Anthony Palmieri, RPh, PharmD, MBA

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Major risk factors for CVD include hypertension, dyslipidemia, age, obesity, tobacco use, lack of physical activity, family history, and diabetes. Among these, dyslipidemia, a complex disease caused by the interplay of genetic, dietary, and physiologic factors, is a major modifiable risk factor for CVD. Low-density lipoprotein cholesterol (LDL-C), a component of cholesterol, accounts for approximately 60% to 70% of total serum cholesterol and is considered to be the element most strongly associated with increased risk of CVD. Risk factors for elevated LDL-C include a diet high in saturated fat or cholesterol, an inactive lifestyle, tobacco use, and a family history of heart disease and diabetes.

 The most common genetic cause of dyslipidemia is familial hypercholesterolemia, which affects 1 in 500 people and results in abnormally high levels of serum cholesterol due to impaired LDL receptor function in the liver.

The World Health Organization estimates that dyslipidemia is associated with more than half of the global cases of heart disease and more than 4 million deaths per year.

 It is estimated that more than 63 million people in the United States (nearly 40% of US adults) have elevated LDL-C, and 12 million of these are not at goal.

 Due to its association with CVD, dyslipidemia places a financial burden on individuals and the healthcare system that is estimated to be in excess of $400 billion annually.

The goal of treatment for dyslipidemia is to decrease levels of LDL-C, leading to reduced risk of major cardiovascular events and comorbidities.

 The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines recommend an LDL-C goal for all patients of less than 100 mg/dL.

 However, if the patient is at high risk of cardiac events, the recommended LDL-C goal is less than 70 mg/dL. Reduction in serum LDL-C has been shown to reduce the risk of heart disease by an average of 30%.

Lifestyle change and statin drug therapy are the treatments of choice for LDL-C reduction. However, even with statin treatment, many patients fail to reach their recommended treatment targets. This is seen in patients with genetic abnormalities, those with extremely elevated levels of LDL-C (>400 mg/dL), and patients with difficulty tolerating high-dose statins. The proprotein convertase subtilisin/kexin 9 (PCSK9) enzyme prevents recycling of the LDL receptors and increases the rate of their degradation, restricting the ability of the receptors to remove circulating LDL-C and leading to elevated serum LDL-C. PCSK9 inhibitors regulate the degradation of LDL receptors and have been shown to signifi cantly reduce LDL-C. Interestingly, statins have been found to

stimulate the production of PCSK9, limiting the statin’s own ability to lower serum cholesterol levels beyond a certain point. Inhibiting the PCSK9 pathway therefore represents an exciting and novel mechanism for increased lowering of LDL-C, and one that has shown promise in several phase 2 trials when used with statins or as monotherapy.

While PCSK9 inhibitors are likely to result in increased pharmacy costs due to patent protection and route of administration (PCSK9 requires injection every 2 to 4 weeks), the argument can be made that this cost will be offset by a decrease in expensive cardiovascular events and associated disability. In this paper we will describe the trends in expenditure on cholesterol-lowering agents, examine the use of low- versus high-dose statin formulations, and consider the implications of introduction of the PCSK9 inhibitor in the market for cholesterol-lowering agents.

This descriptive analysis was conducted using deidentified CVS Caremark pharmacy claims data. Members who had a claim in calendar year 2011 or 2012 were selected from the claims database, and those with a claim for a statin medication were considered. The specific statin medications identified were lovastatin, rosuvastatin, fluvastatin, atorvastatin, pitavastatin, pravastatin, and simvastatin. We classifed a member as being on “high-dose” therapy if their dosage was higher than defined in 

Member pharmacy claims were analyzed for 2011 and 2012, during which time atorvastatin (the generic version of Lipitor) was introduced (November 2011). We also identified members as having diabetes or cardiovascular comorbidities (ie, hypertension, coronary artery disease, or congestive heart failure) based upon their prescribed medications. We report the generic dispensing rate (GDR) and cost per utilizer per day. For this purpose, cost is defined as the total paid charges for the medication by a third-party payer. The member’s age was that noted from the earliest claim.

Our descriptive analyses were conducted using SAS 9.1 (SAS Institute, Cary, North Carolina).

We identified 574,909 members in our sample that filled a prescription for statin medications, indicating a prevalence of statin use in this sample of 10.1%. The average age was 59.0 years (standard deviation [SD] 14.2). The sample was 51% male and 73% were prescribed medication for diabetes, a cardiovascular comorbidity, or both. Of the cardiovascular comorbidities being treated, the most common was hypertension. Of the statin users, 88% were on a low-dose regimen (see 

). Members on the high-dose regimen were more likely to have comorbidities than those on the low-dose regimen (83% vs 72%, 

 we detail the specific comorbidities identified for each group. On average, members on a high-dose regimen were more likely to have diabetes or a cardiovascular comorbidity.

