Decreased Seroreactivity in Individuals Initiating Antiretroviral Therapy during Acute HIV Infection

Manak, Mark M.; Jagodzinski, Linda L.; Shutt, Ashley; Malia, Jennifer; Leos, M; Ouellette, Jason; Akapirat, Siriwat; Colby, Donn; Phanuphak, Nittaya; Eller, Leigh Anne; Robb, Merlin L.; Souza, Mark de; Ananworanich, Jintanat; Peel, Sheila A.

doi:10.1128/jcm.00757-19

“…These data demonstrate that in the context of rapid ART initiation during Fiebig I, antibody tests for the confirmation of HIV infection are unreliable. Similar findings were reported in Thai participants initiating ART during AHI , as well as among infants with perinatally acquired HIV receiving ART early in infection, where subsequent antibody testing remained negative at almost two years of age .…”

Section: Discussionsupporting

confidence: 82%

Challenges of HIV diagnosis and management in the context of pre‐exposure prophylaxis (PrEP), post‐exposure prophylaxis (PEP), test and start and acute HIV infection: a scoping review

Elliott

¹

,

Sanders

²

,

Doherty

³

et al. 2019

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Introduction Knowledge of HIV status relies on accurate HIV testing, and is the first step towards access to HIV treatment and prevention programmes. Globally, HIV‐status unawareness represents a significant challenge for achieving zero new HIV infections and deaths. In order to enhance knowledge of HIV status, the World Health Organisation (WHO) recommends a testing strategy that includes the use of HIV‐specific antibody point‐of‐care tests (POCT). These POCTs do not detect acute HIV infection, the stage of disease when viral load is highest but HIV antibodies are undetectable. Complicating things further, in the presence of antiretroviral therapy (ART) for pre‐exposure prophylaxis (PrEP) or post‐exposure prophylaxis (PEP), other currently available testing technologies, such as viral load detection for diagnosis of acute HIV infection, may yield false‐negative results. In this scoping review, we evaluate the evidence and discuss alternative HIV testing algorithms that may mitigate diagnostic dilemmas in the setting of increased utilization of ART for immediate treatment and prevention of HIV infection. Discussion Missed acute HIV infection prevents people living with HIV (PLHIV) from accessing early treatment, increases likelihood of onward transmission, and allows for inappropriate initiation or continuation of PrEP, which may result in HIV drug resistance. While immediate ART is recommended for all PLHIV, studies have shown that starting ART in the setting of acute HIV infection may result in a delayed or complete absence of development of HIV‐specific antibodies, posing a diagnostic challenge that is particularly pertinent to resource‐limited, high HIV burden settings where HIV‐antibody POCTs are standard of care. Similarly, ART used as PrEP or PEP may supress HIV RNA viral load, complicating current HIV testing algorithms in resource‐wealthy settings where viral detection is included. As rollout of PrEP continues, HIV testing algorithms may need to be modified. Conclusions With increasing use of PrEP and ART in acute infection we anticipate diagnostic challenges using currently available HIV testing strategies. Research and surveillance are needed to determine the most appropriate assays and optimal testing algorithms that are accurate, affordable and sustainable.

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“…One could even argue that as the time of ART initiation approaches the time of infection, the viral rebound dynamics after ART interruption starts to resemble those of an acute infection ( Fig 4B). Similar patterns have been found for HIV-1, where ART initiation during acute HIV infection can lead to an incomplete HIV-specific humoral immune response, as measured by diagnostic assays [38,39]. On the other hand, patients treated during Fiebig stage I or II have been shown to develop detectable HIV-specific CD8 + T-cell responses [40].…”

Section: Discussionsupporting

confidence: 63%

Models of SIV rebound after treatment interruption that involve multiple reactivation events

