Transcript Defining a new standard of care in patients with triple

Najczęstsze błędy w postępowaniu
z chorym po niepowodzeniach
terapeutycznych
Piotr Pulik
Wojewódzki Szpital Zakaźny w
Warszawie
Podsumowanie
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W kolejnym zestawie lekowym stosowanie
minimum 2 aktywnych leków o ile to możliwe z
uwzględnieniem nowej klasy leków
Włączenie PI/r ( najlepiej nowej generacji)
Poprawa parametrów farmakokinetycznych
zestawu poprzez dodanie ritonawiru
Utrzymanie leczenia lamiwudyną u pacjentów ze
stwierdzona mutacją M184V
Podsumowanie
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
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Utrzymanie terapii pomimo nieskuteczności
wirusologicznej
Intensyfikacja leczenia
Brak celowości ponownego stosowania NNRTI
Najczęstsze przyczyny
niepowodzeń…
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Brak współpracy pacjenta
Działania uboczne leków
Nieprzestrzeganie dostępnych rekomendacji przez
osobę leczącą
Brak dostępności do leków i szybkiej diagnostyki
Brak TDM
Błędna interpretacja wyników immunologicznych i
lekooporności
Interrakcje pomiędzy lekami
Rating Scheme for Clinical Practice
Recommendations

Recommendation A: Strong B: Moderate C:
Optional D: Should usually not be offered E:
Should never be offered

Quality of Evidence for Recommendation
I: At least one randomized trial with clinical
results II: Clinical trials with laboratory
results III: Expert opinion
Many factors increase the likelihood of
treatment failure, including:
Baseline patient factors such as:

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earlier calendar year of starting therapy,
higher pretreatment or baseline HIV RNA level (depending
on the specific regimen used),
lower pretreatment or nadir CD4 cell count,
prior AIDS diagnosis, co-morbidities (e.g. depression,
active substance use),
presence of drug- resistant virus, prior treatment failure
with development of drug resistance or cross resistance
Many factors increase the likelihood of
treatment failure, including(2):
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incomplete medication adherence and missed clinic
appointments;
drug side effects and toxicity;
suboptimal pharmacokinetics (variable absorption,
metabolism, and/or penetration into reservoirs,
food/fasting requirements, adverse drug-drug interactions
with concomitant medications);
suboptimal potency of the antiretroviral regimen; and/or
other, unknown reasons.
MANAGEMENT OF THE TREATMENT –
EXPERIENCED PATIENT
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
Virologic failure on treatment can be defined as a
confirmed HIV RNA level >400 copies/mL after 24
weeks, >50 copies/mL after 48 weeks, or a repeated
HIV RNA level >400 copies/mL after prior
suppression of viremia to <400 copies/mL.
Evaluation of antiretroviral treatment failure should
include assessing the severity of HIV disease of the
patient; the antiretroviral treatment history, including
the duration, drugs used, antiretroviral potency,
adherence history, and drug intolerance/toxicity; and
the results of prior drug resistance testing.
MANAGEMENT OF THE TREATMENT –
EXPERIENCED PATIENT

Drug resistance testing should be obtained while the patient is
taking the failing antiretroviral regimen (or within 4 weeks of
treatment discontinuation).

In managing virologic failure, the provider should make a
distinction between limited, intermediate, and extensive prior
treatment exposure and resistance.
The goal of treatment for patients with prior drug exposure and
drug resistance is to re-establish maximal virologic suppression

