing:
    1. Laboratory-based HIV serology. In the context of CAB-LA PrEP use, clinicians must not rely solely on point-of-care HIV rapid tests to determine HIV status, however, HIV point- of-care tests can be used as an adjunct to HIV serology for same-day initiation of CAB-LA (see below).
    2. Renal function testing by serum creatinine and eGFR.
    3. Liver function tests
    4. Screening for sexually transmissible infections and viral hepatitis, as specified in the Australian STI Management Guidelines - https://sti.guidelines.org.au/
  6. Consider as an option, the immediate commencement with the oral lead-in phase using cabotegravir tablets. The purpose of the oral lead-in phase is to exclude significant adverse effects prior to giving the first long-acting cabotegravir injection. However, because no significant safety concerns were identified during the phase III trials, this oral lead-in phase is optional. As further discussed under the heading “Same day initiation”, there are currently insufficient data to indicate that the oral cabotegravir lead-in phase will rapidly control a patient’s HIV risk, and those patients who require rapid HIV protection could immediately start oral TD*/FTC or TAF/FTC while preparing to commence CAB-LA injections.
  7. Provide the patient with a prescription for CAB-LA, in preparation for appointment 2.

Commencement appointment 2 – Preferably within a week after appointment 1

  1. Once the HIV test result is available, initiate injectable CAB-LA, ideally within one week after the HIV test is performed.
  2. Address any other abnormalities found on laboratory testing, e.g., sexually transmitted infections. If renal and/or liver function test results are abnormal, this need not delay initiation of CAB-LA injections, but should prompt appropriate investigation and follow-up. In the case of severe derangements of renal and/or liver function, the clinician may choose to defer commencing CAB-LA pending further investigations and then will need to explore alternative HIV prevention strategies with the patient in the interim.
  3. Administer cabotegravir 600mg IM into the ventrogluteal muscle using a needle that is long enough to deliver this into the intramuscular space. For patients with a body mass index (BMI) of less than 30 this can be achieved with a 1.5-inch (38mm) needle, but for patients with an BMI of 30 or greater this requires a 2.0-inch (50mm) needle.
  4. Educate the patient on how to manage injection site reactions (ISRs) (see section “Safety and Adverse Events”).
  5. Remind the patient that they may not immediately be protected against HIV. The time to optimal protection is unclear, but should be no more than a few days to one week.[6, 13] People who require immediate HIV protection may initiate or continue TD*/FTC or TAF/FTC simultaneously as CAB-LA, and continue TD*/FTC or TAF/FTC for one week after commencement of CAB-LA.
  6. Arrange the next visit one month after the first injection, to receive their second injection.

First follow-up – One month after first CAB-LA injection

  1. Review the patient’s satisfaction with CAB-LA, and review their understanding of the need for ongoing 2-monthly visits after this visit. If the patient does not wish to continue with CAB-LA, then discuss switching to oral PrEP using TD*/FTC or TAF/FTC.
  2. Assess for signs and symptoms of acute HIV infection.
  3. Order repeat laboratory-based HIV serology, eGFR and LFTs.
  4. Arrange an appointment in 2 months’ time for their next CAB-LA injection.

Same-day initiation

In some instances, it may be safe to initiate CAB-LA PrEP at a patient’s first visit. For example, a patient who has had no significant HIV risk or has been adherent to oral PrEP over the preceding six weeks, and whose HIV rapid point of care test is non-reactive on the day of initiation (while awaiting a laboratory HIV serology result).

If a same-day initiation approach is taken, then the patient needs to understand that they must return to the clinic immediately if their laboratory HIV serology returns a positive result, to consider immediate initiation of HIV treatment to avoid generating INSTI resistance mutations.

The patient needs to be informed that same-day initiation may not mean same-day protection, as the time to optimal protection is not known, and may be a few days to one week after initiation.[6, 13] People who need immediately effective HIV prevention can be offered immediate commencement of oral TD*/FTC or TAF/FTC at the same time as CAB-LA, and to continue oral PrEP for one week after starting CAB-LA.

Transferring from oral PrEP (TD*/FTC or TAF/FTC) to CAB-LA PrEP

ASHM recommends a similar approach to transferring from oral PrEP to CAB-LA PrEP as the approach outlined above, with some minor differences:

  1. Patients can continue to use oral TD*/FTC or TAF/FTC for PrEP until the day of their initial CAB-LA injection, instead of using an oral cabotegravir lead-in.
  2. Recent/current oral PrEP use can interfere with the accuracy of HIV tests, both standard serology and rapid tests, in terms of their sensitivity. Hence at the time of transfer to CAB-LA PrEP, clinicians should be careful to ask about PrEP adherence over the preceding six weeks.
  3. Patients with immediate HIV risk can consider continuing on oral PrEP for one week following commencement of CAB-LA.

