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Najczęstsze błędy w postępowaniu z chorym po niepowodzeniach terapeutycznych Piotr Pulik Wojewódzki Szpital Zakaźny w Warszawie Podsumowanie W kolejnym zestawie lekowym stosowanie minimum 2 aktywnych leków o ile to możliwe z uwzględnieniem nowej klasy leków Włączenie PI/r ( najlepiej nowej generacji) Poprawa parametrów farmakokinetycznych zestawu poprzez dodanie ritonawiru Utrzymanie leczenia lamiwudyną u pacjentów ze stwierdzona mutacją M184V Podsumowanie Utrzymanie terapii pomimo nieskuteczności wirusologicznej Intensyfikacja leczenia Brak celowości ponownego stosowania NNRTI Najczęstsze przyczyny niepowodzeń… Brak współpracy pacjenta Działania uboczne leków Nieprzestrzeganie dostępnych rekomendacji przez osobę leczącą Brak dostępności do leków i szybkiej diagnostyki Brak TDM Błędna interpretacja wyników immunologicznych i lekooporności Interrakcje pomiędzy lekami Rating Scheme for Clinical Practice Recommendations Recommendation A: Strong B: Moderate C: Optional D: Should usually not be offered E: Should never be offered Quality of Evidence for Recommendation I: At least one randomized trial with clinical results II: Clinical trials with laboratory results III: Expert opinion Many factors increase the likelihood of treatment failure, including: Baseline patient factors such as: earlier calendar year of starting therapy, higher pretreatment or baseline HIV RNA level (depending on the specific regimen used), lower pretreatment or nadir CD4 cell count, prior AIDS diagnosis, co-morbidities (e.g. depression, active substance use), presence of drug- resistant virus, prior treatment failure with development of drug resistance or cross resistance Many factors increase the likelihood of treatment failure, including(2): incomplete medication adherence and missed clinic appointments; drug side effects and toxicity; suboptimal pharmacokinetics (variable absorption, metabolism, and/or penetration into reservoirs, food/fasting requirements, adverse drug-drug interactions with concomitant medications); suboptimal potency of the antiretroviral regimen; and/or other, unknown reasons. MANAGEMENT OF THE TREATMENT – EXPERIENCED PATIENT Virologic failure on treatment can be defined as a confirmed HIV RNA level >400 copies/mL after 24 weeks, >50 copies/mL after 48 weeks, or a repeated HIV RNA level >400 copies/mL after prior suppression of viremia to <400 copies/mL. Evaluation of antiretroviral treatment failure should include assessing the severity of HIV disease of the patient; the antiretroviral treatment history, including the duration, drugs used, antiretroviral potency, adherence history, and drug intolerance/toxicity; and the results of prior drug resistance testing. MANAGEMENT OF THE TREATMENT – EXPERIENCED PATIENT Drug resistance testing should be obtained while the patient is taking the failing antiretroviral regimen (or within 4 weeks of treatment discontinuation). In managing virologic failure, the provider should make a distinction between limited, intermediate, and extensive prior treatment exposure and resistance. The goal of treatment for patients with prior drug exposure and drug resistance is to re-establish maximal virologic suppression MANAGEMENT OF THE TREATMENT – EXPERIENCED PATIENT For some patients with extensive prior drug exposure and drug resistance where viral suppression is difficult or impossible to achieve with currently available drugs, the goal of treatment is preservation of immune function and prevention of clinical progression. Assessment of Antiretroviral Treatment Failure and Changing Therapy In general, the cause of treatment failure should be explored by reviewing the medical history and performing a physical examination to assess for signs of clinical progression. Important elements of the medical history include: change in HIV RNA and CD4 cell count over time; occurrence of HIV-related clinical events; antiretroviral treatment history and results of prior resistance testing (if any); Assessment of Antiretroviral Treatment Failure and Changing Therapy medication-taking behavior, including adherence to recommended drug doses, dosing frequency and food/fasting requirements; tolerance of the medications; concomitant