HIV/AIDS treatment: Improving the trajectory for all stakeholders

HIV/AIDS viruses. credit: Institute for Bioscience and Biotechnology Research (IBBR)

Since its reign of terror began in the early 1980s, human immunodeficiency virus (HIV) has infected at least 76 million people worldwide. According to the World Health Organization (WHO), by the end of 2017, HIV-related disease had claimed 35 million lives worldwide, and today nearly 37 million people are living with HIV. In the US, there were 991,000 living with HIV in 2016, according to the latest CDC data, and there were 38,281 new diagnoses in 2017. Worldwide, there were 1.8 million new diagnoses in 2016, per WHO—5,000 new infections daily.

According to IQVIA, total spending on HIV drugs has more than tripled since 2007 (2017 figure: $20.6 billion), outpacing the roughly 60% growth in overall drug spending over the same period. In 2017, HIV was the disease category with the highest pharmacy spend for Medicaid, the third highest for health exchange plans, and the fifth highest for commercial plans, according to Express Scripts’ 2017 Drug Trend Report. [1]

In that HIV infection is transmissible, it represents a public health issue as well as one that affects individual patients. The lack of a cure puts the onus on healthcare providers, as well as the patients themselves, to maintain high levels of adherence to the existing antiretroviral therapies (ARTs). ARTs reduce the “viral load” of a patient to levels where the opportunistic infections that characterize AIDS (autoimmune deficiency syndrome) appear, and prevent transmission to others through exchange of bodily fluids (blood, semen, vaginal secretions, breastmilk).

Confronting the epidemic

There are three legs to the HIV “stool”: quickly diagnosing and controlling the viral load of HIV-positive patients; deploying preventive measures to ward off infection in HIV-negative persons, especially for “high risk” individuals; and continuing the search for a cure.

In the 37 years since HIV/AIDS became recognized among developed nations, dozens of vaccines or other treatments have been tested for eliminating the HIV virus, with little to show for it. Nevertheless, efforts continue at organizations like GeoVax, Janssen Pharmaceutical (a subsidiary of Johnson & Johnson) and Gilead Sciences, among others. A publicly funded HIV Vaccine Trials Network (HVTN), headquartered at Seattle’s Fred Hutchinson Cancer Research Center, is currently managing 18 active clinical trials for preventive HIV vaccines, of which three are largescale, in-human efficacy trials. The current research direction focuses on a type of biotechnology, “broadly neutralizing antibodies” (bNAbs), that has shown promise; another avenue is genetic manipulation by inserting DNA into a virus vector to elicit an antiviral response.

According to the Resource Tracking for HIV Prevention Research & Development Working Group [2], funding for HIV vaccines peaked in 2006 at $961 million, but is still running strong in 2017, with funding at $845 million globally (the US, through combined public and private funding, is responsible for 74% of the funding). It is worth noting that, according to the Working Group data, research on vaccines and other preventive steps has been running at around $1 billion per year since 2006, but a cure is still only a goal, not an accomplishment.

ART-the second leg

Lacking a cure, the medical response to HIV is a complex regimen of lifelong treatments: antiretroviral therapy (ART). In the1990s, when the first effective HIV drugs appeared, the approach was to combine several drugs as a “drug cocktail” that could significantly interfere with HIV replication in the patient, and these cocktails continue to be the standard of care.

Because HIV replicates swiftly, creating rapidly evolving variants with mutations that confer resistance to antiretroviral drugs, the traditional approach has been to combine several antiretroviral agents from different therapeutic classes — and an ever-expanding array of novel combinations of them. Today more than 30 different antiretroviral medications have been approved, across a diverse array of therapeutic classes: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNTRIs), protease inhibitors, integrase inhibitors, fusion inhibitors and chemokine receptor antagonists.

However, poor adherence remains one of the biggest obstacles in HIV, and part of the reason is the complexity associated with taking a multi-drug regimen every day and the burden of managing cost issues and side effects. Keeping up with this routine every single day for the rest of their lives creates an enormous physical, psychological and emotional burden on HIV patients, and can depress health outcomes for patients.

“When you ask a person to start a regimen to take medicine every single day for the rest of their lives, any subtle problem becomes cumulative and can really wear them out,” says Steven Deeks, MD, Professor of Medicine in Residence at the University of California (San Francisco), and faculty member in the Div. of HIV, Infectious Diseases and Global Medicine at Zuckerberg San Francisco General Hospital. “Insurance runs out, side effects or toxicity arise, people have a midlife crisis and life intervenes so you stop taking your medicine. Any improvement can help — one pill is much easier to take than two or three, and any ability to reduce side effects like nausea and diarrhea can significantly improve adherence to therapy.”