The introduction of generic atorvastatin in November 2011 was followed by an increase in GDR from 64%= to 81% (

). The increase in GDR was similar for members who were on low-dose (66% to 83%) and highdose (55% to 70%) regimens. This increase led to a 19% decline in the cost per day per utilizer, from $1.76 in 2011 to $1.42 in 2012 (see 

). The decline was larger in the low-dose regimen members ($1.70 to $1.33, or 22%) than that seen among members on high-dose therapy ($2.21 to $2.02, or 9%).

The introduction of atorvastatin led to a substantial increase in the generic dispensing rate and an accompanying decline in the daily cost of treatment. We would expect the loss of patent protection by rosuvastatin (Crestor) in 2016 to have similar impact, but not as substantial due to the smaller market share enjoyed by that medication. The commercialization of the PCSK9 inhibitors is likely to reverse this trend toward a lower cost of treatment of dyslipidemia on a per utilizer basis.

We conducted a preliminary analysis to estimate the consequence of introduction of a PCSK9 inhibitor. In our descriptive analyses, we found that 10.1% of members were on cholesterol-lowering medication. Of these, 12% were on a high-dose regimen. We considered 2 scenarios for use: (1) the PCSK9 inhibitor prescribed as an ancillary therapy in addition to a statin prescribed first line; and (2) the PCSK9 inhibitor prescribed as a replacement for the statin prescribed first line. We also tested 2 assumptions concerning the ultimate indication for use of the PCSK9 inhibitor: (1) A narrow indication with only patients with comorbidities currently on high-dose statin therapy considered medically appropriate use—based upon our analyses, we estimate this would be a maximum of 9% of current statin users; and (2) A broad indication where diabetics who would benefit from aggressive cholesterollowering targets would be considered medically appropriate use&mdash;we estimate that this would be a maximum of 26% of current statin users. The results of our analyses are provided in

We estimated that the incremental per member per year (PMPY) could range from $4.43 based on our most restrictive assumptions concerning indication, uptake, and costs to $393.90 based on aggressive assumptions. Even under conservative utilization and low drug-cost assumptions, the PCSK9 inhibitor would represent one of the more expensive specialty drug programs on the market.

 This disproportionate fi nancial impact is due to the prevalence of dyslipidemia, one of the most common chronic diseases, in contrast to other specialty pharmacy programs that target relatively rare diseases.

Market analysts have recognized that PCSK9 inhibitors have the potential to reach blockbuster status with billions of dollars in annual sales—a view reflected in the substantial investments being made by major pharmaceutical companies toward development of a PCSK9 inhibitor (See 

). The team of Sanofi and Regeneron Pharmaceuticals, Inc, is closest to market with their PCSK9 inhibitor, REGN727. They have completed phase 2 trials and have begun recruiting for phase 3. They are conducting a series of 10 separate clinical trials, collectively referred to as ODYSSEY, to evaluate 22,000 participants over 6 years with the goal of proving safety and efficacy of REGN727 as a monotherapy and in combination with other lipid-lowering agents. The largest of these, ODYSSEY Outcomes, will enroll 18,000 participants who recently suffered acute coronary syndrome.

 If this reflects the indication ultimately sought for REGN727, the market for PCSK9 inhibitors would be at the conservative end of our estimates in Table 3.

If PCSK9 inhibitors ultimately obtain US Food and Drug Administration approval, they will likely obtain well-defined, “add-on” use indications within current treatment parameters and are expected to have significant associated costs.

 Pharmacy benefit managers will likely seek to control costs in this large patient segment by implementing clinically robust guidelines for treatment. We would expect that these guidelines will ensure that the use of PCSK9 inhibitors is limited to patients with hypercholesterolemia who are intolerant to, or unable to meet LDL-C goals with, currently approved, less-costly statin medications. According to the Metabolic and Atherosclerosis Research Center of Cincinnati, this subpopulation is estimated to represent 10% to 20% of patients with high cholesterol

and would result in a PMPY in the mid-range of our estimates in Table 3.

