Monitoring ART in Resource Limited Settings

Elly T Katabira, FRCP

Department of Medicine

Makerere University Medical School

2nd Global Experts Summit: Leading by Example in Public Health Approach to

ART. Vancouver, Canada, 13 Feb 2009

The ART response

• Success story of WHO 3 by 5 campain Over 2M on ART Scaling up access to ART continues with

unprecidented enthusiasm, supported by GFATM, PEPFAR and others

Short term gaols being achievedEmphasis is on putting patients on treatmentMorbidity and mortality down

• Longterm goals needs to be addressed now Monitoring for drug failure, resistence & adherence

ARV therapy coverage in low and middle income countries, Dec 2003

Geographical Region Number of people receiving ARV therapy

Estimated need

Coverage

         

Sub-Saharan Africa 100,000 4,400,000 2%

Latin America and the Caribbean 210,000 250,000 84%

East, South and South-East Asia 60,000 900,000 7%

Europe and Central Asia 15,000  80,000 19%

North Africa and the Middle East 1,000 75,000 5%

Total (All WHO regions) 400,000 5,900,000 7%

ARV therapy coverage in low and middle income countries, Dec 2005

Geographical Region Number of people receiving ARV therapy

Estimated need

Coverage

     (low estimate – high estimate)

   

Sub-Saharan Africa 810,000 (730,000 –890,000) 4,700,000 17%

Latin America and the Caribbean 315,000 (295,000 –335,000) 465,000 68%

East, South and South-East Asia 180,000 (150,000 –210,000) 1,100,000 16%

Europe and Central Asia 21,000  (22,000 – 22,000) 160,000 13%

North Africa and the Middle East 4,000 (3,000 –5,000) 75,000 5%

Total 1,330,000  (1.2 –1.46 million) 6.5 million 15%

Common monitoring practices in Resource Limited Settings

• At the time of ART initiation:Pre- and post-test counseling ART related counselingBaseline screening

FBC, LFTs, RFTs, etc. CD4 cell counts Rarely VL evaluation (in research centers)

Common monitoring practices in Resource Limited Settings

• During follow-upRegular counseling

AdherenceBehavior change

Clinical evaluation looking for:ART complicationsNew or worsening OIs

Lab evaluationCD4 cell counts – 0-2x a year if no problemsLFTs, etc. – only in big sites

Short comings of common ART monitoring strategies

• Quality of clinical monitoring depends on:Quality/experience of monitoring health staff Health seeking behavior of patients

Patient interactions with other providers & relatives/friends

• Lab services inadequate and expensiveLab costs/access are prohibitive at smaller units

• Adherence adversely affected by poor health systems Frequent stock outs, etc.

What happens elsewhere

• HIV care (including ART monitoring) is individualized in the North Expensive screening services

E.g. Resistance testing at ART initiationFrequent vs non-frequent lab tests – CD4 & VL

• In spite of these advances:Primary resistance is on the increaseNeed for multiple, complicated, expensive

regimens on the increase

• A road RLS should avoid at all costs

CDC Survey: Drug-Resistant HIV Among Newly Diagnosed

PatientsPrevalence of Drug Resistance, %

1998[1] (n = 257)

1999[1]

(n = 239)2000[1]

(n = 299)2003-2004[2]

(n = 633)

2003-2006[3]

(n = 3130)

Any drug 5.5 8.8 10.7 14.5 10.4

NRTI 5.1 7.1 7.7 7.1 3.6

NNRTI 0.4 2.1 1.7 8.4 6.9

PI 0 0.8 3.0 2.8 2.4

≥ 2 drug classes 0 1.3 1.3 3.1 1.9

1. Bennett D, et al. CROI 2002. Abstract 372. 2. Bennett D, et al. CROI 2005. Abstract 674.3. Wheeler W, et al. CROI 2007. Abstract 648.