MANAGEMENT OF THE
TREATMENT – EXPERIENCED
PATIENT

For some patients with extensive prior drug
exposure and drug resistance where viral
suppression is difficult or impossible to achieve
with currently available drugs, the goal of
treatment is preservation of immune function
and prevention of clinical progression.
Assessment of Antiretroviral
Treatment Failure and Changing
Therapy
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In general, the cause of treatment failure should
be explored by reviewing the medical history and
performing a physical examination to assess for
signs of clinical progression.
Important elements of the medical history include:
change in HIV RNA and CD4 cell count over time;
occurrence of HIV-related clinical events;
antiretroviral treatment history and results of prior
resistance testing (if any);
Assessment of Antiretroviral Treatment
Failure and Changing Therapy
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medication-taking behavior, including adherence
to recommended drug doses, dosing frequency
and food/fasting requirements;
tolerance of the medications; concomitant
medications (with consideration for adverse drugdrug interactions);
and co-morbidities (including substance use).
In many cases the cause(s) of treatment failure
will be readily apparent. In some cases, no obvious
cause may be identified.
Virologic Failure(1)
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There is no consensus on the optimal time to change
therapy for virologic failure.
The most aggressive approach would be to change for
any repeated, detectable viremia (e.g., two consecutive
HIV RNA >400 copies/mL after suppression to <400
copies/mL in a patient taking the regimen).
Other approaches allow detectable viremia up to an
arbitrary level (e.g., 1,000-5,000 copies/mL).
Virologic Failure(2)
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However, ongoing viral replication in the presence of
antiretroviral drugs promotes the selection of drug
resistance mutations [176] and may limit future
treatment options.
Isolated episodes of viremia ("blips", e.g. single levels
of 50-1,000 copies/mL) may simply represent laboratory
variation [177] and usually are not associated with
subsequent virologic failure, but rebound to higher
observe a patient on the same regimen, rather than changing
the regimen (depending on the stage of HIV disease), if
there are few or no treatment options (BII).
Virologic failure 3
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There is evidence from cohort studies that
continuing therapy, even in the presence of
viremia and the absence of CD4 cell increases,
decreases the risk of disease progression [150].
Other cohort studies suggest continued
immunologic and clinical benefits if the HIV RNA
level is maintained <10,000-20,000 copies/mL [183,
184].
In a patient with a lower CD4 cell count (e.g. <100
cells/mm3), a change in therapy may be critical to
prevent further immunologic decline and clinical
progression and is therefore indicated (BIII).
Virologic failure 3
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A patient with a higher CD4 cell count may not be
at significant risk for clinical progression, so a
change in therapy is optional (CIII).
Discontinuing or briefly interrupting therapy
(even with ongoing viremia) may lead to a rapid
increase in HIV RNA, a decrease in CD4 cell
count, and increases the risk for clinical
progression [185, 186] and therefore is not
recommended (DIII).
Changing an Antiretroviral Therapy
Regimen for Virologic Failure
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• For the patient with virologic failure, perform resistance testing
while the patient still is taking the drug regimen or within 4
weeks after regimen discontinuation (AII).
• Use the treatment history and past and current resistance test
results to identify active agents (preferably at least two fully
active agents) to design a new regimen (AII). A fully active agent
is one likely to demonstrate antiretroviral activity on the basis of
both the treatment history and susceptibility on drug-resistance
testing.
• If at least two fully active agents cannot be identified, consider
pharmacokinetic enhancement of protease inhibitors (with the
exception of nelfinavir) with ritonavir (BII) and/or re-using
other prior antiretroviral agents to provide partial antiretroviral
activity (CIII).
Changing an Antiretroviral Therapy
Regimen for Virologic Failure
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Adding a drug with activity against drug-resistant virus (e.g. a
potent ritonavir-boosted PI) and a drug with a new mechanism
of action (e.g. HIV entry inhibitor) to an optimized background
antiretroviral regimen can provide significant antiretroviral
activity (BII).
In general, one active drug should not be added to a failing
regimen because drug resistance is likely to develop quickly
(DII). However, in patients with advanced HIV disease (e.g. CD4
<100) and higher risk of clinical progression, adding one active
agent (with an optimized background regimen) may provide
clinical benefits and should be offered
General Approach .
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Ideally, one should design a regimen with two or
more fully active drugs (on the basis of resistance
testing or new mechanistic class) (BII) [154, 192].
Some antiretroviral drugs (e.g. NRTIs) may
contribute partial antiretroviral activity to an
antiretroviral regimen.
Note that using "new" drugs that the patient has
not yet taken may not be sufficient because of
cross-resistance within drug classes that reduces
drug activity.
General Approach .
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As such, drug potency is more important than the
number of drugs prescribed.
Early studies of treatment-experienced patients
identified factors associated with better virologic
responses to subsequent regimens [193, 194].They
include: lower HIV RNA at the time of therapy
change, using a new (i.e. not yet taken) class of
drugs (e.g. NNRTI, HIV entry inhibitors), and
using ritonavir-boosted PIs in PI-experienced
patients.
Sequencing and Cross Resistance(1)
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The order of use of some antiretroviral agents may be
important.
Cross-resistance among NRTIs is common but varies by
drug. Most, if not all, NNRTI-associated resistance
mutations confer resistance to all approved NNRTIs.
Novel early mutations to some protease inhibitors (e.g.,
amprenavir, atazanavir, nelfinavir, saquinavir) that do not
confer cross-resistance to other PIs may occur initially, but
then subsequent accumulation of additional mutations
confers broad cross-resistance to the entire protease
inhibitor class.
Sequencing and Cross Resistance(2)
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The order of use of some antiretroviral
agents may be important.
Cross-resistance among NRTIs is common
but varies by drug. Most, if not all, NNRTIassociated resistance mutations confer
resistance to all approved NNRTIs.
Sequencing and Cross Resistance(3)

