From Adherence to Outcomes: Impact of Benefit Design on the HIV Patient

OBJECTIVE: To review the current impact of human immunodeficiency virus (HIV)/ acquired immunodeficiency syndrome (AIDS) and its treatment on the population and on managed care. SUMMARY: In 2006, HIV/AIDS remains as big a problem as ever, with many countries reporting an incidence of 40% or higher among intravenous drug users. While daunting, this does not detract from the many victories that have occurred over the HIV/AIDS landscape. Mortality has declined dramatically since 1995. Treatment with highly active antiretroviral therapy (HAART) has been simplified and offers substantial survivor benefits. The net effect of these advances has been to change the face of HIV/AIDS, from a fatal to a chronic illness. Accordingly, current and evolving management strategies need to encompass long-term care. CONCLUSION: As people live longer, health care management organizations will be looking to balance good outcomes and successful long-term care with acceptable costs.


S17 Continuing Education*: CE Submission Instructions and Posttest Worksheet
This supplement was funded by an educational grant from Gilead Sciences, Inc., and sponsored by AMCP Horizons, LLC and Creative Educational Concepts, Inc. Articles in this supplement are based on the proceedings of a symposium, "From Adherence to Outcomes: Impact of Benefit Design on the HIV Patient," held April 6, 2006, at the Academy of Managed Care Pharmacy' s 18th Annual Meeting and Showcase in Seattle, Washington, which was supported by an educational grant from Gilead Sciences, Inc. and sponsored by AMCP Horizons, LLC and Creative Educational Concepts, Inc.
*A total of 0.20 CEUs (2.0 contact hours) will be awarded for successful completion of this continuing education activity (ACPE Program No. 245-999-06-145-H01). This educational activity is also accredited for a maximum of 2 AMA PRA Category 1 credits. For faculty disclosures, please see pages S5, S11, and S16. For ACPE and ACCME accreditation information, please see page S17. T Ta ar rg ge et t A Au ud di ie en nc ce e Managed health care professionals interested in effective benefit design and appropriate care to ultimately improve health outcomes and cost management L Le ea ar rn ni in ng g O Ob bj je ec ct ti iv ve es s Upon completion of this activity, the participant will be better able to 1. select an appropriate treatment option for the HIV patient according to national guidelines and IAS and DHHS recommendations; 2. discuss successful approaches to increase medication compliance in HIV and recognize how certain managed care practices might inadvertently compromise medication adherence and its downstream ramifications; 3. evaluate the long-term efficacy of FDC-based regimens; 4. analyze the long-term toxicities of the nucleosides backbone and determine the "true" cost of these various nucleoside analogues; 5. demonstrate how pharmacoeconomic studies can be used for the systematic evaluation of pharmaceutical value and cite examples of current outcomes research in the area of HIV; 6. describe the importance of benefit design, access to effective medications, and coordination of care; and 7. distinguish the contribution of each member of the health care team in helping to improve the patient' s quality of life and reduce overall health care costs. M ore than 20 years have passed since the initial scattered reports of an unusual pneumonia and rare cancer-Pneumocystis carinii (since renamed P jiroveci) pneumonia and Kaposi' s sarcoma-occurring in homosexual men provided the first whisperings of what was to become the human immunodeficiency virus (HIV) epidemic. Despite tremendous advances in our understanding and management of HIV and the acquired immunodeficiency syndrome (AIDS), the problem remains one of world-wide proportions. Today, the United States, Canada, Russia, and China as well as parts of Europe, Africa, the Pacific Islands, and South America have become deeply embedded in the HIV landscape, reporting a 40% or higher prevalence of HIV/AIDS among their intravenous drug users ( Figure 1). 1 Population data from 2000 to 2004 in the United States shows a progressive increase in the incidence of AIDS among whites, blacks, Hispanics, Asians, Pacific Islanders, Alaskans, and American Indians (Table 1). 2 The number of AIDS cases continues to grow and is currently highest among non-Hispanic blacks and whites and lowest in American Indians and native Alaskans. SUMMARY: In 2006, HIV/AIDS remains as big a problem as ever, with many countries reporting an incidence of 40% or higher among intravenous drug users. While daunting, this does not detract from the many victories that have occurred over the HIV/AIDS landscape. Mortality has declined dramatically since 1995. Treatment with highly active antiretroviral therapy (HAART) has been simplified and offers substantial survivor benefits. The net effect of these advances has been to change the face of HIV/AIDS, from a fatal to a chronic illness. Accordingly, current and evolving management strategies need to encompass long-term care.
CONCLUSION: As people live longer, health care management organizations will be looking to balance good outcomes and successful long-term care with acceptable costs.
not only to prolong life but also to improve the quality of that life. Many issues influence the quality of life for a patient being treated for HIV/AIDS. These include the regimen itself, dietary restrictions, and side effects. Adverse effects are a particular cause for concern because they contribute to other comorbidities and undermine adherence. Lipodystrophy, which causes disfiguring changes in body shape, is a major side effect of HAART that is distressing for patients. Anemia and fatigue are common as well. Metabolic abnormalities, such as hypercholesterolemia, cause concern about long-term cardiovascular health. All of these issues compound the risk and cost of care.
That is not to say that treatment has not improved-it has. Ten years ago, patients received a regimen of stavudine, lamivudine, and indinavir, 10 tablets or capsules every 8 hours for a total of 30 daily. Patients had to observe food restrictions and drink liquids frequently. This treatment was also plagued by short-and longterm toxicities that decreased tolerability. By 1998, the standard regimen was simplified to a lamivudine/zidovudine coformulation plus efavirenz, 5 tablets or capsules taken twice daily. Although clinicians and patients welcomed more simple dosing schedules, the side effects of the coformulation-gastrointestinal (GI) effects, anemia, neutropenia, central nervous system (CNS) toxicities, and mitochondrial-related toxicities-still hindered patient compliance. By 2002, this drug regimen was further refined to 3 tablets or capsules, twice daily, but issues of toxicity remained. Within 2 years, the HIV treatment paradigm changed again with the introduction of fully once-daily treatment options: efavirenz plus a coformulation of tenofovir disoproxil fumurate/emtricitabine or abacavir/lamivudine, both given as 2 tablets or capsules, once daily. These drug combinations help improve convenience and tolerability for the patient by offering treatments with less frequent daily dosing, reduced pill burden, minimal side effects, and no food restrictions. Moving forward, the goal is to develop a simple 1-tablet, once-daily regimen without side effects, allowing for optimal adherence and outcome despite the need for lifelong treatment. 3 ss Mortality The mortality rates from HIV have declined tremendously since 1995. Data from the Centers for Disease Control and Prevention show that, in 1995, 16 out of 100,000 persons in the United States died from AIDS. 2 By 2003, that figure had declined to roughly 4.4 per 100,000 population. 2 The death rate has dropped as the percentage of patients receiving HAART has increased. In the second quarter of 1992, for instance, there were no patients on HAART, and the number of deaths per 100 person years averaged just over 11. By the second quarter of 2005, 80% of patients were receiving HAART, and the mortality rate was less than 1 per 100 person years ( Figure 2). 4 HAART also offers significant survival benefits. Walensky and colleagues 5 examined surveillance data from 1989 to 2003 in patients receiving treatment for HIV/AIDS in the United States.
As years progressed and treatment improved, patients lived longer. From 1989 to 2003, for example, antiretroviral treatment prolonged life by an average of 3 months. For the second (1993)(1994)(1995) and third (1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003) periods of the study, antiretroviral therapy extended life by 2 and 11 to 13 years, respectively. The authors of this study concluded that the widespread availability of HAART has spared more than 3 million lives.

