Infectious Disease

Medication ‘added a lot of energy to HIV prevention’

September 09, 2022

11 min read

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Marrazzo, Pai, Smith and Thompson report no relevant financial disclosures. Volberding reports serving on data safety and monitoring boards for Gilead and Merck.

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More than 40 years ago, on June 5, 1981, a report of five cases of Pneumocystis pneumonia among young men in Los Angeles marked the first account of what would come to be called AIDS.

More than 30 years into the fight, on July 16, 2012, the FDA approved HIV PrEP, which became a “game-changer” in the decades-long fight to end the pandemic because it created confidence in HIV prevention without requiring major behavioral changes, said Infectious Disease News Chief Medical Editor Paul A. Volberding, MD, professor emeritus of medicine at the University of California, San Francisco.

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“PrEP has been an essential tool to disentangle the stigma and shame of sexual behavior associated with HIV risk from attaining sexual health,” said Infectious Disease News Editorial Board Member Jeanne M. Marrazzo, MD, MPH, director of the division of infectious diseases at the University of Alabama at Birmingham.

“PrEP is not only very effective when used correctly at preventing HIV, it can provide a justified sense of security in people’s ability to express themselves sexually and ensure that they, and their partners, are protected from HIV,” Marrazzo said.

Still, disparities in access to PrEP persist, and uptake has suffered because of that and other issues, including stigma.

We spoke with experts on the 10-year anniversary of the approval of PrEP to discuss the progress and problems surrounding its use.

“While PrEP is highly effective in reducing HIV acquisition, it’s impact is much less than it should have been over a decade,” Melanie Thompson, MD, Infectious Disease News Editorial Board Member and past principal investigator of the AIDS Research Consortium of Atlanta, said.

Approval and uptake

In 2010, The New England Journal of Medicine published results from the iPrEx trial — the first randomized controlled trial of PrEP — in which around 2,500 men or transgender women who have sex with men received either emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) or a placebo each day. Data from the trial, which ran nearly 2 1/2 years, showed that the HIV infection rate was 44% lower in the group that received PrEP. Additionally, men who reported they were able to take the pill daily had a 73% lower infection rate.

Additional favorable data from blood levels of medication showed that when taken daily, PrEP reduces the risk for HIV by more than 90%.

“PrEP added a lot of energy to HIV prevention,” Dawn K. Smith, MD, MSc, MPH, an epidemiologist and medical officer in the CDC’s Division of HIV Prevention, said. “While we wait for an effective vaccine, there was this sense before PrEP came along that we were sort of stuck in a rut. Then, suddenly, we had this new intervention which is highly effective.”

Dawn Smith

Today, there are two pills approved for use as PrEP in the United States — FTC/TDF and FTC/tenofovir alafenamide, which is not approved for people at risk for HIV through receptive vaginal sex because they were not included in the study population. Additionally, the FDA last year approved cabotegravir as the first long-acting injectable for HIV PrEP to prevent getting HIV through sex.

The CDC says PrEP reduces the risk of getting HIV from sex by about 99% when taken as prescribed. Although there is less information about how effective oral PrEP is among people who inject drugs, the CDC says it reduces the risk for HIV by at least 74% when taken as prescribed.

Infectious Disease News Editorial Board Member Gitanjali Pai, MD, AAHIVS, FIDSA, an infectious disease physician at Memorial Hospital and Physicians Clinic in Stilwell, Oklahoma, and chief medical officer for the Oklahoma State Department of Health, explained that although all PrEP-related milestones have been important, one of the most important milestones occurred slowly over time — increased uptake.

In 2018, 7 years after it was approved, PrEP was used by fewer than 20% of the people in the U.S. who could benefit from it, Pai said. In 2020, according to the CDC, approximately 25% of the 1.2 million people for whom PrEP is recommended were prescribed the drug — up from only 3% in 2015.

Gitanjali Pai

“Slow but incremental increases in use of PrEP over the years are important milestones when correlated with the efforts for popularizing and adherence, funding, government support and, of course, the reduction in HIV infection,” Pai said.

