Final Thesis!

Running head: A.R.T. AND ISSUES OF ADHERENCE 1
An Evaluation of Antiretroviral Therapies and Issues of Adherence
William O. Miller
Thesis Supervisor: Dr. Andrew Lampkins
University of Evansville
8 November 2015
Author Note
I have written this paper in fulfillment of the requirements of Dr. John Lakey’s Senior Review
and Senior Thesis Course (PSYC 490) at the University of Evansville. I would like to thank Dr.
Andrew Lampkins, PharmD/PhD for his supervision of my thesis and Jennifer Morris, PharmD
for developing my interest in this field and serving as my mentor.
Any questions regarding this paper should be addressed to wm65@evansville.edu.

A.R.T. AND ISSUES OF ADHERENCE 2
Abstract
The treatment of HIV is an art, in that no two patients can be treated in exactly the same way.
The successful treatment of HIV requires a treatment plan that is personalized and malleable.
Perhaps the most challenging part of this treatment plan involves designing a medication
regimen, a result of the complexity of the virus. As a consequence of the virus’s tendency to
mutate and develop resistance, the recommended therapy for HIV involves a combination of
three medications, which must work in different manners to control viral replication. These
medications work to prevent HIV from replicating, but are not able to completely eradicate the
body of the virus. Unfortunately, this therapy is extremely reliant on high levels of adherence
and must often be taken in a specified manner to be effective. Thus, addressing adherence is one
of the most pressing issues in HIV treatment. To help improve adherence, efforts must be made
on the part of an entire health care team to design a specialized treatment plan and to better
understand the influence of treatment factors, provider factors, and patient factors in the
outcomes of this treatment. By understanding the available medications and the variables that
can influence their success, optimal treatment results can be achieved.
Key Terms and Abbreviations: HIV- Human Immunodeficiency Virus, ART-
Antiretroviral Therapy, HAART- Highly Active Antiretroviral Therapy, NRTIs- nucleoside
reverse transcriptase inhibitors, nnRTIs- non-nucleoside reverse transcriptase inhibitors, PIs-
protease inhibitors, INSTIs- integrase inhibitors, FIs- fusion inhibitors, CCR5 antagonists-
chemokine receptor antagonists, tenofovir DF- tenofovir disoproxil fumarate, STRs- single-tablet
regimens, MTRs- multiple-tablet regimens.

Table of Contents
I. Virus History and Early Treatments 4-5
II. Current Treatments
A. Medication Classes 5-8
B. Formation of a Regimen 10
C. Common Medications & Side Effects 9-16
D. Mutations and Changes in Therapy 16-17
III. Barriers to Adherence
A. Treatment Factors 17-18
B. Provider Factors 18-21
C. Patient Factors
1. Physical, mental, emotional health 21-22
2. Community and Social Factors
a. LGBTQ Community 22
b. Drug Use 23
IV. Discussion- Combination Therapy 23-25
V. Conclusion 26
VI. References 27-32
VII. Appendix

An Evaluation of Antiretroviral Therapies and Issues of Adherence
In 1981, the medical community was puzzled by the emergence of a new disease that led
to severe infections and rare cancers. The perplexing part was that it seemed to only affect
homosexual men. This set into motion the concept of a “gay plague,” which was in theory
discredited two years later with the first documented cases among heterosexual men. Just a few
years later the terms “HIV” and “AIDS” were coined and HIV was found to be the virus that
causes AIDS, but by that time there were already more than 7,000 documented AIDS cases
(Greene, 2007).
Flash-forward just thirty-two years later and it is estimated that more than 39 million
people have died from AIDS since the epidemic began. In 2013 alone, there were 2.1 million
new cases of HIV and 1.5 million deaths from AIDS (CDC). Despite the rapid pharmacological
advances in treatment, the virus is still wrecking havoc across the globe (Greene, 2007). Thus, in
addition to new developments in medicine, it is imperative that progress be made in other areas
as well. Progress must occur in the understanding of factors that influence the therapeutic
success of the available medications, in addition to the medications themselves. It is only by
treating the person rather than treating the disease that the virus will be controlled.
HIV is a retrovirus, a single-stranded positive-sense RNA virus that uses an enzyme
called reverse transcriptase to produce DNA from its RNA genome, the opposite of the usual
pattern described in the central dogma of biology. It then acts to integrate its DNA into the
genome of a host cell to be replicated using the machinery of the host cell, known as a CD4+ cell
(helper T cell). This interaction is fatal for the CD4+ cell, which has a particularly important
role in the adaptive immune system. These cells help to suppress or regulate immune responses
by communicating with other immune cells via cytokines. They are also involved in the

activation and development of cytotoxic T cells (killer T cells), in optimizing the actions of
phagocytes such as macrophages, and in B cell antibody class switching (Klatt, 2015). Loss of
these cells through HIV infection is responsible for the opportunistic infections associated with
the disease. Having fewer than 200 CD4+ cells per mm3 of blood, compared with about 1,000
CD4+ cells for uninfected people, is the key distinction between those who are infected with
HIV and those who are said to have AIDS (Klatt, 2015). At all CD4+ counts greater than 200
cells/mm3, it is incorrect to characterize this condition as AIDS.
In 1987, the FDA approved the first wonder drug for the treatment of HIV (Fischl, 1987).
AZT, under the trade name Retrovir, was the first of a class of drugs called nucleoside reverse
transcriptase inhibitors to be approved in the treatment of HIV. However, AZT has its
limitations and its drawbacks, perhaps the most significant of which being that it in addition to
affecting the replication of the virus, it also affects normal cell replication by partially blocking
the activity of human polymerase enzymes. This has the greatest impact on the muscle cells,
which have a high concentration of mitochondria. Thus, damage to muscle tissue, including the
heart, was common with AZT treatment. An additional unwanted effect was the suppressed
production of red and white blood cells (Fischl, 1987). Due to the rush to get an anti-HIV drug
to the market, little information was known about the mechanism of action or appropriate dosing
for AZT. For many, the improper dosing that often resulted led the drug to be ineffective or be
accompanied by too many severe side effects.
Since the advent of AZT in 1987, the FDA has approved many more medicines for the
treatment of HIV. These treatment options are divided into six classes by their mechanisms of
action: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase
inhibitors (nnRTIs), protease inhibitors (PIs), integrase inhibitors (INSTIs), fusion inhibitors