 

Ongoing Monitoring During CAB-LA PrEP

The aims of laboratory and clinical monitoring during CAB-LA PrEP are similar to those of monitoring during oral PrEP, and consist of testing for HIV and STIs, and monitoring for adverse effects. The main difference between monitoring protocols for CAB-LA PrEP vs oral PrEP is that CAB-LA visits must occur every two months, whereas oral PrEP visits are recommended to occur every three months.

At each bimonthly CAB-LA monitoring visit:

  1. Review satisfaction with CAB-LA PrEP, and ongoing need;
  2. Perform laboratory-based HIV serology;
  3. Perform renal function (serum creatinine) and liver function testing;
  4. Administer CAB-LA injection.

In addition, patients should be offered STI and BBV screening at an interval relevant to their STI/BBV risk profile. For example:

  • For gay, bisexual and other men who have sex with men (GBMSM), including transgender men who have sex with men, and transgender women who have sex with men:
    • Offer STI testing either every visit (i.e. every two months) or every second visit (i.e. every four months), depending on the patient’s preference and STI risk profile. For these populations, in the context of increasing syphilis incidence and its associated morbidity, syphilis serology should be offered at every visit, with screening for chlamydia and gonorrhoea on swabs and urine less frequently.
  • For heterosexually active cisgender women and cisgender men:
    • STI screening is recommended at 6-monthly intervals, and consists of syphilis serology and screening for chlamydia and gonorrhoea, which may not need to be performed at all three anatomical sites. In populations with high rates of syphilis, it is recommended to perform syphilis serology every two months.
  • Hepatitis C antibody testing is generally recommended annually. For people who inject drugs, hepatitis C testing is recommended every six months. Anyone who has previously had a hepatitis C infection should be tested by HCV RNA rather than HCV Ab.

 

Managing Missed CAB-LA Injection Visits

If a patient misses a CAB-LA injection, and if they subsequently acquire HIV, then the low levels of serum cabotegravir may result in the selection of INSTI resistance mutations, which then limit HIV treatment options. As such, it is very important to proactively consider the possibility of missed injection visits, and plan to avoid their occurrence.

CAB-LA injections can be given up to 7 days before, or after the scheduled dosing date without being classed as “missed” injections, and for some patients it may be useful to plan to administer the injections one week early, so that the patient then has a two-week window to reschedule any missed appointments.

If the missed CAB-LA injection is the second injection (i.e. one month after the initiation injection), then:

  • If the CAB-LA injection is administered within 2 months of the initiation injection, then administer the injection and continue with 2-monthly dosing.
  • If the CAB-LA injection is administered more than 2 months after the initiation injection, then re-start the initial dosing schedule. As in, the next injection will be planned for one month after the re-commencement injection, then followed by resumption of the 2-monthly dosing schedule.

If the missed CAB-LA injection is the third or subsequent injection, then:

  • If the CAB-LA injection is administered within 3 months of the last injection, then administer the injection and continue with 2-monthly dosing.
  • If the CAB-LA injection is administered more than 3 months after the last injection, then re-start the individual on one CAB-LA injection, followed by a second CAB-LA injection one month later, then resume the 2-monthly dosing schedule.

If a patient misses their CAB-LA injection appointment by more than 7 days after the 2-month mark, and if this break is not covered by oral PrEP (either cabotegravir, TD*/FTC or TAF/FTC), then they should have a repeat HIV test before re-starting CAB-LA injections, and another HIV test one month after re-starting CAB-LA injections.

If a patient plans to miss their next injection appointment, for example because they are planning a long overseas holiday, then they can be supplied with cabotegravir tablets (30mg) to be taken once daily, starting two months after their last injection visit (i.e. when due for their next CAB-LA injection), for a duration of up to two months, and up until their next injection visit. If the planned break from injections is greater than two months (i.e. more than four months between injection visits), then an alternative oral PrEP regimen is recommended, such as oral TD*/FTC or TAF/FTC, to be continued until the day of their next CAB-LA injection visit.

Following an interruption to 2-monthly CAB-LA dosing, if the time since their last CAB-LA injection is longer than 3 months, then they should follow the re-initiation protocol: re-start the individual on one CAB-LA injection, followed by a second CAB-LA injection one month later, then resume the 2-monthly dosing schedule. This applies even if their interruption was covered by either cabotegravir tablets or oral TD*/FTC or TAF/FTC.

 

Planning for Cessation of CAB-LA PrEP

Patients who wish to cease CAB-LA PrEP should be reminded of the long pharmacokinetic tail of CAB-LA, and hence the risk of developing INSTI resistance mutations if they acquire HIV during the twelve months after their last injection. Patients should be advised to use oral PrEP during the twelve months following their last CAB-LA injection if they have ongoing risk of HIV acquisition.

The following strategy is recommended for people with ongoing HIV risk to mitigate the risk of developing drug-resistant HIV after stopping CAB-LA PrEP:

  1. Two months after their last CAB-LA injection, commence an alternative form of PrEP. For example, people at risk who are frequently sexually active could use daily oral TD*/FTC or TAF/FTC; while people at risk who are infrequently sexually active could use on-demand TD*/FTC for sexual activities that may place them at risk of HIV (but only if they meet the suitability criteria for on-demand PrEP, as outlined in the PrEP guidelines).
  2. In the rare instance when a patient cannot tolerate either daily or on-demand TD*/FTC or daily TAF/FTC, consistent use of condoms is the preferred HIV prevention method.
  3. Attend every three months for HIV serology, for at least 12 months after their last CAB-LA injection.

