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Transcript
European Review for Medical and Pharmacological Sciences
2012; 16: 10-18
Positioning of HIV-protease inhibitors
in clinical practice
M. ANDREONI, C.F. PERNO
Department of Public Health and Cell Biology, School of Medicine, University of Rome Tor Vergata,
Rome (Italy)
Abstract. – The availability of more than
20 drugs for the treatment of HIV infection, and
the success of the current antiretroviral regimens, should not overlook the difficulty of longterm maintaining the control of viral replication.
The therapy needs to be continued for decades,
if not for lifetime, and there are clear evidences
that, even in patients fully suppressed for many
years, HIV starts again its replication cycles in
case antiviral pressure is removed. The development of resistance is a natural event at the time
of virological failure, that needs to be taken into
account in the global strategy against HIV in
each particular patient. Taking all together, therapeutic regiments must be embedded, since the
beginning, in a long-term strategy whose main
task is the stable control of the replication of
HIV. To do so, the choice of the first antiviral regimen has to be highly appropriate to keep the
virus in check, and at the same time maintain future therapeutic options. Change of therapy at
the time of failure has to be also appropriate, in
term of timing, diagnostic strategy, and selection
of drugs. Under these circumstances, the use of
protease inhibitors in the first line acquires a
strong rationale, that balances the greater pure
potency of non-nucleoside reverse transcriptase
inhibitors (NNRTI), and makes them a valuable
options for many patients that need to start antiviral therapy.
Key Words:
HIV, Protease inhibitors, Antiviral therapy, Virus
replication, Resistance.
Introduction
The primary goal of HIV-1 antiretroviral therapy is to extend maximal viral suppression for
the longest possible time (ideally lifetime), to
prevent HIV progression and AIDS complications, and maintain patients in good health.
10
Prospects for long-term virus suppression depend greatly on the choice of initial therapy. The
preferred first regimen consists, today in the large
majority of cases, of two reverse transcriptase inhibitors (NRTI) and either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI) (the choice of an integrase inhibitor represents a rare event today, despite the
great efficacy and low toxicity of this class, mostly
because of the higher costs). These regimens are
highly effective in suppressing HIV-1 RNA to less
than 50 copies/mL (“undetectable”) within the
first 24 weeks in most patients who reliably take
medications. Based on the substantial clinical data
demonstrating efficacy, potency, and tolerability of
these regimens, they have been designated as “preferred” for initial treatment in most of the current
international and national guidelines.
Virological Failure
Despite the excellent performance of today’s
antiretroviral regimens, a small but consistent
minority of patients fail to achieve and/or to
maintain viral replication below the level of detection of common methods for the evaluation of
viral load (usually 50 copies/ml, sometimes 40).
Reasons for virologic failure include lack of adherence, toxicity, suboptimal virologic activity,
and genetic resistance (mostly linked, in first line
regimens, to the acquisition of resistant strains
from treated, failing patients).
The goal of subsequent therapy in patients
with antiretroviral experience is then to restore
maximum virologic suppression. In the past the
perception was that complete virological suppression could be not achievable in highly advanced-, resistant-patients. Therefore, the goals
of therapy were mostly directed to preserve immune function and to prevent clinical disease
progression. Today this approach is no longer
considered acceptable, and complete suppression
of virus replication stands as the gold standard at
Corresponding Author: Massimo Andreoni, MD; e-mail: [email protected]
Positioning of HIV-protease inhibitors in clinical practice
all stages of the disease, in all types of patients.
This result is even more achievable today, when
the number of multiresistant-, highly advancedpatients is shrinking, and the large majority of
failing patients have low viral load virus or, at
worst, had failed therapy with limited appearance
of mutations conferring resistance to one or two
class (thus leaving options for all the others).
This is particularly true if the diagnosis of virological failure is made early, that is when the
virus rebounds, or shortly after having defined
that viral load has not properly fallen to undetectable levels.
