Short-Course Antiretroviral Therapy in Primary HIV Infection

Abstract

BackgroundShort-course antiretroviral therapy (ART) in primary human immunodeficiency virus (HIV) infection may delay disease progression but has not been adequately evaluated. MethodsWe randomly assigned adults with primary HIV infection to ART for 48 weeks, ART for 12 weeks, or no ART (standard of care), with treatment initiated within 6 months after seroconversion. The primary end point was a CD4+ count of less than 350 cells per cubic millimeter or long-term ART initiation. ResultsA total of 366 participants (60% men) underwent randomization to 48-week ART (123 participants), 12-week ART (120), or standard care (123), with an average followup of 4.2 years. The primary end point was reached in 50% of the 48-week ART group, as compared with 61% in each of the 12-week ART and standard-care groups. The average hazard ratio was 0.63 (95% confidence interval [CI], 0.45 to 0.90; P = 0.01) for 48-week ART as compared with standard care and was 0.93 (95% CI, 0.67 to 1.29; P = 0.67) for 12-week ART as compared with standard care. The proportion of participants who had a CD4+ count of less than 350 cells per cubic millimeter was 28% in the 48-week ART group, 40% in the 12-week group, and 40% in the standard-care group. Corresponding values for long-term ART initiation were 22%, 21%, and 22%. The median time to the primary end point was 65 weeks (95% CI, 17 to 114) longer with 48-week ART than with standard care. Post hoc analysis identified a trend toward a greater interval between ART initiation and the primary end point the closer that ART was initiated to estimated seroconversion (P = 0.09), and 48-week ART conferred a reduction in the HIV RNA level of 0.44 log 10 copies per milliliter (95% CI, 0.25 to 0.64) 36 weeks after the completion of short-course therapy. There were no significant between-group differences in the incidence of the acquired immunodeficiency syndrome, death, or serious adverse events. ConclusionsA 48-week course of ART in patients with primary HIV infection delayed disease progression, although not significantly longer than the duration of the treatment. There was no evidence of adverse effects of ART interruption on the clinical outcome. (Funded by the Wellcome Trust; SPARTAC Controlled-Trials.com number, ISRCTN76742797, and EudraCT number, 2004-000446-20.)The Copyright © 2013 Massachusetts Medical Society. All rights reserved.T h e n e w e ng l a n d j o u r na l o f m e dic i n e n engl j med 368;3 nejm.org january 17, 2013 208A lthough the use of highly active antiretroviral therapy (ART) in human immunodeficiency virus (HIV) disease reduces morbidity and mortality, 1-3 the role of ART in the management of primary HIV infection remains controversial. [4][5][6] Immunologic damage after HIV acquisition occurs rapidly and is not wholly reversible by later ART. 7-9 Observational studies have suggested that a short course of ART during primary HIV infection may preserve immune function, 10,11 decrease viral evolution, 12 and limit the viral reservoir. [13][14][15] Two randomized, controlled trial...

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV‐1 infection 2015: optimizing health in preparation for adult life

“…Disappointingly, time off treatment was not significantly longer than the 48‐week treatment period and the increase in CD4 count on long‐term ART was similar across all three groups. In contrast to the SMART trial, there were no adverse effects on clinical outcomes 51, 210. Adult case series from prospective observational cohort studies and the results of the Agence Nationale de Recherche sur le SIDA (ANRS) Virological and Immunological Studies in Controllers after Treatment Interruption (VISCONTI) study suggest that some patients with different genetic characteristics and characteristic CD8 cell response to HIV, after prolonged treatment of primary HIV infection, can control HIV replication post treatment interruption for at least several years 211, 212.…”

Virological failure and development of new resistance mutations according to CD4 count at combination antiretroviral therapy initiation

“…The majority of rebounds in this group occurred following treatment discontinuation, with the proportion of patients experiencing rebound while reportedly still receiving cART being similar across groups. Reasons for treatment discontinuation in this group are unknown; however, it is possible that some of these individuals were enrolled in trials of treatment interruption strategies that were undertaken during this time period 14. However, this trend towards more treatment interruption in those starting cART with a high CD4 count raises some concerns.…”

Long-Term Antiretroviral Treatment Initiated at Primary HIV-1 Infection Affects the Size, Composition, and Decay Kinetics of the Reservoir of HIV-1-Infected CD4 T Cells

“…A series of prior studies have indeed shown that short-term antiretroviral treatment in acute or early HIV-1 infection can preserve B-cell-mediated (6) and T-cellmediated (7) immune function, supports the development of HIV-1-specific CD4 T cell responses (8), limits the diversity of circulating viral strains (9), and in some cases facilitates spontaneous control of low-level HIV-1 viremia after treatment discontinuation (10,11). Recently, data from three prospective, randomized-controlled clinical trials indicated that a 1-to 2-year antiretroviral treatment course started during acute or early HIV-1 infection can lead to reduced HIV-1 set point viremia after treatment discontinuation (12)(13)(14), providing compelling evidence for beneficial effects of antiretroviral therapy initiation dur-ing the earliest stages of HIV-1 infection. Nevertheless, such effects were modest and not sustained long term, indicating that short-term therapy in primary infection may not significantly affect the eventual HIV-1 disease outcome.…”