Title: Antiretroviral Therapy in Year 2003
1Antiretroviral Therapy in Year 2003
- Kiat Ruxrungtham, M.D.
- Faculty of Medicine, Chulalongkorn University and
- Deputy Director, HIV-NAT,
- AIDS Research Centre, TRCS
- Bangkok, Thailand
2Topics
- Evidence based for rational antiretroviral
therapies - Antiretroviral agents
- Practice guidelines and reality
- Lessons and situations of HIV treatment in a SE
Asian country Thailand - State-of-the-Art managing HIV infection
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4??????????? HIV/AIDS ???????
East Europe and Central Asia 1.2 million
W. Europe 570,000
N. America 980,000
N. Africa Middle East 550,000
East Asia and Pacific 1.2 million
Caribbean 440,000
South and SE Asia 6 million
Latin America 1.5 million
Sub-Saharan Africa 29.4 million
Australia and New Zealand 15,000
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6?????????????????? HIV/AIDS ?? 2545
- ?????????????????? (The Thai Working Group)
- ?????????????????? 1,033,500 ??
- ????????????? 398,400 ??
- ?????????????? 635,100 ??
- ???????????? 40,800 ??
- ??????????????????? 53,400 ??
- www.aidsthai.org
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- ???? 2545 ?????????????? 23,700 ??
www.aidsthai.org
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HIV ?????
10What have we learned in the past decades ?in HIV
Medicine
11Natural Course of HIV Infection and Common OIs
1000
Asymptomatic
900
Relative level of Plasma HIV-RNA
Plasma HIV-RNA
800
700
TB
CD4 T cells
CD4 cell Count
600
Acute HIV infection syndrome
500
HZV
400
300
OHL
200
OC
PPE
PCP
100
TB
CM
CMV, MAC
0
0 1 2 3 4 5 1 2 3
4 5 6 7 8 9 10
11
Months
Years After HIV Infection
12Viral Dynamics of HIV Infection
Finzi D, Siliciano R. Cells 1998
Free virion
Productively infected CD4 T lymphoblasts
Resting CD4 T cells with unintegrated HIV-1 DNA
Virion on FDC
Resting Memory CD4 T cells with integrated HIV-1
DNA 43 months
Infected macrophage
0 30 60 90 120 ? Half-life (days)
HIV-NAT
13(No Transcript)
14HIV-1 dynamics after interruption of HAART
Davey RT, et al PNAS 1999 9615109-14 Long-term
suppression of HIV-1 by HAART does not confer on
the host the ability to ultimately control viral
replication once drug therapy is withdrawn. How
to deplete HIV virus from sequestered sites
throughout the body ?
Off HAART
15VL lt 50 vs lt50 and The Risk of Resistance
- Low-level viremia lt50 copies/mL may represent
less of a concern regarding impending drug
failure of current HAART regimens. (Hermankova
JAMA 2001) - Intermittent viremia (gt50 copies/ml) occurred
frequently was not associated with virologic
failure (gt200 copies/ml) in patients receiving
initial combination therapy of AZT/3TC/IDV (ACTG
343 and Merck 035). (Havlir JAMA 2001)
16Current Goal of HAART
CD4 T-cells
Relative Levels
Plasma HIV Viremia
Long term durability ?
Limit of detection
Months
Years After HIV Infection
Acute HIV infection Symptom
17How many antiretrovirals do we currently have ?
