HIV/AIDS Treatment as a Groundbreaking Model
for the Future of Disease Management

By Noah M. Pines, Executive Vice President, GfK V2

If you’d like a glimpse into the future of medicine, one therapeutic area to consider as a model is the treatment of HIV/AIDS. HIV/AIDS not only represents an astoundingly rapid victory of medicine and science over disease, having been essentially downgraded from a death sentence to a chronic, manageable illness in just a decade (in the Western world, at least), but also serves as a looking glass, largely because of three factors:

• HIV treatment has in many respects fulfilled the “promise” of personalized medicine, or the tailoring of treatment to an individual patient.



• HIV treatment has embraced a crucial future trend in chronic disease management – that of co-formulation – and even landmark cooperation among pharmaceutical manufacturers.



• HIV is historically among the most visible treatment areas from the standpoint of consumer activism, patient advocacy and patient involvement in treatment decisions.

As this article will show, other chronic disease areas, most notably hepatitis and oncology, already are looking to and adopting therapeutic archetypes similar to those which are now standard-of-care in treating HIV.

Personalized Medicine

During the 1990s, one popular prognostication with respect to the future of medicine was that by using the patient’s individual genetic blueprint, doctors would be able to tailor treatment for each patient. Futurists predicted a transition from the one-size-fits-all approach to a paradigm where therapy would be guided by genetic and other types of assays that would foretell how a given patient would respond – both in terms of the effectiveness of a medication as well as potential side effects and drug interactions.

That reality is here in the treatment of HIV/AIDS. Physicians routinely utilize both genotype and phenotype screening to determine the antiretroviral (ARV) regimen that is most likely to work both in situations where patients have virologically failed their ARV cocktail and with increasingly treatment-naïve patients to determine whether they have been infected with a virus already laden with mutations. Physicians also are starting to adopt a viral tropism assay to guide their prescribing of novel medications – namely Pfizer’s CCR5 Selzentry® (Maraviroc) – as well as a haplotype assay (the HLA B*5701 test) to determine a patient’s prospective risk of the Abacavir-related hypersensitivity reaction (HSR).

Genotyping

The HIV genotype test amplifies and thus reveals the mutations that have occurred in an individual patient’s viral genome. These mutations are the result of the virus having evolved due to insufficient suppression pressure of antiviral medications (thus underscoring the imperative for near-perfect compliance/adherence, which will be discussed later in this article). Specific mutations that occur during viral replication permit the virus to escape the inhibitory pressure of the medications. The virus’s evolving in order to survive is essentially Darwinism on a cellular level.

The clinical implication is that once these mutations occur, a given drug may no longer work (or may have reduced activity). For example, two common genetic mutations that result when a patient virologically fails the most widely prescribed first-line regimen are the K103N mutation, which causes resistance to Efavirenz (Sustiva®; Bristol-Myers Squibb), and the M184V mutation, which confers resistance to FTC (Emtriva®; Gilead Sciences) or 3TC (Epivir®; GSK).

A genotype assay therefore allows the physician to determine which ARV medications are most likely to continue to work in that specific patient, and thus which ARV regimen to prescribe next. Since mutations accumulate in patients who fail multiple treatment regimens, and because different mutations may have different implications (i.e., some mutations hypersensitize the virus to specific ARVs), the genotype test may become more challenging to interpret and thus less actionable. For example, while the M184V confers resistance to FTC and 3TC, as mentioned above, it makes the virus more sensitive to Tenofovir (Viread®; Gilead Sciences) and AZT (Retrovir®; GSK).

Phenotyping

The phenotype screening assay, on the other hand, evaluates the susceptibility of the virus to specific ARV medications. A true phenotype test involves the exposure of a sample of the patient’s blood in vitro to a panel of existing ARV medications to measure the amount of drug necessary to inhibit viral replication in a mutated virus relative to a standard viral strain. The output of a phenotype test – expressed as a fold change in sensitivity – indicates how active each ARV is likely to be, and thus helps the physician design a therapeutic regimen that is likely to work.

A third type of test, a virtual phenotype, uses matched genotypic samples (i.e., genotypic samples that have been matched to specific phenotypes) to establish a predictive measure as to the likelihood of a patient’s virus responding to a given ARV medication. Virco’s VirtualPhenotype® test offers the advantages of being cheaper and having a more rapid turnaround time than a formal phenotype test.

Other Assays Coming Online

Other tests also are used in HIV management to ascertain an individual patient’s candidacy for a specific medication. Data recently presented at the International AIDS Society meeting in Sydney, Australia, demonstrate the high predictive value of the HLA B*5701 haplotype assay in determining a given patient’s risk of experiencing a potentially life-threatening HSR in patients taking Abacavir. HLA B*5701 detects the presence of a specific allele, the absence of which is correlated with the low risk of developing this HSR. The negative test thus has high negative predictive value. Abacavir is marketed by GSK as Ziagen® and is co-formulated as part of Epzicom® (Lamivudine + Abacavir) and Trizivir® (Zidovudine + Lamivudine + Abacavir).

