Doug Richman INTEREST WORKSHOP

8 May 2015

Principles and reality of HIV drug resistance in sub-Saharan Africa

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PRE RX

PRE RX

GAFFKY COUNT

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SPUTUM CULT.

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WEEKS OF TREATMENT CLINICAL DATA DURING SIXTEEN WEEKS OF INH THERAPY

Coates et al, The Clinical Significance... N Engl J Med 248:1085, 1953

2 4 6 8 10 12 14 16 0 0

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“RESISTANT”

SLIGHT

INTERMEDIATE

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WEEKS OF TREATMENT Coates et al, The Clinical Significance... N Engl J Med 248:1083, 1953

INH SUSCEPTIBILITY OF ISOLATES FROM PATIENTS WITH PULMONARY TB TREATED WITH INH MONOTHERAPY

Colonies Prevalence Number Inoculum* Drug per plate of resistance of plates per plate conc. (actual) mutants µg./ml. 4 5 x 106 INH† 1.0 99.101, 1 in 5 x 104 106,107 4 5 x 107 SM‡ 2.0 55, 59 1 in 1 x 106 64,70 100 1 x 108 INH 1.0 No growth

HIV-1 Drug Resistance is the RESULT and the CAUSE of drug failure

Emergence of drug-resistant virus is an inevitable consequence of the failure to fully suppress HIV-1 (HCV, HBV, influenza virus, TB, etc) replication with antiviral therapy.

Drug resistance is a major factor

contributing to the failure of antiretroviral therapy.

Diversity of RNA Virus Populations

RNA viruses constitute a quasispecies. Genetically distinct viral variants evolve

from an initial monoclonal or oligoclonal virus inoculum. Variants are generated due to error-

prone nature of RT.

Drug-Resistant Mutants Preexist in Untreated Patients

The HIV genome contains 104 nucleotides. The mutation rate of HIV is ~3 x 10-5

nucleotides/ replication cycle. ~1011 virions are generated by 107 - 108

rounds of replication each day.

Preexisting Drug Resistance Mutations

Single mutants produced daily Isolated from treatment-naive patients or

those infected before antiretroviral drug availability

Double mutants less common 3 or more specific resistance mutations

in the same genome rare

Rapid Turnover of Viral Quasispecies

Most of the virus population in plasma is cleared and replaced each day. Rapid turnover allows rapid emergence of drug-

resistant variants under selective pressure. Resistant variants may be replaced by residual

wild-type virus if selective pressure is removed. Resting latently infected cells may continue to

harbor drug-resistant provirus.

HIV-1 infection and a model of the distribution of viral quasispecies in the era of antiretroviral therapy

Metzner, Future Virology 1:377, 2006

HIV drug resistance is generated by one of two major mechanisms

• Both mechanisms are too prevalent. • Prevention strategies for these two mechanisms are completely different.

Acquired resistance following non- suppressive treatment

(secondary resistance) Transmitted resistance (primary resistance)

A036D (20 mos) A036C

(11 mos)

A036B (2 mos)

AZT Susceptibility of Sequential Isolates of HIV-1 From a Patient Administered AZT

Plaq

ue re

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ion

(%) 0

50

100 0.001 0.01 0.1 1 10

AZT (µM)

Larder, Darby and Richman, Science 1989; 243:1731.

HCSUS: Prevalence of HIV Drug Resistance HCSUS population

Representative as possible to all HIV-positive persons receiving medical care in early 1996

1080 samples with HIV RNA >500 copies/mL

Resistance more common Lowest CD4 count nadir Higher HIV RNA More access to care

Resistance less common Patients cared for by the

most experienced providers

Prop

ortio

n W

ith

Phen

otyp

ic R

esis

tanc

e

Any NRTI NNRTI PI >2 3

78% 70%

31%

42% 51%

14%

Richman et al, AIDS 18:1393, 2004

Drug Drug Classes

14

Transmission of Drug-Resistant HIV in Treatment-Naïve Patients

Little SJ, et al. N Engl J Med. 2002;347:385-394

1995 1996 1997 1998 1999 2000 (n=11) (n=56) (n=101) (n=97) (n=90) (n=23)

Phen

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ic R

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e (%

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IC50 >10-fold increase via PhenoSense HIV (ViroLogic)

NNRTI

PI

NRTI

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1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

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ual I

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)

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Increasing proportion of VL levels

How did this reduction in resistance with more expanded treatment happen?

Better drugs More potent and better half-lives

(TDF/FTC, better PIs, integrase inhibitors) More tolerable and less toxic (thymidine

analogues are history) Fixed dose combinations

Better monitoring of failure and then use

of drug resistance testing and better drugs for treatment failure

Aimed to boost efforts to provide access to antiretroviral drugs that have saved hundreds of thousands of lives in Europe and the US to the growing number of people with HIV/AIDS in low and middle income countries who need them.

