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THE 6TH NATIONAL SCIENTIFIC CONFERENCE ON HIV/AIDS Second-line Regimens in Resource-limited Settings Somnuek Sungkanuparph, M.D. Professor of Medicine, Division of Infectious Diseases, Faculty of Medicine Ramathibodi Hospital Mahidol University, Bangkok, Thailand Adjunct Professor, Washington University School of Medicine St Louis, Missouri, United States Outline 1. Background 2. Objectives 3. Methods 4. Results & Discussion 5. Conclusions 6. Recommendations The 6th National Scientific Conference on HIV/AIDS Viral load Effect of Antiretroviral Therapy Immunological response Clinical response CD4 • • • • • less illnesses improved weight better well being back to work better quality of life Limit of detection Virological response Time The 6th National Scientific Conference on HIV/AIDS Clinical failure CD4 HIV-RNA Immunological failure CD4 Viral load Treatment Failure Virological failure Criteria for failure Time The 6th National Scientific Conference on HIV/AIDS Misclassification of First-line ART Failure Based on CD4 Monitoring • Adult patients in western Kenya with first-line ART with suspected immunologic failure (CD4 decreased 25% in 6 months) • Misclassification of treatment failure = immunologic failure but VL < 400 • 149 patients, treated for 23 months criteria number of patients misclassified • 25% decrease in CD4 149 58% • 50% decrease in CD4 42 43% • Immunological failure criteria would lead to a premature switch to second-line regimens Kantor R, et al. Clin Infect Dis 2009. The 6th National Scientific Conference on HIV/AIDS Risk of Disease Progression/Death Cumulative probability of death or a new AIDS-defining event 0.25 Non-responders Immunologic-only responders Virologic-only responders 0.20 Complete responders 0.15 0.10 0.05 0 1 2 3 4 5 Years since start of therapy Viral control is the most important response. There may be a significant immune component of successful therapy Nicastri E, et al. J Med Virol 2005. The 6th National Scientific Conference on HIV/AIDS Treatment Failure and HIV Drug Resistance in A Chinese Cohort The 6th National Scientific Conference on HIV/AIDS Impact of HIV Drug Resistance on Mortality in A Chinese Cohort The 6th National Scientific Conference on HIV/AIDS Impact of HIV Drug Resistance on Mortality in A Chinese Cohort The 6th National Scientific Conference on HIV/AIDS Causes of Treatment Failure Poor Potency Wrong Dose Host Genetics Poor Absorption Social/Personal Issues Regimen Issues Toxicities Poor Adherence Insufficient Drug Level Rapid Clearance Poor Activation Viral Replication in the Presence of Drug Drug Interactions Resistant Virus Transmission Treatment Failure The 6th National Scientific Conference on HIV/AIDS Patients with virological failure (%) Adherence and HIV Drug Resistance 100 Degree of non-adherence was significantly associated with risk for virological failure (P<0.001) 80 60 40 20 0 21.7 54.6 66.7 71.4 82.1 ≥95 90–94.9 80–89.9 70–79.9 <70 Adherence† (%) †Defined as number of pills taken/number of pills prescribed Paterson DL, et al. Ann Intern Med 2000;133:21–30. The 6th National Scientific Conference on HIV/AIDS Suboptimal Adherence to ART in Asia The 6th National Scientific Conference on HIV/AIDS Case 1 Resistance-associated RT Mutations: M184V, Y181C Nucleoside and Nucleotide RT Inhibitors abacavir (ABC) didanosine (ddI) lamivudine (3TC)/emtricitabine (FTC) stavudine (d4T) tenofovir (TDF) zidovudine (AZT) Non-nucleoside RT Inhibitors efavirenz (EFV) etravirine (ETR) nevirapine (NVP) rilpivirine (ETR) Resistance Interpretation No Evidence of Resistance