Viral levels in newborn African infants undergoing primary HIV-1 infection

We examined weekly changes in viral levels in seven untreated infants infected with HIV at birth. Viral levels spiked immediately but reverted quickly to plateau levels typical of infant HIV infection within 2 weeks of first detected viraemia. We speculated that the depletion of naive, susceptible cells is responsible for the rapid decrease in spike levels and that the rapid replacement of lymphocytes in infants causes the high plateau viral levels (105 copies/ml) to be sustained. Infants typically have very high HIV-1 levels compared with adults [1–3]. In our previous study, we found that African infants undergoing perinatal infection had high HIV-1 levels that continued as a plateau during the first year of life [3]. However, that study obtained samples only after one month of age and could have missed a perinatal infection HIV-1 spike if it occurred in the first month. Other investigators have suggested that a viral spike can occur soon after primary infection in infants [4,5]. Although these studies followed infants longitudinally, they presented the results grouped by age rather than for individual subjects. Furthermore, in those studies, the first month visits were non-scheduled, which could have introduced bias into the patterns observed if the reasons for visiting affected viral levels. Changes in HIV levels during primary infection have not been described in individual infants. To evaluate the profile of primary viraemia in infants, we studied HIV-exposed infants, scheduled weekly during their first month of life. After obtaining maternal consent, cord blood samples from newborns in Blantyre, Malawi were tested for HIV-1 antibody (HIV-1 enzyme immunoassay; Genetics Systems, Seattle, WA, USA). Reactive HIV-1 antibody results reflected the presence of passively acquired antibody from an HIV-infected mother. Mothers of vaginally delivered infants whose cord blood samples were HIV-1 antibody positive were asked to bring their infants to our clinic at 1, 2, 3, 4, 6 and 12 weeks of age. At each visit, filter paper samples were obtained by heel stick. Additional samples obtained on days 1 or 2 of life were available from some babies who remained at the hospital after delivery because they or their mothers required an extended stay. The last available sample from each infant was tested for HIV by polymerase chain reaction (PCR). Filter paper samples from PCR-positive infants were then tested for viral levels by a second-generation quantitative isothermal nucleic acid silica-bound amplification assay (NucliSens HIV-1 RNA Q-T kit; Organon Teknika, Durham, NC, USA) previously found to be reliable in filter paper samples [3,6]. To exclude in-utero infections, cord blood samples were also PCR tested and, if positive, these infants were excluded from the study. Viral testing was performed by a laboratory in Canada that also participated in the Virology Quality Assurance Program of the AIDS Clinical Trial Group. All infants were breast-fed and therefore could have become infected by early breast-feeding. No infants were treated with antiretroviral agents. Of 89 infants born to 87 HIV-1-infected women (two sets of twins), 50 had samples obtained at 28 days of life or older and were tested by PCR for HIV-1. One infant was cord blood PCR-positive (in-utero infection), and two infants first tested positive at 90 and 366 days, respectively, indicating transmission that probably occurred via breast milk. Seven subjects were PCR-negative in cord blood samples but positive in the first 28 days of life (1, 7, 14, 14, 14, 24 and 28 days), suggesting infection at or near the time of delivery. Evidence of a spike in viral replication was clearly apparent, with the highest level being 107.6 copies/ml (39 million copies) one week after viraemia was first detected (Fig. 1). Declines to typical plateau levels of approximately 105 copies/ml quickly followed. One infant had a slightly variant pattern, with a PCR-negative cord blood sample but a positive sample (1000 copies/ml) on day 1. During his first month of life, viral levels gradually increased to a slight peak at day 20 before falling to plateau levels.Fig. 1.: HIV-1 viral levels in six infants closely followed through the first month of life. By 30 days, levels were high but stable in all infants.Infants thus follow the pattern of primary viraemia observed in adults, with a spike followed by declines to a plateau [7]. The levels in the post-spike follow-up period between 30 and 90 days were stable in a range usually observed for plateau levels during the first year [3]. Plateau levels in infants (typically 105 copies/ml) were higher than in adults (104 copies/ml) or young children (104.5 copies/ml) [8]. We agree with speculation that the depletion of a subset of susceptible cells that are HIV-naive at the onset of infection contributes importantly to the decline in HIV-1 levels [9,10]. If so, the higher plateau in infants might reflect the more rapid lymphocyte replication observed in infants compared with adults [11], a process that would replenish naive lymphocytes subject to infection. In adults, the decline from the spike levels has been suggested to be caused by an effective immunological response [10,12], but infants are thought to have an immature immune system. A third hypothesis is that the involution of an infected thymus also contributes to the plateau levels in infants [13], but the timing and rapidity of the change do not support this hypothesis. The prevention of infection is clearly the optimal HIV-1 control strategy. However, given the poor prognosis associated with high viral levels in infants [4,5,14], finding ways to reduce the plateau levels could benefit infants who become infected. Short-course antiretroviral therapy administered immediately after delivery for days to a few weeks might be a practical approach for the prevention or reduction of HIV-1 plateau levels in resource-poor areas. In these longitudinally followed infants, plateau levels were established within 30–90 days, suggesting that clinical trials can use a relatively short-term follow-up of treated infants to assess the effectiveness of such therapies on plateau viral levels. Robert J. Biggara Robin Broadheadb Michelle Janesc Newton Kumwendad Taha E. T. Tahae Sharon Cassolc,f

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