Early definition of failure, and the consequent
rapid change of therapy, helps in reducing the
chances of development of full blown resistance,
and consequently the therapeutic options remained available. Therefore, one of the cornerstones of today’s antiviral therapy is the rapid definition of virological failure, and a similarly rapid
therapy change. Patients should never remain in a
failing regimen more than just the time required
for a proper diagnostic assessment; they should
never be suggested, indirectly or directly, to maintain such failing regimen, even if they like it. Indeed, it is true that the driving force of therapeutic
decision is the agreement of patient and doctor in
choosing the best option for each patient, though
this should never let doctors choose therapy on
the basis of what patient likes most, if the doctor
is not fully convinced about the quality of the
therapy prescribed. The responsibility remains in
the hands of the doctors, and the consequent decisions taken stand on their side.
There is another class of failing patients, that
is those that fail therapy with high/very high viral
load. In the large majority, these patients do not
take properly antivirals; therefore, the virological
failure occurs usually without any mutation conferring resistance. In these circumstances, the
chances of achieving undetectable virus are nearly identical to those at the time of first treatment,
provided that the patient takes properly the new
therapy.
It is then clear that we today are in an optimal
position to define a correct strategy aimed at
keeping viral replication under long-term control,
either in first line, or in subsequent lines of therapy.This is because we have many different drugs
available, and the damage at the time of first virological failures is usually limited, if properly
handled. The application of appropriate drug sequencing strategies will help preserving suppressive options over time.
Long-Term Strategies to
Protect Next-Line Regimens
The long-term efficacy and durability of second-line and salvage regimens depends mostly
on preserving NRTI activity within the first regimen1. Not as a paradox, the best ways to preserving next regimens are both the maintenance of a
maximal viral suppression (HIV RNA less than
50 copies/mL) for the longest period of time, and
the improvement of immune function. Initial regimens should then be chosen on the basis of superior efficacy, potency, tolerability, and durability. Not only do these criteria promote optimal
clinical outcome, but they also help limiting the
emergency of resistance.
Resistance to antivirals is one of the primary
reasons for treatment failure. It occurs when mutations conferring resistance to antivirals appear
in the genome of HIV. In order to do so, HIV
must be in replicative cycling. In other words,
non-replicating HIV (because kept fully under
control of antivirals) cannot evolve and develop
mutations. Therefore, one necessary (though not
sufficient) condition for the development of resistance is the presence of ongoing replicative
cycles of HIV (Figure 1)2.
During such replicative cycles, resistance mutations emerge due to viral replication errors:
HIV indeed replicates rapidly and is highly prone
to error. On average, 10 billion HIV particles are
produced and cleared every day, with one new
mutation introduced, on average, in each new
virus genome (mutation rate of 10-4) in the untreated patient3,4.
Antiretroviral drugs by themselves do not
cause resistance, but provide the selective pressure that, in conditions of incomplete control of
virus replication, favours emergency of drug-resistance mutations able to decrease the sensitivity
to drugs. When selected under antiviral pressure,
these drug-resistant strains, over time tend to substitute wild-type virus, and ultimately predominate. As a collateral event, such mutated strain
may be resistant also to other drugs of the same
class. This phenomenon, called cross-resistance,
may burn an entire class through the development
of single mutations directed toward a single drug.
This is the case of TAMs (Thymidine-associated
mutations) that, selected under the pressure only
of AZT and d4T, do cause cross-resistance to the
entire class of NRTI (with a minor exception of
3TC and FTC). Similarly, mutations selected under nevirapine or efavirenz burn both drugs of this
NNRTI class, and may affect, at least some of
11
M. Andreoni, C.F. Perno
Figure 1. Selection of resistant virus under pharmacological pressure. (From
DD Richman, mod.)2.
them, also the second generation NNRTI such as
etravirine and rilpivirine. Finally, mutations for
raltegravir cross-react with elvitegravir (Integrase
inhibitor not-yet in the market) and some of them
affect also dolutegravir (another very promising
drug of the same class of integrase inhibitors). In
other words, intra-class cross-resistance is an expected phenomenon, that may burn many drugs,
despite not yet being used. Cross-resistance is a
phenomenon that needs to be avoided as much as
possible in clinical practice.
