Thai hiv guideline

New Thai HIV Treatment New Thai HIV Treatment Guidelines 2010Guidelines 2010

Wichai Techasathit, MD., MPH.Wichai Techasathit, MD., MPH.Faculty of Medicine Siriraj HospitalFaculty of Medicine Siriraj Hospital

Mahidol University, Bangkok, ThailandMahidol University, Bangkok, Thailand

164187

102

181

200192

87 239

163

97134

179

97100125

12386

122103 53

157 20695

72

Review of data from 2003-2005 from 176 sites in 42 countries (N = 33,008)

Since 2000, CD4+ cell count at initiation in developed countries stable at approximately 150-200 cells/mm3, increasing in sub-Saharan Africa from 50-100 cells/mm3

When is Antiretroviral Therapy Started?

Egger M, et al. CROI 2007. Abstract 62.

Development of Antiretroviral Treatment in Thailand

Before 1992 Treatment of common OI without ARV

1992 AZT mono-therapy

1995 Dual therapy with AZT + ddI, AZT+3TC

1997 Triple therapy through HIV Clinical Research Network

2000 Access to Care (ATC) with 8 pre-assigned regimens

2004 National Access to Antiretroviral Program for PHA (NAPHA)

2004 ARV program by Social Security Office (SSO)

2006 National AIDS Program (NAP) by National Health Security Office (NHSO): ART Benefit Package in Universal Coverage

Thai MOPH Guideline 2007 –

When to Treatอาการทางคลินิก ระดับ CD4

(เซลล/

ลบ.มม.)คําแนะนํา

มีความเจ็บปวยของ ระยะเอดส

(AIDS-defining illness)*

เทาใดก็ตาม เริ่มยาตานเอชไอวี

มีอาการ** เทาใดก็ตาม เริ่มยาตานเอชไอวี

ไมมีอาการ < 200 เริ่มยาตานเอชไอวี

ไมมีอาการ 200

–

350 ยังไมเริ่มยาตานเอชไอวีใหติดตามอาการและตรวจระดับ

CD4 ทุก 3 เดือน

ไมมีอาการ > 350 ยังไมเริ่มยาตานเอชไอวีใหติดตามอาการและตรวจระดับ

CD4 ทุก 6 เดือน

แนวทางการดูแลรักษาผูติดเชื้อเอช ไอ ว ีและผูปวยเอดสในประเทศไทยป พ.ศ.

2549/50

กรมควบคุมโรค กระทรวงสาธารณสุข สมาคมโรคเอดสแหงประเทศไทย สมาคมโรคติดเชื้อในเด็ก

Thai Guideline for ARV 2006-20072

NRTIs NNRTI หรอื PI

1st

line AZT+3TCd4T+3TC

NVPEFVIDV/RTV

2nd

line AZT+ddIddI+3TCTDF+3TCABC+3TC

SQV/RTVNFVATV+RTVLPV/RTV

National Guidelines on HIV/AIDS Diagnosis and Treatment: Thailand 2006-2007

Preferred and Alternative regimens for Initiation of ART -

TAS 2008

J Med Assoc Thai 2008;91(12):1925-36

National Health Security Office (NHSO or NAP)

Effective 1 April 2007

Social Security Office(SSO)

Effective 1 January 2007

1.

Group Ad4T+3TC+NVP (GPOvirS)d4T+3TC+EFVAZT+3TC+NVP(GPOvirZ)AZT+3TC+EFV

2. Group Bd4T+3TC+IDV/rAZT+3TC+IDV/r

3. Group CddI+3TC or TDF+3TC in cases of lipoatrophy (Expert approval)

1.

Basic regimensd4T+3TC+NVPAZT+3TC+NVP

2.

Alternative regimensd4T(AZT)+3TC+EFVd4T(AZT)+3TC+IDV/r

If other regimens neededConsultation for permission

ARV Regimens: NHSO vs. SSO



4.

