Article

Accuracy of immunological criteria for identifying virological failure in children on antiretroviral therapy - The IeDEA Southern Africa Collaboration

School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa.
Tropical Medicine & International Health (Impact Factor: 2.33). 08/2011; 16(11):1367-71. DOI: 10.1111/j.1365-3156.2011.02854.x
Source: PubMed

ABSTRACT

To determine the diagnostic accuracy of World Health Organization (WHO) 2010 and 2006 as well as United States Department of Health and Human Services (DHHS) 2008 definitions of immunological failure for identifying virological failure (VF) in children on antiretroviral therapy (ART).
Analysis of data from children (<16 years at ART initiation) at South African ART sites at which CD4 count/per cent and HIV-RNA monitoring are performed 6-monthly. Incomplete virological suppression (IVS) was defined as failure to achieve ≥1 HIV-RNA ≤400 copies/ml between 6 and 15 months on ART and viral rebound (VR) as confirmed HIV-RNA ≥5000 copies/ml in a child on ART for ≥18 months who had achieved suppression during the first year on treatment.
Among 3115 children [median (interquartile range) age 48 (20-84) months at ART initiation] on treatment for ≥1 year, sensitivity of immunological criteria for IVS was 10%, 6% and 26% for WHO 2006, WHO 2010 and DHHS 2008 criteria, respectively. The corresponding positive predictive values (PPV) were 31%, 20% and 20%. Diagnostic accuracy for VR was determined in 2513 children with ≥18 months of follow-up and virological suppression during the first year on ART with sensitivity of 5% (WHO 2006/2010) and 27% (DHHS 2008). PPV results were 42% (WHO 2010), 43% (WHO 2006) and 20% (DHHS 2008).
Current immunological criteria are unable to correctly identify children failing ART virologically. Improved access to viral load testing is needed to reliably identify VF in children.

Full-text

Available from: Karl-Günter Technau, Dec 20, 2013
Accuracy of immunological criteria for identifying virological
failure in children on antiretroviral therapy The IeDEA
Southern Africa Collaboration
Mary-Ann Davies
1
, Andrew Boulle
1
, Brian Eley
2
, Harry Moultrie
3
, Karl Technau
4
, Helena Rabie
5
,
Gilles van Cutsem
1,6
, Janet Giddy
7
, Robin Wood
8
, Matthias Egger
9
and Olivia Keiser
9
for the International
epidemiologic Databases to Evaluate AIDS Southern Africa (IeDEA-SA) Collaboration
1 School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa
2 Red Cross Children’s Hospital and School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa
3 Wits Institute for Sexual Reproductive Health, HIV & Related Diseases, University of the Witwatersrand, Johannesburg, South Africa
4 Empilweni Service and Research Unit, Rahima Moosa Mother and Child Hospital, University of the Witwatersrand, Johannesburg,
South Africa
5 Tygerberg Academic Hospital, University of Stellenbosch, Stellenbosch, South Africa
6 Khayelitsha ART Programme and Me
´
decins Sans Frontie
`
res, Khayelitsha, South Africa
7 McCord Hospital, Durban, South Africa
8 Gugulethu Community Health Centre and Desmond Tutu HIV Centre, Institute of Infectious Diseases and Molecular Medicine,
University of Cape Town, Cape Town, South Africa
9 Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
Summary objectives To determine the diagnostic accuracy of World Health Organization (WHO) 2010 and
2006 as well as United States Department of Health and Human Services (DHHS) 2008 definitions of
immunological failure for identifying virological failure (VF) in children on antiretroviral therapy
(ART).
methods Analysis of data from children (<16 years at ART initiation) at South African ART sites at
which CD4 count per cent and HIV-RNA monitoring are performed 6-monthly. Incomplete virological
suppression (IVS) was defined as failure to achieve 1 HIV-RNA £400 copies ml between 6 and
15 months on ART and viral rebound (VR) as confirmed HIV-RNA 5000 copies ml in a child on ART
for 18 months who had achieved suppression during the first year on treatment.
