Antiretroviral Drug Resistance

• Basic Knowledge• Global Impact• Utility of Global Surveillance

• Anthony Amoroso, MDAssistant Professor of MedicineUniversity of Maryland School of MedicineInstitute of Human VirologyChief of Infectious Diseases, VA Maryland Health Care System

“ Living with HIV used to be like playing checkers and now it’s like playing chess.”

Becky Trotter, POZ

HIV-1 Viral Dynamics : Basis of HIV-1 Viral Dynamics : Basis of resistanceresistance

• In an HIV-1 infected individual, it is In an HIV-1 infected individual, it is estimated that:estimated that:

– 10.3 x 1010.3 x 109 9 virons are produced virons are produced each dayeach day

– Average life span of an HIV-1 Average life span of an HIV-1 viron in plasma is 5.6hoursviron in plasma is 5.6hours

– Average HIV-1 generation time is Average HIV-1 generation time is 2.6 days2.6 days

HIV-1HIV-1Viral Dynamics - MutationsViral Dynamics - Mutations

• Genome Size - 10Genome Size - 1044 base pairs base pairs• Mutation rate of HIV-1 is estimated to be Mutation rate of HIV-1 is estimated to be

3.4 x 103.4 x 105 5 per base pair per replication per base pair per replication cyclecycle

• If true, then every mutation at every If true, then every mutation at every position on the genome would occur position on the genome would occur numerous times each daynumerous times each day

How Quickly Resistance Can Occur How Quickly Resistance Can Occur Depends on the Viral LoadDepends on the Viral Load

Viral LoadViral Load Days Before Mutation Days Before Mutation ArisesArises

300,000300,000 0.10.1

30,00030,000 11

3,0003,000 1010

300300 100100

3030 1,0001,000Adapted from Siliciano, 2002

mutations

Development of Viral Resistance

PATIENT• Non adherence

• Side effects

VIRUS• High replication rate

• Error prone

• Latent reservoir

Barrier to resistance

DRUG• Subtherapeutic concentrations

• Selective pressure of less potent ARV therapy

Ctrough

Intrinsic activity

Viral Resistance is the Outcome of Viral Replication, Mutation and Selection

Original VirusQuasispecies

Selection Pressureexerted by Drugs

HIV

RN

A L

evel

HIV

RN

A L

evel

New VirusNew VirusQuasispecies Quasispecies

Resistant virus

TimeTime

Minority Quasispecies withreduced susceptibility

0

0.5

1

1.5

0 2 4 8 12 16 20 24

Weeks

Med

ian

dec

reas

e H

IV R

NA

lo

g c

op

ies/

mL 3TC monotherapy

Kuritzkes D, et al. AIDS 1996;10:975-81.

300 mg BID (n=14)

HIV-1 RNA Response in Subjects With M184V (M184V Present by Week 12)

HIVNET-012: Prevalence of NVP Resistance Mutations at 6 to 8 Weeks Postpartum

Eshleman SH, et al. 8th CROI; February 4-8, 2001; Chicago, IL. Abstract 516.

19

46

0

20

40

60

Mothers(n=111)

Infected infants(n=24)

% w

ith r

esis

tanc

e m

utat

ions

Case # 9 – Gulu, Uganda

16 year old female

Pre-ARV HX

• No previous ARV exposure • OIs prior to ARV – Diarrhea and wasting, Genital

ulcerative disease• Baseline weight – 35 kg• WHO stage – III • Baseline CD4 – 37 c/mm3 (11/2004)• ARV start date – 22/12/04• Baseline labs – Hb – 10.3g/dl, AST – 22, ALT –18, Cr –

0.7

ARV therapy

• 14 month duration of therapy• Start 22/12/04: TDF/3TC/EFV• Switch 21/07/0: TDF/FTC/EFV (current)

OIs since ARV start

• Herpes Simplex• Genital Ulcerative Disease• Tonsillitis – 22/02/05• Anal sores – 16/11/05• Perinatal viral warts – 14/03/06

CD4 Trend

37

88

0

20

40

60

80

100

Nov-04

Dec-04

Jan-05

Feb-05

Mar-05

Apr-05

May-05

Jun-05

Date

CD

4 co

unt

Series1

Weight Trend

35

44 46 45

05

101520253035404550

Date

Wei

ght (

kg)

Series1

Adherence

• Patient had treatment preparation, home visits and DOT

• Dispensing frequency – Monthly• No subjective history of missed doses in the past

6 months• No history of missed refills in past 6 months• No history of missed appointments in past 6

months

Viral Load?

