scholarly journals Prevalence and Clinical Outcomes of Poor Immune Response Despite Virologically Suppressive Antiretroviral Therapy Among Children and Adolescents With Human Immunodeficiency Virus in Europe and Thailand: Cohort Study

2019 ◽  
Author(s):  
◽  
Elizabeth Chappell ◽  
Andrew Riordan ◽  
Gonzague Jourdain ◽  
Antoni Soriano-Arandes ◽  
...  
Keyword(s):  
Immune Response ◽  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Multivariable Analysis ◽  
World Health ◽  
Severe Immunosuppression ◽  
Art Initiation ◽  
Cell Counts ◽  
Increased Risk ◽  
Immunodeficiency Virus

Abstract Background In human immunodeficiency virus (HIV)–positive adults, low CD4 cell counts despite fully suppressed HIV-1 RNA on antiretroviral therapy (ART) have been associated with increased risk of morbidity and mortality. We assessed the prevalence and outcomes of poor immune response (PIR) in children receiving suppressive ART. Methods Sixteen cohorts from the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) contributed data. Children <18 years at ART initiation, with sustained viral suppression (VS) (≤400 copies/mL) for ≥1 year were included. The prevalence of PIR (defined as World Health Organization advanced/severe immunosuppression for age) at 1 year of VS was described. Factors associated with PIR were assessed using logistic regression. Rates of acquired immunodeficiency syndrome (AIDS) or death on suppressive ART were calculated by PIR status. Results Of 2318 children included, median age was 6.4 years and 68% had advanced/severe immunosuppression at ART initiation. At 1 year of VS, 12% had PIR. In multivariable analysis, PIR was associated with older age and worse immunological stage at ART start, hepatitis B coinfection, and residing in Thailand (all P ≤ .03). Rates of AIDS/death (95% confidence interval) per 100 000 person-years were 1052 (547, 2022) among PIR versus 261 (166, 409) among immune responders; rate ratio of 4.04 (1.83, 8.92; P < .001). Conclusions One in eight children in our cohort experienced PIR despite sustained VS. While the overall rate of AIDS/death was low, children with PIR had a 4-fold increase in risk of event as compared with immune responders.

scholarly journals Clinical and Immunologic Outcomes After Immediate or Deferred Antiretroviral Therapy Initiation During Primary Human Immunodeficiency Virus Infection: The Sabes Randomized Clinical Study

2020 ◽  
Author(s):  
Javier R Lama ◽  
Rachel A Bender Ignacio ◽  
Ricardo Alfaro ◽  
Jessica Rios ◽  
Jorge Gallardo Cartagena ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Clinical Study ◽  
Antiretroviral Therapy ◽  
World Health ◽  
Open Label ◽  
Art Initiation ◽  
Randomized Clinical Study ◽  
Immune Biomarkers ◽  
Immunodeficiency Virus ◽  
Acute Hiv

Abstract Background In addition to demonstrated public health benefits on reducing transmission, it remains unclear how early antiretroviral therapy (ART) must be started after acquisition of human immunodeficiency virus (HIV) to maximize individual benefits. Methods We conducted an open-label randomized clinical study in Lima, Peru among adult men who have sex with men and transgender women with acute (HIV-antibody negative/HIV-1 RNA positive) or recent (confirmed negative HIV-antibody or RNA test within 3 months) HIV infection, who were randomized to start ART immediately versus defer by 24 weeks. We evaluated outcomes by treatment arm and immunologic markers by days since estimated date of detectible infection (EDDI). Results Of 216 participants, 105 were assigned to immediate arm and 111 to deferred arm (median age 26.8 years, 37% with acute HIV). The incidence of non-ART-related adverse events was lower in immediate versus deferred arm (83 vs 123/100 person-years, IRR 0.67 (95% confidence interval [CI] .47, .95; P = .02), the difference dominated by fewer infections in those treated immediately. After 24 weeks of ART, between-group differences in CD4/CD8 cell ratio lessened (P = .09 overall), but differences between those initiating ART ≤ 30 days from EDDI (median 1.03, interquartile range [IQR] 0.84, 1.37), and those initiating &gt; 90 days (0.88, IQR 0.61, 1.11) remained, P = .02. Principal components analysis of 20 immune biomarkers demonstrated distinct patterns between those starting ART &gt; 90 days from EDDI versus those starting within 30 or 90 days (both P &lt; .001). Conclusions To our knowledge, this is the only evaluation of randomized ART initiation during primary HIV and provides evidence to explicitly consider acute HIV in World Health Organization recommendations for universal ART. Clinical Trials Registration NCT01815580.

