Kiat Ruxrungtham Professor of Medicine Chulalongkorn University and HIVNAT Thai Red Cross AIDS Research Center Three Decades of HIVAIDS Learning and the Future Mid 1990 1981 2012 2014 ID: 801497
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Slide1
HIV MedicineFrom Guidelines to Practice
Kiat RuxrungthamProfessor of Medicine, Chulalongkorn University; andHIV-NAT, Thai Red Cross AIDS Research Center
Slide2Three Decades of HIV/AIDS
Learning and the FutureMid 1990
1981
2012 - 2014
One/ two ARVs
Improve survival
2020
Three ARVs (HAART)
Durable undetectable VL
Earlier HAART
non-AIDS death
Transmission
New TB
New strategies Long-acting ARV ?Cure ?
late 1980
Few ARVsMore toxicity
More class ARVsMore potent –PIsBut high pill burden
More new ARVsMore tolerableMore OD optionsMore FDC optionsSingle tablet regimens
Monthly ARV?Cure ?
Evidences and developments
Availability and treatment options
Slide3MSM
10-30%
HIV/AIDS in Thailand
Slide4Rapid Progressors
Typical Progressors<3 yrs
7-12
yrs
>15
yrs
Normal, Stable CD4+ T cell count
Viral load <500 copies/ml
90%
<
10
%
<
1%
Natural History of HIV Disease Progression
HIV
Infection
Long-term
Non-progressors
Median time to progress
Slide5When to start HAART
CD4 cell count
Years After HIV Infection
Clinical outcomes
No AIDS-complication +
No non-AIDS-complication
500
350
200
?
CIPRA
HT001
START trial
Slide6Current Update on HIV Treatment 2014
Slide7When to start ART by guidelines
GuidelinesCD4NoteU.S. DHHS 2014All
When the patient is ready and committed
to treatment
WHO
2013
<500
Regardless of CD4 for
specific
settings
and the patient is ready and committed
Thai 2014
AllWhen the patient is ready and committed to treatment
Slide8HIV Late Presentation Remains a major challenge worldwide
UK30-50%CD4 <200Thailand40%CD4 <50
India
50%
CD4 <200
USA
60-70%
CD4 <350
Latino, Black
Nigeria
50%
CD4 <200
1
J Int AIDS Soc. 2010; 13(Suppl 4): P107; 2Clin Infect Dis. 2011 Sep;53(5):480-7; 3Interdisciplinary Perspectives on Infect
Dis 2012; 4Afr J Health Sci. 2007; 14:212-215; 5
Curr HIV Res. 2009 May;7(3):340-5
Slide9Incidence of IRIS Following HAART
10-15 % in N. America and Europe20-25 % in resource-limited countriesBonham et al. Biomarker Medicine 2008; 2:349-361Murdoch et al. AIDS Res Therapy 2007; 4:9HIV Coinfection
IRIS
Slide10Timing of IRIS
Viral load
CD4
Time Following HAART
IRIS
Months
Weeks
Years
Photo is from -
Dhasmana
et al.
Drugs 2008; 68 (2): 191-208
Risk Factors
Low BL CD4 count
Rapid decline of VL
Early timing of HAART following OI Rx
Slide11When to start ART in patients with OIs
Type of OICD4
(cell/mm3
)
≤
50
>50
Tuberculosis
within 2 weeks
Severe
Not-severe
within 2 weeks
between
2-8 weeks
Cryptococcosis
between 4-6 weeks
PCP,
MAC,
others
between
2-4
weeks
CMV,
PML,
Cryptosporidium
as soon as possible
Thai Guidelines 2014
Slide12Slide13Current
Antiretroviral
Agents
HIV
RNA
DNA
ds
DNA
RT
Integrase
Transcription
Proviral
DNA
Spliced
mRNA
mRNA
Genomic RNA
Polyprotein
Protein
Protease
Protease Inhibitors
SQV
,
rtv
,
IDV, NFV, AMV, LPV/rtv
,
ATV,
fAMP
,
DRV
RT Inhibitors
NRTI
:
AZT,
ABC
,
ddI
,
,
d
4
T
,
3
TC
,
, FTC,
NNRTI
:
NVP, EFV
,
ETV, RPV
NTRTI:
Tenofovir
(TDF)
1
2
3
4
5
6
Entry Inhibitors
CCR
5
inhbitor
:
Maraviroc
(MVC)
Fusion
gp
41
:
Enfuvirtide
vpr
Integrase
inhibitors
Raltregavir
(RAL)
Elvitegravir
Dolutegravir
Slide14Currently Available Antiretroviral Agents 2014
in Developed Countries (Available =30)Nucleos(t)ide RTIs
Zidovudine
(ZDV)
Didanosine
(
ddI
)
Zalcitabine
