No Treatment versus 24 or 60 Weeks of Antiretroviral Treatment during Primary HIV Infection: The Randomized Primo-SHM Trial

Grijsen, Marlous L.; Steingrover, Radjin; Wit, Ferdinand W. N. M.; Jurriaans, Suzanne; Verbon, Annelies; Brinkman, Kees; Ende, Marchina E. van der; Soetekouw, Robin; Wolf, Frank de; Lange, Joep M. A.; Schuitemaker, Hanneke; Prins, Jan M.

doi:10.1371/journal.pmed.1001196

Cited by 80 publications

(74 citation statements)

References 42 publications

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“…Finally, our results suggest that an early treatment slowing down viral replication during the initial phase of the infection should be beneficial because it gives the immune system time to develop its full breadth. This could explain why early treatment during primary HIV infection can result in decreased viral setpoints and be very beneficial (50)(51)(52)(53).…”

Section: Discussionmentioning

confidence: 99%

The Rate of Immune Escape Vanishes When Multiple Immune Responses Control an HIV Infection

Deutekom

Wijnker

Boer

2013

The Journal of Immunology

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During the first months of HIV infection, the virus typically evolves several immune escape mutations. These mutations are found in epitopes in viral proteins and reduce the impact of the CD8+ T cells specific for these epitopes. Recent data show that only a subset of the epitopes escapes, that most of these escapes evolve early, and that the rate of immune escape slows down considerably. To investigate why the evolution of immune escape slows down over the time of infection, we have extended a consensus mathematical model to allow several immune responses to control the virus together. In the extended model, most escapes also occur early, and the immune escape rate becomes small later, and typically only a minority of the epitopes escape. We show that escaping one of the many immune responses provides little advantage after viral setpoint has been approached because the total killing rate hardly depends on the breadth of the immune response. If the breadth of the immune response slowly wanes during disease progression, the model predicts an increase in the rate of immune escape at late stages of infection. Overall, the most striking prediction of the model is that HIV evolves a small number of immune escapes, in both relative and absolute terms, when the CTL immune response is broad.

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Section: Discussionmentioning

confidence: 99%

The Rate of Immune Escape Vanishes When Multiple Immune Responses Control an HIV Infection

Deutekom

Wijnker

Boer

2013

The Journal of Immunology

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“…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.…”

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confidence: 99%

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

Buzón

Martín‐Gayo

Pereyra

et al. 2014

J Virol

246

189

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Initiation of antiretroviral therapy during the earliest stages of HIV-1 infection may limit the seeding of a long-lasting viral reservoir, but long-term effects of early antiretroviral treatment initiation remain unknown. Here, we analyzed immunological and virological characteristics of nine patients who started antiretroviral therapy at primary HIV-1 infection and remained on suppressive treatment for >10 years; patients with similar treatment duration but initiation of suppressive therapy during chronic HIV-1 infection served as controls. We observed that independently of the timing of treatment initiation, HIV-1 DNA in CD4 T cells decayed primarily during the initial 3 to 4 years of treatment. However, in patients who started antiretroviral therapy in early infection, this decay occurred faster and was more pronounced, leading to substantially lower levels of cell-associated HIV-1 DNA after long-term treatment. Despite this smaller size, the viral CD4 T cell reservoir in persons with early treatment initiation consisted more dominantly of the long-lasting central-memory and T memory stem cells. HIV-1-specific T cell responses remained continuously detectable during antiretroviral therapy, independently of the timing of treatment initiation. Together, these data suggest that early HIV-1 treatment initiation, even when continued for >10 years, is unlikely to lead to viral eradication, but the presence of low viral reservoirs and durable HIV-1 T cell responses may make such patients good candidates for future interventional studies aiming at HIV-1 eradication and cure. IMPORTANCEAntiretroviral therapy can effectively suppress HIV-1 replication to undetectable levels; however, HIV-1 can persist despite treatment, and viral replication rapidly rebounds when treatment is discontinued. This is mainly due to the presence of latently infected CD4 T cells, which are not susceptible to antiretroviral drugs. Starting treatment in the earliest stages of HIV-1 infection can limit the number of these latently infected cells, raising the possibility that these viral reservoirs are naturally eliminated if suppressive antiretroviral treatment is continued for extremely long periods of time. Here, we analyzed nine patients who started on antiretroviral therapy within the earliest weeks of the disease and continued treatment for more than 10 years. Our data show that early treatment accelerated the decay of infected CD4 T cells and led to very low residual levels of detectable HIV-1 after long-term therapy, levels that were otherwise detectable in patients who are able to maintain a spontaneous, drug-free control of HIV-1 replication. Thus, long-term antiretroviral treatment started during early infection cannot eliminate HIV-1, but the reduced reservoirs of HIV-1 infected cells in such patients may increase their chances to respond to clinical interventions aiming at inducing a drug-free remission of HIV-1 infection.

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“…21,32,37,40 Duration of ART at PHI Three randomised controlled trials in PHI reported a modest benefit (delaying the decline in CD4 cell count, or time from PHI, to requiring lifelong ART) following a 48-week 38 or 60-week 39,40 course of ART. Interruption of therapy even if started close to the time of PHI is no longer recommended.…”

Section: 36mentioning

confidence: 99%

Primary HIV infection: a medical and public health emergency requiring rapid specialist management

Fidler

Fox

2016

Clinical Medicine

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No Treatment versus 24 or 60 Weeks of Antiretroviral Treatment during Primary HIV Infection: The Randomized Primo-SHM Trial

Abstract: In a three-arm randomized trial conducted among adult patients in HIV treatment centers in The Netherlands, Marlous Grijsen and colleagues examine the effects of temporary combination antiretroviral therapy during primary HIV infection.

Cited by 80 publications

References 42 publications

The Rate of Immune Escape Vanishes When Multiple Immune Responses Control an HIV Infection

The Rate of Immune Escape Vanishes When Multiple Immune Responses Control an HIV Infection

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

Primary HIV infection: a medical and public health emergency requiring rapid specialist management

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