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Cabotegravir’s FDA breakthrough designation along with adaptive strategies being deployed are the biggest stories in HIV prevention this year.
Last month, the US Food and Drug Administration (FDA) granted a Breakthrough Therapy Designation for cabotegravir for HIV pre-exposure-prophylaxis (PrEP).
This designation was based on efficacy and safety results from the HPTN 083 trial. This trial was a phase 2b/3 randomized, multicenter, double-blind, study which compared long-acting, injectable cabotegravir to a daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF, Truvada) 200 mg and 300 mg for HIV prevention among transgender women, men who have sex with men, and women who are at an increased risk of contracting HIV.
In the final analysis, cabotegravir showed it was 66% more effective at preventing HIV when compared to FTC/TDF tablets. This translated to an HIV incidence rate of 0.41% in the cabotegravir group (95% CI, 0.22%-0.69%) and 1.22% in the FTC/TDF group (95% CI, 0.87%-1.67%) in a study population of 4566 participants.
In a partner HIV prevention trial, HPTN 084 (The LIFE Study), which has been evaluating the safety and efficacy of cabotegravir compared to daily oral FTC/TDF, for PrEP in HIV-uninfected women, it showed even greater efficacy in this patient population. This is the first study of the long-acting injectable for HIV prevention among women.
The study involved 3223 women, ages 18-45 years old, in 20 sites across 7 countries in sub-Saharan Africa (Botswana, Kenya, Malawi, South Africa, eSwatini, Uganda, and Zimbabwe).
A Data Safety Monitoring Board met on November 5 to discuss the trial, and found impressive data to change the course of part of the trial.
“They recommended halting the blinded phase of HPTN 084 because of cabotegravir’s superiority demonstrated over Truvada,” Alex Rinehart, PhD, senior director, Global HIV Prevention Strategy at ViiV Healthcare, said.
Rinehart pointed out the there was a total of 38 HIV infections that occurred in the trial with 34 of those in the Truvada group and 4 of those in cabotegravir group, resulting in an 89% reduction of the number of infections in the trial.
When this news emerged, Carlos Del Rio, MD,tweeted his excitement: “A game changer” in speaking about the therapy. Del Rio is a distinguished professor of Medicine at Emory University School of Medicine and the executive associate dean for Emory at Grady. He is also professor of global health and epidemiology at the Rollins School of Public Health and co-director of the Emory Center for AIDS Research and co-primary investigator of the Emory Vaccine and Treatment Evaluation Unit.
Rinehart reports the overall safety profile was very good and the injections were well-tolerated with only a very small percentage (2.5%) of injection site reactions who reported a grade 2 or higher. These were considered mild to moderate, and none of the participants stopped the trial for injection site reactions.
In terms of the potential benefits of taking cabotegravir over traditional PrEP therapies, Rinehart points out the simplicity of adherence and the privacy aspects of taking the injection every 8 weeks.
“They are discreet…we are talking about taking 6 injections a year as opposed to having to take a pill every day,” Rhinehart said. “This is a really big issue for women because they are able to protect themselves and not have to negotiate HIV prevention with their partners.”
The aforementioned studies are part of the HIV Prevention Trials Network, which is a global, collaborative network of clinical trials, and they bring together investigators to develop and test interventions for HIV.
The breakthrough designation makes it easier for the FDA and the cabotegravir’s manufacturer, ViiV Healthcare, to collaborate and work towards cabotegravir’s approval. “We are looking forward to working closely with the FDA to make this prevention option available to people at risk of acquiring HIV,” Kimberly Smith, MD, MPH, senior vice president, head of Research & Development for ViiV Healthcare, said.
HIV Care Challenges
While an exciting, new therapy such as cabotegravir is in late-stage development, barriers to PrEP care remain. Studies have shown challenges including access and adherence, despite the advancement in therapy and clinical care.
