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An Advocates’ Primer on Long-Acting Injectable Cabotegravir for PrEP

Understanding the Initial Results of HPTN 083 & HPTN 084

April 2021

In 2020, two large-scale efficacy trials found that a long-acting injectable form of pre-exposure prophylaxis (PrEP) provided high levels of protection among people at risk of HIV. Long-acting injectable cabotegravir (CAB-LA) was studied and showed a substantial prevention benefit in gay men and other men who have sex with men, transgender women who have sex with men, and cisgender women. CAB-LA, developed by ViiV Healthcare, is also being used as part of a combination of injectable antiretrovirals for HIV treatment. This document focuses on CAB-LA as PrEP, outlining what’s known and what’s next for this emerging biomedical HIV prevention strategy.

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Table of Contents

TOP-LINE FINDINGS TO DATE

  • In two trials, injections of CAB-LA every two months was safe and substantially lowered HIV risk.
  • In these trials, some people received daily oral PrEP. There were also very low rates of new HIV infections in people taking daily oral PrEP.
  • Both the oral and injectable PrEP strategies worked. Because of the way that the trials were designed, CAB-LA is sometimes described as “superior” to daily oral PrEP.
  • Of the 12 infections in people in HPTN 083 receiving CAB-LA injections, four happened in people who had received all of the injections as scheduled and who had protective drug levels in their blood. When the trial team looked at stored samples, they determined that these four cases were diagnosed using standard HIV testing several weeks after infection actually occurred. It is possible that different diagnostics (tests) will need to be used as this injectable strategy is rolled out.
  • The risk of integrase inhibitor-resistant HIV—at least in HPTN 083—was greater when people acquired HIV while taking CAB-LA as prescribed than it was in people who stopped receiving the injection, i.e., in the context of the “tail”. These resistant mutations were not seen in three people who acquired HIV after stopping injections, but while the drug was still present (i.e., in the “tail phase”). Similar data from HPTN 084 are not yet available.

TOP-LINE ADVOCACY MESSAGES AND QUESTIONS

  • Both oral PrEP and CAB-LA were safe and effective in the trials. Each has unique characteristics, and individuals may prefer a particular PrEP method for any number of reasons. Ensuring informed choice is key. Injectable CAB-LA for PrEP is another strategy to help reduce HIV risk. For some people it will be the right one; for others, daily oral PrEP, the Dapivirine Vaginal Ring or another non ARV-based approach will be right.
  • Adherence still matters—a lot. For CAB-LA, people will need to “adhere” to clinic visits every two months. For oral PrEP, multi-month dispensing could allow less-frequent visits. The most effective product is the one that people use correctly and consistently during their periods of risk.
  • “Superiority” is a statistical term used in clinical trial design and in analyzing results. The term doesn’t reflect which method is best for an individual.
  • Additional testing strategies may be needed for introduction. Limited data to date show that in people on CAB-LA HIV infections can happen, and that standard HIV tests may not detect these infections at the time that they occur. Subsequently, integrase inhibitor-resistant virus can emerge. While the numbers are very small, these findings suggest that CAB-LA will need to be introduced in the context of additional HIV testing strategies, including viral load testing, and with assurance that treatment regimens that are not based on an integrase inhibitor are readily available. In many countries, the shift to dolutegravir-based regimens for first-line therapy has moved programs away from procurement of non-integrase inhibitor-based first-line drugs. Activists and advocates will need to hold countries, ViiV and funders accountable for responsible implementation that also accounts for persistent gaps in access to viral load testing for people living with HIV.
  • Access is critical. ViiV, the product developer for CAB-LA, has not yet set a price for the CAB-LA injection. A recent cost-effectiveness analysis presented at the 2021 Conference on Retroviruses and Opportunistic Infections shows that the injection must be priced in the range of generic daily F/TDF (also known as TDF/FTC or Truvada) to be considered cost effective in comparison to oral PrEP. Advocates must demand pricing transparency and a commitment to investing in choice, not just the cheapest interventions.
  • Planning for expanded access to all PrEP strategies must now accelerate. To support oral PrEP use in the context of COVID-19, some programs have adopted multi-month prescriptions, community-based pickup, telehealth for adherence support, and self-testing, where feasible. These best practices should be made standard.
  • Choice matters. As the PrEP field expands beyond oral F/TDF to include oral F/TAF (also known as TAF/FTC or Descovy), the Dapivirine Vaginal Ring and CAB-LA, clear messages on all available and future options are essential. Key factors to explore include how best to support effective use, side effects, long-term safety, use in pregnant and breastfeeding women and other people who are pregnant and lactating, use in people who inject drugs (PWID) and more.
  • No one can be left behind. It’s vital to expand access to PrEP among diverse populations at risk of HIV.