Novel early mutations to some protease
inhibitors (e.g., amprenavir, atazanavir,
nelfinavir, saquinavir) that do not confer
cross-resistance to other PIs may occur
initially, but then subsequent accumulation
of additional mutations confers broad crossresistance to the entire protease inhibitor
class.
Sequencing and Cross Resistance(4)
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Tipranavir/ritonavir was approved for use in
patients who are highly treatment-experienced or
have HIV-1 strains resistant to multiple PIs based
on its demonstrated activity against PI-resistant
viruses [199, 200].
However, with ongoing viremia and the
accumulation of additional mutations,
antiretroviral activity is time-limited unless the
regimen contains other active drugs (e.g. an HIV
entry inhibitor).
Current Approach (1)
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Several clinical trials illustrate effective therapeutic
strategies for heavily treatment-experienced
patients [195, 196, 199-201]. In these studies,
patients received an antiretroviral regimen
optimized on the basis of resistance testing and
then were randomized to receive a new active
antiretroviral agent or placebo.
Patients who received more active drugs (e.g. an
active ritonavir-boosted PI and enfuvirtide), had a
better and more prolonged virologic response than
those with fewer active drugs in the regimen [197].
Current Approach (2)

These studies illustrate and support the strategy of
conducting resistance testing while a treatmentexperienced patient is taking their failing regimen,
designing a new regimen based on the treatment
history and resistance testing results, and selecting
active antiretroviral drugs for the new treatment
regimen.
Current Approach(3)
In general, using a single active antiretroviral
drug in a new regimen is not recommended
because of the risk of rapidly developing
resistance to that drug.
 However, in patients with advanced HIV disease
with a high likelihood of clinical progression
(e.g., a CD4 cell count less than 100/mm3)

Current Approach(3)
adding a single drug may reduce the risk of
immediate clinical progression, because even
transient decreases in HIV RNA and/or transient
increases in CD4 cell counts have been associated
with clinical benefits.
 Weighing the risks (e.g., selection of drug
resistance) and benefits (.g., antiretroviral
activity) of using a single active drug in the
heavily treatment-experienced patient is
complicated, and consultation with an expert is
advised.
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Summary of Guidelines For Changing
An Antiretroviral Regimen For
Suspected Treatment Regimen Failure
Ponownie….
Patient Assessment (AIII)
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Review antiretroviral treatment history.
• Assess for evidence of clinical progression.(e.g.
physical exam, laboratory and/or radiologic tests)
• Assess adherence, tolerability, and
pharmacokinetic issues.
Patient Assessment (AIII)
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• Distinguish between limited, intermediate, and
extensive prior therapy and drug resistance.
• Perform resistance testing while patient is taking
therapy (or within 4 weeks after regimen
discontinuation).
• Identify active drugs and drug classes to use in
designing the new regimen
Patient Management: Specific
Clinical Scenarios
Limited or intermediate prior treatment with
low (but not suppressed) HIV RNA level (e.g.,
up to 5000 copies/mL):
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The goal of treatment is to re-suppress HIV
RNA to below the level of assay detection.
Consider intensifying with one drug (e.g.,
tenofovir) (BII) or pharmacokinetic
enhancement (use of ritonavir boosting of a
protease inhibitor) (BII)
Limited or intermediate prior treatment with
low (but not suppressed) HIV RNA level (e.g.,
up to 5000 copies/mL):
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perform resistance testing if possible, or most
aggressively,
change two or more drugs in the regimen (CIII).
If continuing the same treatment regimen, HIV
RNA levels should be followed closely because
ongoing viral replication will lead to accumulation
of additional resistance mutations.
Limited or intermediate prior
treatment with resistance to one drug:
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Consider changing the one drug (CIII),
pharmacokinetic enhancement (few data
available) (BII), or, most aggressively,
change two or more drugs in the regimen
(BII).
Limited or intermediate prior
treatment with resistance to more than
one drug:
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The goal of treatment is to suppress viremia
to prevent further selection of resistance
mutations. Consider optimizing the regimen
by changing classes (e.g., PI-based to
NNRTI-based and vice versa) and/or
adding new active drugs (AII).
Prior treatment with no resistance
identified
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Consider the timing of the drug resistance
test (e.g., was the patient off antiretroviral
medications?) and/or nonadherence.
Consider resuming the same regimen or
starting a new regimen and then repeating
genotypic testing early (e.g., 2–4 weeks) to
determine if a resistant viral strain emerges
on treatment (CIII).
Extensive prior treatment and drug
resistance:
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In patients with active antiretroviral agents
available (e.g. an active ritonavir-boosted PI and
enfuvirtide), the goal of therapy is suppression of
viremia.
In patients without active antiretroviral agent
available and with ongoing viremia, the goal of
therapy is preservation of immune responses and
delay of clinical progression.
It is reasonable to continue the same antiretroviral
regimen if there are few or no treatment options
(CIII).
Extensive prior treatment and drug
resistance:
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In general, avoid adding a single active drug
because of the risk for the rapid development of
resistance to that drug.
In advanced HIV disease with a high likelihood of
clinical progression (e.g., CD4 cell count <100
cells/mm3), adding a single drug may reduce the
risk of immediate clinical progression (CIII).
In this complicated scenario, expert advice should
be sought.
Immunologic failure (or blunted CD4
response) with virologic suppression:

