CD4 T-Lymphocyte Recovery in Individuals With Advanced HIV-1 Infection Receiving Potent Antiretroviral Therapy for 4 Years
01 Jan 2017-
TL;DR: In this article, a longitudinally analyzed study of 2235 participants of the Swiss HIV Cohort, commencing HAART between 1996 and 1997, showed that the CD4 Tlymphocyte count increase, the percentage of individuals with a CD4T-cell count of 500/μL or greater and less than 200μL, and the determinants of CD4-cell recovery were evaluated in individuals treated with continuous (CONT; n=985) and discontinuous (DISCONT, n=1250) HAART.
Abstract: Methods: Plasma HIV-1 RNA levels and CD4 and CD8 T-lymphocyte counts were longitudinally analyzed over 4 years in 2235 participants of the Swiss HIV Cohort, commencing HAART between 1996 and 1997. The CD4 Tlymphocyte count increase, the percentage of individuals with a CD4 T-lymphocyte count of 500/μL or greater and less than 200/μL, and the determinants of CD4 Tlymphocyte recovery were evaluated in individuals treated with continuous (CONT; n=985) and discontinuous (DISCONT; n=1250) HAART.
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TL;DR: Strategies to reduce mortality must include earlier diagnosis of HIV infection, strengthening of longitudinal HIV care and timely initiation of antiretroviral treatment, especially in patients who present with advanced immunodeficiency.
Abstract: Two-thirds of the world's HIV-infected people live in sub-Saharan Africa, and more than 1.5 million of them die annually. As access to antiretroviral treatment has expanded within the region; early pessimism concerning the delivery of antiretroviral treatment using a large-scale public health approach has, at least in the short term, proved to be broadly unfounded. Immunological and virological responses to ART are similar to responses in patients treated in high-income countries. Despite this, however, early mortality rates in sub-Saharan Africa are very high; between 8 and 26% of patients die in the first year of antiretroviral treatment, with most deaths occurring in the first few months. Patients typically access antiretroviral treatment with advanced symptomatic disease, and mortality is strongly associated with baseline CD4 cell count less than 50 cells/mul and WHO stage 4 disease (AIDS). Although data are limited, leading causes of death appear to be tuberculosis, acute sepsis, cryptococcal meningitis, malignancy and wasting syndrome. Mortality rates are likely to depend not only on the care delivered by antiretroviral treatment programmes, but more fundamentally on how advanced disease is at programme enrollment and the quality of preceding healthcare. In addition to improving delivery of antiretroviral treatment and providing it free of charge to the patient, strategies to reduce mortality must include earlier diagnosis of HIV infection, strengthening of longitudinal HIV care and timely initiation of antiretroviral treatment. Health systems delays in antiretroviral treatment initiation must be minimized, especially in patients who present with advanced immunodeficiency.
674 citations
TL;DR: High levels of 16S rDNA during therapy are strongly associated with reduced increases in the CD4(+) T lymphocyte count, irrespective of plasma HIV RNA levels, consistent with the importance of microbial translocation in immunodeficiency and T cell homeostasis in chronic HIV infection.
Abstract: The significance of elevated plasma levels of bacterial lipopolysaccharide (LPS) in persons with chronic HIV infectionremainsundefined.WemeasuredLPSlevelsbyuseoflimuluslysateassay,andDNAsequencesencoding bacterial ribosomal 16S RNA (16S rDNA) were assessed by quantitative polymerase chain reactions in plasma samples obtained from 242 donors. Plasma levels of 16S rDNA were significantly higher in human immunodeficiencyvirus(HIV)‐infectedsubjectsthaninuninfectedsubjects,andtheycorrelatedwithLPSlevels.Higherlevels of16SrDNAwereassociatedwithhigherlevelsofTcellactivationandwithlowerlevelsofCD4Tcellrestoration duringantiretroviraltherapy.Antiretroviraltherapyreducesbutdoesnotfullynormalizeplasmalevelsofbacterial16SrDNA,anindexofmicrobialtranslocationfromthegastrointestinaltract.Highlevelsof16SrDNAduring therapy are strongly associated with reduced increases in the CD4 T lymphocyte count, irrespective of plasma HIV RNA levels. These findings are consistent with the importance of microbial translocation in immunodeficiency and T cell homeostasis in chronic HIV infection. Depletion ofcirculating CD4 T cells is the hallmark of the progressive immunodeficiency associated with HIV infection. Although HIV replicates within and can result in the destruction of CD4 T cells [1, 2], the mechanisms
568 citations
TL;DR: In industrialized countries, persons infected sexually with HIV now appear to experience mortality rates similar to those of the general population in the first 5 years following infection, though a mortality excess remains as duration of HIV infection lengthens.