scholarly journals Tuberculosis Incidence and Risk Factors Among Human Immunodeficiency Virus (HIV)-Infected Adults Receiving Antiretroviral Therapy in a Large HIV Program in Nigeria

2015 ◽  
Vol 2 (4) ◽  
Author(s):  
Charlotte A. Chang ◽  
Seema Thakore Meloni ◽  
Geoffrey Eisen ◽  
Beth Chaplin ◽  
Patrick Akande ◽  
...  
Keyword(s):  
Risk Factors ◽  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Incidence Rate ◽  
Clinical Stage ◽  
Cox Proportional Hazards ◽  
World Health ◽  
Clinical Markers ◽  
Art Initiation ◽  
Immunodeficiency Virus

Abstract Background.  Despite the benefits of antiretroviral therapy (ART), tuberculosis (TB) is the leading cause of mortality among human immunodeficiency virus (HIV)-infected persons in Africa. Nigeria bears the highest TB burden in Africa and second highest HIV burden globally. This long-term multicenter study aimed to determine the incidence rate and predictors of TB in adults in the Harvard/AIDS Prevention Initiative in Nigeria (APIN) and President's Emergency Plan for AIDS Relief (PEPFAR) Nigeria ART program. Methods.  This retrospective evaluation used data collected from 2004 to 2012 through the Harvard/APIN PEPFAR program. Risk factors for incident TB were determined using multivariate Cox proportional hazards regression with time-dependent covariates. Results.  Of 50 320 adults enrolled from 2005 to 2010, 11 092 (22%) had laboratory-confirmed active TB disease at ART initiation, and 2021 (4%) developed active TB after commencing ART. During 78 228 total person-years (PY) of follow-up, the TB incidence rate was 25.8 cases per 1000 PY (95% confidence interval [CI], 24.7–27.0) overall, and it decreased significantly both with duration on ART and calendar year. Risk factors at ART initiation for incident TB included the following: earlier ART enrollment year, tenofovir-containing initial ART regimen, and World Health Organization clinical stage above 1. Time-updated risk factors included the following: low body mass index, low CD4+ cell count, unsuppressed viral load, anemia, and ART adherence below 80%. Conclusions.  The rate of incident TB decreased with longer duration on ART and over the program years. The strongest TB risk factors were time-updated clinical markers, reinforcing the importance of consistent clinical and laboratory monitoring of ART patients in prompt diagnosis and treatment of TB and other coinfections.

scholarly journals Estimates of the Time From Seroconversion to Antiretroviral Therapy Initiation Among People Newly Diagnosed With Human Immunodeficiency Virus From 2006 to 2015, New York City

2019 ◽  
Vol 71 (8) ◽  
pp. e308-e315
Author(s):  
McKaylee M Robertson ◽  
Sarah L Braunstein ◽  
Donald R Hoover ◽  
Sheng Li ◽  
Denis Nash
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Hiv Testing ◽  
Mixed Model ◽  
Linear Mixed Model ◽  
Population Based ◽  
Cd4 Count ◽  
Hiv Diagnosis ◽  
Art Initiation ◽  
Immunodeficiency Virus

Abstract Background We estimated the time from human immunodeficiency virus (HIV) seroconversion to antiretroviral therapy (ART) initiation during an era of expanding HIV testing and treatment efforts. Methods Applying CD4 depletion parameters from seroconverter cohort data to our population-based sample, we related the square root of the first pretreatment CD4 count to time of seroconversion through a linear mixed model and estimated the time from seroconversion. Results Among 28 162 people diagnosed with HIV during 2006–2015, 89% initiated ART by June 2017. The median CD4 count at diagnosis increased from 326 (interquartile range [IQR], 132–504) cells/µL to 390 (IQR, 216–571) cells/µL from 2006 to 2015. The median time from estimated seroconversion to ART initiation decreased by 42% from 6.4 (IQR, 3.3–11.4) years in 2006 to 3.7 (IQR, 0.5–8.3) years in 2015. The time from estimated seroconversion to diagnosis decreased by 28%, from a median of 4.6 (IQR, 0.5–10.5) years to 3.3 (IQR, 0–8.1) years from 2006 to 2015, and the time from diagnosis to ART initiation reduced by 60%, from a median of 0.5 (IQR, 0.2–2.1) years to 0.2 (IQR, 0.1–0.3) years from 2006 to 2015. Conclusions The estimated time from seroconversion to ART initiation was reduced in tandem with expanded HIV testing and treatment efforts. While the time from diagnosis to ART initiation decreased to 0.2 years, the time from seroconversion to diagnosis was 3.3 years among people diagnosed in 2015, highlighting the need for more effective strategies for earlier HIV diagnosis.