medications (with consideration for adverse drugdrug interactions); and co-morbidities (including substance use). In many cases the cause(s) of treatment failure will be readily apparent. In some cases, no obvious cause may be identified. Virologic Failure(1) There is no consensus on the optimal time to change therapy for virologic failure. The most aggressive approach would be to change for any repeated, detectable viremia (e.g., two consecutive HIV RNA >400 copies/mL after suppression to <400 copies/mL in a patient taking the regimen). Other approaches allow detectable viremia up to an arbitrary level (e.g., 1,000-5,000 copies/mL). Virologic Failure(2) However, ongoing viral replication in the presence of antiretroviral drugs promotes the selection of drug resistance mutations [176] and may limit future treatment options. Isolated episodes of viremia ("blips", e.g. single levels of 50-1,000 copies/mL) may simply represent laboratory variation [177] and usually are not associated with subsequent virologic failure, but rebound to higher observe a patient on the same regimen, rather than changing the regimen (depending on the stage of HIV disease), if there are few or no treatment options (BII). Virologic failure 3 There is evidence from cohort studies that continuing therapy, even in the presence of viremia and the absence of CD4 cell increases, decreases the risk of disease progression [150]. Other cohort studies suggest continued immunologic and clinical benefits if the HIV RNA level is maintained <10,000-20,000 copies/mL [183, 184]. In a patient with a lower CD4 cell count (e.g. <100 cells/mm3), a change in therapy may be critical to prevent further immunologic decline and clinical progression and is therefore indicated (BIII). Virologic failure 3 A patient with a higher CD4 cell count may not be at significant risk for clinical progression, so a change in therapy is optional (CIII). Discontinuing or briefly interrupting therapy (even with ongoing viremia) may lead to a rapid increase in HIV RNA, a decrease in CD4 cell count, and increases the risk for clinical progression [185, 186] and therefore is not recommended (DIII). Changing an Antiretroviral Therapy Regimen for Virologic Failure • For the patient with virologic failure, perform resistance testing while the patient still is taking the drug regimen or within 4 weeks after regimen discontinuation (AII). • Use the treatment history and past and current resistance test results to identify active agents (preferably at least two fully active agents) to design a new regimen (AII). A fully active agent is one likely to demonstrate antiretroviral activity on the basis of both the treatment history and susceptibility on drug-resistance testing. • If at least two fully active agents cannot be identified, consider pharmacokinetic enhancement of protease inhibitors (with the exception of nelfinavir) with ritonavir (BII) and/or re-using other prior antiretroviral agents to provide partial antiretroviral activity (CIII). Changing an Antiretroviral Therapy Regimen for Virologic Failure Adding a drug with activity against drug-resistant virus (e.g. a potent ritonavir-boosted PI) and a drug with a new mechanism of action (e.g. HIV entry inhibitor) to an optimized background antiretroviral regimen can provide significant antiretroviral activity (BII). In general, one active drug should not be added to a failing regimen because drug resistance is likely to develop quickly (DII). However, in patients with advanced HIV disease (e.g. CD4 <100) and higher risk of clinical progression, adding one active agent (with an optimized background regimen) may provide clinical benefits and should be offered General Approach . Ideally, one should design a regimen with two or more fully active drugs (on the basis of resistance testing or new mechanistic class) (BII) [154, 192]. Some antiretroviral drugs (e.g. NRTIs) may contribute partial antiretroviral activity to an antiretroviral regimen. Note that using "new" drugs that the patient has not yet taken may not be sufficient because of cross-resistance within drug classes that reduces drug activity. General Approach . As such, drug potency is more important than the number of drugs prescribed. Early studies