Group D (After expert approval)

Boosted PI+OBR- d4T+3TC- ddI+3TC- AZT+3TC- AZT+ddI- AZT+TDF- TDF+3TC

Boosted PIs+NVP (or EFV)in only NRTIs resistance

Boosted PIs+AZT+3TC+TDFin NNRTIs & multi NRTIs resistance: Q151M &/or T69Si&/or TAM>4

3.

2nd line regimens(After expert approval)LPV/r+OBRATV/r+OBR (not available)

- ddI+3TC- AZT+3TC- AZT+ddI- AZT+TDF- TDF+3TC



Choices of boosted-PIs1. IDV/r2. LPV/r3. ATV/r

AIDS ExpertsRegional AIDS Consultants; RACBangkok AIDS Consultants; BAC

Choices of boosted-PIs1. IDV/r2. LPV/r3. ATV/r (not available)

AIDS ExpertsGroup of AIDS Consultants

assigned by SSO



Monitoring1. CD4 x 2 times/yr2. VL x 1 time/yr3. Drug resistance x 1 time/yr4. CBC, FBS, Cr, TG, TC, SGPT x

2 times/yr

“To do genotypic drug resistance, VL must >2,000 copies/ml”

Monitoring1. CD4 x 2 times/yr2. VL x 2 time/yr3. Drug resistance x 1 time/yr

“To do genotypic drug resistance, VL should >1,000 copies/ml”

Who is still taking d4T?

28.4

78.6

47.6

77.8

45.8

62.7

7.3

24.0

4.7

8.98.6

25.9

5.26.1

11.2

3.5

11.10

6.01.8 1.3

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

80.0%

90.0%

Cote d'Ivoire Mozambique South Africa Tanzania Zambia

d4T-3TC-NVP d4T-3TC-EFV d4T-FTC-EFVd4T-FTC-NVPAZT-3TC-NVPAZT-3TC-EFVTDF-FTC-EFVTDF-FTC-NVPd4T-3TC-LPV/rOther

1.30.14.6

0.0020.1 0.22.1

9.1

4.6

0.1

Marlink R et al , IAC 2008 (WEAXO106)

Westreich DJ, et al, Tuberculosis treatment and risk of stavudine substitution in first-line antiretroviral therapy, Clin Infect Dis. 2009 Jun 1;48(11):1617-23

Cumulative Patients on 1st and 2nd Line ARV

0

20000

40000

60000

80000

100000

120000

140000

160000

Dec.06

Mar.0

7 Ju

n.07 Sep.0

7Dec.0

7 M

ar.08

Jun.08

Sep.08

Dec.08

Mar.0

9 Ju

n.09 Sep.0

9 Dec.0

9 M

ar.10

1stlin

e re

gim

ens

2ndlin

e re

gim

ens

135,809

6,470

Situation in National AIDS Program, Thailand.

2nd line regimens

4.54%

Data at 7 Mar 2010National Health Security Office (NHSO) Thailand

NAP Data on ARV Regimens

Data at 14 JAN 2008

Not on ARV

Other regimens

Number of Symptomatic and Asymptomatic AIDS needing ART in Baseline Scenario (asymptomatics with CD4 < 200)

0

50,000

100,000

150,000

200,000

250,000

300,000

1990

1995

2000

2005

2010

2015

2020

2025

Not on ARTOn ART

2007 = 245,551 UC = 78,3652008 = 255,178 UC = 110,7702009 = 259,948 UC = 136,7042010 = 260,388 UC = 149,590

CoverageCoverage

ARV in ThailandARV in Thailand Before and After Universal Coverage (UC)

0

50,000

100,000

150,000

200,000

250,000

300,000

2004 2005 2006 2007 2008 2009

ARV Need Current Receiving

32.5 %

42.5 %

51.5 %56.4 %

67.1 %

77.8 %

ARV-UC

Source:

UNGASS 2009

When to Start Antiretroviral Therapy

200200

> 500> 500< 200< 200

350350

CD4

Late clinical stagesLate clinical stages Early Clinical StagesEarly Clinical Stages

Schechter, 2004 (JID 2004;190:1043-1045)

High Viral loadHigh Viral loadAny viral loadAny viral load

CD4+ Count Response Based on Baseline CD4+ Count

• Magnitude of CD4+ increase greatest if therapy started at low CD4+ counts, but greater likelihood of CD4+ count normalization with earlier therapy

Keruly J, et al. CROI 2006. Abstract 529. Gras L, et al. CROI 2006. Abstract 530.