(ddC
) Stavudine (d4T)
Lamivudine (3TC) Abacavir (ABC)
Emtricitabine (FTC)
Tenofovir DF (TDF)
Non-nucleoside
RTIsNevirapine (NVP)
Delavirdine (DLV) Efavirenz (EFV)
Etravirine (ETR)
Rilpivirine (RPV)
Protease Inhibitors
Saquinavir
(SQV)
Ritonavir
(RTV)
Indinavir (IDV)
Nelfinavir (NFV)
Amprenavir
(APV)
Lopinavir
/r (LPV/r)
Atazanavir
(ATV)
Fosamprenavir
(
f
APV
)
Tipranavir
(TPV)
Darunavir
(DRV)
Boosters
Ritonavir (RTV)
Cobicistat* (
cobi
)
Fusion Inhibitor
Enfuvirtide
(T-20)
CCR5 Antagonist
Maraviroc
(MVC)
Integrase Inhibitors
Raltegravir (RAL)
Dolutegravir
Elvitegravir
NRTI =8
NNRTI =5
PI =10
Integrase
inh
=
3
EI=2
EI=2
Slide15Currently Use Antiretroviral Agents 2014
in Developed Countries (current use=17)Nucleos(t)ide RTIs
Zidovudine
(ZDV)
Lamivudine
(3TC)
Abacavir (ABC)
Emtricitabine
(FTC)
Tenofovir DF (TDF)
Non-nucleoside RTIs
Efavirenz (EFV) Etravirine
(ETR) Rilpivirine (RPV)
Nevirapine (NVP)
Protease Inhibitors
Lopinavir/r
(LPV/r) Atazanavir
(ATV)Darunavir
(DRV)
Boosters
Ritonavir (RTV)
Cobicistat
(cobi)
CCR5
Antagonist Maraviroc
(MVC)
Integrase Inhibitors
Raltegravir (RAL)
Dolutegravir
Elvitegravir
NRTI =5
NNRTI =4
PI =3
II =2
EI=1
Booster = 2
EI= entry inhibitor
II =
integrase
inhibitor
Slide16What to start in Resource-rich settings?
NtRTI orNRTI NRTI Cytidine
Analog
NNRTI or
b
PI
or
Integrase
inh
.
+
+
TDFABC*
AZT
FTC3TC
Three drug combination in Naïve Patients
2 Nucleoside RT Inhibitors + NNRTI or Boosted
PI or Integrase inhibitor
Efavirenz
Atazanavir/r
Darunaivr/rRaltegravir
Dolutegravir
Evitegravir/cobi1
Rilpivirine2
1eGFR>70; 2
when VL<100,000 c/mlRemarks
FDC –single table available: Dual NRTI:TDF/FTC, ABC/3TCTriple: TDF/FTC/EFV, TDF/FTC/RPV*if HLA B*5701 is negative
U.S. DHHS Guidelines May 2104
+
+
Slide17Considerations When Selecting First-line Antiretroviral Therapy
Baseline CD4+ cell count/HIV-1 RNA level
Age
Sex
Occupation (eg, work schedule)
Comorbid conditions (eg, CV risk, renal abnormalities)
Plans for pregnancy
Access to care
Concurrent medications
Adherence to other medications
Genetics (eg, HLA-B*5701)
Viral tropism
Patient/Viral Factors
Antiretroviral Drug Factors
Efficacy
Baseline drug resistance
Tolerability
Long-term toxicity/metabolic effects
Drug–drug interactions
Dosing frequency
Pill burden
Pharmacokinetics
Cost
Kuritzkes
D et al. www.clinicaloptions.com
Individualizing First-line Therapy
CircumstanceAgents No genotypeUse boosted PIHigh HIV-1 RNA
Caution with ABC, RPV
Renal
disease
Caution with TDF, ATV/RTV; monitoring complicated with COBI and DTG
Dyslipidemia
RAL, DTG, RPV most lipid neutral
CV
risk factors
Possible association with ABC, ddI, LPV/RTV
No data for DRV/RTV, INSTIs, MVC
Pregnancy
Preferred: ZDV/3TC + NVP, LPV/RTV, or ATV/RTV
EFV can be used after first 5-6 wks
Chronic HBV infection
Preferred TDF + 3TC or FTC
Alternative is entecavirDecreased BMD
Caution with TDFConcerns on CNS effects
Caution with EFV for at least first mo
Kiriztkes
D et al. www.clinicaloptions.com
Slide19When Blood Lipid is the ConcernNNRTI
Rilpivrine (RPV)Integrase inhibitiors: Raltegravir, dolutegravirbPIs: Atazanavir, darunavir (lesser degree of abnormality as compared to other bPIs)
Slide20Prescribing a Simplify regimen
Once-dailySingle tablet regimen (STR)Current Strategy and TrendAtripla® (TDF/FTC/EFV)
Complera
®
(TDF/FTC/RPV)
Slide21Download New AIDS Guidelines 2014
Slide22www.aidsstithai.org/contents/view/60
Slide23Baselines and FU Lab tests
Slide24What to start in Resource-limited settings?
