New Antiretroviral Drugs: what wehave and how to use ? Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital
The Current Role of IntegraseInhibitors in Clinical Practice
Potential Uses of Integrase Inhibitors inClinical Practice Treatment-naive Switch – To simplify or reduce toxicity to a given regimen after virologic suppression achieved Treatment-experienced – First failure – After multiple failures
Clinical Role of IntegraseInhibitors in Treatment-Naive Patients
Potential Uses of Integrase Inhibitors:Treatment-Naive Patients Advantages Disadvantages Novel mechanism of action Twice-daily dosing Efficacy data to 144 wks Cost Rapid HIV-1 RNA decay Some drug-drug interactions (varies by drug) Lack of transmitted drug Fewer data than other agents resistance Low barrier to resistance Excellent safety and tolerability Lack of coformulation Limited lipid effects Limited drug interactions
Summary of RAL Treatment-Naive Data Phase II (Protocol 004, N = 198): RAL comparable to EFV in virologic efficacy at 144 wks – HIV-1 RNA < 50 copies/mL: 78% RAL vs 76% EFV – Fewer CNS adverse events with RAL vs EFV – RAL had less effect on serum lipids vs EFV Phase III (STARTMRK, N = 563): noninferior virologic efficacy of RAL vs EFV at 96 wks – HIV-1 RNA < 50 copies/mL: 81% RAL vs 79% EFV – Fewer CNS adverse events with RAL vs EFV – Lower cholesterol and triglyceride increases with RAL vs EFV1. Gotuzzo E, et al. IAS 2009. Abstract MOPEB030.2. Lennox J, et al. Lancet. 2009;[Epub ahead of print].
D:A:D: Recent and/or Cumulative PI/NNRTI Use and Risk of MI PI* NNRTI 1.2 1.13 1.10 1.00 0.90 IDV NFV LPV/RTV SQV NVP EFV # PYFU: 68,469 56,529 37,136 44,657 61,855 58,946 # MI: 298 197 150 221 228 221 *Approximate test for heterogeneity: P = .02Lundgren JD, et al. CROI 2009. Abstract 44LB. Graphics reproduced with permission.
RAL Drug Interactions Fewer due to alternative metabolism: glucuronidation (UGT1A1) TDF ↑ RAL 49% PI interactions – ATV NNRTI Interactions – ETR and EFV (RAL AUC ↓ 36%) acceptable Rifampin – 40% reduction in RAL AUC; RAL dose increased to 800 mg BID when administered with rifampin – ANRS study (N = 150) of EFV vs RAL 400 mg vs RAL 800 mg for HIV/TB- coinfected patients1. Raltegravir package insert.2. ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00822315.
Can RAL Be Dosed Once Daily? Study ongoing (QDMRK) to determine safety and efficacy of RAL once daily vs twice daily – Treatment-naive patients – RAL 400 mg BID vs RAL 800 mg QD, both plus TDF/FTC – Estimated enrollment: 750 patients Primary outcome: HIV-1 RNA < 50 copies/mL at Wk 48ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00745823.
Treatment-Naive Patients for Whom INSTIs May Be Considered Currently, DHHS guidelines include INSTIs as preferred options for treatment-naive patients Possible patients who might be considered – Patients unable to tolerate NNRTI (rash, CNS toxicity) or PI (any RTV dose) – High lipids or cardiovascular risk – Transmitted NNRTI resistance (care must be taken to ensure activity of other regimen components) – Women who may become pregnantDHHS guidelines. Available at: http://aidsinfo.nih.gov.
Clinical Role of Integrase Inhibitors as Switch Strategy inVirologically Suppressed Patients
Reasons to Switch Antiretrovirals inPatients on a Suppressive Regimen Simplification/convenience – Reduce pill burden, dosing frequency, or avoid other specific dosing requirements Tolerability/toxicity – Improve short-term tolerability, reduce risk of long-term complications Drug-drug interactions Lack of adequate CD4+ response?
Potential Uses of Integrase Inhibitors:Simplify or Reduce Toxicity Advantages Disadvantages Novel mechanism of action Must be used with adequate support from other regimen Potent antiretroviral activity components Excellent safety and tolerability Low barrier to resistance Limited lipid effects Twice-daily dosing Limited drug interactions Cost Some drug interactions Fewer data than other agents Lack of coformulation
Established Switch Regimens Within-class substitutions – NRTI substitutions (eg, change d4T to TDF) – NNRTI substitution (eg, NVP to EFV) – PI substitutions (eg, add boosting, remove boosting, reduce toxicity) Out-of-class substitution – PI to NNRTI Reduce the number of active agents
RAL Switch Regimens RAL substituted for ENF in suppressed patients – Many studies, including 1 randomized, support this use – Rarely, unexpected adverse effects may occur (depression) SWITCHMRK – Predefined criteria for virologic noninferiority not met – Demonstrated lipid benefits – When underlying resistance may be present (eg, experienced patients, transmitted resistance), careful patient selection needed – Lower barrier to resistance with RAL vs boosted PIs1. De Castro N, et al. IAS 2009. Abstract MOPEB066. 2. Harris M, et al. AIDS. 2009;22:1890-1892.3. Eron J, et al. CROI 2009. Abstract 70aLB.