Johns Hopkins HIV Clinical Cohort

Mea

n C

D4+

Cou

nt

(cel

ls/m

m3 )

1000

800

600

400

200

00 48 96 144 192 240 288 336

ATHENA National Cohort

0 1 2 3 4 5

200

400

600

800

0

1000

Years on HAART Weeks From Starting HAART

Clinical Outcome Improved by Starting Therapy at Higher CD4+ Cell Count

• Timing of antiretroviral initiation in treatment-naive subjects (N = 10,885) in Antiretroviral Cohort Collaboration

• HR for progression to AIDS or death by CD4+ cell count at initiation of therapy

– < 200 vs 201-350 cells/mm3

HR: 2.93 (95% CI: 2.41-3.57) – < 350 vs 351-500 cells/mm3

HR: 1.26 (95% CI: 0.94-1.68)• Results suggest a lower risk of

disease progression/death when starting between 351-500 cells/mm3

Cumulative Probability of AIDS/Death by CD4+ Cell Count at HAART Initiation

Years Since Initiation of HAART1 2 3 4 5

0.00

0.02

0.04

0.06

0.08

0.10

0.12

Prob

abili

ty o

f AID

S or

Dea

th

Sterne J, et al. CROI 2006. Abstract 525.

101-200 cells/mm3

201-350 cells/mm3

351-500 cells/mm3

IAS-USA Guidelines: When to StartYear Recommendation

to Begin Immediate Therapy

Recommendation to Consider Immediate Therapy

Recommendation to Delay Therapy

2006 • Active AIDS• No history of

active AIDS, but CD4+ cell count ≤

200 cells/mm3

• No history of active AIDS, but CD4+ cell count from 200-350 cells/mm3

• CD4+ cell count > 350 cells/mm3

but rapid CD4+ cell count decline, HIV-1 RNA > 100,000 copies/mL, CVD risk factors, other non-AIDS risk factors

• CD4+ cell count ≥

350 cells/mm3

2008 • Active AIDS• No history of

active AIDS, but CD4+ cell count < 350 cells/mm3


350 cells/mm3

but rapid CD4+ cell count decline, HIV-1 RNA > 100,000 copies/mL, CVD risk factors, other non-AIDS risk factors


350 cells/mm3

Hammer SM, et al. JAMA. 2008;300:555-570.

DHHS Dec 2009 Guidelines: When to Start Treatment

* Severe symptoms = unexplained fever or diarrhea > 2-4 wks, oral candidiasis, or > 10% unexplained weight loss.

Clinical Category CD4+ Cell Count

Plasma HIV-1 RNA

General Guidelines

AIDS-defining illness or severe symptoms* (AI)

Any value Any value Treat

Asymptomatic (AI) < 350 Any value Treat

Asymptomatic (A/B-II) 350-500 Any value 55% of panel members voted for strong recommendation (A)45% of panel members voted for moderate recommendation (B)

Asymptomatic (B/C-III) > 500 Any value 50% of panel members favor starting ART (B)50% of panel members view treatment is optional (C)

Pregnancy (AI)HIV associated

nephropathy (AII)HBV co-infection when

HBV treatment is indicated (AIII)

Any value Any value Treat

DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Dec 1, 2009

Half of DHHS Panel Recommended ART Initiation at CD4+ Cell Count > 500 c/mm3

Arguments in Favor Arguments Against• Cohort data showing survival

benefit• Available data do not definitively

establish benefit of ART in all patients with CD4+ cell count > 500 cells/mm3

• Untreated HIV infection may be associated with higher risk of non-AIDS conditions

• Benefits of earlier initiation may be outweighed by

• Risks of short- or long-term drug-related adverse events

• Risk of nonadherence in asymptomatic patients

• Potential for development of drug resistance

• Availability of newer regimens with improved efficacy, convenience, and tolerability

• Growing evidence that treatment reduces HIV transmission

DHHS. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.

