Monitoring HIV Drug Resistance In Indonesia

1. MONITORING
HIV DRUG RESISTANCE
IN INDONESIA
National Working Group on HIV DR

2. I. LATAR BELAKANG (1)
 Indonesia adalah negara kepulauan yang luas dengan jumlah
penduduk 237 juta jiwa
 Kasus HIV pertama di temukan pada tahun 1980 di bali
 Peningkatan cepat terjadi tahun 1990-2010
 Pada tahun 2010

3. I. LATAR BELAKANG (2)
• Penularan utama HIV:
sexual dan jarum suntik
(IDUs)
•ART scale up, dimulai
tahun 2004-2005,
•ART center: 182 sites di
123 districts dari 440 and
32 provinsi dari 33
• Kemenkes RI Inisiasi
National Working Group on
HIV-DR tahun 2005
•Kegiatan utama
Monitoring ARV
drug resistances:
• Early Warning
Indicators (EWI)
monitoring
• HIV-DR Surveys
• HIV-DR
Surveillans

4. I. LATAR BELAKANG (3)
 Tingkat resistensi HIV DR <5% adalah rendah
dibandingkan di Eropa (10% - 20% ) dan USA (17% ).
 10% dari pasien dengan viral loads>1000 c/ml, 2/3nya
menunjukkan resistensi terhadap salah satu jenis ARV
di negara berkembang.
 Dari tahun 2006-2010 telah dilakukan 102 surveys EWI
di 52 negara dan menujukkan adanya adherence, drug
stock-out, and lost to follow-up yang problematik dan
membutuhkan perhatian serta monitoring yang terus
menerus.

5. ELEMEN HIV DR DI INDONESIA DAN
PERKEMBANGANNYA (SEBELUM 2013)
Working
Group
HIV DR TS
EWIs
HIV DR
Monitoring
HIV DR
laboratory

6. 1. EWIS INDICATORS (SEBELUM 2013)
indicators used in indonesia:
1. Prescribing practices (target:100%)
2. % lost to follow-up (target: ≤ 20%)
3. Patient retention on first-line ART (≥
70%)
4. On-time ARV Drug pick up (>90%)
5. ART appointment-keeping (>80%)
6. Drug Supply Continuity (target:
>80%)
7. Patient Adherence to ART
8. Viral Load

7. SESUDAH 2013

8. WHO HIV Drug Resistance Surveillance
andSeSesudah 2012 Monitoring Strategy
2012
Monitoring of
HIVDR Early
Warning
Indicators
Surveillance of
Transmitted HIVDR in
Recently Infected
Populations
Surveillance of pre-
treatment HIVDR
in Populations
Initiating ART
Surveillance of
Acquired HIVDR in
Populations Receiving
First-Line ART
Surveillance of
HIVDR in Children
<18 months of Age

9. 3 CATEGORIES OF HIVDR RELEVANT TO
PUBLIC HEALTH
Acquired HIVDR (ADR): occurs when mutations are selected for
by ARV drugs in populations receiving ART
• Suboptimal drug combinations or adherence, treatment
interruptions
Transmitted HIVDR (TDR): occurs when previously uninfected
populations are infected with drug-resistant virus (appropriately
measured in recently infected populations)
Pre-Treatment HIVDR (PDR): detected in individuals starting ART
in which HIVDR can be either transmitted or acquired (previous
ARVs: treatment, PMTCT, PrEP/PEP etc.)