results Among 3115 children [median (interquartile range) age 48 (20–84) months at ART initiation]
on treatment for 1 year, sensitivity of immunological criteria for IVS was 10%, 6% and 26% for WHO
2006, WHO 2010 and DHHS 2008 criteria, respectively. The corresponding positive predictive values
(PPV) were 31%, 20% and 20%. Diagnostic accuracy for VR was determined in 2513 children with
18 months of follow-up and virological suppression during the first year on ART with sensitivity of 5%
(WHO 2006 2010) and 27% (DHHS 2008). PPV results were 42% (WHO 2010), 43% (WHO 2006)
and 20% (DHHS 2008).
conclusion Current immunological criteria are unable to correctly identify children failing ART
virologically. Improved access to viral load testing is needed to reliably identify VF in children.
keywords children, antiretroviral therapy, immunological criteria, sensitivity, specificity,
virological failure
Introduction
Poor access to viral load testing in resource-limited settings
results in reliance on immunological criteria to identify
treatment failure in patients on antiretroviral therapy
(ART). Studies in adults have shown limited value of
immunological criteria to detect virological failure (VF)
(Badri et al. 2008; Mee et al. 2008; Keiser et al. 2009).
While low sensitivity of immunological criteria for identi-
fying VF could result in delayed switching to second-line
treatment with accumulation of resistance mutations, low
positive predictive value (PPV) may incorrectly identify
patients as needing second-line treatment when they are
virologically suppressed. The few paediatric studies of
Tropical Medicine and International Health doi:10.1111/j.1365-3156.2011.02854.x
volume 00 no 00
ª 2011 Blackwell Publishing Ltd 1
Page 1
diagnostic accuracy of immunological criteria for VF are
limited by small cohort size and or VF definition based on
single elevated HIV-RNA measurements (Jittamala et al.
2009; Emmett et al. 2010; Ruel et al. 2010). We analysed
data from routine paediatric ART clinics to determine the
diagnostic accuracy of WHO (2006, 2010) and United
States Department of Health and Human Services (DHHS)
2008 (National Institutes of Health 2008) criteria for
immunological failure for identifying (i) incomplete
virological suppression (IVS) during the first year on ART,
and (ii) confirmed viral rebound (VR).
Methods
Data were collected prospectively from ART-naı
¨
ve chil-
dren (<16 years at ART start) initiating 3 antiretrovirals
at South African sites participating in IeDEA–Southern
Africa (IeDEA-SA, see http://www.iedea-sa.org), all of
which had CD4 and HIV-RNA measurements performed
6-monthly. The characteristics of these sites have been
described previously (Davies et al. 2009). Each site has
institutional ethical approval to contribute data to IeDEA
analyses.
HIV-RNA was measured using Amplicor 1.5 (Roche
Diagnostics) or NucliSens EasyQ assays (bioMerieux),
with good comparability (Stevens et al. 2005). CD4
measurements were performed using standard dual plat-
form flow cytometry or the single platform PanLeucogated
method (Glencross et al. 2008). We defined IVS as failure
to achieve 1 HIV-RNA £400 copies ml between 6 and
15 months on ART and VR as confirmed HIV-RNA
5000 copies ml in a child on ART for 18 months whose
HIV-RNA had suppressed during the first year on treat-
ment. We examined the following immunological criteria:
WHO 2010: No definition for children <2 years; CD4%
<10% or CD4 <200 cells mm
3
(age 2–4 years); CD4
<100 cells mm
3
(age 5 years) (WHO 2010). WHO 2006:
No definition for children <1 year; CD4% <15% (age
1–2 years); CD4% <10% (age 3–4 years); CD4
<100 cells mm
3
(age 5 years) (WHO 2006). DHHS:
During first year on ART: <5 percentage point CD4%
increase from baseline (CD4% <15 and age <5 years at
baseline) or <50 cells mm
3
CD4 increase from baseline
(CD4 <200 cells mm
3
and age 5 years at baseline);
decline of CD4% by 5 percentage points from previous
value, confirmed at subsequent measurement (<365 days
after first low value) (any age); return of CD4 count
£baseline value (age 5 years at baseline) (National Insti-
tutes of Health 2008).
