Najczęstsze błędy w postępowaniu z chorym po niepowodzeniach terapeutycznych

Najczęstsze błędy w Najczęstsze błędy w postępowaniu z chorym postępowaniu z chorym

po niepowodzeniach po niepowodzeniach terapeutycznychterapeutycznych

Piotr PulikPiotr Pulik

Wojewódzki Szpital Zakaźny Wojewódzki Szpital Zakaźny w Warszawiew Warszawie

PodsumowaniePodsumowanie

W kolejnym zestawie lekowym stosowanie W kolejnym zestawie lekowym stosowanie minimum 2 aktywnych leków o ile to minimum 2 aktywnych leków o ile to możliwe z uwzględnieniem nowej klasy możliwe z uwzględnieniem nowej klasy lekówleków

Włączenie PI/r ( najlepiej nowej generacji)Włączenie PI/r ( najlepiej nowej generacji) Poprawa parametrów farmakokinetycznych Poprawa parametrów farmakokinetycznych

zestawu poprzez dodanie ritonawiruzestawu poprzez dodanie ritonawiru Utrzymanie leczenia lamiwudyną u Utrzymanie leczenia lamiwudyną u

pacjentów ze stwierdzona mutacją M184Vpacjentów ze stwierdzona mutacją M184V


Utrzymanie terapii pomimo Utrzymanie terapii pomimo nieskuteczności wirusologicznejnieskuteczności wirusologicznej

Intensyfikacja leczeniaIntensyfikacja leczenia Brak celowości ponownego Brak celowości ponownego

stosowania NNRTIstosowania NNRTI

Najczęstsze przyczyny Najczęstsze przyczyny niepowodzeń…niepowodzeń…

Brak współpracy pacjentaBrak współpracy pacjenta Działania uboczne lekówDziałania uboczne leków Nieprzestrzeganie dostępnych Nieprzestrzeganie dostępnych

rekomendacji przez osobę leczącąrekomendacji przez osobę leczącą Brak dostępności do leków i szybkiej Brak dostępności do leków i szybkiej

diagnostyki diagnostyki Brak TDM Brak TDM Błędna interpretacja wyników Błędna interpretacja wyników

immunologicznych i lekoopornościimmunologicznych i lekooporności Interrakcje pomiędzy lekamiInterrakcje pomiędzy lekami

Rating Scheme for Clinical Rating Scheme for Clinical Practice Recommendations Practice Recommendations

RecommendationRecommendation A: A: Strong Strong B: B: Moderate Moderate C: C: Optional Optional D: D: Should Should usually not be offered usually not be offered E: E: Should never Should never be offered be offered

Quality of Evidence for Recommendation Quality of Evidence for Recommendation I: I: At least one randomized trial with At least one randomized trial with clinical results clinical results II: II: Clinical trials with Clinical trials with laboratory results laboratory results III: III: Expert opinion Expert opinion

Many factors increase the Many factors increase the likelihood of treatment failure, likelihood of treatment failure,

including: including:

Baseline patient factors such as: Baseline patient factors such as: earlier calendar year of starting therapy, earlier calendar year of starting therapy, higher pretreatment or baseline HIV RNA level higher pretreatment or baseline HIV RNA level

(depending on the specific regimen used),(depending on the specific regimen used), lower pretreatment or nadir CD4 cell count, lower pretreatment or nadir CD4 cell count, prior AIDS diagnosis, co-morbidities (e.g. prior AIDS diagnosis, co-morbidities (e.g.

depression, active substance use),depression, active substance use), presence of drug- resistant virus, prior treatment presence of drug- resistant virus, prior treatment

failure with development of drug resistance or failure with development of drug resistance or cross resistancecross resistance

Many factors increase the Many factors increase the likelihood of treatment failure, likelihood of treatment failure,

including(2)including(2): :

incomplete medication adherence and incomplete medication adherence and missed clinic appointments; missed clinic appointments;

drug side effects and toxicity; drug side effects and toxicity; suboptimal pharmacokinetics (variable suboptimal pharmacokinetics (variable

absorption, metabolism, and/or penetration absorption, metabolism, and/or penetration into reservoirs, food/fasting requirements, into reservoirs, food/fasting requirements, adverse drug-drug interactions with adverse drug-drug interactions with concomitant medications); concomitant medications);

suboptimal potency of the antiretroviral suboptimal potency of the antiretroviral regimen; and/or regimen; and/or

other, unknown reasons. other, unknown reasons.

MANAGEMENT OF THE TREATMENT – MANAGEMENT OF THE TREATMENT –

EXPERIENCED PATIENTEXPERIENCED PATIENT

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 – MANAGEMENT OF THE TREATMENT –

EXPERIENCED PATIENTEXPERIENCED 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 In managing virologic failure, the provider should make a distinction between limited, should make a distinction between limited, intermediate, and extensive prior treatment intermediate, and extensive prior treatment exposure and resistance. exposure and resistance.

The goal of treatment for patients with prior The goal of treatment for patients with prior drug exposure and drug resistance is to re-drug exposure and drug resistance is to re-establish maximal virologic suppressionestablish maximal virologic suppression

MANAGEMENT OF THE MANAGEMENT OF THE TREATMENT – TREATMENT –

EXPERIENCED PATIENT EXPERIENCED PATIENT

For some patients with extensive prior For some patients with extensive prior drug exposure and drug resistance drug exposure and drug resistance where viral suppression is difficult or where viral suppression is difficult or impossible to achieve with currently impossible to achieve with currently available drugs, the goal of treatment is available drugs, the goal of treatment is preservation of immune function and preservation of immune function and prevention of clinical progression. prevention of clinical progression.

Assessment of Assessment of Antiretroviral Treatment Antiretroviral Treatment

Failure and Changing Failure and Changing Therapy Therapy

In general, the cause of treatment failure In general, the cause of treatment failure should be explored by reviewing the medical should be explored by reviewing the medical history and performing a physical examination history and performing a physical examination to assess for signs of clinical progression. to assess for signs of clinical progression.

Important elements of the medical history Important elements of the medical history include: change in HIV RNA and CD4 cell include: change in HIV RNA and CD4 cell count over time; occurrence of HIV-related count over time; occurrence of HIV-related clinical events; antiretroviral treatment history clinical events; antiretroviral treatment history and results of prior resistance testing (if any); and results of prior resistance testing (if any);

Assessment of Antiretroviral Assessment of Antiretroviral Treatment Failure and Treatment Failure and

Changing Therapy Changing Therapy

medication-taking behavior, including medication-taking behavior, including adherence to recommended drug doses, adherence to recommended drug doses, dosing frequency and food/fasting dosing frequency and food/fasting requirements; requirements;

tolerance of the medications; concomitant tolerance of the medications; concomitant medications (with consideration for adverse medications (with consideration for adverse drug-drug interactions); drug-drug interactions);

and co-morbidities (including substance use). and co-morbidities (including substance use). In many cases the cause(s) of treatment In many cases the cause(s) of treatment

failure will be readily apparent. In some failure will be readily apparent. In some cases, no obvious cause may be identified. cases, no obvious cause may be identified.

Virologic Failure(1) Virologic Failure(1)

There is no consensus on the optimal time There is no consensus on the optimal time to change therapy for virologic failure. to change therapy for virologic failure.

The most aggressive approach would be to The most aggressive approach would be to change for any repeated, detectable change for any repeated, detectable viremia (e.g., two consecutive HIV RNA viremia (e.g., two consecutive HIV RNA >400 copies/mL after suppression to <400 >400 copies/mL after suppression to <400 copies/mL in a patient taking the copies/mL in a patient taking the regimen). regimen).

Other approaches allow detectable Other approaches allow detectable viremia up to an arbitrary level (e.g., viremia up to an arbitrary level (e.g., 1,000-5,000 copies/mL). 1,000-5,000 copies/mL).