of treatment-experienced patients identified factors associated with better virologic responses to subsequent regimens [193, 194].They include: lower HIV RNA at the time of therapy change, using a new (i.e. not yet taken) class of drugs (e.g. NNRTI, HIV entry inhibitors), and using ritonavir-boosted PIs in PI-experienced patients. Sequencing and Cross Resistance(1) The order of use of some antiretroviral agents may be important. Cross-resistance among NRTIs is common but varies by drug. Most, if not all, NNRTI-associated resistance mutations confer resistance to all approved NNRTIs. Novel early mutations to some protease inhibitors (e.g., amprenavir, atazanavir, nelfinavir, saquinavir) that do not confer cross-resistance to other PIs may occur initially, but then subsequent accumulation of additional mutations confers broad cross-resistance to the entire protease inhibitor class. Sequencing and Cross Resistance(2) The order of use of some antiretroviral agents may be important. Cross-resistance among NRTIs is common but varies by drug. Most, if not all, NNRTIassociated resistance mutations confer resistance to all approved NNRTIs. Sequencing and Cross Resistance(3) Novel early mutations to some protease inhibitors (e.g., amprenavir, atazanavir, nelfinavir, saquinavir) that do not confer cross-resistance to other PIs may occur initially, but then subsequent accumulation of additional mutations confers broad crossresistance to the entire protease inhibitor class. Sequencing and Cross Resistance(4) Tipranavir/ritonavir was approved for use in patients who are highly treatment-experienced or have HIV-1 strains resistant to multiple PIs based on its demonstrated activity against PI-resistant viruses [199, 200]. However, with ongoing viremia and the accumulation of additional mutations, antiretroviral activity is time-limited unless the regimen contains other active drugs (e.g. an HIV entry inhibitor). Current Approach (1) Several clinical trials illustrate effective therapeutic strategies for heavily treatment-experienced patients [195, 196, 199-201]. In these studies, patients received an antiretroviral regimen optimized on the basis of resistance testing and then were randomized to receive a new active antiretroviral agent or placebo. Patients who received more active drugs (e.g. an active ritonavir-boosted PI and enfuvirtide), had a better and more prolonged virologic response than those with fewer active drugs in the regimen [197]. Current Approach (2) These studies illustrate and support the strategy of conducting resistance testing while a treatmentexperienced patient is taking their failing regimen, designing a new regimen based on the treatment history and resistance testing results, and selecting active antiretroviral drugs for the new treatment regimen. Current Approach(3) In general, using a single active antiretroviral drug in a new regimen is not recommended because of the risk of rapidly developing resistance to that drug. However, in patients with advanced HIV disease with a high likelihood of clinical progression (e.g., a CD4 cell count less than 100/mm3) Current Approach(3) adding a single drug may reduce the risk of immediate clinical progression, because even transient decreases in HIV RNA and/or transient increases in CD4 cell counts have been associated with clinical benefits. Weighing the risks (e.g., selection of drug resistance) and benefits (.g., antiretroviral activity) of using a single active drug in the heavily treatment-experienced patient is complicated, and consultation with an expert is advised. Summary of Guidelines For Changing An Antiretroviral Regimen For Suspected Treatment Regimen Failure Ponownie…. Patient Assessment (AIII) Review antiretroviral treatment history. • Assess for evidence of clinical progression.