Long‐Cycle Structured Intermittent versus Continuous Highly Active Antiretroviral Therapy for the Treatment of Chronic Infection with Human Immunodeficiency Virus: Effects on Drug Toxicity and on Immunologic and Virologic Parameters

Abstract

We evaluated the effect of long-cycle structured intermittent therapy (SIT; 4 weeks without highly active antiretroviral therapy [HAART] followed by 8 weeks with HAART) versus continuous HAART. The study was prematurely terminated to new enrollment because of the emergence of genetic mutations associated with resistance to antiretroviral drugs in 5 patients. After 48 weeks, there was no significant difference between groups in lipid, hepatic transaminase, and C-reactive protein levels in 41 patients. Although there were no differences in CD4(+) or CD8(+) T cell counts or the percentage of cells that were CD4(+)CD25(+), CD8(+)CD25(+), or CD4(+)DR(+), patients who received SIT had a significantly higher percentage of CD8(+)CD38(+) and CD8(+)DR(+) cells. There was no clear autoimmunization effect by immunologic or virologic parameters. There was no benefit to long-cycle SIT versus continuous HAART with regard to certain toxicity, immunologic, or virologic parameters.

Structured Treatment Interruptions with Tenofovir Monotherapy for Simian Immunodeficiency Virus-Infected Newborn Macaques

“…The difficulty of using immunologic parameters for blood to accurately predict the virologic outcome of STI is consistent with observations from human studies, where no or a variable correlation was observed between viral load markers and HIV-1-specific CD8 ϩ or CD4 ϩ T-cell responses that were augmented in blood during treatment interruptions (14,17,20,45,49).…”

“…However, clinical trials found that the likelihood of STI to induce immunologic control of HIV replication was generally most favorable for patients who were started on HAART during acute infection, when the immune system was still relatively intact and when early treatment was able to lower the viral RNA set point after drug withdrawal (30,50). When treatment was started during chronic HIV infection, STI regimens were generally able to augment anti-HIV CD8 ϩ cell-mediated immune responses (to approximately pretreatment levels) but were less effective in restoring and maintaining HIV-specific CD4 ϩ cellular immune responses, and treatment interruptions generally led to a viral rebound to near pretreatment levels (17,20,44,45,(47)(48)(49)51).…”

HIV/AIDS epidemiology, pathogenesis, prevention, and treatment

“…If successful, this strategy could limit drug toxicity and reduce treatment costs. 122 Although preliminary findings for this strategy were mixed in terms of benefits, [123][124][125] the recent early closure of the SMART trial was based on increased morbidity and mortality in the treatment interruption arm. 126 Thus, in the absence of clinical benefits, most investigators strongly discourage treatment interruptions except as needed to address treatment intolerance.…”

Virological Outcome after Structured Interruption of Antiretroviral Therapy for Human Immunodeficiency Virus Infection Is Associated with the Functional Profile of Virus-Specific CD8+T Cells

“…Enrollment criteria for the SIT protocol, as previously described (21), were documented HIV infection with a CD4 ϩ T-cell count of Ͼ300 cells/mm 3 and plasma HIV RNA levels of Ͻ50 copies/ml during screening and Ͻ500 copies/ml for Ͼ6 months on a potent ART regimen comprised of a protease inhibitor (indinavir [IDV] or nelfinivir) combined with a nonnucleoside reverse transcriptase inhibitor (nevirapine [NVP] or efavirenz) and/or a nucleoside reverse transcriptase inhibitor (NRTI) (stavudine [d4T], didanosine, or lamivudine [3TC]). The study was designed for 90 patients randomly assigned to continue ART or receive seven cycles of 4 weeks without ART followed by 8 weeks with ART.…”

“…The study was designed for 90 patients randomly assigned to continue ART or receive seven cycles of 4 weeks without ART followed by 8 weeks with ART. However, the study was prematurely terminated due to a high failure rate in the SIT arm after 26 patients in each arm were enrolled (21). Six of the 26 individuals from the treatment interruption arm voluntarily underwent a final cessation of ART after 92 weeks of SIT.…”