Abstract: Context Mortality among human immunodeficiency virus (HIV)–infected individuals has decreased dramatically in countries with good access to treatment and may now be close to mortality in the general uninfected population. Objective To evaluate changes in the mortality gap between HIV-infected individuals and the general uninfected population. Design, Setting, and Population Mortality following HIV seroconversion in a large multinational collaboration of HIV seroconverter cohorts (CASCADE) was compared with expected mortality, calculated by applying general population death rates matched on demographic factors. A Poisson-based model adjusted for duration of infection was constructed to assess changes over calendar time in the excess mortality among HIV-infected individuals. Data pooled in September 2007 were analyzed in March 2008, covering years at risk 1981-2006. Main Outcome Measure Excess mortality among HIV-infected individuals compared with that of the general uninfected population. Results Of 16 534 individuals with median duration of follow-up of 6.3 years (range, 1 day to 23.8 years), 2571 died, compared with 235 deaths expected in an equivalent general population cohort. The excess mortality rate (per 1000 person-years) decreased from 40.8 (95% confidence interval [CI], 38.5-43.0; 1275.9 excess deaths in 31 302 person-years) before the introduction of highly active antiretroviral therapy (pre-1996) to 6.1 (95% CI, 4.8-7.4; 89.6 excess deaths in 14 703 person-years) in 2004-2006 (adjusted excess hazard ratio, 0.05 [95% CI, 0.03-0.09] for 2004-2006 vs pre-1996). By 2004-2006, no excess mortality was observed in the first 5 years following HIV seroconversion among those infected sexually, though a cumulative excess probability of death remained over the longer term (4.8% [95% CI, 2.5%-8.6%] in the first 10 years among those aged 15-24 years). Conclusions Mortality rates for HIV-infected persons have become much closer to general mortality rates since the introduction of highly active antiretroviral therapy. In industrialized countries, persons infected sexually with HIV now appear to experience mortality rates similar to those of the general population in the first 5 years following infection, though a mortality excess remains as duration of HIV infection lengthens.
482 citations
TL;DR: Long-term treated patients who are on an otherwise effective regimen often show persistent immune dysfunction and have higher than expected risk for various non-AIDS-related complications, including heart, bone, liver, kidney, and neurocognitive diseases.
404 citations
TL;DR: HCV serostatus did not affect the risk of HIV-1 disease progression, but therisk of liver disease-related deaths was markedly increased in HCV-seropositive patients.
Abstract: Objective. To assess hepatitis C virus (HCV) antibody prevalence in the EuroSIDA cohort, along with survival, human immunodeficiency virus (HIV)-1 disease progression, virologic response (plasma HIV -1 RNA load of<500 copies/mL), and CD4 cell count recovery by HCV serostatus in patients initiating highly active antiretroviral therapy (HAART). Results. HCV serostatus at or before enrollment was available for 5957 patients; 1960 (33%) and 3997 (67%) were HCV seropositive and seronegative, respectively. No association between an increased incidence of acquired immunodeficiency syndrome-defining illnesses or death and HCV serostatus was seen after adjustment for other prognostic risk factors known at baseline (adjusted incidence rate ratio [IRR], 0.97 [95% confidence interval {CI}, 0.81-1.16]). However, there was a large increase in the incidence of liver disease-related deaths in HCV-seropositive patients in adjusted models (IRR, 11.71 [95% CI, 6.42-21.34]). Among 2260 patients of known HCV serostatus initiating HAART, after adjustment, there was no significant difference between HCV-seropositive and -seronegative patients with respect to virologic response (relative hazard [RH], 1.13 [95% CI, 0.84-1.51]) and immunologic response, whether measured as a ≥50% increase (RH, 0.94 [95% CI, 0.77-1.16]) or a ≥50 cells/μL increase (RH, 0.92 [95% CI, 0.77-1.11]) in CD4 cell count after HAART initiation. Conclusions. HCV serostatus did not affect the risk of HIV-1 disease progression, but the risk of liver disease-related deaths was markedly increased in HCV-seropositive patients. The overall virologic and immunologic responses to HAART were not affected by HCV serostatus.