NtRTI orNRTI Cytidine Analog
NNRTI or
Boosted PIs
+
+
TDF
ABC
AZT
d4T
3TC
FTC
Three drug combination in Naïve Patients
2 Nucleoside RT Inhibitors + NNRTI
or
Boosted PIs
EFV
RPVNVP
+
+
AlternativeLPV/r
ATV/r
Thai Guidelines 2014
Slide25S. Taylor et al. 11th CROI Abs 131
Adherence is critical Potential Concern When Stopping Drugs With Different T1/2Time (Hours)
0
24
48
36
12
Drug Concentration
IC
90
IC
50
Last Dose
Day 1
Day 2-weeks
AZT
3TC
NNRTI
(EFV, NVP, RPV)
Zone of potential replication
MONOTHERAPY
Slide26EFV: Standard doses of Efavirenz associated with a higher exposure in Thais/Asians
van der Lugt J, and Avinhingsanon A. Asian Biomedicine Feb 2009
Slide27A Lady with Very Severe CNS side-effect –couldn’t work and about to give-up her EFV-based HAART
currently she is happy with this regimen and has VL<50 for >2 yrs
EFV level 21.39 mg/LAt EFV
600
mg
qd
EFV –severe CNS AEs with poor
QoL
EFV level 4.5-5.2 mg/L
At EFV
300 mg qd
Slide28Once Start we should not stop HAART
Slide29กรณี ถือศีลอด
Slide30How to detect failure and DR?Time-course of HAART Failure
Clinical
Started HAART
1
2
3
4
5
Non-
Adherence
Viral load
Resistance
CD4 drop
Time (months –years)
Thai NHSO guidelines:
VL q 6 mo, until VL<50, then q 1 yr
CD4: q 6 mo, until CD4 >350, q 1 yr
Slide31Viral Load and CD4 Tests
Slide32Virologic Failure“The inability to achieve or maintain suppression of viral replication”
SettingDHHS 2009DHHS 2011WHO 2009Incomplete suppressionafter 24 weeks>400*
>200*
>5000**
Virologic
Rebound
>50
>200***
>5000
*High Baseline VL (>100,000 c/ml) may take longer than low BL VL
**Values of >5 000 copies/ml are associated with clinical progression and a decline in the CD4 cell count
***>200 is associated with evidence of viral evolution and drug-resistance mutation accumulation
Slide33Slide34Second-line ART controlled studies
StudyNcomparatorsSitesSponsorsEnd point analysisHIV-STAR
200TDF/3TC +LPV/r
LPV/r mono
Thailand
10
sites
HIVNAT, NHSO, Swiss cohort
Nov 2011
SECOND-LINE
550
2NRTI +LPV/r
RAL +LPV/rAll continents
18 countriesKirby Insitute, AustraliaSept 2012ALISA
386TDF/FTC +LPV/rTDF/3TC
+ATV/rAfrica
SA, TanzaniaFrench NIH
May 20132LADY450
TDF/FTC +LPV/rABC/ddI +LPV/rTDF/FTC +
DRV/rAfricaBurkina Faso, Cammaroon, Senegal
ANRS12169Sep 2013
EARNEST1277
2NRTIs +LPV/rRAL +LPV/r
LPV/r monoAfrica
5 countriesMRC, EDCTP
Dec 2013
www.clinicaltrials.gov (assessed 22 Apr 2012)
Slide35HIV-
STAR Results (HIVNAT, TRC-ARC, Thailand initiated trial)Patients with baseline GSS≥ 2 had a better % with VL< 50 c/mlat 48 weeks of treatmentBunupuradah T , et al,. Antiviral therapy 2012 Jul 2. doi: 10.3851
Slide36SECOND-LINE results
Slide37SECOND-LINE Study
RAL/LPV/r
NRTIs/LPV/r
N= 270
N= 271
83%
81%
% patients with VL<200 c/ml
Lancet 2013, June 15; 381: 2091–99
Pros:
Not required DR test
Easy for trained non-medical staffs to deliver care (task shifting)
Easy for drug supply and stock
RAL is less toxicity than NRTS
Cons
: RAL is expensive