18Major Targets of Antiretroviral Agents
Protease Inhibitors SQV,RTV, IDV, NFV, AMV,
LPV/rtv
RT Inhibitors NRTI AZT, ddI, ddC, d4T, 3TC,
ABC NNRTI NVP, DLV, EFV NTRTI Tenofovir
6
ds DNA
Integrase
Genomic RNA
vpr
Protease
HIV
5
DNA
3
Proviral DNA
2
RT
1
Transcription
4
RNA
mRNA
Polyprotein Protein
Spliced mRNA
Entry Inhibitors CXCR4 AMD3100, T22 CCR5 SCH-C,
D TAK779 Fusion gp41 T20
19Antiretroviral Agents 2002 (16 ARVs)
- Nucleoside RT Inhibitors (NRTIs) 6
- AZT, ddI, ddC, d4T, 3TC, abacavir (ABC)
- Non-nucleoside RT Inhibitors (NNRTI) 3
- nevirapine, delaverdine, efavirenz
- Nucleotide RT Inhibitors 1
- Tenofovir
- Protease Inhibitors 6
- Saquinavir (HG, SG), ritonavir, indinavir,
nelfinavir, amprenavir, lopinavir/r
20When to start treating HIV-infected Patients
- Parameter U.S. HHS BHIVA Thai Feb 2002 Mar
2001 May 2002 - Symptomatic HIV treat treat treat
- CD4 counts lt200-350a lt200 lt200
- Plasma VL gt55,000b gt30,000c gt100,000c
a200-350 offer HAART to the patient bbDNA assay
v3.0 or RT-PCR cconsider individually and close
FU
HIV-NAT
21When to Start Therapy ?Do we need to Start Very
Early ?
- Vancouver Study
- Baseline CD4 50-200 vs lt50 cells/mm3
- Managed to at least 95 adherence
- showed a comparable response
- Thus, the answer is it is not necessary
- However, the trade-off of treating very advanced
patients is the increase of toxicity
Julio Montaner IAS 2001, Bueno Ares
22When to Start Therapy ?When is too late to be
treated ?
- A Thai Study Ausda Viphakul et al 2002
- 50 patients with cryptococcosis treated for gt4
weeks - Median Baseline CD417, VL5.1 log10/ml
- Triple ARV d4T/3TC/EFV
- Results At 24 week, 90 showed VL lt50
copies/ml, median increase in CD4 90
BKK Symposium 2002 and Poster Abs the XIV IAS,
Barcelona 2002
23Principles of ARV Combinations
Triple Antiretroviral Treatment 2 Nucleoside RT
Inhibitors NNRTI (EFV) /Boosted PIs
Thymidine Analog
Non-Thymidine Analog
NNRTI (EFV, NVPa) or Boosted PIs or ABCa (NRTI)
3TCa ddIa (ddC)
EFV IDV/rtv SQV/rtv Lopinavir/rtv or NVPb,
or ABCb
AZT d4T
ddI3TCa
Aim of Rx Maximal HIV viral suppression
for the longest duration
a3TC/ddI as a back bone is also currently
recommended bNVP, ABC may not effective in
patients with VLgt100,000/ml
24Pill Load, Frequency and Adherence
25HAART Regimens and Pill Burden
- HAART Pill load per day
- GPOvir (d4T/3TC/NVP) 1 bid 2
- Trizivir (AZT/3TC/ABC) 1 bid 2
- Combivir/NVP 22 4
- Combivir/EFV 23 5
- d4T/ddI-EC/NVP 212 5
- d4T/ddI-EC/EFV 213 6
- Combivir/IDV/rtv 242 8
- AZT/ddI/NVP 432 9
- AZT/ddI/EFV 433 10
- Combivir/SQV/rtv 281 11
- AZT/ddI/NFV 4310 17
26Simple Dosing for Better Adherence
- Once Daily Dosing
- Long plasma half-life or long-intracellular
half-life - NRTIs ddI (25-40 hr), 3TC (12 hr, needs more
clinical support) - NNRTIs
- Nevirapine (40 hr)
- Efavirenz (40-55 hr)
- Boosted PIs (needs more long-term data)
- SQV/RTV 1600/100
- IDV/RTV 1200/100
27New Formulations to Improve Adherence
- ddI EC (enteric coated) for 1 OD, ac
- d4T SR (slow released) for OD
- AZT/3TC/ABC fixed dose combination (TrizivirTM)
for bid - Nelfinavir 625 mg/tab for 2 bid
- Efavirenz 600 mg/tab for 1 OD
28Class specific Adverse effects
- NRTIs Mitochondrial toxicity
- NNRTIs Skin rash
- PIs
- Fat redistribution /Lipodystrophy, buffalo hump,
truncal obesity - Hyperlipidemia
- Hyperglycemia / diabetes mellitus (Insulin
resistance) - Increase bleeding episodes in patients with
hemophilia - Osteoporosis
29State-of-the-ArtManaging HIV Infection
30Clinical and Laboratory Evaluations in HIV
Infection
31Clinical Evaluation of HIV Infection
- Clinical staging
- At what stage the patient is ?