(FIs), and chemokine receptor antagonists (CCR5 antagonists). Each one of the classes works to
disrupt a different phase in the replication process of the virus. Therefore, these treatments do
not and cannot act to kill HIV, but instead work to prevent it from multiplying. Each class will
be discussed in detail and is summarized in the figure below.
Figure 1- Summary of the mechanisms of
actions of each of the common classes of
HIV therapies.
Figure adapted from LaBonte, J., Lebbos, J.,
& Kirkpatrick, P. (2003). Enfuvirtide,
Nature Reviews Drug Discovery, 2(5), 345-
346.
NRTIs interrupt the HIV replication cycle by inhibiting the viral enzyme reverse
transcriptase from functioning normally. As described previously, reverse transcriptase allows
the RNA of the virus to be converted into DNA, so that the host cell will replicate the virus.
NRTIs prevent this from happening as a result of their structure. Their structures are similar
enough to the nitrogenous bases of DNA (A,T,G,C) that they are able to become incorporated
into the virus’s DNA chain as it is being transcribed, thereby halting the transcription process
(Rathbun, 2015). Notable drugs that work in this manner are tenofovir DF (Viread®), lamivudine
(Epivir®), and emtricitabine (Emtriva®).

Tenofovir Adenine
Figure 2- Comparison between the structures of tenofovir (an NRTI) and adenine (a nitrogenous
base of DNA)
nnRTIs disrupt the same stage in the viral replication process as do NRTIs; however, they
do so differently. Instead of incorporating themselves into the DNA, nnRTIs act directly on
reverse transcriptase. Binding of nnRTIs to reverse transcriptase (at the p66 subunit) causes a
conformational change in the enzyme, modifying its active site. This alteration limits the activity
of the enzyme (Rathbun, 2015). Efavirenz (Sustiva®), etravirine (Intelence®), and rilpivirine
(Edurant®) are examples of commonly prescribed ARTs from this class.
PIs exhibit their effect by interfering with an enzyme called protease, which is
responsible for the development and maturation of viruses into their mature state. Specifically, it
cleaves proteins into functional subunits that are needed for the assembly of the viral capsid. PIs
function as competitive inhibitors of this enzyme, preventing it from performing its necessary
functions. Consequently, the viral capsid cannot form properly and the virus is not able to
mature into an infective state (Patick & Potts, 1998). Frequently prescribed medications from
this class include atazanavir (Reyataz®), darunavir (Prezista®), and lopinavir/ritonavir (Kaletra®).
INSTIs work by interfering with yet another enzyme that is necessary for HIV to
replicate: integrase. HIV integrase is needed for the virus to be able to incorporate its DNA

(which has just been converted from RNA) into the DNA of the host cell. INSTIs inhibit this
enzyme by binding metallic ions to its active site (Rathbun, 2015). This causes the strands of
viral DNA to be unable to covalently attach to the DNA of the host cell, effectively preventing
the DNA from being able to be replicated. INSTIs are comprised of compounds such as
raltegravir (Isentress®) and dolutegravir (Tivicay®). PIs and INSTIs are distinguished from
NRTIs and nnRTIs in that they do not interfere with the production of viral DNA. Instead, they
allow the DNA to be made, but prevent it from being reproduced.
FIs are distinguished from the previous classes of ARTs because they were the first class
of drugs to be developed that target the virus extracellularly. They work to prevent the fusion of
HIV with CD4+ cells. Specifically, FIs block the second step in the fusion pathway by
preventing the conformational change of a glycoprotein (gp41) that is necessary for proper
folding in the final step of the fusion process (Rathbun, 2015). There has only been one FI to
gain FDA approval thus far- enfuvirtide (Fuzeon®).
The most recent class of ARTs to be developed and approved were the CCR5
antagonists, which join FIs as drugs that block the entry of the virus into the cell. CCR5
antagonists prevent a different step in the fusion process, not allowing the V3 loop to be able to
bind to a chemokine coreceptor (Rao, 2009). This binding is necessary for the virus glycoprotein
to be able to insert itself into the host cell, and this is precisely what CCR5 antagonists work to
prevent. As CCR5 antagonists are the newest class of drug, there is currently only one drug from
this class on the market, maraviroc (Selzentry®).

Figure 3- Mechanism of action of CCR5 antagonists. CCR5 antagonists internalize the CCR5
receptor, preventing it from being expressed on the cell surface, so that the V3 loop of the HIV
glycoproteins are unable to bind to it.
Figure taken from Duri, K. (2012). Coreceptor Usage in HIV Infection. INTECH Open Access
Publisher.
Brand name Generic name Drug class Standard dosage
Viread® tenofovir disoproxil fumarate NRTI 1 tablet once daily
Emtriva® emtricitabine NRTI 1 capsule once daily
Ziagen® abacavir NRTI 1 tablet twice daily
Sustiva® efavirenz nnRTI 1 tablet once daily
Reyataz® atazanavir PI 2 tablets once daily
Prezista® darunavir PI 1 tablet once daily*
Isentress® raltegravir INSTI 1 tablet twice daily
Tivicay® dolutegravir INSTI 1 tablet once daily**
Fuzeon® enfuvirtide FI 2 injections daily
Selzentry® maraviroc CCR5 antagonist 1 tablet twice daily
*Must be boosted with Norvir® (ritonavir)
** Dosing may be increased to twice daily
Figure 4- Common HIV medications