10. WHO HIVDR SURVEILLANCE IN A NUTSHELL:
POPULATIONS AND PUBLIC HEALTH RELEVANCE
Population
Public Health
Relevance
Programatic
assessment
(ART clinic
level)
1. Early Warning
Indicators
Adults and children on
ART
Identifies clinic level
weaknesses allowing
corrective action
(National
Level)
2. Pre-treatment
HIVDR (PDR)
Adults initiating 1st-
line ART
1st-line, Prep, PEP,
regimen selection
3. Acquired HIVDR
(ADR)
Adults on ART for
12(±3) and ≥48 months
2nd-line (and beyond)
regimen selection
4. HIVDR in infants
<18 months
Infants <18 months,
ART naive & recently
diagnosed with HIV
1st-line paediatric
regimen selection
5. Transmitted HIVDR
(TDR)
ARV-naïve recently
infected adults
Monitor level of transmission
of HIVDR;
Inform on programme
quality (indirect indicator)
and future first-line
HIVDR
Survey

11. 2012 REVISED EWI INDICATOR PACKAGE
Early Warning Indicator Target
1. On-time pill pick-up  Red: <80%
 Amber: 80–90%
 Green: >90%
2. Retention in care *  Red: <75% retained after 12 months of ART
 Amber: 75–85% retained after 12 months of ART
 Green: >85% retained after 12 months of ART
3. Pharmacy stock-outs  Red: <100% of a 12-month period with no stock-outs
 Green: 100% of a 12-month period with no stock-outs
4. Dispensing practices  Red: >0% dispensing of mono- or dual therapy
 Green: 0% dispensing of mono- or dual therapy
5. Viral load suppression
at 12 months #dfg
 Red: <70% viral load suppression after 12 months of ART
 Amber: 70–85% viral load suppression after 12 months of ART
 Green: >85% viral load suppression after 12 months of ART
* Retention in care definition equal to UNGASS #24 and PEPFAR #T1.3.D; #Targets for virological
suppression in children <2 years old; Red <60%; Amber 60–70%; Green >70%

12. RESULTS OF HIV DR ACTIVITIES
2004-2014

13. 1. EWIS INDICATORS
 Lokasi: Pilot di 5 ART sites di DKI Jakarta
 Sudah dilatih 17 ART Sites di 6 Provinsi di Indonesia
 Tahun 2013-201 dilatih 22 provinsi dengan cara pelatihan TOT

14. HASIL EWIS MONITORING DI 13 ARV CENTER

15. 2. HIV-DR TRESHOLD SURVEY
RESULTS 2007 AT JAKARTA AND 2013 AT
BALI
Prevalensi ARV Resistansi< 5 % (2
atau kurang (+) diantara 47 sampel)
di Jakarta 2007
Prevalensi ARV resistensi <5% di
Bali 2013

16. 3. HIV-DR MONITORING SURVEY
 Data Collection : 23 Sept 2008 to 31 July
2009 (Cohort 12 months): Eligible sample: 165
persons
 Retention rate: 78%
 Kepatuhan minum obat: 60-70%
 Monitoring Survey at RSHS Bandung and RS Dr.
Soetomo sdg dalam analysis

17. 4. HIV DR NATIONAL LABORATORY
Microbiology Department of UI as national lab
for HIV-DR
BSL2 and BSL3 available
Sequencer was available (Funded by Global
Fund) in Oct 2009
HIVDR Genotyping Assay: Virosec and
inhouse genotyping
Planned to be WHO accredited next year
2016...

18. Rencana Kegiatan HIV DR
Tahun 2016-2019

19. 1. EWIS
• Tahun 2015-2018 dilatih 34 provinsi
dengan cara pelatihan TOT dan provinsi
melatih kabupaten (refreshing)
• Supervisi dan peran provinsi dalam
EWIs monitoring ditingkatkan

20. 2. HIV DR MONITORING DAN SURVEY
• PDR tahun 2016 seluruh Indonesia
• ADR tahun 2017 seluruh Indonesia

21. 3. HIV DR GENOTYPING LABORATORY
Departemen Mikrobiologi sbg laboratorium
yang terakreditasi WHO sebagai national
HIVDR reference laboratory 2016
in 2012, dan Pengembangan laboratory
for genotyping dalam rangka mencakup
pelayanan wilayah timur Indonesia
setelah akreditasi WHO