- History taking
- Physical examination
- Lab. Investigation
- Immunological staging CD4 count
- Virological staging plasma HIV-RNA
32History Taking
- 1. Estimate the duration of HIV infection
- Timing of HIV seroconversion ? Or when was the
first HIV serodiagnosis - 2. Past medical illnesses
- HZV
- Constitutional symptoms
- chronic fever, wt. Loss, diarrhea
- Oral candidiasis, OHL
- Pulmonary infection PCP, TB
- CNS infection Cryptococcosis
- Eye CMV
33Physical examination
- General fever, thin, cachexic, acutely or
chronically ill - Oral cavity OHL, OC, ulcer, HSV
- Lymph nodes size, symmetrical, appearance
- Skin PPE, seborrheic dermatitis, papulonecrotic
lesions (disseminated mycosis) - Lung dypnea, cough
- CNS headachcevomiting, focal sign
- Eyes retinitis (CMV)
- Abdomen mass (L.N.), organomegaly
34Laboratory Evaluation
- General assessment
- CBC, LFT (SGOT/SGPT), amylase, Cr
- Immunological assessment
- CD4 count
- Virological assesment
- plasma HIV-RNA
- Assessment for latent or reactivated infection
esp., TB and Ois - VDRL, chest X-ray, tuberculin test, others
cryptococcal Ag, toxoplasma Ab etc.
35CD4 T cell count
- CD4 count Risk of OI in 3 yrs
- gt500 very low
- 200-500 Intermediate risk of minor symptoms
shingles, OHL, OC, contitutional symptoms - lt200 High risk of PCP, disseminated TB,
crytosporidiosis, isosporosis - lt100 High risk of cryptococcosis,
penicillosis - lt70 High risk of CMV, MAC
Crowe 1991, Masur 1989, Ruxrungtham 1996
36How to Monitor ART
1. Clinical AIDS-related illness 2. CD4 cell
counts lt200 PCP prophylaxis lt100
Crytococcal prophylaxis lt70 CMV , MAC
prophylaxis (Costly !!) 3. Viral load (Plasma
HIV-RNA) 4. Adherence 5. Potential drug
interaction 6. Quality of life
37CD4 T cell count
- Four purposes of CD4 T cell counts
- To stage HIV disease
- For differential diagnosis of current complaint
or symptoms - To consider of OI prophylaxis
- To make decision of initiating ART
Bartlett 1998
CHULA HIV-NAT
38CD4 T cell count
- Three-steps of absolute CD4 T cell count
- Obtained value (s)
- 1. CBC Total WBC
- 2. Differential count lymphocytes,
calculated total lymphocyte count (TLC) - 3. CD4/CD3 FACS CD4 T cell
- calculated absolute number of CD4
count)
CDC 1997
CHULA HIV-NAT
39CD4 T cell count
- Total lymphocyte count lymphocytes x WBC
- (TLC) 100
- Absolute CD4 T cell CD4 T cell x TLC
- 100
-
CHULA HIV-NAT
40Normal CD4 T cell counts
- U.S. values 800-1050 cells/mm3
- Thais 428-1404 cells/mm3
- 840 /- 240 cells/mm3 or
- 730 /- 190 cells/mm3 or
- 910/-300 cells/mm3
Webster 1996, Vithayasai 1997
CHULA HIV-NAT
41Viral Load Plasma HIV-1 RNA
Company Test Sensitivity Dynamic Range
