HIV Medicine From Guidelines to Practice - PowerPoint Presentation

Slide1

HIV MedicineFrom Guidelines to Practice

Kiat RuxrungthamProfessor of Medicine, Chulalongkorn University; andHIV-NAT, Thai Red Cross AIDS Research CenterSlide2

Three 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 optionsSlide3

MSM

10-30%

HIV/AIDS in ThailandSlide4

Rapid 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 progressSlide5

When 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 trialSlide6

Current Update on HIV Treatment 2014Slide7

When 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 treatmentSlide8

HIV 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):340-5Slide9

Incidence 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

IRISSlide10

Timing 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 RxSlide11

When to start ART in patients with OIs

Type of OICD4 (cell/mm

3

)

≤

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 2014Slide12
Slide13

Current

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

DolutegravirSlide14

Currently 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 Slide15

Currently 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

inhibitorSlide16

What 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

/rDarunaivr/r

RaltegravirDolutegravir

Evitegravir/cobi1

Rilpivirine2

1eGFR>70; 2

when VL<100,000 c/ml

Remarks 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

+

+Slide17

Considerations 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

Slide18

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.comSlide19

When Blood Lipid is the ConcernNNRTI

Rilpivrine (RPV)Integrase inhibitiors: Raltegravir, dolutegravirbPIs: Atazanavir, darunavir (lesser degree of abnormality as compared to other bPIs)Slide20

Prescribing a Simplify regimen

Once-dailySingle tablet regimen (STR)Current Strategy and TrendAtripla® (TDF/FTC/EFV)

Complera

®

(TDF/FTC/RPV)Slide21

Download New AIDS Guidelines 2014Slide22

www.aidsstithai.org/contents/view/60Slide23

Baselines and FU Lab testsSlide24

What 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 2014Slide25

S. 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

MONOTHERAPYSlide26

EFV: Standard doses of Efavirenz associated with a higher exposure in Thais/Asians

van der Lugt J, and Avinhingsanon A. Asian Biomedicine Feb 2009Slide27

A 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 qdSlide28

Once Start we should not stop HAARTSlide29

กรณี ถือศีลอดSlide30

How 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 yrSlide31

Viral Load and CD4 TestsSlide32

Virologic 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 Slide33
Slide34

Second-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/r

TDF/3TC +ATV/r

AfricaSA, TanzaniaFrench NIH

May 20132LADY450

TDF/FTC +LPV/rABC/ddI +LPV/rTDF/FTC +

DRV/rAfricaBurkina Faso, Cammaroon

, SenegalANRS12169

Sep 2013EARNEST1277

2NRTIs +LPV/rRAL +LPV/r

LPV/r mono

Africa5 countriesMRC, EDCTP

Dec 2013

www.clinicaltrials.gov (assessed 22 Apr 2012)Slide35

HIV-

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: 10.3851Slide36

SECOND-LINE resultsSlide37

SECOND-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-regimensSlide38

Options 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/3TCSlide39

boosted 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.Slide40

Ergotism 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 AEsSlide41

Standard doses of boosted protease inhibitors (bPIs

) associated with a high exposure in Asianvan der Lugt J, and Avinhingsanon A. Asian Biomedicine Feb 2009Slide42

Cost 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/yrSlide43

ATV/r: atazanavor/ritonavir, PI: protease inhibitor, HAART: highly active antiretroviral therapy, OD: once daily, TDF: tenofovir

Complete enrollment: Dec 2013, expected results by Jan 2015Slide44

Life 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 yearsSlide45

Date 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 cellsSlide46

Thailand: Age and gender distributionHIV/AIDS statistic, BOE, MOPH (data up to Nov 2011)

Aging

Future Trend

Male

FemaleSlide47

Reduced 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

4Slide48

Drug 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

Slide49

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 interactionNo 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

Slide50

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 Slide51

Cardiologist

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 physicianSlide52

Can we be the AIDS Free Generation?Slide53

Ending AIDS PolicyHow and

When?THAILAND

Petchsri

Sirinirund

Advisor on HIV/AIDS Policy and

Programme

Department of Disease Control, Thailand

ICAAP 11, 21 Nov 2013, BangkokSlide54

50% reduction

New InfectionIn 5 YearsEnd AIDSIn 20 yearsEnding AIDS Working Definition

New infection <1000/yrMTCT rate = 0

Target population treatment is well coverage Slide55

CD4 <350 will prevent

6000 new infectionAny CD4 level

Prevent additional11,000 new infectionSlide56

Treatment at CD4 <200Slide57
Slide58

Continuum of ART in the NAP, Thailand2012

73%78%79 %

ITT =55 %

OT = 89%

Median CD4 count = 120

Only 34% asymptomaticSlide59
Slide60

Thai Red Cross AIDS Research CenterSlide61

HIV-

NAT founded in 1996 Slide62

Can we be the AIDS Free Generation?Slide63

Let’s Have a BreakQ&A