The most common treatment for HIV involves the use of three drugs from two different
classes of medications, the combination of which is commonly referred to as a regimen
(AIDSinfo: What to Start, 2015). In treatment-naïve patients, there are two common courses of
treatment, one that is INSTI-based and one that is PI-based. INSTI-based regimens involve the
use of one INSTI and two NRTIs. PI-based regimens are comprised of one PI and two NRTIs
(AIDSinfo: Guidelines, 2009). Combinations of agents that have been recommended by the
Department of Health and Human Services include dolutegravir/abacavir/lamivudine,
dolutegravir/tenofovir DF/emtricitabine, elvitegravir/cobicistat/tenofovir DF/emtricitabine, and
raltegravir/tenofovir DF/emtricitabine. Thus, if taken individually, it is usually necessary to take
three to six pills each day. However, with these therapies it is possible to decrease the viral load
(number of copies of HIV RNA per milliliter of blood) from more than 100,000 copies/mL to an
undetectable level (less than 50 copies/mL) and increase the number of healthy CD4+ cells (De
Clercq, 2009). The immediately proceeding paragraphs will take a closer look at a few of the
most commonly prescribed medications among these.
Tenofovir disoproxil fumarate is one of the most commonly prescribed NRTIs, gaining
approval from the FDA in 2001. As shown in Figure 1, tenofovir DF is an adenine 5’
monophosphate analogue. In a 24-week randomized study, treatment-naïve patients who were
administered the standard dose of 300 mg tenofovir DF once daily experienced a 1.6 log10
copies/mL decrease in their viral load in just 21 days and treatment-experienced patients had a
0.6 log10 copies/mL decrease. Overall, 82% of total patients administered tenofovir DF had an
undetectable viral load by the end of the study and a mean increase of 264 CD4+ cells/mm3 was
seen (Gallant & Deresinski, 2003). However, there are some drawbacks to the drug that have a
negative effect on adherence. More than 10% of patients taking tenofovir DF report adverse

reactions including a rash, diarrhea, depression, or nausea (among others). More seriously,
tenofovir DF also contains warnings that worsening renal impairment (should not be used in
patients with a creatinine clearance of <50 mL/min), decreased bone density, and fat
redistribution are common side effects that must be continually monitored. Additionally,
tenofovir DF interacts with PIs to increase its own concentration and decrease the concentration
of the PI (Gallant & Deresinski, 2003). Thus, PI dosage must be adjusted in those taking PI-
based regimens.
Emtricitabine (FTC) and abacavir are two other commonly prescribed NRTIs. FTC is a
prodrug that must be phosphorylated into its active form. Once phosphorylated, like other
NRTIs, it is incorporated into elongated viral DNA to stop the replication of the virus. It also,
like other NRTIs, has the potential to impair mitochondrial DNA polymerases. Additionally,
skin discoloration is a very common side effect of FTC, along with the standard adverse
reactions associated with HIV medications (headache, depression, nausea, etc.). However, over
the course of phase I and phase II clinical trials, patients experienced a 1.3 log10 copies/mL
decrease in viral load with FTC as their only therapy. Furthermore, there are no known drug
interactions with FTC (Saravolatz & Saag, 2006). Abacavir also has the potential of achieving
great therapeutic success. In a 12 week study of patients treated with abacavir monotherapy,
11% of patients had undetectable viral loads, a 1.11-1.77 log10 copies/mL overall decrease was
seen in viral loads, and increases in CD4+ count were seen in all patients who completed the
study (Saag et al., 1998). Another benefit of abacavir (as is also the case with other NRTIs) is
that it is not required to be taken with food, eliminating one barrier to adherence. However,
abacavir is associated with a higher risk of adverse reactions, the most significant of which is a
hypersensitivity reaction. Hypersensitivity to abacavir occurs in 3.7% of patients and is a life-

threatening reaction that results in flu-like symptoms, including a fever and rash. Because of this
serious reaction, it is necessary to conduct the HLA-B 5701 test to look for hypersensitivity
before prescribing the therapy. Even with a negative result, therapy should be changed as soon
as possible should the symptoms of hypersensitivity become apparent (Hewitt, 2002).
In 1998, the FDA approved the use of another drug in the treatment of HIV- efavirenz (an
nnRTI). Since its introduction, efavirenz has had an essential role in HIV treatment. Studies
have shown that efavirenz has greater virological efficiency than either lopinavir/ritonavir or
abacavir (Maggiolo, 2009). It is commonly used as an alternative to PI-based regimens or
INSTI-based regimens, serving as the third agent to two NRTIs. In a Phase 2 double-blind,
randomized trial, after 48 weeks, 89% of patients treated with efavirenz as a third agent in
addition to two NRTIs had undetectable viral loads, a great success rate (Gazzard et al., 2011).
Thus, it is often used as part of a first-line treatment for HIV, with a 600mg dose once daily.
However, approximately 50% of subjects taking efavirenz experience neuropsychiatric
disturbances, such as vivid dreams, insomnia, and mood changes. This is exacerbated by the
need to take efavirenz at bedtime and on an empty stomach in order to minimize dizziness,
drowsiness, and impaired concentration. Efavirenz also can affect PI concentration and cause an
increase from baseline cholesterol levels, so these must be monitored as well (Kenedi & Goforth,
2011). As a result, the frequency of its use is declining and it is no longer recommended as a
part of first-line treatment.
Atazanavir and darunavir are among the most prescribed of the PIs, a growing class that
also includes the drugs lopinavir/ritonavir (Kaletra®), fosamprenavir (Lexiva®), and nelfinavir
(Viracept®). Atazanavir was the first PI approved for once daily dosing; however, it is necessary
to take either two 200mg capsules at a time or one 300 mg capsule that is boosted by 100mg