384 citations
References
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TL;DR: The recent declines in morbidity and mortality due to AIDS are attributable to the use of more intensive antiretroviral therapies.
Abstract: Background and Methods National surveillance data show recent, marked reductions in morbidity and mortality associated with the acquired immunodeficiency syndrome (AIDS). To evaluate these declines, we analyzed data on 1255 patients, each of whom had at least one CD4+ count below 100 cells per cubic millimeter, who were seen at nine clinics specializing in the treatment of human immunodeficiency virus (HIV) infection in eight U.S. cities from January 1994 through June 1997. Results Mortality among the patients declined from 29.4 per 100 person-years in 1995 to 8.8 per 100 person-years in the second quarter of 1997. There were reductions in mortality regardless of sex, race, age, and risk factors for transmission of HIV. The incidence of any of three major opportunistic infections (Pneumocystis carinii pneumonia, Mycobacterium avium complex disease, and cytomegalovirus retinitis) declined from 21.9 per 100 person-years in 1994 to 3.7 per 100 person-years by mid-1997. In a failure-rate model, increases in t...
9,116 citations
TL;DR: A study was conducted to evaluate the impact of protease inhibitors on the rates of selected opportunistic processes and mortality in patients with AIDS and found similar results.
Abstract: To the Editor: Palella et al. (March 26 issue)1 reported that the use of more intensive antiretroviral therapies is responsible for declines in both morbidity and mortality in patients with AIDS. We conducted a study to evaluate the impact of protease inhibitors on the rates of selected opportunistic processes and mortality and found similar results. Our study population came from a public human immunodeficiency virus (HIV) outpatient clinic in New Orleans. All subjects and data were from the Adult Spectrum of Disease study, a prospective study funded by the Centers for Disease Control and Prevention examining the natural history of . . .
4,921 citations
TL;DR: It is found that, although thymic function declines with age, substantial output is maintained into late adulthood and this results indicate that the adult thymus can contribute to immune reconstitution following HAART.
Abstract: The thymus represents the major site of the production and generation of T cells expressing alphabeta-type T-cell antigen receptors. Age-related involution may affect the ability of the thymus to reconstitute T cells expressing CD4 cell-surface antigens that are lost during HIV infection; this effect has been seen after chemotherapy and bone-marrow transplantation. Adult HIV-infected patients treated with highly active antiretroviral therapy (HAART) show a progressive increase in their number of naive CD4-positive T cells. These cells could arise through expansion of existing naive T cells in the periphery or through thymic production of new naive T cells. Here we quantify thymic output by measuring the excisional DNA products of TCR-gene rearrangement. We find that, although thymic function declines with age, substantial output is maintained into late adulthood. HIV infection leads to a decrease in thymic function that can be measured in the peripheral blood and lymphoid tissues. In adults treated with HAART, there is a rapid and sustained increase in thymic output in most subjects. These results indicate that the adult thymus can contribute to immune reconstitution following HAART.
1,849 citations
TL;DR: The CD4 cell count at initiation was the dominant prognostic factor in patients starting HAART, and should be taken into account in future treatment guidelines.
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TL;DR: Death rates across Europe among patients infected with HIV-1 have been falling since September, 1995, and at the beginning of 1998 were less than a fifth of their previous level.
1,301 citations