Immunologic failure (or blunted CD4 cell
response) may not warrant a change in therapy in
the setting of suppressed viremia. Assess for other
causes of immunosuppression (e.g. HIV-2, HTLV1, drug toxicity). The combination of didanosine
and tenofovir has been associated with CD4 cell
declines or blunted CD4 cell responses.
Immunologic failure (or blunted CD4
response) with virologic suppression:
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.In the setting of immunologic failure (or blunted
CD4 response), it would be reasonable to change
one of these drugs (BIII).
Intensifying with additional antiretroviral drugs or
the use of immune-based therapies (e.g.
interleukin-2) to improve immunologic responses
remain unproven strategies and generally should
not be offered (DII).
Novel Strategies To Consider For
Treatment-Experienced Patients
With Few Available Active Treatment
Options
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Pharmacokinetic enhancement with ritonavir
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Therapeutic Drug Monitoring
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Re-treating with prior medications
Novel Strategies To Consider For
Treatment-Experienced Patients With
Few Available Active Treatment
Options
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The use of empiric multi-drug regimens
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New antiretroviral drugs
Novel Strategy Not Recommended at This Time:
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• Structured treatment interruptions in the setting of
virologic failure have been investigated prospectively,
but most trials have shown limited or no virologic
benefit
Pharmacokinetic enhancement with
ritonavir
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may increase drug concentrations of most
PIs (except nelfinavir) and may overcome
some degree of drug resistance
Re-treating with prior
medications
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may be useful, particularly if they were
discontinued previously for toxicities that can now
be better addressed (BII).
Reusing prior medications (even with documented
drug resistance) may provide some degree of
partial antiretroviral activity.
Continued drug therapy and maintenance of
drug-resistant virus may compromise viral fitness,
but it is not known if this has clinical applicability.
The use of empiric multi-drug
regimens
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including up to 3 PIs and/or 2 NNRTIs)
has been advocated by some [318, 319], but
may be limited ultimately by complexity,
poor tolerability, and unfavorable drug-drug
interactions (CII)
New antiretroviral drugs (1)
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Drugs in existing classes with activity against
resistant viral strains, or new drug classes with
novel mechanisms of action) including those
available on expanded access (Table 30) or through
clinical trials may be used.
For example, the PI tipranavir (in combination
with low-dose ritonavir) was approved for use in
treatment-experienced patients as part of a
combination antiretroviral regimen based on
providing superior antiretroviral activity to an
investigator-selected comparator PI [199, 200].
New antiretroviral drugs (2)

The first approved HIV-1 entry inhibitor,
enfuvirtide (T-20) was approved for use in the
treatment-experienced patient with ongoing
viremia on the basis of antiretroviral activity in this
population [195, 196]. Optimally, a new active
agent should be used with one or more other active
agents in the regimen (e.g. a ritonavir-boosted PI
and enfuvirtide) (BII).
Algorytm leczenia: 1999
1-szy rzut
Schemat oparty na
NRTI/NNRTI
2-gi rzut
Schemat oparty na
PI/r
Celem leczenia jest uzyskanie
zahamowania replikacji wirusa
Terapia ratująca
Ograniczona liczba działających leków ARV
jest powodem ponownego zastosowania leków
Celem leczenia jest zachowanie
funkcji immunologicznych
i obniżenie wiremiii
Algorytm leczenia: 1999
1-szy rzut
Schemat oparty na
NRTI/NNRTI
Terapia ratująca
2-gi rzut
Schemat oparty na PI/r
Celem leczenia jest uzyskanie
zahamowania replikacji wirusa
Ograniczona liczba działających leków ARV
jest powodem ponownego zastosowania leków
Celem leczenia jest zachowanie
funkcji immunologicznych
i obniżenie wiremiii
W jaki sposób poprawić wyniki leczenia
po wielu niepowodzeniach?
Dołączenie do leczenia leku z nowej klasy
zwiększa odsetek odpowiedzi nawet, jeżeli
stwierdza się aktywność 3 lub więcej leków
RESIST
FUZEON + OB
OB
100
75
52
32
19
25
0
46
44
50
9
20
19
8
0
0
1
2
3
4
Wyjściowe GSS
Miralles et al. HIV7 2004. Abstract P17
% pacjentów z obniżeniem 1 log10 w 24 tyg
%pacjentów z HIV RNA <400 kopii/ml,
48 tyg
TORO
TPV/r
porównywany PI/r
100
80
60
55
46
37
40
20
13
34
20
13
9
0
0
1
2
3
Liczba aktywnych leków ARV
Cooper et al. CROI 2005. Abstract 560
W badaniach TORO ponowne zastosowanie nie
działających leków ARV prowadziło do
niezadowalających wyników
% pacjentów z odpowiedzią
wirusologiczną
100
OB
80
60
<400 kopii/mL
<50 kopii/mL
40
20
15%
12%
6%
8%
Tydz
24
Tydz
48
0
Tydz
24
Tydz
48
Katlama et al. IAS 2003. Abstract LB02
ITT: przewanie leczenia=niepowodzenie
FUZEON powodował podwojenie odsetka
pacjentów z odpowiedzią wirusologiczną, jakkolwiek
tylko 30% pacjentów uzyskało HIV RNA <400
kopii/ml
% pacjentów z odpowiedzia
wirusologiczną
100
FUZEON + OB
OB
80
60
<400 kopii/mL
40
20
33%
15%
<50 kopii/mL
30%
18%
16%
12%
6%
8%
0
Tydz
24
Tydz
48
Tydz
24
Tydz
48
p < 0.0001 dla wszystkich porównań
Katlama et al. IAS 2003. Abstract LB02
ITT: przewanie leczenia=niepowodzenie
Dowody naukowe:
Schematy oparte na stosowaniu preparatu FUZEON
jako standard leczenia u pacjentów eksponowanych
na 3 klasy leków ARV
Badanie
FUZEON plus działający PI/r*
TORO 1 & 2
FUZEON + LPV/r
RESIST 1 & 2
FUZEON + TPV/r
POWER 1 & 2
FUZEON + TMC 114/r
* Wzmocniony rytonawirem aktywny PI
Badania RESIST (faza III) tipranavir (TPV)