Clinical Role of Integrase Inhibitors in Treatment- Experienced Patients
Potential Uses of Integrase Inhibitors:First Failure Advantages Disadvantages Novel mechanism of action No data specific to first failures Expectation that activity would be excellent What to combine (is a boosted PI required?) Excellent safety and tolerability Twice-daily dosing Limited lipid effects Cost Limited drug interactions Low barrier to resistance Lack of coformulation
Principles Guiding Second-LineIntegrase Inhibitor–Containing Regimens Key strategy for success with integrase inhibitor–containing regimens is inclusion of ≥ 2 active agents If resistance at VF with first-line NNRTI- or PI-based regimen involves NRTI-associated mutations, NRTIs in subsequent regimen cannot be considered fully active – Integrase inhibitor + 2 NRTIs may not be sufficient in these cases In patients who discontinued first-line regimen, negative genotypic resistance test does not necessarily indicate absence of resistant viral population – Particularly for M184V Use of RAL + boosted PI merits further study in 2 NRTI + NNRTI failure patients
Potential Uses of Integrase Inhibitors:Multiple Failures Advantages Disadvantages Novel mechanism of action Must be used with other active agents Well-established data Does a boosted PI always Excellent safety and tolerability need to be included? Limited lipid effects Low barrier to resistance Limited drug interactions Cross resistance between RAL and ELV
Focus on Number of Active Agents DHHS ARV guidelines: ≥ 2, preferably 3, fully active agents in new regimen Highest rate of virologic suppression in patients receiving investigational drug plus OBR containing ≥ 1 other active agent[1-4] Trend toward greater benefit with 3 vs 2 fully active agents[1-4] – Not statistically significant – Must also consider potential drug-drug interactions, adverse events, pill burden, absence of future options – Contribution of “partially active” agents (eg, 3TC) difficult to calculate No added benefit from using 4 vs 3 fully active agents1. Cooper DA, et al. N Engl J Med. 2008;359:355-365. 2. Haubrich R, et al. CROI 2008. Abstract 790.3. Johnson M, et al. CROI 2008. Abstract 791. 4. Gulick RM, et al. N Engl J Med. 2008;359:1429-1441.
BENCHMRK 1 & 2: HIV-1 RNA < 50 c/mL by New Agents in OBR, Wk 48 Enfuvirtide Darunavir n Patients (%) 112 89 + + 65 68 166 80 + - 92 57 166 69 - + 92 47 - - 158 60 68 20 0 20 40 60 80 100Cooper DA, et al. N Engl J Med. 2008;359:355-365.
RAL + MVC + ETR in Triple Class– Experienced Patients Nonrandomized cohort study RAL + MVC + ETR (n = 28) RAL + MVC or ETR + PI (n = 28) RAL + MVC or ETR (n = 20) RAL + PI (n = 19) HIV-1 RNA < 50 c/mL, % 300 Mean CD4+ Cell Count Increase (cells/mm3) 100 80 200 60 40 100 20 0 BL 4 12 24 36 48 0 Wks RegimenNozza S, et al. Glasgow 2008. Abstract P45. Reproduced with permission.
BRAVO: Efficacy of RAL Without a PI? Retrospective cohort (chart review) 100 of RAL with or without PI RAL + Pl (n = 332) HIV-1 RNA < 75 copies/mL (%) – PI cohort: 87% DRV, 36% ETR, 10% ENF (mean prior ARV: 4.1) 80 No Pl (n = 110) – No PI cohort: 66% ETR, 17% ENF, 13% MVC (mean prior ARV: 3.8; P < .01 vs PI cohort) 60 – Most pts received NRTI TDF + FTC GSS (similar between groups) a 40 significant predictor of Wk 12 response (P = .04) 20 – Treatment group (PI vs non-PI) and number of ARVs not predictive of virologic success 0 Additional follow-up needed to evaluate Baseline Wk 4 Wk 12 Wk 24 RAL without PI n = 442 336 373 195Skiest D, et al. IAS 2009. Abstract MOPE072. Reproduced with permission.