Virologic Failure(2) Virologic Failure(2)

However, ongoing viral replication in the However, ongoing viral replication in the presence of antiretroviral drugs promotes the presence of antiretroviral drugs promotes the selection of drug resistance mutations selection of drug resistance mutations [176] [176] and may limit future treatment options.and may limit future treatment options.

Isolated episodes of viremia ("blips", e.g. Isolated episodes of viremia ("blips", e.g. single levels of 50-1,000 copies/mL) may single levels of 50-1,000 copies/mL) may simply represent laboratory variation simply represent laboratory variation [177] [177] and usually are not associated with and usually are not associated with subsequent virologic failure, but rebound to subsequent virologic failure, but rebound to higher higher observe a patient on the same regimen, observe a patient on the same regimen, rather than changing the regimen (depending on rather than changing the regimen (depending on the stage of HIV disease), if there are few or no the stage of HIV disease), if there are few or no treatment options (treatment options (BIIBII). ).

Virologic failure 3Virologic failure 3 There is evidence from cohort studies that There is evidence from cohort studies that

continuing therapy, even in the presence of continuing therapy, even in the presence of viremia and the absence of CD4 cell viremia and the absence of CD4 cell increases, decreases the risk of disease increases, decreases the risk of disease progression progression [150][150]. .

Other cohort studies suggest continued Other cohort studies suggest continued immunologic and clinical benefits if the HIV immunologic and clinical benefits if the HIV RNA level is maintained <10,000-20,000 RNA level is maintained <10,000-20,000 copies/mL copies/mL [183, 184][183, 184]. .

In a patient with a lower CD4 cell count (e.g. In a patient with a lower CD4 cell count (e.g. <100 cells/mm3), a change in therapy may <100 cells/mm3), a change in therapy may be critical to prevent further immunologic be critical to prevent further immunologic decline and clinical progression and is decline and clinical progression and is therefore indicated (therefore indicated (BIIIBIII). ).

Virologic failure 3Virologic failure 3

A patient with a higher CD4 cell count A patient with a higher CD4 cell count may not be at significant risk for may not be at significant risk for clinical progression, so a change in clinical progression, so a change in therapy is optional (therapy is optional (CIIICIII).).

Discontinuing or briefly interrupting Discontinuing or briefly interrupting therapy (even with ongoing viremia) therapy (even with ongoing viremia) may lead to a rapid increase in HIV may lead to a rapid increase in HIV RNA, a decrease in CD4 cell count, RNA, a decrease in CD4 cell count, and increases the risk for clinical and increases the risk for clinical progression progression [185, 186] [185, 186] and therefore and therefore is not recommended (is not recommended (DIIIDIII). ).

Changing an Antiretroviral Changing an Antiretroviral Therapy Regimen for Therapy Regimen for

Virologic Failure Virologic Failure • • For the patient with virologic failure, perform resistance For the patient with virologic failure, perform resistance

testing while the patient still is taking the drug regimen or testing while the patient still is taking the drug regimen or within 4 weeks after regimen discontinuation (AII). within 4 weeks after regimen discontinuation (AII).

• • Use the treatment history and past and current Use the treatment history and past and current resistance test results to identify active agents (preferably resistance test results to identify active agents (preferably at least two fully active agents) to design a new regimen at least two fully active agents) to design a new regimen (AII). A fully active agent is one likely to demonstrate (AII). A fully active agent is one likely to demonstrate antiretroviral activity on the basis of both the treatment antiretroviral activity on the basis of both the treatment history and susceptibility on drug-resistance testing. history and susceptibility on drug-resistance testing.

• • If at least two fully active agents cannot be identified, If at least two fully active agents cannot be identified, consider pharmacokinetic enhancement of protease consider pharmacokinetic enhancement of protease inhibitors (with the exception of nelfinavir) with ritonavir inhibitors (with the exception of nelfinavir) with ritonavir (BII) and/or re-using other prior antiretroviral agents to (BII) and/or re-using other prior antiretroviral agents to provide partial antiretroviral activity (CIII). provide partial antiretroviral activity (CIII).

Changing an Antiretroviral Changing an Antiretroviral Therapy Regimen for Therapy Regimen for

Virologic Failure Virologic Failure Adding a drug with activity against drug-resistant virus Adding a drug with activity against drug-resistant virus

(e.g. a potent ritonavir-boosted PI) and a drug with a (e.g. a potent ritonavir-boosted PI) and a drug with a new mechanism of action (e.g. HIV entry inhibitor) to new mechanism of action (e.g. HIV entry inhibitor) to an optimized background antiretroviral regimen can an optimized background antiretroviral regimen can provide significant antiretroviral activity (BII). provide significant antiretroviral activity (BII).

In general, one active drug should not be added to a In general, one active drug should not be added to a failing regimen because drug resistance is likely to failing regimen because drug resistance is likely to develop quickly (DII). However, in patients with develop quickly (DII). However, in patients with advanced HIV disease (e.g. CD4 <100) and higher risk advanced HIV disease (e.g. CD4 <100) and higher risk of clinical progression, adding one active agent (with of clinical progression, adding one active agent (with an optimized background regimen) may provide clinical an optimized background regimen) may provide clinical benefits and should be offeredbenefits and should be offered

General Approach General Approach . .

Ideally, one should design a regimen Ideally, one should design a regimen with two or more fully active drugs (on with two or more fully active drugs (on the basis of resistance testing or new the basis of resistance testing or new mechanistic class) mechanistic class) (BII) (BII) [154, 192][154, 192]. .

Some antiretroviral drugs (e.g. NRTIs) Some antiretroviral drugs (e.g. NRTIs) may contribute partial antiretroviral may contribute partial antiretroviral activity to an antiretroviral regimen. activity to an antiretroviral regimen.

Note that using "new" drugs that the Note that using "new" drugs that the patient has not yet taken may not be patient has not yet taken may not be sufficient because of cross-resistance sufficient because of cross-resistance within drug classes that reduces drug within drug classes that reduces drug activity. activity.

General Approach General Approach . .

As such, drug potency is more As such, drug potency is more important than the number of drugs important than the number of drugs prescribed. prescribed.

Early studies of treatment-experienced Early studies of treatment-experienced patients identified factors associated patients identified factors associated with better virologic responses to with better virologic responses to subsequent regimens subsequent regimens [193, 194][193, 194].They .They include: lower HIV RNA at the time of include: lower HIV RNA at the time of therapy change, using a new (i.e. not therapy change, using a new (i.e. not yet taken) class of drugs (e.g. NNRTI, yet taken) class of drugs (e.g. NNRTI, HIV entry inhibitors), and using HIV entry inhibitors), and using ritonavir-boosted PIs in PI-experienced ritonavir-boosted PIs in PI-experienced patients. patients.

Sequencing and Cross Sequencing and Cross Resistance(1) Resistance(1)

The order of use of some antiretroviral agents The order of use of some antiretroviral agents may be important.may be important.

Cross-resistance among NRTIs is common but Cross-resistance among NRTIs is common but varies by drug. Most, if not all, NNRTI-associated varies by drug. Most, if not all, NNRTI-associated resistance mutations confer resistance to all resistance mutations confer resistance to all approved NNRTIs. approved NNRTIs.

Novel early mutations to some protease Novel early mutations to some protease inhibitors (e.g., amprenavir, atazanavir, inhibitors (e.g., amprenavir, atazanavir, nelfinavir, saquinavir) that do not confer cross-nelfinavir, saquinavir) that do not confer cross-resistance to other PIs may occur initially, but resistance to other PIs may occur initially, but then subsequent accumulation of additional then subsequent accumulation of additional mutations confers broad cross-resistance to the mutations confers broad cross-resistance to the entire protease inhibitor classentire protease inhibitor class. .


The order of use of some The order of use of some antiretroviral agents may be antiretroviral agents may be important.important.