23. HIV IN INDONESIA
 UNAIDS (2009):
 HIV/AIDS in Indonesia is one of Asia’s fastest growing
epidemics
 Sharp increase in the number of People Living with
HIV/AIDS (PLHA) :
 7,195 (2006)  76,879 (2011)

24. HIV Prevalence in 15-49 years of age (%)
Number of People Living with HIV/AIDS

25. PERBANDINGAN JUMLAH ORANG DENGAN HIV-
AIDS DENGAN TOTAL PENGELUARAN UNTUK
INFEKSI HIV-AIDS
0
2
4
6
8
10
12
2006 2010 2011
PLH
Cost
Linear (PLH)
Linear (Cost)

26. Clinical Course of HIV Infection

27. “State of the Art”
Management of HIV infection
• Decrease in “Viral Load”
• Increase in the number of CD4+ T-
Cells

28. VIRAL LOAD AND HIV INFECTION
CONTROL AND PREVENTION
 INCREASE IN VIRAL LOAD IN HIV INFECTED
INDIVIDUALS  INCREASED RATE OF
TRANSMISSION
 ADMINISTRATION OF HAART  DECREASE OF
VIRAL LOAD

29. ANTIRETROVIRAL THERAPY
 Decrease the replication of “wild type” virus that is
more sensitive to therapy
 Strain that is less sensitive to antiretroviral
treatment will continue to develop
 Under selection pressure of antiretroviral treatment
resistant virus will replicate  become dominant
strain in infected person  reduced efficacy of
antiretroviral treatment

30. ANTIRETROVIRAL RESISTANCE
 High mutation rates of HIV:
 Emergence of Antiretroviral Resistance
 Primary transmission of antiretroviral drug resistant
virus  Occurence of Anti HIV resistance prior to
initiation of therapy

31. SELECTIVE PRESSURES OF THERAPY
Selection of resistant
quasispecies
Incomplete suppression
• Inadequate potency
• Inadequate drug levels
• Inadequate adherence
• Pre-existing resistance
Viralload
Time
Drug-susceptible quasispecies
Drug-resistant quasispecies
Treatment begins
http://clinicaloptions.com

32. Antiretroviral resistance testing
• Phenotypic
• Based on viral ability to replicate in cell culture in the presence of
antireretroviral drug
• Easy to understand
• Time consuming, expensive, complicated, less sensitive, only
available in very few laboratories
• Genotypic Assay
• More available, more widely used, rapid, predictive,
semiquantitative, less complicated
• The result is not easy to interprete, the detection capacity is
limited, expensive, requires special expertise
• Have been performed under routine Quality Assurance Program
(Treat Asia Quality Assurance Scheme) at the Department of
Microbiology, Faculty of Medicine, University of Indonesia/
IHVCB-UI

33. Distribution of drug resistance mutations
within the HIV 1 protease and RT genes

34. ANTIRETROVIRAL RESISTANCE TEST
 Patient population that are under treatment by
physician with access to resistance data
(particularly genotypic) have a better response
compared with control population treated by
physician without resistance data.
 Anti HIV Resistance test is recommended in
anti-HIV treatment : EXPENSIVE!!

35.  HIV's high mutation rate and the need for lifelong
treatment  The emergence of HIVDR is
inevitable
 In countries with years of ART experience,
 a high percentage of treated individuals have resistant HIV,
and
 transmitted resistance to some drugs and drug classes is
reported in 5%-20% of newly infected drug naïve persons

36. Study n Definition Year Prevalence
CATCH1 596 Clinical 1996-2002 10%
CDC2 182 STARHS* 1997-2001 12%
San Francisco3 180 < 1 year 2000-2002 26%
North Carolina4 30 < 30 days 1998-2003 13%
Canada†5 144 STARHS* 1997-2001 10%
Montreal6 170 < 1 year 1996-2003 12%
France7 296 < 6 months 2001-2002 11%
UK8 157 < 18 months 1996-2003 17%
Madrid9 74 < 1 year 1997-2002 19%
Switzerland10 453 < 1 year 1996-2002 11%
1, Resistance Workshop 2003, Abstract 117, 2, Ibid, Abstract 119, 3, Ibid, Abstract 120, 4, CROI, 2004,
Abstract 682, 5, Resistance Workshop 2003, Abstract 121, 6, Ibid, Abstract 122, 7, Ibid, Abstract 123,
8, Ibid, Abstract 124, 9, Ibid, Abstract 130, 10, CROI, 2004, Abstract 680,
* STARHS : Serologic Testing Algorithm for Recent HIV Seroconversions; † surveillance data
PREVALENCE OF HIVDR IN PERSONS WITH ACUTE
PRIMARY INFECTION