“Poor adherence under messy real-world conditions also dilutes strong clinical trial data related to clinical efficacy and safety, potentially undermining trust in the medication among both physicians and patients,” says John Doyle, SVP & GM, Real-world & Analytic Services, IQVIA, and faculty member, Department of Epidemiology, Mailman School of Public Health, Columbia University.

Single-pill treatment options

Over the past year, several of the leading drug developers in HIV have received regulatory approval for HIV treatments that aim to combine two or three antiretrovirals from different therapeutic classes into a single pill, to streamline and simplify the medication regimen for patients, and in some cases, reduce side effects, toxicity and overall costs.

While different pharma manufacturers will argue the relative benefits of their particular antiretroviral pairings and will argue the merits of using two versus three antiretrovirals in a single pill, the overall trend toward single-pill treatment options offers a simpler, more convenient lifelong treatment regimen, which has the potential to improve long-term adherence to therapy. “Such improvements in convenience not only have a qualitative effect for the patient, but have potentially enormous economic and public health implications, as well, since improved adherence is critical for keeping HIV patients healthy (thereby offsetting other long-term healthcare costs) and reducing their risk of transmitting the virus,” says Doyle.

“When patients with HIV are forced to manage complex, multi-drug regimens, they run the risk of partial adherence, which, if undetected by the attending physician, is worse than complete non-adherence. Doyle continues: “With HIV, partial adherence can lead to the emergence of drug-resistant strains, dilutes the clinical efficacy findings demonstrated in clinical trials, undermines the real-world economic impact of the drug, and not only impacts not only the long-term health of the patient, but can put sexual partners and others at risk, by allowing the transmission of HIV infection that could have been avoided by proper medication adherence.”

Among the recently approved multi-drug, single-pill treatment options in HIV:

• October 2018 — GlaxoSmithKline (GSK) subsidiary Viiv Healthcare used a Priority Review Voucher (PRV) to expedite FDA approval of its two-drug, single-tablet HIV treatment combining dolutegravir and lamivudine. The tropical disease PRV — which FDA had granted to GSK earlier in July 2018 when GSK won approval of a new malaria drug Krintafel (tafenoquine) — allows ViiV to get an expedited FDA review of its new investigational HIV combination pill, cutting four months from the standard 10-month review process.

• August 2018 — Merck received FDA approval for Delstrigo (doravirine/lamivudine/tenofovir disoproxil fumarate), a once-daily, fixed-dose combination tablet, and Pifeltro (doravirine), a new addition to the non-nucleoside class NNRTI.

• August 2018 — Gilead’s Genvoya (elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide), a single tablet regimen, received regulatory approval from China National Drug Administration; US approval occurred in 2016.

• July 2018 — Johnson & Johnson subsidiary Janssen Pharmaceuticals received FDA approval for the once-daily combination medicine Symtuza, which combines darunavir (an HIV-1 protease inhibitor), cobicistat (a CYP3A inhibitor) and emtricitabine and tenofovir alafenamide (two HIV-nucleoside analog reverse transcriptase inhibitors).

• March 2018 —Mylan NV received FDA approval for its triple-combination once-daily treatment Symfi (efavirnenz, lamivudine and tenofovir disoproxil fumarate). The FDA nod was the third the company has earned for single-pill combination treatments for HIV, following Cimduo (lamivudine and tenofovir disoproxil fumarate) and Symfi Lo (efanvirenz, lamivudine and tenofovir disoproxil fumarate)

• February 2018 — Gilead received FDA approval for Biktarvy, a single-pill therapy that combines three antiretrovirals (bictegravir and emtricitabine/tenofovir alafenamide)

• November 2017 — ViiV Healthcare partnered with Johnson & Johnson subsidiary Janssen Pharmaceuticals to launch Juluca (dolutegravir and rilpivirine)

• June 2017 —GSK and Viiv applied another PRV it had acquired in a $130-million transaction (with a company it has not revealed), to speed FDA approval of its single-tablet treatment combining dolutegravir and rilpivirine

Today, the ability to prescribe these streamlined multi-drug regimens in a single-pill format is already being credited with helping to reduce the overall drug spend in HIV. For instance, according to the Express Scripts 2017 Drug Trend Report [1], while HIV represents the largest spend category among the top 15 therapy classes for Medicaid, Express Scripts notes that within the Medicaid drug spend, the use of HIV drugs in 2017 decreased by 7.6% from the prior year — thanks in part to greater use of the newer combination therapies, which require fewer separate prescriptions.

