Title: How accurately do the WHO 2010 immunological or clinical criteria predict virological failure in adults and children receiving ART? Contents

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Title: How accurately do the WHO 2010 immunological or clinical criteria predict virological failure in adults and children receiving ART?

1. PICT question

P People living with HIV

I 2010 WHO clinical and immunological criteria*

C Other clinical and immunological criteria T Treatment failure

2. Search strategy

PubMed search strategy: Predicting treatment failure

Search Query

#5 Search #1 AND #2 AND #3 AND #4

#4 Search (HIV Infections[MeSH] OR HIV[MeSH] OR hiv[tiab] OR hiv-1[tiab] OR hiv-2*[tiab]

OR hiv1[tiab] OR hiv2[tiab] OR hiv infect*[tiab] OR human immunodeficiency virus[tiab]OR human immune deficiency virus[tiab] OR human immuno-deficiency virus[tiab] OR human immune-deficiency virus[tiab] OR ((human immun*)

AND(deficiency virus[tiab])) OR acquired immunodeficiency syndromes[tiab] OR acquired immune deficiency syndrome[ tiab] OR acquired immuno-deficiency syndrome[ tiab] OR acquired immune-deficiency syndrome[ tiab] OR ((acquired immun*) AND (deficiency syndrome[tiab]) or “sexually transmitted diseases, viral”[mh]) OR HIV[tiab] OR HIV/AIDS[tiab] OR HIV-infected[tiab] OR HIV[title] OR HIV/AIDS[title] OR HIV- infected[title])

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Search Query

#3 Search ("CD4-Positive T-Lymphocytes"[Mesh] OR CD4[tw]) OR ("Viral Load"[Mesh] OR

"viral load"[tw])

#2 Search "Predictive Value of Tests"[Mesh] OR "Sensitivity and Specificity"[Mesh] OR

"Diagnostic Techniques and Procedures"[Mesh] OR ((clin*[tiab] OR immun*[tiab]) AND criteri*[tiab]) OR (("World Health Organization"[Mesh]) OR "World Health

Organization"[tiab] AND criteri*[tiab]) OR diagnos*[tiab]

#1 Search "Treatment Failure"[Mesh] OR "Drug Monitoring"[Mesh] OR "Drug Resistance, Viral"[Mesh] OR "treatment failure"[tiab] OR "viral failure"[tiab] OR "virologic

failure"[tiab] OR "virological failure"[tiab] OR (monitor*[tiab] AND switch*[tiab])

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3. Flow diagram of screening process

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4. Evidence summaries

4.1.Treatment

failure among

adults

In 2006, WHO published clinical and immunological criteria for diagnosing treatment failure (WHO 2006). These criteria were:

• a new or recurrent WHO stage 4 condition, which is not immune reconstitution inflammatory syndrome (IRIS) (clinical criterion);

• fall of CD4 count to baseline or below OR 50% fall in CD4 count from on-treatment peak value OR persistent CD4 levels below 100 cells/mm³ in the absence of concomitant infection that can cause a transient CD4 cell count decline (immunological criterion).

In 2010, this definition was expanded to include viral load testing, which is triggered when clinical or immunological criteria are met, with a threshold value of 5000 copies/ml. Thus, the 2010 definition is:

• a new or recurrent WHO stage 4 condition, which is not IRIS;

OR

• fall of CD4 count to baseline or below OR 50% fall in CD4 count from on-treatment peak value OR persistent CD4 levels below 100 cells/mm³ in the absence of concomitant infection that can cause a transient CD4 cell count decline;

AND

• plasma viral load >5000 copies/ml.

We identified 25 studies conducted in adults that addressed various aspects of how to define treatment failure. Of these, 14 actually assessed the WHO definition of treatment failure comparing immunological and/or clinical criteria to different plasma viral load levels and provide sufficient data to calculate individual cell sizes. Three studies reported how these criteria predicted a plasma viral load >5000 copies/ml (Labhardt, 2012; Moore, 2009; Reynolds, 2009); one of these provided sufficient data to calculate positive predictive value only (Labhardt, 2012). The overall performance characteristics of the immunological criterion were a sensitivity of 68.8%, a specificity of 92.1%, a positive predictive value of 27.0% and a negative predictive value of 98.6% (of these, only positive predictive value was calculated using data from all three studies). Only one study (Labhardt 2012) reported the performance of clinical criteria and either immunological or clinical criteria. In this study, the clinical criterion had a positive predictive value of 100% (based on a single patient), and either immunological or clinical criteria had a positive predictive value of 51.1%.