s ss s HIV Infection as a Chronic Disease
The impact of these treatments in reducing mortality has transformed HIV/AIDS from a terminal disease to a chronic disease. As a result, the focus of management shifts from mortality to promoting adherence, minimizing treatment-and disease-related morbidities, optimizing outcome, and controlling the costs of ongoing treatment.

Number of HIV Diagnoses in the United States from 2000 to 2004
Medco Health Solutions tracked spending, utilization, and unit cost of specialty versus average outpatient prescription drugs for the period 2004 to 2005 ( Figure 3). 6 Specialty pharmacy is defined here as products used to treat chronic, high-cost, or rare diseases; injectable pharmaceutical and/or biologic products; products delivered through special delivery or requiring special handling; injectable and infusion therapies delivered in ambulatory settings and high-cost ($5,000 and up per patient per year); and/or "high-touch" therapies (therapies requiring high levels of patient training and physician interaction). Spending, utilization, and unit cost were all higher for specialty drugs. The increased spending in the specialty drug category will be scrutinized closely by those involved in managing health care costs.

ss Looking Ahead
Currently, there are 197 specialty drugs on the market to treat various chronic conditions. However, there are more than 800 such drugs in various states of development. By 2010, 325 specialty drugs are projected to be available to physicians. 7 Managed care organizations will be closely examining how physicians prioritize therapy expenditures and associated outcomes.
In 2005, the Health Strategies Group surveyed 60 pharmacy directors to determine how their managed care organizations handled various specialty therapies, including drugs for HIV/AIDS. 8 Responses-specifically about their number of interventions and specialty formularies, use of direct contracting, and policies mandating use of specialty pharmacy management for the various specialty therapies-ranked HIV/AIDS treatments, along with hemophilia and cancer supportive therapy, among medium priority specialties. Office and oral oncologic medications were low priority and medications for psoriasis, rheumatoid arthritis, multiple sclerosis, human growth hormone deficiency, and hepatitis were high priority. HIV/AIDS specialty medications are beginning to garner attention from managed care organizations concerned with ensuring that treatments are being prescribed appropriately. While there are no firm criteria for prioritizing specialties, managed care interests generally focus on areas with the potential to offer savings with management, i.e., multiple high-cost therapies available with high potential for unnecessary utilization.
Because so many AIDS victims are of working age, the business sector sees many of the effects of HIV/AIDS. 9 Therefore, many employers are examining the impact of this disease on the workforce and total health-related costs. The Integrated Benefits Institute surveyed chief financial and executive officers about how HIV/AIDS affected their companies. 10 The results showed that AIDS-related group health and workers' compensation accounted for about 19% of total health care expenditures, while 10% of health costs went to disability coverage. Lost productivity consumed 71% of the health care budget. Studies are under way to further determine the impact of HIV-related health care costs and benefits on the workforce. This is something that will need to be examined when assessing the overall value and benefit of treatments prescribed for working adults who have HIV/AIDS.

ss Designing a Care Plan
The care plan for persons with HIV/AIDS is multifaceted and requires careful coordination. At the plan level, coverage, plan designs, and education programs need to be developed to promote appropriate access and adherence. In a managed care environment, the physician usually provides the initial point of care. Patients need to be educated about the disease and the treatment being offered to them. The pharmacist is another crucial point of care; he or she may provide specialty pharmacy management or direct the patient to an appropriate resource. All of these services need to be coordinated. It is also essential that the various caregivers involved in the treatment plan deliver a consistent message; patients who receive (or perceive) different messages from various caregivers can easily become confused, which detracts from their ability to fully adhere to treatment.
It is critical for care plans to be designed in consideration of appropriate access for patients to services. Optimal outcomes can only be achieved when patients can access appropriate care and comply with therapy.

s ss s Summary
While HIV/AIDS remains serious, treatment regimens are becoming progressively streamlined and oriented toward long-term care. As people with HIV/AIDS continue to live longer, the financial burden of their care will continue to escalate. Managed care organizations will be studying these expenses and looking to develop strategies that optimize value by providing a practical, achievable balance of outcomes and cost.