(copies/ml) (copies/ml)
Roche AmplicorTM lt400 400 to
750,000 Ultrasens lt50 50 to
75,000 Bayer Quantiplex v3.0 lt50 50 to
500,000 Organon Nuclisens v1.0 lt500
400 to 10,000,000 Nuclisnes v2.0
lt50
CHULA HIV-NAT
42Managing HIV-infection in Thailand
- Clinical Assessment Clinical staging
- Financial Assessment
- Affordability to ART, monitoring assays
- Immunological Assessment
- CD4 count (gtUSD 10)
- Virological Assessment
- Plasma HIV RNA (gtUSD 80)
CHULA HIV-NAT
43Common Infections among Thai AIDS Patients
Source CDC, MOPH, Thailand 1998
44Primary Prophylaxis of OIs
CD4 Type of OI Primary Prophylaxis lt200 PCP
Cotrimoxazole 2 tab OD lt100 Cryptococcosis
Fluconazole 400 mg weekly lt70 CMV Oral
ganciclovir ?!? lt50 MAC Azithromycin
1000-1250 mg once weekly
The National HIV/AIDS treatment guidelines 2002
CHULA MRC HIV-NAT
45When to start treating HIV-infected Patients
- Parameter U.S. HHS BHIVA Thai Feb 2002 Mar
2001 May 2002 - Symptomatic HIV treat treat treat
- CD4 counts lt200-350a lt200 lt200
- Plasma VL gt55,000b gt30,000c gt100,000c
a200-350 offer HAART to the patient bbDNA assay
v3.0 or RT-PCR cconsider individually and close
FU
HIV-NAT
46Practice Guidelines Realityin HAART
Implementationin Thailand
47HIV Epidemiology in Thailand 1989-2000
Conscript
ANC
Blood donor
Source Sentinel Serosurveillance, Division of
Epidemiology, Ministry of Public Health. Remark
Switching from bi-annually (June and
December) to annually in June since 1995
Conscript data in November of each
year since 1995 were not shown here
48The Estimation by Division of Epidemiology, CDC,
MoPH, Thailand
- As of Dec 2001
- 975,000 Thais living with HIV/AIDS
- 45,000 Newly infected/year
- Infection rate in adult 1 50 (2)
49Access to Antiretroviral therapy in Thailand
- Supported by MoPH via some special access to care
programs - Co-payment system supported by the government
- Pay by their own
- Participating in clinical trials
50ART in Thailand
- 1992 AZT Monotherapy (MoPH supplied)
- 1995 AZT/ddI or AZT/ddC (N1,500)
- 2000-2002 HAART as part of an expanded
comprehensive care package - The first phase of the National Access to Care
program (ATC) was initiated selecting 109
hospitals (N2000 in year 2000, and N10,000 in
year 2002) - By the next 3 years (2005) HAART is aimed to be
included in the Nation Universal Health Care
package by the Government
Thai CDC, MoPH Ying-Ru Low. WHO 2002
51ARV Access in 2002-2003 MOPH, Thailand
- Clinical research network
- Expand access to care
- Global funds
- ??????
- 90 ??????? 3000 ??
- 160 ??????? 7400 ??
- 320 ??????? 12000 ??
- 50 ??????? 2000 ??
- ??? 24000 ??
