Silvia Bertagnolio, MDWorld Health OrganizationGeneva, Switzerland

Assessment Strategies and Interventions to Minimize the Selection and Transmission of Drug Resistant HIV in Resource Limited Settings

ART in Resource-Limited Settings

6.6 million on ART in low- and middle-income countries at the end of 2010

- 22-fold increase since 2001- 1.4 million people started ART in 2010

WHO surveys of Transmitted Drug Resistance (n=2788)

NNRTI NRTI PI

Overall prevalence of any DRM: 3.7% (95% CI 3%-4.4%)

Gupta et al., Antivir Ther, 2011: Overall Transmitted HIVDR: 2.5% - 4 %

Bertagnolio S et al., CROI 2011; Jordan M et al, Antiviral Therapy, 2011

Recently infected populations

WHO surveys: HIVDR (n=1503)

NNRTI NRTI PI

≥1 TAMs: 1.3% (N = 19; 13 pathway 2)≥3 TAMS: 0.3% (N = 4)

Chronically Infected, ARVs-naive populations

Bertagnolio S, CROI 2011 Jordan M, Antiviral Therapy, 2011

Hamers R et al., CROI 2011 # 6225.7% (95% CI 4.8-6.7)2.2%1.4%3.4%1.3%1.1%

Number of people receiving ART in low and middle income countries

Source: WHO, 2010

Emergence of HIVDR is inevitable• Time since start of ART scale-up a risk

factor for TDR (OR 1.38 per year, p<0.001)

Hammers R et al, CROI, 2011

HIVDR testing realities: RLS

• TDR is associated with poor virological outcome Wittkop, Lanc Infect Dis, 2011

• Individualized approach for HIVDR testing currently not routinely available nor recommended• Expensive: would take away resources from other important

priorities • Complex: limited capacity and infrastructure

• Limited treatment options leave little room for regimen change based on genotyping results

• Lack of accessible individual HIVDR testing should not be an excuse to limit optimization of patient care and global efforts to minimize HIVDR

Jordan M, CID, 2011

• Earlier treatment initiation of ART (CD4 <350): estimated 50% increase in the number of people eligible for ART (UNAIDS, 2010)

• Median time from seroconversion to CD4 <200 and <350 cell/mm3: 4.19 and 7.93 years, respectively

• Additional 3.7 years of exposure to ART(S.Lodi, CID, in press)

• The longer the exposure to ARVs, the greater the risk of developing HIVDR

What is the public health impact of expanded ART access on HIVDR?

• Will HIVDR increase to alarming levels?• Yes• No• Maybe

YES!HIVDR in an inevitable consequence of expanded ART coverage and prevention interventions using ARVs

More people on ART=more people failing ARTMore people failing ART=more people with HIVDR

virusTherefore, the relative contribution to new infections

from people that are failing ART with HIVDR will increase

Increased proportion of new infections that are resistant among those which are not averted

R.F.Baggaley et al. Curr Opin HIV and AIDS, 2011

NO!"Expanded coverage can reduce HIV incidence in populations, and therefore the actual number of new resistant infections"

Gill VS et al. Clin Infect Dis. 2010

• MAYBE…. 1. Fear of resistance should not be an argument against

expansion of ART coverage 2. Routine, standardized, population-based surveillance

of HIVDR is imperative 3. Robust programmatic evaluation of factors associated

with HIVDR is a critical component of successful ART scale-up

4. Operational research to identify best practices is essential

What can countries do to

minimize emergence and transmission of

HIVDR?

Factors critical to the success of global ART scale-up and the minimization of HIVDR

1. Patient factors

2. Antiretroviral drug/regimen factors

3. ART programmatic factors

1. Patient factorsStigma/discrimination

3 times more likely to be non-adherent

Lance S Rintamaki, et al. AIDS Patient Care and STDs. 2006

AdherenceTreatment interruption of 48 hours or

more associated with virological failure and selection of drug resistant HIV

Oyugi JH, et al. AIDS 2007

2. Drug/regimen factorsSuboptimal regimens- Inappropriate prescribing practices - Use of non QA drugs- Sd-NVP (PMTCT)- Drug-drug interactions- Drug toxicity- High pill burden

• Boulle A, JAMA 2008; Maartens G, Antivir Ther 2009; Parienti l, CID, 2009; Shah Sl, AIDS Res Hum Retr 2011;

• 3. Programmatic factors Burden on the health system:- Increasing demand of services- Limited human resources and infrastructure- Fragile drug procurement and supply

management systems- Lack of routine VL monitoring- Sustaining high quality service while

decentralizing care - Weak M&E system assessing quality of care and

treatment outcomes

Four-Step Approach Step 1: Assess HIVDR

1. Assess transmitted and acquired HIVDR using standardized methods

2. Routine monitoring of patients, clinic and programmatic factors contributing to HIVDR

Step 2: Operational Research

• Use findings from step 1 to guide operational research– Characterize areas of programmatic weakness– Identify appropriate targeted interventions

Step 3: Implement targeted intervention

• Using operational research findings (step 2).