• >750,000 copies/ml

Why?

• Poor adherence to safe sexual practices is been closely linked to poor adherence to ARVs.

• Adolescents are notoriously horrible at taking chronic medications

What is major concern in this case?

• This pt is at high risk for spreading resistance virus.

• Is secondary prevention counseling going to have any effect on this patient’s behavior?

Surveillance

Rise in ARV Resistance Among Treatment-Naive Patients

0

2

4

6

8

10

NNRTIs PIs 1999-2000

Pat

ien

ts (

%)

1996-19981999-2000

1 drug

2 drugs

>10-Fold Resistance

Little. 8th CROI; 2001; Chicago. Abstract 756

Patients With >10-Fold Resistance N = 408

P = .05P = .001

0

5

10

15

20

1996 1997 1998 1999 2000

Per

cen

tag

eP

erce

nta

ge

NRTINNRTIPI

Reduced Susceptibility (>10 Fold) of Transmitted HIV during Primary Infection

15

YearYear

718810632n

Little SJ. 8th CROI, Chicago, 2001. #756

Prevalence of Drug Resistance1080/1906 patients

* Assumes no resistance in samples with HIV RNA <500 copies/mL* Assumes no resistance in samples with HIV RNA <500 copies/mL** Represents 63% of total study population** Represents 63% of total study population

Total StudyPopulation*

Population with HIV RNA >500 copies/mL**

78%70%

42%31%

51%

14%

50%

0%

20%

40%

60%

80%

100%

Drug resistance detected

Dru

g r

es

ista

nc

e

Richmond

Causes of Resistance: Lessons Learned • Learning curve during applications of consensus

treatment guidelines– AZT monotherapy– Sequential monotherapy– 2NRTI and PI ( i.e. AZT, 3TC and non-boosted PI)

• Borderline therapeutic drug levels and significant drug interactions

• High Adherence Requirements

Global resistance in naïve patients study• WATCH: Worldwide Analysis of resistance Transmission over time of

Chronically and acute infected HIV-1 Patients1

• RT & PI mutations from 6,054 naïve pts

• Source: Europe 3252, Africa 1162, Asia 653, Latin America 806, North America 290

• Results: 8.9% >1 mutation

– Europe 11.3%; NA 9.3%, Africa 5.7%, Latin America 5%, East Asia 9.4%, S/SE Asia 5.3%, 1.8% multiclass resistance

1. Bowles E, et al. XVI IAS, Toronto 2006, MOPE0388; 2. Bowles E, et al. 4th EHDRW, Monte Carlo 2006, #7

Resistance by ARV class

Primary resistance in ARV-naïve adolescents

• Study of resistance in pts age 12-24 from 15 US cities (n=55)• HIV-infected w/in 180 days using “detuned” assay• Genotype (GT) and Phenotype (PT) obtained• Major mutations defined by IAS-USA Drug Resistance Mutations

Group

• 1 pt had GT + PT resistance to ARV in all 3 classes

Viani R, et al. 13th CROI, Denver, CO, February 5-8, 2006. 13th CROI, Denver, CO, February 5-8, 2006. Abst. 21

Genotype Phenotype

Overall 18% 22%NRTI 4% 4%

NNRTI 15% 18%

PI 3.6% 5.5%

The HIV Family

HIV-1 HIV-2

Group: O M N

Clade: A,C,F B E Others

(Africa) (US, Europe) (SE Asia)

HIV-1

(Cameroon)

less pathogenic

Levy JA. HIV and the Pathogenesis of AIDS. 2nd ed. Washington, DC: American Society for Microbiology; 1998:152-158.

Distribution of HIV-1 Subtypes in Africa

Eastern10.5

North

0.2

A/G

C

C

AWestern

5.0

Southern20.0

Horn11.0

Central6.0

A/G

Can Resistance Testing Be Used forNon-Clade B HIV-1 Subtypes?

• Do the assays yield any results?– Yes, at least for kit-based genotyping assays

• Do the results have the same interpretation?– Mostly yes– Exception

• Some secondary PI mutations are more common in non-clade B viruses

• M36I, for example, is wild type for clade C

SDNVP and Resistance2005

• Resistance in child: 13% - 52% • Resistance in mothers: 39% - 75% resistance

– Clade A 19%– Clade D 36%– Clade C 69%

Conclusions

• Different HIV-1 subtypes seem to possess distinct potentials for drug related resistance mutation acquisition, including alternative routes and substitutions.