37. Study n Year Prevalence
CATCH1 379 1996-2002 7%
CDC2 900 1996-2002 7%
Canada
(surveillance)3 378 1997-2001 5%
France4 363 2001 6%
UK5 1 966 1996-2003 14%
1, Resistance Workshop, 2003;8:S131, Abstract 117, 2, Ibid, Abstract 119,
3, Ibid, Abstract 121, 4, Ibid, Abstract 123, 5, Ibid, Abstract 124,,
PREVALENCE OF RESISTANCE IN NAIVE CHRONICALLY
INFECTED PERSONS

38. ANTIRETROVIRAL TREATMENT IN
INDONESIA
 First-line:
 NRTI:
 stavudine [d4T]
 zidovudine [ZDV]
 lamivudine [3TC]
 NNRTI:
 nevirapine [NVP]
 efavirenz [EFV])
 Second-line :
 NRTI:
 Tenofovir (TDF)
 Protease Inhibitor:
 lopinavir/ritonavir [LPV/r])

39. HIV-DR TRESHOLD AND MONITORING SURVEY IN
INDONESIA
DRUGS RESISTANCE THAT CAN BE IDENTIFIED USING
GENOTYPIC METHOD
A.Protease Inhibitor (PI)
– saquinavir + ritonavir (SQV/r)
– indinavir (IDV)
– IDV/r **
– nelfinavir (NFV)
– amprenavir (APV)/fosamprenavir
(FPV)
– APV/r or FPV/r **
– lopinavir + ritonavir (LPV/r)
– atazanavir (ATV)
– atazanavir + ritonavir (ATV/r) **
– tipranavir + ritonavir (TPV/r)
– darunavir + ritonavir (DRV/r)
B.Nucleoside and Nucleotide
RT Inhibitors (NRTI)
 zidovudine (AZT)
 didanosine (ddl)
 lamivudine (3TC)/emtricitabine
(FTC)
 stavudine (d4T)
 abacavir (ABC)
 tenofovir (TDF)
C.NNRTI
 nevirapine (NVP)
 efavirenz (EFV)

40. HIV-DR TRESHOLD SURVEY IN INDONESIA
 Period of Survey : Oct 2006 – Aug 2007
 Sample: 47 samples
 Criteria (inclusion & exclusion) :
IDU, HIV (+), age < 21, Asymptomatic, Not
under Antiretroviral Therapy
 ARV Resistance Prevalence (Primary
Transmission):
 < 5 % (2 or less resistance out of 47 samples)
(WHO protocol, binomial sequential sampling
technique)

41. HIV-DR MONITORING SURVEY IN INDONESIA
 Location : Piloting in Prof.Sulianti Saroso Hospital in
Jakarta
 Survey Design : Cohort
 Criteria inclusion: PLHA, > 15 years old, initiated an
adult first-line ART regimen at the site
 Data Collection done among 110 cohort

42. HIV-DR MONITORING SURVEY IN INDONESIA
 Data Collection : 23 Sept 2008 to 31 July 2009
(Cohort 12 months)
 Number sample included into study (voluntary)
(Baseline): 110 persons
 Number of sample tested for viral load at baseline
(pretreatment): 110 persons
 Number of sample tested for viral load at endline (post-
treatment): 68 persons

