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in Resource-limited Settings
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 Background Objectives Methods Results & Discussion Conclusions
Recommendations Effect of Antiretroviral Therapy
Immunological response Viral load Clinical response less illnesses improved weight better well being back to work better quality of life CD4 Limit of detection Virological response Time Immunological failure
Treatment Failure Clinical failure CD4 HIV-RNA Viral load Immunological failure CD4 Virological failure Criteria for failure Time 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 patientsmisclassified 25% decrease in CD % 50% decrease in CD % Immunological failure criteria would lead to a premature switch to second-line regimens Kantor R, et al. Clin Infect Dis 2009. Risk of Disease Progression/Death
Years since start of therapy 1 Cumulative probability of deathor a new AIDS-defining event 0.05 0.10 0.15 0.20 0.25 2 3 4 5 Non-responders Immunologic-only responders Virologic-only responders Complete responders 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. Treatment Failure and HIV Drug Resistance in A Chinese Cohort Impact of HIV Drug Resistance on Mortality in A Chinese Cohort Impact of HIV Drug Resistance on Mortality in A Chinese Cohort Insufficient Drug Level Viral Replication in the
Causes of Treatment Failure Social/Personal Issues Regimen Issues Poor Potency Toxicities Wrong Dose Poor Adherence Host Genetics Poor Absorption Insufficient Drug Level Rapid Clearance Poor Activation Viral Replication in the Presence of Drug Drug Interactions Resistant Virus Transmission Treatment Failure Patients with virological failure (%)
Adherence and HIV Drug Resistance Patients with virological failure (%) Adherence (%) Degree of non-adherence was significantly associated with risk for virological failure (P1,000 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 second-line ART Multi-NRTI RAMs = presence of either Q151M; 69Ins; 2 TAMs; or M184V+ 1 TAM HIV Drug Resistance at First-line ART Failure in Asia HIV Drug Resistance at First-line ART Failure in Asia HIV Drug Resistance at First-line ART Failure in Asia
Factors associated with multi-NRTI RAMs were CD4 200 cells/L at genotyping (OR=4.43, 95%CI ) 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 ) Case 2 Resistance-associated RT Mutations: Y181C, M184V
Nucleoside and Nucleotide RT InhibitorsResistance Interpretation abacavir (ABC)Possible Resistance didanosine (ddI)Possible Resistance lamivudine (3TC)/emtricitabine (FTC)Resistance stavudine (d4T)Resistance tenofovir (TDF)Possible Resistance zidovudine (AZT)Resistance Non-nucleoside RT InhibitorsResistance Interpretation efavirenz (EFV)Resistance etravirine (ETR)Possible Resistance nevirapine (NVP)Resistance rilpivirine (ETR)Possible Resistance Resistance-associated PR Mutations: K20I, M36I Protease InhibitorsResistance 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 Case 3 Resistance-associated RT Mutations: D67N, K70R, V108I, Y181C, M184V Nucleoside and Nucleotide RT InhibitorsResistance Interpretation abacavir (ABC)Possible Resistance didanosine (ddI)Possible Resistance lamivudine (3TC)/emtricitabine (FTC)Resistance stavudine (d4T)Resistance tenofovir (TDF)No Evidence of Resistance zidovudine (AZT)Resistance Non-nucleoside RT InhibitorsResistance Interpretation efavirenz (EFV)Resistance etravirine (ETR)Possible Resistance nevirapine (NVP)Resistance rilpivirine (ETR)Possible Resistance Resistance-associated PR Mutations: K20I, M36I Protease InhibitorsResistance 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 Case 4 Resistance-associated RT Mutations: D67N, K70R, V108I, Y181C, M184V, T215F, K219E Nucleoside and Nucleotide RT InhibitorsResistance Interpretation abacavir (ABC)Possible Resistance didanosine (ddI)Possible Resistance lamivudine (3TC)/emtricitabine (FTC)Resistance stavudine (d4T)Resistance tenofovir (TDF)Possible Resistance zidovudine (AZT)Resistance Non-nucleoside RT InhibitorsResistance Interpretation efavirenz (EFV)Resistance etravirine (ETR)Possible Resistance nevirapine (NVP)Resistance rilpivirine (ETR)Possible Resistance Resistance-associated PR Mutations: K20I, M36I Protease InhibitorsResistance 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 log < 4 log > 4 log P = 0.105 P = 0.763 P = 0.041 P = 0.008 P = 0.031 P = 1.000 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 CLINICAL FAILURE CD4 COUNT Note to Speaker: This is a key slide in the presentation and should be strongly emphasized. Key Points: As virologic treatment failure occurs, the CD4 goes down (immunologic failure) and ultimately clinical failure ensues. Virologic and sometimes immunologic failure, go unrecognized if VL and/or CD4 monitoring is not occurring.In this case, the patient stays on a failing regimen for a prolonged period of time, during which time resistance can occur. This will ultimately lead to increased morbidity and mortality, as discussed, and lead to fewer options in the future.The next few slides explain this process by sharing some data. HIV DRUG RESISTANCE VIRAL LOAD Murri R, et al. JAIDS Sungkanuparph S, et al. CID 2007. Pillay D, et al. 14th CROI 2007, # Losina E et al, 15th CROI 2008, #823 25 25 Resistance patterns after failure of common NRTI backbones
Development of NRTI Resistance Mutations Resistance patterns after failure of common NRTI backbones AZT/3TC d4T/3TC Q151M K65R (d4T) M184V TAMs TDF/3TC TDF/FTC M184V K65R Q151M? ABC/3TC ddI/3TC M184V L74V or K65R Q151M? 3TC, lamivudine; ABC, abacavir; d4T, stavudine; FTC, emtricitabine; TAMs, thymidine-associated mutations; TDF, tenofovir; ZDV, zidovudine. This slide demonstrates the resistance pattern after the initial failure of common NRTI backbones. When patients start with zidovudine/lamivudine, stavudine + lamivudine, or the triple-NRTI combination of zidovudine/lamivudine/abacavir, they first develop M184V and subsequently develop thymidineassociated mutations. When abacavir/lamivudine is chosen as initial therapy, M184V is the first mutation to develop and is usually followed by L74V and sometimes K65R. When tenofovir/emtricitabine is the first choice, M184V emerges first, followed shortly thereafter by K65R. The important takehome point from this slide is that the M184V resistance mutation emerges first, followed by a gradual accumulation of either thymidine-associated mutations or either L74V or K65R, depending on the initial NRTIs chosen. Early detection of treatment failure allows more options for the next regimen NNRTI resistance Gallant JE.Top HIV Med 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 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 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 Recommended second regimens
Switching the ART Regimen After Treatment Failure: Treatment Options First regimen Recommended second regimens 2 NRTIs + NNRTI Boosted PI + 2 active NRTIs indicated by genotype testing results 2 NRTIs + boosted PI 1) active boosted PI + 2 active NRTIs indicated by genotype testing 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 Asian Biomed 2010;4: 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 cells/mm3 and 4.1 log10 copies/mL, respectively Boosted PI + 2 NRTIs, indicated by genotype results, was used as 2nd-line regimen At 6, 12, 24, and 36 months of 2nd-line ART, 67%, 62%, 84%, and 90% achieved HIV RNA