Patients failed NNRTI-regimens
Slide38Options after First-line Failure
NRTI in the failing regimenNRTI option
Third ARV option
TDF failure
Guided by resistance test results, or
Consider :
AZT/3TC
Preferred :
Lopinavir
/
ritonavir
(LPV/r)*
Alternative
:
Atazanavir
/
ritonavir
(ATV/r),
darunavir/ritonavir
(DRV/r)
AZT or ABC failure
Guided by resistance test results, or
Consider
:
TDF/FTC or TDF/3TC
Slide39boosted PI : WARNING Serious Drug Interaction
Ergotism: ergotamineRhadomyolysis: statins (simvastatin, etc.) Alternatives: pravastatin, fluvastatin and fibrate
derivativesExcessive sedation
:
benzodiazeoines
(diazepam,
alprazolam
,
midazolam
,..)except lorazepam
Hypotension: Ca-blockers (amlodipine, nifedipine, felopdipine
), beta-blockersCushing syndrome, adrenal insufficiency: with fluticasone
Torsades de Pointes (prolong QT and ventricular arrhythmia): cisapride, pimozide;
ditiazem; antiarrhythmic –flecanide, amiodarone, quinidine etc.
Slide40Ergotism and bPI is not common
in patients who were well VL control and on bPIsThai reportN=23All had VL<50, CD4 >25020 hospitalization (4-20 days)
3 gangrene
2 Amputation
1death
Avihingsanond
A. et al in submission 2012
a HCW case–was prescribed
bPI
as a PEP regimen
bPI
–Ergotamine AEs
Slide41Standard doses of boosted protease inhibitors (bPIs
) associated with a high exposure in Asianvan der Lugt J, and Avinhingsanon A. Asian Biomedicine Feb 2009
Slide42Cost Saving When Using a Lower Dose
Atazanavir : from 300 to 200 mg5 year savings = ≥6900 million Baht to treat 5000 cases with a 5% cases increased/yr
Slide43ATV/r: atazanavor/ritonavir, PI: protease inhibitor, HAART: highly active antiretroviral therapy, OD: once daily, TDF: tenofovir
Complete enrollment: Dec 2013, expected results by Jan 2015
Slide44Life Expectancy approaches normal
in a High-income country after HAARTThe Netherlands N = 17,580 person-yearMedian CD4 = 480 (24 wks of Dx)Life expectancy from 25 yo
Men = 52.7 yearsWomen =57.8 years
Slide45Date of download: 8/25/2012
Copyright © The American College of Physicians. All rights reserved.From: Life Expectancy of Persons Receiving Combination Antiretroviral Therapy in Low-Income Countries: A Cohort Analysis From UgandaAnn Intern Med. 2011;155(4):209-216. doi:10.1059/0003-4819-155-4-201108160-00358
Uganda (N=22,315)
Life expectancy at 30
yo
CD4 <50 = 14 years
CD4 >150 = 40 years
The life expectancy can be near normal with antiretroviral therapy, especially when ART was initiated at CD4>150 cells
Slide46Thailand: Age and gender distributionHIV/AIDS statistic, BOE, MOPH (data up to Nov 2011)
Aging
Future Trend
Male
Female
Slide47Reduced bone mineral density
Renal dysfunction30% of HIV+ patients have abnormal kidney function1
Increased
prevalence
63%
of HIV+ patients
2
Emerging co-morbidities in HIV
Gupta SK et al.
Clin
Infect
Dis
2005;40:1559–1585. ,
Brown TT et al.
J Clin Endocrinol Metab 2004;89(3):1200–1206, Clifford DB. Top HIV Med 2008;16(2):94–98
Triant VA et al.