Breaking the grip of daily medications

In addition to efforts to commercialize single-pill options for daily medication, considerable effort is also underway in the HIV arena to develop longer-acting therapies that could be taken weekly, monthly and even yearly. Such efforts are based on the use of longer-acting drugs and non-pill form drug-administration options, such as transdermal patches, injections and slow-dosing biodegradable and refillable drug implants that would carry a month or even a year’s worth of drug payload. To facilitate efforts in this regard, the NIAID has established the LEAP program — for Long-Acting/Extended release Antiretroviral Resource Program — which includes a consortium of scientists and clinicians from academia, industry and government, as well as patient advocates.

“There is already a lot of precedent in other chronic disease states where going from a daily dose regimen to a weekly or longer-duration dosing provided adherence-related and economic advantages,” notes Doyle of IQVIA.

In August 2018, Viiv Healthcare released Phase III trial results for its investigational monthly or bi-monthly injectable HIV treatment, which combines two antiretrovirals — its own cabotegraviv (an integrase inhibitor) with Janssen’s rilpivirine (a non-nucleoside reverse transcriptase inhibitor), with promising results. If it receives FDA approval in 2020, this formulation would be the first long-acting injectable HIV treatment option — a game changer allowing patients to manage 12 treatment days per year, rather than managing their medications every day.

Pep for PReP

The third leg of the HIV stool is to prevent HIV infection in the first place. An important innovation toward this end came in 2012 when Gilead’s Truvada (a single-pill regimen that combines emtricitabine and tenofovir disoproxil fumarate) was approved as the first so-called Pre-Exposure Prophylaxis (PrEP) treatment option against HIV. It is indicated for “high-risk” HIV-negative men and women whose sexual and injection-drug-use behaviors increase their risk of acquiring HIV. To date, Truvada remains the only approved PrEP option.

When taken consistently, PrEP has been shown to reduce the risk of HIV infection by 92%, according to CDC. Similarly, according to a recent retrospective study of Truvada use across all 50 states and the District of Columbia, which was released by Gilead in July, the company found that the 10 states with the highest utilization of Truvada had a significant decrease in the average number of new HIV diagnoses (down by 47% during the study period 2012 to 2016), while the 10 states with the lowest rate of Truvada use experienced a 1% increase in new HIV diagnoses over that span. [3]

Despite Truvada’s widely demonstrated clinical effectiveness, healthcare advocates note that this PrEP option is grossly underutilized. Such findings “demonstrate that if we can scale up PrEP use in a targeted way to people who need it most, we can see a dramatic reduction in new infections rapidly. That’s a game changer,” said James Krellenstein, a founding member of the Prevention of HIV Action Group at advocacy group ACT UP/New York, and co-founder of the PrEP4All Collaboration, at the time Gilead’s retrospective study was released.

PrEP remains underutilized for a variety of reasons, with cost being one of the more prominent ones; the prescription cost runs about $20,000 annually. For instance, a recent CDC study [4] indicates that in 2016, Truvada was prescribed to only 7% of the estimated 1.1 million persons who were eligible to receive it, including just 2.1% of women with PrEP indications — indicating a missed opportunity with significant health outcomes and economic consequences. Disparities by racial background are also recognized: while roughly 11% of PrEP users were African-American, that group constitutes 40% of two-thirds of high-risk HIV persons. “CDC data on PrEP use indicates that while the use of PrEP is increasing, it’s not increasing fast enough,” says Ya-lin Huang, PhD, Health Scientist with CDC’s Division of HIV/AIDs Prevention, and author of the study. “More than 90% of people who could benefit from PrEP are not getting it.”

“These data should be a call to action to address the social and structural reasons for lower access and uptake and not exacerbate the already unacceptable racial/ethnic HIV disparities in the US,” adds Hyman Scott, MD, Research Scientist at Bridge HIV and Assistant Clinical Professor of Medicine at the University of California (San Francisco). “We need a comprehensive approach to increase PrEP use, from tailored inclusive marketing campaigns, interventions that focus on PrEP education and uptake, improved navigation to providers, and structural interventions to reduce care system barriers to improve access to PrEP. The cost of PREP continues to be a barrier for many people to start and stay on PrEP, especially in the event they change or lose insurance.”