No Evidence of Resistance No Evidence of Resistance No Evidence of Resistance No Evidence of Resistance No Evidence of Resistance Resistance Interpretation No Evidence of Resistance No Evidence of Resistance No Evidence of Resistance No Evidence of Resistance Resistance-associated PR Mutations: Protease Inhibitors Resistance Interpretation atazanavir (ATV) No Evidence of Resistance ATV + ritonavir (ATV/r) No Evidence of Resistance fosamprenavir + ritonavir (FPV/r) No Evidence of Resistance darunavir + ritonavir (DRV/r) No Evidence of Resistance indinavir + ritonavir ((IDV/r) No Evidence of Resistance lopinavir + ritonavir (LPV/r) No Evidence of Resistance saquinavir + ritonavir (SQV/r) No Evidence of Resistance tipranavir + ritonavir (TPV/r) No Evidence of Resistance The 6th National Scientific Conference on HIV/AIDS Predicting Factors for Genotypic Resistance Test Results that Associated with Poor Adherence The 6th National Scientific Conference on HIV/AIDS Durability of d4T/3TC/NVP regimen A 144-week Prospective Study Thailand: 140 patients Manosuthi W, et al. BMC Infect Dis 2008; 8:136. The 6th National Scientific Conference on HIV/AIDS HIV Drug Resistance after Failing d4T/3TC/NVP regimen 9% (13 of 140) had HIV RNA >1,000 copies/mL • 10 had M184V/I • 1 had TAMs • 2 had K65R • 8 had Y181C/I • 1 had K103N Manosuthi W, et al. BMC Infect Dis 2008; 8:136. The 6th National Scientific Conference on HIV/AIDS HIV Drug Resistance at First-line ART Failure in Asia • First-line ART failure often results from the development of resistance-associated mutations (RAMs) • 3 patterns are associated with resistance to multiple NRTIs and may compromise treatment options for second-line ART: thymidine analogue mutations (TAMs) 69 Insertion (69Ins) Q151M complex • To study patterns and factors associated with multi-NRTI RAMs at first-line failure in patients Impact on virological responses at 12 months after switching to secondline ART o Multi-NRTI RAMs = presence of either Q151M; 69Ins; ≥ 2 TAMs; or M184V+≥ 1 TAM The 6th National Scientific Conference on HIV/AIDS HIV Drug Resistance at First-line ART Failure in Asia The 6th National Scientific Conference on HIV/AIDS HIV Drug Resistance at First-line ART Failure in Asia The 6th National Scientific Conference on HIV/AIDS HIV Drug Resistance at First-line ART Failure in Asia • Factors associated with multi-NRTI RAMs were CD4 ≤ 200 cells/µL at genotyping (OR=4.43, 95%CI 1.59-12.37) • After switch to second-line ART, virological suppression was achieved in 85% Patients with ART adherence ≥ 95% were more likely to be virologically suppressed (OR=9.33, 95%CI 2.43-35.81) The 6th National Scientific Conference on HIV/AIDS Case 2 Resistance-associated RT Mutations: Y181C, M184V Nucleoside and Nucleotide RT Inhibitors abacavir (ABC) didanosine (ddI) lamivudine (3TC)/emtricitabine (FTC) stavudine (d4T) tenofovir (TDF) zidovudine (AZT) Non-nucleoside RT Inhibitors Resistance Interpretation Possible Resistance Possible Resistance Resistance Resistance Possible Resistance Resistance Resistance Interpretation efavirenz (EFV) etravirine (ETR) nevirapine (NVP) rilpivirine (ETR) Resistance Possible Resistance Resistance Possible Resistance Resistance-associated PR Mutations: K20I, M36I Protease Inhibitors Resistance Interpretation atazanavir (ATV) No Evidence of Resistance ATV + ritonavir (ATV/r) No Evidence of Resistance darunavir + ritonavir (DRV/r) No Evidence of Resistance fosamprenavir + ritonavir (FPV/r) No Evidence of Resistance indinavir + ritonavir ((IDV/r) No Evidence of Resistance lopinavir + ritonavir (LPV/r) No Evidence of Resistance saquinavir + ritonavir (SQV/r) No Evidence of Resistance tipranavir + ritonavir (TPV/r) No Evidence of Resistance The 6th National Scientific Conference on HIV/AIDS Case 3 Resistance-associated RT Mutations: D67N, K70R, V108I, Y181C, M184V Nucleoside and Nucleotide RT Inhibitors abacavir (ABC) didanosine (ddI) lamivudine (3TC)/emtricitabine (FTC) stavudine (d4T) tenofovir (TDF) zidovudine (AZT) Non-nucleoside RT Inhibitors Resistance Interpretation Possible Resistance Possible Resistance Resistance Resistance No Evidence of Resistance Resistance Resistance Interpretation efavirenz (EFV) etravirine (ETR) nevirapine (NVP) rilpivirine (ETR) Resistance Possible Resistance Resistance Possible Resistance Resistance-associated PR Mutations: K20I, M36I Protease Inhibitors Resistance Interpretation atazanavir (ATV) No Evidence of Resistance ATV + ritonavir (ATV/r) No Evidence of Resistance darunavir + ritonavir (DRV/r) No Evidence of Resistance fosamprenavir + ritonavir (FPV/r) No Evidence of Resistance indinavir + ritonavir ((IDV/r) No Evidence of Resistance lopinavir + ritonavir (LPV/r) No Evidence of Resistance saquinavir + ritonavir (SQV/r) No Evidence of Resistance tipranavir + ritonavir (TPV/r) No Evidence of Resistance The 6th National Scientific Conference on HIV/AIDS Case 4 Resistance-associated RT Mutations: D67N, K70R, V108I, Y181C, M184V, T215F, K219E Nucleoside and Nucleotide RT Inhibitors abacavir (ABC) didanosine (ddI) lamivudine (3TC)/emtricitabine (FTC) stavudine (d4T) tenofovir (TDF) zidovudine (AZT) Non-nucleoside RT Inhibitors Resistance Interpretation Possible Resistance Possible Resistance Resistance Resistance Possible Resistance Resistance Resistance Interpretation efavirenz (EFV) etravirine (ETR) nevirapine (NVP) rilpivirine (ETR) Resistance Possible Resistance Resistance Possible Resistance Resistance-associated PR Mutations: K20I, M36I Protease Inhibitors Resistance Interpretation atazanavir (ATV) No Evidence of Resistance ATV + ritonavir (ATV/r) No Evidence of Resistance darunavir + ritonavir (DRV/r) No Evidence of Resistance fosamprenavir + ritonavir (FPV/r) No Evidence of Resistance indinavir + ritonavir ((IDV/r) No Evidence of Resistance lopinavir + ritonavir (LPV/r) No Evidence of Resistance saquinavir + ritonavir (SQV/r) No Evidence of Resistance tipranavir + ritonavir (TPV/r) No Evidence of Resistance The 6th National Scientific Conference on HIV/AIDS HIV Drug Resistance Mutations in Patients Failing d4T/3TC/NVP Detected at HIV RNA <4 vs. >4 log < 4 log > 4 log P = 0.105 P = 0.763 100% 90% 80% 70% 60% 50% P = 0.041 40% 30% P = 0.031 20% P = 0.008 P = 1.000 10% 0% TAMs K65R Q151M M184V/I NNRTIPImutation mutation Sungkanuparph S, et al. The 6th National Scientific Conference on HIV/AIDS HIV Drug Resistance and Time to Detection of Treatment Failure VIROLOGIC FAILURE IMMUNOLOGIC FAILURE CD4 COUNT HIV DRUG RESISTANCE VIRAL LOAD Murri R, et al. JAIDS. 2006. Pillay D, et al. 14th CROI 2007, #642. 25 Sungkanuparph S, et al. CID 2007. Losina E et al, 15th CROI 2008, #823 The 6th National Scientific Conference on HIV/AIDS CLINICAL FAILURE Development of NRTI Resistance Mutations • Resistance patterns after failure of common NRTI backbones AZT/3TC d4T/3TC M184V TDF/3TC Q151M K65R (d4T) TAMs M184V K65R Q151M? TDF/FTC ABC/3TC ddI/3TC M184V NNRTI L74V or K65R Q151M? Early detection of treatment failure allows more options for the next regimen resistance Gallant JE. Top HIV Med. 2005. Sungkanuparph S, et al. CID 2007. The 6th National Scientific Conference on HIV/AIDS Assessment of Treatment Failure • Review antiretroviral history • Physical exam for signs of