Resistance and Adherence
What is the best condition for the development
of resistance. As another (only apparent) paradox, the optimal situation for the development of
resistance is the suboptimal suppression of viral
replication. As mentioned above, the drug-induced, complete suppression of viral lifecycle
excludes the possibility of developing mutations
and resistance. At the same time, just at the opposite, the complete absence of antiviral pressure
let virus replicate freely, and so resistant viral
strains, being usually characterized by a fitness
lower than wild type, do not emerge. This emergency occurs only when an incomplete antiviral
pressure, sufficient to eliminate wild type virus,
let virus replicate enough to generate and select a
viral strain that is resistant to such drugs. Under
these conditions, these mutations are expected to
emerge quite rapidly, also at low viral load.
How do conditions of incomplete viral suppression occur in clinical practice? While many
factors may play a role in this game (erratic ab12
sorption by the gut, drug-drug interactions, improper dosage and combination of drugs, lack of
booster, etc), the major cause is the lack of complete adherence to prescribed drugs. Suboptimal
adherence reduces the ability to suppress virus
and accelerates the emergence of resistant
strains5-7. There are different levels of non-adherence associated for each class to the development
of resistance, nevertheless it has been calculated
that leaving adherence to levels lower than 85%
represents a condition that highly favours the development of resistance for all classes8. In practice, this means that forgetting only one out of
six doses (that is, one daily dose in a week or so)
is already a potentially dangerous condition! This
brings again the issue of adherence as a top factor in the maintenance of virological success, and
the avoidance of resistance development.
Therapeutic Sequencing
The process of applying knowledge of resistance patterns to the selection of initial and subsequent therapy, better known as “sequencing,”
begins with the recommended choices for initial
and subsequent therapy. These choices are indicated based on efficacy, tolerability and safety,
convenience, and disease stage.
From this point of view, an early initiation of
therapy in the natural history of infection may
have several advantages: earlier suppression of
viral replication, preservation of immune function, prolongation of disease-free survival, lower
risk of resistance with complete viral suppression
and decreased risk of HIV transmission.
Positioning of HIV-protease inhibitors in clinical practice
Protease inhibitor (PI)-based regimens have
demonstrated virologic potency, durability, and
high barriers to resistance. In patients who experience virologic failure during their first PI-based
regimen, few or no PI mutations are detected at
failure. So, despite the fact that each PI has its
own virologic potency, adverse effect profile, and
pharmacokinetic properties, in case of failure of
a first regimen containing a boosted PI, all PIs
behave similarly in preventing the accumulation
of mutations. This is mostly driven by the so
called “high genetic barrier”, that makes virus
less prone to develop mutations to these drugs,
since many mutations (and not a single one, as it
is for NNRTIs) are required to make virus fully
resistant to a PI (Figure 2)9,10. This result also
suggests that, under conditions of first line therapy, in the majority of cases all commonly used
PIs are sufficient to warrant therapeutic success,
provided that there are appropriate companion
drugs, that the adherence to therapy is proper,
and that the choice of drugs takes into proper account potential drug-drug interactions.
In selecting a boosted PI-based regimen for a
treatment-naïve patient, clinicians should consider factors such as dosing frequency, food requirements, pill burden, daily ritonavir dose, drug interaction potential, baseline hepatic function,
toxicity profile of the individual PI, and pregnancy status.
A number of metabolic abnormalities, including dyslipidemia and insulin resistance, have
been associated with PI use. The currently available PIs differ in their propensity to cause these
metabolic complications, which are also dependent on the dose of ritonavir used as a pharmacokinetic boosting agent. These complications may
result in adverse long-term consequences, such
as increased cardiovascular events.
The potent inhibitory effect of ritonavir on the
cytochrome P450 3A4 isoenzyme has allowed
the addition of low-dose ritonavir to other PIs
(with the exception of nelfinavir) as a pharmacokinetic booster to increase drug exposure and
prolong plasma half-lives of the active PI. This
allows for reduced dosing frequency and/or pill
burden, which may improve overall adherence to
the regimen. The increased trough concentration
(Cmin) may improve the antiretroviral activity of
the active PI, which can be beneficial when the
patient harbors HIV strains with reduced susceptibility to the PI11-13, and also may contribute to
the lower risk of resistance upon virologic failure
compared to unboosted PIs.
In the case of ritonavir-boosted darunavir
(800/100 mg once daily) and atazanavir (300/100
mg once daily), there are large numbers of headto-head trials demonstrating non inferiority or superiority compared with lopinavir/ritonavir, with
less gastrointestinal and lipid toxicity.