ritonavir. In combination with zidovudine (AZT), atazanavir succeeded in lowering viral loads
to an undetectable level in 37% of patients in a 48-week study (Havlir & O’Marro, 2004).
Atazanavir boosted with ritonavir is a popular first-line treatment among clinicians because it has
a low pill burden (the addition of 100mg ritonavir causes 300mg atazanavir to function as well as
600mg atazanavir in isolation) and functions well with tenofovir as the backbone of the treatment
(Havlir & O’Marro, 2004). Darunavir has also taken on a large role in recent HIV therapy
trends. It is also taken once daily (unless previous mutations decrease its effectiveness, then
twice daily) in combination with ritonavir. In a 192-week trial, ritonavir-boosted darunavir
monotherapy led to an undetectable viral load in 68.8% of patients (Orkin et al., 2013).
Darunavir is known for its potency, thus it is often used in patients with very high viral loads
(>100,000 copies/mL). Another benefit of darunavir is that the development of resistance via
mutations is very rare in treatment-naïve patients (Orkin et al., 2013). Despite the great benefits
of protease inhibitors and their growing role in HIV therapy, there are several drawbacks. First,
PIs must often be boosted with ritonavir and are usually dosed more than once daily (with the
exceptions of atazanavir and darunavir). Second, nearly all PIs must be taken with food. Both of
these can be barriers to adherence, particularly in low-income communities, where the
availability of two well-balanced meals each day cannot be taken for granted. Third, PIs are
associated with metabolic abnormalities such as lipodystrophy (fat redistribution), significant
hyperlipidemia, and insulin resistance. This is complicated by the fact that the most common
and inexpensive treatments for hyperlipidemia (simvastatin and lovastatin) are unable to be used
because they are metabolized by the same enzymes as PIs (CYP3A4). Other medicines such as
atorvastatin and fenofibrate may be used, but their levels can be affected as well, so treatment for
hyperlipidemia caused by PIs remains difficult (Penzak & Chuck, 2002).

INSTIs may also be used as the third agent in an HIV regimen. Both of the INSTIs that
have been approved by the FDA are widely used. The first INSTI to be approved, raltegravir,
when used in combination with tenofovir DF and lamivudine (NRTIs), saw 83% of its 198
recipients achieve undetectable viral loads (Hicks & Gulick, 2009). It has been noted to work
much more quickly than other therapies such as efavirenz, thus it has benefit in cases involving
extremely high viral loads and very low CD4+ counts. The development of raltegravir was an
important advancement in HIV treatment options, as there are many aspects that set raltegravir
apart from other treatments. First, raltegravir (and dolutegravir) affect the integrase enzyme, of
which there is no homolog in humans, allowing for specificity of the drug target. Second,
raltegravir is metabolized differently than other HIV therapies. Instead of being metabolized
hepatically, raltegravir is metabolized via glucuronidation, which is illustrated in the figure
below. Because it is metabolized differently, the potential for drug-drug interactions is
decreased greatly (Hicks & Gulick, 2009).

Figure 4 (above)- Contrasting the metabolism of raltegravir via glucuronidation with the
metabolism of tenofovir DF via a hepatic mechanism.
Raltegravir metabolism figure taken from Kassahun, K., McIntosh, I., Cui, D., Hreniuk, D.,
Merschman, S., Lasseter, K., ... & Wenning, L. A. (2007). Metabolism and disposition in
humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency
virus 1 integrase enzyme. Drug Metabolism and Disposition, 35(9), 1657-1663.
Tenofovir DF metabolism figure taken from Andrade, C. H., Freitas, L. M. D., & Oliveira, V. D.
(2011). Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism. Brazilian
Journal of Pharmaceutical Sciences, 47(2), 209-230.
Unfortunately, in order to reap all the benefits associated with raltegravir treatment, an extremely
high adherence rate is required. This occurs because resistance rates are extremely high among
those who experience virologic failure (Hicks & Gulick, 2009). Multiple mutations (most
commonly Y143, Q148, and N155) lead to this resistance, which is especially common in
patients who had a high viral load at the beginning of treatment. Raltegravir does not have a
food requirement, but it must be taken twice daily. Dolutegravir, the other commonly prescribed
INSTI) performs similarly to raltegravir. The differences lie in that dolutegravir is partially
metabolized by CYP3A (although primarily by glucuronidation), so comparatively there is an
increased risk of drug-drug interactions (including interactions with products containing
aluminum, iron, magnesium, and calcium, among others), that there is a chance of
hypersensitivity (though not as large as with abacavir), and that it has the benefit of once daily
administration (Osterholzer & Goldman, 2014).
Enfuvirtide is distinct from other treatments discussed so far in multiple ways. First, it is
the only injectable treatment used in the treatment of HIV. This alone greatly decreases the
frequency in which it is utilized, as the majority of the population prefers orally administered
regimens. Second, it exhibits its effect on the virus before it is even able to enter the host cell.
Thus, studies have found it to be very effective, evidenced by substantial decreases in the viral

load at 24 weeks, a fewer than normal number of occurrences of virologic failure, and an
increase in the CD4+ cell count (Lalezari et al., 2003). Enfuvirtide is most commonly used in
patients with multi-drug resistance, in combination with two other agents. However, the
introduction of novel integrase inhibitors and the high cost and parental administration of
enfuvirtide limit its use.
Maraviroc is the only drug to have been approved for the treatment of HIV thus far that
exerts its effect on a host protein, rather than on the virus. By blocking the chemokine receptor
CCR5, it prevents the virus from entering the cell in the majority of cases. In the other 10% of
cases, HIV enters the cell via the CXCR4 receptor, in which cases maraviroc is ineffective.
Thus, a tropism assay (e.g. Monogram Bioscience's Trofile) must be completed to determine
which receptor the virus uses for entry before beginning treatment with maraviroc. Maraviroc is
a substrate of CYP3A, so it is necessary to closely monitor the potential for drug-drug
interactions. Resistance to maraviroc can occur if the virus becomes able to utilize the CXCR4
receptor or if mutations occur along the V3 loop (MacArthur & Novak, 2008). Because of the
elevated risk of resistance or ineffectiveness, maraviroc is used only in combination with two
other agents (both of which cannot be nucleoside analogue reverse transcriptase inhibitors) and
can only be used in those who are treatment-experienced. However, in those situations in which
it is approved for use, maraviroc has been associated with a substantial mean viral load reduction
of 1.42 log10 copies/mL (MacArthur & Novak, 2008). Maraviroc is dosed two times daily and
does not have any dietary requirements.
The use of three therapeutic agents in the treatment of HIV is a direct consequence of the
rapid replication of the virus. Such quick replication inevitably leads to more mutations, which
are not corrected due to HIV’s lack of a proofreading enzyme. Some estimates put this mutation