For IVS, we assessed the diagnostic accuracy of never
achieving a CD4 above the immunological thresholds
between 6 and 15 months on ART for identifying a child
who never had HIV-RNA £400 copies ml during the same
period. Only children followed up for 1 year with 1
HIV-RNA measurement between 6 and 15 months were
included. For VR, CD4 and HIV-RNA measurements were
carried forward for up to 3 months where tests were
performed asynchronously. For each unique paired CD4
and HIV-RNA measurement, we determined the diagnostic
value of CD4-based criteria for identifying VR, using
robust standard errors to account for multiple measures
per patient. Immunological results for which there was still
no concurrent virological diagnosis after carrying forward
results were not evaluated. Further, the last immunological
result before the end of follow-up database closure was
excluded to ensure that there was sufficient follow-up for
a confirmatory low viral load measurement to have been
performed. Separate sensitivity analyses were performed
requiring either consecutive (within 365 days) CD4
measurements meeting immunological criteria or using an
HIV-RNA threshold of 1000 copies ml to define
confirmed VR.
Results
Of 3640 children with 1 year of follow-up, 3115 (86%)
had 1 HIV-RNA measurement between 6 and 15 months
on ART. At ART initiation, median [interquartile range
(IQR)] age was 48 (20–84) months. Most children were
severely ill at ART initiation: WHO-defined severe immune
suppression was present in 81% of 2911 children with
baseline CD4 measures recorded, and 68% of 2294
children with WHO Clinical Stage data had Stage 3 4
disease (WHO 2006). In keeping with South African
guidelines recommending protease inhibitor- (PI-) based
first-line therapy in children <3 years old (National
Department of Health South Africa 2005), 35% of children
were on PI-based first-line treatment with non-nucleoside
reverse transcriptase-based therapy in the remainder. IVS
occurred in 12.6% of children and sensitivity of immuno-
logical criteria for identifying IVS ranged from 6% (WHO
2010) to 26% (DHHS) and PPV from 20% (WHO 2010
and DHHS) to 31% (WHO 2006) (Table 1a).
The accuracy of immunological criteria for identifying
VR was assessed in 2513 children with at least 18 months
follow-up on ART whose HIV-RNA had suppressed
during the first year on treatment. The cumulative prob-
ability of VR in the following 2 years (by 42 months since
ART start) was 5.5% [95% confidence interval (CI):
4.2–7.1]. Sensitivity of immunological criteria for identi-
fying VR ranged from 5% (WHO 2006 2010) to 27%
(DHHS) and PPV from 20% (DHHS) to 43% (WHO
2006) (Table 1b). For diagnosing both IVS and VR,
requiring consecutive CD4 counts to meet immunological
Tropical Medicine and International Health volume 00 no 00
M.-A. Davies et al. Accuracy of immunological criteria
2 ª 2011 Blackwell Publishing Ltd
Page 2
Table 1 Diagnostic value of immunological criteria for identifying children (a) with incomplete virological suppression during first year on
ART and (b) with viral rebound
(a)
Comparison of immunological failure diagnosis
(based on highest CD4 between 6 and 15 months on
ART) with failure of viral suppression in same period
