Age at antiretroviral therapy initiation and cell-associated HIV-1 DNA levels in HIV-1-infected children

Abstract

BackgroundThe latent viral reservoir is the major obstacle to achieving HIV remission and necessitates life-long antiretroviral therapy (ART) for HIV-infected individuals. Studies in adults and children have found that initiating ART soon after infection is associated with a reduction in the size of the HIV-1 reservoir. Here we quantified cell-associated HIV-1 DNA in early-treated but currently older HIV-infected children suppressed on ART.MethodsThe study participants comprised of a cohort of 146 early-treated children with HIV-1 RNA <50 copies/ml enrolled as part of a clinical trial in Johannesburg, South Africa. A stored buffy coat sample collected after a median 4.3 years on ART and where HIV-1 RNA was <50 copies/ml was tested for cell-associated HIV-1 DNA levels. An in-house, semi-nested real-time quantitative hydrolysis probe PCR assay to detect total HIV-1 subtype C proviral DNA was used. Children were followed prospectively for up to 3 years after this measurement to investigate subsequent HIV-1 RNA rebound/failure while remaining on ART. Age at ART initiation, HIV-1 RNA decline prior to HIV-1 DNA measurement and other factors were investigated.ResultsA gradient between age at ART initiation and later HIV-1 DNA levels was observed. When ART was started <2 months of age, the lowest levels of cell-associated HIV-1 DNA (median 1.4 log10copies/106 cells, interquartile range [IQR] 0.95–1.55) were observed compared to ART started at 2–4 months (median 1.68, IQR 1.26–1.97) or 5–14 months of age (median1.98, IQR 1.69–2.25). A low CD4 T-cell count pre-treatment predicted higher levels of HIV-1 DNA on later testing. The probability of HIV-1 RNA rebound >50 copies/ml whilst on ART within 3 years after the DNA measurement was 2.07 (95% CI: 1.352–3.167) times greater if the HIV-1 DNA level was above the median of 55 copies/106 cells.ConclusionsCell-associated HIV-1 DNA levels measured after more than 4 years on ART were lower the younger the age of the child when ART was initiated. This marker of the size of the viral reservoir also predicted subsequent viral rebound/treatment failure while ART was sustained. The results provide additional evidence of the benefits of prompt diagnosis and early ART initiation in newborns and infants.

Impact of Early Antiretroviral Therapy on Detection of Cell-Associated HIV-1 Nucleic Acid in Blood by the Roche Cobas TaqMan Test

“…Similar results have been reported for adults who initiate ART earlier in infection, who achieve lower levels of residual reservoirs of cell-associated HIV DNA (9,50,51). The residual HIV reservoir decreased faster and achieved significantly lower levels, as detected by measurement of cell-associated HIV DNA, after 1 to 5 years of therapy in infants who initiated ART at a very early age than in those who delayed the start of therapy (14,17).…”

“…This reservoir, established early in infection, continues to serve as a source of viral replication upon discontinuation of ART (9)(10)(11)(12). Initiation of ART during acute infection results in a dramatic decrease in the levels of HIV-1 DNA in peripheral CD4 ϩ T cells, with the greatest reduction being observed in individuals treated at the earliest stage of acute infection (Fiebig stage I [FI]) (9,12,13) or during the treatment of perinatally HIV-1-infected infants (14)(15)(16)(17). The impact of early treatment on the HIV-1 reservoir burden, however, does not equate to clearance of virus or viral cure.…”

Decreased Seroreactivity in Individuals Initiating Antiretroviral Therapy during Acute HIV Infection

“…Only 27/57 (47%) of RNA-positive individuals who were infected while on PrEP were found to be reactive by the Bio-Rad GS HIV Combo Ag/Ab EIA, and none were HIV-1 positive by either the HIV-1 WB or the Geenius assay (53). Alternative approaches, such as testing for cell-associated HIV total nucleic acid (RNA and DNA), may be required to rule out HIV-1 infections in individuals with inconclusive HIV diagnostic test results and may be helpful to confirm infections in such cases (6,54). decision, unless so designated by other documentation.…”

“…At 2 years of age, about half of all HIV-1-infected infants who initiated ART within 2 weeks of birth were seronegative by HIV immunoassays and rapid device tests, whereas 11% were seronegative if ART was initiated at 12 and 24 weeks of age. All children initiating ART later than 24 weeks of age were seropositive by HIV immunoassays at 2 years of age (6,16). In the absence of ongoing antigenic stimulation, seroconversion, as determined by second-generation immunoassay Ab tests, also failed to occur among adult participants treated during AHI (9,15,17,18).…”

Clinical round-up

“…This study by Kuhn et al 3 consisted of a cohort of 146 early treated HIV-infected children who were part of an efavirenz-switch study in Johannesburg; all children were over 3 years old, undetectable at study baseline, had been started on ART between 6 weeks and 14 months old, and had been on treatment for a median of 4.3 years when blood samples were measured for cell-associated HIV-1 DNA, as a marker of the viral reservoir. ART initiation at a younger age was associated with lower levels of HIV-1 DNA; specifically under 2 months of age, the lowest levels were found (median 1.4 log 10 copies/10 6 cells, IQR 0.95–1.55) versus over 5 months of age (median 1.98 log 10 copies/10 6 cells, IQR 1.69–2.25).…”