rate as high as one mutation per 70 polymerized nucleotides (Roberts et al., 1988). Many of
these mutations are harmless or harmful to the virus, but some mutations are beneficial. The
virus’s beneficial mutations could make it resistant to a certain type of therapy or a certain drug
in particular. By treating with three drugs from two different classes, the greatest chance at
controlling the virus is realized. Two of the most commonly seen mutations are M184V and
K103N. The M184V mutation is both beneficial and detrimental to the virus. It is beneficial in
that with this mutation it incurs high levels of resistance to lamivudine and emtricitabine, but is
detrimental in that the virus becomes more susceptible to other NRTIs. Thus, in the treatment of
the virus, the number of possible antiretroviral agents is decreased, but those that remain have
the potential of being more effective (Gallant, 2006). Meanwhile, the K103N mutation knocks
out the effects of efavirenz and nevirapine by a factor of fifty (Mackie, 2006). Fortunately, these
mutations are largely preventable. By achieving high levels of adherence (meaning “to stick
firmly” to an HIV regimen) with the prescribed treatment, it is unlikely that these mutations will
occur (AIDSinfo: HIV, 2015). Low levels of adherence or frequent missed doses allow the virus
to replicate more quickly, increasing the chance of such a mutation. Due to the relatively small
number of possible therapies and the challenging process of changing therapies, it is extremely
important to minimize these mutations. Thus, high adherence rates are essential in the treatment
of HIV, more so than with nearly any other condition. Minor lapses in treatment can have long-
lasting effects. Therefore, it is critical that a great deal of emphasis be placed on adherence and
finding ways to help patients improve their adherence.
There are many factors other than mere forgetfulness that affects a patient’s adherence in
taking their medications. To improve their adherence, it is important to understand these factors.
The first of these factors are the medications themselves. As described above, there are many

potential side effects associated with each medicine. The need to take three medicines increases
the risk that there will be at least one adverse reaction. It is not uncommon for patients to quit
taking their medicines until their next appointment with their health care provider if one of the
side effects becomes too bothersome.
Additional factors associated with the medication itself that may impede adherence are
the complexity of the regimen and the cost. As described previously, each medication has
certain dosing schedules and certain nutritional requirements that must be met in order for the
therapy to be effective. Simple pill burden can be a big factor. A regimen that requires four
different medications twice daily (three active agents plus boosting with ritonavir) is much less
likely to achieve high adherence rates than is a regimen that requires one pill once daily. This
complex dosing schedule can be even further complicated by the other medicines that a patient
must take. Medications for seizures (phenobarbital, phenytoin, and carbamazepine), GERD
(gastroesophageal reflux disease), high cholesterol (simvastatin and lovastatin) and vitamin
supplements (iron and calcium) must usually be avoided altogether or taken at a different time
than the regimen drugs are taken (Sidhpura, 2015). This could result in a patient needing to take
medication four to five times a day, an unrealistic expectation for those with a busy schedule.
Surprising to many is that perhaps the most challenging part of meeting medication requirements
is fulfilling the food requirement. For many who live in poverty, live migrant lifestyles, or work
erratic schedules, the timing of their next meal is often unpredictable. Struggling to meet the
food requirements of a drug has the potential to decrease the effectiveness of the drug and have a
negative impact on patient adherence.
The average yearly cost for ART is $23,000 (CDC, 2015). This is a huge number that
would seem an insurmountable amount to many. As a result, it would be reasonable to think that

an inability to afford medications would be the greatest barrier to adherence. However, this need
not be the case. Cost is an issue that usually can be resolved by effective communication and a
strong relationship between a patient and his or her providers, as well as by communication
between providers. The most challenging part of financing HIV medication involves securing
health insurance. Once this coverage is acquired, insurance companies are usually willing to pay
for ART in order to prevent higher medical costs in the future. If they are not, the role of the
pharmacist becomes especially important. By working with the insurance company and
physician, pharmacists are usually able to secure coverage for the treatment through a series of
prior authorizations and appeals. If one has difficulty finding health insurance, there are
programs available that are willing to cover the cost of ART therapy, such as the Ryan White
CARE Act and the AIDS Drug Assistance Program (ADAP), as long as income requirements are
met (Buchanan & Smith, 2008). If funding is not able to be obtained through insurance or one of
these programs, drug companies are often willing to supply the medication at highly discounted
rates or for no charge. It is critical that the provider makes the patient aware of their options so
that treatment adherence is not affected by limited access to financial resources.
The provider is responsible for promoting adherence in other manners as well. Providers
can accomplish this by establishing a positive patient-provider relationship, educating the patient
about the most important aspects of their therapy, getting to know the patient on a personal level,
and by keeping the patient accountable via routine monitoring. The quality of a patient-provider
relationship is often determined by the patient’s perceptions of provider competence,
“communication quality and clarity, compassion, willingness to include patients in treatment
decisions, adequacy of referrals, and convenience of visiting the doctor” (Chesney, 2000).
Patients need to feel that the provider is on their side and is there to do the best he or she can do

to help them. By making an effort to communicate clearly and including the patient in their own
healthcare decisions, adherence is likely to be less of an issue.
It is also critical for the provider to focus on educating the patient, rather than simply
treating them. If a patient has at least a basic understanding of his or her therapy, long-term
benefits are likely to be seen in treatment efficacy. It is important that the patient understands
the timing and dosing of medications (and are presented with ideas on how to best manage this),
the need to check with the provider before self-medicating, and the urgency of adherence in
order to minimize medication errors, reduce the possibility of treatment resistance, and achieve
the maximum possible benefit of a therapy (Chesney, 1997; Fogarty et al., 2002).
The importance of getting to know the patient on a personal level extends beyond the
need for a strong patient-provider relationship. To optimally treat a patient, a provider should be
aware of their patient’s lifestyle, home life, and mental and emotional health. This is vital for the
formation of a treatment plan that is specific for the patient and meets his or her needs. For
example, a patient who is unemployed and lives in a homeless shelter is more at-risk for
complications related to a failure to meet the nutritional requirements of medications. Another
patient who has a history of repeated suicide attempts must not be considered for treatment with
efavirenz. Other patients might not have the luxury of a secure home life. For these patients it is
important that the provider serve as a source of support and offer suggestions for how to best
handle their situation in order to improve the patient’s health and well being. All of these
scenarios would give the provider insight into the motivations of the patient in order to formulate
the optimal course of therapy that is personalized for the patient.
Lastly, providers need to do their best to hold the patient accountable for their own
treatment. Physicians should perform routine tests of viral load and CD4+ counts and should