What is CAB-LA?

Cabotegravir is an antiretroviral drug (ARV) developed by ViiV Healthcare and formulated as an injectable for long-lasting pre-exposure prophylaxis (PrEP). It is an integrase inhibitor, the same class of drugs that includes the widely-used treatment drug dolutegravir.

Injectable cabotegravir in combination with injectable rilpivirine has been developed as a treatment option to maintain virologic suppression in people living with HIV. The combination has been approved for treatment use in Canada and the US. This document focuses on CAB-LA for prevention.

Where are the CAB-LA trials for prevention happening, and in what populations?

Two large-scale efficacy trials, HPTN 083 and HPTN 084, are testing CAB-LA as PrEP. Smaller sub-studies are gathering additional data on the use of CAB-LA in adolescents, who were not included in the original studies. See table below.

HPTN 083 is ongoing in 4,570 cisgender men who have sex with men (MSM) and transgender women at sites in the Americas, Asia and South Africa. Over 50 percent of trial participants in the US identify as Black, and 12 percent are transgender women. Two-thirds of participants are 30 years old or younger. This study has been particularly effective at recruiting a younger and more diverse participant population. Similar efforts should be funded and prioritized across HIV prevention trials.

HPTN 084 is ongoing in nearly 3,200 cisgender women at sites in Botswana, Eswatini, Kenya, Malawi, South Africa, Uganda and Zimbabwe. Fifty-seven percent of participants are 18-25 years old, with an average age of 26. Fifty-five percent reported two or more partners in the past month, with 34 percent having a primary partner who is reported to be living with HIV or having an unknown HIV status.

efficacy study design Ongoing CAB-LA trials

What questions do HPTN 083 and 084 answer?

HPTN 083 and 084 were designed to evaluate two primary questions:

  • How safe is CAB-LA delivered every two months (preceded by a month of oral cabotegravir) when compared to daily oral F/TDF?
  • How effective is this method compared to daily oral F/TDF for HIV prevention?

HPTN 083 is a non-inferiority trial—a study that compares a new product (CAB-LA) and an approved product (oral PrEP with TDF/FTC) to determine if the new product is just as safe and effective—or “non-inferior” —to the approved product. As part of the trial design, statisticians and regulators set criteria for whether the experimental product is as good as or better than a proven strategy.

HPTN 084 is a superiority trial—a study that compares two products, asking if the experimental product is safe and statistically even more effective than an approved product.

There are additional sub-studies within HPTN 083 and 084 as well as a separate study in pregnant women that will allow researchers to gather additional information. See the table above.

What data have been shared from HPTN 083 and 084?

What data have been shared from HPTN 083 and 084?

Efficacy

HPTN 083
On May 14, 2020, the study’s Data and Safety Monitoring Board (DSMB) met as scheduled for a periodic evaluation of data on participant safety, study conduct and progress, and efficacy. Because the study results were trending so strongly at that time toward positive findings on safety and efficacy, the DSMB recommended that the results be reported, that participants be told which active drug (CAB-LA or F/TDF) they were receiving, that the placebo products be dropped from the study, and that participants be given the option to choose either product through the end of the study, as soon as sufficient CAB-LA drug supply is delivered to study sites. Advocates should track that this supply becomes available as soon as possible, with no unnecessary delays in access to CAB-LA for all trial participants who want it.