Thirteen studies evaluated the clinical and immunological criteria using lower plasma viral load values, ranging from 400 to 1000 copies/ml (Abouyannis, 2011; Chaiwarth, 2007; Hosseinipour, 2011; Kantor, 2009; Labhardt, 2012; Mee, 2006; Mee 2008; Meya, 2009; Moore, 2008; Rawizza, 2011; Rewari, 2010;

Reynolds, 2009; van Oosterhout, 2009), and two evaluated a less stringent plasma viral load level of 10 000 copies/ml (Mee, 2008; Rewari 2010). Of those defining virological failure based on plasma viral loads <5000 copies/ml, 12 reported the performance of immunological criteria, seven the performance of clinical criteria and seven the performance of either immunological or clinical criteria (Table 1).

Two studies used a higher plasma viral load (>10 000 copies/ml) to define virological failure (Keiser, 2009; Reynolds, 2009). Comparing WHO immunological criteria, they found a sensitivity of 16.8%, a specificity of 95.5%, a positive predictive value of 15.0% and a negative predictive value of 96.0%.

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4.2.Treatment

failure among children

Table 1. Ability of WHO immunological and criteria to predict viral failure (plasma viral load 50–

1000 copies/ml

Criterion Studies Sensitivity Specificity Positive

predictive value

Negative predictive value Immunological Abouyannis 2011;

Chaiwarth 2007; Kantor 2009; Labhardt 2012; Mee 2006; Mee 2008; Meya 2009; Moore 2008;

Rawizza 2011; Rewari 2010; Reynolds 2009; van Oosterhout 2009

55.6% 74.5% 29.8% 89.6%

Clinical Chaiwarth 2007;

Hosseinipour 2011;

Labhardt 2012; Mee 2006;

Mee 2008; Rewari 2010;

van Oosterhout 2009

54.8% 86.3% 45.2% 90.2%

Immunological or clinical

Abouyannis 2011;

Chaiwarth 2007; Labhardt 2012; Mee 2008; Meya 2009; Rewari 2010; van Oosterhout 2009

75.1% 76.9% 49.4% 91.1%

For 2- to 4-year-old children, WHO defines immunological failure as a CD4 count of <200 cells/mm³ or a CD4 percentage of <10% and <100 cells/mm³ for children ≥5 years old and virological failure as >5000 copies/ml. There are not comparable clear-cut clinical criteria as there are for adults. The guidance reads:

“New or recurrent WHO clinical stage 4 conditions may warrant a switch in treatment regimen, although if the CD4 value remains above the age-related thresholds, it may be acceptable to delay switching.” Thus, we evaluated the performance of immunological criteria for predicting virological failure.

We identified nine studies. Four studies compared the 2010 WHO immunological failure criteria with viral load in children. Three studies used >5000 copies/ml to define virological failure (Barlow-Mosha 2012; Davies, 2012; Westley 2012) and evaluated a total of 4100 patients. In combination, these studies found that WHO immunological criteria had a sensitivity of 4.5%, a specificity of 99.2%, a positive predictive value of 54.9% and a negative predictive value of 85.4%. One study evaluated the 2010 criteria using a definition of virological failure of >400 copies/ml (Davies, 2011), evaluating 2256 patients. The investigators found that the immunological criteria had a sensitivity of 6.3%, a specificity of 97.7%, a positive predictive value of 20% and a negative predictive value of 91.8% using the more stringent virological failure criteria.

Table 2 summarizes the results for adults and children.

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Table 2. Ability of WHO immunological criteria to predict virological failure, adults and children on antiretroviral therapy, by viral load

Populatio n

Viral load No. of studie

s

n Sensitivit y

Specificit y

Positive predictive

value

Negative predictive

value

Adults >5 000 copies/ml 3 2288 68.9% 92.1% 27.0% 98.6%

Adults 50–4 999

copies/ml

12 15581 55.6% 74.5% 29.8% 89.6%

Adults >10 000 copies/ml 2 3142 16.8% 95.5% 15.0% 96.0%

Children >5 000 copies/ml 3 4100 4.5% 99.3% 54.9% 85.5%

Children >400 copies/ml 1 2256 6.3% 97.7% 20.0% 91.8%

4.3.References

Abouyannis M, Menten J, Kiragga A, et al. Development and validation of systems for rational use of viral load testing in adults receiving first-line ART in sub-Saharan Africa. AIDS 2011; 25: 1627-35.