(e.g. physical exam, laboratory and/or radiologic tests) • Assess adherence, tolerability, and pharmacokinetic issues. Patient Assessment (AIII) • Distinguish between limited, intermediate, and extensive prior therapy and drug resistance. • Perform resistance testing while patient is taking therapy (or within 4 weeks after regimen discontinuation). • Identify active drugs and drug classes to use in designing the new regimen Patient Management: Specific Clinical Scenarios Limited or intermediate prior treatment with low (but not suppressed) HIV RNA level (e.g., up to 5000 copies/mL): The goal of treatment is to re-suppress HIV RNA to below the level of assay detection. Consider intensifying with one drug (e.g., tenofovir) (BII) or pharmacokinetic enhancement (use of ritonavir boosting of a protease inhibitor) (BII) Limited or intermediate prior treatment with low (but not suppressed) HIV RNA level (e.g., up to 5000 copies/mL): perform resistance testing if possible, or most aggressively, change two or more drugs in the regimen (CIII). If continuing the same treatment regimen, HIV RNA levels should be followed closely because ongoing viral replication will lead to accumulation of additional resistance mutations. Limited or intermediate prior treatment with resistance to one drug: Consider changing the one drug (CIII), pharmacokinetic enhancement (few data available) (BII), or, most aggressively, change two or more drugs in the regimen (BII). Limited or intermediate prior treatment with resistance to more than one drug: The goal of treatment is to suppress viremia to prevent further selection of resistance mutations. Consider optimizing the regimen by changing classes (e.g., PI-based to NNRTI-based and vice versa) and/or adding new active drugs (AII). Prior treatment with no resistance identified Consider the timing of the drug resistance test (e.g., was the patient off antiretroviral medications?) and/or nonadherence. Consider resuming the same regimen or starting a new regimen and then repeating genotypic testing early (e.g., 2–4 weeks) to determine if a resistant viral strain emerges on treatment (CIII). Extensive prior treatment and drug resistance: In patients with active antiretroviral agents available (e.g. an active ritonavir-boosted PI and enfuvirtide), the goal of therapy is suppression of viremia. In patients without active antiretroviral agent available and with ongoing viremia, the goal of therapy is preservation of immune responses and delay of clinical progression. It is reasonable to continue the same antiretroviral regimen if there are few or no treatment options (CIII). Extensive prior treatment and drug resistance: In general, avoid adding a single active drug because of the risk for the rapid development of resistance to that drug. In advanced HIV disease with a high likelihood of clinical progression (e.g., CD4 cell count <100 cells/mm3), adding a single drug may reduce the risk of immediate clinical progression (CIII). In this complicated scenario, expert advice should be sought. Immunologic failure (or blunted CD4 response) with virologic suppression: Immunologic failure (or blunted CD4 cell response) may not warrant a change in therapy in the setting of suppressed viremia. Assess for other causes of immunosuppression (e.g. HIV-2, HTLV1, drug toxicity). The combination of didanosine and tenofovir has been associated with CD4 cell declines or blunted CD4 cell responses. Immunologic failure (or blunted CD4 response) with virologic suppression: .In the setting of immunologic failure (or blunted CD4 response), it would be reasonable to change one of these drugs (BIII). Intensifying with additional antiretroviral drugs or the use of immune-based therapies (e.g. interleukin-2) to improve immunologic responses remain unproven strategies and generally should not be offered (DII). Novel Strategies To Consider For Treatment-Experienced Patients With Few Available Active Treatment Options Pharmacokinetic enhancement with ritonavir Therapeutic Drug Monitoring Re-treating with prior medications Novel Strategies To Consider For Treatment-Experienced Patients With Few Available Active Treatment Options The use of empiric multi-drug regimens New antiretroviral drugs 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 Pharmacokinetic enhancement with ritonavir may increase drug concentrations of most PIs (except nelfinavir) and may overcome some degree of drug resistance Re-treating with prior medications may be useful, particularly if they were discontinued previously for toxicities that can now be better addressed (BII). Reusing prior medications (even with documented drug resistance) may provide some degree of partial