 

Managing an ambiguous HIV result during CAB-LA PrEP

An ambiguous or inconclusive HIV result may occur when a 4th generation Ag-Ab screening test is reactive and confirmatory testing, such as a Western Blot, is indeterminate. This may be due to recent infection or may represent a false-reactive result. Urgent HIV nucleic acid amplification testing is required to determine the individual’s HIV status, especially in the setting of CAB-LA PrEP use.

  1. Ask the patient to return to the clinic as soon as possible.
  2. If the CAB-LA prescriber is not an experienced HIV prescriber, then they should seek immediate advice from a local tertiary HIV service or an expert HIV clinician.
  3. The prescriber is advised to speak to the testing laboratory to confirm which follow-up tests should be requested when the patient returns to the clinic. This will likely include a dedicated whole blood sample for HIV proviral DNA and/or qualitative HIV RNA testing. Also consider collecting a whole blood sample for a HIV genotype resistance assay (GRA) including INSTI mutations, in case the HIV result is confirmed to be a true positive.
  4. When the patient returns to the clinic:
    1. Explain the inconclusive HIV result and need for further testing.
    2. Perform further testing as advised by the laboratory.
    3. Discuss the possibility of immediate commencement of protease inhibitor-based treatment (e.g. Symtuza®), while awaiting confirmatory results. This will require discussion with a tertiary HIV service, as 3-drug antiviral regimens are only available on the PBS for people with confirmed HIV, and a private prescription is likely to be cost-prohibitive.
    4. Offer the patient linkage to a counsellor or peer-support organisation.
    5. Arrange clinical review once further HIV testing results are available.
  5. Liaise with the laboratory to advise that specimens are being sent for urgent testing and request urgent notification of results as soon as they are available.
  6. If 4th generation Ag-Ab testing is reactive and HIV is confirmed by detection of HIV via nucleic acid amplification testing (proviral DNA and/or qualitative RNA), the patient should be managed as a new diagnosis of HIV as discussed in the section below.
  7. If HIV is not detected via nucleic acid amplification testing (proviral DNA and/or qualitative RNA), a plan for close laboratory follow-up and the ongoing PrEP regimen should be made with a multidisciplinary team, including the local tertiary HIV service or expert community-based HIV clinician and the testing laboratory.

 

Managing an HIV Diagnosis during CAB-LA PrEP

In Australia an HIV diagnosis is made when a person has a positive HIV Ag/Ab test result which is confirmed by either a Western blot, or HIV nucleic acid testing (RNA or DNA), or with p24 Ag testing.

Please see the section above for the management of those patients who have an ambiguous HIV test result.

Managing a new HIV diagnosis during CAB-LA PrEP use may present a challenge for the clinician because evolution of HIV test results may be delayed by the presence of cabotegravir, and the patient may have developed resistance to the INSTI drug class. ASHM recommends the following approach to managing HIV diagnoses during CAB-LA PrEP use, or in the twelve months following a CAB-LA injection in someone who has ceased CAB-LA PrEP.

  1. Ask the patient to return to the clinic as soon as possible.
  2. If the CAB-LA prescriber is not an experienced HIV prescriber, then they should seek immediate advice from a local tertiary HIV service or an expert HIV clinician.
  3. When the patient returns to the clinic:
    1. Explain the HIV result.
    2. Arrange for further testing, including a repeat HIV serology, plasma HIV RNA testing, CD4 lymphocyte count and HIV genotype resistance assay including INSTI mutations. Liaise with the receiving laboratory to ensure that the correct types and quantities of pathology tubes are collected.
    3. Either immediately commence 3-drug therapy using a PI-based regimen (e.g., Symtuza®), or arrange for urgent review by an expert HIV clinician. Do not wait for the additional test results to become available before initiating treatment.
    4. Offer the patient linkage to a counsellor or peer-support organisation.
    5. Arrange clinical review one week later to review progress.

 

REFERENCES

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  2. Landovitz, R.J., et al., Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women. N Engl J Med, 2021. 385(7): p. 595-608.
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  8. Eshleman, S.H., et al., HIV RNA Screening Reduces Integrase Strand Transfer Inhibitor Resistance Risk in Persons Receiving Long-Acting Cabotegravir for HIV Prevention. J Infect Dis, 2022. 226(12): p. 2170-2180.
  9. US Public Health Service. Preexposure Prophylaxis for the Prevention of HIV Infection in the United States – 2021 Update Clinical Practice Guideline. 2021; Available from: https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2021.pdf.
  10. World Health Organization. Guidelines on long-acting injectable cabotegravir for HIV prevention. 2022; Available from: https://www.who.int/publications/i/item/9789240054097.
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