Comparison of immunological failure diagnosis
(based on highest CD4 between 6 and 15 months
on ART and confirmed on a subsequent
measurement) with failure of viral suppression
in same period
WHO 2006* WHO 2010 USA WHO 2006* WHO 2010 USA
Number of children (%) 90 2714 (3.3) 61 2380 (2.6) 355 2585 (13.7) 13 2502 (0.5) 9 2217 (0.4) 72 2277 (3.2)
Number of children with
paired dataà
2581 2256 2470 2405 2126 2190
Sensitivity (%) 10 (7–14) 6 (3–10) 26 (21–31) 2 (0–4) 2 (0–4) 9 (5–12)
Specificity (%) 97 (97–98) 98 (97–98) 87 (86–89) 99 (99–100) 99 (99–100) 97 (97–98)
PPV (%) 31 (22–41) 20 (10–30) 20 (16–24) 38 (8–69) 33 (0–72) 27 (16–38)
NPV (%) 90 (89–91) 92 (91–93) 91 (89–92) 90 (89–91) 92 (91–93) 90 (89–92)
Number of true positives 28 12 69 5 3 19
Number of true negatives 2242 2017 1928 2151 1945 1916
Number of false negatives 250 179 197 241 172 204
Number of false positives 61 48 276 8 6 51
LR+ 3.80 2.70 2.07 5.49 5.57 3.29
LR) 0.92 0.95 0.85 0.98 0.99 0.94
Area under ROC curve 0.537 0.520 0.567 0.508 0.507 0.530
ART, antiretroviral therapy; PPV, positive predictive value; NPV, negative predictive value; LR+, likelihood ratio of a positive test; LR),
likelihood ratio of a negative test; ROC, receiver operating characteristic.
*Only determined for children >12 months of age.
Only determined for children >24 months of age.
àNumber of children with paired data (both CD4 and HIV-RNA measures available and CD4 criteria evaluable in terms of immunological
criteria) differs for different definitions because of different age and data requirements for each definition.
(b)
Comparison of immunological failure diagnosis (based
on single CD4 measure meeting criteria) with
confirmed HIV-RNA >5000 copies ml
Comparison of immunological failure diagnosis
(based on consecutive CD4 measures meeting
criteria) with confirmed HIV-RNA >5000 copies ml
WHO 2006 WHO 2010* USA WHO 2006 WHO 2010* USA
Cumulative probability
by 2 years
2.2% (1.5–3.2) 2.3% (1.5–3.3) 28.1% (25.2–31.3) 0.4% (0.2–1.0) 0.3% (0.1–0.9) 10.4% (8.6–12.6)
Number of evaluable
pairs of data
2499 2593 2191 2395 2507 2110
Sensitivity (%) 5 (2–9) 5 (2–9) 27 (19–35) 2 (0–5) 2 (0–4) 13 (6–21)
Specificity (%) 99 (99–100) 99 (99–100) 88 (86–90) 100 (99–100) 100 (99–100) 95 (94–96)
PPV (%) 43 (23–63) 42 (22–61) 20 (13–26) 50 (19–81) 44 (14–75) 21 (10–32)
NPV (%) 91 (89–93) 91 (89–93) 92 (90–94) 91 (89–93) 91 (89–93) 91 (89–93)
Number of true positives 13 13 58 5 4 26
Number of true negatives 2245 2327 1740 2168 2269 1816
Number of false negatives 224 235 157 217 229 172
Number of false positives 17 18 236 5 5 96
LR+ 7.30 6.83 2.26 9.79 7.81 2.62
LR) 0.95 0.95 0.83 0.98 0.98 0.91
Area under ROC curve 0.524 0.522 0.575 0.510 0.508 0.541
PPV, positive predictive value; NPV, negative predictive value; LR+, likelihood ratio of a positive test; LR), likelihood ratio of a negative
test; ROC, receiver operating characteristic.
*Only determined for children >24 months of age.
Paired data created from carrying forward asynchronously measured CD4 and HIV-RNA results for up to 3 months; Number of children
with paired data differs for different definitions because of different age and data requirements for each definition.