antiretroviral activity. Continued drug therapy and maintenance of drug-resistant virus may compromise viral fitness, but it is not known if this has clinical applicability. The use of empiric multi-drug regimens including up to 3 PIs and/or 2 NNRTIs) has been advocated by some [318, 319], but may be limited ultimately by complexity, poor tolerability, and unfavorable drug-drug interactions (CII) New antiretroviral drugs (1) Drugs in existing classes with activity against resistant viral strains, or new drug classes with novel mechanisms of action) including those available on expanded access (Table 30) or through clinical trials may be used. For example, the PI tipranavir (in combination with low-dose ritonavir) was approved for use in treatment-experienced patients as part of a combination antiretroviral regimen based on providing superior antiretroviral activity to an investigator-selected comparator PI [199, 200]. New antiretroviral drugs (2) The first approved HIV-1 entry inhibitor, enfuvirtide (T-20) was approved for use in the treatment-experienced patient with ongoing viremia on the basis of antiretroviral activity in this population [195, 196]. Optimally, a new active agent should be used with one or more other active agents in the regimen (e.g. a ritonavir-boosted PI and enfuvirtide) (BII). Algorytm leczenia: 1999 1-szy rzut 2-gi rzut Schemat oparty na Schemat oparty na PI/r NRTI/NNRTI Celem leczenia jest uzyskanie zahamowania replikacji wirusa Terapia ratująca Ograniczona liczba działających leków ARV jest powodem ponownego zastosowania leków Celem leczenia jest zachowanie funkcji immunologicznych i obniżenie wiremiii Algorytm leczenia: 1999 1-szy rzut Schemat oparty na NRTI/NNRTI Terapia ratująca 2-gi rzut Schemat oparty na PI/r Celem leczenia jest uzyskanie zahamowania replikacji wirusa Ograniczona liczba działających leków ARV jest powodem ponownego zastosowania leków Celem leczenia jest zachowanie funkcji immunologicznych i obniżenie wiremiii W jaki sposób poprawić wyniki leczenia po wielu niepowodzeniach? Dołączenie do leczenia leku z nowej klasy zwiększa odsetek odpowiedzi nawet, jeżeli stwierdza się aktywność 3 lub więcej leków RESIST FUZEON + OB OB 100 75 52 32 19 25 0 46 44 50 9 20 19 8 0 0 1 2 3 4 Wyjściowe GSS Miralles et al. HIV7 2004. Abstract P17 % pacjentów z obniżeniem 1 log10 w 24 tyg %pacjentów z HIV RNA <400 kopii/ml, 48 tyg TORO TPV/r porównywany PI/r 100 80 60 55 46 37 40 20 13 34 20 13 9 0 0 1 2 3 Liczba aktywnych leków ARV Cooper et al. CROI 2005. Abstract 560 W badaniach TORO ponowne zastosowanie nie działających leków ARV prowadziło do niezadowalających wyników % pacjentów z odpowiedzią wirusologiczną 100 OB 80 60 <400 kopii/mL <50 kopii/mL 40 20 15% 12% 6% 8% Tydz 24 Tydz 48 0 Tydz 24 Tydz 48 Katlama et al. IAS 2003. Abstract LB02 ITT: przewanie leczenia=niepowodzenie FUZEON powodował podwojenie odsetka pacjentów z odpowiedzią wirusologiczną, jakkolwiek tylko 30% pacjentów uzyskało HIV RNA <400 kopii/ml % pacjentów z odpowiedzia wirusologiczną 100 FUZEON + OB OB 80 60 <400 kopii/mL 40 20 33% 15% <50 kopii/mL 30% 18% 16% 12% 6% 8% 0 Tydz 24 Tydz 48 Tydz 24 Tydz 48 p < 0.0001 dla wszystkich porównań Katlama et al. IAS 2003. Abstract LB02 ITT: przewanie leczenia=niepowodzenie Dowody naukowe: Schematy oparte na stosowaniu preparatu FUZEON jako standard leczenia u pacjentów eksponowanych na 3 klasy leków ARV Badanie FUZEON plus działający PI/r* TORO 1 & 2 FUZEON + LPV/r RESIST 1 & 2 FUZEON + TPV/r POWER 1 & 2 FUZEON + TMC 114/r * Wzmocniony rytonawirem aktywny PI Badania RESIST (faza III) tipranavir (TPV) 2 badania (n = 1159): RESIST 1 (USA, Australia) RESIST 2 (Europa, Południowa Ameryka) Cel badania: Porównanie skuteczności schematu zawierającego wzmocniony rytonawirem tipranawir (TPV/r) z innym inhibitorem proteazy (PI/r) FUZEON stosowano u 25% pacjentów Cooper et al. CROI 2005. Abstract 560 Uprzednio stosowano FUZEON u 12% Badanie RESIST: najlepsza odpowiedź w grupie otrzymującej TPV/r i FUZEON 100 % pacjentów z odpowiedzią wirusologiczną (≥1 log spadek w porównaniu do BL) w 24 tyg Bez enfuwirtydu (FUZEON) FUZEON (uprzednio leczeni) 80 60 40 31% 18% 20 7% 9% 0 Tipranavir/r Cooper et al. CROI 2005. Abstract 560 Porównywany PI/r 0 –0.2 -0.5 (log10 