Additionally, with the recent launch of Pfizer’s CCR5 antagonist, Selzentry®, patients will be required to undergo HIV co-receptor tropism testing (Monogram’s Trofile® assay) to ascertain whether their virus is either R5- or X4- tropic and thus whether Selzentry® will be effective. Selzentry® is indicated for patients whose virus uses the CCR5 or “R5” co-receptor only (the co-receptor being a means by which a viral particle docks with a healthy cell).

Combination Therapy and Co-formulation

The watershed or turning point in the treatment of HIV – the point at which ARV medications were truly able to help patients live a full-length life – took place in 1995-1996 with the advent of HIV protease inhibitors and the recognition that lifelong combination therapy is required to keep the virus at bay. It is increasingly recognized that combination therapy is important in the management of other long-term illnesses, that is, that optimal management can only be produced by a cocktail of medications. This is true in cardiovascular medicine, diabetes and certain cancers.

The recognition of the need for combination therapy in the management of HIV, as well as the imperative to maintain a high degree of adherence (compliance), has led several companies to co-formulate their ARV medications. While co-formulation was previously frowned upon by physicians (due to the inability to identify the specific source of a side effect and/or inability to adjust doses of the individual medications), the adherence imperative in treating a chronic viral infection has superseded these concerns. Companies such as Gilead Sciences, GSK, Abbott and BMS have co-formulated their ARV medications to reduce the pill burden (number of pills that need to be taken by the patient) and thus facilitate long-term adherence.

Atripla®, a once-daily, one pill co-formulation of Gilead Sciences’ Truvada® and BMS’ Sustiva®, represents landmark cross-class cooperation among pharmaceutical manufacturers and is now an extremely popular first-line regimen in the treatment of HIV/AIDS.

Although there are no data to support this contention, physicians widely credit co-formulation of ARVs (as well as the advent of more well-tolerated ARVs and other factors) as having contributed to patients being able to remain on-treatment more long term and to less virologic failure. Additionally, physicians point to perceptual benefits of co-formulation in the sense that patients perceive themselves to be less sick if they have to take fewer pills (and thus have a more favorable outlook on taking their medicine, especially in an asymptomatic chronic condition where a pill is a reminder of their having a disease). Not only that, co-formulation also means patients with insurance pay fewer out-of-pocket co-pays.

Co-formulation is now being both considered and embraced in other therapeutic areas where synergies among medications afford better therapeutic responses (e.g., Vytorin® for hyperlipidemia, Caduet® for hypertension and hyperlipidemia).

The Active, Informed Patient

HIV treatment also serves as a groundbreaking model from the standpoint of both patient involvement in encouraging the development of new medications and involvement in the therapeutic decision-making process. From a historical perspective, the backlash of HIV activists against the Reagan Administration’s staggering lack of attention to HIV/AIDS during the early to mid-1980s was a key factor that promoted the accelerated development and approval of new ARV medications.

Groups such as ACT UP and Gay Men’s Health Crisis were highly influential in focusing popular attention and research dollars on HIV, producing rapid advancements starting with AZT in the late 1980s, other nucleoside reserve transcriptase inhibitors (NRTIs) in the early 1990s (e.g., d4T, ddI, ddC) and then the protease inhibitor revolution in the mid-1990s. Of note is the fact that many HIV care providers came from affected communities and identified intensely with the patients in their frustration with perceived governmental or industry’s lack of commitment.

Additionally, the initial dearth of agents and long-term data about these agents during the late 1980s and early 1990s led to patients empowering themselves with knowledge and essentially self-prescribing. Atripla® is a recent example of patient empowerment – as a result of its direct-to-consumer (DTC) exposure; patients are frequently coming into physicians’ offices requesting “the one pill.”

As a function of the life-long nature of treatment, experienced physicians who manage HIV/AIDS take the realistic standpoint that selecting a regimen depends on key patient lifestyle issues – their job, dosing frequency preferences, housing status, mental health issues, etc. Therefore, physicians actively involve the patient in the process of choosing a combination that will meet their lifestyle needs and thus foster greater likelihood of long-term adherence.

Conclusion

As this piece aims to show, the current treatment of HIV/AIDS offers a perspective on the future of medicine, especially the way in which cocktails of treatments are being personalized to a given patient’s virus characteristics. As well, recent progress in the management of HIV, including co-formulation and the involvement of patients in therapeutic decision making, has made HIV/AIDS a model for the management of chronic illness.

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