DISCLOSURES
This article is based on the proceedings of a symposium held on April 6, 2006, at the Academy of Managed Care Pharmacy' s 2006 Educational Conference in Seattle, Washington, which was sponsored jointly by AMCP Horizons, LLC and Creative Educational Concepts, Inc. and was supported through an educational grant from Gilead Sciences, Inc. The author received an honorarium from Gilead Sciences, Inc. for participation in the symposium. She discloses that she serves as a consultant to Boehringer Ingelheim, Healthways, Inc., Genzyme, Johnson & Johnson Healthcare Systems, Novartis, Novo-Nordisk, and sanofi-aventis. She discloses no potential bias or conflict of interest relating to this article. T reatment for human immunodeficiency virus (HIV) has progressed substantially since the introduction of zidovudine (traditionally referred to as AZT) 2 decades ago. Since then, the therapeutic arsenal for HIV/AIDS (acquired immunodeficiency syndrome) has expanded to include 20 different antiretroviral drugs ( Table 1). The lifelong nature of HIV and the critical importance of long-term patient adherence to their antiretroviral regimen underscore the importance of individualizing therapy to the patient' s needs and tolerance. Providers are continually challenged to combine available antiretroviral agents into a regimen that will best control the disease, while minimizing adverse events.

s ss s Goal of HIV Treatment
The primary goal of antiretroviral therapy is to suppress viral replication. Early research showed that suppressing or preventing HIV viral replication would control infection, significantly reducing damage to the immune system, and allow the immune system to recover from the damage done from uncontrolled HIV replication.
HIV specifically recognizes a key cell type of the human immune system, the CD4+ T lymphocyte. Once HIV enters the CD4+ cell, HIV integrates its RNA into the host cell' s genetic processes for viral replication. At the end of the HIV life cycle, the immune cell is destroyed, while approximately 100 new virions are produced and released. These new virions infect and replicate in other CD4+ cells. Effective antiretroviral therapy suppresses this viral replication, causing the number of HIV RNA copies, or viral load, to decrease, and the CD4+ count to increase. A rise in CD4+ count indicates that the patient' s immune status is improving given historic demonstrations that these higher CD4+ counts are protective against opportunistic infections.
The plasma HIV RNA level and CD4+ cell count are useful surrogate markers for measuring virologic and immunologic changes, respectively, in HIV-infected patients. These markers continue to be used to monitor the progression of HIV disease and the effectiveness of treatment. SUMMARY: The range of antiretroviral agents available for treating patients who have HIV/AIDS (acquired immunodeficiency syndrome) has expanded to 20 medications since the first, zidovudine, was approved in 1987. While the exact choice of drugs to use in treatment must be tailored to the patient, depending on safety and tolerance, the ultimate goal is durable suppression of the HIV virus. Highly active antiretroviral treatment (HAART) is the current standard of care and involves treating the patient with a combination of antiretrovirals. First-line regimens usually contain a combination of 2 nucleoside reverse transcriptase inhibitors plus either one nonnucleoside or protease inhibitor. Differences in side effects have become more important than differences in efficacy in determining the choice of the initial antiretroviral regimen. To prevent the development of viral resistance to treatment, it is essential to begin treatment with all medications simultaneously, rather than sequentially. If the initial HAART regimen fails, more complex regimens that involve adding at least 2 new antiretrovirals can often reestablish control, even in patients with extensive pretreatment and in whom there was the development of viral resistance.
CONCLUSION: For patients with HIV/AIDS embarking on treatment today, the durability of HIV suppression in optimal regimens suggests that a normal lifespan is now a realistic outcome of HIV treatment.   Until 1991, the nucleoside reverse transcriptase inhibitor (NRTI) zidovudine was the only approved antiretroviral drug available for treating HIV infection. However, zidovudine appeared to be effective: many patients responded to monotherapy with a transient decrease in viral load (or, more commonly measured at that time, a decline in the p24 antigen level) and a transient increase in CD4+ count ( Figure 1). As research continued, investigators began testing the effects of treatment with a combination of zidovudine plus an investigational NRTI, didanosine. Results were favorable and superior to what was observed with monotherapy, and once didanosine was approved in 1991, combination therapy became the new standard of care for patients with HIV/AIDS. One problem, as illustrated in Figure 1, was that the effectiveness of NRTI therapy-whether given as monotherapy or combination therapy-was often not sustained. Eventually, patients became viremic since viral suppression was not durable, and as the viral load rebounded, the CD4+ count declined. Better treatment was needed to overcome this problem of resistance to mono or dual NRTI therapy.

ss The Era of Highly Active Antiretroviral Therapy (HAART)
Studies involving a new class of antiretroviral drugs-HIV protease inhibitors (PIs)-showed that PI-containing 3-drug regimens were more potent than dual NRTI therapy in suppressing viral replication. The potent suppression led to more durable suppression as well, lasting years instead of months as was previously the case ( Figure 1). The approval of several PIs in 1995 and 1996 ushered in the era of what became known as highly active antiretroviral therapy (HAART).
During the early days of HAART, most patients who had started treatment with zidovudine monotherapy had new drugs sequentially added to their regimen as they became available. This type of sequential therapy, even in the HAART era, led to a substantially lower response compared with a regimen involving simultaneous administration of the same drugs ( Figure 2). 1 The lessons learned from this observation engendered a new standard of HIV/AIDS care, in which treatment-naïve patients are simultaneously started on a HAART regimen consisting of a dual NRTI backbone plus a PI or a nonnucleoside reverse transcriptase inhibitor (NNRTI). High levels of viral suppression can be achieved by combination of 1, 2, or even 3 classes of antiretrovirals. The current standard of care for initial HAART, which has been defined based on the results from numerous randomized studies, consists of 2 NRTIs and either an NNRTI or a ritonavir-boosted PI (i.e., a PI that is simultaneously given with low-dose ritonavir). Boosting is done to increase the exposure to the drug (increased trough and/or area under the curve), which results in greater antiviral activity than that with an unboosted PI, as well as a simplified dosing schedule.
Incomplete suppression of viral replication still occurs and is problematic. On an individual level, it leads to treatment failure and, with the loss of CD4+ cell counts, a higher risk of disease progression. On a broader scale, incomplete suppression leads to the following undesirable scenarios: • Partial or complete loss of drug activity. Ongoing viral replication during treatment usually results in a mutated HIV strain that is resistant to the antiviral effects of one or more of the drugs in the patient' s antiretroviral regimen.