2 badania (n = 1159):
RESIST 1 (USA, Australia)
 RESIST 2 (Europa, Południowa Ameryka)


Cel badania:

Porównanie skuteczności schematu zawierającego
wzmocniony rytonawirem tipranawir (TPV/r) z
innym inhibitorem proteazy (PI/r)
FUZEON stosowano u 25% pacjentów
Cooper
et al. CROI 2005. Abstract
560
 Uprzednio
stosowano
FUZEON u 12%

Badanie RESIST: najlepsza
odpowiedź w grupie otrzymującej
TPV/r i FUZEON
% pacjentów z odpowiedzią wirusologiczną
(≥1 log spadek w porównaniu do BL) w 24 tyg
100
Bez enfuwirtydu (FUZEON)
FUZEON (uprzednio leczeni)
80
60
40
31%
18%
20
7%
9%
0
Tipranavir/r
Cooper et al. CROI 2005. Abstract 560
Porównywany PI/r
0
–0.2
-0.5
(log10 kopii/ml)
Spadek HIV RNA w 24 tyg
w porównaniu do wartości wyjściowych
Trzykrotnie większe obniżenie wiremii w
ramieniu otrzymującym FUZEON plus
TPV/r
–0.4
–0.6
-1
Bez ENF (FUZEON)
-1.5
FUZEON (uprzednio leczeni i nieleczeni)
-2
–2.1
-2.5
Tipranavir/r
Porównywany PI/r
http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4139b1-02-boehringer.pdf
Wzrost liczby limfocytów CD4 w 24 tyg w porównaniu
do wartości wyjściowych (kom/mm3)
Dwukrotnie większy wzrost
liczby limfocytów CD4 w grupie
TPV/r
+ FUZEON
+55
60
Bez ENF (FUZEON)
FUZEON (uprzednio leczeni i nieleczeni)
40
+27
20
+6
+3
0
Tipranavir/r
Porównywany PI/r
http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4139b1-02-boehringer.pdf
FUZEON zapewnia lepszą i niezależną od
wyjściowej ilości mutacji w genie PI odpowiedź
wirusologiczną*
Tygodnie
0
2
4
8
16
24
Obniżenie VL HIV RNA
(log10 kopii/ml)
0
-0.5
Bez leczenia
FUZEON
-1
-1.5
-2
Leczenie
FUZEON
-2.5
TPV/r 1–4 (n = 328)
TPV/r 1–4 (n = 70)
TPV/r 5+ (n = 215)
TPV/r 5+ (n = 88)
*Substytucje w kodonach 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 lub 90
http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4139b1-02-boehringer.pdf
Badania POWER (faza II) TMC114

2 badania (n = 497):



Cel:



