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Epidemiology of HIV Transmissed Drug Resistance Mutations.

Amilcar Tanuri, MD, PhD.Head of Laboratório de Virologia Molecular, UFRJ, Brazil.

Senior Lab Advisor ICAP, Columbia University, NY, USA.

Sic Transit Gloria Mundi. Ad Majorem Dei Gloriam In

Hoc Signo Vinces.

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ARV Resistance in Treated Individuals

• HIV DR Decreasing since initiation of triple therapy

• DR is low in those using RTV boosted PI's• DR can be managed by new drugs within

existing classes and new classes

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Transmission of Drug Resistance in HIV

• ARV treated individuals living longer• Incident infections continue to increase

worldwide• Transmitted resistance well recognised in

countries with wide ARV coverage

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Transmission of Resistance in Europe

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Overall prevalence of TDR in German Seroconverter Cohort 1997–2007.

Barbara Bartmeyer et al. PLoS ONE, 2010 , (5)10: e12718.

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Trend of TDR in San Francisco , USA

Vivek Jain et al. PLoS ONE, December 2010 (5) Issue 12, e15510.

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Trend of TDR in San Francisco , USA

Vivek Jain et al. PLoS ONE, December 2010 (5) Issue 12, e15510.

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Prevalence of Mutations with Reduced Antiretroviral-Drug

Susceptibility

Weinstock et al. JID 2004;189:2174-80.

1082 HIV-infected Persons in the U.S.

02468

10121416

Men who have sex with men

Heterosexual men

Women

African

Hispanic

White

%

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In resource rich world, transmitted resistance appears to be stabilising or even

reducing (UK data)

UK Collaborative Group on HIV Drug Resistance.AIDS 2007;21:1035-9.

Chronic infection

Acute infection

14

12

10

8

6

4

2

0

1997 1998 1999 2000 2001 2002 2003 2004 2005

Year of sample

Sam

ple

s w

ith

IA

S m

uta

tio

n(s

) (%

)

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Trend of TDRM rate found in different surveys done in Rio de Janeiro .

0

2

4

6

8

10

12

1996 1998 2000 2002 2003/4 2007/8 2009/10

DRM rate

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Trend of TDRM Pattern in Rio de Janeiro, Brazil.

0

1

2

3

4

5

6

7

1996

1998

2000

2002

2003/4

2007/8

2009/10

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HIV Carrying DRM can be tramissed and can give rise to micro-epidemics

Brenner et al. 2008; AIDS, 22(18): 2509–2515

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17

119

5

Rep

licati

on

Cap

acit

y

Wrin T, 40th ICAAC 2000

Impact in RC of DRM

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Retention of DRM without ARV selection in B na C isolates in vitro.

5 10 15 20 25 30 35 40 45 50 55 60 650

10

20

30

40

50

60

70

80

90

100

WASH OUT PR B Vs. C

M46I-B

M46I-C

54V-B

54V-C

82A-B

82A-C

90M-B

90M-C

CULTURE DAYS

% R

ES

IST

AN

CE

MU

TA

TIO

N

Gonzalez LM. et al. J Gen Virol. 2006 (5):1303-9.

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Persistence of Transmitted Resistance in Primary HIV Infection

n=9Persistent resistance

n=2Reversion to wild type

n=14Persistent resistance

n=2Reversion to wild type

Variable persistence according to mutations: TAMs persist, K103N persists, some PI persist (M46I, L90M), MDR can persist

n=11Primary resistance

US; F/U median 9 months

n=16Primary resistance

UK; F/U up to 3 years

Little et al. 11th CROI 2004, San Francisco, CA. Abs 36LB.Pao et al. JAIDS 2004;37:1570-3.

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DART TRIAL ZDV/3TC/TDF

MutationWeek 24(n=24)

Week 48(n=41*)

M184V 15 (62%)

32 (78%)

K65R 3 (12%)

6 (15%)

M41L 7 (29%)

17 41%)

D67NG 9 (38%)

23 (56%)

K70R 8 (33%)

23 (56%)

L210W 0 (0%)

3 (7%)

T215FY 7 (29%)

17 (41%)

K219QEN 1 (4%)

9 (22%)

Total TAMs: 01–34–6

10 (42%)

13 (54%)

1 (4%)

11 (27%)18 (44%)12 (39%)

TAM Group** I II

I and II

5 (36%)

4 (11%)

5 (36%)

2 (7%)11 (37%)17 (57%)

Pillay et al. CROI 2007. Abstr. 642.

Prevalence of mutations at 24 and 48 weeks in absence of virological monitoring

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Baseline Resistance in DART Trial

• 8/91 with resistance (9%)• 41L, • 108I, • 103N+190A, • 41L+70R+184V• 41L, • 103N+184V, • 103N+181C+184V, • 67N+181C+184V

Drugs Compromised

Nucleoside analogues: 41L, 70R, 67N

3TC: 184V

NNRTI: 103N, 190A, 181C, 108I

Pillay et al. CROI 2007. Abstr. 642.

• Undisclosed Prior ART !!!!.• Maybe it is important to

monitore cronic infected individuals in RLC.

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Summary

• Resistance develops following failure of therapy.• Resistance can be transmitted• Improvements in ARV regimens reduces

emergence and transmission of resistance• Extensive resistance may develop in absence of

cautious monitoring of ARV use.• Transmitted resistance is an important element in

the new approach of “test and treat” to tackle HIV transmission.

• Undisclosed prior ART in Resource Poor Settings can be an important element.

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Global distribution of HIV-1 subtypes and recombinants

in 2000–2003 and 2004–2007.• The global and regional

distributions of individual subtypes and recombinants are broadly stable.

• subtype C still accounts for nearly half (48%) of all global infections.

• CRF2_ AG doubled in 5 years.

Joris Hemelaar et al. AIDS 2011, 25:679–689

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HIV-2 in the world

• HIV-2 is prevalent in West Africa but can be also be found in other African Regions (Angola and Mozambique), and in Spain, Portugal, France, India, and Macau in micro-epidemics.

• The proportion of HIV-2 in AIDS Epidemic in Angola and Mozambique is 0.6% and 0.25% , respectively.

• HIV-2 is naturally resistant to NNRTI • HIV-2 accumulate more frequently

Q151M mutation when compared to HIV-1 individuals treated with AZT or d4T.

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Dinamics of HIV-2 infection in west Africa (Guine Bissau)- Project Bandim

• The amount of HIV-1/HIV-2 coinfection in west Africa is increasing and this can pose a threat to HAART therapies which target more the HIV-1.

• HIV-1/HIV-2 coinfection in west Africa can also be a important problem for the PMTCT interventions.

%

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Final Remarks

• The best way to prevent the spread of HIV DR is to prevent HIV infection.

• The best way to prevent the spread of HIV DR is to keep the patients in ARV with undetectable VL.

• In RLS the VL is not available in large scale.• 2nd line potent regimens are not available in

RLS.• We need to make na effort to implement VL and

make available potent 2nd line regimens to curb the spread of HIV DR.

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Grazie

Thank you

Obrigado