FIGURE 2
Difference in patient response to a highly active triple-drug regimen when patients are exposed to antiretroviral medications simultaneously versus sequentially. Patient response to treatment was defined as achieving an HIV RNA level below 50 copies/mL. Data

Typical Virologic and Immunologic Responses Over the 3 Antiretroviral Treatment Eras
• Development of cross-resistance. Certain viral mutations can result in the development of drug-resistant viruses that will be less susceptible to other antiretroviral agents that have not yet been used (that is, cross-resistance).

s ss s The Need for Multiple Drug Regimens
Any antiretroviral drug can select for resistance when given as monotherapy, which is why physicians now prescribe combination treatment. With multiple drugs from various classes on board, the virus is less likely to develop resistance to a single antiretroviral drug since the other medications reduce the ability of the mutant virus to replicate.
Clinicians soon discovered, however, that it was not enough to just add a third drug to a failing 2-drug combination. Doing so would lead to resistance against the third medication if HIV had already selected for resistance to the first one or two antivirals because of incomplete suppression. As a result, many treatment options were lost through resistance. Today, several thousand patients in the United States have triple-class resistance to HIV, meaning they have some degree of resistance to 3 classes of antiviral medications. Controlling viremia is very difficult in these patients (see Case Study: Managing Triple Resistance to HIV).

s ss s CD4+ Response
The phenomenon of CD4+ stability despite ongoing HIV replication while on treatment has become the focus of intensive research. A study by Deeks and colleagues examined changes in CD4+ cell count and in HIV RNA that occur over time in persons receiving HIV treatment (Figure 3). 2 This study showed that patients achieving viral suppression to "undetectable levels" have the best increase in their CD4+ cell counts, often as much as 200 cells by the end of a year.
Under conditions of partial viral suppression, the CD4+ count still does well, increasing by about 100 cells and then remaining stable for about 3 years; this trajectory in the presence of viremia was understood to have multiple determinants, one of which was the degree of partial suppression conferred despite some degree of HIV resistance to treatment. Early on, physicians and patients alike were satisfied if the CD4+ count simply increased, regardless of complete viral suppression.

s ss s Importance of Complete Suppression
If the patient' s CD4+ count has gone up and his or her risk of opportunistic infection has declined, why care about complete viral suppression? Some medications will lose complete activity as the result of development of drug resistance over time.
An example of this has been demonstrated in an early study of nevirapine. 3 In this study, persons who were on a stable regimen of zidovudine monotherapy had nevirapine added to their treatment. In response, the viral load declined about 1.5 logs but returned to baseline within 2 weeks. Thus, adding nevirapine to a stable regimen of zidovudine provides a benefit that lasts only

CASE STUDY
JH was a 53-year-old man who was diagnosed with human immunodeficiency virus (HIV) in 1995. His initial CD4+ count was 259; HIV viral load was nearly 40,000 copies/mL. These values were similar on repeat determination. JH was willing to start treatment but did not want any "experimental" or "cocktail" therapies. At the time, the recommended treatment consisted of 2 drugs, such as zidovudine and lamivudine.
JH responded fairly well to this treatment. Within 2 months, his viral load dropped below 400 copies/mL, and his CD4+ count increased to 360. However, the treatment did not offer durable protection, and by month 12, his viral load had increased to around 4,000 copies/mL. JH' s CD4+ count remained stable.
JH was treated with a series of PIs, all of which involved cumbersome regimens that were not well tolerated. Because of cross-resistance, the next regimen-ritonavir-boosted lopinavir with amprenavir, supplemented with lamivudine and abacavir-was not completely suppressive and again was poorly tolerated. JH stopped treatment and, ultimately, this led to a CD4+ count of 10 and a viral load exceeding 1,000,000 copies/mL.
Resistance testing showed that JH had become resistant to all then-available PIs. The only drugs with some hint of activity against HIV were some of the nucleosides, one of which was tenofovir. Some new medications had become available since JH had first presented, among them were tipranavir and enfuvirtide.
The addition of enfuvirtide rounded out JH' s treatment program to zidovudine, lamivudine, tenofovir, lopinavir (the only PI that JH could tolerate), and enfuvirtide. The viral load dropped by 3 logs in the first month of treatment, then came up by about 1 log in the second month, ending at 10,000 copies/mL. JH maintained this 2-log drop in HIV count for more than 1 year. The next year, his CD4+ increased from 10 to more than 320.
JH has done well. His CD4+ count has stabilized at 320, and he is very adherent with treatment and follow-up. about 2 weeks; after which, HIV changes its genetic structure so that a mutated form can once again flourish-this time in the presence of nevirapine.

CD4+ Stability Despite Ongoing Viremia
Sometimes, HIV does pay a price to become resistant to other antiretroviral drugs. One example is lamivudine. Adding lamivudine to the treatment plan causes an initial 1.5 log decline in HIV viral load. 4 Even though HIV can develop resistance to lamivudine, the viral load does not return to baseline in the face of continued lamivudine therapy but is durably suppressed by about 0.5 logs.

s ss s Drug Resistance and Cross-Resistance
Partial suppression is not a desirable outcome of HIV treatment, in part due to the potential for cross-resistance. A state of partial HIV suppression compromises the efficacy of medications the patient is taking-both now and in the future-because the more the virus replicates, the greater the likelihood of mutations being introduced. In turn, with more mutations occurring, the greater the chance is that these mutations will allow the virus to become resistant not only to the antiretroviral effects of the drugs to which it is being exposed but also to other drugs not yet used from the therapeutic arsenal (referred to as cross-resistance). In short, drug resistance undermines the ability to achieve life-long HIV suppression.
Melby and colleagues 5 reported the effects of partial viral suppression over time in patients taking a coformulation of zidovudine, lamivudine, and abacavir. Patients who did not achieve complete suppression usually had a rebound in their viral load, with viral isolates initially showing only a single mutation associated with NNRTI drug resistance but soon developing other resistance mutations. With drug therapy that provides only partial suppression of viral replication, HIV will augment the number of mutations conferring resistance. This will have 2 implications: • The viral load of HIV will increase toward its original level, and partial suppression will typically be lost over time. • HIV mutations resulting from partial suppression lead to resistance to currently used medications and, potentially, cross-resistance to other medications of that class. In the Melby study, the mutations selected by zidovudine, lamivudine, and abacavir can confer resistance to the entire class of NRTIs. Thus, a single failing regimen may render an entire class of drugs less useful in a matter of a few years if there is ongoing viremia.