scholarly journals Highly Active Antiretroviral Therapy in Human Immunodeficiency Virus Type 1-Infected Children: Analysis of Cellular Immune Responses

2001 ◽  
Vol 8 (5) ◽  
pp. 943-948 ◽  
Author(s):  
Vesna Blazevic ◽  
Shirley Jankelevich ◽  
Seth M. Steinberg ◽  
Freda Jacobsen ◽  
Robert Yarchoan ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Highly Active Antiretroviral Therapy ◽  
Delayed Type Hypersensitivity ◽  
Strong Increase ◽  
Highly Active ◽  
Cell Counts ◽  
Immunodeficiency Virus

ABSTRACT The present study analyzes the effect of highly active antiretroviral therapy (HAART) on restoration of cellular immunity in human immunodeficiency virus (HIV)-infected children over a 24-week period following initiation of HAART with ritonavir, nevirapine, and stavudine. The immunological parameters evaluated at four time points (at enrollment and at 4, 12, and 24 weeks of therapy) included cytokine production by monocytes as well as T-cell proliferation in response to mitogen, alloantigen, and recall antigens including HIV type 1 envelope peptides. Circulating levels of interleukin-16 (IL-16) were measured, in addition to CD4+ T-cell counts, plasma HIV RNA levels, and the delayed-type hypersensitivity (DTH) response. At enrollment the children exhibited defects in several immune parameters measured. Therapy increased CD4+ T-cell counts and decreased viral loads significantly. By contrast, the only immunological parameter that was significantly increased was IL-12 p70 production by monocytes; the DTH response to Candida albicans also showed a strong increase in patients becoming positive. In conclusion, these results demonstrate that HAART in HIV-infected children affects the dynamics of HIV replication and the CD4+ T-cell count over 24 weeks, similar to the pattern seen in HIV-infected adults. Furthermore, these data indicate improvement in antigen-presenting cell immunological function in HIV-infected children induced by HAART.

scholarly journals Occurrence of Accelerated Epigenetic Aging and Methylation Disruptions in Human Immunodeficiency Virus Infection Before Antiretroviral Therapy

2020 ◽  
Author(s):  
Chen Xi Yang ◽  
Emma Schon ◽  
Ma’en Obeidat ◽  
Michael S Kobor ◽  
Lisa McEwen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Cellular Aging ◽  
Epigenetic Clock ◽  
Cell Counts ◽  
Immunodeficiency Virus ◽  
Negative Controls ◽  
Hiv Negative

Abstract Background Whether accelerated aging develops over the course of chronic human immunodeficiency virus (HIV) infection or can be observed before significant immunosuppression on is unknown. We studied DNA methylation in blood to estimate cellular aging in persons living with HIV (PLWH) before the initiation of antiretroviral therapy (ART). Methods A total of 378 ART-naive PLWH who had CD4 T-cell counts &gt;500/µL and were enrolled in the Strategic Timing of Antiretroviral Therapy trial (Pulmonary Substudy) were compared with 34 HIV-negative controls. DNA methylation was performed using the Illumina MethylationEPIC BeadChip. Differentially methylated positions (DMPs) and differentially methylated regions (DMRs) in PLWH compared with controls were identified using a robust linear model. Methylation age was calculated using a previously described epigenetic clock. Results There were a total of 56 639 DMPs and 6103 DMRs at a false discovery rate of &lt;0.1. The top 5 DMPs corresponded to genes NLRC5, VRK2, B2M, and GPR6 and were highly enriched for cancer-related pathways. PLWH had significantly higher methylation age than HIV-negative controls (P = .001), with black race, low CD4 and high CD8 T-cell counts, and duration of HIV being risk factors for age acceleration. Conclusions PLWH before the initiation of ART and with preserved immune status show evidence of advanced methylation aging.

scholarly journals Cryptococcal Antigenemia in Human Immunodeficiency Virus Antiretroviral Therapy–Experienced Ugandans With Virologic Failure

2019 ◽  
Vol 71 (7) ◽  
pp. 1726-1731 ◽  
Author(s):  
Edward Mpoza ◽  
Radha Rajasingham ◽  
Lillian Tugume ◽  
Joshua Rhein ◽  
Maria Sarah Nabaggala ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Load ◽  
Antiretroviral Therapy ◽  
Cryptococcal Meningitis ◽  
Virologic Failure ◽  
Cost Effective ◽  
World Health ◽  
Load Testing ◽  
Viral Loads ◽  
Immunodeficiency Virus

