Short-cycle structured intermittent treatment of chronic HIV infection with highly active antiretroviral therapy: Effects on virologic, immunologic, and toxicity parameters

Abstract

Although continuous highly active antiretroviral therapy (HAART)is effective for many HIV-infected patients, it can be toxic and prohibitive in cost. By decreasing the total amount of time patients receive medications, intermittent HAART could reduce toxicity and cost. Therefore, we initiated a pilot study in which 10 HIV-infected individuals receiving effective therapy that resulted in levels of HIV RNA <50 copies per ml of plasma and CD4 ؉ T cell counts >300 cells per mm 3 of whole blood received repeated cycles of 7 days on HAART followed by 7 days off of HAART. Patients maintained suppression of plasma viremia for 32-68 weeks. There was no significant increase in HIV proviral DNA or replication-competent HIV in peripheral CD4 ؉ T cells or HIV RNA in peripheral blood or lymph node mononuclear cells. There was no significant change in CD4 ؉ T cell counts, no significant increase in CD4 ؉ or CD8 ؉ T cells expressing activation markers or producing IFN-␥ in response to HIV, no increase in CD4 ؉ T cell proliferation to p24 antigen, and no evidence for the development of resistance to HAART medications. There was a significant decrease in serum cholesterol and triglyceride levels. Thus, in this proof-of-concept study, short-cycle intermittent HAART maintained suppression of plasma viremia as well as HIV replication in reservoir sites while preserving CD4 ؉ T cell counts. In addition, there was a decrease in serum cholesterol and triglyceride levels. Intermittent therapy may be an important strategy to reduce cost and toxicity for HIV-infected individuals.

Productive Infection Maintains a Dynamic Steady State of Residual Viremia in Human Immunodeficiency Virus Type 1-Infected Persons Treated with Suppressive Antiretroviral Therapy for Five Years

“…Therapeutic vaccines may be most likely to produce virologic remission in patients with the lowest levels of residual replication (3). Likewise, structured intermittent therapy may be most successful in patients with maximal suppression prior to therapy interruption (17). Finally, the ability to predict levels of residual replication may permit assessments of antiviral potency required to sustain virologic suppression and minimize drug toxicity.…”

Mechanistic Effect of NMSO3 on Replication of Human Immunodeficiency Virus

“…Advances in the understanding of the replication cycle have revealed which events can be selectively inhibited. Although HAART has made significant progress with the development of several promising agents (Debul et al, 2001), additional agents with distinct mechanisms of action are still needed for effective anti-HIV-1 therapy. Furthermore, the importance of being able to treat chronic infection is anticipated from the pathology of HIV-1 infection in vivo (Koup, 2001).…”

Physiological Levels of Virion-Associated Human Immunodeficiency Virus Type 1 Envelope Induce Coreceptor-Dependent Calcium Flux

“…Signal induced by a single virion is not improbable, since Irvine et al (34) found that a single peptide ligand could activate TCR signaling in T cells and Baylor et al (11) showed that retinal cells of the eye could detect single photons, indicating a maximum sensitivity for these signal transduction systems to minimal respective stimuli. The probability that two or three virions bind a CD4 ϩ T-cell in vivo is very likely based on the range of plasma HIV RNA copies and CD4 ϩ T-cell counts in chronically infected patients (21,46,68). Importantly, this signaling takes place in the absence of infection, since resting CD4 ϩ T cells are refractory to infection.…”