s ss s Possible Solutions
In the early days of HIV treatment, physicians would simply add or switch to another drug when they felt that the patient' s current medication was failing. Physicians have since discovered that the success of changing medication depends on the approach used. Gulick and colleagues compared the outcomes achieved when indinavir and lamivudine were added sequentially versus simultaneously while patients were viremic during treatment with zidovudine. 1 They discovered that the key to success was not in the number of drugs given but in how those drugs were started ( Figure 2). Adding 2 new drugs simultaneously, rather than sequentially, produced a higher percentage of patients with an HIV count of <50 copies/mL. By treating with a sufficient number of effective drugs concomitantly, the physician can reestablish control and maintain suppression of HIV in the majority, rather than minority, of patients.

s ss s New Medications
Treatment options for persons with HIV/AIDS have recently expanded with the introduction of new PIs like darunavir and tipranavir and the first entry inhibitor enfuvirtide. Tipranavir was developed specifically for protease-resistant HIV. Enfuvirtide, an injectable antiviral, is in its own new class of drugs so there is no cross-resistance from the use of other antiretroviral medications. Cahn and colleagues studied tipranavir in an optimized background of other antivirals versus other approved PIs in about 1,000 patients worldwide who were infected with highly PI-resistant viruses. 6 Tipranavir was about 2.5 times more successful at controlling HIV than any of the other comparator PIs.
As with all antiretrovirals, tipranavir data show that patients with fewer PI mutations respond better to tipranavir than those with many such mutations (Figure 4). 7 Whatever greater activity tipranavir may initially have, however, can be lost when it is used in a highly PI-resistant population unless the rest of the regimen has some activity as well. Giving tipranavir with a second fully active drug-enfuvirtide, for instance-significantly improves results (Figure 4). 7 The combination of tipranavir and enfuvirtide produces a stable, durable 2-log drop in HIV count that can main-   Administration, 2005. 7 tain suppression in most patients.

Median viral load change from baseline by the number of baseline protease inhibitor (PI) mutations in the tipranavir (TPV) RESIST (Randomized Evaluation of Strategic Intervention in Multi-Drug Resistant Patients with Tipranavir) studies when enfuvirtide was added and withheld. Adapted from the U.S. Food and Drug
New medications from existing and new antiretroviral classes (that is, CCR5 inhibitors and integrase inhibitors) are being developed, some that will probably become available to clinicians within the next 12 months.

s ss s Cost Concerns
The medications we have today are effective for most patients, but they are also very expensive. Enfuvirtide is probably the most expensive, costing about between $15,000 and $20,000 a year. Tipranavir is similarly expensive at more than $10,000 per year.
Is treatment that includes such antiretrovirals worth the cost? Evidence indicates that treatment with enfuvirtide is still cost effective, when it successfully interferes with HIV replication. 8 In so doing, antiretrovirals minimize the risk of comorbid illnesses that contribute to significant morbidity and therefore decrease the overall cost of care by decreasing hospitalization rates.

s ss s Approach to Treatment
While the specific choice of medications is subject to debate, the 3-drug regimens used for initial treatment are also favorable from a cost perspective. Based on a recent randomized study of initial therapy, there is clear evidence that 3 drugs are sufficient and that adding a fourth drug to a combination of 2 nucleosides and a third drug (for example adding a third NRTI to a combination containing 2 NRTIs and 1 NNRTI) does not add any demonstrable benefit. 9 In the time since this presentation was given, a single tablet containing a combination of 2 nucleosides and 1 nonnucleoside taken once a day has become available. The single tablet contains tenofovir, emtricitabine, and efavirenz-a combination that has been validated from an ongoing randomized study 10 and supported by a previous study containing lamivudine instead of emtricitabine, 11 drugs understood to be largely interchangeable. This combination has been shown to be among the best first-line regimens in terms of efficacy and safety criteria. As a result of this further reduction in pill burden, it is reasonable to expect this treatment to be among the most successful for HIV infection in those starting therapy.
The number of people with virologic failure continues to decline. Evidence now demonstrates sustained virologic response 4 years into treatment with tenofovir, lamivudine, and efavirenz. [12][13][14] It is reasonable to assume that if HIV resistance has not been observed after 4 years of treatment, resistance is unlikely as long as "adequate" patient adherence to treatment is preserved over time. It should be noted that there is considerable ambiguity with regard to the degree of adherence that is required to maintain suppression, and a goal of ongoing research is to define the minimum adherence patterns that maintain suppression of HIV replication with current regimens.
Studies involving the ritonavir-boosted PI approach, where patients also receive 2 nucleosides, show a similar very high response rate and good tolerance. When patients tolerate the treatment well initially, medications are likely to work effectively for a long period given good adherence to therapy.

s ss s Adherence
The other key focus of care is making sure the patient can and does take all medications. Mannheimer and colleagues examined the issue of whether adherence can be altered. 15 Two interventions were tested: a nurse trained in adherence counseling and an automated beeper/pill reminder. Some patients were randomized to counseling by the nurse, some to the beeper, and some to both. The control group patients were given no adherence aids. Incidence of virologic failure was lowest (28%) in patients who received counseling by the nurse and highest (42%) in patients who received only the beeper. Thirty percent of the study participants who received no help and 33% of those who got both the nurse and the beeper had virologic failure in the first year. Therefore, the beeper/pill reminder actually detracted from adherence.
One insight into issues of adherence comes from a study done by Rode and colleagues. 16 The team looked at adherence with once-versus twice-daily treatment with the same HAART regimen over a period of 2 years. The adherence with twice-daily treatment had declined to 81% by study end. Once-daily adherence remained greater than 90% after 2 years. This occurred despite a higher incidence of diarrhea on the once-daily regimen, strongly suggesting that once-daily treatment is simpler to adhere to.

s ss s Simpler Antiretroviral Regimens
Clinical studies reporting high response rates with potent drug regimens that are less complex and better tolerated suggest that   Rode et al., 2005. 16 such regimens are allowing patients to better adhere to and remain on their treatment ( Figure 5). One randomized study examined the difference between zidovudine plus lamivudine versus tenofovir plus emtricitabine in efavirenz-containing regimens. 17 Tenofovir/emtricitabine was found to be superior to zidovudine/ lamivudine primarily because it caused less toxicity.