kopii/ml) Spadek HIV RNA w 24 tyg w porównaniu do wartości wyjściowych Trzykrotnie większe obniżenie wiremii w ramieniu otrzymującym FUZEON plus TPV/r –0.4 –0.6 -1 Bez ENF (FUZEON) -1.5 FUZEON (uprzednio leczeni i nieleczeni) -2 –2.1 -2.5 Tipranavir/r Porównywany PI/r http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4139b1-02-boehringer.pdf Wzrost liczby limfocytów CD4 w 24 tyg w porównaniu do wartości wyjściowych (kom/mm3) Dwukrotnie większy wzrost liczby limfocytów CD4 w grupie TPV/r + FUZEON +55 60 Bez ENF (FUZEON) FUZEON (uprzednio leczeni i nieleczeni) 40 +27 20 +6 +3 0 Tipranavir/r Porównywany PI/r http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4139b1-02-boehringer.pdf FUZEON zapewnia lepszą i niezależną od wyjściowej ilości mutacji w genie PI odpowiedź wirusologiczną* Tygodnie 0 2 4 8 16 24 Obniżenie VL HIV RNA (log10 kopii/ml) 0 -0.5 Bez leczenia FUZEON -1 -1.5 -2 Leczenie FUZEON -2.5 TPV/r 1–4 (n = 328) TPV/r 1–4 (n = 70) TPV/r 5+ (n = 215) TPV/r 5+ (n = 88) *Substytucje w kodonach 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 lub 90 http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4139b1-02-boehringer.pdf Badania POWER (faza II) TMC114 2 badania (n = 497): Cel: 202 (USA) 213 (EU, Australia, Brazylia, Kanada) Określenie zależnej od dawki skuteczności leczenia w porównaniu z uprzednio wybranym PI/r w tygodniu 24 leczenia FUZEON stosowano u 48% pacjentów Uprzednio leczeni preparatem FUZEON - 15% Katlama et al. CROI 2005. Abstract 164LB 67% pacjentów uzyskało HIV RNA <50 kopii/ml w grupie FUZEON + TMC114 % pacjentów z odpowiedzią HIV RNA <50 kopii/ml w 24 tyg 100 Bez ENF (FUZEON) FUZEON (uprzednio nieleczeni ) 80 67% 60 40 37% 20 8% 16% 0 TMC114/r (600 2xdobę) Katlama et al. CROI 2005. Abstract 164LB Porównywany PI/r Ograniczenia badania lekooporności Dobry wynik badania nie zapewnia pełnej aktywności leku Pacjenci z trzema “aktywnymi” lekami wykazują zwiększoną częstość skuteczności leczenia przy zastosowaniu enfuwirtydu w porównaniu z OBT % pacjentów z nieoznaczalnym HIV RNA (<400 copies/ml) Pacjenci z „aktywnym” LPV/r i 2 inne “aktywne” ARVs 100 80 Leczenie FUZEON (n = 98) 60 52% 40 27% Bez leczenia FUZEON (n = 59) 20 0 0 4 8 12 16 20 24 28 32 36 40 44 48 Tygodnie Miralles and DeMasi. IDSA 2004. Abstract 921 p < 0.05 ; ITT Pojedynczy wynik genotypowania może nie odzwierciedlać faktycznie występującej lekooporności Poprzednie wyniki Ostatni wynik Różnica Lamiwudyna (M184 V/I) 58.8% 25.5% 33.3% Inne NRTIs 46.0% 27.7% 18.3% NNRTIs 38.5% 24.5% 14.0% PIs 27.9% 15.6% 12.3% • Interpretacja wyników lekooporności powinna być szczególnie ostrożna i uzupełniona o wywiad dotyczący leczenia Harrigan PR, Wynhoven B, Brumme ZL, et al., J. Infect. Dis. 2005 15;191(8):1325–30. Podsumowanie TORO, RESIST i POWER - niezależnie, we wszystkich badaniach wykazano znaczący wpływ FUZEON w połączeniu z aktywnym PI/r (LPV/r, TPV/r or TMC114/r) na skuteczność leczenia: FUZEON podwajał odpowiedź na leczenie w porównaniu z zastosowaniem samego PI/r 55−67% leczonych pacjentów osiagnęło poziom HIV RNA poniżej progu oznaczalności w 24−48 tygodniu leczenia. Algorytm leczniczy: Obecnie 1-szy rzut Schemat oparty na 2NRTTI/NNRTI 2-gi rzut Po leczeniu 3 klasami ARV Schemat oparty na NRTI + PI/r Schemat oparty na FUZEON + aktywny PI/r Cel: zahamowanie replikacji HIV Terapia ratująca Backups OpenMind study: Background Objectives: To explore the perceptions of injectable ARVs among HIVtreating physicians and treatment-experienced HIV-infected patients To identify the attitudes that might act as motivators or barriers to the initiation of injectable ARVs Interviewed: 603 treatment-experienced patients (≥ 8 ARVs) 499 HIV-treating physicians Locations: Germany, France, Italy, Spain, the UK and the USA Horne et al. EACS 2005. PE7.3/25 Youle et al. EACS 2005. PE7.3/24 OpenMind study: Results Physicians’ perceptions Superior treatment outcomes with enfuvirtide 76% Increased non-compliance and treatment refusal with enfuvirtide 0% 48% 20% 40% 60% 80% 100% Physicians that broadly agree with belief* * Defined as a rating of > 4 on a 7-point scale, where ‘1’ means ‘strongly disagree’ and ‘7’ means ‘strongly agree’ N = 603 Youle et al. EACS 2005. PE7.3/24 OpenMind study: Results Patients’ perceptions