Barlow-Mosha L, Mudilpe P, Massavon W, et al. Validation of WHO 2010 immunologic criteria in predicting pediatric first-line antiretroviral treatment (ART) failure in ART-experienced children in Uganda: CD4 is a poor surrogate for virologic monitoring of pediatric ART failure [Abstract THPE062].

19th International AIDS Conference, Washington, DC, 22-27 July 2012.

Chaiwarith R, Wachirakaphan C, Kotarathitutium W, Praparatanaphan J, Sirisanthan T, Supparatpinyo K.

Sensitivity and specificity of using CD4⁺ measurement and clinical evaluation to determine antiretroviral treatment failure in Thailand. Int J Infect Dis 2007; 11:413-16.

Davies M-A, Boulle A, Eley B, et al. Accuracy of immunological criteria for identifying virological failure in children on antiretroviral therapy – the IeDEA Southern Africa Collaboration. Trop Med Int Health 2011;16:1367-71.

Davies M-A, Boulle A, Technau K, et al. The role of targeted viral load testing in diagnosing virological failure in children on antiretroviral therapy with immunological failure. Trop Med Int Health 2012 Sep 14.

doi: 10.1111/j.1365-3156.2012.03073.x. [Epub ahead of print]

Hosseinipour M, van Oosterhout J, Weigel R, et al. Validating clinical and immunological definitions of antiretroviral treatment failure in Malawi [Abstract WEAB101]. 4th IAS Conference on HIV

Pathogenesis, Treatment and Prevention, Sydney, Australia, 22-25 July 2007.

Kantor R, Diero L, DeLong A, et al. Misclassification of first-line antiretroviral treatment failure based on immunological monitoring of HIV infection in resource-limited settings. Clin Infect Dis 2009; 49:454-62.

Keiser O, MacPhail P, Boulle A, et al. Accuracy of WHO CD4 cell count criteria for virological failure of antiretroviral therapy. Trop Med Int Health 2009; 14:1220-25.

Labhardt ND, Lejone T, Setoko M, et al. A clinical prediction score in addition to WHO criteria for antiretroviral treatment failure in resource-limited settings - expeirence from Lesotho. PLoS ONE 2012;

7(10):e47937.

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Mee P, Fielding K, Charalambous S, et al. Evaluation of World Health Organization criteria for

antiretroviral treatment failure in resource-limited settings [Abstract WEPE065]. XVI International AIDS Conference, Toronto, Canada, 13-18 August 2006.

Mee P, Fielding KL, Charalmbous S, Churchyard GJ, Grant AD. Evaluation of WHO criteria for antiretroviral treatment failure among adults in South Africa. AIDS 2008; 22:1971-77.

Meya D, Spacek LA, Tibenderana H, et al. Development and evaluation of a clinical algorithm to monitor patients on antiretrovirals in resource-limited settings using adherence, clinical and CD4 cell count criteria. J Int AIDS Soc 2009; 12:3.

Moore DM, Awor A, Downing R, Kaplan J, Montaner JSG, Hancock J, Were W, Mermin J. CD4⁺ T-cell count monitoring does not accurately identify HIV-infected adults with virologic failure receiving antiretroviral therapy. J Acquir Immune Defic Syndr 2008; 49:477-84.

Rawizza HE, Chaplin B, Meloni ST, et al. Immunologic criteria are poor predictors of virologic outcome:

implications for HIV treatment monitoring in resource-limited settings. Clin Infect Dis 2011; 53:1283-90.

Rewari BB, Bachani D, Rajasekaran S, Deshpande A, Chan PL, Srikantiah P. Evaluating patients for second-line antiretroviral therapy in India: the role of targeted viral load testing. J Acquir Immune Defic Syndr 2010; 55:610-14.

Reynolds SJ, Nakigozi G, Newell K, et al. Failure of immunologic criteria to appropriately identify antiretroviral treatment failure in Uganda. AIDS 2009; 23:697-700.

van Oosterhout JJG, Brown L, Weigel R, et al. Diagnosis of antiretroviral therapy failure in Malawi: poor performance of clinical and immunological WHO criteria. Trop Med Int Health 2009; 14:856-61.

Westley BP, DeLong AK, Tray CS, et al. Prediction of treatment failures using 2010 World Health Organization guidelines is associated with high misclassification rate and drug resistance among HIV- infected Cambodian children. Clin Infect Dis 2012; 55:432-40.