Effect of once-daily (QD) versus twice-daily (BID) dosing on patient adherence to antiretroviral treatment. In this study, both groups received a regimen of tenofovir (TDF) and emtricitabine (FTC) given QD plus lopinavir/ ritonavir (LPV/r) given QD or BID. Patient adherence was determined through the use of Medication Event Monitoring System (MEMS) caps. Adapted from
Safety differences also are a concern when choosing a drug, especially considering that HIV/AIDS treatment is now so prolonged. In this study, tenofovir caused less elevation in cholesterol levels than did zidovudine.
This study 17 also examined the incidence of lipodystrophy, which is a cosmetically disfiguring side effect. People with lipoatrophy or lipodystrophy may look ill since there can be fat loss in the face or limbs, suggesting a wasting-like illness. Using dualenergy X-ray absorptiometry, which is a rigorous method for measuring limb fat, those on tenofovir/emtricitabine showed a greater amount of limb fat after 1 year compared with those taking zidovudine/lamivudine.

s ss s Summary
There has been continued evolution in the number of HIV treatments available for use. However, the lessons learned as result of treatment have been intact for the past decade. Effective and durable suppression can be achieved in a majority of patients when at least 2 active antiretrovirals are initiated simultaneously and patient adherence is maintained. When virus replication is suppressed on a well-tolerated combination to "undetectable" levels, the observations of years of improved health associated with the control of HIV replication can confidently be anticipated to translate to decades of a healthy life despite HIV infection.

DISCLOSURES
This article is based on the proceedings of a symposium held on April 6, 2006, at the Academy of Managed Care Pharmacy' s 2006 Educational Conference in Seattle, Washington, which was sponsored jointly by AMCP Horizons, LLC and Creative Educational Concepts, Inc. and was supported through an educational grant from Gilead Sciences, Inc. The author received an honorarium from Gilead Sciences, Inc. for participation in the symposium. He receives grant/research support, serves as a consultant and clinical investigator, and serves on the speaker' s bureau for Abbott, GlaxoSmithKline, Bristol-Myers Squibb, Gilead Sciences, Inc., Roche, and Tibotec. He discloses no potential bias or conflict of interest relating to this article.
SUMMARY: The most critical barrier to successfully managing HIV disease is suboptimal patient adherence to antiretroviral therapy. Managing HIV infection is unique in that the risk of treatment failure increases remarkably with even relatively minor lapses in patient adherence. The incremental cost of HIV treatment failure has been approximated at $26,000 per patient per year. Treatment failure, of course, also drives mortality related to HIV and acquired immunodeficiency syndrome (AIDS). Benefit design, specialty medication management strategies, and care management programs can be integrated to deliver high-quality, efficient care that optimizes clinical outcomes for populations of HIV-infected individuals.
CONCLUSION: Managed care programs can be structured to provide HIV care that allows optimal patient adherence and clinical outcomes.
KEYWORDS: HIV/AIDS, Antiretroviral therapy, Medication adherence, Benefits management J Manag Care Pharm. 2006;12(7)(suppl S-b):S12-S16 A n integrated approach to health benefits management is essential to optimizing the quality and efficiency of pharmaceutical care. Such an approach is particularly important when managing care for patients infected with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). Since the introduction of multidrug, highly active antiretroviral therapy (HAART), the mortality rate for persons with HIV/AIDS has declined. Effective antiretroviral drug regimens have changed the consequences of HIV infection from an inevitable death sentence to a manageable chronic illness.
However, in order for long-term treatment of HIV infection to be effective, a high degree of patient adherence to antiretroviral drug regimens must be achieved. Unfortunately, the complexity and tolerability of HAART therapy have challenged patients' ability to maintain optimal adherence. As shown in Figure 1, even relatively small declines of 25% in patient adherence to antiretroviral treatment increase the rate of treatment failure. 1 High but suboptimal levels of adherence can expose HIV to subinhibitory drug concentrations and thereby open the door to viral mutations and antiretroviral drug resistance. As a result, suboptimal patient adherence to treatment increases the economic burden of managing HIV/AIDS. Benefit design, specialty network management, and pharmaceutical care programs play pivotal roles in addressing the issue of patient adherence to treatment and in optimizing HIV-related outcomes. Evidence-based principles form the foundation of each of these components in the delivery of a total health care benefit solution. Prescription drug list (PDL) tier placement should represent a drug' s total health care value, which is driven by pharmacoeconomic evidence, clinical effectiveness, and net acquisition cost. Specialty medication networks should be formed around evidence-based metrics that integrate clinical, economic, and humanistic outcomes. In addition, care management, disease management, and medication therapy management programs need to be driven by the very same evidence-based criteria and case assessments. The purpose of this report is to describe how these principles can be applied to successfully managing pharmaceutical benefits for HIV-infected patients.