202 (USA)
213 (EU, Australia, Brazylia, Kanada)
Określenie zależnej od dawki skuteczności leczenia w
porównaniu z uprzednio wybranym PI/r w tygodniu 24
leczenia
FUZEON stosowano u 48% pacjentów
Uprzednio leczeni preparatem FUZEON - 15%
Katlama et al. CROI 2005. Abstract 164LB
67% pacjentów uzyskało HIV RNA
<50 kopii/ml w grupie FUZEON + TMC114
% pacjentów z odpowiedzią
HIV RNA <50 kopii/ml w 24 tyg
100
Bez ENF (FUZEON)
FUZEON (uprzednio nieleczeni )
80
67%
60
40
37%
20
8%
16%
0
TMC114/r (600 2xdobę)
Katlama et al. CROI 2005. Abstract 164LB
Porównywany PI/r
Ograniczenia badania
lekooporności
Dobry wynik badania nie zapewnia
pełnej aktywności leku
Pacjenci z trzema “aktywnymi” lekami wykazują
zwiększoną częstość skuteczności leczenia przy
zastosowaniu enfuwirtydu w porównaniu z OBT
% pacjentów z nieoznaczalnym
HIV RNA (<400 copies/ml)
Pacjenci z „aktywnym” LPV/r i 2 inne “aktywne” ARVs
100
80
Leczenie FUZEON (n = 98)
60
52%
40
27%
Bez leczenia FUZEON (n = 59)
20
0
0
4
8
12
16
20
24
28
32
36
40
44
48
Tygodnie
Miralles and DeMasi. IDSA 2004. Abstract 921
p < 0.05 ; ITT
Pojedynczy wynik genotypowania
może nie odzwierciedlać faktycznie
występującej lekooporności
Poprzednie
wyniki
Ostatni wynik
Różnica
Lamiwudyna (M184 V/I)
58.8%
25.5%
33.3%
Inne NRTIs
46.0%
27.7%
18.3%
NNRTIs
38.5%
24.5%
14.0%
PIs
27.9%
15.6%
12.3%
•
Interpretacja wyników lekooporności powinna być szczególnie ostrożna i
uzupełniona o wywiad dotyczący leczenia
Harrigan PR, Wynhoven B, Brumme ZL, et al., J. Infect. Dis. 2005 15;191(8):1325–30.
Podsumowanie

TORO, RESIST i POWER - niezależnie, we
wszystkich badaniach wykazano znaczący wpływ
FUZEON w połączeniu z aktywnym PI/r
(LPV/r, TPV/r or TMC114/r) na skuteczność
leczenia:
FUZEON podwajał odpowiedź na leczenie w
porównaniu z zastosowaniem samego PI/r
 55−67% leczonych pacjentów osiagnęło poziom
HIV RNA poniżej progu oznaczalności w 24−48
tygodniu leczenia.

Algorytm leczniczy: Obecnie
1-szy rzut
Schemat oparty na
2NRTTI/NNRTI
2-gi rzut
Po leczeniu 3 klasami ARV
Schemat oparty na
NRTI + PI/r
Schemat oparty na
FUZEON + aktywny PI/r
Cel: zahamowanie replikacji HIV
Terapia
ratująca
Backups
OpenMind study: Background



Objectives:
 To explore the perceptions of injectable ARVs among HIVtreating physicians and treatment-experienced HIV-infected
patients
 To identify the attitudes that might act as motivators or
barriers to the initiation of injectable ARVs
Interviewed:
 603 treatment-experienced patients (≥ 8 ARVs)
 499 HIV-treating physicians
Locations:
 Germany, France, Italy, Spain, the UK and the USA
Horne et al. EACS 2005. PE7.3/25
Youle et al. EACS 2005. PE7.3/24
OpenMind study: Results
Physicians’ perceptions
Superior treatment
outcomes with
enfuvirtide
76%
Increased non-compliance
and treatment refusal
with enfuvirtide
0%
48%
20%
40%
60%
80%
100%
Physicians that broadly agree with belief*
* Defined as a rating of > 4 on a 7-point scale, where ‘1’ means ‘strongly disagree’ and ‘7’ means ‘strongly agree’
N = 603
Youle et al. EACS 2005. PE7.3/24
OpenMind study: Results
Patients’ perceptions

Patients were shown a
full description of
enfuvirtide during the
interview
100%
80%
Very likely to
accept
35%
60%

