Correspondence
Control of HIV despite the Discontinuation of Antiretroviral Therapy
N Engl J Med 1999; 340:1683May 27, 1999
- Article
To the Editor:
Eradication of the human immunodeficiency virus (HIV) is a difficult goal to achieve, because a reservoir of replication-competent HIV is established in resting CD4 T lymphocytes soon after infection and persists after years of highly active antiretroviral treatment.1 A more realistic alternative to lifelong cumbersome, toxic, and expensive treatments is to control HIV, as occurs in patients with long-term nonprogression of the disease.
A patient, who has become known as “the Berlin patient,” was treated soon after acute HIV infection, before complete seroconversion on Western blotting, with a combination of hydroxyurea (400 mg three times daily),2 didanosine (200 mg twice daily), and indinavir (800 mg three times daily).3 Before treatment, base-line measurements obtained seven days apart showed similar levels of HIV in the plasma (80,041 and 89,390 copies per milliliter), suggesting that the steady state of plasma viremia had already been reached. After levels of HIV RNA became undetectable in plasma, viremia recurred during a temporary suspension of treatment (Figure 1Figure 1
Plasma Levels of HIV RNA in the Patient.). However, no viral rebound was documented during a second temporary suspension of treatment, despite a concomitant infection with hepatitis A, which is known to activate the immune system and accelerate the rate of replication of HIV.4 The patient elected to stop treatment permanently after 176 days. No viral rebound was observed during the following 551 days. However, traces of HIV RNA were detected in a lymph node, and replication-competent virus1 was isolated from resting CD4 T lymphocytes at very low frequencies (Table 1Table 1
Measurements of Cellular HIV, T-Lymphocyte Phenotypic Markers, and HIV Immune Response.), demonstrating that HIV had not been eradicated.Despite 19 months without treatment, phenotypic markers, such as the CD4 count, the ratio of CD4 to CD8 T lymphocytes, and the proportion of naive CD4 and CD8 T lymphocytes (cells in which an immune response has not yet been activated) increased to normal levels (Table 1). No HIV-neutralizing antibodies were detected. In contrast, the vigorous HIV-specific helper T response5 progressively increased during two years of follow-up in the absence of treatment. There was also a consistently strong response of CD8 cytotoxic T lymphocytes to a p17 gag epitope on both a tetrameric-complex assay and an enzyme-linked immunospot assay (Elispot). No responses to reverse transcriptase or envelope epitopes were observed. If cytotoxic T lymphocytes do control the rebound effect, the lack of a broad immune response to epitopes in this patient suggests the potential for future viral breakthrough.
In this patient viral control has been maintained for two years despite the discontinuation of intermittent antiretroviral treatment with hydroxyurea, didanosine, and indinavir. The presence of vigorous, HIV-specific responses of CD4 helper T lymphocytes and CD8 cytotoxic T lymphocytes in the absence of neutralizing antibodies suggests a role for the cellular arm of the immune system in keeping HIV replication under control. However, the immunologic correlates that predict control of viremia after the discontinuation of therapy, as well as the relative contribution of the elements required to induce such control, need to be analyzed in randomized, controlled clinical studies.
5 ReferencesJulianna Lisziewicz, Ph.D.
Research Institute for Genetic and Human Therapy, Washington, DC 20007Eric Rosenberg, M.D.
Massachusetts General Hospital, Boston, MA 02114Judy Lieberman, M.D., Ph.D.
Harvard Medical School, Boston, MA 02115Heiko Jessen, M.D.
Praxis Jessen, 10777 Berlin, GermanyLucia Lopalco, M.D.
San Raffaele Scientific Institute, 20127 Milan, ItalyRobert Siliciano, M.D.
Johns Hopkins University, Baltimore, MD 21205Bruce Walker, M.D.
Massachusetts General Hospital, Charlestown, MA 02129Franco Lori, M.D.
Research Institute for Genetic and Human Therapy, Washington, DC 200071
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