s ss s Economic Burden of Antiretroviral Nonadherence
Antiretroviral medications are a prime example of drugs that provide a good return on investment. According to Bozzette et al., 2 HIV-associated drug costs have steadily increased as a percentage of total HIV-related health care spending (Figure 2). While the cost of drug therapy has increased in this population, the total cost of managing HIV has declined-from about $1,800 per patient per month (PPPM) in 1996 to just more than $1,500 PPPM in 1999. Viewed from a managed care perspective, such data show that antiretroviral medications represent a sound return on investment and an excellent example of pharmaceutical value.
Suboptimal adherence to treatment has serious consequences for the HIV-infected patient. The resultant decline in immune status, as indicated by a fall in the CD4+ cell count, signals disease progression, and as the rate of treatment failure increases, the overall costs of treatment subsequently increase. Another finding in the study by Bozzette et al. 2 showed that the cost of managing HIV-infected patients increases from $500 PPPM to approximately $2,500 PPPM when the CD4+ count drops from 500 cells/mm 3 to less than 50 cells/mm 3 . That cost-the incremental cost of treatment failure-is approximately $26,700 per year (adjusted to 2006 U.S. health care dollars).
Claims data can be used to identify patients who are nonadherent to medication. At any one time, 3% of HIV-treated enrollees are nonadherent (defined as a mean possession ratio of less than 0.85) to therapy (unpublished data; UnitedHealthcare, Edina, Minnesota;. Applying this prevalence figure of 3% to the costs derived from the Bozzette study reveals that the estimated direct health care costs of antiretroviral medication nonadherence is $0.03 PPPM. Moreover, applying this nonadherence rate to the estimated life expectancy after an HIV diagnosis (20 years) and to the yearly earnings of HIV-infected workers ($32,400) correlates to an estimated humanistic burden of 31.4 quality-adjusted lifeyears per 100,000 covered lives and an associated annual loss in productivity of $1.02 million.

s ss s Predictors of Nonadherence
To establish the determinants of patient adherence to antiretroviral therapy, Stone et al. 3 surveyed 299 patients infected with HIV on their opinions regarding 7 diverse HAART regimens, with each regimen rated according to 10 different attributes: number of pills (i.e., tablets and capsules) per day; tablet and capsule size; adverse effects; dietary restrictions; dosing frequency; need for dosing at bedtime; and the number of prescriptions, refills, medicine bottles, and required copayments. The survey results suggested that the main driver of antiretroviral adherence was "total pills per day," followed by "dosing frequency" and "adverse effects" (Figure 3). Respondents most preferred the regimen choice that included 2 pills twice daily with no food restrictions, 1 prescription, 1 refill, 1 medication bottle, and 1 copayment. (A fully oncedaily regimen was not available at the time of the survey and thus was not an option.) Although copayments ranked seventh in importance in the survey by Stone et al., a more recent study by Shrank et al. 4 found that formulary tier status was the leading predictor of adherence in a general population of health plan enrollees (i.e., the study was not specific to HIV-infected patients). Generic drugs were most strongly correlated with adherence (odds ratio [OR] 1.62; 95% confidence interval [CI], 1.39-1.89), followed by preferred brands (OR 1.3; 95% CI, 1.15-1.47). Other drivers of adherence were annual income and male gender; that is, higher rates of adherence are more likely in men and in those who have higher incomes. Differences in the findings from this study with those of Stone et al. may indicate that, relative to a general population of health plan enrollees, medication adherence among HIV-infected enrollees is less sensitive to formulary tier status and the associated member cost share.

s ss s Benefit Designs for Optimizing Outcomes
Designing simplified, easy-to-understand benefit plans for the HIV-infected patient is another way to optimize treatment outcomes. Benefit design needs to be based on total health value ( Figure 4). Formulary (or PDL) tier placement should represent a drug' s total health care value based on pharmacoeconomic evidence, clinical effectiveness, and net acquisition cost. If coordinated with effective consumer communication strategies, PDL placement can drive consumer decision making. In cases where a class of drugs is known to have great value (e.g., insulin and insulin test strips), and copayments could be a barrier to adherence, managed care organizations may even position branded products as first tier. This strategy drives total health care value when applied to therapeutic categories associated with both medication adherence issues and relatively large offsets in direct and indirect health care costs.

s ss s HIV Treatment: Progress and Continued Challenges
Treatment for HIV infection has advanced rapidly in the past decade. In 1996, 10 tablets or capsules 3 times daily was a typical regimen. Today, once-daily antiretroviral regimens with as few as 1 pill a day represent the standard of care. This evolution in the treatment of HIV infection has ameliorated the 2 biggest drivers of antiretroviral medication nonadherence: pill burden and dosing frequency.
Progress has also been made in reducing the adverse effects of antiretroviral therapies that have been associated with suboptimal adherence and treatment discontinuation. However, toxicity issues with many antiretroviral therapies remain an important consideration in the design of highly effective drug regimens. In 1998, Munk 5 showed that the common side effects associated with antiretroviral drugs-vomiting, nausea, diarrhea, headache, and fatigue-are all causes of missed doses, which subsequently lead to treatment failure and drug resistance.
Clinical research has shown that different combinations of antiretroviral drugs can have substantially different short-and longterm side-effect profiles. With more persons surviving HIV infection because of newer and more effective treatments, the long-term drug toxicities, such as those that impact cardiovascular risk, have become an important focus of HIV clinicians. 6 In an efficacy and safety randomized controlled trial by Gallant et al., 7 600 treatmentnaïve patients received either tenofovir disoproxil famurate (DF) (n = 299) or stavudine (n = 301) in combination with 2 other antiretroviral drugs. In an analysis of treatment effect on serum lipid levels, which was a secondary study end point, marked differences were noted between the tenofovir DF and stavudine treatment arms with respect to increases in triglyceride and cholesterol

