General introduction PASER

Collaboration with SATuRN

Prof Tobias Rinke de Wit

Thursday, November 21, 2013Bloemfontein, South Africa

PASER & TASER networks

PASER objectives

To build capacity on the monitoring and surveillance of

HIV drug resistance in Africa by: Network development

Clinics, laboratories, research groups

Training and mentoring of medical & lab staff

Observational studies

Prospective cohort of acquired HIVDR [PASER-M]

Cross-sectional surveys of transmitted HIVDR [PASER-S]

International clinical databases + HIV sequence databases

Laboratory Quality Assurance network (TAQAS)

To disseminate information, perform advocacy and realize

policy support

PASER sitesselected from >50

Country

Site Type Admin Setting ARV exp Total HAART

ARVs free

Research exp

Patient tracing

Zambia LTH General hospital Private Urban 1997 No No No

KAR ARV/TB clinic NGO Urban 2004 870 Yes No Yes

CHC ARV clinic in general hospital

FBO Urban 2006 494 Yes No Yes

RSA MMH HIV GP practice Private Urban 2000 No Yes Yes

TLC ARV clinic in general hospital

Public Urban 2004 9500 Yes Yes Yes

ACC ARV clinic NGO Rural 2005 1000 Yes No Yes

Kenya CRH ARV clinic in general hospital

Public Urban 2003 4439 Yes Yes No

MAT ARV clinic in general hospital

FBO Urban 2007 501 Yes No Yes

Uganda JCR ARV clinic Public Urban 1992 7200 Yes Yes Yes

JFP ARV clinic Public Rural 2003 1800 Yes No Yes

MBA ARV clinic Public Rural 2001 1230 Yes No Yes

Zim CON ARV clinic NGO Urban 2004 1000 Yes Yes Yes

Nigeria LUT ARV clinic in teaching hospital

Public Urban 2002 4237 Yes No Yes

Situations at date of patient enrolment (2007-2009)

PASER covers all important African 1st line ART regimens

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Over

all

Zambia

South Af

rica

Ugan

da

Keny

a

Zimba

bwe

Nige

ria

ZDV*

TDF*

D4T*

ABC*

PI-based

*+ 3TC/FTC

+ EFV/NVP

PASER represents all major HIV-1 subtypes in Africa

pol sequences, REGA and STAR algorithms (n=2436)

Zambia South Africa Uganda

Kenya Zimbabwe Nigeria

Total

A C D G CRF02 Other

Graphs by country

PASER numbers

2733 patients initiating 1st line followed up for at least 24 month

250 patients enrolled at second line switch followed up for 24 months

6 countries13 clinical sitesEnrolment Mar 2007 – Sept 2009 PASER M

2 cross sectional cohorts of ART-naive newly infected individuals

• 81 patients in Mombasa

• 77 patients in Kampala

PASER S

Baseline HIVDR in ARV-naive individuals by region and drug class

Risk of primary HIVDR rose by 38% for each additional year since local ART roll-out

Hamers et al. Lancet Inf Dis 2011

Confirmed by WHO data

Gupta RK et al., Lancet 380, 1250-8, 2012

• 26,102 patients from Africa, Asia, Latin America

• 32.9% annual increase of HIVDR in East Africa

No PDR (n=2404)

PDR and fully-active

ART (n=52)

PDR and partially-ac-

tive ART (n=123)

0.0

0.5

1.0

1.5

2.0

2.5Virological failure

Multivariate analysis adjusted for sex, age, calendar year, WHO clinical stage, BMI, pretherapy HIVRNA and CD4, prior ARV use, type of NRTI and NNRTI.

P<0.0001

P=0.001

Hamers et al. Lancet Inf Dis 2012

Baseline HIVDR doubles 1st year risk of VF and acquired HIVDR

Odds

rati

o

Slower recovery of CD4 in patients with baseline (pre-treatment) HIVDR

PASER-S studies indicate moderate TDR in Kampala and Mombasa

Overall NRTI NNRTI PI

Kampala

2 VCT, ‘09/’10

D67G, L210W G190A, G190S, K101E N88D

Prevalence 6/70 = 8.6% (3.2-17.7) 2.9% (2) 4.3% (3) 1.4% (1)

WHO-TSS* Moderate (4/47) Low (2) Low (1) Low (1)

Mombasa

4 VCT, ‘09/’10

K70R K103N (5) I85V, N88D, L90M

Prevalence 9/68 = 13.2% (6.2-

23.6)

1.5% (1) 7.4% (5) 4.4% (3)

WHO-TSS* Moderate (5/47) Low (0) Moderate (3) Low (2)