Cross-resistance among NRTIs is Cross-resistance among NRTIs is common but varies by drug. common but varies by drug. Most, if not all, NNRTI-Most, if not all, NNRTI-associated resistance mutations associated resistance mutations confer resistance to all approved confer resistance to all approved NNRTIs. NNRTIs.


Novel early mutations to some Novel early mutations to some protease inhibitors (e.g., amprenavir, protease inhibitors (e.g., amprenavir, atazanavir, nelfinavir, saquinavir) atazanavir, nelfinavir, saquinavir) that do not confer cross-resistance to that do not confer cross-resistance to other PIs may occur initially, but other PIs may occur initially, but then subsequent accumulation of then subsequent accumulation of additional mutations confers broad additional mutations confers broad cross-resistance to the entire cross-resistance to the entire protease inhibitor class. protease inhibitor class.

Sequencing and Cross Sequencing and Cross Resistance(4)Resistance(4)

Tipranavir/ritonavir was approved for use in Tipranavir/ritonavir was approved for use in patients who are highly treatment-patients who are highly treatment-experienced or have HIV-1 strains resistant experienced or have HIV-1 strains resistant to multiple PIs based on its demonstrated to multiple PIs based on its demonstrated activity against PI-resistant viruses activity against PI-resistant viruses [199, [199, 200]200]. .

However, with ongoing viremia and the However, with ongoing viremia and the accumulation of additional mutations, accumulation of additional mutations, antiretroviral activity is time-limited unless antiretroviral activity is time-limited unless the regimen contains other active drugs (e.g. the regimen contains other active drugs (e.g. an HIV entry inhibitor). an HIV entry inhibitor).

Current Approach (1)Current Approach (1)

Several clinical trials illustrate effective Several clinical trials illustrate effective therapeutic strategies for heavily therapeutic strategies for heavily treatment-experienced patients treatment-experienced patients [195, 196, [195, 196, 199-201]199-201]. In these studies, patients received . In these studies, patients received an antiretroviral regimen optimized on the an antiretroviral regimen optimized on the basis of resistance testing and then were basis of resistance testing and then were randomized to receive a new active randomized to receive a new active antiretroviral agent or placebo. antiretroviral agent or placebo.

Patients who received more active drugs Patients who received more active drugs (e.g. an active ritonavir-boosted PI and (e.g. an active ritonavir-boosted PI and enfuvirtide), had a better and more enfuvirtide), had a better and more prolonged virologic response than those prolonged virologic response than those with fewer active drugs in the regimen with fewer active drugs in the regimen [197][197]. .

Current Approach (2)Current Approach (2)

These studies illustrate and support These studies illustrate and support the strategy of conducting resistance the strategy of conducting resistance testing while a treatment-experienced testing while a treatment-experienced patient is taking their failing patient is taking their failing regimen, designing a new regimen regimen, designing a new regimen based on the treatment history and based on the treatment history and resistance testing results, and resistance testing results, and selecting active antiretroviral drugs selecting active antiretroviral drugs for the new treatment regimen. for the new treatment regimen.

Current ApproachCurrent Approach(3) (3)

In general, using a single active In general, using a single active antiretroviral drug in a new regimen antiretroviral drug in a new regimen is not recommended because of the is not recommended because of the risk of rapidly developing resistance risk of rapidly developing resistance to that drug.to that drug.

However, in patients with advanced However, in patients with advanced HIV disease with a high likelihood of HIV disease with a high likelihood of clinical progression (e.g., a CD4 cell clinical progression (e.g., a CD4 cell count less than 100/mm3)count less than 100/mm3)

Current ApproachCurrent Approach(3) (3)

adding a single drug may reduce the risk adding a single drug may reduce the risk of immediate clinical progression, of immediate clinical progression, because even transient decreases in HIV because even transient decreases in HIV RNA and/or transient increases in CD4 RNA and/or transient increases in CD4 cell counts have been associated with cell counts have been associated with clinical benefits.clinical benefits.

Weighing the risks (e.g., selection of Weighing the risks (e.g., selection of drug resistance) and benefits (.g., drug resistance) and benefits (.g., antiretroviral activity) of using a single antiretroviral activity) of using a single active drug in the heavily treatment-active drug in the heavily treatment-experienced patient is complicated, and experienced patient is complicated, and consultation with an expert is advised. consultation with an expert is advised.

Summary of Guidelines For Summary of Guidelines For Changing An Antiretroviral Changing An Antiretroviral

Regimen For Suspected Regimen For Suspected Treatment Regimen Failure Treatment Regimen Failure

Ponownie….Ponownie….

Patient Assessment Patient Assessment (AIII) (AIII)

Review antiretroviral treatment Review antiretroviral treatment history. history.

• • Assess for evidence of clinical Assess for evidence of clinical progression.(e.g. physical exam, progression.(e.g. physical exam, laboratory and/or radiologic tests) laboratory and/or radiologic tests)

• • Assess adherence, tolerability, and Assess adherence, tolerability, and pharmacokinetic issues. pharmacokinetic issues.

Patient Assessment Patient Assessment (AIII) (AIII)

• • Distinguish between limited, Distinguish between limited, intermediate, and extensive prior intermediate, and extensive prior therapy and drug resistance. therapy and drug resistance.

• • Perform resistance testing while Perform resistance testing while patient is taking therapy (or within 4 patient is taking therapy (or within 4 weeks after regimen discontinuation). weeks after regimen discontinuation).

• • Identify active drugs and drug Identify active drugs and drug classes to use in designing the new classes to use in designing the new regimen regimen

Patient Management: Patient Management: Specific Clinical Scenarios Specific Clinical Scenarios

Limited or intermediate prior Limited or intermediate prior treatment with low (but not treatment with low (but not

suppressed) HIV RNA level (e.g., suppressed) HIV RNA level (e.g., up to 5000 copies/mL):up to 5000 copies/mL):

The goal of treatment is to re-The goal of treatment is to re-suppress HIV RNA to below the level suppress HIV RNA to below the level of assay detection. of assay detection.

Consider intensifying with one drug Consider intensifying with one drug (e.g., tenofovir) (e.g., tenofovir) (BII) (BII) or or pharmacokinetic enhancement (use pharmacokinetic enhancement (use of ritonavir boosting of a protease of ritonavir boosting of a protease inhibitor) inhibitor) (BII)(BII)

Limited or intermediate prior Limited or intermediate prior treatment with low (but not treatment with low (but not

suppressed) HIV RNA level (e.g., suppressed) HIV RNA level (e.g., up to 5000 copies/mL): up to 5000 copies/mL):

perform resistance testing if possible, or perform resistance testing if possible, or most aggressively, most aggressively,

change two or more drugs in the regimen change two or more drugs in the regimen (CIII)(CIII)..

If continuing the same treatment If continuing the same treatment regimen, HIV RNA levels should be regimen, HIV RNA levels should be followed closely because ongoing viral followed closely because ongoing viral replication will lead to accumulation of replication will lead to accumulation of additional resistance mutationsadditional resistance mutations. .

Limited or intermediate Limited or intermediate prior treatment with prior treatment with

resistance to one drug: resistance to one drug:

Consider changing the one drug Consider changing the one drug (CIII)(CIII), pharmacokinetic , pharmacokinetic enhancement (few data enhancement (few data available) available) (BII)(BII), or, most , or, most aggressively, change two or more aggressively, change two or more drugs in the regimen drugs in the regimen (BII)(BII). .

Limited or intermediate Limited or intermediate prior treatment with prior treatment with

resistance to more than one resistance to more than one drug: drug:

The goal of treatment is to The goal of treatment is to suppress viremia to prevent suppress viremia to prevent further selection of resistance further selection of resistance mutations. Consider optimizing mutations. Consider optimizing the regimen by changing classes the regimen by changing classes (e.g., PI-based to NNRTI-based (e.g., PI-based to NNRTI-based and vice versa) and/or adding new and vice versa) and/or adding new active drugs active drugs (AII)(AII). .

