Seroreversion of HIV antibodies in patients with prolonged suppression of viraemia under HAART
Amor, Aranzazua; Toro, Carlosb; Jiménez, Victoriab; Simón, Ainhoab; Ramos, Belénb; Soriano, Vincentb
aService of Microbiology, Spain
bDepartment of Infectious Diseases, Hospital Carlos III, Madrid, Spain.
Received 17 April, 2006
Accepted 3 May, 2006
Prolonged virus suppression in chronically HIV-infected patients could hypothetically lead to antibody seroreversion. Eighty-four HIV-positive individuals with undetectable viraemia for longer than 5 years under HAART were examined. Only one individual, who had initiated HAART shortly after primary HIV infection, showed seroreversion. In contrast, the cure of hepatitis C virus (HCV) with interferon in 25 controls led to the loss of HCV antibodies in most cases. This information indirectly reflects that whereas HCV may be eradicable HIV is not.
Incomplete antibody response or antibody seroreversion have both recently been described in acutely HIV-1-infected individuals in whom HAART was prescribed early [1–3]. As exposure to adequate levels of antigenic stimulation seems to be required to mount an appropriate antibody response, infection in the absence of HIV-1 antibodies in these patients was attributed to minimal HIV-1 replication and consequently a lack of antigenic stimulation. What is unknown at this time is whether the persistence of the HIV-1 antibody response might be preserved in chronically HIV-1-infected patients with long-lasting suppression of viral replication under antiretroviral therapy. Anecdotal reports of declines in HIV-1 antibody titres have been described with the use of HAART . Moreover, in other chronic viral infections, such as hepatitis C virus (HCV), seroreversion has been reported after viral clearance with treatment . HIV-1 infection cannot be eradicated, however, and therefore serological tests are not routinely requested for chronically HIV-1-infected patients who have long-lasting virological suppression under antiretroviral therapy. If seroreversion occurs in this subset of patients, a pool of HIV-seronegative but infected individuals could exist, which might have diagnostic and epidemiological implications.
In this study, we investigated the HIV antibody evolution in a relatively large group of chronically HIV-1-infected subjects with undetectable viraemia for long periods of time. As a reference, we examined the evolution of antibody reactivity to HCV in a control group of individuals with baseline HCV antibodies who had cleared the virus either spontaneously or after a course of interferon-based therapy.
All HIV-1-infected patients on regular follow-up at our institution under HAART with plasma HIV-RNA levels of less than 50 copies/ml in all measurements performed during at least the past 5 years were identified. Two serum samples from each patient with at least an interval of 5 years were tested for HIV antibodies using a single enzyme immunoassay (EIA; Genscreen HIV-1/2 v2; Bio-Rad, Marnes la Coquette, France) and Western blot (New Lav Blot I; Bio-Rad). In the control group, HCV antibody reactivity was examined using a lineal immunoassay (INNO-LIA HCV Ab III; Innogenetics NV, Ghent, Belgium) in a group of individuals with previous HCV exposure who had cleared HCV infection either spontaneously or after a course of interferon-based therapy, in all cases at least 5 years earlier. Serum reactivity to HIV and HCV antibodies in the screening tests as well as in the serological confirmatory tests were compared at baseline and after more than 5 years of undetectable viraemia. Comparisons of means were assessed using the Student's t-test.
A total of 84 HIV-1-positive subjects (75 men and nine women with a mean age of 45.4 years, range 32–73) was identified. All showed high CD4 T-cell counts (mean 691 cells/μl, range 305–1655) during the whole study period, which ranged from 60 to 97 months. All maintained HIV-1 EIA seroreactivity, and no significant differences between optical densities were noticed at the two different time points. Furthermore, Western blot antibody patterns and the intensity of the main bands (gp160, gp120, gp41, p24) did not differ in paired specimens. One subject showed a significantly reduced reactivity in all Western blot bands and the disappearance of reactivity to anti-gp41 using synthetic peptides (Pepti-Lav; Fig. 1). This patient, a 32-year-old promiscuous homosexual male, experienced an asymptomatic episode of primary HIV-1 infection (HIV Ab-negative two months before the first positive test) in 1988. At the time of diagnosis, plasma HIV-RNA was 8,100 copies/mL and the CD4 cell count was 766 cells/mm3. Six months later he had 23,393 HIV-RNA copies/mL and 788 CD4 T cells/mm3, but requested initiation of HAART. He began treatment with didanosine, stavudine and nevirapine at standard doses. Plasma viremia soon became undetectable and viral suppression has remained for the following 8 years to date.
In the control group, 25 HCV-seropositive individuals were reassessed after a minimum interval of 5 years of undetectable HCV-RNA either after spontaneous clearance (n = 11) or a course of interferon therapy (n = 14). A significant decline in HCV antibody reactivity against bands C1 and C2 of core (P < 0.01) and non-structural viral proteins NS3, NS4 and NS5 (P < 0.05) was recognized.
Recent reports of seroreversion in patients with acute and early HIV-1 infection treated with antiretroviral therapy [1–3] have raised the question of whether this finding could be associated with a loss of HIV antigenic stimulation. Our results demonstrate that seroreversion in chronically HIV-1-infected patients under HAART with long-standing undetectable viraemia is a very rare event. However, it may occur in individuals who are treated shortly after primary HIV-1 infection. These data are in concordance with previous reports that showed a gradual decline in antibody titres when HAART is given within the first 2 years of infection, whereas antiretroviral therapy has little effect on the antibody response when it is initiated several years after infection [4,6]. It may be that patients with chronic HIV-1 infection harbour sufficient antigen trapped on follicular dendritic cells to maintain antibody production; therefore a decline in the amount of circulating antigen would have little impact [6,7]. Taken together, all these data suggest that seroreversion in HIV-infected subjects who maintain long-standing undetectable viraemia could occur in the subset of patients who initiated HAART shortly after HIV-1 infection.
Seroreversion does not mean viral eradication . HIV-1 antibodies rapidly reappear after the cessation of HAART in patients treated during acute or early HIV-1 infection [2,3], or after immune restoration in patients with profound immunodeficiency . In contrast to HIV-1 infection, HCV antibodies tended to decline over time in our study population after HCV eradication either spontaneously or after successful interferon treatment. These results are in agreement with other recently reported findings that noted HCV seroreversion in subjects who attained sustained virological response with an interferon-based therapy . Although a few reports have claimed that HCV could persist in some sustained virological responders [10,11], our data and those from others  are more in favour of a real eradication of HCV infection in this subset of patients.
It is noteworthy that although EIA and Western blot maintained reactivity in the single patient who partly seroreverted in our study, a total lack of reactivity was observed using a confirmatory test based on synthetic peptides. Similar findings have been reported with rapid tests in patients who initiated HAART early after HIV-1 infection and achieved undetectable viral loads . Therefore, a misdiagnosis of HIV-1 infection could occur using tests based only on synthetic peptides, which should ideally be avoided for screening purposes.
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© 2006 Lippincott Williams & Wilkins, Inc.
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