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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
Global Health Sciences Literature Digest
Published February 28, 2011
Journal Article

Oliveira R, Krauss M, Essama-Bibi S, Hofer C, Robert Harris D, Tiraboschi A, 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(11):1325-33.

Objective

To determine the extent to which viral load is an independent predictor of WHO stage 3 or 4 events, among HIV infected children on HAART.

Settimg/Population

Clinical sites in Brazil, Mexico, Argentina, Peru and Jamaica that are part of the NISDI study (National Institute of Child Health and Human Development International Site Development Initiative).(1) NISDI is an ongoing prospective cohort study of HIV-infected and HIV-exposed children ≤21 yrs at multiple sites in Latin America.

Study Design

Prospective observational cohort

Population

Perinatally HIV-infected children on HAART

Main Outcome Measures

First occurrence of new WHO stage 3 or 4 events following enrolment; Cox-proportional hazards modeling was used to assess time to WHO events as a function of immunological status, viral load and hemoglobin (Hgb) level.

Methods

Data from children enrolled in the NISDI trial from 2002-2007 were included if they were <15 years of age and had been on HAART for at least 6 months. Children were evaluated at baseline and every 6 months with viral load, WHO age-related immunological classification (severe, advanced, mild, no immunosuppression),(2) Hgb, growth assessments (age and sex adjusted z-scores) and other clinical and laboratory parameters. Viral load was classified as undetectable (<400 copies/mL), indicative of treatment failure by WHO definition(3) (<5000 copies per ml), and as a continuous measure. Data was censored at the time of WHO stage 3 or 4 occurrence, or if the child reached 15 yrs. Laboratory values prior to the development of an event, or the last value obtained were used in analyses.

Results

Of 1629 children enrolled in NISDI during the study period, 584 were perinatally infected and on HAART and were included in analyses; 63% of these children were born in Brazil, 46% were male, 37% were <5 yrs old, 30% were on their first HAART regimen, and 26% had been on ≥3 previous treatment regimens; 12% were below -2 z-scores in weight-for-age, 22% had advanced or severe immunosuppresssion, 42% had >5000 viral copies/mL, 38% had undetectable viral load (<400 copies/mL) and 5% had Hgb≤10g/dL. The median followup was 2.7 years. On followup, 92 (15.8%) had a new WHO event, 79% of which were WHO stage 3, and which occurred at a median time of 1 yr (range 4dys-3.9yrs). Among all children, 21% had at least one regimen change during followup but this was not different between those who did and did not have a WHO event; length on HAART at baseline also did not differ between these two groups. In multivariable models, severe (aHR= 3.4, 95% CI [1.7-6.8]), and mild/advanced immunosupression (aHR=2.4, CI 1.3-4.3) vs no suppression, Hbg level per 1 g/dL decrease (aHR=1.3 9 CI 1.1-1.6), and viral load >5000 copies/mL (aHR=1.8, CI 1.1-3.1) were all significantly associated with having a WHO event; when a viral load of ≥400 copies/mL was used in the model, the aHR did not reach statistical significance.

Conclusions

This study shows that among perinatally infected children on treatment, viral load measurements, particularly if >5000 copies/mL, can be an independent predictor of WHO stage 3 and 4 events, even after adjusting for other cofactors, including CD4-based immunosuppression. The authors conclude that viral load monitoring is useful for monitoring children on HAART and should be routinely included in treatment settings.

Quality Rating

This was a high quality observational study. Some important data were not presented, however, such as loss-to-follow up and mortality.

In Context

Studies in adults have indicated that viral load with CD4 cell counts perform better than CD4 values alone in identifying those at greater risk of clinical illness.(4, 5) However, in many resource limited settings, virological testing is not widely available. However, predicting failure by clinical and immunological assessments alone has been shown to lack both sensitivity and specificity.(6, 7, 8) During the first months of HAART, uncorrected malnutrition, pre-existing illnesses and immune reconstitution inflammatory syndrome (IRIS) often cause poor outcomes and death among children.(9, 10) Because the children in this study had been on treatment for at least 6 months, it is unlikely that such early elevated risk of illness accounted for the WHO events.

Programmatic Implications

This study shows that viral load testing provides some additional information in predicting children who will do poorly on HAART, in addition to monitoring by CD4 immunosuppression. However, level of immunosuppression and falling Hgb levels were more predictive of WHO events than viral load. In settings where viral load monitoring is possible, this may assist clinicians in identifying children who are developing treatment failure due to non-adherence, drug resistance, less potent drug regimens, or a combination of causes. The current WHO definition of viral failure of >5000 copies/mL was shown to be a useful predictor in this study; this is encouraging, as it may be more easily obtained using dried blood spots, compared to viral detection assays sensitive to 50 or 400 copies/mL.

References

  1. Hazra R, Stoszek SK, Freimanis-Hance L, et al. Cohort profile: NICHD International Site Development Initiative (NISDI)-a prospective,observational study of HIV-exposed and HIV-infected children at clinical sites in Latin American and Caribbean countries. Int J Epidemiol 2009; 38(5):1207-1214.
  2. World Health Organization (WHO). Chapter 7 HIV Staging in Children Using Clinical and Immunological Criteria. Management of HIV infection in infants and children.
  3. World Health Organization. Antiretroviral therapy for HIV infection in children: towards universal access-recommendations for a public health approach, 2010 revision. 2010.
  4. Ferry T, Raffi F, Collin-Filleul F, et al; ANRS CO8 (APROCO-COPILOTE) Study Group. Uncontrolled viral replication as a risk factor for non-AIDS severe clinical events in HIV-infected patients on long-term antiretroviral therapy: APROCO/COPILOTE (ANRS CO8) cohort study. J Acquir Immune Defic Syndr 2009; 51(4):407-415.
  5. Grabar S, Le Moing V, Goujard C, et al. Response to highly active antiretroviral therapy at 6 months and long-term disease progression in HIV-1 infection. J Acquir Immune Defic Syndr 2005; 39(3):284-292.
  6. Mee P, Fielding KL, Charalambous S, Churchyard GJ, Grant AD. Evaluation of the WHO criteria for antiretroviral treatment failure among adults in South Africa. AIDS 2008; 22:1971-1977.
  7. Bagchi S, Kempf MC, Westfall AO, et al. Can routine clinical markers be used longitudinally to monitor antiretroviral therapy success in resource-limited settings? Clin Infect Dis 2007; 44(1):135-138.
  8. Moore DM, Awor A, Downing R, et al. 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(5):477-484.
  9. Callens SF, Shabani N, Lusiama J, et al; SARA team. Mortality and associated factors after initiation of pediatric antiretroviral treatment in the Democratic Republic of the Congo. Pediatr Infect Dis J 2009;28(1):35-40.
  10. Bolton-Moore C, Mubiana-Mbewe M, Cantrell RA, et al. Clinical outcomes and CD4 cell response in children receiving antiretroviral therapy at primary health care facilities in Zambia. JAMA 2007; 298(16):1888-1899.