Prior treatment with no Prior treatment with no resistance identified resistance identified

Consider the timing of the drug Consider the timing of the drug resistance test (e.g., was the patient resistance test (e.g., was the patient off antiretroviral medications?) off antiretroviral medications?) and/or nonadherence. Consider and/or nonadherence. Consider resuming the same regimen or resuming the same regimen or starting a new regimen and then starting a new regimen and then repeating genotypic testing early repeating genotypic testing early (e.g., 2–4 weeks) to determine if a (e.g., 2–4 weeks) to determine if a resistant viral strain emerges on resistant viral strain emerges on treatment treatment (CIII). (CIII).

Extensive prior treatment Extensive prior treatment and drug resistanceand drug resistance: :

In patients with active antiretroviral In patients with active antiretroviral agents available (e.g. an active ritonavir-agents available (e.g. an active ritonavir-boosted PI and enfuvirtide), the goal of boosted PI and enfuvirtide), the goal of therapy is suppression of viremia. therapy is suppression of viremia.

In patients without active antiretroviral In patients without active antiretroviral agent available and with ongoing viremia, agent available and with ongoing viremia, the goal of therapy is preservation of the goal of therapy is preservation of immune responses and delay of clinical immune responses and delay of clinical progression.progression.

It is reasonable to continue the same It is reasonable to continue the same antiretroviral regimen if there are few or antiretroviral regimen if there are few or no treatment options no treatment options (CIII)(CIII). .

Extensive prior treatment Extensive prior treatment and drug resistance: and drug resistance:

In general, avoid adding a single active In general, avoid adding a single active drug because of the risk for the rapid drug because of the risk for the rapid development of resistance to that drug.development of resistance to that drug.

In advanced HIV disease with a high In advanced HIV disease with a high likelihood of clinical progression (e.g., likelihood of clinical progression (e.g., CD4 cell count <100 cells/mm3), adding CD4 cell count <100 cells/mm3), adding a single drug may reduce the risk of a single drug may reduce the risk of immediate clinical progression immediate clinical progression (CIII)(CIII)..

In this complicated scenario, expert In this complicated scenario, expert advice should be sought. advice should be sought.

Immunologic failure (or Immunologic failure (or blunted CD4 response) with blunted CD4 response) with

virologic suppression:virologic suppression:

Immunologic failure (or blunted CD4 cell Immunologic failure (or blunted CD4 cell response) may not warrant a change in response) may not warrant a change in therapy in the setting of suppressed viremia. therapy in the setting of suppressed viremia. Assess for other causes of Assess for other causes of immunosuppression (e.g. HIV-2, HTLV-1, immunosuppression (e.g. HIV-2, HTLV-1, drug toxicity). The combination of didanosine drug toxicity). The combination of didanosine and tenofovir has been associated with CD4 and tenofovir has been associated with CD4 cell declines or blunted CD4 cell responses. cell declines or blunted CD4 cell responses.

Immunologic failure (or Immunologic failure (or blunted CD4 response) with blunted CD4 response) with

virologic suppressionvirologic suppression: :

.In the setting of immunologic failure (or .In the setting of immunologic failure (or blunted CD4 response), it would be blunted CD4 response), it would be reasonable to change one of these drugs reasonable to change one of these drugs (BIII)(BIII). .

Intensifying with additional antiretroviral Intensifying with additional antiretroviral drugs or the use of immune-based therapies drugs or the use of immune-based therapies (e.g. interleukin-2) to improve immunologic (e.g. interleukin-2) to improve immunologic responses remain unproven strategies and responses remain unproven strategies and generally should not be offered generally should not be offered (DII). (DII).

Novel Strategies To Novel Strategies To Consider For Treatment-Consider For Treatment-

Experienced Patients With Experienced Patients With Few Available Active Few Available Active Treatment Options Treatment Options

Pharmacokinetic enhancement Pharmacokinetic enhancement with with ritonavir ritonavir

Therapeutic Drug Monitoring Therapeutic Drug Monitoring

Re-treating with prior medications Re-treating with prior medications

Novel Strategies To Novel Strategies To Consider For Treatment-Consider For Treatment-

Experienced Patients With Experienced Patients With Few Available Active Few Available Active Treatment Options Treatment Options

The use of empiric multi-drug regimens The use of empiric multi-drug regimens New antiretroviral drugs New antiretroviral drugs Novel Strategy Not Recommended at This Novel Strategy Not Recommended at This

Time: Time: • • Structured treatment interruptions Structured treatment interruptions in the in the

setting of virologic failure have been setting of virologic failure have been investigated prospectively, but most trials investigated prospectively, but most trials have shown limited or no virologic benefit have shown limited or no virologic benefit

Pharmacokinetic Pharmacokinetic enhancement enhancement with ritonavir with ritonavir

may increase drug may increase drug concentrations of most PIs concentrations of most PIs (except nelfinavir) and may (except nelfinavir) and may overcome some degree of drug overcome some degree of drug resistance resistance

Re-treating with prior Re-treating with prior medications medications

may be useful, particularly if they were may be useful, particularly if they were discontinued previously for toxicities that discontinued previously for toxicities that can now be better addressed can now be better addressed (BII)(BII). .

Reusing prior medications (even with Reusing prior medications (even with documented drug resistance) may provide documented drug resistance) may provide some degree of partial antiretroviral some degree of partial antiretroviral activity.activity.

Continued drug therapy and maintenance Continued drug therapy and maintenance of drug-resistant virus may compromise of drug-resistant virus may compromise viral fitness, but it is not known if this has viral fitness, but it is not known if this has clinical applicability. clinical applicability.

The use of empiric The use of empiric multi-drug regimens multi-drug regimens

including up to 3 PIs and/or 2 including up to 3 PIs and/or 2 NNRTIs) has been advocated by NNRTIs) has been advocated by some some [318, 319][318, 319], but may be , but may be limited ultimately by complexity, limited ultimately by complexity, poor tolerability, and unfavorable poor tolerability, and unfavorable drug-drug interactions drug-drug interactions (CII) (CII)

New antiretroviral drugs New antiretroviral drugs (1)(1)

Drugs in existing classes with activity Drugs in existing classes with activity against resistant viral strains, or new against resistant viral strains, or new drug classes with novel mechanisms of drug classes with novel mechanisms of action) including those available on action) including those available on expanded access (expanded access (Table 30Table 30) or through ) or through clinical trials may be used. clinical trials may be used.

For example, the PI tipranavir (in For example, the PI tipranavir (in combination with low-dose ritonavir) was combination with low-dose ritonavir) was approved for use in treatment-approved for use in treatment-experienced patients as part of a experienced patients as part of a combination antiretroviral regimen based combination antiretroviral regimen based on providing superior antiretroviral on providing superior antiretroviral activity to an investigator-selected activity to an investigator-selected comparator PI comparator PI [199, 200][199, 200]. .

New antiretroviral drugs New antiretroviral drugs (2)(2)

The first approved HIV-1 entry The first approved HIV-1 entry inhibitor, enfuvirtide (T-20) was inhibitor, enfuvirtide (T-20) was approved for use in the treatment-approved for use in the treatment-experienced patient with ongoing experienced patient with ongoing viremia on the basis of antiretroviral viremia on the basis of antiretroviral activity in this population activity in this population [195, 196][195, 196]. . Optimally, a new active agent should Optimally, a new active agent should be used with one or more other active be used with one or more other active agents in the regimen (e.g. a agents in the regimen (e.g. a ritonavir-boosted PI and enfuvirtide) ritonavir-boosted PI and enfuvirtide) (BII)(BII). .

