Presentation is loading. Please wait.

Presentation is loading. Please wait.

Najczęstsze błędy w postępowaniu z chorym po niepowodzeniach terapeutycznych Piotr Pulik Wojewódzki Szpital Zakaźny w Warszawie.

Similar presentations


Presentation on theme: "Najczęstsze błędy w postępowaniu z chorym po niepowodzeniach terapeutycznych Piotr Pulik Wojewódzki Szpital Zakaźny w Warszawie."— Presentation transcript:

1 Najczęstsze błędy w postępowaniu z chorym po niepowodzeniach terapeutycznych Piotr Pulik Wojewódzki Szpital Zakaźny w Warszawie

2 Podsumowanie W kolejnym zestawie lekowym stosowanie minimum 2 aktywnych leków o ile to możliwe z uwzględnieniem nowej klasy leków W kolejnym zestawie lekowym stosowanie minimum 2 aktywnych leków o ile to możliwe z uwzględnieniem nowej klasy leków Włączenie PI/r ( najlepiej nowej generacji) Włączenie PI/r ( najlepiej nowej generacji) Poprawa parametrów farmakokinetycznych zestawu poprzez dodanie ritonawiru Poprawa parametrów farmakokinetycznych zestawu poprzez dodanie ritonawiru Utrzymanie leczenia lamiwudyną u pacjentów ze stwierdzona mutacją M184V Utrzymanie leczenia lamiwudyną u pacjentów ze stwierdzona mutacją M184V

3 Podsumowanie Utrzymanie terapii pomimo nieskuteczności wirusologicznej Utrzymanie terapii pomimo nieskuteczności wirusologicznej Intensyfikacja leczenia Intensyfikacja leczenia Brak celowości ponownego stosowania NNRTI Brak celowości ponownego stosowania NNRTI

4 Najczęstsze przyczyny niepowodzeń… Brak współpracy pacjenta Brak współpracy pacjenta Działania uboczne leków Działania uboczne leków Nieprzestrzeganie dostępnych rekomendacji przez osobę leczącą Nieprzestrzeganie dostępnych rekomendacji przez osobę leczącą Brak dostępności do leków i szybkiej diagnostyki Brak dostępności do leków i szybkiej diagnostyki Brak TDM Brak TDM Błędna interpretacja wyników immunologicznych i lekooporności Błędna interpretacja wyników immunologicznych i lekooporności Interrakcje pomiędzy lekami Interrakcje pomiędzy lekami

5 Rating Scheme for Clinical Practice Recommendations Recommendation A: Strong B: Moderate C: Optional D: Should usually not be offered E: Should never be offered 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 Quality of Evidence for Recommendation I: At least one randomized trial with clinical results II: Clinical trials with laboratory results III: Expert opinion

6 Many factors increase the likelihood of treatment failure, including: Baseline patient factors such as: earlier calendar year of starting therapy, earlier calendar year of starting therapy, higher pretreatment or baseline HIV RNA level (depending on the specific regimen used), higher pretreatment or baseline HIV RNA level (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. depression, active substance use), 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 presence of drug- resistant virus, prior treatment failure with development of drug resistance or cross resistance

7 Many factors increase the likelihood of treatment failure, including(2) : incomplete medication adherence and missed clinic appointments; incomplete medication adherence and missed clinic appointments; drug side effects and toxicity; 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 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 suboptimal potency of the antiretroviral regimen; and/or other, unknown reasons. other, unknown reasons.

8 MANAGEMENT OF THE TREATMENT – EXPERIENCED 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.

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

10 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. 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.

11 Assessment of Antiretroviral Treatment Failure and Changing Therapy 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. 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); 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);

12 Assessment of Antiretroviral Treatment Failure and Changing Therapy medication-taking behavior, including adherence to recommended drug doses, dosing frequency and food/fasting requirements; 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 drug- drug interactions); tolerance of the medications; concomitant medications (with consideration for adverse drug- drug interactions); and co-morbidities (including substance use). 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. In many cases the cause(s) of treatment failure will be readily apparent. In some cases, no obvious cause may be identified.