Abstract Background Detectable serum or plasma cryptococcal antigen (CrAg) precedes symptomatic cryptococcal meningitis. The World Health Organization recommends CrAg screening for human immunodeficiency virus–positive persons with CD4 count &lt;100 cells/μL initiating antiretroviral therapy (ART). However, an increasing proportion of patients with cryptococcosis are now ART experienced. Whether CrAg screening is cost-effective in those with virologic failure is unknown. Methods We retrospectively performed nationwide plasma CrAg testing among ART-experienced Ugandan adults with virologic failure (≥1000 copies/mL) using leftover plasma after viral load testing during September 2017–January 2018. For those who were CrAg positive, we obtained ART history, meningitis occurrence, and 6-month survival via medical records review. Results Among 1186 subjects with virologic failure, 35 (3.0%) were CrAg positive with median ART duration of 41 months (interquartile range, 10–84 months). Among 25 subjects with 6-month outcomes, 16 (64%) survived, 7 (28%) died, and 2 (8%) were lost. One survivor had suffered cryptococcal meningitis 2 years prior. Two others developed cryptococcal meningitis and survived. Five survivors were known to have received fluconazole. Thus, meningitis-free survival at 6 months was 61% (14/23). Overall, 91% (32/35) of CrAg-positive persons had viral load ≥5000 copies/mL compared with 64% (735/1151) of CrAg-negative persons (odds ratio, 6.0 [95% confidence interval, 1.8–19.8]; P = .001). CrAg prevalence was 4.2% (32/768) among those with viral loads ≥5000 copies/mL and 0.7% (3/419) among those with viral loads &lt;5000 copies/mL. Conclusions In addition to the CD4 threshold of &lt;100 cells/μL, reflexive CrAg screening should be considered in persons failing ART in Uganda with viral loads ≥5000 copies/mL.

scholarly journals Outcomes of Coronavirus Disease 2019 (COVID-19) Related Hospitalization Among People With Human Immunodeficiency Virus (HIV) in the ISARIC World Health Organization (WHO) Clinical Characterization Protocol (UK): A Prospective Observational Study

2020 ◽  
Author(s):  
Anna Maria Geretti ◽  
Alexander J Stockdale ◽  
Sophie H Kelly ◽  
Muge Cevik ◽  
Simon Collins ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
World Health Organization ◽  
Cox Regression ◽  
World Health ◽  
Rank Test ◽  
Hiv Positive ◽  
Protein Levels ◽  
Increased Risk ◽  
Immunodeficiency Virus ◽  
Health Organization

Abstract Background Evidence is conflicting about how human immunodeficiency virus (HIV) modulates coronavirus disease 2019 (COVID-19). We compared the presentation characteristics and outcomes of adults with and without HIV who were hospitalized with COVID-19 at 207 centers across the United Kingdom and whose data were prospectively captured by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) World Health Organization (WHO) Clinical Characterization Protocol (CCP) study. Methods We used Kaplan-Meier methods and Cox regression to describe the association between HIV status and day-28 mortality, after separate adjustment for sex, ethnicity, age, hospital acquisition of COVID-19 (definite hospital acquisition excluded), presentation date, 10 individual comorbidities, and disease severity at presentation (as defined by hypoxia or oxygen therapy). Results Among 47 592 patients, 122 (0.26%) had confirmed HIV infection, and 112/122 (91.8%) had a record of antiretroviral therapy. At presentation, HIV-positive people were younger (median 56 vs 74 years; P &lt; .001) and had fewer comorbidities, more systemic symptoms and higher lymphocyte counts and C-reactive protein levels. The cumulative day-28 mortality was similar in the HIV-positive versus HIV-negative groups (26.7% vs. 32.1%; P = .16), but in those under 60 years of age HIV-positive status was associated with increased mortality (21.3% vs. 9.6%; P &lt; .001 [log-rank test]). Mortality was higher among people with HIV after adjusting for age (adjusted hazard ratio [aHR] 1.47, 95% confidence interval [CI] 1.01–2.14; P = .05), and the association persisted after adjusting for the other variables (aHR 1.69; 95% CI 1.15–2.48; P = .008) and when restricting the analysis to people aged &lt;60 years (aHR 2.87; 95% CI 1.70–4.84; P &lt; .001). Conclusions HIV-positive status was associated with an increased risk of day-28 mortality among patients hospitalized for COVID-19.