December 2009 DHHS Guidelines: Preferred Initial Regimens

Preferred regimens: those with optimal and durable efficacy, favorable tolerability and toxicity profile, and ease of use NNRTI based • EFV/TDF/FTCBoosted PI based

• ATV/RTV + TDF/FTC• DRV/RTV + TDF/FTC

INSTI based • RAL + TDF/FTC

DHHS. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.

NRTI Choice: The Major Factor Driving Lipoatrophy Risk

Highest Risk

Intermediate Risk

Lowest Risk Unknown

d4T ZDV 3TC ddI + 3TCd4T + ddI ABC

FTCTDF

ART and Lipoatrophy

Study 934 Median Total Limb Fat (Q1, Q3) Through Week 144 for Patients with Week 48 Data

7.4*

6.0*

‡For change from week 48 within arm

*P = 0.0350

2

4

6

8

10

12

14

0

Kilo

gram

s

48 96 144

AZT+3TCTDF+FTC

FTC+TDF+EFVAZT+3TC+EFV

†P < 0.001

8.1†

5.5†

4944

‡P < 0.001

8.3†‡

4.9†‡

4838

5149

Weeks

Data on file, Gilead Sciences.

ACTG 5142: Lipoatrophy at Week 96

Haubrich R, et al. CROI 2007. Abstract 38.

Lipoatrophy defined as > 20% loss of extremity fat by DEXA

NRTI-Containing Regimens

EFV + 2 NRTIs

LPV/RTV + 2 NRTIs

EFV + LPV/RTV

17

Overall TDF

612

d4T

33

51

ZDV

40

16

0

15

30

45

60

9

32

Patie

nts

With

Lip

oatr

ophy

(%)

ACTG 5142: Drug-Associated Risk for Lipoatrophy

Haubrich R, et al. CROI 2007. Abstract 38.

Drug-Associated Risk for Lipoatrophy at Week 96 (Logistic Regression)*

Factor OR (95% CI) P ValueEFV vs LPV/RTV 2.7 (1.5-4.6) < .001d4T vs ZDV 1.9 (1.1-3.5) .029TDF vs ZDV 0.24 (0.12-0.50) < .001

*Excludes NRTI-sparing arm.

Study 903E: Patients Switching From d4T to TDF Mean (95% Cl) Total Limb Fat –

Years 2-6

8.8

1 2 3 4 5 6Yearn = 69 69 65 61 58n = 74 74 74 71 68

P=0.04

Mea

n Li

mb

Fat i

n kg

8.28.08.18.0

4.6 5.05.5 5.8

P<0.001

0

2

4

6

8

10

TDF+3TC+EFV

d4T+3TC+EFV

5.0

Cassetti I. HIV8; 2006; Glasgow, UK. Poster P152. Data on file, Gilead Sciences.

Madruga JVR. HIV8, 2006 Glasgow, UK. Poster P120.

NRTIs: Lipid Changes From Baseline in Recent Prospective Clinical Trials

Study and Drugs Compared

TC, mg/dL

TG, mg/dL Conclusion

GS 934 (144 wks)[1]

ZDV/3TC ↑

TC (P = .005) and TG (P = .047) more than TDF + FTC• EFV + TDF + FTC +24 +4

• EFV + ZDV/3TC +36 +36SWEET (24 wks)[2]

ZDV/3TC ↑

TC (P = .008) and TG (P < .001) more than TDF/FTC• TDF/FTC -13 -22

• ZDV/3TC -1 +22BICOMBO (48 wks)[3] ABC/3TC ↑

TC (P = .001), HDL (P < .0001), LDL (P < .0001), and

TG (P = .01) more than TDF/FTC

• ABC/3TC +12 +0

• TDF/FTC -9 -16

RAVE (48 wks)[4]

ABC ↑

TC (P < .0001) more than TDF• TDF -19.3 -26.6

• ABC +7.7 +8.9

1. Arribas JR, et al. IAS 2007. Abstract WEPEB029. 2. Moyle G, et al. IAS 2007. Abstract WEPEB028. 3. Martinez E, et al. IAS 2007. Abstract WESS102. 4. Moyle GJ, et al. ICAAC. Abstract H-340.