On March 9, 2021, at the Conference on Retroviruses and Opportunistic Infections, Raphael Landowitz, an investigator on HPTN 083, presented extensive analysis of the study data, including rates and timing of infections in both study arms. He reported that there were 12 HIV infections in the CAB-LA arm (incidence rate 0.37%) and 39 in the F/TDF arm (incidence rate 1.22%). The trial team also reported on the hazard ratio, which is a comparison of the probability of an event, in this case HIV infection, in one group (CAB-LA recipients) versus another (people using daily oral F/TDF). The final calculation showed a hazard ratio of 0.32 (95 percent confidence interval of 0.16-0.58), which corresponds to a 68 percent reduction in incidence rates in study participants randomized to receive CAB-LA compared to F/TDF. This finding met the pre-specified criteria for concluding that CAB-LA was superior to daily oral PrEP in reducing HIV risk amongst the trial population.

Among the 39 people who acquired HIV in the F/TDF arm of HPTN 083, 37 had levels of tenofovir diphosphate (a form F/TDF takes when it has been processed in the body) that were classified as suboptimal or non-adherent. The trial did not compare HIV infection rates in people adherent to daily oral PrEP compared to those receiving the injection. CAB-LA is “superior” to daily oral PrEP when people do not take PrEP pills correctly and consistently.

HPTN 084
On November 5, 2020, the study’s DSMB met as scheduled for a periodic evaluation of data on participant safety, study conduct and progress, and efficacy. The data showed that CAB-LA injected every two months was superior to daily F/TDF. The DSMB recommended that all trial participants be told which active drug (CAB-LA or F/TDF) they were receiving, that the placebos be dropped from the study and that participants be given the option to choose either product through the end of the study. HPTN has said “participants taking active F/TDF who wish to use CAB-LA will be able to do so as soon as it is available.” Advocates should track that this supply becomes available as soon as possible, with no unnecessary delays in access to CAB-LA for all trial participants who want it.

In HPTN 084, 38 women acquired HIV. In that group, four were in the CAB-LA study arm (incidence rate of 0.21 percent) and 34 were in the F/TDF arm (incidence rate of 1.79 percent). The hazard ratio for the CAB-LA versus F/TDF arms was 0.11 (95 percent confidence interval: 0.04-0.32), which corresponds to an 89 percent reduction in incidence among those who received active CAB-LA compared to those who received F/TDF. As with the 083 trial, researchers have not determined whether CAB-LA is inherently more effective than daily oral PrEP or whether the differences in infection rates has to do with product use, and potentially low adherence, in people taking daily oral PrEP.

Safety

HPTN 083
CAB-LA and oral F/TDF were both safe and well-tolerated in HPTN 083. Injection-site reactions, raised body temperature, fever, swollen nasal passages and elevated blood pressure were more common in participants in the CAB-LA arm. Reduced kidney function was the most common side effect in participants receiving oral F/TDF. The most commonly cited adverse event was injection-site reactions, with 80 percent of those in the CAB-LA arm reporting at least some injection-site reaction versus 30 percent of those who received the placebo injection. This discomfort led a small percentage of participants—about two percent of those receiving active CAB-LA—to stop injections and discontinue their participation in the study.

HPTN 084
CAB-LA and oral F/TDF were also both safe and well-tolerated in HPTN 084. Mild to moderate pain or tenderness at the injection site was more common among participants in the CAB-LA arm (32 percent) as compared to those receiving the placebo injection of CAB-LA (nine percent). There were no discontinuations due to injection-site reactions. Gastrointestinal disorders and nausea were more common in the F/TDF arm.

Rates of other sexually transmitted infections

Participants in both arms of HPTN 083 had high rates of other sexually transmitted infections, including new diagnoses of syphilis, chlamydia and gonorrhea, during the course of the trial. This is consistent with STI rates in the context of oral PrEP use both inside and outside of clinical trials. This finding reinforces the need for all PrEP strategies to be delivered in the context of comprehensive, integrated services that include counseling, basic healthcare, contraception and other sexual and reproductive health services, and linkages to HIV treatment and care as needed.