Dyslipidemia is one of the most common chronic conditions experienced by people in the United States. Treatment of high cholesterol is primarily addressed through the use of generic, once-daily oral medications with a high level of tolerability. That paradigm will likely be challenged by the inclusion of PCSK9 inhibitors as addon agents to aid patients who cannot achieve cholesterol treatment targets on statins alone. Clinical trials such as ODYSSEY represent large investments by pharmaceutical manufacturers and indicate their belief in the potential of these medications to gain broad acceptance due to improved clinical outcomes. Even if PCSK9 inhibitors gain the acceptance anticipated by manufacturers, statins will likely retain their well established role as first-line therapy due to their low cost and the overwhelming clinical evidence supporting their use.

Articles

Generic atorvastatin led to an increase in generic dispensing rate and a reduction in the cost of treatment for patients requiring cholesterol-lowering treatment. The upcoming introduction of the PCSK9 inhibitor may change this trend.

Trends in Statin Treatment Costs and Potential Impact of Novel Therapies

The prevention and treatment of human immunodeficiency virus (HIV) is a topic of interest among many in public health and managed care. The Centers for Disease Control and Prevention (CDC) estimates that as of 2008, approximately 1.2 million people in the United States were living with HIV infection; 1 in 5 are undiagnosed.

 The annual number of new HIV infections has remained relatively stable recently, with roughly 50,000 Americans newly diagnosed with the disease each year.

 Of the HIV diagnoses made in 2008, the CDC calculated that 1 in 3 (33%) were late, often made after the development of AIDS.

Progression of HIV infection to acquired immune defi ciency syndrome (AIDS) can be delayed—often for many years&mdash;by using various combinations of currently approved antiretroviral therapy (ART). Frequently, these expensive ART medications comprise a high portion of the total pharmacy costs for prescription drug plan sponsors.

The main goal of HIV ART is to reduce morbidity and mortality associated with the disease via the inhibition of HIV replication, which keeps the viral load below detectable levels and allows immune reconstitution to begin.

 There are a number of HIV drug-treatment protocols with varying degrees of complexity and cost; in fact, there are over 20 approved antiretroviral (ARV) medications in 6 therapeutic classes that are available to design combination ART regimens.

 These 6 HIV ARV classes include nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors (FIs), CCR5 antagonists, and integrase strand transfer inhibitors (INSTIs).

Combination therapy with multipleclass drugs is the standard of care, and treatment-naïve patients require at least 3 active agents. HIV therapy selection must be done on a patient-specific basis based on factors such as comorbid conditions, concomitant medications, and potential barriers to adherence.

The cost of HIV treatment depends on multiple factors, including infection and diagnosis rates, the lifespan of patients with the disease, and costs and availability of various treatment options. Recent approval of preventive therapy and an over-the-counter HIV test may further increase the costs of HIV-related therapy. To establish the baseline costs which prescription drug plan sponsors have been incurring prior to these approvals, this study examines the recent trends in 1-year costs of HIV ART therapy in therapy-naïve patients.

The purpose of this study was to measure costs and demographic characteristics associated with new HIV therapy initiators in a nationally representative population sample over a 4-year period and to determine factors associated with changing prescription costs over time. A retrospective, longitudinal study was conducted on prescription claims data from CVS Caremark from July 1, 2006, to June 30, 2012. HIV therapy utilizers were identifi ed based on an index fill in the period between January 1, 2007, and June 30, 2011. To be included in the study, patients had to be continuously eligible for pharmacy benefi ts for at least 18 months (6 months prior to the index fill and 12 months after the index fill). A patient was considered therapy-naïve at index fill if there was no HIV medication prescription filled within 6 months prior to the index fill of an HIV medication. Study outcomes were measured over 12 months from the index fill and included total costs of HIV therapy (plan-paid plus member out-of-pocket cost) per 1-day supply of medication. Patient characteristics, including gender, age, region of residence, and Censusbased income and college education in the zip code, as a proxy for socioeconomic status, were also measured. A linear regression model of total costs was constructed to evaluate the impact of demographic covariates on drug costs during the first year of utilization. Descriptive and ANOVA analyses were conducted using SAS Version 9.1 with SAS/STAT. HIV medications were determined using a Medi-Span indicator for HIV therapy.

There were a total of 86,455 new initiators over the study period, with an average of 17,291 per year. Annual demographic characteristics of HIV therapy initiators are presented in 

, with the 2012 statistics refl ecting the mid-year measures. While the age of new therapy initiators over the 4.5 years of the study remained relatively stable at approximately 45 years, there was a relative decrease in initiatiors in the 35 to 44 year age groups, with relative increases in every other age group. The majority of HIV therapy initiators were male (75.01%). For most new HIV therapy initiators, the median annual household income was $35,001 to $55,000 (44.95%), with 50.72% of new initiators living in a zip code where only 8% to 20% of the population was college-educated. The majority of HIV therapy initiators lived in the southern part of the United States (45.7%).