In Africa, PrEP users in 3 Sub-Saharan countries were found to cycle on and off the medication, according to a large study. These findings were presented at the International AIDS Society (IAS) AIDS 2020 Virtual Sessions earlier this year.
This study looked at 41,459 patients in Kenya, Lesotho, and Tanzania. Their PrEP regimen included daily dosing that was not event driven. Amongst these 3 countries, 10,809 (26.1%) discontinued and subsequently restarted PrEP at least once, with 20.7%, 27.5%, and 51.8% remaining off of PrEP for <30, 30-60, and 61+ days, respectively.
These findings show PrEP users are not doing indefinite, continuous use, which would suggest it’s not the goal of the patients according to the investigators.
This is an issue that is also being experienced in the United States. In the study, PrEP Continuum of Care and New HIV infections: Long-Term Follow-Up in a Large Clinical Cohort, which was conducted by the Kaiser Permanente San Francisco Medical Center, they witnessed adherence issues as well. The investigators followed people for several years starting from when they were identified as being potential beneficiaries of this therapy.
“When we did have drop off in the PrEP continuum, and they were lost in follow-up, it was primarily in the first year. After the first year of treatment, most people maintained and stayed on the medication,” Jonathan Volk, MD, MPH, infectious disease clinician, Kaiser Permanente San Francisco Medical Center, and study investigator, said.
He said there was a 27% drop off within the first year.
In an interview with Contagion earlier this year, Volk spoke of the many steps needed to start and continue on a PrEP regimen including receiving a prescription, having it filled and starting therapy.
If these steps are not done, they noted this could lead to HIV infections.
“There were two keys steps where we lost folks on the continuum and we had preventable HIV infections that we observed,” Volk noted. “The first was the link to care where they had a PrEP referral and they had a clinical encounter where they never received a prescription. The second were patients who were linked to care, started on treatment, and later stopped.”
In both of these groups, Volk noted they saw a more than 1% HIV infection rate in the follow-up period.
In the study, investigators also reported that Blacks were less likely to receive a prescription, less likely to initiate PrEP, and more likely to discontinue PrEP.
Volk also noted access to care issues. For example, he said the cost of prescriptions and their perceived costs as being barriers to PrEP. However, with this latter barrier, many people do not realize they can get assistance for their prescriptions.
“PrEP, this last year, received a grade A recommendation from the US Preventative Task Force and because of that, we are able to offer PrEP free of charge to almost all of our patients,” Volk stated.
As such, he says more awareness is needed to overcome this barrier to care.
Obviously, with the COVID-19 pandemic, it has been challenging to do in-person clinic visits. As such, Kaiser Permanente has adapted to virtual visits and secured emails with patients.
With these online visits and email communications, Volk said they are talking with patients about PrEP and initiating it remotely.
One of the other proactive strategies they are putting in place is the ability to identify potential PrEP beneficiaries earlier.
“We are trying to identify people further upstream from linkage to care,” Volk stated. “These might be people who are candidates for PrEP but are not being linked to care.”
They are looking to achieve this in part by examining electronic medical records of their patients and taking the existing HIV prediction model and expanding the number of variables within the model to identify new potential patients for PrEP.
Volk said new variables include whether patients have had STI testing, medication prescriptions for erectile dysfunction and penicillin, and mental health diagnosis. The new prediction model has over 40 variables.
“We were able to identify about 50% of our incidence infections in our male populations by flagging our top 1% or 2% risk course in our population,” Volk said. “One of things that was very exciting for us was this model performed equally as well for our Black patients as it did in our White patients in terms of predicting HIV risk.”
Volk said one of their projects was to take this new prediction model and put it in the primary care setting, so it can help facilitate discussions between patients and clinicians and specifically linkage to care for PrEP when appropriate.
These types of conversations between clinicians and patients can help chip away at traditional care barriers such as access and adherence, and move towards getting more people who could benefit from PrEP therapy in the care continuum.