Algorytm leczeniaAlgorytm leczenia: 1999: 1999

Schemat oparty na NRTI/NNRTI

Schemat oparty na PI/r

Ograniczona liczba działających leków ARVjest powodem ponownego zastosowania leków

Terapia ratująca1-szy rzut 2-gi rzut

Celem leczenia jest uzyskanie zahamowania replikacji wirusa

Celem leczenia jest zachowanie funkcji immunologicznych

i obniżenie wiremiii

Algorytm leczeniaAlgorytm leczenia: 1999: 1999

W jaki sposób poprawić wyniki leczeniapo wielu niepowodzeniach?

Terapia ratująca1-szy rzut 2-gi rzut

Schemat oparty na NRTI/NNRTI

Schemat oparty na PI/r

Ograniczona liczba działających leków ARVjest powodem ponownego zastosowania leków

Celem leczenia jest uzyskanie zahamowania replikacji wirusa

Celem leczenia jest zachowanie funkcji immunologicznych

i obniżenie wiremiii

Dołączenie do leczenia leku z Dołączenie do leczenia leku z nowej klasy zwiększa odsetek nowej klasy zwiększa odsetek

odpowiedzi nawet, jeżeli stwierdza odpowiedzi nawet, jeżeli stwierdza się aktywność 3 lub więcej lekówsię aktywność 3 lub więcej leków

9

32

44 4652

08

19 20 19

0

25

50

75

100

0 1 2 3 4

Wyjściowe GSS

%pa

cjen

tów

z H

IV R

NA

<40

0 ko

pii/m

l, 4

8 ty

g

TORO

% p

acj

en

tów

z o

bn

iże

nie

m

1 lo

g10

w 2

4 t

yg

0

20

40

60

80

100

0 1 2 3

5546

37

13

34

2013

9

Liczba aktywnych leków ARV

RESISTFUZEON + OB OB TPV/r porównywany PI/r

Miralles et al. HIV7 2004. Abstract P17 Cooper et al. CROI 2005. Abstract 560

W badaniachW badaniach TORO TORO ponowne ponowne zastosowanie nie działających lekówzastosowanie nie działających leków

ARV ARV prowadziło do niezadowalających prowadziło do niezadowalających wynikówwyników

Katlama et al. IAS 2003. Abstract LB02 ITT: przewanie leczenia=niepowodzenie

12%15%

6% 8%

0

20

40

60

80

100OB

Tydz 48

Tydz 48

Tydz 24

Tydz 24

<50 kopii/mL<400 kopii/mL

% p

acje

ntów

z o

dpow

iedz

ią

wiru

solo

gicz

ną

FUZEON FUZEON powodował podwojenie powodował podwojenie odsetka pacjentów z odpowiedzią odsetka pacjentów z odpowiedzią

wirusologiczną, jakkolwiek tylko wirusologiczną, jakkolwiek tylko 30% 30% pacjentów uzyskało HIV RNApacjentów uzyskało HIV RNA <400 <400

kopiikopii/ml/ml

Katlama et al. IAS 2003. Abstract LB02

33% 30%

16% 18%12%

15%

6% 8%

0

20

40

60

80

100FUZEON + OB OB

Tydz 48

Tydz 48

Tydz 24

Tydz 24

<50 kopii/mL<400 kopii/mL

p < 0.0001 dla wszystkich porównańITT: przewanie leczenia=niepowodzenie

% p

acje

ntów

z o

dpow

iedz

ia

wiru

solo

gicz

ną

Dowody naukoweDowody naukowe: : Schematy oparte na stosowaniu Schematy oparte na stosowaniu

preparatu preparatu FUZEONFUZEON jako standard jako standard leczenia leczenia u pacjentów eksponowanych u pacjentów eksponowanych

na 3 klasy leków ARVna 3 klasy leków ARVBadanieBadanie

FUZEON plus FUZEON plus działającydziałający PI/rPI/r**

TORO 1 & 2TORO 1 & 2 FUZEON FUZEON + LPV/r+ LPV/r

RESIST 1 & 2RESIST 1 & 2 FUZEON FUZEON + TPV/r+ TPV/r

POWER 1 & 2POWER 1 & 2 FUZEON FUZEON + TMC 114/r+ TMC 114/r

* Wzmocniony rytonawirem aktywny PI

Badania Badania RESIST RESIST (faza(faza IIIIII) - tipranavir) - tipranavir ((TPVTPV))

2 badania2 badania (n = 1159): (n = 1159): RESIST 1 (USRESIST 1 (USAA, Australia), Australia) RESIST 2 (EuropRESIST 2 (Europaa, , PołudniowaPołudniowa Amer Amerykyka)a)

Cel badaniaCel badania:: Porównanie skutecznościPorównanie skuteczności schematu zawierającego schematu zawierającego

wzmocniony rytonawirem wzmocniony rytonawirem tipranatipranawwirir (TPV/r)(TPV/r) z z innym inhibitorem proteazy innym inhibitorem proteazy (PI/r)(PI/r)

FUZEON FUZEON stosowanostosowano uu 25% 25% pacjentówpacjentów Uprzednio stosowanoUprzednio stosowano FUZEON FUZEON uu 12% 12%

pacjentówpacjentów

Cooper et al. CROI 2005. Abstract 560

Cooper et al. CROI 2005. Abstract 560

0

20

40

60

80

100

% p

acje

ntó

w z

od

pow

ied

zią

wir

usolo

gic

zną

(≥1

log

sp

ad

ek w

poró

wn

an

iu d

o

BL)

w 2

4 t

yg

Tipranavir/r

7% 9%

31%

18%

FUZEON (uprzednio leczeni)

Bez enfuwirtydu (FUZEON)

Badanie Badanie RESIST: RESIST: najlepsza odpowiedź w najlepsza odpowiedź w

grupie otrzymującejgrupie otrzymującej TPV/r TPV/r ii FUZEON FUZEON

Porównywany PI/r

Trzykrotnie większe obniżenie Trzykrotnie większe obniżenie wiremii w ramieniu otrzymującym wiremii w ramieniu otrzymującym

FUZEON plus TPV/rFUZEON plus TPV/r

Spa

dek

HIV

RN

A w

24

tyg

w p

orów

nani

u do

war

tośc

i wyj

ścio

wyc

h(lo

g 10

kopi

i/ml)

Bez ENF (FUZEON)

–2.1

–0.6

–0.2–0.4

-2.5

-2

-1.5

-1

-0.5

0

Tipranavir/r Porównywany PI/r

FUZEON (uprzednio leczeni i nieleczeni)

http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4139b1-02-boehringer.pdf

Dwukrotnie większy Dwukrotnie większy wzrost liczby limfocytówwzrost liczby limfocytów CD4 CD4 w grupie w grupie TPV/r TPV/r ++

FUZEONFUZEON

Wzr

ost l

iczb

y lim

focy

tów

CD

4 w

24

tyg

w p

orów

nani

udo

war

tośc

i wyj

ścio

wyc

h (k

om/m

m3 )

+55

+27

+3

+6

0

20

40

60

Tipranavir/r Porównywany PI/r

Bez ENF (FUZEON)

FUZEON (uprzednio leczeni i nieleczeni)


TPV/r 1–4 (n = 328)

TPV/r 5+ (n = 215)

FUZEON FUZEON zapewnia lepszą i niezależną zapewnia lepszą i niezależną od wyjściowej ilości mutacji w genie od wyjściowej ilości mutacji w genie

PI odpowiedź wirusologicznąPI odpowiedź wirusologiczną**

0

-2.5

-2

-1.5

-1

-0.5

0 2 4 8 16 24Tygodnie

TPV/r 1–4 (n = 70)

TPV/r 5+ (n = 88)

LeczenieFUZEON

Bez leczeniaFUZEON

*Substytucje w kodonach 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 lub 90

Obn

iżen

ie V

L H

IV R

NA

(log 1

0 ko

pii/m

l)