Summary: Potential Uses of IntegraseInhibitors in Clinical Practice Treatment naive Switch Treatment experienced – First failure – After multiple failures
Impact of NNRTI and NRTIresistance on the response to theregimen of Etravirine plus twoNRTIs in study Etravirine-C227
Etravirine-C227: study design •48 weeks • Primary analysis 24 weeks •Active control: 1 PI + 2 NRTIs n=57•Screening •Etravirine 800mg bid + 2 NRTIs n=59 PI naïve NNRTI experienced, screening viral load >1,000 copies/mL – ≥1 NNRTI resistance-associated mutation (historical or at screening) Active control group: investigator-selected PI – 95% used boosted PI (61% LPV/r, 32% ATV/r) Both control and Etravirine groups: two investigator-selected NRTIs based on screening Virco®TYPE HIV-1 or treatment history Etravirine arm discontinued after DSMB review Woodfall B, et al. HIV8, 2006. Abstract PL5.6
Region and countryRegion All patients •CladeCountry, n (%) (n=116) •AEAsia and South Africa 66 (56.9) South Africa 48 (41.4) •B Thailand 18 (15.5)Europe 13 (11.2) Russia 5 (4.3) •C Spain 6 (5.2) UK 2 (1.7)Latin America 37 (31.9) Argentina 8 (6.9) •AE 13.8% •A1 2.6% Brazil 27 (23.3) •BF 2.6% •C 42.2% Mexico 2 (1.7) •F1 2.6% •B 36.2% Woodfall B, et al. HIV8, 2006. Abstract PL5.6
Etravirine-C227: baseline detectableNRTI mutations •4 •5 •6 •7 •0 •1 •2 •3 A large number of NRTI •100 •1.7 •1.8 resistance-associated•IAS-USA NRTI resistance-associated mutations (%) •6.8 •8.8 mutations were noted in •90 •16.9 this first-line failure •10.5 population •80 •7.0 •70 •10.2 Many NRTIs were •10.5 recycled in this study* •60 •15.3 •38.6 – Etravirine group •50 •28.8 – 37% recycled one, •40 9% recycled two •30 – control group •20 •22.8 •20.3 – 35% recycled •10 one, 12% •0 recycled two •Etravirine •Control •*Guided by resistance testing •Group Woodfall B, et al. HIV8, 2006. Abstract PL5.6
Etravirine-C227: baseline detectableNNRTI mutations •0* •1 •2 •3 •4 •100 A large number of NNRTI •5.1 •5.3 mutations* were noted in •23.7•Tibotec NNRTI resistance-associated •90 •22.8 this first-line failure population •80 Median fold change to: •70 •40.7 •43.9 EFV 129.8 mutations (%) •60 NVP 88.0 •50 Etravirine 2.0 •40 •Tibotec list of NNRTI mutations •A98G - L100I - K101E/P/Q •30 •K103H/N/S/T •23.7 •19.3 •V106A/M - V108I - E138G/K/Q •20 •V179D/E/F/G/I - Y181C/I/V •Y188C/H/L - G190A/C/E/Q/S •10 •P225H - F227C/L - M230I/L - P236L •6.8 •8.8 •K238N/T - Y318F •0 •Etravirine •Control group •*All patients had NNRTI mutations at screening or from prior genotyping Woodfall B, et al. HIV8, 2006. Abstract PL5.6
Etravirine-C227: change in viral load(observed) •0 •Initial 1.3 log decline in viral load was not sustained past 8 weeks, possibly affected by limited activity of the BR •Change in log viral load (mean) •Etravirine •Control •−1 •−2 •−3 •0 •4 •8 •12 •16 •Weeks•n (Etravirine)= •59 •59 •56 •46 •36 •2 • n (control)= •57 •57 •55 •49 •33 9 •29 Woodfall B, et al. HIV8, 2006. Abstract PL5.6
Etravirine arm (C227): median viral load change at week12, by baseline Etravirine fold change and number ofTAMs + M184V •Median change in viral load at week 12 •0 •4 •3 •Number of •5 TAMs + •−0.5 M184V •−1 •2 •−1.5 •1 •−2 •0 •−2.5 •1 •10 •100 •Etravirine fold change Use of recycled NRTIs in Etravirine group: 37% recycled one, 9% two Woodfall B, et al. HIV8, 2006. Abstract PL5.6
C227 educational messages While demonstrating a substantial decrease in viral load, use of Etravirine was associated with a lower virological response versus the control PI group – this is most likely due to high NRTI resistance and NRTI recycling – C227 study included a large proportion of patients from resource-limited settings. Baseline NRTI and NNRTI resistance was higher than is usual in countries where monitoring of viral load is standard of care and virological failure is determined early – patients were PI-naïve, therefore, the PI group was not as affected by the compromised backbone and the pre-existing NNRTI resistance Etravirine had a better tolerability profile than control PI treatment – compared with the PI regimen, Etravirine was better tolerated for gastrointestinal, lipid and liver- related events – rash was higher in the Etravirine group, but this was generally mild and not associated with discontinuation In contrast to the results of C227, the results of the large Phase III DUET trials showed that Etravirine provides substantial virological and immunological benefits in patients with NNRTI- and PI-resistant virus The results of the C227 study demonstrate