Role of adherence

Adherence to oral PrEP in the 083 study was reasonably good. A sub-study of 372 people randomly selected from the F/TDF study arm showed that 87 percent had detectable drug levels and 75 percent had detectable drug levels consistent with daily dosing. Adherence data on those in the F/TDF study arm who acquired HIV during the trial are being analyzed and are not yet available. Adherence to CAB-LA is known, since participants received the injection at the study sites. Three of the 13 participants in the CAB-LA arm acquired HIV during the oral lead-in phase; analysis is ongoing to understand how drug levels and other factors affected HIV risk in this arm.

HPTN 084 also conducted a sub-study on adherence, evaluating 362 participants from the arm of the study receiving F/TDF. The trial has so far reported that drug levels suggest that the study population was more adherent to F/TDF than had been anticipated, conferring even higher protection against HIV for those taking F/TDF than was planned for in the trial design. Analysis is ongoing to understand drug levels of both cabotegravir and F/TDF among those who acquired HIV.

What adherence support was provided in each trial?

Oral PrEP adherence in both HPTN 083 and 084 was higher than has been observed in many other trials and programs. Both trials employed a model that the study teams dubbed “best real-world adherence” to support consistent and correct oral PrEP use in the study. The model draws from in-country adherence tools and is designed to be practical for clinical sites globally. It featured an adherence module deployed at every visit, with enhanced resources for participants who met prespecified criteria for additional support or in cases where the participant or study team thought additional support would be beneficial. This level and type of support seemed to be quite effective—above and beyond the findings related to CAB-LA—and should be adapted to support oral PrEP programs.

When is a licensure application for CAB-LA for prevention expected?

ViiV, the developer of CAB-LA, publicly stated its commitment to file for regulatory approval for all populations at risk and are in the process of compiling data and discussing pathways with various regulatory agencies, focused initially on countries where the trials took place, for a submission in mid-2021. ViiV has said that it is speaking with the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), the South African Health Products Regulatory Authority (SAHPRA) and the WHO, all agencies that have a role to play in regulatory approvals for, guidance on and introduction of CAB-LA. With possible expedited review by the FDA, CAB-LA for prevention could be approved as soon as early 2022—at least two years earlier than was originally envisioned, given the early results from HPTN 083 and 084. This means that introduction planning by all stakeholders is happening in a compressed timeline.

AVAC and its partners have a range of ongoing engagements to ensure swift and ethical introduction of a full range of biomedical strategies. We are working alongside cisgender, MSM and transgender activists to demand that ViiV create standing civil society advisory boards to review questions and share updates. We are also working in coalition to ensure that donors and countries begin now to map out their product introduction strategies and funding needs for guidelines development, provider training and communication, and that PEPFAR and the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) fund these strategies. AVAC is also working to establish a novel, multi- stakeholder mechanism to plan for rapid introduction and access to a range of products. The Biomedical Prevention Implementation ColIaborative (BioPIC) has helped to convene over 100 stakeholders to advance a common agenda for CAB-LA introduction that is intended to move the field more swiftly in introducing this and future products than it did with oral PrEP.

If approved, when will CAB-LA be available and what will it cost?

The earliest an approval is expected is 2022. ViiV has not specified or estimated the cost of the injection per dose, an omission that makes it difficult for advocates to mobilize demand for this new strategy. A recent cost- effectiveness analysis presented at the 2021 Conference on Retroviruses and Opportunistic Infections shows that the injection must be priced in the range of generic daily F/TDF to be considered cost-effective in comparison to oral PrEP. AVAC and its civil society allies will be working to demand pricing transparency, with an emphasis on setting a cost that supports widespread use in PrEP programs in low- and lower-middle-income countries and a commitment to investing in choice, not just the least expensive interventions. AVAC and its allies are also working through the PEPFAR annual planning processes and GFATM and UNAIDS strategy development processes to secure investments in prevention “platforms” that are equipped to deliver oral PrEP, injectable PrEP and the Dapivirine Vaginal Ring—and to ensure that there is transparency about the budget lines available for each of these commodities and related program activities.