clinical progression • Assess adherence, tolerability, pharmacokinetic issues • Resistance testing (while patient is on therapy) • Clarify goals: undetectable vs. maximal virological suppression • Identify treatment options • Base treatment choices on ⁻ expected efficacy - future treatment options ⁻ tolerability - past medication history ⁻ adherence - resistance testing results The 6th National Scientific Conference on HIV/AIDS Second-line ART for Adults: DHHS Panel Recommendations • Goal of treatment for ART-experienced patients with drug resistance who are experiencing virologic failure is to establish virologic suppression (AI) • A new regimen should include at least 2, and preferably 3, fully active agents (AI) • Adding a single ARV agent to a virologically failing regimen is not recommended because this may risk the development of resistance to all drugs in the regimen (BII) DHHS Guidelines, April 2015. The 6th National Scientific Conference on HIV/AIDS Second-line ART for Adults: WHO Recommendations • Second-line ART should consist of 2NRTIs + boosted PI • The following sequence of second-line NRTI options is recommended – After failure on TDF+3TC (or FTC), use AZT+3TC – After failure on AZT/d4T+3TC, use TDF+3TC • Use of NRTI backbones as FDC is preferred approach • Heat-stable FDCs of ATV/RTV and LPV/RTV are the preferred boosted PI options for second-line FDC, fixed-dose combination WHO. Consolidated guidelines , June 2013; pp 146. The 6th National Scientific Conference on HIV/AIDS Switching the ART Regimen After Treatment Failure: Treatment Options First regimen 2 NRTIs + NNRTI Recommended second regimens Boosted PI + 2 active NRTIs indicated by genotype testing results 2 NRTIs + 1) active boosted PI + 2 active NRTIs indicated by genotype testing boosted PI 2) active boosted PI + 1 NNRTI ± 1 NRTI indicated by genotype testing 3) NNRTI + 2 active NRTIs indicated by genotype testing* *This option can be used only when there are 2 active NRTIs and the patient has never been exposed to NNRTI, or NRTI monotherapy or duotherapy. Sungkanuparph S, et al. Thai National Guidelines 2010. Asian Biomed 2010;4:515-28. The 6th National Scientific Conference on HIV/AIDS Outcomes of the Second-Line Regimens in Thailand • An observational cohort of patients with 1st-line ART failure • Of 95 patients, mean age 39 years, 65% were male • Median CD4 and HIV RNA at 2nd-line ART initiation were 158 cells/mm3 and 4.1 log10 copies/mL, respectively • Boosted PI + 2 NRTIs, indicated by genotype results, was used as 2ndline regimen • At 6, 12, 24, and 36 months of 2nd-line ART, – 67%, 62%, 84%, and 90% achieved HIV RNA <50 copies/mL – Median CD4 were 258, 366, 444, and 522 cells/mm3 • Good adherence, high baseline CD4, and early CDC staging were associated with virologic success (P < .05) Win MM, et al. J Int Assoc Physicians AIDS Care 2011; 10:57-63. The 6th National Scientific Conference on HIV/AIDS Choosing LPV/r vs ATV/r for 2nd Regimens PI/r LPV/r Advantages Disadvantages Potent activity (more evidence of successful LPV/r monotherapy) Metabolic complications due to both LPV and RTV esp. hypertriglyceridemia Resistance to LPV/r is less often at virologic failure GI intolerance e.g. diarrhea Low risk of additional NRTI resistance with boosted PI failure Insulin resistance and lipodystrophy More pills (4/days) Currently only co-formulated PI ATV/r Least metabolic complications due to ATV and less with RTV OD Less evidence of ATV/r monotherapy Once-daily dose Resistance to ATV is more often at virologic failure, but less with ATV/r Less pills (2/day) Not a co-formulated PI Can be given unboosted (if not using TDF in the regimen) Increased unconjugated bilirubin (4-9%) Absorption impaired with PPI Food requirement for dosing The 6th National Scientific Conference on HIV/AIDS The HIV Second-line Therapy AntiRetroviral Study in Patients Who Failed NNRTI-based Regimens Variable Total (N =195) Age, years 37.5 (6.9) Male, % 58 Weight, kg 58.3 (10.7) CDC clinical classification A:B:C, % 23:22:55 Baseline CD4 count, cells/mm3 204 (135) Baseline HIV-RNA, log10 copies/mL 4.1 (0.6) Genotypic resistance for NRTI, % M184V/I 82 K65R 7 Multi NRTI resistance* 18 * Multi-NRTI mutations were defined as having ≥4thymidine analog mutations (TAMs) or Q151M complex or 69insertion Bunupuradah T et al. Antiviral Ther 2012;17:1351-61. The 6th National Scientific Conference on HIV/AIDS The HIV Second-line Therapy AntiRetroviral Study in Patients Who Failed NNRTI-based Regimens 100 90 80 % Virological suppression 70 HIV-RNA ≥400 copies/mL HIV-RNA <400 copies/mL HIV-RNA <200 copies/mL HIV-RNA <50 copies/mL 60 50 40 30 20 10 0 Mono-LPV/r-arm HIV-RNA TDF/3TC/LPV/r-arm Mono-LPV/r (%) TDF/3TC/LPV/r (%) P-value <400 75 86 0.053 <200 69 86 0.01 <50 61 83 <0.01 (copies/mL) Bunupuradah T et al. Antiviral Ther 2012;17:1351-61. The 6th National Scientific Conference on HIV/AIDS Genetic Barrier to Resistance and Potency of Antiretroviral Agents The 6th National Scientific Conference on HIV/AIDS Lamivudine, M184V/I , and Viral Fitness Lamivudine M184V Time • HIV with M184V/I mutations does not replicate as fast as wild-type virus = less fit Schuurman R, et al. J Infect Dis 1995; 171: 1411-9. The 6th National Scientific Conference on HIV/AIDS Lamivudine Monotherapy in HIV-1-Infected Patients Harboring A Lamivudine-Resistant Virus In HIV-1-infected patients harbouring a lamivudine-resistant virus, lamivudine monotherapy may lead to a better immunological and clinical outcome than complete therapy interruption. AIDS. 2006;20(6):795-803. The 6th National Scientific Conference on HIV/AIDS EARNEST Study: Design HIV positive adolescents/adults (n=1277) First-line NNRTI-based regimen >12 months; > 90% adherence last 1 month failure by WHO (2010) clinical, CD4 count (VL-confirmed) or VL criteria Randomised PI + RAL (12 week induction) PI + 2-3 NRTIs (NRTIs according to local standard of care) PI + RAL PI (monotherapy) Follow-up for 144 weeks Primary outcome at Week 96: good HIV disease control defined as all of • Alive and no new WHO 4 events from 0–96 weeks and • CD4 cell count >250 cells/μL at 96 weeks and • VL<10,000 or >10,000 copies/mL without PI mutations at 96 weeks Paton NI, et al. N Engl J Med 2014;371:234–47. RAL, raltegravir The 6th National Scientific Conference on HIV/AIDS EARNEST Study: VL Suppression* PI/RAL vs PI/NRTI P=0.36 P=0.87 P=0.97 P=0.88 Mono+ vs PI/NRTI P=0.002 P<0.001 P<0.001 P<0.001 88 87 86 86 % patients suppressed 100 91 93 83 80 67 60 *at week 96 74 73 61 44 PI/NRTI 40 PI/RAL 20 PI mono+ 0 <10,000 <1000 <400 Viral load (copies/mL) Paton NI, et al. N Engl J Med 2014;371:234–47. <50 RAL, Raltegravir The 6th National Scientific Conference on HIV/AIDS EARNEST Study: Drug Resistance *at week 96 Paton NI, et al. N Engl J Med 2014;371:234–47. The 6th National Scientific Conference on HIV/AIDS Choices of NRTIs for 2nd-line ART • When genotypic resistance testing is not available The 6th National Scientific Conference on HIV/AIDS Choices of Main ARV for 2nd-line ART • When genotypic resistance testing is not available The 6th National Scientific Conference on HIV/AIDS The 6th National Scientific Conference on HIV/AIDS The 6th National Scientific Conference on HIV/AIDS Rilpivirine