Patients were shown a full description of enfuvirtide during the interview 100% 80% Very likely to accept 35% 60% 76% patients said they would be likely to accept enfuvirtide 40% 20% Likely to accept Unlikely to accept 0% Horne et al. EACS 2005. PE7.3/25 N = 516 41% 24% POWER1: Subgroup Analyses of Response to TMC114/r 600/100 BID 53% (n = 60) Overall 18% (n = 60) 63% (n = 19) ENF Used (Naive) 22% (n = 18) 56% (n = 34) ENF Not Used 19% (n = 36) 59% (n = 29) 3 Primary PI Mut 9% (n = 35) TMC114 FC > 4 46% (n = 28) 16% (n = 25) TMC114/r 600/100 BID Control 17% (n = 12) No Sensitive ARV in OBR 0% (n = 9) 0 20 40 60 80 100 Patients With HIV-1 RNA < 50 copies/mL at Week 24 (%) (ITT NC=F) Katlama C, et al. IAS 2005. Abstract WeOaLB0102. POWER 2: Subgroup Analyses of Response to TMC114/r 600/100 BID 39% (n = 57) Overall 7% (n = 53) 64% (n = 14) ENF Used (Naive) 7% (n = 14) 30% (n = 20) ENF Not Used 4% (n = 24) 35% (n = 23) 3 Primary PI Mut 7% (n = 28) TMC114/r 600/100 BID Control 18% (n = 11) No Sensitive NRTI in OBR 0% (n = 7) 0 20 40 60 80 Patients With HIV-1 RNA < 50 copies/mL at Week 24 (%) Wilkin T, et al. ICAAC 2005. Abstract H-413. 100 POWER 2: Subgroup Analyses of Response to TMC114/r 600/100 BID 39% (n = 57) Overall 7% (n = 53) 64% (n = 14) ENF Used (Naive) 7% (n = 14) 30% (n = 20) ENF Not Used 4% (n = 24) 35% (n = 23) 3 Primary PI Mut 7% (n = 28) TMC114/r 600/100 BID Control 18% (n = 11) No Sensitive NRTI in OBR 0% (n = 7) 0 20 40 60 80 Patients With HIV-1 RNA < 50 copies/mL at Week 24 (%) Wilkin T, et al. ICAAC 2005. Abstract H-413. 100 A New Drug is Not Necessarily an Active Drug Patient on ZDV/3TC/ABC + LPV/r CD4+ 269; VL 67,000 Cumulative resistance profile: RT: 41L, 184V, 210W, 215Y, 103N PR: 30N, 63P, 71V, 77I, 82A, 84V, 90M Clinician proposed a combination of 3 “new” drugs: FTC + ATV + ENF 0.4 n = 14 0.2 0.0 -0.2 -0.4 -6 -4 -2 0 2 4 6 8 Median Change in CD4+ Cell Count (cells/mm3) Median Change in HIV-1 RNA (log10 copies/mL) The Cost of Treatment Interruption in TreatmentExperienced Patients 50 25 0 -25 n = 14 -50 -75 -100 -6 -4 -2 Weeks Before and After WT Switch Deeks SG, et al. N Engl J Med. 2001;344:472-480. 0 2 4 6 Partial Treatment Interruption Demonstrates Residual NRTI Activity Discontinue PIs, continue NRTIs (n = 15) Discontinue NRTIs, continue PIs (n = 5) 100 Wk 8 Change in CD4+ Cell Count (cells/mm3) Change in HIV-1 RNA (log10 copies/mL) 1.5 1.0 0.5 0 -0.5 Wk 8 Wk 12 Wk 16 Deeks SG, et al. J Infect Dis. 2005;192:1537-1544. 50 0 -50 -100 -150 Wk 12 Wk 16 Guidelines for Choosing a Nonsuppressive “Holding Regimen” Never use an NNRTI Always use 3TC or FTC NNRTI mutations have no beneficial impact on fitness Accumulation of additional mutations may result in crossresistance to 2nd generation NNRTIs Simple and well tolerated drugs M184V decreases fitness Increases activity of d4T, TDF, ZDV Choose PIs and/or NRTIs based on resistance and tolerability/toxicity considerations Jednoczesne stosowanie enfuwirtydu i LPV/r w OB stanowi czynnik prognostyczny odpowiedzi na terapię HIV-1 RNA <400 kopii/ml w 48 tyg FUZEON Wyjściowa liczba CD4 (per 100 kom/mm3) Wyjściowy HIV-1 RNA (per log10) Uprzednia ekspozycja lopinavir/r Uprzednie leczenier ARVs (n) Liczba aktywnych ARVs w OB (n) Lopinavir/r w OB 0.1 1 10 Wsp. Ryzyka dla HIV-1 RNA <400 kopii/ml (95% CI) Gorsza odpowiedź Montaner et al. 15th IAC 2004. Abstract TuPe4483 Lepsza odpowiedź FUZEON plus LPV/r: 37% pacjentów osiągnęło HIV RNA <50 kopii/ml po 24 tyg 100 % pacjentów z HIV RNA (<50 kopii/ml) w 24 tyg No FUZEON FUZEON (naive) 80 60 40 * 20 8% 4% 1% 0 LPV/r in OB: Prior LPV/r: * 13% 57 158 No LPV/r 77 LPV/r LPV/r experienced DRAFT Roche data on file 171 30% * 37% 17% 7% 58 93 142 No LPV/r 239 LPV/r LPV/r naive *p < 0.01, ITT, D/C + Switch = Failure Lamivudine Partially Suppresses Multidrug-resistant HIV-1 Despite Presence of M184V Mutation Slideset on: Campbell TB, Shulman NS, Johnson SC, et al. Antiviral activity of lamivudine in salvage therapy for multidrug-resistant HIV-1 infection. Clin Infect Dis. 2005;41:236-242. Background and Rationale HIV-1 RNA suppression to undetectable levels may not be possible for some patients with multidrug-resistant virus However, continuation of lamivudine therapy despite high-level lamivudine