Dorp

¹

,

Conway

²

,

Barouch

³

et al. 2020

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In order to assess the efficacy of novel HIV-1 treatments leading to a functional cure, the time to viral rebound is frequently used as a surrogate endpoint. The longer the time to viral rebound, the more efficacious the therapy. In support of such an approach, mathematical models serve as a connection between the size of the latent reservoir and the time to HIV-1 rebound after treatment interruption. The simplest of such models assumes that a single successful latent cell reactivation event leads to observable viremia after a period of exponential viral growth. Here we consider a generalization developed by Pinkevych et al. and Hill et al. of this simple model in which multiple reactivation events can occur, each contributing to the exponential growth of the viral load. We formalize and improve the previous derivation of the dynamics predicted by this model, and use the model to estimate relevant biological parameters from SIV rebound data. We confirm a previously described effect of very early antiretroviral therapy (ART) initiation on the rate of recrudescence and the viral load growth rate after treatment interruption. We find that every day ART initiation is delayed results in a 39% increase in the recrudescence rate (95% credible interval: [18%, 62%]), and a 11% decrease of the viral growth rate (95% credible interval: [4%, 20%]). We show that when viral rebound occurs early relative to the viral load doubling time, a model with multiple successful reactivation events fits the data better than a model with only a single successful reactivation event.

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“…One could even argue that as the time of ART initiation approaches the time of infection, the viral rebound dynamics after ART interruption starts to resemble those of an acute infection ( Fig 4B). Similar patterns have been found for HIV-1, where ART initiation during acute HIV infection can lead to an incomplete HIV-specific humoral immune response, as measured by diagnostic assays [12,25]. On the other hand, patients treated during Fiebig stage I or II have been shown to develop detectable HIV-specific CD8 + T-cell responses [27].…”

Section: Discussionsupporting

confidence: 63%

Models of SIV rebound after treatment interruption that involve multiple reactivation events

Dorp

¹

,

Conway

²

,

Whitney

³

et al. 2020

Preprint

0

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In order to assess the efficacy of novel HIV-1 treatments leading to a functional cure, the time to viral rebound is frequently used as a surrogate endpoint. The longer the time to viral rebound, the more efficacious the therapy. In support of such an approach, mathematical models serve as a connection between the size of the latent reservoir and the time to HIV-1 rebound after treatment interruption. The simplest of such models assumes that a single successful latent cell reactivation event leads to observable viremia after a period of exponential viral growth. Here we consider a generalization developed by Pinkevych et al. and Hill et al. of this simple model in which multiple reactivation events can occur, each contributing to the exponential growth of the viral load. We formalize and improve the previous derivation of the dynamics predicted by this model, and use the model to estimate relevant biological parameters from SIV rebound data. We confirm a previously described effect of very early antiretroviral therapy (ART) initiation on the rate of recrudescence and the viral load growth rate after treatment interruption. We find that every day ART initiation is delayed results in a 39% increase in the recrudescence rate, and a 11% decrease of the viral growth rate. We show that when viral rebound occurs early relative to the viral load doubling time, a model with multiple successful reactivation events fits the data better than a model with only a single successful reactivation event.Author SummaryHIV-1 persists during suppressive antiretroviral therapy (ART) due to a reservoir of latently infected cells. When ART is stopped, HIV generally rebounds within a few weeks. However, there is a small fraction of patients that do not rebound over a period of months or years. A variety of treatments are being tested for their ability to reduce the size of the latent reservoir, to induce effective immune responses against the virus, or to prevent or prolong the time to viral rebound after ART interruption. These novel treatments are typically first tested in SIV infected macaques, and the efficacy of the treatment assessed by interrupting ART and measuring the time to viral rebound. Here, we develop and test a mathematical and statistical model that describes the process of viral rebound. The model can be used for statistical inference of the efficacy of newly developed treatments. Importantly, the model takes into account that multiple recrudescence events can precede rebound. We test the model using data from early treated SIV infected macaques.

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Decreased Seroreactivity in Individuals Initiating Antiretroviral Therapy during Acute HIV Infection

Cited by 27 publications

References 52 publications

Challenges of HIV diagnosis and management in the context of pre‐exposure prophylaxis (PrEP), post‐exposure prophylaxis (PEP), test and start and acute HIV infection: a scoping review

Challenges of HIV diagnosis and management in the context of pre‐exposure prophylaxis (PrEP), post‐exposure prophylaxis (PEP), test and start and acute HIV infection: a scoping review

Models of SIV rebound after treatment interruption that involve multiple reactivation events

Models of SIV rebound after treatment interruption that involve multiple reactivation events

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