52 ARVs Prices, Prices, Prices, Prices, price
- Ways to bring the ARV cost down
- competition, bulk purchasing, and
- generic manufacturing of AZT, d4T, ddI, 3TC,
AZT/3TC combination, nevirapine, d4T/3TC/NVP by
the Government Pharmaceutical Organization (GPO) - Prices for ARVs decreased substantially over the
last years
53HAART Affordability The Gap is Getting Closer
- HAART Year Cost Baht/month
- 2NRTIsPI lt2000 gt25,000
- 2NRTIsboosted PIs 2001 13,000
- 2NRTIsNNRTI lt2000 15,000
- Early 2001 13,000
- Mid 2001 lt6,000
- Late 2001 2,300
- Mid 2002 1,200
(lt30 US/month)
Generic SQV will be available by the end of 2003
54STACCATO
Clinical Trials and Access to ARVs
009
D4T ER
ESPRIT scIL-2
HIV-NAT Studies gt1,500 patients on treatment
2NN
ACTT 002
007
005
004 scIL-2 Vanguard
003.2
003.1
003
002.2 extension
002.2
001.4
002.1
001.3
002
001.2
001.1
001
Mid 1996 1997 1998
1999 2000 2001 2002
55Access to Laboratory MonitoringHow to make it
possible ?
- The Ministry of University Affair, Thailand has
recently allocated a Research Fund to initiate
RD researches in - Non-flowcytometer-based CD4 count testing
- In house plasma HIV-1 RNA assays
- The Thai CDC, MoPH is also funding a group of
investigators to evaluate the boosted HIV-1 p24
antigen assay to see if it is reliable as a HAART
monitoring test
56The Lessons of Dual Therapy in Thailand
57Summary of HIV-NAT 2 NRTI Trials
Baseline HIV-NAT 001 002 003
Mean CD4 340 255 349 Range CD4
100-500 150-350 100-500 Mean VL log10
4.7 4.3 3.83 N 58 63 53
58Summary of HIV-NAT Dual NRTI Trials
Baseline HIV-NAT 001 002 003
Mean CD4 340 255 349 Range CD4
100-500 150-350 100-500 Mean VL log10
4.7 4.3 3.83 Sample size 58 63 53
59HIV-NAT Dual NRTI Treated Cohorts
gt500 /mL
60NRTI Resistant Mutations
IAS-USA update, Topic in Med Dec 2001
151
MDR
151 complex
69 insertion
69S
41
67 70
210, 215, 219
NAMs
AZT
d4T
61Nucleoside Resistance in HIV-1 Subtype A/E
HIV-NAT cohorts
In patients with VLgt1000 at least 48 weeks
(n17)
(n11)
(n5)
(n9)
Sirivichayakul S et al 2001
62Nucleoside Resistance
AZT/ddI Failure patients with VLgt1000 treated
for median of 2 years (0.5-6 years), N45
Sirivichayakul S et al 2001
63NNRTI Resistant Mutations
103N
188L
181C
64HIV-NAT 001.1 Virological Results
AZT/ddC pretreated patients (N95) ITT Analysis
86
70
p0.098
65HIV-NAT 005 Virological resultsIDV 800 tid vs
IDV/rtv 800/100 bid
AZT/ddI or AZT/ddC experienced patients
ITT analysis
pns
66Treatment Options after Dual NRTIs Failure
- Two new classes combination
- EFV plus boosted PIs
- HIV-NAT 009 study preliminary results 85 have
VLlt50 - AZT/3TC plus boosted PIs
67Treatment Options after the first triple failure
??
- 2NRTsNNRTI failure
- 2NRTIs boosted PI failure
- A big challenge !!!
- Less options
- Much more costly
68Adherence is one of the most important keys in
the Long-term Durability in HAART
69High HAART Virologic Failure in Clinical Practice
!!!
- According to a meta-analysis of 18 trials (J.
Bartlett 2000) - In naïve patients, after 24 weeks of HAART (PI or
NNRTI), durable viral suppression (VLlt50
copies/ml) was only 50 - In a large urban clinic setting, only 38 of
HAART treating patients showed undetectable HIV
RNA (Lucas et al 2000)
70Adherence issues in HAART ?