Ritonavir boosting of atazanavir, given as a total of two pills once daily, enhances the concentrations of atazanavir and improves virologic activity compared with unboosted atazanavir in a
clinical trial 14] The CASTLE study compared
once-daily atazanavir/ritonavir with twice-daily
lopinavir/ritonavir, each in combination with
tenofovir/emtricitabine, in 883 antiretroviral-
Figure 2. Genetic barriers of NNRTI and protease inhibitors. (From AD Luber; DA Katzenstein, mod.)9,10.
13
M. Andreoni, C.F. Perno
naïve participants. In this open-label, noninferiority study, analysis at 48 weeks 15 and at 96
weeks16 showed similar virologic and CD4 T-cell
count responses of the two regimens. More hyperbilirubinemia and less gastrointestinal toxicity
were seen in the ritonavir-boosted atazanavir
arm. This study supports the designation of
boosted atazanavir in combination with tenofovir/emtricitabine as a preferred regimen in
most international guidelines.
The ARTEMIS study compared darunavir/ritonavir (800/100 mg once daily, three pills per
day) with lopinavir/ritonavir (once or twice daily), both in combination with tenofovir/emtricitabine, in a randomized, open-label, noninferiority trial. The study enrolled 689 treatment-naïve
participants who had a median CD4 count of 225
cells/mm3 and a median plasma HIV RNA level
of 4.85 log10 copies/mL. At 48 weeks, darunavir/
ritonavir was non-inferior to lopinavir/ritonavir
(p < 0.001). The virologic response rates were
lower in the lopinavir/ritonavir arm among those
participants whose baseline HIV RNA levels
were > 100,000 copies/mL (p < 0.05). Grades 2
to 4 adverse events, primarily diarrhea, were seen
more frequently in lopinavir/ritonavir recipients
(p < 0.01)17. At 96 weeks, virologic response to
darunavir/ritonavir was superior to response to
lopinavir/ritonavir (p = 0.012). It should be said
that the study was not designed for superiority, so
straight conclusions need to taken with great caution at this time18 (Figure 3).
The KLEAN trial compared twice-daily ritonavir-boosted fosamprenavir with lopinavir/ritonavir, each in combination with abacavir and
lamivudine, in treatment-naïve patients. At
weeks 48 and 144, similar percentages of subjects achieved viral loads of < 400 copies/mL19,20.
Clinical and laboratory adverse events did not
differ between the regimens. In this study of
treatment-naïve participants, twice-daily ritonavir-boosted fosamprenavir was noninferior to
twice-daily lopinavir/ritonavir. Metabolic adverse
effects occurred at similar frequencies with
boosted fosamprenavir as with lopinavir/ritonavir
in the KLEAN study.
Figure 3. Boosted PIs in ARV-Naive Pts: virologic suppression at Wk48. (From JM Molina et al; R Ortiz et al; J Jr Eron et al;
S Walmsley et al, mod.)15,17,19,23.
14
Positioning of HIV-protease inhibitors in clinical practice
Lopinavir/ritonavir is the only available coformulated boosted PI. In Italian guidelines it is
indicated, such as atazanavir/ritonavir and
darunavir/ritonavir, as a first choice of protease
inhibitor for the third agent for the initial therapy21. However, the need for 200 mg/day of ritonavir, and the higher rate of gastrointestinal
side effects and hyperlipidemia when compared
with boosted PIs using ritonavir 100 mg/day,
make it, in DHHS guidelines22, an alternative
rather than preferred PI for PI-naïve patients.
Nevertheless, several clinical trials show that
regimens containing twice-daily lopinavir/ritonavir with two NRTIs have virologic activity
in treatment-naïve patients.
Finally, the GEMINI study compared
saquinavir/ritonavir (1,000/100 mg twice daily)
with lopinavir/ritonavir, both given twice daily,
in combination with tenofovir/emtricitabine given once daily, in 337 treatment-naïve participants
who were monitored over 48 weeks. Similar levels of viral suppression (64.7% vs. 63.5%) and
increases in CD4 counts were seen in both
arms 23. Triglyceride levels were significantly
higher in the lopinavir/ritonavir arm. The higher
pill burden (6 pills per day), need for twice-daily
dosing, and use of 200mg of ritonavir make (at
best) ritonavir-boosted saquinavir at best an alternative PI for treatment-naive patients, despite the
fact that recent EACS guidelines do not discriminate between PIs, provided that there are non-inferiority, comparative data supporting such
choice.
