Download maximizing the effectiveness of highly active

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MAXIMIZING THE EFFECTIVENESS OF
HIGHLY ACTIVE ANTIRETROVIRAL THERAPY:
IS THERE A ROLE FOR QUADRUPLE REGIMENS?*
—
François Raffi, MD, PhD
ABSTRACT
Although many highly active antiretroviral
therapy (HAART) regimens using 3 drugs have
demonstrated potent and durable antiretroviral
effects, cohort studies have shown that treatment
failure occurs in about 30% to 50% of patients.
This failure rate prompts a closer look into the
causes of treatment failure and how to modify or
overcome these causes with new and more effective therapeutic regimens.
Adherence to therapy may be the single most
important factor affecting treatment outcomes
with HAART. Factors affecting adherence include
side effects of therapy, regimen complexity, total
number of pills per day, pill size, food restrictions, water requirements, and dosing frequency.
To improve adherence to HAART, dosing regimens must be simplified by reducing tablet load,
removing food restrictions, and reducing dosing
frequency. However, increased regimen convenience to achieve maximal adherence must be
balanced with antiretroviral potency to achieve
the lowest possible nadir.
With a larger proportion of patients now
beginning therapy with high viral loads and low
*This article is based on a presentation given by Prof
Raffi at the XIVth International AIDS Conference.
Address correspondence to: François Raffi, MD, PhD,
Infectious and Tropical Diseases, HIV Research Unit, University
Hospital Nantes, Hôtel-Dieu, Place Ricardeau, 44035
Nantes, Cedex 1, France. E-mail: [email protected].
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CD4 cell counts, it is likely that many may not reach
nadir on standard HAART regimens with 3 drugs.
Therefore, maximized HAART regimens and 4drug (quadruple) regimens have been suggested
and are being investigated. When given as initial
HAART, quadruple regimens have shown promising preliminary results in recently completed studies
and in ongoing comparative studies.
(Advanced Studies in Medicine. 2002;2(23):827-831)
any highly active antiretroviral therapy (HAART) regimens using 3
drugs have shown potent and
durable antiretroviral effects in
reducing plasma human immunodeficiency virus-1 (HIV-1) ribonucleic acid (RNA) in
HIV-infected individuals. Despite initial declines in
plasma HIV-1 RNA with triple HAART regimens,
however, cohort studies have shown that treatment
failure occurs in about 30% to 50% of patients.1
Causes of treatment failure include nonadherence to
therapy because of side effects, complex regimens, and
lifestyle conflicts, treatment-limiting toxicity, pharmacologic variations in potency and durability, and the
emergence of drug-resistant HIV-1.
Whatever the reasons, the high failure rate of initial
triple therapy has prompted investigators to consider
therapy with 4 agents—quadruple therapy—with
enhanced potency, good adherence to therapy, and no
increase in adverse side effects or toxicity to ensure
M
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maximal viral suppression in today’s HIV treatment
population, which is characterized by higher viral
loads and lower CD4 levels.
ADHERENCE TO THERAPY
Thus, to improve adherence to HAART, dosing
regimens must be simplified by reducing tablet load,
removing food restrictions, and reducing dose frequency. Tablet load and dosing frequency can be
reduced by using fixed-dose combinations and consistent dosing (ie, all drugs are taken twice a day) so that
all drugs can be taken at the same time.
Adherence to therapy may be the single most
important factor affecting treatment outcomes with
ONCE-DAILY DOSING
HAART. In the absence of active drug concentrations,
viral replication continues and inevitably leads to
A once-daily dosing regimen would appear to fulincreased genetic diversity and viral load, thereby
fill most of the criteria for improving adherence to
increasing the risk of drug-resistant mutations.
HAART. However, there are advantages, disadvanIn addition to adverse side effects, many other factages, and dietary, timing, and other restrictions assotors contribute to nonadherence to therapy. These
include patient characteristics, clinical-care
settings, patient-provider relationships, and
drug-regimen characteristics.