76% patients said they
would be likely to accept
enfuvirtide
40%
20%
Likely to accept
Unlikely to
accept
0%
Horne et al. EACS 2005. PE7.3/25
N = 516
41%
24%
POWER1: Subgroup Analyses of
Response to TMC114/r 600/100
BID
53% (n = 60)
Overall
18% (n = 60)
63% (n = 19)
ENF Used (Naive)
22% (n = 18)
56% (n = 34)
ENF Not Used
19% (n = 36)
59% (n = 29)
 3 Primary PI Mut
9% (n = 35)
TMC114 FC > 4
46% (n = 28)
16% (n = 25)
TMC114/r 600/100 BID
Control
17% (n = 12)
No Sensitive
ARV in OBR
0% (n = 9)
0
20
40
60
80
100
Patients With HIV-1 RNA < 50 copies/mL at Week 24 (%) (ITT NC=F)
Katlama C, et al. IAS 2005. Abstract WeOaLB0102.
POWER 2: Subgroup Analyses of
Response to TMC114/r 600/100
BID
39% (n = 57)
Overall
7% (n = 53)
64% (n = 14)
ENF Used (Naive)
7% (n = 14)
30% (n = 20)
ENF Not Used
4% (n = 24)
35% (n = 23)
 3 Primary PI Mut
7% (n = 28)
TMC114/r 600/100 BID
Control
18% (n = 11)
No Sensitive
NRTI in OBR
0% (n = 7)
0
20
40
60
80
Patients With HIV-1 RNA < 50 copies/mL at Week 24 (%)
Wilkin T, et al. ICAAC 2005. Abstract H-413.
100
POWER 2: Subgroup Analyses of
Response to TMC114/r 600/100
BID
39% (n = 57)
Overall
7% (n = 53)
64% (n = 14)
ENF Used (Naive)
7% (n = 14)
30% (n = 20)
ENF Not Used
4% (n = 24)
35% (n = 23)
 3 Primary PI Mut
7% (n = 28)
TMC114/r 600/100 BID
Control
18% (n = 11)
No Sensitive
NRTI in OBR
0% (n = 7)
0
20
40
60
80
Patients With HIV-1 RNA < 50 copies/mL at Week 24 (%)
Wilkin T, et al. ICAAC 2005. Abstract H-413.
100
A New Drug is Not Necessarily
an Active Drug

Patient on ZDV/3TC/ABC + LPV/r


CD4+ 269; VL 67,000
Cumulative resistance profile:
RT: 41L, 184V, 210W, 215Y, 103N
 PR: 30N, 63P, 71V, 77I, 82A, 84V, 90M


Clinician proposed a combination of 3 “new”
drugs:
FTC + ATV + ENF
0.4
n = 14
0.2
0.0
-0.2
-0.4
-6 -4 -2 0
2
4
6
8
Median Change in CD4+
Cell Count (cells/mm3)
Median Change in HIV-1
RNA (log10 copies/mL)
The Cost of Treatment
Interruption in TreatmentExperienced Patients
50
25
0
-25
n = 14
-50
-75
-100
-6 -4 -2
Weeks Before and After WT Switch
Deeks SG, et al. N Engl J Med. 2001;344:472-480.
0
2
4
6
Partial Treatment Interruption
Demonstrates Residual NRTI
Activity
Discontinue PIs, continue NRTIs (n = 15)
Discontinue NRTIs, continue PIs (n = 5)
100
Wk 8
Change in CD4+ Cell
Count (cells/mm3)
Change in HIV-1 RNA
(log10 copies/mL)
1.5
1.0
0.5
0
-0.5
Wk 8
Wk 12
Wk 16
Deeks SG, et al. J Infect Dis. 2005;192:1537-1544.
50
0
-50
-100
-150
Wk 12
Wk 16

Guidelines for Choosing a
Nonsuppressive “Holding
Regimen”
Never use an NNRTI



Always use 3TC or FTC




NNRTI mutations have no beneficial impact on fitness
Accumulation of additional mutations may result in crossresistance to 2nd generation NNRTIs
Simple and well tolerated drugs
M184V decreases fitness
Increases activity of d4T, TDF, ZDV
Choose PIs and/or NRTIs based on resistance
and tolerability/toxicity considerations
Jednoczesne stosowanie enfuwirtydu i LPV/r w OB
stanowi czynnik prognostyczny odpowiedzi na
terapię
HIV-1 RNA <400 kopii/ml w 48 tyg
FUZEON
Wyjściowa liczba CD4 (per 100 kom/mm3)
Wyjściowy HIV-1 RNA (per log10)
Uprzednia ekspozycja lopinavir/r
Uprzednie leczenier ARVs (n)
Liczba aktywnych ARVs w OB (n)
Lopinavir/r w OB
0.1
1
10
Wsp. Ryzyka dla HIV-1 RNA <400 kopii/ml (95% CI)
Gorsza odpowiedź
Montaner et al. 15th IAC 2004. Abstract TuPe4483
Lepsza
odpowiedź
FUZEON plus LPV/r: 37%
pacjentów osiągnęło HIV RNA
<50 kopii/ml po 24 tyg
100
% pacjentów z HIV RNA
(<50 kopii/ml) w 24 tyg
No FUZEON
FUZEON (naive)
80
60
40
30%
*
37%
*
20
8%
4%
1%
0
LPV/r in OB:
Prior LPV/r:
*
13%
57
158
No LPV/r
77
LPV/r
LPV/r experienced
DRAFT Roche data on file
171
17%
7%
58
93
142
No LPV/r
239
LPV/r
LPV/r naive
*p < 0.01, ITT, D/C + Switch = Failure
Lamivudine Partially Suppresses
Multidrug-resistant HIV-1 Despite
Presence of M184V Mutation
Slideset on:
Campbell TB, Shulman NS, Johnson SC, et al.
Antiviral activity of lamivudine in salvage therapy
for multidrug-resistant HIV-1 infection. Clin Infect
Dis. 2005;41:236-242.
Background and Rationale