43. VIRAL LOAD VALUE AND GENOTYPING OF
POST TREATMENT SAMPLES (N = 68)
 35 undetectable Viral Load
 33 Detectable Viral Load
 23 samples could not be amplified for Genotyping:
 Genotyping sensitivity : viral load of > 1000 copies/mL
 18 samples: 100 – 1000 copies/mL
 4 samples : > 1000 and < 10000 copies/mL
 1 sample : > 10000 copies/mL
 10 samples could be amplified for Genotyping:
 2 samples with VL < 500 copies/mL
 3 samples with VL >1000 and <10000 copies/mL
 1 samples with VL > 10000 and < 100000 copies/mL
 4 samples with VL > 100000 and < 1000000 copies/mL

44. HIV DRUG RESISTANCE IN PRE-TREATMENT
SAMPLES, N=110 (INITIAL RESULT OF HIV-DR
MONITORING SURVEY IN INDONESIA)
 Resistance to Protease Inhibitors (PI): 1.8% (2/110)
 V11IV, L33F
 1 patient
 Low-level resistance to fosamprenavir/r (FPV/r)
 Potential low-level resistance to tipranavir/r (TPV/r)
 L33F :
 1 patient
 Potential low-level resistance to fosamprenavir/r (FPV/r)
 Potential low-level resistance to tipranavir/r (TPV/r)

45. HIV DRUG RESISTANCE IN POST TREATMENT
SAMPLES, N= 68 (INITIAL RESULT OF HIV-DR
MONITORING SURVEY IN INDONESIA)
 Only 10 samples could be tested for HIVDR genotyping
out of 68 endline samples (low to undetectable viral
load in samples that could not be tested)
 Resistance to Protease Inhibitors (PI):
 L33F
 1 patient (was found with low level resistance to FPV/r in pre treatment
specimen)
 Potential low-level resistance to fosamprenavir/r (FPV/r)
 Potential low-level resistance to tipranavir/r (TPV/r)

46. PROTEASE INHIBITOR RESISTANCE IN PRE AND POST
TREATMENT SAMPLES
0
0.5
1
1.5
2
2.5
Pre-treatment Post-treatment
L33F (LLR FPV/r, PLLR TPV/r)
L33F (LLR FPV/r, PLLR
TPV/r)
(initial result of HIV-DR Monitoring Survey in Indonesia)

47. HIV DRUG RESISTANCE IN PRE-TREATMENT
SAMPLES, N=110 (INITIAL RESULT OF HIV-DR
MONITORING SURVEY IN INDONESIA)
 Resistance to Nucleot(s)ide Reverse Transcriptase Inhibitors
(NRTIs): 9.7% (10/110)
 Potential low level resistance (PLR), Low Level Resistance (LLR)
, Intermediate Resistance (IR):
 Lamivudine (3TC) : 3/110 (all PLR)
 Zidovudine (AZT): 3/110 (all LR)
 Stavudine (D4T) : 10/110 (8 PLR, 2 LR)
 Didanosine (DDI) : 9/110 (7 PLV, 1 LR, 1IR)
 Tenofovir (TDF) : 1/110 (1 PLR)

48. HIV DRUG RESISTANCE IN POST-TREATMENT
SAMPLES, N=110 (INITIAL RESULT OF HIV-DR
MONITORING SURVEY IN INDONESIA)
 Resistance to Nucleot(s)ide Reverse Transcriptase Inhibitors
(NRTIs):
 Potential low level resistance (PLR) , Low Level Resistance (LR) ,
Intermediate Resistance (IR), High Level Resistance (HR)
 Lamivudine (3TC) : 1 IR, 6 HR
 Zidovudine (AZT): 1 HR
 Stavudine (D4T) : 2 LR, 2 IR
 Didanosine (DDI) : 1 PLR, 3 IR
 Tenofovir (TDF) : 1 LR, 1 IR

49. NRTI Resistance in Pre and Post treatment
samples
Potential low level resistance (PLR), Low Level Resistance (LLR) , Intermediate Resistance (IR), High Level Resistance (HR):