13 Virologic Failure(1) There is no consensus on the optimal time to change therapy for virologic failure. 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 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). Other approaches allow detectable viremia up to an arbitrary level (e.g., 1,000-5,000 copies/mL).

14 Virologic Failure(2) However, ongoing viral replication in the presence of antiretroviral drugs promotes the selection of drug resistance mutations [176] and may limit future treatment options. 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). 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).

15 Virologic failure 3 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]. 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]. 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). 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).

16 Virologic failure 3 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). 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). 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).

17 Changing an Antiretroviral Therapy Regimen for Virologic Failure 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). 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. 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). 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).

18 Changing an Antiretroviral Therapy Regimen for Virologic Failure 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). 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 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

19 General Approach. 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]. 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. 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. 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.

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

21 Sequencing and Cross Resistance(1) The order of use of some antiretroviral agents may be important. 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. 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. 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.

22 Sequencing and Cross Resistance(2) The order of use of some antiretroviral agents may be important. 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. Cross-resistance among NRTIs is common but varies by drug. Most, if not all, NNRTI- associated resistance mutations confer resistance to all approved NNRTIs.

23 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 cross- resistance to the entire protease inhibitor class. 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.

24 Sequencing and Cross Resistance(4) 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]. 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). 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).

25 Current Approach (1) 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. 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]. 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].

26 Current Approach (2) These studies illustrate and support the strategy of conducting resistance testing while a treatment- experienced 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. These studies illustrate and support the strategy of conducting resistance testing while a treatment- experienced 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.

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

28 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. 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. 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.

29 Summary of Guidelines For Changing An Antiretroviral Regimen For Suspected Treatment Regimen Failure Ponownie….

30 Patient Assessment (AIII) Review antiretroviral treatment history. Review antiretroviral treatment history. Assess for evidence of clinical progression.(e.g. physical exam, laboratory and/or radiologic tests) Assess for evidence of clinical progression.(e.g. physical exam, laboratory and/or radiologic tests) Assess adherence, tolerability, and pharmacokinetic issues. Assess adherence, tolerability, and pharmacokinetic issues.

31 Patient Assessment (AIII) Distinguish between limited, intermediate, and extensive prior therapy and drug resistance. 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). 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 Identify active drugs and drug classes to use in designing the new regimen

32 Patient Management: Specific Clinical Scenarios

33 Limited or intermediate prior treatment with low (but not suppressed) HIV RNA level (e.g., up to 5000 copies/mL): The goal of treatment is to re-suppress HIV RNA to below the level of assay detection. 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) Consider intensifying with one drug (e.g., tenofovir) (BII) or pharmacokinetic enhancement (use of ritonavir boosting of a protease inhibitor) (BII)

34 Limited or intermediate prior treatment with low (but not suppressed) HIV RNA level (e.g., up to 5000 copies/mL): perform resistance testing if possible, or most aggressively, perform resistance testing if possible, or most aggressively, change two or more drugs in the regimen (CIII). 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. 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.

35 Limited or intermediate prior treatment with resistance to one drug: Consider changing the one drug (CIII), pharmacokinetic enhancement (few data available) (BII), or, most aggressively, change two or more drugs in the regimen (BII). Consider changing the one drug (CIII), pharmacokinetic enhancement (few data available) (BII), or, most aggressively, change two or more drugs in the regimen (BII).

36 Limited or intermediate prior treatment with resistance to more than one drug: 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). 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).

37 Prior treatment with no resistance identified 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). 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).

38 Extensive prior treatment and drug resistance: 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 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. 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). It is reasonable to continue the same antiretroviral regimen if there are few or no treatment options (CIII).

39 Extensive prior treatment and drug resistance: In general, avoid adding a single active drug because of the risk for the rapid development of resistance to that drug. 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 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. In this complicated scenario, expert advice should be sought.