Protease Inhibitors for
Therapeutic Sequencing
These results support a number of thoughts.
The first, is that protease inhibitors represent a
valid option in first line therapy of HIV-infected
patients. The second, potency is crucial for the
achievement of remarkable success, but, in first
line therapy, all major PIs seem to behave similarly; this is an indirect sign that their intrinsic
potency is on average sufficient to achieve virological success at this stage of the disease. The
third, is that PIs represent an important option for
sequencing, if one of the major objectives of first
line therapy is to maintain viable all therapeutic
choices also in case of virological failure. Indeed,
the lack of mutations in the protease at the time
of failure is an event that has been confirmed in
many trials and observational studies beside
those described in this article. In addition, when
combined with NRTIs, the use of PIs markedly
decreases also the rate of mutations in reverse
transcriptase, limiting them to a number of
M184Vs (typical of 3TC or FTC) that remains
far lower than that detected at the time of failure
of NNRTI-based regimens (Figure 4)24.
Taken together, the high genetic barrier of PIs
represents a hurdle that the virus has difficulties
to overcome. Thus, potential failures of 1st lines
based on PIs still leave all therapeutic options
available. The full drugs availability represents
today, as it will be for the future, one of the most
important conditions to maintain the virus under
control for decades.
From these points of view atazanavir offers
several characteristics that favour initial use, including once-daily administration, little or no adverse effects on blood lipids, and a distinctive resistance profile. The antiviral activity of
atazanavir has been established in treatmentnaive and treatment-experienced patients25-28. The
genotypic resistance to atazanavir is rare. The
signature resistance mutation selected by
atazanavir is I50 L, which has been detected in
isolates from patients treated with unboosted
atazanavir, and in multifailing patients; its detection in patients failing first-line regimen including boosted atazanavir is a rare (or even absent!)
event. Of note, mutations I50L is irrelevant for
the large majority of the other PIs and, if something, in-vitro phenotypic susceptibility to other
PIs may be enhanced in the presence of I50 L.
By contrast, atazanavir, as other PIs, looses efficacy when general primary PIs mutation accumulate under the pressure of other PIs. Therefore, PI-mutations need to be avoided in all cases
in which this is possible (that is, rapid change of
failing regimens)29,30.
Conclusions
The goal of antiretroviral drug sequencing is
to maintain suppressive treatment options over
the patient’s life span. This goal can be accomplished in several ways:
Early treatment (CD4+ cell count >350
cells/mm3) with a maximally suppressive regimen. A widely accepted initial regimen includes
2 NRTI/NtRTIs with an NNRTI or a PI. Current
international guidelines offer specific examples
of preferred and alternate regimens. In addition
to virological activity, factors such as tolerability
and adherence must also be considered when se15
M. Andreoni, C.F. Perno
Figure 4. Resistance is significantly lower in patients starting ritonavir-boosted protease inhibitors versus NNRTI-countaing
regimen. (From R Gupta et al, mod.)24.
lecting the first regimen. Primary resistance testing (genotype more than phenotype) is always
advisable, and may be particularly crucial in areas with a high rate of primary resistance.
Selection of antiviral treatment based on drug
resistance profile is essential to maintaining optimal response to therapy. Studies have shown the
relative benefit of genotype- and phenotypeguided treatment decisions compared with
choosing HAART regimens arbitrarily based on
prior treatment history31-36.
If results of resistance testing at the time of virological failure, indicate resistance to one or
more drugs, the regimen should be changed as
soon as possible, to one that includes as many active drugs as possible. All other measures to ensure optimal virological response must be considered: tolerability, patient preference, adherence, etc.
This paper describes several strategies to maximize suppressive options over the continuum of
16
HIV care, using NRTI backbone and NNRTI- or
PI-based regimens for the cornerstone. New
treatment options, such as the integrase inhibitor
or CCR5 inhibitor, and strategies, such as induction maintenance, may extend the potential for
maximal and durable viral suppression.
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