Tropical Medicine and International Health volume 00 no 00
M.-A. Davies et al. Accuracy of immunological criteria
ª 2011 Blackwell Publishing Ltd 3
Page 3
criteria increased PPV only slightly at the expense of
sensitivity, without any improvement in the receiver
operating characteristic curve (Table 1). For VR, lowering
the VR threshold to 1000 copies ml and using confirmed
CD4 values to define immunological criteria yielded
sensitivity (95% CI) of 2% (0–5%) (WHO 2006); 2%
(0–4%) (WHO 2010) and 14% (8–19%) (DHHS); and
PPV (95% CI) of 90% (72–100%) (WHO 2006); 89%
(68–100%) (WHO 2010) and 38% (26–50%) (DHHS).
Discussion
In this large longitudinal study, we found that sensitivity
and PPV were low for identifying VF using WHO and
DHHS immunological criteria. For example, using con-
firmed HIV-RNA 5000 copies ml after initial virological
suppression to define VR, sensitivity was only 4% using
either WHO 2006 or 2010 criteria. Fewer than half of
children meeting WHO 2006 2010 criteria would have
HIV-RNA 5000 copies ml.
These results concur with those of previous small studies
from resource-limited settings. Among 116 children in
Uganda, 20 (17%) had sustained viraemia (400 cop-
ies ml) beyond 24 weeks on ART (Ruel et al. 2010). Only
two of these ever met WHO 2006 immunological criteria
and did so after >550 days of viraemia, while none met
WHO 2010 criteria (Ruel et al. 2010). Similarly, in a
cross-sectional study of 206 children in Tanzania on ART
for a median duration of 2.4 years, 32% had a single
HIV-RNA 400 copies ml (Emmett et al. 2010). WHO
2006 clinical and immunological failure criteria combined
had a PPV of 100% but identified only 3.5% of children
with HIV-RNA 400 copies ml (Emmett et al. 2010). In
Thailand, the sensitivity and PPV of DHHS immunological
criteria for identifying children with a single HIV-RNA
>1000 copies ml were 15% and 16%, respectively
(Jittamala et al. 2009).
The poor sensitivity of immunological criteria for
identifying VF is disappointing; however, perhaps, an even
greater concern is preventing the incorrect diagnosis of
treatment failure in a virologically suppressed child, with
unnecessary switch to second-line treatment, hence the
importance of PPV. While PPV reached 89% for identify-
ing VR 1000 copies ml using a confirmed CD4 value
meeting WHO 2010 criteria, given that the WHO 2010
guidelines HIV-RNA threshold for switching to second-line
is 5000 copies ml, in most instances the number of false
positives using immunological criteria is unacceptably
high. Further, absence of immunological failure on ART
provides no assurance that a child is virologically sup-
pressed and not accumulating resistance mutations, and
even high CD4 thresholds (e.g. DHHS criteria) have low
sensitivity for VF (PENPACT1 Study Team 2011).
Improved access to HIV-RNA monitoring both to assess
adherence and identify VF is therefore needed (Wilson
et al. 2009; Ford & Calmy 2010).
There are several limitations to this analysis of routinely
collected data. Missing baseline CD4 values limited the
evaluation of DHHS criteria. Baseline CD4 values are
often unavailable to clinicians if children initiate ART on
clinical criteria, records are lost or a child changes
treatment site after ART initiation, highlighting the value
of simple criteria using current or recent measurements.
The accuracy of WHO 2006 and 2010 criteria could not
be evaluated in children <1 and <2 years old, respectively.
Work-up bias may occur if either the reference (HIV-
RNA) or index (CD4) tests are not applied consistently
(Whiting et al. 2004). In particular, rigorous confirmation
of low CD4 values is seldom performed in South Africa,
owing to access to HIV-RNA measurements to diagnose
treatment failure. Exclusion of intercurrent illness as a
cause of low CD4, as advised in WHO guidelines (WHO
2010), was not possible because of limited data on
episodes of clinical illness. Immunological criteria may
have performed better if only low CD4 counts not
explained by intercurrent illness had been considered. PPV
is dependent on the VF incidence in different programs;
however, the incidence in this cohort was similar to that of
other studies (Kamya et al. 2007; Jittamala et al. 2009;
Davies et al. 2011).