40 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, HTLV- 1, 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 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, HTLV- 1, drug toxicity). The combination of didanosine and tenofovir has been associated with CD4 cell declines or blunted CD4 cell responses.

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

42 Novel Strategies To Consider For Treatment-Experienced Patients With Few Available Active Treatment Options Pharmacokinetic enhancement with ritonavir Pharmacokinetic enhancement with ritonavir Therapeutic Drug Monitoring Therapeutic Drug Monitoring Re-treating with prior medications Re-treating with prior medications

43 Novel Strategies To Consider For Treatment-Experienced Patients With Few Available Active 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 Time: Novel Strategy Not Recommended at This Time: Structured treatment interruptions in the setting of virologic failure have been investigated prospectively, but most trials have shown limited or no virologic benefit Structured treatment interruptions in the setting of virologic failure have been investigated prospectively, but most trials have shown limited or no virologic benefit

44 Pharmacokinetic enhancement with ritonavir may increase drug concentrations of most PIs (except nelfinavir) and may overcome some degree of drug resistance may increase drug concentrations of most PIs (except nelfinavir) and may overcome some degree of drug resistance

45 Re-treating with prior medications may be useful, particularly if they were discontinued previously for toxicities that can now be better addressed (BII). 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. 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. Continued drug therapy and maintenance of drug- resistant virus may compromise viral fitness, but it is not known if this has clinical applicability.

46 The use of empiric multi-drug regimens 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) 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)

47 New antiretroviral drugs (1) 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. 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]. 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].

48 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). 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).

49 Algorytm leczenia: 1999 Schemat oparty na NRTI/NNRTI Schemat oparty na PI/r Ograniczona liczba działających leków ARV jest powodem ponownego zastosowania leków Terapia ratująca 1-szy rzut2-gi rzut Celem leczenia jest uzyskanie zahamowania replikacji wirusa Celem leczenia jest zachowanie funkcji immunologicznych i obniżenie wiremiii

50 Algorytm leczenia: 1999 W jaki sposób poprawić wyniki leczenia po wielu niepowodzeniach? Terapia ratująca 1-szy rzut2-gi rzut Schemat oparty na NRTI/NNRTI Schemat oparty na PI/r Ograniczona liczba działających leków ARV jest powodem ponownego zastosowania leków Celem leczenia jest uzyskanie zahamowania replikacji wirusa Celem leczenia jest zachowanie funkcji immunologicznych i obniżenie wiremiii

51 Dołączenie do leczenia leku z nowej klasy zwiększa odsetek odpowiedzi nawet, jeżeli stwierdza się aktywność 3 lub więcej leków 9 32 44 46 52 0 8 19 20 19 0 25 50 75 100 01234 Wyjściowe GSS %pacjentów z HIV RNA <400 kopii/ml, 48 tyg TORO % pacjentów z obniżeniem 1 log 10 w 24 tyg 0 20 40 60 80 100 012 3 55 46 37 13 34 20 13 9 Liczba aktywnych leków ARV RESIST FUZEON + OBOBTPV/r porównywany PI/r Miralles et al. HIV7 2004. Abstract P17Cooper et al. CROI 2005. Abstract 560

52 W badaniach TORO ponowne zastosowanie nie działających leków ARV prowadziło do niezadowalających wyników Katlama et al. IAS 2003. Abstract LB02 ITT: przewanie leczenia=niepowodzenie 12% 15% 6% 8% 0 20 40 60 80 100 OB Tydz 48 Tydz 24 <50 kopii/mL<400 kopii/mL % pacjentów z odpowiedzią wirusologiczną

53 FUZEON powodował podwojenie odsetka pacjentów z odpowiedzią wirusologiczną, jakkolwiek tylko 30% pacjentów uzyskało HIV RNA <400 kopii/ml Katlama et al. IAS 2003. Abstract LB02 33% 30% 16% 18% 12% 15% 6% 8% 0 20 40 60 80 100 FUZEON + OBOB Tydz 48 Tydz 24 <50 kopii/mL<400 kopii/mL p < 0.0001 dla wszystkich porównań ITT: przewanie leczenia=niepowodzenie % pacjentów z odpowiedzia wirusologiczną