5. Bibliography of included studies 5.1. Population: adults

1. Abouyannis M, Menten J, Kiragga A, et al. Development and validation of systems for rational use of viral load testing in adults receiving first-line ART in sub-Saharan Africa. AIDS 2011; 25: 1627-35.

2. Chaiwarith R, Wachirakaphan C, Kotarathitutium W, Praparatanaphan J, Sirisanthan T,

Supparatpinyo K. Sensitivity and specificity of using CD4⁺ measurement and clinical evaluation to determine antiretroviral treatment failure in Thailand. Int J Infect Dis 2007; 11:413-16.

3. Hosseinipour M, van Oosterhout J, Weigel R, et al. Validating clinical and immunological definitions of antiretroviral treatment failure in Malawi [Abstract WEAB101]. 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, Australia, 22-25 July 2007.

4. Kantor R, Diero L, DeLong A, et al. Misclassification of first-line antiretroviral treatment failure based on immunological monitoring of HIV infection in resource-limited settings. Clin Infect Dis 2009; 49:454-62.

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5. Keiser O, MacPhail P, Boulle A, et al. Accuracy of WHO CD4 cell count criteria for virological failure of antiretroviral therapy. Trop Med Int Health 2009; 14:1220-25.

6. Labhardt ND, Lejone T, Setoko M, et al. A clinical prediction score in addition to WHO criteria for anti-retroviral treatment failure in resource-limited settings – expeirence from Lesotho. PLoS ONE 2012; 7(10):e47937.

7. Mee P, Fielding K, Charalambous S, et al. Evaluation of World Health Organization criteria for antiretroviral treatment failure in resource-limited settings [Abstract WEPE065]. XVI International AIDS Conference, Toronto, Canada, 13-18 August 2006.

8. Mee P, Fielding KL, Charalmbous S, Churchyard GJ, Grant AD. Evaluation of WHO criteria for antiretroviral treatment failure among adults in South Africa. AIDS 2008; 22:1971-77.

9. Meya D, Spacek LA, Tibenderana H, et al. Development and evaluation of a clinical algorithm to monitor patients on antiretrovirals in resource-limited settings using adherence, clinical and CD4 cell count criteria. J Int AIDS Soc 2009; 12:3.

10. Moore DM, Awor A, Downing R, Kaplan J, Montaner JSG, Hancock J, Were W, Mermin J. CD4⁺ T- cell count monitoring does not accurately identify HIV-infected adults with virologic failure receviing antiretroviral therapy. J Acquir Immune Defic Syndr 2008; 49:477-84.

11. Rawizza HE, Chaplin B, Meloni ST, et al. Immunologic criteria are poor predictors of virologic outcome: implications for HIV treatment monitoring in resource-limited settings. Clin Infect Dis 2011;

53:1283-90.

12. Rewari BB, Bachani D, Rajasekaran S, Deshpande A, Chan PL, Srikantiah P. Evaluating patients for second-line antiretroviral therapy in India: the role of targeted viral load testing. J Acquir Immune Defic Syndr 2010; 55:610-14.

13. Reynolds SJ, Nakigozi G, Newell K, et al. Failure of immunologic criteria to appropriately identify antiretroviral treatment failure in Uganda. AIDS 2009; 23:697-700.

14. van Oosterhout JJG, Brown L, Weigel R, et al. Diagnosis of antiretroviral therapy failure in Malawi:

poor performance of clinical and immunological WHO criteria. Trop Med Int Health 2009; 14:856-61.

5.2. Population: children

1. Barlow-Mosha L, Mudilpe P, Massavon W, et al. Validation of WHO 2010 immunologic criteria in predicting pediatric first-line antiretroviral treatment (ART) failure in ART-experienced children in Uganda: CD4 is a poor surrogate for virologic monitoring of pediatric ART failure [Abstract THPE062]. 19th International AIDS Conference, Washington, DC, July 22-27, 2012.

2. Davies M-A, Boulle A, Eley B, et al. Accuracy of immunological criteria for identifying virological failure in children on antiretroviral therapy – the IeDEA Southern Africa Collaboration. Trop Med Int Health 2011;16:1367-71.