The average total cost per day of HIV ART therapy in the first year post-initiation has risen from $26.48 in 2008 to $33.29 by mid-2012 (

). Despite total cost increases, patient out-of-pocket spend has remained stable at approximately 7% of the total cost. Additionally, some therapies have seen substantial infl ation in cost per day’s supply over the study time period (

), especially when compared with the United States general infl ation trend of 6% between 2008 and mid-2012, and even the prescription medications infl ation trend of 16% during the same time period.

Of several different combinations of ART started by new initiators over the entire study period, Atripla was the predominant triple therapy HIV medication utilized solely (utilized by 27.7% of new initiators by mid-2012), whereas Truvada was the predominant double therapy medication utilized in combination with other medication(s) (

There were significant demographic differences in total costs across groups over the study period. Patients younger than 65 years had higher costs compared with patients 65 years and older. Patients in the West incurred lower costs compared with patients residing in other geographic areas. Gender and socioeconomic status were not significant predictors of therapy costs (

This study found signifi cant increases in the cost of ART therapy over the last several years for therapy initiators, and significant increases in costs of individual therapies, which are part of complex treatment regimens. In addition to demographic and drug costs drivers of HIV treatment costs, recent developments will impact the cost of HIV therapy.

In July 2012, the US Food and Drug Administration (FDA) granted supplemental approval to Truvada (emtricitabine/ tenofovir) as the first pharmaceutical approved to reduce the risk of HIV infection in uninfected individuals who are at high risk of HIV infection and who may engage in sexual activity with HIV-infected partners. Truvada, taken daily, is to be used for pre-exposure prophylaxis (PrEP) in combination with safer sex practices to reduce the risk of sexually acquired HIV infection in adults at high risk. Truvada has been available since 2004 for use in combination with other antiretroviral agents for the treatment of HIV-infected adults and children 12 years or older.

 Truvada’s existing boxed warning was revised to state that PrEP must only be used in individuals who are confirmed to be HIV negative prior to prescribing and who test negative for the infection at least every 3 months during PrEP use. The drug is contraindicated for PrEP in individuals with unknown or positive HIV status.

Although the added indication for Truvada was recognized by most as a victory in the fight against HIV/ AIDS, concerns have been raised due to nonadherence, improper use by those already infected by HIV (which could lead to viral resistance), signifi cantly increased medication cost in an otherwise healthy population, and increased risky behavior due to behavioral compensation (eg, the idea of being “bulletproof” may infl uence individuals to engage in sexual practices such as abandoning the use of condoms, which are a cornerstone of HIV prevention).

The new indication of Truvada for prophylactic use will likely be expensive. The AIDS Healthcare Foundation recently estimated the cost of a year’s supply of Truvada to be $14,130.

 However, the lifetime treatment cost of an HIV infection can be used as a measure of the value in averting a single infection. Currently, the lifetime treatment cost of an HIV infection is estimated at $379,668 (in 2010 dollars); therefore a prevention intervention is deemed cost-saving if its cost-effectiveness ratio is less than $379,668 per infection averted.

Detection of HIV is critically important in controlling transmission of the virus because treating patients with the appropriate anti-retroviral therapy can lower transmission person to person by as much as 96%.

 Home medical tests are popular with consumers because of their convenience and the privacy they provide. In July 2012, the FDA approved OraSure Technologies’ Ora Quick ADVANCE Rapid HIV-1/2 Antibody Test as the first such OTC product for consumers to determine their HIV status in the privacy of their own home via the collection of an oral fluid sample. The usability of the test is on par with the ease of home pregnancy tests and is seen as an important step in the normalization of a disease that has historically been stigmatized within the community.

The test is able to detect antibodies to HIV-1 and HIV-2 in 20 minutes. OraQuick does not use saliva, but rather absorbs antibodies directly from the blood vessels in the mucous membranes of the mouth; it detects antibodies for HIV, not the virus itself.

According to Phase III data presented by OraSure and reviewed by the FDA that represent a more realworld scenario, OraQuick has about a 92.9% sensitivity (the percentage of users with HIV in whom the virus was correctly detected) rate, or 1 false negative result per 12 tests—as well as 99.98% specifi city (the percent of patients correctly identifi ed as not being infected with HIV), or 1 false-positive result in every 5000 tests.