Ndembi et al. AIDS, 2011

Sigaloff et al. Aids Res Hum Retro 2011

WHO-recommended proxy criteria for recent infection: • Newly HIV-1 diagnosed and aged ≥18 and <25 years, or lab evidence of recent HIV-1

infection

Adding to WHO data

72 surveys

20 moderate level (5-15%)

WHO HIV Drug Resistance Report, S Bertagnolio, IAS Conference July 26, 2012

14

The importance of VL testing: 4x less unnecessary switches

Clinical + CD4 count (n=64)

Clinical + CD4 count + targeted VL (n=186)

Sigaloff et al. JAIDS 2011

10

90%

27%73

% 57%

43%

42%

58%

Cohort 1 (n=100)Virological failure by

routine pVL test, 12 mo ART

3TC FTC AZT d4T ddI TDFABC EFV NVP ETR RPV0

10

20

30

40

50

60

70

80

90

100High-level resistance

Intermediate resistance

Low-level resistance

Potential low-level resistance

Susceptible

Reverse-transcriptase inhibitors

% o

f s

equ

en

ce

s

Lack of VL monitoring more HIVDR

Cohort 2 (n=161)Clinico-immunological

failure, 26 mo ART

Hamers CID12; Sigaloff JID12Stanford hivdb algorithm

MARCH-Uganda study

ART initiation

or switch

~310 (75%)

first-line

ARV-naive PMTCT

~ 50 (15%)

second-line

• Prospective cohort study of 360 children in Uganda

on ART• Initiated in January 2010• Funded by EDCTP, NACCAP

>40 publications: international journals

• Hamers, R.L., Schuurman R., van Vugt, M., Derdelinckx, I. and Rinke de Wit, T.F. De ontwikkeling van hiv-1 resistentiesurveillance in Afrika. Ned

Tijdschr Geneeskd 151, 2666-2671, 2007.• Hamers, R., de Beer IH, Kaura, H., van Vugt, M., Caparos, L. and Rinke de Wit, T.F. Diagnostic accuracy of 2 oral fluid-based tests for HIV surveillance

in Namibia. JAIDS 48, 116-118, 2008.• Hamers, R.L., Derdelinckx, I., van Vugt, M., Stevens, W., Rinke de Wit, T.F. and Schuurman, R. The status of HIV-1 resistance to antiretroviral drugs in

sub-Saharan Africa. Antivir. Ther. 13, 625-639, 2008.• Hamers, R.L., Rinke de Wit, T.F., Schellekens, O.P. and van Vugt, M. Aidsbehandeling in Afrika. Ned Tijdschr Geneeskd 152, 654, 2008.• Hamers, R.L., Smit, P., Stevens W., Schuurman, R. and Rinke de Wit, T.F. Dried fluid spots for HIV type-1 viral load and resistance genotyping: a

systematic review. Antiviral Therapy 14, 619-629, 2009.• Wallis C., Papathanasopoulos, M., Rinke de Wit, T.F. and Stevens, W. Affordable in-house drug resistance assay with good performance in non-

subtype B HIV-1. J Virol Meth 168, 505-508, 2010.• Hamers, R.L., Siwale, M., Wallis, C.L., Labib, M., van Hasselt, R., Stevens, W., Schuurman, R., van Vugt, M. And Rinke de Wit, T.F. Baseline drug-

resistant HIV-1 at initiation of first-line antiretroviral therapy in Lusaka, Zambia. JAIDS 55, 95-101, 2010.• Hamers, R.L., Oyomopito R., Kityo, C., Phanuphak, P., Siwale, M., Sungkannuparph S., Conradie, F., Kumarasamy, N., Botes, Sirisanthana, T., M.E.,

Abdallah, S., Li, P.C.K., Ngorima N., Kantipong P., Osibogun, A., Lee, C.K.C., Stevens, Kamarulzaman, A., W.S., Derdelinckx, I., Arthur Chen, Y.-M.,

Schuurman, R., van Vugt, M. and Rinke de Wit, T.F. Cohort profile: the PharmAccess African (PASER-M) and the TREAT Asia (TASER-M) monitoring

studies to evaluate resistance – HIV drug resistance in sub-Saharan Africa and the Asia-Pacific. Int J Epidemiol, Epub, Nov 2010.• Steegen, K., Bronze, M., van Craenenbroeck, E., Winters, B., van der Borght, K., Wallis, C.L., Stevens, W., Rinke de Wit, T.F. and Stuyver, L. A

comparative analysis of HIV drug resistance interpretation based on short reverse transcriptase sequencfes versus full sequences. AIDS Res & Ther