In summary, our results suggest that current immuno-
logical criteria are unable to correctly identify children
failing ART virologically. Improved access to viral load
testing appears to be the only feasible approach at this
stage for reliably identifying VF in children on ART.
There are several existing technologies for the measure-
ment of viral load (Stevens & Marshall 2010), and
expanded access should be supported by governments and
donors.
Acknowledgements
This study was supported by the National Institute of
Allergy and Infectious Diseases and the Eunice Kennedy
Shriver National Institute of Child Health and Human
Development (grant 1 U01 AI069924-01). The funders
had no role in study design, data collection and analysis,
decision to publish or preparation of the manuscript. We
thank all the children whose data were used in this
analysis, as well as their caregivers. We also thank all staff
at participating sites for providing clinical patient care,
and preparation of data contributed to the IeDEA South-
ern Africa collaboration. Many thanks to Nicola Maxwell
for preparing the combined data for analysis and
Tropical Medicine and International Health volume 00 no 00
M.-A. Davies et al. Accuracy of immunological criteria
4 ª 2011 Blackwell Publishing Ltd
Page 4
to Morna Cornell and Claire Graber for project
management.
References
Badri M, Lawn SD & Wood R (2008) Utility of CD4 cell counts
for early prediction of virological failure during antiretroviral
therapy in a resource-limited setting. BMC Infectious Diseases
8, 89.
Davies M, Keiser O, Technau K et al. (2009) Outcomes of the
South African National Antiretroviral Treatment (ART)
programme for children The IeDEA Southern Africa
Collaboration. South African Medical Journal 99, 730–737.
Davies M, Moultrie H, Eley B et al. (2011) Virologic failure and
second-line antiretroviral therapy in children in South Africa:
The IeDEA Southern Africa collaboration. Journal of Acquired
Immune Deficiency Syndromes 56, 270–278.
Emmett SD, Cunningham C, Mmbaga BT et al. (2010) Predicting
virologic failure among HIV-1 infected children receiving
antiretroviral therapy in Tanzania: a cross-sectional study.
Journal of Acquired Immune Deficiency Syndromes 54,
368–375.
Ford N & Calmy A (2010) Improving first-line antiretroviral
therapy in resource-limited settings. Current Opinion in HIV
and AIDS 5, 38–47.
Glencross DK, Janossy G, Coetzee LM et al. (2008) Large-scale
affordable PanLeucogated CD4+ testing with proactive internal
and external quality assessment: in support of the South African
national comprehensive care, treatment and management
programme for HIV and AIDS. Cytometry. Part B, Clinical
Cytometry 74, S131–S140.
Jittamala P, Puthanakit T, Chaiinseeard S & Sirisanthana V (2009)
Predictors of virologic failure and genotypic resistance mutation
patterns in Thai children receiving non-nucleoside reverse
transcriptase inhibitor-based antiretroviral therapy. Pediatric
Infectious Disease Journal 28, 826–830.
Kamya MR, Mayanja-Kizza H, Kambugu A et al. (2007) Predic-
tors of long-term viral failure among Ugandan children and
adults treated with antiretroviral therapy. Journal of Acquired
Immune Deficiency Syndromes 46, 187–193.
Keiser O, MacPhail P, Boulle A et al. (2009) Accuracy of WHO
CD4 cell count criteria for virological failure of antiretroviral
therapy. Tropical Medicine and International Health 14,
1220–1225.
Mee P, Fielding KL, Charalambous S, Churchyard GJ & Grant AD
(2008) Evaluation of the WHO criteria for antiretroviral
treatment failure among adults in South Africa. AIDS 22,
1971–1977.
National Department of Health South Africa (2005) Guidelines
for the management of HIV-infected children in South Africa.
Jacana.