The OraQuick ADVANCE Rapid HIV-1/2 antibody test was originally approved as a rapid antibody test for use with fingerstick whole blood specimens in 2002. In June 2004, OraSure obtained approval for use of the test with oral fluid and since that time over 20 million units have been used for HIV testing in this country. The FDA’s approval of the OTC antibody test included a requirement that a call center for consumers to access be made available 24 hours a day, 7 days a week. The support center for the OTC test will be operated by full-time dedicated representatives with bilingual capability (English and Spanish) that have undergone 120 hours of training to ensure the highest standards of support. OraSure’s launch plan for the test also included extensive pharmacist and physician education tools to ensure they are aware of not only how the test works, but of all the support services available to their customers.

Many experts believe that the approval and use of this home test for HIV represents a positive step forward in controlling a 30-year-old epidemic.

 Certainly, any process that can provide rapid results, especially to the population unaware of their infected status, would be seen as an important component of controlling the spread of the disease. In fact, 41% of pivotal study participants for the home test found to be HIV positive reported they had never before been tested and likely would not have been tested without the OTC self-testing option.

“We shouldn’t let the perfect be the enemy of the good,”

 a statement from an FDA advisory committee member, Dr Brooks Jackson, gets to the heart of one of the more controversial issues with the in-home test: the high rate of false negative results that could lead to recklessness and endangering of sexual partners. In addition to this high rate of false negative outcomes, several other issues have been raised regarding the approval of this test.

One of the main concerns involves the lack of full comprehension surrounding the results and the limitations of a screening test, such as the length and meaning of the “window period”—denoting the time for a measurable antibody response from recent exposure. This timeline may take up to 90 days in certain patients to reach detectable levels and could therefore lead to inaccurate interpretation of HIV status.

This is particularly important because most people are most infectious right after they are first exposed to the HIV virus and more than half of HIV transmissions are believed to pass from an infected person to a new victim during the infected person’s first 60 to 90 days of exposure.

Additionally, the lack of live counseling raises the potential for adverse outcomes if the user obtains an unexpected result without concurrent live support and context. Furthermore, the inability to reach individuals testing at home for medical follow-up, partner notifi cation, and public health reporting represent further downside to the use of the test in the home setting.

In the immediate wake of its approval, OraSure has priced the OraQuick test at $34.00, available directly from the manufacturer via its website.

 It remains to be seen if this price point will be a barrier to use for patients who should properly be self-testing at intervals several times during the year, which is the recommended interval for some high-risk groups. Therefore the pricing of the OTC version may be as critical to the overall public health impact as the test itself.

 OraQuick is expected to be launched for retail sale in October.

There is a push for HIV testing to be paid for by third party payers. With implementation of the Affordable Care Act, coverage of HIV testing has already expanded and will greatly increase in the future.

Another issue with the test involves consumers who were involved in the HIV vaccine trials. According to the investigators from the study, over 40% of the participants developed antibodies to the vaccine, which would crossreact with the in-home test and cause a falsely positive outcome. Therefore vaccine trial participants need to be made aware of this issue with using the OTC product.

Despite some serious and valid concerns, the FDA concluded that if just 1% of Americans use the test, OraQuick could identify up to 45,000 previously undetected HIVpositive people and prevent close to 4000 new infections each year. So it basically comes down to a risk/benefit for the individual versus the community as a whole—the risk for the 1 in 12 false negative individuals versus the societal benefi ts from the projected thousands of consumers who are identifi ed as HIV positive and can obtain earlier treatment and prevent further transmission.

There are reportedly 60 new drugs currently in development for the treatment of HIV. Selected products anticipated to come to market in the near future include:

 In May 2012, the FDA’s Antiviral Drugs Advisory Committee voted in favor of Gilead Sciences’ Quad (elvitegravir/cobicistat/emtricitabine/ tenofovir) fixed-dose 4-drug-in-1 HIV pill for treatment-naïve adults despite renal toxicity concerns.

Quad has shown similar efficacy as Atripla and while nausea was more significant with Quad, dizziness, abnormal dreams, insomnia, and rash were signifi cantly more frequent with Atripla.

Part of the Quad combination product, stand-alone elvitegravir could open up the integrase-inhibitor market. In a study submitted in support of approval the single-agent, once-daily elvitegravir proved comparable to Merck’s twicedaily blockbuster Isentress, the only commercially available integrase inhibitor. Approved for both treatment-experienced and treatment-naïve patients, Isentress brought in sales of almost $1.4 billion in 2011, up 25% from the previous year. In spite of the market success to date, attempts at making a once-daily version of Isentress have not been successful, which could jeopardize future growth.

HIV is of interest among many in managed care. This paper focuses on the costs and demographic characteristics associated with new HIV therapy initiators.