GENEVA/DAKAR, 12 DECEMBER 2002 - HIV Treatment Access Coalition (ITAC)

Joep Lange the then president of the IAS: “if we can get cold Coca Cola to every remote corner of Africa, it should not be impossible to do the same with drugs”

7,2

11,1

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6 to 11 12 to 23 24 to 35 ≥36

% o

f Pat

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Months on ART Figure 1. Changes in rates of acquired HIVDR to any drug class according duration of treatment. HIVDR=human immunodeficiency virus drug resistance. ART=antiretroviral therapy.

Stadeli and Richman, Antiviral Therapy 18(1):115-23, 2013

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nce

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NRTI

NNRTI

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Figure 2. Distribution of acquired HIVDR to individual drug classes according to time on antiretroviral therapy Stadeli and Richman, Antiviral Therapy 18(1):115-23, 2013

4,0

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Pham et al, AIDS, 2014

Cost of continuing a regimen failing as defined by virologic criteria

♦ CNA3005: ZDV/3TC/ABC vs. ZDV/3TC/IDV

♦ “First genotype” performed at time of rebound

♦ “Last genotype” performed prior to changing ART

♦ Early breakthrough with wild type or M184V

♦ Increasing NRTI mutations associated with cross-resistance to all RTIs

Melby T, et al. 8th CROI; 2001; Chicago, Ill. Abstract 448

0

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0–8 9–16 17–24 25–32 33–40 41–48 Weeks

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ent o

f Pat

ient

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M184V + other NRTI mutation M184V or wild type

39 34 28 24 20 16 n =

Rapid accumulation of DRMs when first-line ART is continued despite virological failure

Steep increase in TAMs (+250%) and K65R (+100%) NNRTI susceptibility is already lost at first detection of VF

Precedes WHO-defined failure criteria

Barth et al. Antiviral Therapy 2012

Longitudinal genotyping analysis at first detection of VF (t1) and 6-12 months after (t2)

How much will resistance impact the benefits of the antiretroviral rollout in resource-limited countries?

We have been using suboptimal regimens for treatment and for MTCT.

We are assessing failure by clinical or CD4 endpoints.

We are not optimally monitoring virologic failure in individuals or resistance in populations (both acquired and transmitted).

Access to antiretroviral therapy has been a remarkable achievement with a dramatic impact on almost 12 million individuals in resource-limited countries; however,

FCHR-HCV DRAG

Say NO To CRAP Therapy

Continued Replication under Antiviral Pressure

Continued replication in the presence of drug will likely

lead to further evolution of the viral population. In theory, further evolution can result in a more fit, drug-

resistant viral population that may remain enriched in the patient, even in the absence of drug pressure.

This should be prevented by discontinuing the direct

acting antiviral if a patient has a confirmed increase in HCV RNA levels while adhering to therapy.

Stuart Ray

Prevention of acquired drug resistance requires addressing the causes

The patient adherence

The prescribing care provider selecting an optimal regimen counseling the patient

The drugs Potency tolerability pharmacokinetics

Additional factors specific to LMIC that contribute to the emergence of HIV

drug resistance

Suboptimal Regimens Thymidine analogues Insufficient second-line and salvage regimens

Failure of methods and resources to monitor viral loads

Drug distribution (stock-outs) Perinatal PMTC rather than treating pregnant

women with ART (option B+)

Summary

The principles of HIV drug resistance are well established (Darwinian evolution).

The mistakes and lessons learned in the developed world are being recapitulated in low and middle income countries.

Prevention of further increases in drug resistance Better regimens Avoid stockouts Monitor viral load Interventions to improve adherence and

reduced risk behaviors

Principles and reality of HIV drug resistance �in sub-Saharan AfricaSlide Number 2Slide Number 3Slide Number 4HIV-1 Drug Resistance is the RESULT and the CAUSE of drug failureDiversity of RNA Virus PopulationsDrug-Resistant Mutants Preexist in Untreated PatientsPreexisting Drug Resistance MutationsRapid Turnover of Viral QuasispeciesSlide Number 10Slide Number 11Slide Number 12HCSUS:�Prevalence of HIV Drug ResistanceTransmission of Drug-Resistant HIV�in Treatment-Naïve PatientsImproved Virologic Outcomes Concomitant with Decreasing Incidence of Drug ResistanceSlide Number 16Slide Number 17GENEVA/DAKAR, 12 DECEMBER 2002�- HIV Treatment Access Coalition (ITAC) Acquired Drug ResistanceAcquired Drug ResistanceTransmitted Drug ResistanceSlide Number 22Cost of continuing a regimen failing as defined by virologic criteriaRapid accumulation of DRMs when first-line ART is continued despite virological failureHow much will resistance impact the benefits of the antiretroviral rollout in resource-limited countries?Say NO To CRAP TherapyPrevention of acquired drug resistance requires addressing the causesAdditional factors specific to LMIC that contribute to the emergence of HIV drug resistanceSummary