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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.
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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.
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Suboptimal Adherence to ART in Asia
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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
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Predicting Factors for Genotypic Resistance Test
Results that Associated with Poor Adherence
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Durability of d4T/3TC/NVP regimen
A 144-week Prospective Study
Thailand: 140 patients
Manosuthi W, et al. BMC Infect Dis 2008; 8:136.
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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.
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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)
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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
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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
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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
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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
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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.
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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
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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.
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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.
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Choices of NRTIs for 2nd-line ART
• When genotypic resistance testing is not available
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Choices of Main ARV for 2nd-line ART
• When genotypic resistance testing is not available
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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.
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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
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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