discuss missed doses and adherence-related issues with their patients. This not only increases
the chances of improved adherence, but also allows physicians to change from reacting to viral
rebound toward working to proactively prevent it and formulate alternative plans of action. This
helps guide providers in regimen selection and helps prevent complications associated with
nonadherence (Bangsberg, 2008). Pharmacists also play an important role in holding the patient
accountable by giving refill reminders, inquiring about missed doses, and supplying the patient
with resources to increase his or her organization and adherence.
The treatment of a person afflicted with HIV must not be the sole responsibility of the
physician and the pharmacist. It is essential to not just treat the disease with medication, but to
devise a combination of treatments that is best for the patient’s physical, mental, and emotional
well-being. This may require a team of therapists, social workers, family counselors, drug and
addiction counselors, support groups, and friends and family, among others. The focus on
treating the patient rather than the disease is sure to lead to the best outcome for the patient. As
issues such as stress, age, mental illness, substance abuse, and lack of support from friends and
family can all have negative effects on adherence and on overall therapy success, these
additional members of the health care team are critical.
For most patients, nonadherence is neither always a matter of forgetfulness, nor is it a
deliberate choice. It is often a result of one or more behavioral, structural, and psychosocial
barriers, such as “depression and other mental illnesses, neurocognitive impairment, low health
literacy, low levels of social support, stressful life events, high levels of alcohol consumption and
active substance use, homelessness, poverty, nondisclosure of HIV serostatus, denial, stigma,
and inconsistent access to medications” (AIDSinfo: Guidelines, 2009). This is why the
collaboration of a team of health care workers is necessary to optimally treat a patient. Without

fulfilling all the patient’s physical, mental, and emotional needs, all types of treatment are likely
to be less successful. For example, adolescent patients as a group have been seen to have more
difficulty achieving necessary levels of adherence than adult patients. Thus, in general, they
require a greater level of attention than adult patients. In other cases where forgetfulness really
is the root of adherence problems, techniques such as linking the act of taking medication to
daily activities or using a medication reminder app or a pill organizer should be suggested
(AIDSinfo: Guidelines, 2009).
According to the CDC (Centers for Disease Control and Prevention), men who have sex
with men make up approximately 2% of the United States population, but make up the majority
of those affected by HIV. In 2011, it was reported that 57% of those diagnosed with HIV were
gay or bisexual men (Wejnert et al., 2013). Research has found that this population finds that
coming to terms with the diagnosis and learning to take medication on a daily basis are among
the greatest barriers to adherence. This is said to be alleviated by finding motivating factors,
such as obligations to others or the fear of dying, and by depending on others, such as partners
and family members (Brion & Menke, 2008). However, the factor that most influences
adherence rates among members of the gay community is the stigma, perceived or real, of having
HIV and taking medications. A 2008 study of gay men showed that concerns about the negative
impact that their condition could have on areas of their lives such as employment, insurance, and
relationships with friends and family were detrimental to adherence, as many patients reported
that hiding their status was easier before they began taking medications. To cover up their
medication use, many resorted to missing doses or changing schedules. This is a direct example
of how social situations can affect medication adherence. Thus, it is pertinent for providers to
offer support for these patients and work to help them “own the disease” (Brion & Menke, 2008).

Intravenous drug users also make up a large percentage of the HIV-infected population.
In the case of this population, their drug use not only gives them the condition, but it also makes
it less likely that they will be adherent. A study by Halkitis and Palamar in 2008 examined a
sample of drug users among a population of HIV-infected gay and bisexual men and found that
94.1% of non-drug users reported high levels of adherence, whereas 87.7% of drug users
reported high levels of adherence. Drug use was also found to be associated with higher
incidences of poverty and mental illness, which are both risk factors for lower levels of
adherence (Halkitis & Palamar, 2008). Therefore, drug users require a much higher level of care
that demands the attention of an entire health care team, with emphasis on addiction and drug
counseling.
In addition to the above-mentioned ways of improving adherence, pharmaceutical
companies have begun to tackle the issue in the last fifteen years. Instead of focusing most of
their attention on developing novel therapies, these companies are working to produce fixed-dose
combination pills. The idea is that by decreasing pill burden (to the eventual goal of one tablet
once daily) adherence rates will be positively affected. The fixed-dose combination therapies
that have been approved by the FDA are summarized in the table below.
Brand name Drug Names FDA Approval Date
Combivir® lamivudine & zidovudine September 26, 1997
Kaletra® lopinavir & ritonavir September 15, 2000
Trizivir® abacavir, lamivudine, & zidovudine November 15, 2000
Epzicom® abacavir & lamivudine August 2, 2004
Truvada® tenofovir & emtricitabine August 2, 2004
Atripla®* emtricitabine, tenofovir, & efavirenz July 12, 2006

Complera®* emtricitabine, rilpivirine, & tenofovir August 10, 2011
Stribld®* elvitegravir, cobicistat, emtricitabine, &
tenofovir DF
August 27, 2012
Triumeq®* abacavir, dolutegravir, & lamivudine August 22, 2014
Evotaz® atazanavir & cobicistat January 29, 2015
Prezcobix® darunavir & cobicistat January 29, 2015
Dutrebis® lamivudine & raltegravir February 6, 2015
Genvoya®* elvitegravir, cobicistat, emtricitabine, &
tenofovir AF
November 5, 2015
*A complete one-pill, once daily regimen
Figure 5- Approved fixed dose combinations in the United States
These fixed-dose combination therapies allow the daily pill burden of the approved first-line
ART to decrease as follows: dolutegravir/abacavir/lamivudine: 4 to 1,
dolutegravir/tenofovir DF/emtricitabine: 3 to 2, elvitegravir/cobicistat/tenofovir
DF/emtricitabine: 4 to 1, and raltegravir/tenofovir DF/emtricitabine: 4 to 3.
In a series of study results that were provided for the purpose of this review by Gilead
Sciences (provided in Appendix A), single-tablet regimens (STRs) were compared to multi-tablet
regimens (2 NRTIs plus nnRTI/PI/INSTI) (MTRs) in terms of adherence, number of
hospitalizations, and rates of virologic suppression. All these variables were benefitted by the
use of a single-tablet regimen. Adherence rates above 95% were seen 75% of the time in
patients taking STRs, versus only 56% of the time in patients taking MTRs. This difference was
also seen at a threshold of 80% adherence, with 90% of STR patients meeting this threshold, in