Step 4: Evaluate impact of intervention

• Ideally, using same methods applied in step 1

Four-Step Approach

Laboratories undergoing assessment

Countries Implementing One or More WHO HIVDR Surveys (Feb 2011)

Laboratories accredited by WHO

Step 1

Step 1 WHO HIVDR Global Assessment Strategy

Transmission of DR HIV in recently

infected population

Surveillance

Genotyping Laboratory

TDR classified

<5%

5-15%

>15%

*Surveys to monitor HIV DR prevention and associated factors in sentinel ARV treatment sites

Emergence of HIVDR in treated

patients

Monitoring Surveys *

Genotyping, VL Laboratory

HIVDR prior ART and at 12 months; VL suppression at 12 months; use results

for programmatic adjustments

ART site factors

associated with HIVDR Emergence

Early Warning Indicators

Areas to directly target for improvement

PUBLIC HEALTH ACTION

Non-Laboratory; Data collection

only

WHO HIVDR EWI • 50 countries monitored HIVDR EWI• 131,686 patients initiating ART in the period 2004–09• 2,107 ART clinics

Bennett DE et al. (unpublished data)

Indicator% clinics

meeting target Target

Lost to follow-up (LTFU) at 12 months 69% ≤20%

Retention on appropriate 1st line ART at 12 months

67% ≥ 70%

On time pill pick-up 17% ≥90%On time appointment keeping 58% ≥ 80%Drug stock out at the level of ART clinic 65% 0%

LTFU Study (Malawi, Lilongwe)

• Assessment: of 3846 ever started ART, 48% LTFU• Operation research goals: – Understand true outcomes of LTFU– Risk factors for tracing success

• Findings: 1800 pts LTFU consented tracing

74% traced

Weigel R, et al BMC Infectious Diseases 2011

60% untraceable (no phone or address)

40% possible to trace

41% died59% alive

50% on ART at clinic40% on ART in other clinics10% stopped ART

LTFU Study (Malawi, Lilongwe)Step 2OPERATIONAL

RESEARCH

Step 3INTERVENTION

Step 4IMPACT

ASSESSMENT Having a phone number recorded doubled odds of successful tracing (aOR 2.07, p<0.001)

Regular collection of contact information introduced

Clinic is now able to successfully trace 85% (instead of 40%) of LTFU

50% of LTFU were alive and still on ART at the clinic: "2 wks after last missed visit is too early to trigger active tracing"

Time before active tracing altered from 2 to 3 weeks after last missed visit

Not assessed

40% of LTFU were silent transfer out

Improved information transfer between facilities prevent costly tracing (Not implemented)

Not assessed

Sustainability of HIV response

• In 2010, international resources forHIV declined – 2011: 16 billion $ earmarked of 24 billions $

estimated to be needed

• In 56 countries, international donors account for at least 70% of HIV resources

HIVDR surveillance sustainability

• Global Fund to fight AIDS, Tuberculosis and Malaria (GF)– largest funder of HIV programs internationally

• In 2002, mechanisms to encourage countries to implement HIVDR surveillance

• We reviewed documentation for funded HIV grants to assess grantee use of GF resources to support HIVDR Surveillance

HIVDR surveillance sustainability

• 147 HIV grants funded (2004-2008)–Only 22% (32/147) requested funding for

HIVDR Surveillance

• Baseline information and field experience suggest countries make limited use of GF resources to support national HIVDR surveillance activities

Kelley K et al. (submitted to CID)

Additional assessments will be required to evaluate the barriers to using Global Fund grants to support HIVDR Surveillance

Take-Home Messages

Fear of resistance -- not an argument against expansion of ART

Robust programmatic evaluation of factors associated with HIVDR -- a critical component of successful ART scale-up

Routine, standardized, population-based surveillance of HIVDR is imperative --- must be integrated into routine M & E programmes

Operational research to identify best practices essentialFunders and national governments must step up to

support and sustain population based HIVDR surveillance and efforts optimizing patient care

AcknowledgmentsThe Bill and Melinda Gates Foundation

Michael R. Jordan Neil ParkinAndrew PhillipsAndrea De LucaMarco Vitoria

My son Alessandro….who was born 2months ago and actively attempted to abort the preparation of thispresentation …..