In adults, loss of HIV antibodies (seroreversion) following antiretroviral therapy (ART) is extremely rare and has been reported only in patients treated shortly after primary HIV infection [1,2]. In children of HIV-infected mothers, seroreversion during the first year of life is considered as a marker of absence of vertical infection. However, in children with proven HIV infection, seroreversion after virus suppression due to ART has also been described in a few instances [3–5]. Here, we report on four vertically HIV-1-infected children with HIV-1 seroreversion after early and successful ART. Such HIV-infected patients with undetectable plasma viral load and negative HIV antibody tests might be misclassified as not infected, which has implications on the safety of blood products. The fact that this seroreversion was maintained throughout the period of suppressive ART in all four children for up to 11 years suggests that seroreversion is the rule rather than an exception in those vertically infected children treated early, continuously and successfully.
Details of the four cases are presented in Table 1. None of the mothers received ART during pregnancy. In all four children, viral load above 100 000 copies/ml was observed in the first month of life, suggesting intrauterine infection. Three of the children (cases 1, 3 and 4) received postnatal AZT prophylaxis before ART was started. Undetectable viral load was observed already after 1 week of therapy in case 1 and 4, 6 and 8 months after start of ART in cases 2, 3 and 4, respectively. In cases 1–3, viral load remained undetectable throughout the follow-up, whereas case 4 experienced treatment failure due to adherence problems during his second year of life. Viremia peaked at 13 000 copies/ml, but returned to undetectable levels again after 11 months of treatment.
All four children developed regularly without clinical signs of HIV infection, and their CD4 cell counts were always in the normal range. Humoral immune responses after active immunization against diphtheria and tetanus were normal (tested on at least three occasions in each of the children). In all four children, highly sensitive HIV screening tests (fourth generation combined HIV antigen/antibody assays) became negative during follow-up as observed in noninfected children of HIV-positive women and remained negative throughout the follow-up of up to 10 years. However, antibodies against p24 antigen were still detectable by western blot in two children. The only exception was patient 4, in whom the rebound of viral load during treatment failure was followed by a rapid seroconversion in the second year of life. Although viral load could be suppressed below the limit of detection again by ART, this antibody response persisted and no seroreversion was observed.
The lack of persistent HIV antibodies as determined by anti-HIV testing in these infected children contrasts with the seroconversion in adults who receive antiretroviral therapy within a few weeks after primary infection [3,6]. In all presented cases, infection of the children was proven by the detection of high levels of HIV-1-RNA before ART. During ART, viral load declined below detection limit within the first year of life. Due to the loss of maternal antibodies, the children seroreverted. Since this loss of HIV antibodies was similar to uninfected infants of HIV-positive women, it can be assumed that they did not actively or only partially generate HIV antibodies . Despite this seroreversion, persistent infection remains and the restored immune system can respond to viral rebounds with HIV seroconversion as seen in case 4.
The lack of HIV seroconversion in our patients was surprising given the high levels of plasma virus prior to therapy, which should have served as appropriate stimulus for humoral immune response. The absence of persistently detectable HIV antibodies suggests that there may be a period during which the generation of immune responses is inefficient in infants [7,8]. Contributing factors include exposure to HIV in the presence of maternal antibodies or a selective depletion of HIV-1-specific CD4 T cells. If the antigenic stimuli are no longer present due to successful ART when the immune system of the children has fully developed, an inappropriate antibody response is quite likely to occur. This negativity in both serological and nucleic acid tests despite persisting HIV infection may have negative consequences in several regards. For the individual, it may lead to a decision to stop ART (with the consequence of a massive viral rebound) if the healthcare provider is not aware of the full history of the patient. Furthermore, if those children reach adulthood, they may be erroneously accepted as blood donors, since they are not detectable as HIV-infected by the assays used for donor screening. The cases presented in this study suggest that, in vertically HIV-infected children treated early and efficiently, seroreversion is the rule rather than an exception.
1. Hare C, Pappalardo BL, Busch MP, Karlsson AC, Phelps BH, Alexander SS, et al
. Seroreversion in subjects receiving antiretroviral therapy during acute/early HIV infection. Clin Infect Dis 2006; 42:700–708.
2. Amor A, Toro C, Jimenez V, Simon A, Ramos B, Soriano V. Seroreversion of HIV antibodies in patients with prolonged suppression of viraemia under HAART. AIDS 2006; 20:1460–1462.
3. Luzuriaga K, McManus M, Catalina M, Mayack S, Sharkey M, Stevenson M, Sullivan JL, for the PACTG 356 investigators. Early therapy of vertical human immunodeficiency virus type 1 (HIV-1) infection: control of viral replication and absence of persistent HIV-1-specific immune responses. J Virol 2000; 47:6984–6991.
4. Hainaut M, Peltier CA, Gerard M, Marissens D, Zissis G, Levy J. Effectiveness of antiretroviral therapy initiated before the age of 2 months in infants vertically infected with human immunodeficiency virus type 1. Eur J Pediatr 2000; 159:778–782.
5. Neubert J, Laws H-J, Adams O, Münk C, Krämer M, Niehues T, et al
. HIV-1 seroreversion following antiretroviral therapy in an HIV-infected child initially presenting with acquired immunodeficiency syndrome. AIDS 2010; 24:327–330.
6. Markowitz M, Vesanen M, Tenner-Racz K, Cao Y, Binley JM, Talal A, et al
. The effect of commencing combination antiretroviral therapy soon after human immunodeficiency type 1 infection on viral replication and antiviral immune responses. J Infect Dis 1999; 179:525–537.
7. Winchester R, Pitt J, Charurat M, Magder LS, Göring HH, Landay A, et al
. Mother-to-child transmission of HIV-1: strong association with certain maternal HLA-B alleles independent of viral load implicates innate immune mechanisms. J Acquir Immune Defic Syndr 2004; 36:659–670.
8. Blish CA, Blay WM, Haigwood NL, Overbaugh J. Transmission of HIV-1 in the face of neutralizing antibodies. Curr HIV Res 2007; 5:578–587.