Globally, data presented at the HIV Research for Prevention virtual conference in 2021 showed that PrEP uptake increased sixfold from 2016 through 2020, although it still remained short of the UNAIDS target of 3 million users and annual growth slowed over time.

Paul Volberding

“I’m surprised, in retrospect, that it took so long for PrEP to catch on,” Volberding said. “We got used to thinking of HIV as a complicated, very difficult to treat infection, so I think the ease of PrEP almost made people hesitate.”

Equity

Despite being a proven intervention, PrEP rollout was and remains uneven because of challenges associated with implementation, scale-up and adherence, leading to serious discrepancies between populations who could benefit most from PrEP and those currently accessing it, experts said.

Data presented this year at the International AIDS Conference showed worsening disparities in PrEP uptake. The study used commercial pharmacy data to count PrEP users by race and U.S. Census region from 2012 to 2021. Overall, the data demonstrated that the PrEP-to-need ratio (PnR) — a metric of PrEP equity — increased from 2012 to 2021 for all races and regions, but levels of PrEP use were not consistent across regions and were not equitable by race/ethnicity.

Specifically, the study showed that across all regions, PnR was highest for white people and lowest for Black people. By region, the highest region- and race-specific PnR was for white people in the Northeast in 2021 (48.7), whereas it was only 4.2 for Black people.

“Sadly, this is not news,” Thompson said. “This is in line with multiple other health disparities, including rates of new HIV diagnoses in Georgia, where 73% of new diagnoses are among people who are Black.”

Melanie Thompson

Thompson said structural racism, homophobia and transphobia “create social disparities that worsen access to care and trust in health entities.”

Other studies over the last decade have shown that some of these populations have experienced persistent uptake, adherence and equity issues.

Many studies have shown that populations disproportionately impacted by HIV were less likely to be engaged in PrEP to begin with. One study showed that African Americans, Latino individuals, women and individuals with substance use disorders were less likely to receive a PrEP prescription (HR = 0.74, 0.88, 0.56 and 0.88, respectively) as well as initiate PrEP (HR = 0.87, 0.9, 0.71 and 0.88, respectively) compared with white people. These groups were also more likely to discontinue PrEP if they initiated it (HR = 1.36, 1.33, 1.99 and 1.23, respectively).

One study — the first to assess PrEP abandonment at retail pharmacies in the U.S. — found that almost 9% of patients aged 16 years or older failed to pick up their prescriptions in 2019. The study also showed that prescriptions were abandoned more often by patients who were newly prescribed PrEP (12.9%) compared with established patients (4.5%); women (13.3%) compared with men (8.1%); patients aged younger than 25 years (11.2%) vs. patients aged 65 years or older (14.3%); people who paid with cash (64.5%) or through a drug assistance program (13.2%) vs. other third-party payers; and patients with a copayment exceeding $500 (30.3%) compared with those with a lower copayment.

“Some of our most serious concerns are the racial and ethnic disparities in PrEP use. They’re not getting better over time, and we are working hard to understand how we can reverse that trend,” Smith said. “If we’re talking about ending the HIV pandemic, it can’t be done without also ending the disparities in PrEP use.”

‘Plenty of stigma to go around’

Across most populations facing these issues is a root problem — stigma.

“There are so many stigmas that are affecting all kinds of HIV issues,” Smith said. “I don’t think it’s possible to say what effect HIV stigma or racial and ethnic stigma or gay stigma or any of the other stigmas have had specifically on PrEP, except that PrEP and treatment and testing are all interventions occurring in a time when there is plenty of stigma to go around.”

Regardless, experts agreed that stigma has played a persistent role in preventing many populations from initiating and adhering to PrEP regimens.

“Stigma additionally drives reluctance even to get tested for HIV, much less to take medication to protect against HIV,” Thompson said.

There have been other obstacles to PrEP uptake over time. Thompson said Gilead Sciences was initially reluctant to aggressively market the medication over concerns of liability if people seroconverted on PrEP.

“I’m not one who generally thinks that pharmaceutical advertising is a positive thing, but this was a huge obstacle to broadcasting the good news about PrEP,” she said.

Clinician awareness

Clinicians play a role in making sure patients have all the information they need to make decisions about HIV prevention, especially because patients become more interested in PrEP the more they know about it, according to Pai.