54 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

55 Badania RESIST (faza III) - tipranavir (TPV) 2 badania (n = 1159): 2 badania (n = 1159): RESIST 1 (USA, Australia) RESIST 1 (USA, Australia) RESIST 2 (Europa, Południowa Ameryka) RESIST 2 (Europa, Południowa Ameryka) Cel badania: Cel badania: Porównanie skuteczności schematu zawierającego wzmocniony rytonawirem tipranawir (TPV/r) z innym inhibitorem proteazy (PI/r) Porównanie skuteczności schematu zawierającego wzmocniony rytonawirem tipranawir (TPV/r) z innym inhibitorem proteazy (PI/r) FUZEON stosowano u 25% pacjentów FUZEON stosowano u 25% pacjentów Uprzednio stosowano FUZEON u 12% pacjentów Uprzednio stosowano FUZEON u 12% pacjentów Cooper et al. CROI 2005. Abstract 560

56 0 20 40 60 80 100 % pacjentów z odpowiedzią wirusologiczną (1 log spadek w porównaniu do BL) w 24 tyg Tipranavir/r 7% 9% 31% 18% FUZEON (uprzednio leczeni) Bez enfuwirtydu (FUZEON) Badanie RESIST: najlepsza odpowiedź w grupie otrzymującej TPV/r i FUZEON Porównywany PI/r

57 Trzykrotnie większe obniżenie wiremii w ramieniu otrzymującym FUZEON plus TPV/r Spadek HIV RNA w 24 tyg w porównaniu do wartości wyjściowych (log 10 kopii/ml) Bez ENF (FUZEON) –2.1 –0.6 –0.2 –0.4 -2.5 -2 -1.5 -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

58 Dwukrotnie większy wzrost liczby limfocytów CD4 w grupie TPV/r + FUZEON Wzrost liczby limfocytów CD4 w 24 tyg w porównaniu do wartości wyjściowych (kom/mm 3 ) +55 +27 +3 +6 0 20 40 60 Tipranavir/r Porównywany PI/r Bez ENF (FUZEON) FUZEON (uprzednio leczeni i nieleczeni) http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4139b1-02-boehringer.pdf

59 TPV/r 1–4 (n = 328) TPV/r 5+ (n = 215) FUZEON zapewnia lepszą i niezależną od wyjściowej ilości mutacji w genie PI odpowiedź wirusologiczną* 0 -2.5 -2 -1.5 -0.5 02481624 Tygodnie TPV/r 1–4 (n = 70) TPV/r 5+ (n = 88) Leczenie FUZEON Bez leczenia FUZEON *Substytucje w kodonach 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 lub 90 Obniżenie VL HIV RNA (log 10 kopii/ml) http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4139b1-02-boehringer.pdf

60 Badania POWER (faza II) - TMC114 2 badania (n = 497): 2 badania (n = 497): 202 (USA) 202 (USA) 213 (EU, Australia, Brazylia, Kanada) 213 (EU, Australia, Brazylia, Kanada) Cel: Cel: Określenie zależnej od dawki skuteczności leczenia w porównaniu z uprzednio wybranym PI/r w tygodniu 24 leczenia Określenie zależnej od dawki skuteczności leczenia w porównaniu z uprzednio wybranym PI/r w tygodniu 24 leczenia FUZEON stosowano u 48% pacjentów FUZEON stosowano u 48% pacjentów Uprzednio leczeni preparatem FUZEON - 15% pacjentów Uprzednio leczeni preparatem FUZEON - 15% pacjentów Katlama et al. CROI 2005. Abstract 164LB