If approved, how might countries, programs and individuals integrate a range of biomedical options, including oral PrEP, CAB-LA and the Dapivirine Vaginal Ring?

Biomedical primary prevention is at a historic turning point, but only if countries and funders heed evidence-based demands that programs should emphasize choice rather than individual products.

Informed choice must be the governing principle that guides policy and planning for access to the array of proven options for HIV prevention. Informed choice means setting ambitious targets and funding plans for integrated contraceptive and HIV services. Programs need the capacity to innovate, adapt and offer the full range of proven products. Countries, normative agencies, implementers and funders must work with civil society to meet these needs.

What is the CAB-LA “tail”, and how will it figure into potential regulatory approval and use of CAB-LA?

The tail refers to a time period after injections have stopped, but a slowly-diminishing amount of cabotegravir remains in the body of someone who received CAB-LA injections. Per WHO, “these small amounts of drug may not be enough to protect against HIV infection and could result in development of drug resistant HIV following exposure during this time. It is not yet understood if this long pharmacokinetic tail will have any significant effect on drug resistance.”

Data from HPTN 083, presented at CROI in March 2021, showed that resistance happens among people taking CAB-LA but not necessarily during the “tail”. There’s been real concern about drug resistance arising in people who acquire HIV during the tail. But in the three people who fell into this category in HPTN 083, none had HIV with genetic mutations that render it resistant to integrase inhibitors, the class of drug that includes cabotegravir. This number is too small to support conclusions about the risk of resistance, but in this handful of people, resistance didn’t emerge during the tail.

When integrase inhibitor resistance did emerge in HPTN 083 participants, it was in people who were infected and also receiving the injections: one of the people who had HIV at the time of enrollment developed resistance, as did two people who acquired HIV during the oral lead-in phase (a trial period where individuals took the pill form of CAB-LA before receiving the injection, to ensure that the drug was well-tolerated). Two people who acquired HIV while receiving CAB-LA injections also developed integrase inhibitor resistance; two others had so little virus in their blood that the team could not get a resistance test. The take-home message—at least from HPTN 083—is that the risk of resistance is greater when people acquire HIV while taking CAB-LA as prescribed than it is in people who’ve stopped receiving the injection, i.e., in the context of the “tail”.

Part of the regulatory process will entail outlining and investing in plans and systems to monitor adverse effects and resistance (i.e., post-marketing surveillance). Advocates must demand transparency and interrogate ViiV’s pharmacovigilance plans.

CAB-LA, pregnancy and breastfeeding

More research is needed to understand CAB-LA and the tail for women and people who are pregnant or breastfeeding. A number of participants in 084 became pregnant during the study. While no negative impacts on the health of the mothers or babies were reported, the study was not designed to answer questions about pregnancy and health. Because this trial was not large enough to detect any rare adverse events, ongoing research will be needed to determine whether CAB-LA is safe for people who are pregnant or breastfeeding. More information may come through the open-label extension studies, and any ultimate licensure for CAB-LA should include guidance for people who are pregnant or breastfeeding.

How did COVID-19 affect the trials (e.g., timing of visits)?

Each trial site adjusted the study procedures to respond to COVID-19 based on guidance from their local ethics committees. Some sites had to close, but in many locations the trial staff were able to implement policies that allowed the studies to remain open, including pausing enrollment (in HPTN 084), limiting the number of staff or participants at trial sites and adding new safety protocols. Remote access through Zoom or phone calls facilitated follow-up visits outside of the clinic, and some sites delivered study products to participants. Despite the challenges, these innovations enabled the sites to maintain the integrity of their data.

Why is the oral lead-in optional in the HPTN 083 and 084 open-label extension trials?

Because an injection can’t be removed from the body once it’s administered, researchers began each of the CAB-LA efficacy studies, HPTN 083 and 084, with a short-acting pill of the drug that would be easy to stop taking if participants experienced a reaction. Once participants had taken the pill for about one month, they switched to the injection. That oral “lead-in” period helped ensure participant safety. There were no major reactions in participants during the oral lead-in during the trials.

