HIV-positive children in resource-limited settings can achieve good virological outcomes without routine viral load or CD4 cell count monitoring

HIV-positive children can achieve good virological outcomes without routine monitoring of CD4 cell count or viral load, investigators report in PLOS Medicine. The research was conducted in Uganda and Zimbabwe and involved children starting antiretroviral therapy (ART). None had viral load (VL) monitoring over four years of follow-up. Viral load testing at the end of the study showed that three-quarters of children had viral suppression, and rates did not differ between children who had regular CD4 cell counts and those who had clinical monitoring only.

“No virological monitoring was undertaken…furthermore, VL suppression did not differ between children with or without CD4 monitoring, showing that good virological outcomes are achievable even with clinical monitoring, which can be done at low-level health facilities,” comment the authors. “Absence of VL monitoring should not be a barrier to providing first-line or switching to second-line ART given the considerable morbidity and mortality benefits of treatment.”

Worldwide, an estimated 1.8 million children are living with HIV, 80% of whom live in sub-Saharan Africa. As of 2015, only 49% of HIV-positive children globally were receiving ART.

Glossary

second-line treatment

The second preferred therapy for a particular condition, used after first-line treatment fails or if a person cannot tolerate first-line drugs.

resistance testing

Laboratory testing to determine if an individual’s HIV strain is resistant to anti-HIV drugs. 

virological suppression

Halting of the function or replication of a virus. In HIV, optimal viral suppression is measured as the reduction of viral load (HIV RNA) to undetectable levels and is the goal of antiretroviral therapy.

genotypic resistance testing

In HIV, genotypic resistance tests are assays that identify mutations of the virus that can confer antiretroviral drug resistance. Resistance testing can be used to guide selection of an HIV regimen when initiating or changing antiretroviral therapy (ART). See also ‘phenotypic resistance testing’.

first-line therapy

The regimen used when starting treatment for the first time.

Current World Health Organization (WHO) ART guidelines recommend viral load monitoring six and 12 months after starting treatment and annual assessments thereafter. A viral load above 1000 copies/ml is defined as virological failure and should be accompanied by a switch to second-line ART.

Despite this guidance, access to viral load monitoring in poorer countries remains scare. An international team of researchers therefore investigated long-term viral load and resistance outcomes in 1206 children in Uganda and Zimbabwe whose HIV therapy was managed without routine viral load monitoring.

The children were enrolled in the ARROW study and started ART between 2007 and 2008. They were randomised to monitoring with or without CD4 cell counts. Two-thirds were randomised to receive a WHO recommend regimen of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a non-nucleoside reverse trancriptase inhibitor (NNRTI), the other children receiving a triple NRTI combination. In the present study, the investigators limited their analyses to children taking NNRTI-containing therapy.

Viral load was measured retrospectively after four years of treatment. Samples with a viral load above 1000 copies/ml were sent for resistance testing. The investigators compared virological outcomes according to CD4 monitoring strategy. They also examined how viral load changed and resistance developed.

At the time of recruitment, the children had a median age of 6 years and had moderate immune suppression (CD4 cell percentage of 12%).

Viral load monitoring at the end of the study showed that 74% of children treated with a recommended NNRTI-based regimen had viral suppression (below 80 copies/ml). The rate did not differ according to CD4 monitoring strategy (75% with vs 73% without).

A total of 110 children with a viral load above 1000 copies/ml had genotypic resistance testing. This showed that 82% had resistance to lamivudine, the rate comparable for patients with and without CD4 cell monitoring. Intermediate/high-level resistance to tenofovir or zidovudine was present in 15% and 9%, respectively.

Viral load monitoring of stored blood samples showed that for 60% of follow-up time the children had a viral load below limit of detection; this increased to 85% when transient low-level viral load “blips” were included. Only 5% of time was spent with a persistent low-level viral load (80-4,999 copies/ml) and 10% with a rebound in viral load to above 5000 copies/ml.

Mean viral load among children with persistent low-level viraemia was 780 copies/ml and did not increase significantly with duration of follow-up.

Mean viral load for children experiencing rebound was 42,000 copies/ml.

Genotypic resistance testing detected a median of 2.3 resistance-conferring mutations per child. Additional mutations developed slowly and had little impact on predicted drug susceptibility.  

Approximately a fifth of viral load measurements above 1000 copies/ml were immediately followed by viral load resuppression. However, this depended on viral load level and no child with a confirmed viral load rebound above 5000 copies/ml experienced spontaneous suppression of viral load to below 80 copies/ml.

“We found that virological and resistance outcomes were good in this study, and that neither VL suppression nor predicted susceptibility of second-line treatment options were impacted by monitoring with or without CD4 counts over median 4 years follow-up in children initiating ART,” conclude the authors. “Annual VL monitoring, as recommend by WHO, is a reasonably and pragmatic approach for HIV-infected children on first-line ART in resource-limited settings.”

References

Szubert AJ et al. Virological response and resistance among HIV-infected children receiving long-term antiretroviral therapy without virological monitoring in Uganda and Zimbabwe: observational analyses within the randomised ARROW trial. PLOS Med 14 (11): e1002432, https://doi.org/10.1371/journal.pmed.1002432 (2017)