resistance (ie, M184V/I) maintains partial HIV-1 RNA suppression Discontinuation of lamivudine causes increased HIV-1 RNA levels and reversion to wild-type virus Current study evaluated antiretroviral activity of lamivudine against lamivudine-resistant virus by withdrawing lamivudine therapy in patients with multidrug-resistant HIV-1 Summary of Study Design Results of 2 studies combined for analysis University of Colorado General Clinical Research Center Stanford University School of Medicine Subjects discontinued lamivudine but continued taking all other antiretrovirals in pre-entry regimen HIV-1 RNA, CD4+ cell count, genotypic and phenotypic resistance testing, and plasma concentrations of lamivudine, stavudine, and zidovudine regularly evaluated during lamivudine withdrawal Baseline Characteristics N=6 Median age: 48 years (range, 43-64 years) Male: 100% High-level lamivudine resistance (presence of M184V and inhibitory concentration 50% > 300 fold-change): 100% Median HIV-1 RNA: 20,000 copies/mL Range of plasma lamivudine concentration: 3742026 ng/mL Main Findings Lamivudine withdrawal associated with median HIV-1 RNA increase of 0.5 log10 copies/mL at Week 6 (P = .04) Duration of withdrawal, 8-22 weeks Lamivudine concentration undetectable (< 20 ng/mL) in all patients by Week 6 No wild-type reversion of M184VM detected by Week 6 Early increases in HIV-1 RNA associated with T215Y/F and M41L mutations at baseline, and reduced phenotypic susceptibility to NRTIs, excluding lamivudine (75% vs 10% for those with and without mutations and reduced susceptibility, respectively; P = .001) Main Findings Reversion of M184VM detected at least once in 4/6 patients during withdrawal Median time to detection of M184VM reversion, 12 weeks (range, 8-14 weeks) Trend toward higher HIV-1 RNA at first appearance of M184VM Median HIV-1 RNA, +0.3 log10 copies/mL (P = .07) Median HIV-1 replication capacity increased to 60% at time of reversion vs 41% at baseline (P = .07) Reversion not associated with changes in CD4+ cell count Main Findings All patients resumed lamivudine at their own or their doctor’s request and not due to resumption criteria Median HIV-1 RNA 0.6 log10 copies/mL (range, 0.1-0.6) above baseline at time of resumption (P = .03) HIV-1 RNA not significantly different from baseline after 8 weeks of lamivudine treatment (P = .2) Reappearance of M184V mutation at 8 weeks after lamivudine resumption Key Conclusions Lamivudine treatment in patients with multidrug-resistant HIV-1 suppressed HIV-1 RNA by ~ 0.5 log10 copies/mL After lamivudine withdrawal, increase in HIV-1 RNA observed prior to 184VM reversion Suggests that lamivudine contributes to viral suppression despite presence of M184V resistance mutation Replication capacity increased after M184VM reversion in absence of lamivudine Panel’s Recommendations: If the decision is made to initiate therapy in a person with acute HIV infection, it is likely that resistance testing at baseline will optimize virologic response; this strategy should be considered (BIII). • Drug resistance testing at baseline in antiretroviral-naïve, chronically infected patients is an untested strategy. However, it may be reasonable to consider resistance testing when there is a significant probability that the patient was infected with a drug-resistance virus, i.e., if the patient is thought to have been infected by a person who was receiving antiretroviral drugs (CIII). • Drug resistance testing is not advised for persons with viral load <1,000 copies/mL, since amplification of the virus is unreliable (DIII). Panel’s Recommendations: • HIV drug resistance testing should be performed to assist in selecting active drugs when changing antiretroviral regimens in cases of virologic failure (BII). • Drug resistance testing should also be considered when managing suboptimal viral load reduction (BIII). • Drug resistance testing in the setting of virologic failure should be performed while the patient is taking his/her antiretroviral drugs, or immediately (i.e., within 4 weeks) after discontinuing therapy (BII). Dyskusja Brak weryfikacji sposobu przyjmowania leków w trakcie prowadzenia terapii ARV Zbyt późna zmiana terapii ARV Nadkażenie szczepami wielolekoopornymi ????