National Institutes of Health (2008) Guidelines for the use of
antiretroviral agents in Pediatric HIV infection (Online). NIH.
http://AIDSinfo.nih.gov (accessed 17 December 2008).
PENPACT1 Study Team (2011) First-line antiretroviral therapy
with a protease inhibitor versus non-nucleoside reverse trans-
criptase inhibitor and switch at higher versus low viral load in
HIV-infected children: an open-label, randomised phase 2 3
trial. The Lancet Infectious Diseases 11, 273–283.
Ruel TD, Achan J, Charlebois E, Havlir D & Kamya M (2010)
Sustained viremia is common among HIV-infected Ugandan
children receiving antiretroviral therapy and not detected by
WHO CD4 criteria. 18th International AIDS Conference.
Vienna, Austria.
Stevens WS & Marshall TM (2010) Challenges in implementing
HIV load testing in South Africa. Journal of Infectious Diseases
201(Suppl. 1), S78–S84.
Stevens W, Wiggill T, Horsfield P, Coetzee L & Scott LE (2005)
Evaluation of the NucliSensEasyQ assay in HIV-1-infected
individuals in South Africa. Journal of Virological Methods 124,
105–110.
Whiting P, Rutjes AW, Reitsma JB, Glas AS, Bossuyt PM &
Kleijnen J (2004) Sources of variation and bias in studies of
diagnostic accuracy: a systematic review. Annals of Internal
Medicine 140, 189–202.
WHO (2006). Antiretroviral therapy of HIV infection in infants
and children: towards universal access (Online). WHO,
Switzerland. http://www.who.int/hiv/pub/paediatric/infants/en/
index.html (accessed 9 February 2007).
WHO (2010) Antiretroviral therapy for HIV infection in infants
and children: towards universal access. Recommendations for
a public health approach: 2010 revision (Online). http://
www.who.int/hiv/pub/paediatric/infants2010/en/index.html
(accessed 19 October 2010).
Wilson D, Keiluhu AK, Kogrum S et al. (2009) HIV-1 viral load
monitoring: an opportunity to reinforce treatment adherence in
a resource-limited setting in Thailand. Transactions of the Royal
Society of Tropical Medicine and Hygiene 103, 601–606.
Corresponding Author Mary-Ann Davies, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925,
Cape Town, South Africa. Tel.: +27 21 4066051; Fax: +27 21 4066764; E-mail: mary-ann.davies@uct.ac.za
Tropical Medicine and International Health volume 00 no 00
M.-A. Davies et al. Accuracy of immunological criteria
ª 2011 Blackwell Publishing Ltd 5
Page 5
  • Source
    • "HIV viral load (VL) is routinely monitored in paediatric antiretroviral therapy (ART) programmes in high-income countries whereas in sub-Saharan Africa most programmes rely on CD4 count or clinical monitoring to detect treatment failure [1]. However, clinical and immunological criteria are poor predictors of virological failure for both children and adults [2, 3] . The lack of VL monitoring can lead to delayed and unnecessary switches to secondline therapy, promoting the development of resistance and limiting future treatment options [4, 5]. "
    [Show abstract] [Hide abstract] ABSTRACT: Objectives: Many paediatric antiretroviral therapy (ART) programmes in Southern Africa rely on CD4⁺ to monitor ART. We assessed the benefit of replacing CD4⁺ by viral load monitoring. Design: A mathematical modelling study. Methods: A simulation model of HIV progression over 5 years in children on ART, parameterized by data from seven South African cohorts. We simulated treatment programmes with 6-monthly CD4⁺ or 6- or 12-monthly viral load monitoring. We compared mortality, second-line ART use, immunological failure and time spent on failing ART. In further analyses, we varied the rate of virological failure, and assumed that the rate is higher with CD4⁺ than with viral load monitoring. Results: About 7% of children were predicted to die within 5 years, independent of the monitoring strategy. Compared with CD4⁺ monitoring, 12-monthly viral load monitoring reduced the 5-year risk of immunological failure from 1.6 to 1.0% and the mean time spent on failing ART from 6.6 to 3.6 months; 1% of children with CD4⁺ compared with 12% with viral load monitoring switched to second-line ART. Differences became larger when assuming higher rates of virological failure. When assuming higher virological failure rates with CD4⁺ than with viral load monitoring, up to 4.2% of children with CD4⁺ compared with 1.5% with viral load monitoring experienced immunological failure; the mean time spent on failing ART was 27.3 months with CD4⁺ monitoring and 6.0 months with viral load monitoring. Conclusion: Viral load monitoring did not affect 5-year mortality, but reduced time on failing ART, improved immunological response and increased switching to second-line ART.
