Abundant HIV-infected cells in blood and tissues are rapidly cleared upon ART initiation during acute HIV infection

The timing and location of the establishment of the viral reservoir during acute HIV infection remain unclear. Using longitudinal blood and tissue samples obtained from HIV-infected individuals at the earliest stage of infection, we demonstrate that frequencies of infected cells reach maximal values in gut-associated lymphoid tissue and lymph nodes as early as Fiebig stage II, before seroconversion. Both tissues displayed higher frequencies of infected cells than blood until Fiebig stage III, after which infected cells were equally distributed in all compartments examined. Initiation of antiretroviral therapy (ART) at Fiebig stages I to III led to a profound decrease in the frequency of infected cells to nearly undetectable level in all compartments. The rare infected cells that persisted were preferentially found in the lymphoid tissues. Initiation of ART at later stages (Fiebig stages IV/V and chronic infection) induced only a modest reduction in the frequency of infected cells. Quantification of HIV DNA in memory CD4+ T cell subsets confirmed the unstable nature of most of the infected cells at Fiebig stages I to III and the emergence of persistently infected cells during the transition to Fiebig stage IV. Our results indicate that although a large pool of cells is infected during acute HIV infection, most of these early targets are rapidly cleared upon ART initiation. Therefore, infected cells present after peak viremia have a greater ability to persist.

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A Novel HIV-1 RNA Testing Intervention to Detect Acute and Prevalent HIV Infection in Young Adults and Reduce HIV Transmission in Kenya: Protocol for a Randomized Controlled Trial (Preprint)

10.2196/preprints.16198 ◽

2019 ◽

Author(s):

Susan M Graham ◽

Clara Agutu ◽

Elise van der Elst ◽

Amin S Hassan ◽

Evanson Gichuru ◽

...

Keyword(s):

Young Adults ◽

Hiv Infection ◽

Hiv Testing ◽

Hiv Transmission ◽

Partner Notification ◽

Newly Diagnosed ◽

Intervention Period ◽

Acute Hiv Infection ◽

Art Initiation ◽

Acute Hiv

BACKGROUND Detection and management of acute HIV infection (AHI) is a clinical and public health priority, and HIV infections diagnosed among young adults aged 18 to 39 years are usually recent. Young adults with recent HIV acquisition frequently seek care for symptoms and could potentially be diagnosed through the health care system. Early recognition of HIV infection provides considerable individual and public health benefits, including linkage to treatment as prevention, access to risk reduction counseling and treatment, and notification of partners in need of HIV testing. OBJECTIVE The Tambua Mapema Plus study aims to (1) test 1500 young adults (aged 18-39 years) identified by an AHI screening algorithm for acute and prevalent (ie, seropositive) HIV, linking all newly diagnosed HIV-infected patients to care and offering immediate treatment; (2) offer assisted HIV partner notification services to all patients with HIV, testing partners for acute and prevalent HIV infection and identifying local sexual networks; and (3) model the potential impact of these two interventions on the Kenyan HIV epidemic, estimating incremental costs per HIV infection averted, death averted, and disability-adjusted life year averted using data on study outcomes. METHODS A modified stepped-wedge design is evaluating the yield of this HIV testing intervention at 4 public and 2 private health facilities in coastal Kenya before and after intervention delivery. The intervention uses point-of-care HIV-1 RNA testing combined with standard rapid antibody tests to diagnose AHI and prevalent HIV among young adults presenting for care, employs HIV partner notification services to identify linked acute and prevalent infections, and follows all newly diagnosed patients and their partners for 12 months to ascertain clinical outcomes, including linkage to care, antiretroviral therapy (ART) initiation and virologic suppression in HIV-infected patients, and pre-exposure prophylaxis uptake in uninfected individuals in discordant partnerships. RESULTS Enrollment started in December 2017. As of April 2020, 1374 participants have been enrolled in the observation period and 1500 participants have been enrolled in the intervention period, with 13 new diagnoses (0.95%) in the observation period and 37 new diagnoses (2.47%), including 2 AHI diagnoses, in the intervention period. Analysis is ongoing and will include adjusted comparisons of the odds of the following outcomes in the observation and intervention periods: being tested for HIV infection, newly diagnosed with prevalent or acute HIV infection, linked to care, and starting ART by week 6 following HIV diagnosis. Participants newly diagnosed with acute or prevalent HIV infection in the intervention period are being followed for outcomes, including viral suppression by month 6 and month 12 following ART initiation and partner testing outcomes. CONCLUSIONS The Tambua Mapema Plus study will provide foundational data on the potential of this novel combination HIV prevention intervention to reduce ongoing HIV transmission in Kenya and other high-prevalence African settings. CLINICALTRIAL ClinicalTrials.gov NCT03508908; https://clinicaltrials.gov/ct2/show/NCT03508908 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/16198

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A Novel HIV-1 RNA Testing Intervention to Detect Acute and Prevalent HIV Infection in Young Adults and Reduce HIV Transmission in Kenya: Protocol for a Randomized Controlled Trial

JMIR Research Protocols ◽

10.2196/16198 ◽

2020 ◽

Vol 9 (8) ◽

pp. e16198

Author(s):

Susan M Graham ◽

Clara Agutu ◽

Elise van der Elst ◽

Amin S Hassan ◽

Evanson Gichuru ◽

...