Badania Badania POWER POWER (faza(faza II II) ) - - TMC114TMC114

2 badania2 badania (n = 497): (n = 497): 202 (US202 (USAA)) 213 (EU, Australia, Braz213 (EU, Australia, Brazyylliaia, , KKanada)anada)

CelCel: : Określenie zależnej od dawki skuteczności leczenia w Określenie zależnej od dawki skuteczności leczenia w

porównaniu z uprzednio wybranym PI/r w tygodniu 24 porównaniu z uprzednio wybranym PI/r w tygodniu 24 leczenialeczenia

FUZEON FUZEON stosowano ustosowano u 48% 48% pacjentówpacjentów Uprzednio leczeni preparatemUprzednio leczeni preparatem FUZEON FUZEON - - 15% 15%

pacjentówpacjentów

Katlama et al. CROI 2005. Abstract 164LB

TMC114/r (600 2xdobę) Porównywany PI/r

37%

8%

67%

16%

Katlama et al. CROI 2005. Abstract 164LB

67% 67% pacjentów uzyskało HIV RNApacjentów uzyskało HIV RNA <50 <50 kopiikopii/ml /ml w grupie w grupie FUZEON FUZEON ++

TMC114TMC114

FUZEON (uprzednio nieleczeni )

Bez ENF (FUZEON)

0

20

40

60

80

100

% p

acje

ntów

z o

dpow

iedz

iąH

IV R

NA

<50

kop

ii/m

l w 2

4 ty

g

Ograniczenia Ograniczenia badania badania

lekoopornościlekoopornościDobry wynik badania nie Dobry wynik badania nie

zapewnia pełnej aktywności zapewnia pełnej aktywności lekuleku

PaPacjenci z trzema cjenci z trzema “a “aktywnymiktywnymi” ” lekami lekami wykazują zwiększoną częstość wykazują zwiększoną częstość

skuteczności leczenia przy skuteczności leczenia przy zastosowaniu enfuwirtydu w zastosowaniu enfuwirtydu w

porównaniu z OBTporównaniu z OBT

Leczenie FUZEON (n = 98)

Bez leczenia FUZEON (n = 59)

Tygodnie

0

20

40

60

80

100

0 4 8 12 16 20 24 28 32 36 40 44 48

Miralles and DeMasi. IDSA 2004. Abstract 921

% p

acje

ntów

z

nieo

znac

zaln

ym

HIV

RN

A

(<40

0 co

pies

/ml)

52%

27%

Pacjenci z „aktywnym” LPV/r i 2 inne “aktywne” ARVs

p < 0.05 ; ITT

Pojedynczy wynik Pojedynczy wynik genotypowania może nie genotypowania może nie odzwierciedlać faktycznie odzwierciedlać faktycznie

występującej lekoopornościwystępującej lekoopornościPoprzedniPoprzednie wynikie wyniki

Ostatni Ostatni wynikwynik RóżnicaRóżnica

LamiLamiwudynawudyna (M184 (M184 V/I)V/I) 58.8%58.8% 25.5%25.5% 33.3%33.3%

InneInne NRTIs NRTIs 46.0%46.0% 27.7%27.7% 18.3%18.3%

NNRTIsNNRTIs 38.5%38.5% 24.5%24.5% 14.0%14.0%

PIsPIs 27.9%27.9% 15.6%15.6% 12.3%12.3%

Harrigan PR, Wynhoven B, Brumme ZL, et al., J. Infect. Dis. 2005 15;191(8):1325–30.

• Interpretacja wyników lekooporności powinna być szczególnie ostrożna i

uzupełniona o wywiad dotyczący leczenia


TORO, RESIST TORO, RESIST ii POWER POWER - niezależnie, - niezależnie, we wszystkich badaniach wykazano we wszystkich badaniach wykazano znaczący wpływ znaczący wpływ FUZEON FUZEON w połączeniu w połączeniu z aktywnymz aktywnym PI PI/r/r (LPV/r, TPV/r or (LPV/r, TPV/r or TMC114/r)TMC114/r) na skuteczność leczenia na skuteczność leczenia:: FUZEON FUZEON podwajałpodwajał odpowiedź na leczenie w odpowiedź na leczenie w

porównaniu z zastosowaniem samego PI/r porównaniu z zastosowaniem samego PI/r 5555−−67% 67% leczonych pacjentów osiagnęło leczonych pacjentów osiagnęło

poziom HIV RNA poniżej progu poziom HIV RNA poniżej progu oznaczalnościoznaczalności ww 24 24−−48 48 tygodniu leczenia.tygodniu leczenia.

Algorytm leczniczyAlgorytm leczniczy: : ObecnieObecnie

Schemat oparty na 2NRTTI/NNRTI

Schemat oparty na NRTI + PI/r

Schemat oparty na FUZEON + aktywny PI/r

Cel: zahamowanie replikacji HIV

Terapia ratując

a

1-szy rzut Po leczeniu 3 klasami ARV2-gi rzut

BackupsBackups

OpenMind study: OpenMind study: BackgroundBackground

Objectives:Objectives: To explore the perceptions of injectable ARVs To explore the perceptions of injectable ARVs

among HIV-treating physicians and treatment-among HIV-treating physicians and treatment-experienced HIV-infected patientsexperienced HIV-infected patients

To identify the attitudes that might act as To identify the attitudes that might act as motivators or barriers to the initiation of motivators or barriers to the initiation of injectable ARVsinjectable ARVs

Interviewed:Interviewed: 603 treatment-experienced patients (603 treatment-experienced patients (≥ 8 ARVs)≥ 8 ARVs) 499 HIV-treating physicians499 HIV-treating physicians

Locations: Locations: Germany, France, Italy, Spain, the UK and the Germany, France, Italy, Spain, the UK and the

USAUSAHorne et al. EACS 2005. PE7.3/25Youle et al. EACS 2005. PE7.3/24

OpenMind study: ResultsOpenMind study: ResultsPhysicians’ perceptionsPhysicians’ perceptions

* Defined as a rating of > 4 on a 7-point scale, where ‘1’ means ‘strongly disagree’ and ‘7’ means ‘strongly agree’

Youle et al. EACS 2005. PE7.3/24

0% 20% 40% 60% 80% 100%

Superior treatmentoutcomes with

enfuvirtide

Increased non-complianceand treatment refusal

with enfuvirtide48%

76%

Physicians that broadly agree with belief*

N = 603

OpenMind study: ResultsOpenMind study: ResultsPatients’ perceptionsPatients’ perceptions

Patients were Patients were shown a full shown a full description of description of enfuvirtide during enfuvirtide during the interviewthe interview

76% patients said 76% patients said they would be they would be likely to accept likely to accept enfuvirtideenfuvirtide

Unlikely to accept

Likely to accept

Very likely to accept

0%

20%

40%

60%

80%

100%

Horne et al. EACS 2005. PE7.3/25

35%

41%

24%

N = 516

POWER1: Subgroup POWER1: Subgroup Analyses of Response to Analyses of Response to TMC114/r 600/100 BIDTMC114/r 600/100 BID

Katlama C, et al. IAS 2005. Abstract WeOaLB0102.

Patients With HIV-1 RNA < 50 copies/mL at Week 24 (%) (ITT NC=F)

63% (n = 19)22% (n = 18)

56% (n = 34)19% (n = 36)

59% (n = 29)9% (n = 35)

46% (n = 28)16% (n = 25)

17% (n = 12)0% (n = 9)

ENF Used (Naive)

ENF Not Used

3 Primary PI Mut

TMC114 FC > 4

No Sensitive ARV in OBR

0 20 40 60 80

TMC114/r 600/100 BIDControl

53% (n = 60)18% (n = 60)Overall

100

POWER 2: Subgroup POWER 2: Subgroup Analyses of Response to Analyses of Response to TMC114/r 600/100 BIDTMC114/r 600/100 BID

Patients With HIV-1 RNA < 50 copies/mL at Week 24 (%)

64% (n = 14)7% (n = 14)

30% (n = 20)4% (n = 24)

35% (n = 23)7% (n = 28)

18% (n = 11)0% (n = 7)

ENF Used (Naive)

ENF Not Used

3 Primary PI Mut

No Sensitive NRTI in OBR

0 20 40 60 80


39% (n = 57)7% (n = 53)Overall

100

Wilkin T, et al. ICAAC 2005. Abstract H-413.