comparison to 78% of MTR patients. This improvement in adherence seen with STRs is likely
due to eliminating the possibility of partial adherence, defined as failing to take one or more
components of the daily regimen. While complete non-adherence rates were comparable to
those of MTR patients (10%), partial adherence was not a factor for STR patients, as it was in
those taking MTRs (an additional 11% had only partial adherence). Therefore, STR patients had
significantly more days with a complete regimen (90% versus 79%). STRs were also associated
with greatly decreased hospitalization rates (17.7% versus 30.7%), which reflect the better
overall average health of those taking STRs and greatly reduce the total cost of treatment. Also
likely a consequence of better adherence, patients with STR were associated with numerically
greater rates of virologic suppression and CD4+ > 500 cells/mm3 (STR: 96% virologic
suppression and 61% CD4+ > 500 cells/mm3; MTR: 84% average virologic suppression and
44% CD4+ > 500 cells/mm3). This data was been replicated in several other studies, showing
that the focus of pharmaceutical companies on fixed-dose combination products is worthwhile,
as it has remarkable effects on adherence (Bangsberg et al., 2010).
Despite the notable benefits of fixed-dose combination therapies, they are not appropriate
for everyone. These therapies are often not possible for patients who have incurred resistance to
multiple agents. Others who failed their first ART regimen, have severely impaired kidney
function, or have debilitating psychiatric conditions may not have the ability to take advantage of
fixed-dose combination therapies (Squires et al., 2004). These patients will likely need a more
specialized regimen that consists of individually chosen agents. Additionally, by combining
medications it becomes difficult to discern which agent is the cause of any side effects that might
be experienced. This is problematic when the side effects are severe enough to warrant a change
in therapy.

Recent advances in medication therapy have provided ample options for the management
of HIV, such that regimens can be specialized to patients on a case-by-case basis. However, low
adherence rates prevent the medications from reaching their maximal therapeutic value and
increase the probability of treatment failure as a result of viral mutations. Therefore, it is crucial
to take steps to increase adherence rates. This is accomplished by the collaboration of an entire
team to provide the best care for the patient. The physician and pharmacist must work together
with the patient to design a regimen that is most effective and causes the fewest adverse effects
in the patient, to develop a strong patient-provider relationship, to educate the patient, to hold the
patient accountable, and to keep the patient involved in their own health care. Therapists,
support groups, and friends and family must work together to promote the physical, mental,
emotional, and social well-being of the patient. Patients must take responsibility for their own
health by becoming educated about their treatments and taking measures to ensure adherence,
such as using pill organizers or medication reminder apps. Recent developments regarding
fixed-dose combination therapies open the door for simplified regimens that lead to drastic
improvements in adherence rates and greater patient health and satisfaction. Only by
implementing all of these aspects into the treatment of a patient is the patient sure to have the
best possible care and quality of life.

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Appendix
Gilead Sciences Research Findings- Provided Powerpoint Slides
1
‡
Disclaimer
These non-promotional slides are intended to
be used as educational material only in
response to an unsolicited question or request.
The double-dagger (‡) symbol indicates that
these slides may contain information that is not
within FDA approved product labeling and has
not otherwise been approved by the FDA.
2
‡
Better Adherence for STRs vs Multi-tablet Regimens (MTRs)
§ After adjusting for covariates at
study entry, STR patients were
two times more likely to be
adherent compared to MTR
patients
VA Study: STR vs. MTR
STR: Single-tablet regimen, MTR: multiple tablet regimen
Rao GA, et al. ICAAC 2013. Denver, CO. #H-1464
90
7578
56
0%
20%
40%
60%
80%
100%
≥80% ≥95%
%ofPatients
Adherence Threshold
STR MTR
* Calculated using pharmacy claims data [medication possession ratio (MPR)] = [sum of days supply to all HAART regimen components (excluding days of last fill)/last fill
date-first fill date] X 100%
Adherence threshold Odd Ratio† (95% CI)
≥ 80% 2.16 (1.92,2.43)
≥ 95% 1.98 (1.81,2.17)
P<0.001P<0.001
Significantly higher proportion of patients were adherent by either the 95% or 80%
adherence threshold with STR compared to MTR
† Odds ratio adjusted for covariates at study entry: age, race,
geographic region, Charlson comorbidity index, mental health
disorders, drug/alcohol abuse disorders, index year, treatment-
naïve status, undetectable viral load
Evaluation of adherence and hospitalization in patients receiving STR (n=6,191) or
MTR ≥ 2 tablets/day (n=9,411) from Jan 2006 - July 2012
# 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) plus a third agent non-nucleoside/nucleotide reverse transcriptase inhibitor (NNRTI), protease inhibitor
(PI), another NRTI, chemokine receptor 5 antagonist (CCR5), or integrase inhibitor (INI)