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3. Davies M-A, Boulle A, Technau K, et al. The role of targeted viral load testing in diagnosing virological failure in children on antiretroviral therapy with immunological failure. Trop Med Int Health 2012 Sep 14. doi: 10.1111/j.1365-3156.2012.03073.x. [Epub ahead of print]

4. Westley BP, DeLong AK, Tray CS, et al. Prediction of treatment failures using 2010 World Health Organization guidelines is associated with high misclassification rate and drug resistance among HIV-infected Cambodian children. Clin Infect Dis 2012; 55:432-40.

6. Excluded studies 6.1. Population: adults

1. Badri M, Lawn SD, Wood R. Utility of CD4 cell counts for early prediction of virological failure during antiretroviral therapy in a resource-limited setting. BMC Infect Dis 2008; 8:89.

2. Bisson GP, Gross R, Stram J, et al. Diagnostic accuracy of CD4 cell count increase for virologic response after initiating highly active antiretroviral therapy. AIDS 2006; 20:1613-19.

3. Castelnuovo B, Sempa J, Kiragga AN, Kamya MR, Manabe YC. Evaluation of WHO criteria for viral failure in patients on antiretroviral treatment in resource-limited settings. AIDS Res Treatment 2011;

2011:736938.

4. De Luca A, Marazzi MC, Mancinelli S, et al. Prognostic value of virological and immunological responses after 6 months of antiretroviral treatment in adults with HIV-1 infection in sub-Saharan Africa. J Acquir Immune Defic Syndr 2012; 59:236-44.

5. Jourdain G, Ngo-Giang-Huong N, LeCoeur S, et al. PHPT-3: a randomized clinical trials comparing CD4 vs viral load ART monitoring/switching strategies in Thailand [Abstract 44]. Conference on Retroviruses and Opportunistic Infections, Boston, Massachusetts, 27 February-2 March, 2011.

6. Kanapathipillai R, McGuire M, Mogha R, Szumilin E, Heinzelmann A, Pujades-Rodriguez M.

Benefit of viral load testing for confirmation of immunological failure in HIV patients treated in rural Malawi. Trop Med Int Health 2011; 16:1495-1500.

7. Kiragga AN, Castelnuovo B, Kamya MR, Moore R, Manabe YC. Regional differences in predictive accuracy of WHO immunological failure criteria. AIDS 2012; 26:768-70.

8. Koethe JR, Westfall AO, Luhanga DK, et al. A cluster randomized trial of routine HIV-1 viral load monitoring in Zambia: study design, implementation, and baseline cohort characteristics. PLoS ONE 2010;5(3): e9680.

9. Lynen L, An S, Koole O, et al. An algorithm to optimize viral load testing in HIV-positive patients with suspected first-line antiretroviral therapy failure in Cambodia. J Acquir Immune Defic Syndr 2009; 52:40-48.

10. Lynen L, Thai S, De Munter P, et al. The added value of a CD4 count to identify patients eligible for highly active antiretroviral therapy among HIV-positive adults in Cambodia. J Acquir Immune Defic Syndr 2006; 42: 322-24.

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11. Mermin J, Ekwaru JP, Were W, et al. Utility of routine viral load, CD4 cell count, and clinical monitoring among adults with HIV receiving antretroviral therapy in Uganda: randomised trial. BMJ 2011; 343:d6792.

6.2. Population: children

1. Davies M-A, Bolton-Moore C, Eley B, et al. Predicting 1-year mortatliy using CD4 percent and count in children receiving ART [Presentation]. 3rd International Workshop on HIV Pediatrics, Rome, Italy, July 15-16, 2011.

2. Germanaud D, Derache A, Traore M, et al. Level of viral load and antiretroviral resistance after 6 months of non-nucleoside reverse transcriptase inhibitor first-line therapy in HIV-1-infected children in Mali. J Antimicrob Chemother 2010; 65:118-24.

3. Oliveira R, Krauss M, Essama-Bibi S, et al. Viral load predicts new world health organization stage 3 and 4 events in HIV-infected children receiving highly active antiretroviral therapy, independent of CD4 T lymphocyte value. Clin Infect Dis 2010; 51:1325-33.

4. PENPACT-1 (PENTA 9/PACTG 390) Study Team. First-line antiretroviral therapy with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor and switch at higher versus low viral load in HIV-infected children: an open-label, randomised phase 2/3 tirals. Lancet Infect Dis 2011;

111:273-84.

5. Siberry GK, Harris DR, Oliveira RH, et al. Evaluation of viral load thresholds for predicting new World Health Organization stage 3 and 4 events in HIV-infected children receiving highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2012; 60:214-18.