61 TMC114/r (600 2xdobę) Porównywany PI/r 37% 8% 67% 16% Katlama et al. CROI 2005. Abstract 164LB 67% pacjentów uzyskało HIV RNA <50 kopii/ml w grupie FUZEON + TMC114 FUZEON (uprzednio nieleczeni ) Bez ENF (FUZEON) 0 20 40 60 80 100 % pacjentów z odpowiedzią HIV RNA <50 kopii/ml w 24 tyg

62 Ograniczenia badania lekooporności Dobry wynik badania nie zapewnia pełnej aktywności leku

63 Pacjenci z trzema aktywnymi lekami wykazują zwiększoną częstość skuteczności leczenia przy zastosowaniu enfuwirtydu w porównaniu z OBT Leczenie FUZEON (n = 98) Bez leczenia FUZEON (n = 59) Tygodnie 0 20 40 60 80 100 04812162024283236404448 Miralles and DeMasi. IDSA 2004. Abstract 921 % pacjentów z nieoznaczalnym HIV RNA (<400 copies/ml) 52% 27% Pacjenci z aktywnym LPV/r i 2 inne aktywne ARVs p < 0.05 ; ITT

64 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% NNRTIs38.5%24.5%14.0% PIs27.9%15.6%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

65 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: 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 FUZEON podwajał odpowiedź na leczenie w porównaniu z zastosowaniem samego PI/r 5567% leczonych pacjentów osiagnęło poziom HIV RNA poniżej progu oznaczalności w 2448 tygodniu leczenia. 5567% leczonych pacjentów osiagnęło poziom HIV RNA poniżej progu oznaczalności w 2448 tygodniu leczenia.

66 Algorytm leczniczy: Obecnie Schemat oparty na 2NRTTI/NNRTI Schemat oparty na NRTI + PI/r Schemat oparty na FUZEON + aktywny PI/r Cel: zahamowanie replikacji HIV Terapia ratująca 1-szy rzut Po leczeniu 3 klasami ARV 2-gi rzut

67 Backups

68 OpenMind study: Background Objectives: Objectives: To explore the perceptions of injectable ARVs among HIV- treating physicians and treatment-experienced HIV-infected patients To explore the perceptions of injectable ARVs among HIV- treating physicians and treatment-experienced HIV-infected patients To identify the attitudes that might act as motivators or barriers to the initiation of injectable ARVs To identify the attitudes that might act as motivators or barriers to the initiation of injectable ARVs Interviewed: Interviewed: 603 treatment-experienced patients ( 8 ARVs) 603 treatment-experienced patients ( 8 ARVs) 499 HIV-treating physicians 499 HIV-treating physicians Locations: Locations: Germany, France, Italy, Spain, the UK and the USA 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

69 OpenMind study: Results Physicians 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 treatment outcomes with enfuvirtide Increased non-compliance and treatment refusal with enfuvirtide 48% 76% Physicians that broadly agree with belief* N = 603

70 OpenMind study: Results Patients perceptions Patients were shown a full description of enfuvirtide during the interview Patients were shown a full description of enfuvirtide during the interview 76% patients said they would be likely to accept enfuvirtide 76% patients said they would be likely to accept enfuvirtide 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

71 POWER1: Subgroup Analyses of Response to TMC114/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 020406080 TMC114/r 600/100 BID Control 53% (n = 60) 18% (n = 60) Overall 100

72 POWER 2: Subgroup Analyses of Response to TMC114/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 020406080 TMC114/r 600/100 BID Control 39% (n = 57) 7% (n = 53) Overall 100 Wilkin T, et al. ICAAC 2005. Abstract H-413.

73 POWER 2: Subgroup Analyses of Response to TMC114/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 020406080 TMC114/r 600/100 BID Control 39% (n = 57) 7% (n = 53) Overall 100 Wilkin T, et al. ICAAC 2005. Abstract H-413.

