Transmitted ARV drug resistance: what’s next?

Raph Hamers, MD PhDAcademic Medical Center of the University of AmsterdamAmsterdam Institute for Global Health and Development

SATuRN-PASER workshop, Bloemfontein20-22 November 2013

WHO/UNAIDS

Global scale-up of ART

• Standard ART regimens

• Restricted drug options• Limited lab monitoring• Decentralized service

delivery and task shifting

WHO public health model

Should we fear a dramatic increase in HIVDR?

"Widespread, unregulated access to ARV drugs in sub-Saharan Africa could lead to the rapid emergence of resistant viral strains, spelling doom for the individual, curtailing future treatment options, and leading to transmission of resistant virus."

"If compliance and careful follow-up of patients is not achieved, we will see a dramatic increase in multidrug-resistant HIV mutants…"Robert C. Gallo and Luc Montagnier. Prospects for the Future. Science 2002

"If compliance and careful follow-up of patients is not achieved, we will see a dramatic increase in multidrug-resistant HIV mutants…"Robert C. Gallo and Luc Montagnier. Prospects for the Future. Science 2002

Lancet 2001

Transmitted HIVDR in MSM and HSX is stabilizing in Europe

Wensing, on behalf of SPREADeacs-conference Oct 2011

Prevalence of resistance over time

year

Pre

vale

nce

0

5

10

15

1/2003 1/2004 1/2005 1/2006 1/2007

any class

NRTI

NNRTI PI

0.37

0.44

0.004 (increase in MSM only)

0.001

P=

WHO 2009 Surveillance Drug Resistance Mutation list

N=4317

PASER-M: Pre-ART HIVDR in 6 African countries

Pre-ART HIVDR prevalence Yearly increase risk of pre-therapy HIVDR:Overall: 5.6% 38% (p=0.001, multivariate analysis) Pretoria: 1.1%Kampala: 12.3%

Hamers et al., The Lancet Inf Dis 2011

2436 sequences from 2590 participants

Recent data suggest increasing TDR in certain geographics areas (mostly to NNRTIs)

ANC

Aghokeng et alAIDS 2011

Ndembi et alAIDS 2011

02468

101214

1996-1999 2001 2002 2007

%TD

R

Axis Title

Drug resistance mutations in ARV naïve Cameroonians (n=369)

Roll out of

26,102 patients from 191 datasets from 42

countries in Africa, Asia, Latin America

Prevalence of HIVDR in ARV-naïve individuals, by time since ARV rollout

Every circle is a study and the size of the circle is proportional to the precision of the estimate from the individual study

Gupta et al. Lancet 2012

29%/yr (95%CI 15-45; p=0.0001) 14%/yr (0-29; p=0.05)

3%/yr (–0.9-16; p=0.618)

East Africa Southern Africa

Latin America+CaribbeanWest and Central Africa

NNRTI: 36%/yr (21-52; p<0.0001)

NNRTI: 23%/yr (7-42; p=0.0049)

NNRTI: 15%/yr (–1-32; p=0.0646)

p=0.960

WHO transmitted HIVDR surveys 2004-2010

72 surveys

20 moderate level (5-

15%)

WHO HIV Drug Resistance Report 2012

WHO transmitted HIVDR surveysMutation Prevalence n=3588, pooled analysis from 82 surveys

WHO 2009 Surveillance Drug Resistance Mutation list

Overall prevalence: 3.1%

K103N or S: 0.8%

D67N/G, K101E/P, Y181C and M184V: between 0.3 – 0.4%

WHO HIV Drug Resistance Report 2012

TDR to NNRTIs is related to ART coverage in LMIC

WHO HIV Drug Resistance Report 2012

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

Pretherapy HIVDR doubles 1st year risk of VF and acquired HIVDR PASER-M cohort in 6 African countries

Odds

rati

o

91%

86%

75%

% Viral suppression

WHO HIV Drug Resistance Report 2012

Routine VL monitoring helps to reduce new HIV infections with transmitted drug resistance

• Mathematical model: VL testing every 6 months, switch >500 c/mL.

• To preserve current 1st-line for long term, there is an eventual need for (affordable) VL monitoring in low-middle income countries Phillips AIDS2011

TDR

New ART strategies: eligibility is increasing

Gottfried Hirnschall WHO, IAS Conference July 26, 2012

*Cohen HTPN052 NEJMNewel KZN Science

Treatment as Prevention

PMTCT Option B+

Early ART for HIV prevention at the cost of HIVDR?

Early ART initiation: model based on cohort data from Kampala and Mombasa

Effect of initiating ART

at different CD4 thresholds

TDR prevalenceInfections averted

Over 10-year period

Nichols et al. AIDS2013

TDR prevalence will increase:<200 cells/μL: 9.4%-12.3%<350 cells/μL: 11.6%-13.4%<500 cells/μL: 17.8%-18.7%

Nichols et al. AIDS2013

The preventive effect of early ART outweighs the increase of TDR

18 46 22 32

Number of new HIV infections averted for each incident case of TDR

Early ART: TDR increase eliminated if patients with VF are timely switched to 2nd-line ART

Nichols et al. AIDS2013

PrEP and HIVDR

• TDF-FTC effective in iPREX, Partners PrEP, TDF2; not

effective in FEM-PREP and VOICE (TDF) because of non-

adherence

• Concerns, in regard to HIVDR:

1. Already HIV-infected when starting PrEP

2. Non-adherent and infected while on PrEP

3. TDF-FTC also in first-line treatment: loss of future

drug options?

• 5 cases of HIVDR have been detected in iPrEx, Partners

PrEP, TDF2 (total of 118 infections averted) All had unrecognized (acute) infections

van de Vijver, AIDS2013

PrEP: limited impact on TDR prevalence in sub-Saharan Africa

Comparison of 3 independent mathematical models in sub-Saharan Africa

Proportional contribution of events contributing to HIV-1 drug resistance 20 years after the introduction of preexposure prophylaxis (PrEP).

Conclusions – 1

• Pre-ART and TDR are on the rise, particularly in southern

and East Africa, mostly confined to NNRTI, associated

with duration and coverage of national ART programs

• Currently, measured levels are of concern, but not at

unexpected levels and rates, far majority of patients

receive effective regimens

• Lack of routine HIVDR surveillance data not up-to-date

Conclusions – 2

• Interventions to reduce TDR include:

• Strengthening of program functioning, retention and

adherence

• Routine VL monitoring in conjunction with access to

2nd line ART

• Exciting evidence that early ART prevents new infections

• However, implementation of novel TasP strategies will

need to be closely monitored to assess the consequences

for retention-adherence-HIVDR

Acknowledgements

PASER network Tobias Rinke de Wit (PI), Kim Sigaloff, Pascale Ondoa, Joep Lange, Michèle van Vugt, Rob Schuurman, Wendy Stevens, Kim Steegen, Carole Wallis, Margaret Siwale, Kishor Mandaliya, Prudence Ive, Ian Sanne, Mariette Botes, Maureen Wellington, Ruedy Luthy, Akin Osibogun, Cissy Kityo, Peter Mugyenyi, Nicaise Ndembi and many others

WHO HIVResNet in particular Silvia Bertagnolio, Michael Jordan

Other collaboratorsRavi Gupta – UCLDavid van de Vijver, Brooke Nichols – Erasmus MC