J Clin
Endocrinol Metab
2007;92:2506–2512, Patel P et al. Ann Intern Med 2008;148:728–736
Cardiovasculardisease
Neurocognitive
dysfunction
I
mpairment present in
≥50% HIV+ patients3
Cancer
Increased risk of non-AIDS-defining cancers
e.g. anal, vaginal, liver, lung, melanoma, leukemia, colorectal and renal
5
75%
increase in risk of acute MI
4
Slide48Drug Interactions with First-line ART and Lipid-Lowering Therapy
Antiretroviral ContraindicatedTitrate DoseNo Dose Adjustment
RPV[1]
Atorvastatin
EVG/COBI/TDF/
FTC
[1]
Lovastatin
Simvastatin
Atorvastatin
Rosuvastatin
DTG
[2]
ATV/RTV
[1]
Lovastatin
Simvastatin
AtorvastatinRosuvastatin
PitavastatinDRV/RTV[1]
LovastatinSimvastatin
Atorvastatin
PravastatinRosuvastatin
Pitavastatin
EFV[1]
AtorvastatinSimvastatin
PravastatinRosuvastatin
RAL[1]
1. DHHS Adult Guidelines. February 2013. 2.
Dolutegravir
[package insert].
Kuritzkes
D et al. www.clinicaloptions.com
Drug Interactions With Oral Contraceptive Pills (OCPs)
Antiretroviral Effect on OCPDosing RecommendationRPV[1,2]
Ethinyl estradiol AUC
14%
Norethindrone: no significant change
No dose adjustment
EVG/COBI
TDF/FTC
[1,3]
Ethinyl estradiol AUC
25%
Norgestimate
Weigh the risks and benefits of norgestimate and consider alternative contraceptive
DTG[4]No clinically
relevant interactionNo dose adjustment
ATV/RTV[1,2]
Ethinyl estradiol AUC Norgestimate
OCP should contain ≥ 35 mcg ethinyl estradiolDRV/RTV[1,2]
Ethinyl estradiol AUC 44%
Norethindrone AUC 14%
Additional methods of contraception recommended
EFV[1,2]No effect on ethinyl estradiol
Active metabolites of norgestimate
A reliable method of barrier contraception must be used in addition to hormonal contraceptivesRAL
[1,2]No clinically relevant interaction
No dose adjustment
1. DHHS Adult Guidelines. February 2013. 2. DHHS Perinatal Guidelines. July 2012.
3. TDF/FTC/EVG/COBI [package insert]. 4.
Dolutegravir
[package insert].
Kuritzkes
D et al. www.clinicaloptions.com
Drug–Drug Interactions Acid-Reducing Medications and Newer ARVs
ARVAntacidsH2-Receptor AntagonistsProton Pump InhibitorsRPV[1]
Give antacids at least
2 hrs before or at
least 4 hrs after RPV
Give H2-receptor antagonists at least 12 hrs before or at least 4 hrs after RPV
Contraindicated
EVG/COBI
TDF/FTC
[1]
Separate EVG/COBI/ FTC/TDF and antacid
administration by > 2 hrs
No
clinically relevant
No
clinically relevant DTG[2]
RALDTG should be given
2 hrs before or 6 hrs after taking medications containing polyvalentcations
No clinically relevant
1. DHHS Adult Guidelines. February 2013. 2.
Dolutegravir [package insert].
Kuritzkes D et al. www.clinicaloptions.com
Slide51Cardiologist
Lifetime HIV care
Requires an integrated multidisciplinary approach
Hepatologist
Plastic surgeon
Nephrologist
Neurologist
Endocrinologist
Nutritionalist
Smoking
cessation
Gynecologist
Adpated
From
Anna Maria
Geretti
. London
HIV physician
Slide52Can we be the AIDS Free Generation?
Slide53Ending AIDS PolicyHow and
When?THAILAND
Petchsri
Sirinirund
Advisor on HIV/AIDS Policy and
Programme
Department of Disease Control, Thailand
ICAAP 11, 21 Nov 2013, Bangkok
Slide5450% reduction
New InfectionIn 5 YearsEnd AIDSIn 20 yearsEnding AIDS Working Definition
New infection <1000/yrMTCT rate = 0
Target population treatment is well coverage
Slide55CD4 <350 will prevent
6000 new infectionAny CD4 level
Prevent additional11,000 new infection
Slide56Treatment at CD4 <200
Slide57Slide58Continuum of ART in the NAP, Thailand2012
73%78%79 %
ITT =55 %
OT = 89%
Median CD4 count = 120
Only 34% asymptomatic
Slide59Slide60Thai Red Cross AIDS Research Center
Slide61HIV-
NAT founded in 1996
Slide62Can we be the AIDS Free Generation?
Slide63Let’s Have a BreakQ&A