The final word on safety usually involves more people treated over a greater length of time than exists yet for any form of cabotegravir, and some investigators, providers or participants may not be comfortable skipping the oral lead-in. Making the oral lead-in an option is the next safe, logical step. As more data are collected, the oral lead-in should become increasingly unnecessary. Whether an oral lead-in will be recommended by regulators remains to be seen.

What do HPTN 083 and HPTN 084 data mean for the standard of prevention in HIV prevention trials?

In the recently updated Ethical considerations in HIV prevention trials, WHO and UNAIDS state that, “When new HIV prevention methods are scientifically validated and recommended by WHO, they should be added to the standard of prevention as soon as is practically possible based on consultation among relevant stakeholders, including community stakeholders.”

As WHO considers its recommendations for CAB-LA, the field must resolve how to integrate CAB-LA (as well as the Dapivirine Vaginal Ring) into trials’ standard of prevention, the package of interventions every participant in HIV prevention trials receives to help reduce their risk of HIV. Activists and advocates will, as always, need to guide decisions.

Does either trial provide insight into how a CAB-LA-based PrEP strategy compares to F/TAF?

In October 2019, the US FDA approved a second form of oral PrEP that uses the drugs F/TAF (also known as TAF/FTC or Descovy). This second tenofovir-based oral PrEP strategy is currently approved for daily PrEP in the US for people at risk of HIV, excluding those at risk via vaginal sex. Because HPTN 083 and 084 compared CAB-LA to oral F/TDF only, the data cannot tell us anything definitive about how CAB-LA might compare to oral PrEP with F/TAF.

What is, or should be, happening now?

  • AVAC’s advocacy team and partners, including COMPASS, CASPR, Advocacy Fellows and others, are working with cisgender African women and allies to 1) hold ViiV accountable for comprehensive, ongoing community engagement; 2) ensure that PEPFAR, GFATM and UNAIDS strategies and 2021 plans include investments in the policies and programs needed to support comprehensive prevention; and 3) advance an agenda that ties CAB-LA to contraceptive and sexual and reproductive health and rights programs and to the activism and priorities of LGBTQ+ and other key populations.
  • The Biomedical Prevention Implementation Collaborative (BioPIC) is advancing planning for well-designed, well-timed and well-funded product introduction and supporting global and country decision-makers in this effort. Funded by the Bill & Melinda Gates Foundation as part of the AVAC and CHAI HIV Prevention Market Manager project, BioPIC spearheaded an overall introduction strategy. Central to this strategy will be a funded operational research agenda to find out how health systems can be strengthened to deliver CAB-LA should it be approved for use; to establish how best to support community and individual access to and demand for CAB-LA; and to learn what the product and the programs to deliver it might cost and which funders might support this. BioPIC is also exploring how this approach can be adapted to jump-start planning for other HIV biomedical prevention products in development.
  • WHO and UNAIDS, both of which are participating in BioPIC, must work together to lead the development of clear messages, normative guidance, access plans and scale-up plans for PrEP programs, emphasizing the need for informed choice.

WHAT CAN ADVOCATES DO NOW?

  • Talk to your community. What do the results mean for them? Understanding specific questions and concerns will help frame advocacy priorities. Help communities understand the results of 083 and 084, the significance of CAB-LA as an experimental long-acting product that is currently only available in the context of a clinical trial, the regulatory process and the importance of scaling up oral PrEP programs in the meantime.
  • Demand funding, targets and innovation to support equitable oral PrEP access, with modifications for COVID-19 contexts. The best understood, proven strategy is still not available to all who need it. Multi-month prescriptions, self-testing and user-centered services are essential.
  • Hold decision-makers on CAB-LA accountable. Is there clarity about next steps? Are there targets and milestones in place? Is there adequate funding to support rollout? How might decisions be made about who would get the product first, if it’s licensed and introduced through phased rollout?
  • Work locally with research sites. Bring your advocacy know-how to sites for planned and ongoing research to ensure that communication, access and continued work meet your needs.
  • Track the supply of CAB-LA at trial sites to prevent unnecessary delays in access to CAB-LA for all trial participants who want it.

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