Etravirine-C227: conclusions The level of both NRTI and NNRTI resistance was higher than what might have been expected from a first-line failure population – many patients recycled previously used NRTIs, which was guided by resistance testing Increasing numbers of TAMs and M184V were associated with increased NNRTI resistance The combination of high-level NRTI and NNRTI resistance adversely impacted the Etravirine arm – less likely to have affected the PI arm in this PI-naïve population Consistent with treatment guidelines, patients failing a first-generation NNRTI should immediately switch their regimen to avoid the accumulation of resistance-associated mutations and maximise future treatment options Woodfall B, et al. HIV8, 2006. Abstract PL5.6
DUET study designand major inclusion criteria •Screening •48-week treatment period •Follow-up •6 weeks with optional 48-week extension •4 weeks •24-week primary analysis •Etravirine + BR* •600 patientstarget per trial •Placebo + BR* •*All patients received a BR of DRV/r with optimised NRTIs and optional ENF DUET-1 and DUET-2 differed only in geographical location; pooled analysis was pre-specified Major inclusion criteria – plasma VL >5,000 copies/mL and stable therapy for ≥8 weeks – ≥1 NNRTI mutations,‡ at screening or in documented historical genotype – ≥3 primary PI mutations at screening Patients recruited from Thailand, Australia, Europe and the Americas ‡ From extended list of NNRTI mutations (Tambuyzer L et al. EHDRW 2007. Abstract 67) •Madruga JV et al. Lancet 2007;370:29–38; Lazzarin A et al. Lancet 2007;370:39–48
DUET trials: dosing DRV/r dosed at 600/100mg bid – 300mg tablets of DRV (i.e. two tablets bid) Etravirine dosed at 200mg bid – 100mg tablets (i.e. two tablets bid of Phase III formulation) Etravirine matching placebo: two tablets bid Both drugs were to be taken twice daily following a meal – less restrictive food requirements than Phase II trials •Madruga JV et al. Lancet 2007;370:29–38; Lazzarin A et al. Lancet 2007;370:39–48
Week 96: patients with VL <50 copies/mL (ITT-TLOVR) •100 •Etravirine + BR •90 •Placebo + BR<50 copies/mL at Week 96 (%) •80 •Patients with VL •70 •60% •60 •57% •50 •39% •40 •36% •30 •20 •p<0.0001* •10 •0• Baseline 2 4 8 12 16 20 24 32 40 48 56 64 72 84 96 •Time (weeks) 57% of patients in the Etravirine + BR group achieved confirmed undetectable VL (<50 copies/mL TLOVR) compared with 36% in the placebo group This represents only a 3% drop from Week 48 for patients in each group •*Logistic regression model controlling for baseline VL, ENF use and study number •Trottier B et al. CAHR 2009. Abstract P148
Week 96: response (VL <50 copies/mL TLOVR)by PSS* •10 0 •Etravirine + BR (n=497) •Placebo + BR (n=477) •90 •p<0.0001 <50 copies/mL at Week 96 (%) •80 •76% •p<0.0001 •70 •Patients with VL •61% •59% •60 •p<0.0001 •50 •46% •40 •29% •30 •20 •10 •6% •39/84 •5/81 •117/191 •52/181 •168/222 •126/215 •0 •0 •1 •≥2 •Number of active background ARVs (PSS) Patients in the Etravirine + BR group achieved consistently higher response rates than patients in the placebo + BR group, irrespective of number of active background agents; the difference was most apparent in patients with no active background agents •*DRV considered sensitive if FC ≤10; ENF counted as sensitive if used de novo; Etravirine not included in the PSS calculation; analysis excludes patients who discontinued except for VF •Trottier B et al. CAHR 2009. Abstract P148
•Predicting response to Etravirine: weighted scores for eachindividual RAM combined to produce a total weighted score •Weight for individual Etravirine RAMs •Total weighted score Vingerhoets J et al. IHDRW 2008. Abstract 24