In a randomized study (CNA3014) comparing abacavir plus a single tablet of lamivudine +
zidovudine with indinavir plus the combination
tablet as initial therapy in a real-life setting in
Table 1. Once-Daily Dosing Considerations and Restrictions
antiretroviral-naïve adults, the investigators
found that HIV-1 RNA efficacy declined as
adherence to therapy declined and that adherADVANTAGES
ence levels above 95% were associated with the
• Convenience to patient
best treatment effect.2 In a survey evaluating reg• Benefits in certain settings (eg, prison, methadone clinic)
imen convenience and adherence at week 48 of
• Potential to improve adherence
therapy in this study, 72% of patients receiving
– Consistent timing of morning meals
abacavir with lamivudine + zidovudine achieved
– Even easier if no dietary restrictions
– No issues for people who work late or go out for an evening
greater than 95% adherence vs 45% of patients
receiving indinavir plus the combination (P <
DISADVANTAGES
• No demonstrated benefit in adherence in once-daily vs twice-daily dosing
.001); 91% of patients vs 62% of patients,
• Impact of missed dose(s) linked to differential pharmacokinetics
respectively, reported that none of their drugs
• Resistance rates may increase
were difficult to take (P < .001).3
• Trade-off between pharmacokinetics and convenience
A study evaluating the impact of different
– Higher Cmax may increase toxicity
– Lower Ctrough may blunt efficacy, durability, resistance selection
regimen characteristics on patient adherence
– May increase interpatient and intrapatient variability
(RESA41071) found that the total number of
– May require therapeutic drug monitoring
pills per day, dosing frequency, and food restric• Limited availability of other once-daily drugs to support regimen
tions or water requirements had the largest
• Pill burden
impact on adherence.4 Specifically, regimens
RESTRICTIONS
with 2 to 5 pills per day, small- or medium-sized
• Dietary/timing restrictions
pills, single-drug therapy or 2-drug combina– Some drugs must be taken with food (eg, tenofovir)
– Some drugs must be taken on an empty stomach (eg, didanosine)
tions, no food or water restrictions/require– Some drugs must be taken at bedtime (eg, efavirenz)
ments, and once- or twice-daily dosing
• Once-daily regimens may have to be split (“false” once-daily regimens)
frequency helped adherence. Regimens with 10
• Once-daily regimens are associated with different drug-combination products
to 16 pills per day, large pills, 3 doses per day,
and at least 3 pills per day
• Some once-daily regimens are associated with unpleasant adverse effects
and food restrictions, such as having to take the
• Once-daily regimens are less forgiving
pills on an empty stomach or avoiding high-fat
foods, hurt adherence.
Cmax = maximum drug level; Ctrough = minimum drug level.
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ciated with once-daily dosing (Table 1). Thus, the net
benefit of any once-daily regimen depends on total
daily pill burden and on whether all the drugs in the
regimen can be taken at the same time and without
any dietary or timing restrictions.
Increased regimen convenience, however, must be
balanced with antiretroviral potency, with the aim
being to achieve the lowest possible nadir for maximum potency and durability. With current treatment
guidelines calling for the delay of therapy until the
CD4 cell count is below 350 cells/mm3, a larger proportion of patients are beginning therapy with high
viral loads and low CD4 cell counts. As a result, many
patients receiving standard HAART (triple) regimens
may not reach nadir (or may reach it at a slower rate
because of the high baseline viral load) but will continue to replicate at low, undetectable levels.5-7 Other
possible consequences are that therapy has no effect on
sanctuaries and cellular reservoirs, full immunologic
recovery is impaired, there is a greater risk of selection
of resistance mutations, and response is less durable.5-7
patients8 and CNAF3008 with 31 patients,9 showed
that the compact quadruple regimen of abacavir,
lamivudine + zidovudine, and efavirenz had potent
and durable antiviral activity over 48 weeks in therapynaïve patients who presented with high plasma viral
Table 2. Attributes of an Ideal Quadruple Regimen
• Increased potency compared with 3-drug regimens
• Increased durability compared with 3-drug regimens
• Low pill burden
• Convenient dosing schedule
• No food or fluid restrictions
• Low potential for drug interactions
• Well tolerated, both short term and long term
MAXIMIZED HAART AND QUADRUPLE REGIMENS
To ensure maximal viral suppression in today’s
HIV treatment population, maximized antiretroviral
therapy (ART) and HAART regimens as well as quadruple regimens have been suggested and are being investigated. The objective of any ART regimen should be
maximal suppression of HIV replication, and the first
ART regimen chosen should be a potent one with longlasting efficacy, because subsequent regimens are always
less effective. HAART potency should be tailored to the
patient’s baseline disease stage, CD4 count, and plasma
viral load. Moreover, the regimen chosen should fit the
needs and expectations of the patient regarding convenience and tolerability.