POWER 2: Subgroup POWER 2: Subgroup Analyses of Response to Analyses of Response to TMC114/r 600/100 BIDTMC114/r 600/100 BID

Patients With HIV-1 RNA < 50 copies/mL at Week 24 (%)

64% (n = 14)7% (n = 14)

30% (n = 20)4% (n = 24)

35% (n = 23)7% (n = 28)

18% (n = 11)0% (n = 7)

ENF Used (Naive)

ENF Not Used

3 Primary PI Mut

No Sensitive NRTI in OBR

0 20 40 60 80


39% (n = 57)7% (n = 53)Overall

100

Wilkin T, et al. ICAAC 2005. Abstract H-413.

A New Drug is Not A New Drug is Not Necessarily Necessarily

an Active Drugan Active Drug Patient on ZDV/3TC/ABC + LPV/rPatient on ZDV/3TC/ABC + LPV/r

CD4+ 269; VL 67,000CD4+ 269; VL 67,000 Cumulative resistance profile:Cumulative resistance profile:

RT: 41L, 184V, 210W, 215Y, 103NRT: 41L, 184V, 210W, 215Y, 103N PR: 30N, 63P, 71V, 77I, 82A, 84V, 90MPR: 30N, 63P, 71V, 77I, 82A, 84V, 90M

Clinician proposed a combination of Clinician proposed a combination of 3 “new” drugs: 3 “new” drugs: FTC + ATV + ENFFTC + ATV + ENF

The Cost of Treatment The Cost of Treatment Interruption in Interruption in

Treatment-Experienced Treatment-Experienced Patients Patients

Deeks SG, et al. N Engl J Med. 2001;344:472-480.

Weeks Before and After WT Switch

-100

-75

-50

-25

25

50

0

-6 -4 -2 0 2 4 6Med

ian

Ch

ang

e in

CD

4+

Cel

l Co

un

t (c

ells

/mm

3 )

n = 14

Med

ian

Ch

ang

e in

HIV

-1

RN

A (

log

10 c

op

ies/

mL

)

-0.4

-0.2

0.0

0.2

0.4

-6 -4 -2 0 2 4 6 8

n = 14

Deeks SG, et al. J Infect Dis. 2005;192:1537-1544.

Discontinue PIs, continue NRTIs (n = 15)

Discontinue NRTIs, continue PIs (n = 5)

Ch

ang

e in

HIV

-1 R

NA

(l

og

10 c

op

ies/

mL

)

1.5

1.0

0.5

0

-0.5 Wk 8 Wk 12 Wk 16

100

50

0

-50

-100

-150

Wk 8 Wk 12 Wk 16

Ch

ang

e in

CD

4+ C

ell

Co

un

t (c

ells

/mm

3 )

Partial Treatment Partial Treatment Interruption Interruption

Demonstrates Residual Demonstrates Residual NRTI ActivityNRTI Activity

Guidelines for Choosing Guidelines for Choosing a Nonsuppressive a Nonsuppressive

“Holding Regimen”“Holding Regimen” NeverNever use an NNRTI use an NNRTI

NNRTI mutations have no beneficial impact on fitnessNNRTI mutations have no beneficial impact on fitness Accumulation of additional mutations may result in Accumulation of additional mutations may result in

cross-resistance to 2nd generation NNRTIscross-resistance to 2nd generation NNRTIs

Always Always use 3TC or FTCuse 3TC or FTC Simple and well tolerated drugsSimple and well tolerated drugs M184V decreases fitnessM184V decreases fitness Increases activity of d4T, TDF, ZDVIncreases activity of d4T, TDF, ZDV

Choose PIs and/or NRTIs based on Choose PIs and/or NRTIs based on resistance and tolerability/toxicity resistance and tolerability/toxicity considerationsconsiderations

Jednoczesne stosowanie enfuwirtydu i Jednoczesne stosowanie enfuwirtydu i LPV/r LPV/r ww OB OB stanowi czynnik stanowi czynnik

prognostyczny odpowiedzi na terapięprognostyczny odpowiedzi na terapię

Gorsza odpowiedźLepsza odpowiedź

Wsp. Ryzyka dla HIV-1 RNA <400 kopii/ml (95% CI)

FUZEON

Wyjściowy HIV-1 RNA (per log10)

Wyjściowa liczba CD4 (per 100 kom/mm3)

Uprzednia ekspozycja lopinavir/r

Uprzednie leczenier ARVs (n)

Liczba aktywnych ARVs w OB (n)

Lopinavir/r w OB

0.1 1 10

Montaner et al. 15th IAC 2004. Abstract TuPe4483

HIV-1 RNA <400 kopii/ml w 48 tyg

FUZEON plus LPV/r: 37% FUZEON plus LPV/r: 37% pacjentów osiągnęło HIV pacjentów osiągnęło HIV RNARNA <50 <50 kopiikopii/ml /ml po po 24 24

tygtyg

LPV/r naive

No LPV/r LPV/rNo LPV/r LPV/r

LPV/r experienced

LPV/r in OB:

Prior LPV/r:

8% 13%

30%37%

1% 4%7%

17%

0

20

40

60

80

100

DRAFT Roche data on file

57 5817177158 93 239142

*p < 0.01, ITT, D/C + Switch = Failure

% p

acje

ntów

z H

IV R

NA

(<50

kop

ii/m

l) w

24

tyg FUZEON (naive)

No FUZEON

*

**

Lamivudine Partially Lamivudine Partially Suppresses Multidrug-Suppresses Multidrug-resistant HIV-1 Despite resistant HIV-1 Despite

Presence of M184V MutationPresence of M184V MutationSlideset on:Slideset on:

Campbell TB, Shulman NS, Johnson SC, Campbell TB, Shulman NS, Johnson SC, et al. Antiviral activity of lamivudine in et al. Antiviral activity of lamivudine in salvage therapy for multidrug-resistant salvage therapy for multidrug-resistant

HIV-1 infection. Clin Infect Dis. HIV-1 infection. Clin Infect Dis. 2005;41:236-242.2005;41:236-242.

Background and Background and RationaleRationale

HIV-1 RNA suppression to undetectable HIV-1 RNA suppression to undetectable levels may not be possible for some patients levels may not be possible for some patients with multidrug-resistant viruswith multidrug-resistant virus

However, continuation of lamivudine therapy However, continuation of lamivudine therapy despite high-level lamivudine resistance (ie, despite high-level lamivudine resistance (ie, M184V/I) maintains partial HIV-1 RNA M184V/I) maintains partial HIV-1 RNA suppressionsuppression Discontinuation of lamivudine causes increased Discontinuation of lamivudine causes increased

HIV-1 RNA levels and reversion to wild-type virusHIV-1 RNA levels and reversion to wild-type virus Current study evaluated antiretroviral Current study evaluated antiretroviral

activity of lamivudine against lamivudine-activity of lamivudine against lamivudine-resistant virus by withdrawing lamivudine resistant virus by withdrawing lamivudine therapy in patients with multidrug-resistant therapy in patients with multidrug-resistant HIV-1HIV-1

Summary of Study Summary of Study DesignDesign

Results of 2 studies combined for analysisResults of 2 studies combined for analysis University of Colorado General Clinical Research University of Colorado General Clinical Research

CenterCenter Stanford University School of MedicineStanford University School of Medicine