Resistance • Presence of 1 of the 16 well established mutations: K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, H221Y, F227C, M230I/L, Y188L • Presence of 2 or more of L100I, V106I, M230I • L100I alone not reduced susceptibility of RPV. It has to combine with K103N/S or combine with K103R+V179D to reduce susceptibility of RPV. The 6th National Scientific Conference on HIV/AIDS The 6th National Scientific Conference on HIV/AIDS HIV-infected Patients and Dyslipidemia 2 Strategies to manage dyslipidemia Switching strategy LPV/rtv ATV/rtv Adding strategy LPV/rtv + lipid-lowering agent LPV/rtv = Lopinavir/ritonavir ATV/rtv = Atazanavir/ritonavir The 6th National Scientific Conference on HIV/AIDS ATAZIP Study: Switch LPV/r to ATV/r Fasting plasma lipids changes from baseline to week 48 Median change from baseline (mg/dL) 200 p < 0.001 p < 0.001 100 p = 0.149 p = 0.185 0 -100 -200 -300 Triglycerides Switch to ATV/r 300/100 qd (N = 121) Total cholesterol LDL HDL cholesterol cholesterol Continue on LPV/r 400/100 bid (N = 127) Mallolas J, et al. J Acquir Immune Defic Syndr. 2009; 51: 29-36. The 6th National Scientific Conference on HIV/AIDS DHHS Guidelines: ARV Switching Adverse event Switch from Switch to Dyslipidemia Hypertriglyceridemia (with or without high low-density LDL level) RTV- or cobiboosted regimens or EFV RAL, DTG, RPV, NVP, or unboosted ATV* *Elevated TG and LDL levels are more common with LPV/r and FPV/r than with other RTV-boosted PIs. Improved TG and LDL levels have been seen following a switch from LPV/r to RTV-boosted and -unboosted ATV DHHS Guidelines, May 2014. The 6th National Scientific Conference on HIV/AIDS Lipid-Lowering Therapy vs PI Switching • 130 patients • 60% male; mean age 39 years mg/dL • 12-month, open-label study • Stable on first ART regimen randomized to: 350 300 250 200 150 100 50 0 PI EFV (n = 34) 0 PI NVP (n = 29) • Pravastatin or bezafibrate significantly more effective than switching ART to NNRTI mg/dL Add bezafibrate (n = 31) Add pravastatin (n = 36) Mean Plasma Triglycerides 350 300 250 200 150 100 50 0 3 6 Months 9 12 Mean Plasma Cholesterol 0 3 6 Calza L et al. AIDS 2005;19:1051-8. Months The 6th National Scientific Conference on HIV/AIDS 9 12 Switching LPV/r to ATV/r vs Adding Atorvastatin Switching Group ATV/r LPV/r • • • • Randomized Adding group > 18 years old On LPV/rtv > 1 year HIV RNA < 50 copies/mL TC > 200 mg/dL Follow-up time (weeks) LPV/r + Atorvastatin 20 mg/day* 0 12 Clinical condition Adverse events Lipid profiles (TC, LDL, HDL, TG) CD4 cell count HIV RNA Wangpatharawanit P, et al. IAS 2015. Abstract WEPEB349. The 6th National Scientific Conference on HIV/AIDS 24 Switching LPV/r to ATV/r vs Adding Atorvastatin TC LDL 20 HDL 7.2 TG Switching Adding 2.3 0 -2.2 mg/dL -20 -19 -40 -60 -80 -34.6 -55.4 ** -57.4 * -100 -96.8 -120 * p = 0.004 ** p < 0.001 Mean change lipid profile levels at week 24 Wangpatharawanit P, et al. IAS 2015. Abstract WEPEB349. The 6th National Scientific Conference on HIV/AIDS SUMMARY • Causes of treatment failure must be determined: patient-related factors vs ARV drug-related factors • Treatment failure and HIV drug resistance are correlated with increased mortality • Virologic failure is the most accurate method to define treatment failure • Late detection of treatment failure can limit options for second-line regimens • The patterns of drug-resistance mutations and cross-resistance are often predictable • Second-line ART should consist of 2 active NRTIs + boosted PI • An optimal second-line regimen can lead to complete virologic suppression The 6th National Scientific Conference on HIV/AIDS