3
‡
Clinical Outcomes: Higher rates of viral suppression for STRs
§ After accounting for viral load
detectability and other
covariates at study entry, the
STR cohort had 21% greater
odds of having an
undetectable viral load during
follow up
– OR* (95% CI): 1.21 (1.11,
1.32) P<0.001
VA Study: STR vs. MTR
*Odds ratio adjusted for covariates at study entry: age, race, geographic region, Charlson comorbidity index, mental health disorders,
drug/alcohol abuse disorders, Index year, treatment-naïve status, undetectable viral load
STR: Single-tablet regimen, MTR: multiple tablet regimen
42%
64%
46%
60%
0%
20%
40%
60%
80%
100%
At Index Date Follow-up
STR MTR
P<0.001
P<0.001
%withundetectableviralload
Significantly higher rates of undetectable viral load during follow-up with STR vs. MTR
Evaluation of adherence and hospitalization in patients receiving STR (n=6,191) or
MTR ≥ 2 tablets/day (n=9,411) from Jan 2006 - July 2012
4
‡
Partial and Complete
Non-Adherence to ART Regimens
LifeLink Database
PercentageofDays
Complete
Non-adherence
NNRTI
n=657
STR
n=1,751
Boosted PI
n=1,601
Raltegravir
n=522
Retrospective analysis of US healthcare claims for commercially insured population
(n=4,588) receiving 2 NRTIs plus NNRTI or PI or INSTI based ART (2009 – 2011)
11% 8%
7%
0%
10%
20%
10%
8%
12%
10%
P<0.0001
P<0.0001
P<0.0001
20%
15%
21%
Partial Adherence
10%
STR patients had significantly more days with a complete regimen
Cohen C, et al. ICAAC 2012; San Francisco, CA. #H-211

5
‡
Adherence and Clinical Outcomes
of STR vs. Multi-Pill Regimens
Evaluation of outcomes in observational, retrospective cohort of 1,604 HIV+ pts
(2008-2010)
COMPACT: Italy
Antinori A, et al. HIV-11 2012; Glasgow. P14
14
13
20
3
23
6
20
0
10
20
30
40
STR PI NNRTI RAL
%offollow-up
Non-Adherence to cART Regimens (days)
Complete Non-Adherence Selective Non-Adherence
61
44 48
42
96
78
88 87
0
20
40
60
80
100
STR PI NNRTI RAL
%Patients
CD4 > 500 cells/mm HIV-1 RNA <50c/mL
Viral Load and CD4 at End of Follow-Up
(n=709)
STR was associated with higher adherence vs. multi-pill regimens and with
numerically greater rates of virologic suppression and CD4 > 500 cells/mm3
20
29
23
27
3
n=159 n=878 n=523 n=44
6
‡
Real-World Adherence with STR versus MTR
Evaluation of published associations among use of STR vs. MTR, ART adherence
and treatment efficacy/effectiveness
STR vs. MTR: A Systematic Review and Meta-Analysis of Real World Adherence
Sweet D, et al. IAC 2014. Melbourne, Australia. #THPE421
Meta-analysis: odds of achieving ≥95% real-world
adherence with STR vs. MTR
In comparative real-world studies, patients receiving STRs vs.
MTRs had a 70% greater odds of achieving ≥95% adherence

7
‡
Risk without Hospitalization
STR subjects had 31% lower risk of hospitalization vs. MTR (P<0.001)
VA Study: STR vs. Multiple Tablet Regimen (MTR)
* Hazard ratio adjusted for covariates at study entry: age, race, geographic region, Charlson comorbidity index, mental health disorders, drug/alcohol abuse
disorders, index year, treatment-naïve status, undetectable viral load
† Supported by funding from Gilead Sciences
STR: 66.2%
MTR: 58.7%
Hazard ratio* (95% CI): 0.69 (0.64, 0.74)
Time to first hospitalization in days
Proportionofsubjectswithout
Hospitalizations,%
Retrospective analysis of 15,602 HIV+ patients in the US VA database evaluating the impact of
STR (n=6,191) vs. MTR (≥2 tablets/day; n=9,411) on adherence & hospitalization risk (1/06-7/12)†
0%
20%
40%
60%
80%
100 %
0 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080
8
‡
Association of Adherence and Hospitalization Rate
LifeLink Database
N/A
Complete and Partial Non Adherence*Complete Non-adherence only
Hospitalization rate adjusted for differences between groups including complete non-adherence, treatment status
at index, age, geographic location, plan and types.
* Partial Adherence: Patients with at least 5% of days with either no NRTIs or no 3rd agents.
OR: 1.43
P<0.0001
OR: 1.54
P<0.0001
OR: 1.50
P<0.0001
Among non-STR cohorts, patients who were completely and partially non-adherent were
significantly more likely to be hospitalized vs. those only completely non adherent
AdjustedHospitalizationRate,%Patients
Cohen C, et al. ICAAC 2012; San Francisco, CA. #H-211
NNRTI
n=657
STR
n=1,751
Boosted PI
n=1,601
Raltegravir
n=522
10% 10% 10% 10%
15%
16% 15%
0%
5%
10%
15%
20%
25%

9
‡
Partial Adherence to ART & Hospitalizations
Medicaid Database
Cohen C, et al. HIV-11 2012; Glasgow, UK. P1
Retrospective analysis of US Medicaid Claims Database (n=6,938)
receiving 2 NRTIs plus NNRTI or PI or INSTI based ART (2009 – 2011)
%ofARTduration
14%
16%
14% 14%
12% 7%
7%
0%
10%
20%
30%
STR based
HAART
(n=1,878)
NNRTI based HAART
(n=775)
Boosted PI based
HAART (n=3,556)
Raltegravir based
HAART (n=729)
P<0.0001
P<0.0001
P<0.0001
• Complete non-adherence was similar across regimens, while partial adherence was only
seen with non-STR regimens
• Patients on a STR had significantly better complete adherence to their HIV regimen
Partial Adherence
(not all ARV available)
Complete Non-adherence
(no ARV)
26%
23%
14%
21%
10
‡
Association of Adherence and Hospitalization Rate
Medicaid Database
Partial adherence to non-STR regimens associated with a significant increased risk of
hospitalization (43-54%) in addition to the risk associated with complete non-adherence
AdjustedHospitalizationRate,%Patients
Cohen C, et al. HIV-11 2012; Glasgow, UK. P1.
Keith Davis. Personal communication. April 29, 2012.
20.9%
19.7% 18.7% 17.7%
30.7%
29.0% 29.0%
0%
10%
20%
30%
STR based
HAART
(n=1,878)
NNRTI based
HAART
(n=775)
Boosted PI
based HAART
(n=3,556)
Raltegravir
based HAART
(n=729)
OR: 1.43
P<0.0001
OR: 1.54
P<0.0001
OR: 1.50
P<0.0001
N/A
and Partial Adherence
only

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