- Patient and doctor attitude and education on
HIV medicine - Simplified regimen
- Timing of dosing bid should prescribed as q 12
hr - Missed dose as minimal as possible or none(lt1 of
20) - Delayed-dosing no gt 30 minutes
- Meal restriction only ddI needs AC
- IDV needs high fluid intake (water gt2 L/day)
- Drug interaction buffered ddI vs IDV, Rifampin
vs PI, NNRTIs
CHULA MRC
71A case study SSon HAART (gt5 years)
CD4 count (cells/mm3)
Plasma HIV-RNA (copies/ml)
AZT/ddI/NFV
Lipodystrophy
AZT/ddI/EFV
VL lt50
CHULA MRC
72TW Male, on HAART (gt3 years)
CD4 count (cells/mm3)
Plasma HIV-RNA (copies/ml)
AZT/3TC/NFV
AZT/3TC/EFV
VL lt50
CHULA MRC
73If HAART is available but the monitoring is
limited-No CD4, no viral loadCan we treat a
patients ?When to start ?How to monitor ?
74Long-term Efficacy of HAART No Magic Bullet, No
miracle
- Good attitude, knowledgeable doctors
- Simplified and potent HAART
- Proper monitoring
- Committed patients
Adherence adherence adherence
Adherence adherence adherence
Good adherence to HAART
Ultimate Goal Long-term durable viral
suppression Normalized CD4 cell counts
CHULA MRC
75Acknowledgments Key Supporters
- Faculty of Medicine, Chula MRC, Chulalongkorn
University - AIDS Division, MOPH, Thailand NIAID, NIH, USA
- H. Clifford Lane
- Government Pharmaceutical Organization (GPO)
- Bristol-Myers Squibb Company
- Bristol-Myers Squibb (Thailand)
- Jim Sapirstein
- Niwat Montreewasuwat
- Urampa Kattinanon
- Siriphen Chunharas
- Boehringer-Ingelheim
- GlaxoWellcome RD
- GlaxoWellcome (Thailand) Ltd.
- Dorothy Bray
- Sunettra Chinapa
- Wipaporn Rungsiyapornrat
- Merck Co, Inc., MSD (Thailand)
- Michael Stek, Chris Tan, Suchai, Decha, Sunthinee
- N V Organon
- Roche
- Guenther Froster
- Aeumporn Srigritsanapol
- Roche Diagnostics, Molecular System
76Acknowledgements
- HIV-NAT DSMB
- Scott Hammer, Columbia University, New York
- Surapol Suwannagool, Siriraj Hospital, Bangkok
- Piyalamporn Havanond, Chulalongkorn University,
Bangkok - HIV-NAT (Bangkok, Amsterdam, Sydney)
- Praphan Phanuphak Mark Boyd Gerrit-Jan
Weverling - Joep M.A. Lange Nongluk Yimsuan Nadine Pakker
- David A. Cooper Wassana Worarien Richard
Hoetelmans - Kiat Ruxrungtham Chowalit Phadungphon Matthew
Law - Chris Duncombe Joedjan Saetiaw Sean Emery
- Chaiwat Ungsedhapand Jeerakan Janhom Anja
Schreijer - Eugene Kroon Sasiwimol Ubolyam David Burger
- Chokechai Rongkavilit Sunee Sirivichayakul Elly
Hassink - Jintanat Ananworanich Apicha Mahanontharit Preey
aporn Srasuebkul - Mana Khongphattanayothin Supraeea
Buranapraditkul Rolf P.G. van Heeswijk - Teshinee Chuenyam Somboon Nookhai
- Somsong Teeratakulpisarn Theeradej Boonmangum
- Jettanong Klawsongkram Remko van Leeuwen
All the participants
77Acknowledgements
Collaborating sites Siriraj Hospital, Mahidol
University Surapol Suwanagool and
colleagues Srinakarind Hospital, Khon Khan
University Ploenchan Chetchokesakd and
colleagues Chonburi Regional Hospital Chureeratta
na Bowonwattnawong and colleagues Chiang Rai
Regional Hospital Patcharee Kantipong and
colleagues ACTT002 participating Hospitals (16
sites)