74 A New Drug is Not Necessarily an Active Drug Patient on ZDV/3TC/ABC + LPV/r Patient on ZDV/3TC/ABC + LPV/r CD4+ 269; VL 67,000 CD4+ 269; VL 67,000 Cumulative resistance profile: Cumulative resistance profile: RT: 41L, 184V, 210W, 215Y, 103N RT: 41L, 184V, 210W, 215Y, 103N PR: 30N, 63P, 71V, 77I, 82A, 84V, 90M PR: 30N, 63P, 71V, 77I, 82A, 84V, 90M Clinician proposed a combination of 3 new drugs: FTC + ATV + ENF Clinician proposed a combination of 3 new drugs: FTC + ATV + ENF

75 The Cost of Treatment Interruption in Treatment- Experienced 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 -6-4-20246 Median Change in CD4+ Cell Count (cells/mm 3 ) n = 14 Median Change in HIV-1 RNA (log 10 copies/mL) -0.4 -0.2 0.0 0.2 0.4 -6-4-202468 n = 14

76 Deeks SG, et al. J Infect Dis. 2005;192:1537-1544. Discontinue PIs, continue NRTIs (n = 15) Discontinue NRTIs, continue PIs (n = 5) Change in HIV-1 RNA (log 10 copies/mL) 1.5 1.0 0.5 0 -0.5 Wk 8 Wk 12Wk 16 100 50 0 -50 -100 -150 Wk 8 Wk 12Wk 16 Change in CD4+ Cell Count (cells/mm 3 ) Partial Treatment Interruption Demonstrates Residual NRTI Activity

77 Guidelines for Choosing a Nonsuppressive Holding Regimen Never use an NNRTI Never use an NNRTI NNRTI mutations have no beneficial impact on fitness NNRTI mutations have no beneficial impact on fitness Accumulation of additional mutations may result in cross- resistance to 2nd generation NNRTIs Accumulation of additional mutations may result in cross- resistance to 2nd generation NNRTIs Always use 3TC or FTC Always use 3TC or FTC Simple and well tolerated drugs Simple and well tolerated drugs M184V decreases fitness M184V decreases fitness Increases activity of d4T, TDF, ZDV Increases activity of d4T, TDF, ZDV Choose PIs and/or NRTIs based on resistance and tolerability/toxicity considerations Choose PIs and/or NRTIs based on resistance and tolerability/toxicity considerations

78 Jednoczesne stosowanie enfuwirtydu i LPV/r w OB stanowi czynnik prognostyczny odpowiedzi na terapię Gorsza odpowiedź Lepsza odpowiedź Wsp. Ryzyka dla HIV-1 RNA <400 kopii/ml (95% CI) FUZEON Wyjściowy HIV-1 RNA (per log 10 ) Wyjściowa liczba CD4 (per 100 kom/mm 3 ) Uprzednia ekspozycja lopinavir/r Uprzednie leczenier ARVs (n) Liczba aktywnych ARVs w OB (n) Lopinavir/r w OB 0.1110 Montaner et al. 15th IAC 2004. Abstract TuPe4483 HIV-1 RNA <400 kopii/ml w 48 tyg

79 FUZEON plus LPV/r: 37% pacjentów osiągnęło HIV RNA <50 kopii/ml po 24 tyg LPV/r naive No LPV/rLPV/rNo LPV/rLPV/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 581717715893239142 *p < 0.01, ITT, D/C + Switch = Failure % pacjentów z HIV RNA (<50 kopii/ml) w 24 tyg FUZEON (naive) No FUZEON * * *

80 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.