7, 38, 2010: http://www.aidsrestherapy.com/content/7/1/38.• Ndembi, N., Hamers, R.L., Sigaloff, K.C.E., Lyagoba, F., Magambo, B., Nanteza, B., Watera, C., Kaleebu, P. and Rinke de Wit, T.F. Transmitted

antiretroviral drug resistance among newly HIV-1 diagnosed young individuals in Kampala. AIDS 25, 905-910, 2011.• Sigaloff, K.C.E., Hamers, R.L., Wallis, C.L., Kityo, C., Siwale, M., Ive, P., Botes, M.E., Mandaliya, K., Wellington, M., Osibogun, A., Stevens, W.S., van

Vugt, M. and Rinke de Wit, T.F. Unnecessary antiretroviral treatment switches and accumulation of HIV resistance mutations; two arguments for viral

load monitoring in Africa. J.Acquir.Immune Defic. Syndr, 58, 23-31, 2011.• Hamers, R.L., Wallis, C.L., Kityo, C., Siwale, M.M., Mandaliya, K., Conradie, F., Botes, M.E., Wellington, M., Osibogun, A., Sigaloff, K., Nankya, I.,

Schuurman, R., Wit, F., Stevens, W., van Vugt, M. and Rinke de Wit, T.F. HIV-1 drug resistance among antiretroviral-naïve individuals in sub-Saharan

Africa after rollout of antiretroviral therapy: multicentre observational study. Lancet Inf. Dis., DOI:10.1061/S1473-3099(11)70149-9, published on

line, July 28, 2011.• Sigaloff K.C.E., Calis, J.C., Geelen, S.P., van Vugt, M. and Rinke de Wit, T.F. Resistance-associated mutations among children on antiretroviral

treatment in resource-poor settings: a systematic review. Lancet Inf. Dis., DOI:10.1016/S1473-3099(11)70141-4, August 26, 2011.• Hamers, R.L., Schuurman, R., Sigaloff, K.C.E., Wallis, C.L., Kityo, C., Siwale, M., Mandaliya, K., Ive, P., Botes, M.E., Wellington, M., Osibogun, A., Wit,

F.W., van Vugt, M., Stevens, W. and Rinke de Wit, T.F. Effect of pre-treatment drug-resistance on immunological, virological and drug-resistance

outcomes after the first year of antiretroviral therapy for HIV-1: multicentre cohort in six African countries. Lancet Inf Dis, DOI:10.1016/S1473-

3099(11)70255-9, published online, October 28, 2011.• Sigaloff, K.C., Mandaliya, K., Hamers, R.L., Otieno, F., Jao, I.M., Lyagoba, F., Magambo, B., Kapaata, A., Ndembi, N. and Rinke de Wit, T.F. High

prevalence of transmitted antiretroviral drug resistance among newly HIV type 1 diagnosed adults in Mombasa, Kenya. AIDS Res. Hum. Retrovir.,

2012 (Epub ahead of print).

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Capacity building:Regional Workshops & on-site training

* ARTA = Affordable Resistance Testing for Africa

Advocacy: keep HIVDR on the map

STAR, South Africa March 7, 2011

The Nation, Kenya August 1, 2011

Daily Monitor, Uganda April 25,2012

Collaboration PASER – SATuRN Expansion of clinical and laboratory databases on

African HIV drug resistance, incl. new HIV subtypes (non-C)

and incl. retrospective data >2007 Strengthened joint training programs for African HIV

clinicians Strengthened joint advocacy of HIVDR through

presentations at conferences, papers in journals, grey

literature, mass media, websites, twitter, etc. Improved advice to African HIV clinicians r.e. treatment

of patients who are failing ART Coordinated development, validation and marketing of

more affordable HIVDR tests Improved joint research options with increased data

available; coordinated grant proposal writing (NIH, UNITAID,

EDCTP)

Acknowledgements

PharmAccess FoundationDept of Global Health AMC-UvAAmsterdam Institute for Global

Healthand Development Elske StraatsmaJohn DekkerAnnedien PlantengaNicole SpiekerRaph HamersKim SigaloffDesiree LathouwersAletta KliphuisPeggy van LeeuwenCorry MantingPascale OndoaJoep LangeMichèle van VugtTobias Rinke de Wit

UMCU Virology, The NetherlandsRob SchuurmanAnnemarie Wensing

Clinical sites

PIs and study teams

Study participants

University of the

Witwatersrand,

South Africa

Wendy Stevens

Carole Wallis

Kim Steegen

JCRC, Uganda

Cissy Kityo

Peter Mugyenyi

MRC/UVRI, Uganda

Nicaise Ndembi

Pontiano Kaleebu