• This may affect the future design of antiretroviralregimens and salvage regimens in distinct areas of the world where non-B isolates dominate the HIV/AIDS epidemic.

Why new strategies are needed to avoid resistance

The mainstream strategy of sequencing, as a whole, has not been successful.

– Cross-resistance is a major problem and can prevent rational sequencing of drugs

– Novel drugs or “new drugs” in a class may not be available or effective once resistance develops

The Impact of Cross Resistance “First shot is your best shot”

Regimen

Cohort

Virologic failure (VL >500 c/ml)

Immune and clinical failure (composite)

Clinical events

1st HAART 40% 20% 5%

2nd HAART 50% 30% 24%

3rd HAART 67% 40% 25%

Rate of Treatment Failure in EuroSIDA Cohort (n = 8507) in EuroSIDA Cohort (n = 8507)

Mocroft, et al, Antivir Ther, 2000.

Viral Suppression by Country (by Year 1 Sites)

0102030405060708090

100

ART drug resistance mutations in ART experienced patients in Nigeria

E. Idigbe, T. Salawu, B. Osotimehin, B. Chaplin,J-L Sankalé, J Idoko, E Ekong, R Murphy , PJ Kanki

Nigerian Institute of Medical Research (NIMR), Lagos Nigeria Federal Ministry of Health, Abuja, Nigeria National Action Committee AIDS, Abuja, NigeriaHarvard School of Public Health, Boston, MA, USAJos University Teaching Hospital, Jos, NigeriaHarvard PEPFAR (APIN Plus), Lagos, Nigeria. Northwestern University, Chicago USA

Supported by AIDS Prevention Initiative Nigeria – funded by the Bill & Melinda Gates Foundation, DAIDS-NIAID/NIH, the Federal Ministry of Health and NACA.

Resistance Patterns to the Baseline Regimen of Patients with viral loads greater 3000 c/ml .

Lam Stav NVP TOTAL

Res Res Res 19%

Res Int Res 26%

Res Susc Res 40%

Susc Susc Res 3%

Susc Susc Susc 11%

# 144

Response to d4T/3TC/NVP in mothers based on previous history of single-dose NVP

0

10

20

30

40

50

60

70

80

Baseline 6 months

No NVP

NVP no mutation

NVP +mutation

68%*

52%*

38%*

% W

ith

Vir

olog

ic S

uppr

essi

on

N=40 N=119 N=61N=47 N=143 N=66

*significantJoudain et al. NEJM 4/04

What will we do with surveillance information?

DHHS Guidelines: Recommendations for Using Drug-resistance Assays (Updated 5/04/06)

Adapted from DHHS Guidelines (5/04/06). Available at: http://aidsinfo.nih.gov. Accessed May 9, 2006.

Drug-resistance assay recommended• In acute HIV infection*

– If the decision is made to initiate therapy at this time, testing is recommended prior to initiation of treatment. A genotypic assay is generally preferred

– If treatment is deferred, resistance testing at this time should still be considered

• In chronic HIV infection*– Drug resistance testing is recommended prior to initiation of therapy. A genotypic assay

is generally preferred– Resistance testing earlier in the course of HIV infection may be considered

• With virologic failure during combination antiretroviral therapy

• With suboptimal suppression of viral load after antiretroviral therapy initiation

*New recommendations as of DHHS Guidelines update 5/04/06.

0%

20%

40%

60%

80%

100%

1st 2nd 3rd 4th+

Q1 2006

Other

3NRTIs

PI/r-based

PI-based

NNRTI-based

Base: All treated patients Q1 2006 data

Regimen Selection by Line of Therapy

Line of therapy change defined as a switch of any component of the patient’s ARV regimen.

n=951 n=601 n=369 n=451

Line of Therapy

ISIS market research data, Synovate US HIV Monitor Q1 2006.

Per

cen

tag

e

Public Health Approach to Treatment

• Utilize 1st line regimens with predictable mutations and “dead end mutational pattern”

• Utilize 1st line regimens which allow for rational 2nd line therapies

• Be willing to change 1st line therapeutic approach based on resistance data despite costs

• Invest more heavily on community treatment support/adherence programs to ensure high level initial adherence