scholarly journals Timing of Antiretroviral Therapy Initiation and Risk of Cancer Among Persons Living With Human Immunodeficiency Virus

2020 ◽  
Author(s):  
Michael J Silverberg ◽  
Wendy Leyden ◽  
Raúl U Hernández-Ramírez ◽  
Li Qin ◽  
Haiqun Lin ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Kaposi Sarcoma ◽  
Risk Difference ◽  
Right Censoring ◽  
Transmission Risk ◽  
Adjusted Risk ◽  
Art Initiation ◽  
Immunodeficiency Virus ◽  
Risk Of Cancer

Abstract Background Persons living with human immunodeficiency virus (HIV; PLWH) experience a high burden of cancer. It remains unknown which cancer types are reduced in PLWH with earlier initiation of antiretroviral therapy (ART). Methods We evaluated AIDS-free, ART-naive PLWH during 1996–2014 from 22 cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. PLWH were followed from first observed CD4 of 350–500 cells/µL (baseline) until incident cancer, death, lost-to-follow-up, or December 2014. Outcomes included 6 cancer groups and 5 individual cancers that were confirmed by chart review or cancer registry linkage. We evaluated the effect of earlier (in the first 6 months after baseline) versus deferred ART initiation on cancer risk. Marginal structural models were used with inverse probability weighting to account for time-dependent confounding and informative right-censoring, with weights informed by subject’s age, sex, cohort, baseline year, race/ethnicity, HIV transmission risk, smoking, viral hepatitis, CD4, and AIDS diagnoses. Results Protective results for earlier ART were found for any cancer (adjusted hazard ratio [HR] 0.57; 95% confidence interval [CI], .37–.86), AIDS-defining cancers (HR 0.23; 95% CI, .11–.49), any virus-related cancer (HR 0.30; 95% CI, .16–.54), Kaposi sarcoma (HR 0.25; 95% CI, .10–.61), and non-Hodgkin lymphoma (HR 0.22; 95% CI, .06–.73). By 15 years, there was also an observed reduced risk with earlier ART for virus-related NADCs (0.6% vs 2.3%; adjusted risk difference −1.6; 95% CI, −2.8, −.5). Conclusions Earlier ART initiation has potential to reduce the burden of virus-related cancers in PLWH but not non-AIDS-defining cancers (NADCs) without known or suspected viral etiology.

scholarly journals Continuous Prophylactic Antiretrovirals/Antiretroviral Therapy Since Birth Reduces Seeding and Persistence of the Viral Reservoir in Children Vertically Infected With Human Immunodeficiency Virus

2020 ◽  
Author(s):  
Marta Massanella ◽  
Thanyawee Puthanakit ◽  
Louise Leyre ◽  
Thidarat Jupimai ◽  
Panadda Sawangsinth ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Cross Sectional Study ◽  
Viral Reservoir ◽  
Cross Sectional ◽  
Hiv Reservoir ◽  
Hiv Dna ◽  
Art Initiation ◽  
Immunodeficiency Virus ◽  
Infected Cells

Abstract Background Early antiretroviral therapy (ART) restricts the size of the human immunodeficiency virus (HIV) reservoir in infants. However, whether antiretroviral (ARV) prophylaxis given to exposed vertically infected children exerts similar effects remains unknown. Methods We measured total and integrated HIV DNA, as well as the frequency of CD4 T cells producing multiply spliced RNA (msRNA) after stimulation (inducible reservoir) in vertically infected Thai infants. Eighty-five infants were followed longitudinally for up to 3 years. We compared the size of the reservoir in children who received continuous ARV prophylaxis since birth vs those who never received or discontinued prophylaxis before initiating ART. We used samples from a cross-sectional cohort of 37 Thai children who had initiated ART within 6 months of life to validate our findings. Results Before ART, levels of HIV DNA and the frequencies of cells producing msRNA were significantly lower in infants who received continuous ARV prophylaxis since birth compared to those in whom ARV prophylaxis was discontinued or never initiated (P &lt; .020 and P &lt; .001, respectively). Upon ART initiation, total and integrated HIV DNA levels decayed significantly in both groups (P &lt; .01 in all cases). Interestingly, the initial differences in the frequencies of infected cells persisted during 3 years on ART. The beneficial effect of prophylaxis on the size of the HIV reservoir was confirmed in the cross-sectional study. Importantly, no differences were observed between children who discontinued prophylactic ARVs before starting ART and those who delayed ART initiation without receiving prior prophylaxis. Conclusions Neonatal ARV prophylaxis with direct transition to ART durably limits the size of the HIV reservoir.

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