81 Background and Rationale HIV-1 RNA suppression to undetectable levels may not be possible for some patients with multidrug-resistant virus 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 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 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 Current study evaluated antiretroviral activity of lamivudine against lamivudine-resistant virus by withdrawing lamivudine therapy in patients with multidrug-resistant HIV-1

82 Summary of Study Design Results of 2 studies combined for analysis Results of 2 studies combined for analysis University of Colorado General Clinical Research Center University of Colorado General Clinical Research Center Stanford University School of Medicine Stanford University School of Medicine Subjects discontinued lamivudine but continued taking all other antiretrovirals in pre-entry regimen 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 HIV-1 RNA, CD4+ cell count, genotypic and phenotypic resistance testing, and plasma concentrations of lamivudine, stavudine, and zidovudine regularly evaluated during lamivudine withdrawal

83 Baseline Characteristics N = 6 N = 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 of M184V and inhibitory concentration 50% > 300 fold-change): 100% High-level lamivudine resistance (presence of M184V and inhibitory concentration 50% > 300 fold-change): 100% Median HIV-1 RNA: 20,000 copies/mL Median HIV-1 RNA: 20,000 copies/mL Range of plasma lamivudine concentration: 374- 2026 ng/mL Range of plasma lamivudine concentration: 374- 2026 ng/mL

84 Main Findings Lamivudine withdrawal associated with median HIV-1 RNA increase of 0.5 log 10 copies/mL at Week 6 (P =.04) Lamivudine withdrawal associated with median HIV-1 RNA increase of 0.5 log 10 copies/mL at Week 6 (P =.04) Duration of withdrawal, 8-22 weeks Duration of withdrawal, 8-22 weeks Lamivudine concentration undetectable (< 20 ng/mL) in all patients by Week 6 Lamivudine concentration undetectable (< 20 ng/mL) in all patients by Week 6 No wild-type reversion of M184V M detected 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) 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)

85 Main Findings Reversion of M184V M detected at least once in 4/6 patients during withdrawal 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) 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 Trend toward higher HIV-1 RNA at first appearance of M184V M Median HIV-1 RNA, +0.3 log 10 copies/mL (P =.07) Median HIV-1 RNA, +0.3 log 10 copies/mL (P =.07) Median HIV-1 replication capacity increased to 60% at time of reversion vs 41% at baseline (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 Reversion not associated with changes in CD4+ cell count

86 Main Findings All patients resumed lamivudine at their own or their doctors request and not due to resumption criteria All patients resumed lamivudine at their own or their doctors request and not due to resumption criteria Median HIV-1 RNA 0.6 log 10 copies/mL (range, 0.1-0.6) above baseline at time of resumption (P =.03) Median HIV-1 RNA 0.6 log 10 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) 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 Reappearance of M184V mutation at 8 weeks after lamivudine resumption Median HIV-1 replication capacity returned to near- baseline value (P =.9) as did susceptibility to antiretroviral drugs in regimen Median HIV-1 replication capacity returned to near- baseline value (P =.9) as did susceptibility to antiretroviral drugs in regimen

87 Key Conclusions Lamivudine treatment in patients with multidrug-resistant HIV-1 suppressed HIV-1 RNA by ~ 0.5 log 10 copies/mL Lamivudine treatment in patients with multidrug-resistant HIV-1 suppressed HIV-1 RNA by ~ 0.5 log 10 copies/mL After lamivudine withdrawal, increase in HIV-1 RNA observed prior to 184V M reversion 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 Suggests that lamivudine contributes to viral suppression despite presence of M184V resistance mutation Replication capacity increased after M184V M reversion in absence of lamivudine Replication capacity increased after M184V M reversion in absence of lamivudine Suggests that lamivudine may also contribute to viral suppression by maintaining M184V mutation Suggests that lamivudine may also contribute to viral suppression by maintaining M184V mutation

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

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

90 Dyskusja Brak weryfikacji sposobu przyjmowania leków w trakcie prowadzenia terapii ARV Brak weryfikacji sposobu przyjmowania leków w trakcie prowadzenia terapii ARV Zbyt późna zmiana terapii ARV Zbyt późna zmiana terapii ARV Nadkażenie szczepami wielolekoopornymi ???? Nadkażenie szczepami wielolekoopornymi ????


Download ppt "Najczęstsze błędy w postępowaniu z chorym po niepowodzeniach terapeutycznych Piotr Pulik Wojewódzki Szpital Zakaźny w Warszawie."

Similar presentations


Ads by Google