HIV-1 RNA suppression to undetectable levels
may not be possible for some patients with
multidrug-resistant virus
However, continuation of lamivudine therapy
despite high-level lamivudine resistance (ie,
M184V/I) maintains partial HIV-1 RNA
suppression


Discontinuation of lamivudine causes increased
HIV-1 RNA levels and reversion to wild-type virus
Current study evaluated antiretroviral activity of
lamivudine against lamivudine-resistant virus by
withdrawing lamivudine therapy in patients with
multidrug-resistant HIV-1
Summary of Study Design



Results of 2 studies combined for analysis
 University of Colorado General Clinical Research Center
 Stanford University School of Medicine
Subjects discontinued lamivudine but continued taking all other
antiretrovirals in pre-entry regimen
HIV-1 RNA, CD4+ cell count, genotypic and phenotypic
resistance testing, and plasma concentrations of lamivudine,
stavudine, and zidovudine regularly evaluated during
lamivudine withdrawal
Baseline Characteristics

N=6
Median age: 48 years (range, 43-64 years)
 Male: 100%
 High-level lamivudine resistance (presence of
M184V and inhibitory concentration 50% > 300
fold-change): 100%
 Median HIV-1 RNA: 20,000 copies/mL
 Range of plasma lamivudine concentration: 3742026 ng/mL

Main Findings

Lamivudine withdrawal associated with median
HIV-1 RNA increase of 0.5 log10 copies/mL at
Week 6 (P = .04)
Duration of withdrawal, 8-22 weeks
 Lamivudine concentration undetectable (< 20
ng/mL) in all patients by Week 6
 No wild-type reversion of M184VM detected by
Week 6
 Early increases in HIV-1 RNA associated with
T215Y/F and M41L mutations at baseline, and
reduced phenotypic susceptibility to NRTIs,
excluding lamivudine (75% vs 10% for those with
and without mutations and reduced susceptibility,
respectively; P = .001)

Main Findings

Reversion of M184VM detected at least once
in 4/6 patients during withdrawal
Median time to detection of M184VM reversion,
12 weeks (range, 8-14 weeks)
 Trend toward higher HIV-1 RNA at first appearance
of M184VM



Median HIV-1 RNA, +0.3 log10 copies/mL (P = .07)
Median HIV-1 replication capacity increased to 60%
at time of reversion vs 41% at baseline (P = .07)

Reversion not associated with changes in CD4+ cell count
Main Findings


All patients resumed lamivudine at their own or
their doctor’s request and not due to resumption
criteria
Median HIV-1 RNA 0.6 log10 copies/mL (range,
0.1-0.6) above baseline at time of resumption (P
= .03)


HIV-1 RNA not significantly different from baseline
after 8 weeks of lamivudine treatment (P = .2)
Reappearance of M184V mutation at 8 weeks
after lamivudine resumption
Key Conclusions


Lamivudine treatment in patients with
multidrug-resistant HIV-1 suppressed HIV-1
RNA by ~ 0.5 log10 copies/mL
After lamivudine withdrawal, increase in HIV-1
RNA observed prior to 184VM reversion


Suggests that lamivudine contributes to viral
suppression despite presence of M184V resistance
mutation
Replication capacity increased after M184VM
reversion in absence of lamivudine
Panel’s Recommendations:



If the decision is made to initiate therapy in a person with acute HIV
infection, it is likely that resistance testing at baseline will optimize virologic
response; this strategy should be considered (BIII).
• Drug resistance testing at baseline in antiretroviral-naïve, chronically
infected patients is an untested strategy. However, it may be reasonable to
consider resistance testing when there is a significant probability that the
patient was infected with a drug-resistance virus, i.e., if the patient is
thought to have been infected by a person who was receiving antiretroviral
drugs (CIII).
• Drug resistance testing is not advised for persons with viral load <1,000
copies/mL, since amplification of the virus is unreliable (DIII).
Panel’s Recommendations:



• HIV drug resistance testing should be performed to assist in
selecting active drugs when changing antiretroviral regimens in
cases of virologic failure (BII).
• Drug resistance testing should also be considered when
managing suboptimal viral load reduction (BIII).
• Drug resistance testing in the setting of virologic failure should
be performed while the patient is taking his/her antiretroviral
drugs, or immediately (i.e., within 4 weeks) after discontinuing
therapy (BII).
Dyskusja

Brak weryfikacji sposobu przyjmowania leków w
trakcie prowadzenia terapii ARV

Zbyt późna zmiana terapii ARV

Nadkażenie szczepami wielolekoopornymi ????