Keyword(s):

Young Adults ◽

Hiv Infection ◽

Hiv Testing ◽

Hiv Transmission ◽

Partner Notification ◽

Newly Diagnosed ◽

Intervention Period ◽

Acute Hiv Infection ◽

Art Initiation ◽

Acute Hiv

Background Detection and management of acute HIV infection (AHI) is a clinical and public health priority, and HIV infections diagnosed among young adults aged 18 to 39 years are usually recent. Young adults with recent HIV acquisition frequently seek care for symptoms and could potentially be diagnosed through the health care system. Early recognition of HIV infection provides considerable individual and public health benefits, including linkage to treatment as prevention, access to risk reduction counseling and treatment, and notification of partners in need of HIV testing. Objective The Tambua Mapema Plus study aims to (1) test 1500 young adults (aged 18-39 years) identified by an AHI screening algorithm for acute and prevalent (ie, seropositive) HIV, linking all newly diagnosed HIV-infected patients to care and offering immediate treatment; (2) offer assisted HIV partner notification services to all patients with HIV, testing partners for acute and prevalent HIV infection and identifying local sexual networks; and (3) model the potential impact of these two interventions on the Kenyan HIV epidemic, estimating incremental costs per HIV infection averted, death averted, and disability-adjusted life year averted using data on study outcomes. Methods A modified stepped-wedge design is evaluating the yield of this HIV testing intervention at 4 public and 2 private health facilities in coastal Kenya before and after intervention delivery. The intervention uses point-of-care HIV-1 RNA testing combined with standard rapid antibody tests to diagnose AHI and prevalent HIV among young adults presenting for care, employs HIV partner notification services to identify linked acute and prevalent infections, and follows all newly diagnosed patients and their partners for 12 months to ascertain clinical outcomes, including linkage to care, antiretroviral therapy (ART) initiation and virologic suppression in HIV-infected patients, and pre-exposure prophylaxis uptake in uninfected individuals in discordant partnerships. Results Enrollment started in December 2017. As of April 2020, 1374 participants have been enrolled in the observation period and 1500 participants have been enrolled in the intervention period, with 13 new diagnoses (0.95%) in the observation period and 37 new diagnoses (2.47%), including 2 AHI diagnoses, in the intervention period. Analysis is ongoing and will include adjusted comparisons of the odds of the following outcomes in the observation and intervention periods: being tested for HIV infection, newly diagnosed with prevalent or acute HIV infection, linked to care, and starting ART by week 6 following HIV diagnosis. Participants newly diagnosed with acute or prevalent HIV infection in the intervention period are being followed for outcomes, including viral suppression by month 6 and month 12 following ART initiation and partner testing outcomes. Conclusions The Tambua Mapema Plus study will provide foundational data on the potential of this novel combination HIV prevention intervention to reduce ongoing HIV transmission in Kenya and other high-prevalence African settings. Trial Registration ClinicalTrials.gov NCT03508908; https://clinicaltrials.gov/ct2/show/NCT03508908 International Registered Report Identifier (IRRID) DERR1-10.2196/16198

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Impact of Acute HIV Infection and Early Antiretroviral Therapy on the Human Gut Microbiome

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz367 ◽

2019 ◽

Vol 7 (12) ◽

Cited By ~ 3

Author(s):

Ornella Sortino ◽

Nittaya Phanuphak ◽

Alexandra Schuetz ◽

Alexandra M Ortiz ◽

Nitiya Chomchey ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Hiv Infection ◽

Inflammatory Markers ◽

Acute Infection ◽

Fecal Microbiota ◽

Acute Hiv Infection ◽

Gut Dysbiosis ◽

Art Initiation ◽

Rdna Sequencing ◽

Acute Hiv

Abstract Background Intestinal microbial dysbiosis is evident in chronic HIV-infected individuals and may underlie inflammation that persists even during antiretroviral therapy (ART). It remains unclear, however, how early after HIV infection gut dysbiosis emerges and how it is affected by early ART. Methods Fecal microbiota were studied by 16s rDNA sequencing in 52 Thai men who have sex with men (MSM), at diagnosis of acute HIV infection (AHI), Fiebig Stages 1–5 (F1-5), and after 6 months of ART initiation, and in 7 Thai MSM HIV-uninfected controls. Dysbiotic bacterial taxa were associated with relevant inflammatory markers. Results Fecal microbiota profiling of AHI pre-ART vs HIV-uninfected controls showed a mild dysbiosis. Transition from F1-3 of acute infection was characterized by enrichment in pro-inflammatory bacteria. Lower proportions of Bacteroidetes and higher frequencies of Proteobacteria and Fusobacteria members were observed post-ART compared with pre-ART. Fusobacteria members were positively correlated with levels of soluble CD14 in AHI post-ART. Conclusions Evidence of gut dysbiosis was observed during early acute HIV infection and was partially restored upon early ART initiation. The association of dysbiotic bacterial taxa with inflammatory markers suggests that a potential relationship between altered gut microbiota and systemic inflammation may also be established during AHI.