50. HIV DRUG RESISTANCE IN PRE-TREATMENT
SAMPLES, N=110 (INITIAL RESULT OF HIV-DR
MONITORING SURVEY IN INDONESIA)
 Resistance to Non-Nucleot(s)ide Reverse Transcriptase
Inhibitors (nNRTIs): 3.6% (4/110)
 Potential low level resistance (PLR) , Low Level Resistance
(LLR), Intermediate Resistance(I R), High Level Resistance (HR):
 Efavirenz (EFV): 4/110 (1PLR, 1 LR, 1IR, 1 HR)
 Nevirapine (NVP) : 4/110 (1 PLR, 1LR, 2 HR)

51. HIV DRUG RESISTANCE IN POST-TREATMENT
SAMPLES, N=110 (INITIAL RESULT OF HIV-DR
MONITORING SURVEY IN INDONESIA)
 Resistance to Non-Nucleot(s)ide Reverse Transcriptase
Inhibitors (nNRTIs):
 Potential low level resistance (PLR) , Low Level Resistance
(LLR), Intermediate Resistance(I R), High Level Resistance (HR):
 Efavirenz (EFV): 1 LR, 1 IR, 5 HR
 Nevirapine (NVP) : 7 HR

52. NNRTI RESISTANCE IN PRE AND POST
TREATMENT SAMPLES
Potential low level resistance (PLR), Low Level Resistance (LLR) , Intermediate Resistance (IR), High Level Resistance (HR):

53. SUMMARY AND CONCLUSION
 The prevalence of antiretroviral resistance was low in antiretroviral naive patients
 possibly indicating the low coverage of ART in People Living with HIV/AIDS
 Resistance NRTIs and nNRTIs drugs was found in respectively 9.7% and 3.6% of
pre-treatment cohort in HIVDR monitoring survey (23 Sept 2008 to 31 July
2009) at Sulianti Saroso Hospital, Jakarta)
 No resistance against the Protease inhibitors used in the HAART regimen in
Indonesia (lopinavir+ritonavir) was observed
 High Level Resistance resistance against Efavirenz and Nevirapine was observed
in pre treatment samples
 Increased resistance to antiretroviral drugs occurs after treatment
 Unique features in the development of antiretroviral resistance may be observed
in Indonesia, due to HIV-1 evolution and host genetics specific to the country
 More economical HIV drug resistance test should be developed for increased
identification of HIV drug resistance in people with HIV/AIDS under
antiretroviral therapy

55. Pre Treatment Post Treatment
Sample
No
PI Resistance
Mutations
RT resistance
mutation
Sample
No
PI Resistance
Mutations RT resistance mutation Note
5 None T69NT 5 ND ND VL < 150
9 None K219EK 9 ND ND VL Undetected
15 None None 15 None
D67G, K70R, V75IV, M184V, T215I,
K219E, N348I, V108IV, Y181IV
18 None T69NT 18 ND ND VL 282
19 None None 19 None K65R, K103N, Y181C
38 None T69N, Y181C 38 None M184V, N348I, V108I, Y181C VL>140000
39 None None 39 None M184V, N348IT, Y188L
67 None D67DE, T69N 67 ND ND Terminated
70
L10I
(susceptible)
T69N, L74IL,
V179D 70 ND ND Terminated
71 V11IV, L33F T69N 71 L33F
D67DE, T69N, V75IMV, M184I,
N348IN, Y181C, M230LM
78 None K103N 78 ND ND
not yet
analysed,
83 L33F None 83 ND ND VL < 150
84 None V179D 84 ND ND VL 94
85 None None 85 None
D67DN, K70KR, M184V,
K219DEKN, N348I, Y181C
91 None None 91 None M184MV, K101HKNQ, G190A
95
L10L
(susceptible) T69NSTY 95 ND ND Terminated
97 None L210LW 97 ND ND Terminated
104 None T69N 104 ND ND
post treatment
sample not
been tested