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