FIGURE 4
Flowchart for developing formulary design based on total health value. ER = emergency room; FDA = U.S. Food and Drug Administration; P&T = pharmacy and therapeutics; Rx = prescription. levels. After 3 years of follow-up, 3 times as many patients treated with the stavudine-containing regimen experienced lipid abnormalities requiring treatment with lipid-lowering agents ( Figure 5). 8 Further, the results of a 48-week extension of this study reported by Madruga et al. demonstrated that stavudine-induced serum lipid abnormalities could be reversed by switching patients to a tenofovir-containing regimen. 9 The 85 patients evaluated in this extension study by Madruga et al. had received the stavudinecontaining regimen for a median duration of 152 weeks prior to being switched over into the tenofovir DF treatment arm.
The research published by Gallant and Madruga have major implications for managed care. Claims analyses of United-Healthcare databases revealed that 22% of 355 patients on antiretroviral treatment were also being prescribed lipid-lowering drugs, which not only directly increases the cost of care but also indirectly increases the cost because of the potential for unwanted drug-drug interactions (unpublished data; UnitedHealthcare, Edina, Minnesota; 2006). Of these, 74% of patients were being treated with antiretroviral agents most associated with lipid abnormalities (i.e., zalcitabine, didanosine, stavudine, or zidovudine). Such claims data analyses can help to identify treatment gaps and can be used as opportunities to provide information to patients and physicians to improve outcomes.
Anemia is another side effect of certain antiretroviral agents, particularly zidovudine. A recently reported study of treatmentrelated anemia showed that hemoglobin and hematocrit levels dropped significantly following treatment initiation with regimens that contained zidovudine. 10 Claims analyses have shown that 2% of HIV-infected patients are prescribed recombinant erythropoietin (EPO) to treat their anemia. Twenty-eight percent of these EPO users concomitantly received a zidovudine-containing regimen (unpublished data; UnitedHealthcare, Edina, Minnesota; 2006).

s ss s Evidence-Based Clinical Programs
Total health benefit management involves integrating evidencebased decision making into both clinical programs and benefit design to optimize the quality and efficiency of pharmaceutical care. Evidence-based medicine (EBM) criteria applied to claims databases can form the basis for integrating care coordination, disease management, and medication therapy management programs. EBM criteria may be used to identify cases of antiretroviral medication nonadherence, missing laboratory values (e.g., CD4+ count and viral load measurements), and lapsed clinic visits.

s ss s An Example of Clinical Care Integration
The following case demonstrates how evidence-based clinical programs can be integrated to optimize the quality and efficiency of pharmaceutical care for an HIV-infected enrollee.
EJ is a 43-year-old man with a diagnostic history of HIV/AIDS, depression, Pneumocystis carinii pneumonia (PCP), and oropharyngeal candidiasis. A query of his prescription drug claims history revealed that EJ was being treated with a HAART regimen, comprising zidovudine and lamivudine (Epivir) plus efavirenz (Sustiva), along with recombinant erythropoietin (Procrit), escitalopram (Lexapro), clarithromycin, lansoprazole (Prevacid), trimethoprim-sulfamethoxazole, and fenofibrate (Tricor). A proprietary EBM-rules engine identified 2 treatment gaps: the patient appeared to be nonadherent to efavirenz and to be concomitantly receiving zidovudine and erythropoietin. In addition to these treatment gaps, the rules engine revealed 2 opportunities on which EJ could act to reduce his out-of-pocket prescription drug expenses. If deemed appropriate by EJ and his physician, EJ could save money by using omeprazole (Prilosec OTC) rather than Prevacid and by participating in his health plan' s Lexapro tablet-splitting program. Medication therapy management letters were sent to EJ and each of his prescribing physicians to inform them of the treatment gaps and savings opportunities identified by the EBM-rules engine.
In addition to the information mailed to EJ and his physicians, EJ also received a customer service call from his health plan representative, during which EJ participated in an interactive voice response (IVR)-based assessment of his medication utilization patterns. The IVR-based assessment revealed 2 causes of EJ' s problems with medication adherence: (1) taking medications more than once a day is inconvenient for EJ and (2) sometimes he just forgets to take his medications as prescribed. Based on this assessment, the IVR system delivered customized advice that EJ could use to stay more adherent with his antiretroviral therapy. As a follow-up to the phone call, EJ' s health plan mailed to him the results of the IVR-based assessment, along with customized medication adherence "helpful hints." On receiving the results of his IVR-based assessment, EJ called his plan' s health information support line. The health information nurse confirmed EJ' s HIV diagnosis and provided him with coaching related to his health conditions, particularly stressing www.amcp.org Vol. 12, No. 7, S-b September 2006 JMCP Supplement to Journal of Managed Care Pharmacy S15

FIGURE 5
Comparison of antiretroviral drug regimens for time from start of treatment to use of first lipid-lowering agent. Adapted from Gallant et al., 2004. 8 the importance of adhering to his HAART regimen. The nurse also advised EJ to visit his HIV physician every 6 months and reinforced the money-saving advice that EJ received in the medication therapy management letters (i.e., the advice to use an over-the-counter alternative to Prevacid and to use tabletsplitting with Lexapro). Finally, the nurse guided EJ to his health plan' s Web site where he could access other information about the health conditions and services available to health plan enrollees.

s ss s Conclusions
Recent advancements in the treatment of HIV infection have dramatically improved survival rates among those infected with the virus. HIV has been transformed from a death sentence to a chronic condition that can be effectively managed through treatment. Today, the most critical barrier to successfully managing HIV disease is suboptimal patient adherence to antiretroviral therapy. Managing HIV infection is unique in that the risk of treatment failure increases remarkably with even relatively minor lapses in patient adherence. Treatment failure has been shown to increase by 13% when patient adherence falls to 75%. 1 This drop-off in adherence also drives HIV drug resistance, which, in turn, further increases the total cost of managing this disease.
The incremental cost of HIV treatment failure has been approximated at $26,000 per patient per year. Treatment failure, of course, also drives HIV/AIDS-related mortality. Benefit design, specialty medication management strategies, and care management programs can be integrated to deliver high-quality, efficient care to HIV-infected patients that reduces the risk of treatment failure.

DISCLOSURES
This article is based on the proceedings of a symposium held on April 6, 2006, at the Academy of Managed Care Pharmacy' s 2006 Educational Conference in Seattle, Washington, which was sponsored jointly by and AMCP Horizons, LLC and Creative Educational Concepts, Inc. and was supported through an educational grant from Gilead Sciences, Inc. The author received an honorarium from Gilead Sciences, Inc. for participation in the symposium. He discloses no potential bias or conflict of interest relating to this article.