    Full-text · Article · Oct 2014 · AIDS (London, England)
  • Source
    • "In low- and middle-income countries (LMICs), there are added difficulties in identifying treatment failure early enough to prevent accumulation of drug resistance mutations [15]. Current World Health Organization (WHO) criteria to assess paediatric failure have been repeatedly shown to be inaccurate for predicting failure [16, 17]. The sensitivity of the 2006 and 2010 WHO immunologic failure guidelines was as low as 6% in a multicentre South African study [16] and 5% in a Cambodian study [17]. "
    [Show abstract] [Hide abstract] ABSTRACT: The global paediatric HIV epidemic is shifting into a new phase as children on antiretroviral therapy (ART) move into adolescence and adulthood, and face new challenges of living with HIV. UNAIDS reports that 3.4 million children aged below 15 years and 2 million adolescents aged between 10 and 19 years have HIV. Although the vast majority of children were perinatally infected, older children are combined with behaviourally infected adolescents and youth in global reporting, making it difficult to keep track of their outcomes. Perinatally HIV-infected adolescents (PHIVA) are a highly unique patient sub-population, having been infected before development of their immune systems, been subject to suboptimal ART options and formulations, and now face transition from complete dependence on adult caregivers to becoming their own caregivers. As we are unable to track long-term complications and survival of PHIVA through national and global reporting systems, local and regional cohorts are the main sources for surveillance and research among PHIVA. This global review will utilize those data to highlight the epidemiology of PHIVA infection, treatment challenges and chronic disease risks. Unless mechanisms are created to count and separate out PHIVA outcomes, we will have few opportunities to characterize the negative consequences of life-long HIV infection in order to find ways to prevent them.
    Full-text · Article · Jun 2013 · Journal of the International AIDS Society
  • Source
    • "WHO guidelines define immunological failure as a CD4 count falling to or below the baseline value, or a 50% fall from the on-treatment peak or persistent CD4 values below 100 cells/µl [16]. However, CD4 testing has a poor accuracy and low positive predictive value in both adults [10,18] and children [8] for diagnosing treatment failure. Thus, viral load remains the gold standard. "
    [Show abstract] [Hide abstract] ABSTRACT: Though the advantages of routine virological monitoring for patients on anti-retroviral therapy have been established, cost and complexity limit its full implementation. Monitoring is important for diagnosing virological failure early on, before the development of drug resistance mutations, and to trigger early adherence interventions. Simple and cost-effective viral load tests that facilitate simplification and decentralization of testing and strategies, such as the use of dried blood spots and pooled sample testing, which further aid simplification, are becoming available. In addition, replacing immunological monitoring with virological monitoring in non-viremic patients in a phased manner will reduce the costs associated with dual immuno-virological monitoring. Going forward, the simplification of testing paired with price reducing strategies that will allow for healthy competition between multiple manufacturers will enable the implementation of viral load testing in resource-poor settings. It is important that future HIV and AIDS treatment guidelines provide clear recommendations for routine virological monitoring and that governments and donors fund the implementation of accurate and operationally proven testing platforms in a comprehensive manner.
    Full-text · Article · Oct 2012 · Journal of the International AIDS Society
Show more