Increasing prevalence of NNRTI-associated drug-resistance mutations in patients with

acute, early HIV in San Francisco

Prevalence of Drug-Resistance Mutations

2003 (n = 58)

2004(n = 54)

2005 (n = 43)

2006(n = 29)

2007(n = 40)

Any resistance 10% 11% 19% 17% 28%

NRTI 7% 6% 12% 7% 15%

NNRTI 2% 6% 9% 10% 8%

PI 9% 4% 0% 7% 8%

Jain V et al. UCSF San Francisco – CROI 2009 Abstract 673

When to Use Resistance Testing

1. Hirsch MS, et al. Clin Infect Dis. 2008;47:266-285. 2. DHHS guidelines. Available at: http://www.aidsinfo.nih.gov. Accessed January 12, 2009. 3. EACS Guidelines Version 3.

Available at: http://www.eacs.eu/guide/index.htm. Accessed October 24, 2008.

*Test source patient especially if treated with antiretroviral drugs.

IAS-USA[1] DHHS[2] European[3]

Primary/acute Recommend Recommend Recommend

Postexposure prophylaxis

-- -- Recommend*

Chronic, tx naive Recommend Recommend Recommend

Failure Recommend Recommend Recommend

Pregnancy Recommend Recommend Recommend

Pediatric -- Recommend Recommend

PREDICT-1: HLA-B*5701 Allele Screening to Reduce ABC-HSR

6-week observation period

Screen for HLA-B*5701(n = 980)

No Screening ControlABC regimen + standard

monitoring for HSR(n = 976) HLA-B*5701–positive

subjects excluded from ABC treatment

HLA-B*5701–negative subjects* treated with ABC +standard monitoring for HSR

HIV-infectedabacavir-naive

patients

(N = 1956)

*Physicians not informed of screening status.

Incidence of ABC HSR Screened for HLA-B*5701,

% (n/N)

Not Screened, % (n/N)

OR (95% CI)

P Value

Clinically suspected 3.4 (27/803) 7.8 (66/847) 0.40 (0.25-0.62) < .001

Skin patch test positive 0 (0/802) 2.7 (23/842) 0.03 (0-0.18) < .001

Mallal S, et al. N Engl J Med. 2008;358:568-579.

Possible solutions

• WHO guidelines – based on expert opinions Probably not sensitive or specific enough

• Intensified & improved clinical monitoring But poorly reflects Virologic failure

• More frequent CD4 (immunological monitoring)But also poorly reflects Virologic failure

• VL monitoring, though superior over CD4, no significant benefit to CD4 monitoring

Performance of WHO immunologic failure criteria at various viral load thresholds

Sensitivity Specificity PPV NPV

Viral load > 10,000 copies /mL

23% (18/80) 90% (946/1053)

14% (18/125)

94% (946/1008)

Viral load > 10,000 copies /mL

28% (10/36) 90% (982/1097)

8% (10/125)

97% (982/1008)

Viral load > 400 copies /mL

23% (26/112)

90% (922/1021)

21% (26/125)

91% (922/1008)

They propose periodic viral load measurements as a better alternative

Reynolds S et al. Rakai, Uganda – CROI 2009 Abstract 144

HIV-related symptoms or signs predicting treatment failure

• Prurigo• Unexplained persistent diarrhea• Unexplained persistent fever• Unexplained weight loss• Unexplained polynueritis• Unexplained cognitive impairment• Loss of individual milestones in children• Growth retardation in children

Colebunders et al. The Lancet Vol 6 2006

Proposed steps to assess virological treatment failure

• Colebunders et al – The Lancet vol 6 2006Obtain an ART treatment history

Including monotherapy for PMTCT

Assess quality of HAART regimen and concomitant medication

Assess adherence to treatmentNeed good and experienced counselors

Assess clinical symptom development and lab test resultsVL testing in selected patients

Some suggested monitoring strategies

• Selected VL for problem casesNeed guidelines for selection criteria

OR for effectiveness of such guidelines

• Refine clinical monitoring with enhanced supervision – The Senegal model

• Use CD4 count gain to triage for VL VL if CD4 gain <50 cells/µl in 6 months –

particularly if had low BL CD4 countBisson G et al. AIDS 2006, 20:1613-1619

Conclusions

• All patients on ART should have a VL at least once a year

• Clinical monitoring, adherence profile and CD4 testing should be used to prioritize VL needs

• Operation research should be done to refine the criteria as who should have a VL when resources are limited