Draft Thai ART Guidelines 2010 (Adult 1)Clinical

Presentations

CD4

(cells/mm3)Recommendations

AIDS-defining illness Any Treat

HIV-related Symptomatic Any Treat

Asymptomatic <350 Treat

Asymptomatic >350Defer Rx, follow clinical status and CD4

every 6 months

Pregnancy AnyTreat, discontinue ARV after delivery if

pre-treat CD4 >350 cells/mm3

Bureau of AIDS,TB, and STIs and Thai AIDS Society (TAS)

Special consideration for ART initiation• HBV or HCV co-infection: any CD4 if treatment of HBV or HCV needed• Age >50: CD4 350-500 with at least one of these following conditions (DM, HT, Dyslipidemia)

Draft Thai ART Guidelines 2010 (Adult 2)

NRTIs

+

NNRTIs

or

(If can not

tolerate NNRTIs)

PIs

Preferred

EFV

NVP

Preferred

AZT + 3TC

TDF + 3TC/FTC

LPV/r

Alternative Alternative

ABC

+ 3TC

d4T + 3TC

ddI + 3TC

ATV/r

DRV/r

SQV/r


**In alphabetic order**

Draft d4T Phase-Out Plan 1. Patients on d4T or AZT with lipoatrophy

d4T or AZT TDF2. Patients on d4T without lipoatrophy

d4T AZT• 1st priority: patients with the longest

duration on d4T• If patients could not tolerate AZT or start

to develop lipoatrophy (after 6 months of AZT) then switch to TDF

**Viral load <50 before switching to TDF**

CD4

(cells/mm3)Regimen

Timing

Start After delivery

<350 AZT+3TC+LPV/r

(all q 12 hrs)

immediate Continue ARV(could be switched to NNRTI-based

regimens)

>350 AZT+3TC+LPV/r

(all q 12 hrs)

After 14 wks

gestation

Discontinue ARV

Draft Thai ART Guidelines 2010 (PMTCT)


Draft Thai ART Guidelines 2010 (Pediatric)

Age

<

1 ป Age

1-5 ป Age >

5 ป

Clinical Presentations Treat CDC category B, C

or

WHO stage 3, 4

CDC category B, C

or

WHO stage 3, 4

CD4 levels

%CD4 or absolute CD4 Treat %CD4

<25 CD4 <350cells/mm3


Case 140 year-old man was diagnosed with HIV in Dec 2001. No other

medical history is available.

CD4 VL

May 2002 43 - GPOvir (30)(d4T+3TC+NVP)

Jan 2003 14 -

Jun 2004 55 -

Nov 2004 13 -

Mar 2005 29 -

Case 1

CD4 VL

Sep 2005 29 25,631 Do nothing ???

Mar 2006 23 -

Oct 2006 17 -

May 2007 3 -

Jul 2007 - 27,000 Do nothing ???

40 year-old man was diagnosed with HIV in Dec 2001. No other medical history is available.

Case 1CD4 VL

Nov 2007 4 -

May 2008 74 - Lipoatrophy

Jun 2008 - 5,500 GPO (Z250)(AZT+3TC+NVP)

Nov 2008 20 - Anemia from AZT (Hb 8 gm)Switched to TDF then

Feb 2009 - 29,000 Genotypic drug resistance ???

M41L, K65R, M184V, T215Y, Y181C, G190A

Case 234 yrs male, IVDU, Dx HIV+ May 2002 presented with

Pulmonary TBCD4

VL

Sep 03 134Oct 03 - 82,742 Started GPOvirMay 04 289 -Mar 05 351 <50Dec 05 419 -Aug 06 357 33,700 Genotype

Feb 07 415 2,784Jul 07 358 12,367 Genotype

No Mutation

M41L, Q151M, M184V, T215Y, Y181C

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