Maximized regimens diverge from the “hit hard
and early” ART paradigm of 1996 to 1998, and reflect
the new ART paradigm: that is, when you hit, hit
hard(er). With more drugs, more options, and more
compact and convenient regimens available, hitting
harder is possible with simple regimens.
Quadruple regimens that are under investigation
exhibit balanced potency and good adherence to therapy without compromising safety and future treatment options. The attributes of an ideal quadruple
regimen are listed in Table 2.
Two small pilot studies, COL30336 with 38
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Figure. Quadruple Induction Therapy With
Abacavir, Lamivudine + Zidovudine, and Efavirenz
(CNAF3008) and Maintenance with Abacavir +
Lamivudine + Zidovudine Alone (AZLF3002)
HIV-1 = human immunodeficiency virus-1; pVL = plasma viral load; RNA =
ribonucleic acid.
Adapted from de Truchis et al.10
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loads and low CD4 cell counts. In study COL30336,
patients were given abacavir, lamivudine + zidovudine,
and efavirenz for 48 weeks. In study CNAF3008, all
31 patients were given abacavir, lamivudine + zidovudine, and efavirenz for 48 weeks, and 20 patients with
plasma viral loads below 50 copies/mL were switched
to therapy with a single tablet containing abacavir +
lamivudine + zidovudine for an additional 48 weeks
(study AZLF3002).10 After the switch to the singletablet triple therapy, viral suppression seen after the
first 48 weeks of quadruple therapy was successfully
maintained, and the median CD4 level continued to
rise significantly (Figure).
Quadruple regimens raise issues as well as opportunities regarding sequencing of therapy. For example, 2class quadruple regimens may be better at preserving
future treatment options compared with 3-class regimens. Also, the induction/maintenance strategy could
limit exposure to the second class while sparing the
third class.
The safety and tolerability profile of quadruple
therapy in the pilot studies was similar to that of triple
therapy regimens. In the COL30336 study, the most
frequently cited adverse events related to treatment
were bad dreams (13%), nausea (13%), dizziness
(8%), sleep disorders (8%), decreased white blood cells
(8%), malaise and fatigue (8%), and suspected hypersensitivity to abacavir (8%).8
When compared with triple therapy as initial
HAART, quadruple therapy including the single tablet
of abacavir + lamivudine + zidovudine is associated with
increased potency and durability, equal or increased salvageability, decreased short-term tolerability related to
potential risk of abacavir hypersensitivity (incidence,
5%),11 and equal or increased long-term tolerability.
Adherence to therapy is the same with both regimens
because the pill burden, dosing frequency, and dietary
constraints are the same. In terms of maximizing
HAART effectiveness, however, initial quadruple therapy appears to have the edge; it has increased potency and
a greater likelihood of improving adherence because of
its lack of long-term toxicity and adverse events. It is also
a convenient, compact, and patient-friendly regimen,
particularly if 3 of the 4 drugs are taken as a single tablet.
CONCLUSIONS
With regard to maximizing HAART effectiveness,
currently used triple therapy regimens are probably
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suboptimal in many patients, and probably suboptimal in most patients with advanced disease. Both a
pathophysiologic rationale and drug availability are
needed to construct maximized HAART regimens.
Regimens that incorporate both increased potency
to decrease viral load and increase CD4 cell counts and
maximal adherence to therapy are likely to facilitate
long-term management of HIV-infected patients. Just
as HAART effectiveness should not be compromised
in the quest for optimal therapy, neither should convenience, adherence, and tolerability.
As initial HAART, quadruple regimens based on a
single tablet of abacavir + lamivudine + zidovudine
have shown promising preliminary results in recently
completed investigations and in ongoing comparative
studies. Induction/maintenance strategies need to be
refined, but quadruple regimens may represent a new
standard in therapy, perhaps in patients with high plasma viral loads.
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Advanced Studies in Medicine
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