Overlooked in this debate is the fact that if everyone at risk of HIV everywhere had PrEP access, HIV could effectively be eliminated in a manner comparable to childhood vaccinations or polio. “One of the most fundamental things we – pharmacists, providers, manufacturers, anyone within healthcare – can do is educate the public on how easy it is to control the spread of HIV with one single, daily tablet. In fact, we could almost eliminate the transmission of HIV around the world,” says Kevin deMass, RPh, the owner of Apothecary Shoppe, a Salt Lake City, UT, pharmacy that supports over 650 HIV patients. (Apothecary Shoppe is a member of the Good Neighbor pharmacy network, operated by wholesaler AmerisourceBergen; DeMass is also a member of the Good Neighbor Pharmacy National Advisory Council of that firm.)

The awareness part of this dilemma is recognized: DeMass notes that he and his wife recently went to see Bohemian Rhapsody, the biopic about Queen lead singer Freddie Mercury, who was HIV-positive. “Before the movie, a Gilead commercial from its new marketing campaign for Truvada, called ‘I’m on the Pill,’ played and educated the audience about PrEP,” he says. “Everyone sitting in that theater was learning about PrEP, and I had goosebumps. I was so excited because the problem with PrEP is that no one knows about it.”

Who pays?

According to 2016 IQVIA data, 55% of HIV patients are supported by public insurance, while commercial insurance covers 42% (the remainder pay out of pocket). The public component comprises a range of programs: Medicare (for the elderly); Medicaid (for the indigent) and—specific to the HIV population—ADAP, the state or federally funded AIDS Drug Assistance Programs, which started in the aftermath of the passage of the Ryan White Comprehensive AIDS Resources Emergency (CARE) Act in 1990; state programs followed shortly after, and exist in 21 states.

The cost of providing medications for HIV/AIDS patients can range from a few thousand to approximately $40,000 per year, depending on whether generic or branded products are prescribed and the condition of the patient. (The latest trend in this regard is to treat the combination of HIV and hepatitis C infection—a condition affecting about a quarter of HIV patients.) The PrEP program is another element—it is for high-risk individuals yet who do not have the HIV virus, and the criteria by which an insurer is willing to fund this treatment varies significantly.

From a pharmacy-benefit management (PBM) perspective, the first option would naturally be to mandate generic products. However, since the value of combination therapies, as well as the value of less-frequently administered drugs on improved adherence (both of which tend to be higher-cost branded products), have been proven, the reflexive use of generics is questionable.

Here’s how the HHS Panel on Antiretroviral Guidelines, a group of medical specialists and patient advocates, put it in their latest update [5]:

To the extent that pill burden, rather than drug frequency, results in reduced adherence, generic ART could lead to decreased costs but at the potential expense of worsening virologic suppression rates and poorer clinical outcomes. Furthermore, prescribing the individual, less-expensive generic components of a branded coformulated product rather than the branded product itself could, under some insurance plans, lead to higher copays—an out-of-pocket cost increase that may reduce medication adherence.

A more dramatic perspective comes from pharmacist Kevin DeMass. “HIV patients have some of the most complicated therapy regimens of any population, and single pill antiretrovials significantly reduce their pill burden, making it easier for them to stay on treatment. For example, a relatively healthy HIV patient’s current antiretroviral therapy may require them to take two tablets of three different drugs twice per day – or 12 pills daily. It’s likely that patient may also be on medications for anxiety, depression, diabetes, hypertension and high-cholesterol, meaning he or she could be on a regimen of at least 25+ pills per day. If we can combine the patient’s antiretrovirals into one tablet, we can reduce that pill count by nearly half. And, we eliminate 11 opportunities to miss a critical dose.”

Surrounding the private and public insurance programs are an array of charities, foundations and advocacy groups, many of which provide financial support, and a good bit of that having pharma-industry funding in the background. Among the bewildering array of prescribing options, PBM formulary provisions and charitable support, HIV patients have a lot to deal with beyond taking their meds.

References

• http://lab.express-scripts.com/lab/drug-trend-report/2017-dtr
• https://www.avac.org/sites/default/files/resource-files/HIV_resourceTracking2017.pdf
• https://www.gilead.com/news-and-press/press-room/press-releases/2018/7/gilead-announces-new-data-on-the-impact-of-truvada-emtricitabine-and-tenofovir-disoproxil-fumarate-for-preexposure-prophylaxis-prep-on-the-numbe
• Huang, Ya-lin, et al, HIV Preexposure Prophylaxis, by Race and Ethnicity, US, 2014-2016, Weekly, October 19, 2018, 67(41);1147-1150; www.cdc.gov/mmwr/volumes/67/wr/mm6741a3.htm
• https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/459/cost-considerations-and-antiretroviral-therapy