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Very Early Initiation of Antiretroviral Therapy During Acute HIV Infection Is Associated With Normalized Levels of Immune Activation Markers in Cerebrospinal Fluid but Not in Plasma

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz030 ◽

2019 ◽

Vol 220 (12) ◽

pp. 1885-1891 ◽

Cited By ~ 8

Author(s):

Joanna Hellmuth ◽

Bonnie M Slike ◽

Carlo Sacdalan ◽

John Best ◽

Eugene Kroon ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Antiretroviral Therapy ◽

Hiv Infection ◽

Immune Activation ◽

Acute Hiv Infection ◽

Activation Markers ◽

Art Initiation ◽

Markers Of Inflammation ◽

Median Plasma ◽

Acute Hiv

Abstract Background Chronic immune activation in the blood and central nervous system is a consequence of human immunodeficiency virus (HIV) infection that contributes to disease morbidity and can occur despite virally suppressive antiretroviral therapy (ART). The trajectory of HIV-related inflammation may vary with the timing of ART initiation. We examined immune activation markers in cerebrospinal fluid (CSF) and blood specimens collected over 96 weeks from participants who initiated ART during acute HIV infection (AHI). Methods RV254/SEARCH010 study participants with AHI underwent CSF (n = 89) and plasma (n = 146) sampling before initiating ART and at weeks 24 and 96 of treatment. A majority participants (64.4%) received a standard ART regimen (hereafter, “standard ART”), with some (34.7%) also receiving maraviroc and raltegravir for the first 24 weeks (hereafter, “ART plus”). We compared neopterin, CXCL10, CCL2, and interleukin 6 (IL-6) levels in the AHI group to those in 18 healthy, uninfected controls. Results Following 24 and 96 weeks of treatment, levels of all CSF markers normalized while levels of several plasma markers remained elevated in the AHI group (P < .001). Participants receiving the ART-plus regimen had lower median plasma CCL2 levels at week 24 and lower plasma neopterin levels at week 96. Conclusions ART initiation during AHI differentially impacts the brain compartment, with markers of inflammation returning to normal levels in the CSF, where they were sustained at week 96, but not in plasma.

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Cohort profile: the Netherlands Cohort Study on Acute HIV infection (NOVA), a prospective cohort study of people with acute or early HIV infection who immediately initiate HIV treatment

BMJ Open ◽

10.1136/bmjopen-2020-048582 ◽

2021 ◽

Vol 11 (11) ◽

pp. e048582

Author(s):

Maartje Dijkstra ◽

Henrieke Prins ◽

Jan M Prins ◽

Peter Reiss ◽

Charles Boucher ◽

...

Keyword(s):

Cohort Study ◽

The Netherlands ◽

Hiv Infection ◽

Prospective Cohort Study ◽

Prospective Cohort ◽

Viral Reservoir ◽

Study Group ◽

Hiv Cure ◽

Acute Hiv Infection ◽

Acute Hiv

PurposeInitiation of combination antiretroviral therapy (cART) during acute or early HIV-infection (AEHI) limits the size of the viral reservoir and preserves immune function. This renders individuals who started cART during AEHI promising participants in HIV-cure trials. Therefore, we established a multicentre prospective cohort study in the Netherlands that enrols people with AEHI. In anticipation of future cure trials, we will longitudinally investigate the properties of the viral reservoir size and HIV-specific immune responses among cohort participants.ParticipantsParticipants immediately initiate intensified cART: dolutegravir, emtricitabine/tenofovir and darunavir/ritonavir (DRV/r). After 4 weeks, once baseline resistance data are available, DRV/r is discontinued. Three study groups are assembled based on the preparedness of individuals to participate in the extensiveness of sampling. Participants accepting immediate treatment and follow-up but declining additional sampling are included in study group 1 (‘standard’) and routine diagnostic procedures are performed. Participants willing to undergo blood, leukapheresis and semen sampling are included in study group 2 (‘less invasive’). In study group 3 (‘extended’), additional tissue (gut-associated lymphoid tissue, peripheral lymph node) and cerebrospinal fluid sampling are performed.Findings to dateBetween 2015 and 2020, 140 individuals with AEHI have been enrolled at nine study sites. At enrolment, median age was 36 (IQR 28–47) years, and 134 (95.7%) participants were men. Distribution of Fiebig stages was as follows: Fiebig I, 3 (2.1%); II, 20 (14.3%); III, 7 (5.0%); IV, 49 (35.0%); V, 39 (27.9%); VI, 22 (15.7%). Median plasma HIV RNA was 5.9 (IQR 4.7–6.7) log10 copies/mL and CD4 count 510 (IQR 370–700) cells/mm3. Median time from cART initiation to viral suppression was 8.0 (IQR 4.0–16.0) weeks.Future plansThe Netherlands Cohort Study on Acute HIV infection remains open for participant enrolment and for additional sites to join the network. This cohort provides a unique nationwide platform for conducting future in-depth virological, immunological, host genetic and interventional studies investigating HIV-cure strategies.

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