“Patients have been more open and willing to consider this option, whereas in the past, there was ignorance as well as hesitancy,” Pai said, adding that one of her biggest concerns surrounding PrEP has been a lack of awareness among health care providers about it.

“This has direct bearing on offering this option to patients,” she said. “Health care providers are a trusted resource for patients, and hence it’s critical that providers stay abreast of PrEP options for their high-risk populations.”

Studies have demonstrated the need for clinicians to step in and help improve PrEP awareness and uptake, particularly among the most vulnerable populations.

The results of a survey published last year revealed systematic biases against people who inject drugs among primary and HIV care providers that may impact patients’ access to PrEP. Researchers surveyed 370 primary and HIV care providers, asking them to review a fictitious medical record of a patient seeking PrEP. The records varied by patient race and risk behaviors. Overall, the responses demonstrated that clinicians judged people who inject drugs as less responsible, less safety conscious and less likely to be adherent to PrEP. Additionally, responses showed there were limited biases based on sexual orientation and no evidence of biases based on race.

Another study by experts in the CDC’s Division of HIV Prevention used 2019 testing data from a CDC-funded national HIV prevention program to measure PrEP awareness and referrals among Hispanic/Latino patients. According to the study, more than 2.34 million CDC-funded HIV tests were conducted in the U.S. that year. Among patients with PrEP-related data, PrEP awareness was slightly higher among Hispanic/Latino people (27.4%) than Black people (26.2%; prevalence rate [PR] = 1.05; 95% CI, 1.04-1.06), but lower compared with white people (31.4%; PR = 0.87; 95% CI, 0.87-0.88). Hispanic/Latino people were more likely to be referred to a PrEP provider (22%) compared with Black people (20.8%; PR = 1.06; 95% CI, 1.04-1.07) but less likely compared with white people (25.9%; PR = 0.85; 95% CI, 0.84-0.86).

“Patients can’t seek it if they are not aware of it,” Pai said.

According to Smith, conversations with patients regarding PrEP have gotten easier and more productive over the course of the decade.

“During the initial conversations, PrEP was a new thing and we spent a lot of time explaining the trial results and explaining how PrEP worked, really getting deep into the science before even offering it to the patients,” she said.

Smith said these conversations put patients at ease, informing them that they could receive a cutting-edge new therapy. On the other hand, it also may have conveyed a sense that the medication was still experimental — something that was “amplified by people who were not really fans of PrEP.”

“Conversations with patients got a little more complicated from there because they would say, ‘Well, I read this online’ or ‘I heard this person say,’ or, ‘Well, there’s a lawsuit about this,’” Smith said.

Luckily, she added, conversations are much more straightforward now.

“It’s a much more streamlined conversation now and much more focused on helping patients to understand what the potential benefit of PrEP is,” she said, “and then to support them in getting the financial coverage for PrEP, adhering to PrEP, and coming in for their follow-up visits.”

Smith said physicians have a better understanding of what PrEP is and how to best offer it to patients. In discussions with clinicians, she often likens it to counseling patients who are prediabetic. These patients are advised to watch their diet, get more exercise and lose weight. However, they are also prescribed metformin to help delay the onset of diabetes itself.

“By giving providers those kinds of examples, we have helped them understand that you need to take a sexual history in a nonjudgmental manner, and if a person is engaging in risky behaviors, they should be offered PrEP,” she said. “It’s not a clinician’s job to judge their life,” she said.

Long-acting options

Another recent development has the power to potentially impact the future of PrEP, experts said — long-acting injectable options.

“Long-acting PrEP is the need of the hour, and there has been an increasing interest in long-acting PREP, for which we do now have an available option,” Pai said. “It can be highly effective by contributing to improved adherence, which is the crux of its efficacy.”

In December 2021, the FDA approved ViiV Healthcare’s cabotegravir as the first long-acting injectable for HIV PrEP. The medication, known as Apretude, is administered every 2 months after two initial injections that are given 1 month apart.