Subjects discontinued lamivudine but continued Subjects discontinued lamivudine but continued taking all other antiretrovirals in pre-entry regimentaking all other antiretrovirals in pre-entry regimen

HIV-1 RNA, CD4+ cell count, genotypic and HIV-1 RNA, CD4+ cell count, genotypic and phenotypic resistance testing, and plasma phenotypic resistance testing, and plasma concentrations of lamivudine, stavudine, and concentrations of lamivudine, stavudine, and

zidovudine regularly evaluated duringzidovudine regularly evaluated during lamivudine withdrawallamivudine withdrawal

Baseline CharacteristicsBaseline Characteristics

N = 6N = 6 Median age: 48 years (range, 43-64 years)Median age: 48 years (range, 43-64 years) Male: 100%Male: 100% High-level lamivudine resistance (presence High-level lamivudine resistance (presence

of M184V and inhibitory concentration 50% of M184V and inhibitory concentration 50% > 300 fold-change): 100%> 300 fold-change): 100%

Median HIV-1 RNA: 20,000 copies/mLMedian HIV-1 RNA: 20,000 copies/mL Range of plasma lamivudine concentration: Range of plasma lamivudine concentration:

374-2026 ng/mL374-2026 ng/mL

Main FindingsMain Findings Lamivudine withdrawal associated with Lamivudine withdrawal associated with

median HIV-1 RNA increase of 0.5 logmedian HIV-1 RNA increase of 0.5 log1010 copies/mL at Week 6 (copies/mL at Week 6 (PP = .04) = .04) Duration of withdrawal, 8-22 weeksDuration of withdrawal, 8-22 weeks Lamivudine concentration undetectable (< 20 Lamivudine concentration undetectable (< 20

ng/mL) in all patients by Week 6ng/mL) in all patients by Week 6 No wild-type reversion of M184VNo wild-type reversion of M184VM detected by M detected by

Week 6Week 6 Early increases in HIV-1 RNA associated with Early increases in HIV-1 RNA associated with

T215Y/F and M41L mutations at baseline, and T215Y/F and M41L mutations at baseline, and reduced phenotypic susceptibility to NRTIs, reduced phenotypic susceptibility to NRTIs, excluding lamivudine (75% vs 10% for those with excluding lamivudine (75% vs 10% for those with and without mutations and reduced and without mutations and reduced susceptibility, respectively; susceptibility, respectively; PP = .001) = .001)

Main FindingsMain Findings

Reversion of M184VReversion of M184VM detected at least M detected at least once in 4/6 patients during withdrawalonce in 4/6 patients during withdrawal Median time to detection of M184VMedian time to detection of M184VM M

reversion, 12 weeks (range, 8-14 weeks)reversion, 12 weeks (range, 8-14 weeks) Trend toward higher HIV-1 RNA at first Trend toward higher HIV-1 RNA at first

appearance of M184Vappearance of M184VMM Median HIV-1 RNA, +0.3 logMedian HIV-1 RNA, +0.3 log1010 copies/mL ( copies/mL (PP = .07) = .07)

Median HIV-1 replication capacity increased to Median HIV-1 replication capacity increased to 60% at time of reversion vs 41% at baseline (60% at time of reversion vs 41% at baseline (PP = = .07).07) Reversion not associated with changes in CD4+ cell Reversion not associated with changes in CD4+ cell

countcount

Main FindingsMain Findings All patients resumed lamivudine at their own or All patients resumed lamivudine at their own or

their doctor’s request and not due to resumption their doctor’s request and not due to resumption criteriacriteria

Median HIV-1 RNA 0.6 logMedian HIV-1 RNA 0.6 log1010 copies/mL (range, 0.1- copies/mL (range, 0.1-0.6) above baseline at time of resumption (0.6) above baseline at time of resumption (PP = .03) = .03) HIV-1 RNA not significantly different from baseline HIV-1 RNA not significantly different from baseline

after 8 weeks of lamivudine treatment (after 8 weeks of lamivudine treatment (PP = .2) = .2) Reappearance of M184V mutation at 8 weeks after Reappearance of M184V mutation at 8 weeks after

lamivudine resumptionlamivudine resumption Median HIV-1 replication capacity returned to near-Median HIV-1 replication capacity returned to near-

baseline value (baseline value (PP = .9) as did susceptibility to = .9) as did susceptibility to antiretroviral drugs in regimenantiretroviral drugs in regimen

Key ConclusionsKey Conclusions Lamivudine treatment in patients with multidrug-Lamivudine treatment in patients with multidrug-

resistant HIV-1 suppressed HIV-1 RNA by ~ 0.5 resistant HIV-1 suppressed HIV-1 RNA by ~ 0.5 loglog1010 copies/mL copies/mL

After lamivudine withdrawal, increase in HIV-1 After lamivudine withdrawal, increase in HIV-1 RNA observed prior to 184VRNA observed prior to 184VM reversion M reversion Suggests that lamivudine contributes to viral Suggests that lamivudine contributes to viral

suppression despite presence of M184V resistance suppression despite presence of M184V resistance mutationmutation

Replication capacity increased after M184VReplication capacity increased after M184VM M reversion in absence of lamivudinereversion in absence of lamivudine Suggests that lamivudine may also contribute to viral Suggests that lamivudine may also contribute to viral

suppression by maintaining M184V mutationsuppression by maintaining M184V mutation

Panel’s Panel’s Recommendations:Recommendations:

If the decision is made to initiate therapy in a person If the decision is made to initiate therapy in a person with acute HIV infection, it is likely that resistance with acute HIV infection, it is likely that resistance testing at baseline will optimize virologic response; this testing at baseline will optimize virologic response; this strategy should be considered (BIII). strategy should be considered (BIII).

• • Drug resistance testing at baseline in antiretroviral-Drug resistance testing at baseline in antiretroviral-naïve, chronically infected patients is an untested naïve, chronically infected patients is an untested strategy. However, it may be reasonable to consider strategy. However, it may be reasonable to consider resistance testing when there is a significant probability resistance testing when there is a significant probability that the patient was infected with a drug-resistance that the patient was infected with a drug-resistance virus, i.e., if the patient is thought to have been infected virus, i.e., if the patient is thought to have been infected by a person who was receiving antiretroviral drugs (CIII). by a person who was receiving antiretroviral drugs (CIII).

• • Drug resistance testing is not advised for persons with Drug resistance testing is not advised for persons with viral load <1,000 copies/mL, since amplification of the viral load <1,000 copies/mL, since amplification of the virus is unreliable (DIII). virus is unreliable (DIII).

Panel’s Panel’s Recommendations:Recommendations:

• • HIV drug resistance testing should be HIV drug resistance testing should be performed to assist in selecting active drugs performed to assist in selecting active drugs when changing antiretroviral regimens in cases when changing antiretroviral regimens in cases of virologic failure (BII). of virologic failure (BII).

• • Drug resistance testing should also be Drug resistance testing should also be considered when managing suboptimal viral load considered when managing suboptimal viral load reduction (BIII). reduction (BIII).

• • Drug resistance testing in the setting of Drug resistance testing in the setting of virologic failure should be performed while the virologic failure should be performed while the patient is taking his/her antiretroviral drugs, or patient is taking his/her antiretroviral drugs, or immediately (i.e., within 4 weeks) after immediately (i.e., within 4 weeks) after discontinuing therapy (BII). discontinuing therapy (BII).

DyskusjaDyskusja

Brak weryfikacji sposobu Brak weryfikacji sposobu przyjmowania leków w trakcie przyjmowania leków w trakcie prowadzenia terapii ARVprowadzenia terapii ARV

Zbyt późna zmiana terapii ARVZbyt późna zmiana terapii ARV

Nadkażenie szczepami Nadkażenie szczepami wielolekoopornymi ????wielolekoopornymi ????

Najczęstsze błędy w postępowaniu z chorym po niepowodzeniach terapeutycznych

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