The FDA approved it for at-risk adults and adolescents weighing at least 77 pounds after study findings assessing transgender women, cisgender men who have sex with men and cisgender women showed cabotegravir administered every 8 weeks prevented HIV infection.

Jeanne Marrazzo

“At best, long-acting PrEP has the potential to be the equivalent of a vaccine,” Marrazzo said.

Volberding concurred, saying the future of PrEP absolutely includes these long-acting approaches.

“Ideally, you would like a very long-acting oral PrEP, but I think the experience has so far been that long-acting injections are well tolerated and well accepted by people,” he said.

Thompson said injections are not right for everyone but many people hate taking a daily pill and adherence has always been “the Achilles’ heel of PrEP.”

“The big challenge is equitable access. The price is extraordinarily high, especially compared with generic TDF/FTC,” she added.

Thompson also noted that PrEP in pill form can be mailed to patients and taken at home, whereas injectable PrEP requires an office visit and a trained professional to give the shots.

“The burden on the health system is greater, and the recipients must be able to go somewhere to receive the injections more frequently than they would usually make visits,” she said. “We identify and treat a lot of STIs in persons on PrEP, and we also can’t drop that service for people on injectables.”

In terms of cost, ViiV announced during a press conference at the International AIDS Conference that it signed a voluntary licensing agreement with the Medicines Patent Pool to grant selected generic manufacturers the opportunity to develop, manufacture and supply generic versions of long-acting cabotegravir in 90 countries.

“There’s still a lot of work to do,” Volberding said. “I think that’s going to be a big part of what happens next because many of the same issues that drive interest in long-acting PrEP in the U.S. and other wealthy countries are going to be the same that drive it in other places.”

Smith said there are other forms of PrEP in the research pipeline that will likely become available over time and will increase patients’ options.

“I hope the future will be bright,” Thompson said.

 

References:

Calabrese SK, et al. AIDS Behav. 2021;doi:10.1007/s10461-021-03495-3.

CDC. HIV – PrEP effectiveness. https://www.cdc.gov/hiv/basics/prep/prep-effectiveness.html. Accessed on Aug. 21, 2022.

FDA approves first drug for reducing the risk of sexually acquired HIV infection. https://www.hiv.gov/blog/fda-approves-first-drug-for-reducing-the-risk-of-sexually-acquired-hiv-infection. Posted July 16, 2012. Accessed Aug. 21, 2022.

FDA approves first injectable treatment for HIV pre-exposure prevention. https://www.fda.gov/news-events/press-announcements/fda-approves-first-injectable-treatment-hiv-pre-exposure-prevention. Published Dec. 20, 2021. Accessed Aug. 21, 2021.

Grant RM, et al. N Engl J Med. 2010;doi:10.1056/NEJMoa1011205.

HIV.gov. A timeline of HIV and AIDS. https://www.hiv.gov/hiv-basics/overview/history/hiv-and-aids-timeline. Accessed Aug. 29, 2022.

Hojilla JC, et al. JAMA Netw Open. 2021;doi:10.1001/jamanetworkopen.2021.22692.

Huang YA, et al. Clin Infect Dis. 2021;doi:10.1093/cid/ciac009.

McCormack S, et al. Lancet. 2016;doi:10.1016/S0140-6736(15)00056-2.

Rao S, et al. MMWR Morb Mortal Wkly Rep. 2021;doi:10.15585/mmwr.mm7040a1.

Segal K, et al. Abstract 1346. Presented at: HIV Research for Prevention; Jan. 27-28 and Feb. 3-4, 2021 (virtual meeting).

Sullivan P, et al. Abstract LBX0106. Presented at: International AIDS Conference; July 27-Aug. 2, 2022; Montreal (hybrid meeting).

 

For More Information:

Jeanne M. Marrazzo, MD, MPH, can be reached at jmarrazzo@uabmc.edu.

Gitanjali Pai, MD, AAHIVS, FIDSA, can be reached at gpai@stilwellmemorial.com.

Dawn K. Smith, MD, MSc, MPH, can be reached at media@cdc.gov.

Melanie Thompson, MD, can be reached at drmt@mindspring.com.

Paul A. Volberding, MD, can be reached at paul.volberding@ucsf.edu.

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