Cohort Of HIV-infected Individuals Research Articles

Comparing albuvirtide plus ritonavir-boosted lopinavir regimen to two nucleotide reverse transcriptase inhibitors plus ritonavir-boosted lopinavir in HIV-infected individuals who failed initial treatment: a retrospective comparative cohort study.

Albuvirtide (ABT), a fusion inhibitor against human immunodeficiency virus (HIV) infection, has good efficacy and tolerability for HIV treatment. However, there is a paucity of data regarding ABT-based regimen as second-line therapy. This current study evaluated the efficacy and safety of switching to ABT + ritonavir-boosted lopinavir (LPV/r) treatment in a cohort of HIV-infected individuals who failed initial treatment. This retrospective comparative cohort study included patients who failed initial treatment and switched to either ABT + LPV/r (the ABT group) or two nucleotide reverse transcriptase inhibitors (NRTIs) + LPV/r (the NRTI group) between November 2019 and December 2020 in the People's Hospital of Zhaojue County in Liangshan Yi Autonomous Prefecture, China. All individuals were followed up from baseline to 12 weeks after conversion, or until the patient developed unacceptable toxic effects or was loss of follow-up. The proportion of patients who achieved virological suppression (viral load <50 copies/mL) at week 12 was considered a primary efficacy endpoint. Safety outcomes included the incidence of adverse events and laboratory abnormalities. All participants underwent resistance testing before regimen conversion. The linear regression model was applied to evaluate the association of CD4+ T cell count with the patient's clinical characteristics. A total of 71 patients were included in this study, the two groups were comparable at baseline in terms of age, sex, CD4+ T cell count, and viral load. The suppression of HIV-1 RNA to levels <50 copies/mL was achieved in 82.4% (28/31) and 29.7% (11/34) of patients in the ABT group and the NRTI group, respectively (P<0.001). Older age (P=0.016) and higher alkaline phosphatase (ALP) levels (P=0.038), but not rescue regimen, were associated with attenuated CD4+ T cell recovery. Most adverse events mild in severity, with abdominal pain as the most reported event in two groups (26.8%, 19/71), and no severe adverse events were detected. Conversion to ABT + LPV/r therapy appears to be an effective and safe strategy. This treatment regimen has great potential to be generalized in the HIV-infected population, although further testing in a larger patient population is required to verify these results.

Immune recovery in HIV-1 infected patients with sustained viral suppression under long-term antiretroviral therapy in Ethiopia.

BackgroundThere is very little data on long-term immune recovery responses in patients on suppressive antiretroviral therapy (ART) in the setting of sub-Saharan Africa (SSA). Thus, we sought to determine CD4+ T-cell, CD8+ T-cell and CD4/CD8 ratio responses in a cohort of HIV infected individuals on sustained suppressive ART followed up for more than a decade.MethodsThe cohort comprised adult patients who started ART between 2001 and 2007 and followed for up to 14 years. Trends in median CD4+ T-cells, CD8+ T-cells and CD4/CD8 ratio were reviewed retrospectively. Poisson regression models were used to identify factors associated with achieving normalized T-cell biomarkers. Kaplan-Meier curves were used to estimate the probability of attaining normalized counts while on suppressive ART.ResultsA total of 227 patients with a median duration of follow-up on ART of 12 (IQR: 10.5–13.0) years were included. CD4 cell count increased from baseline median of 138 cells (IQR: 70–202) to 555 cells (IQR: 417–830). CD4 cell increased continuously up until 5 years, after which it plateaued up until 14 years of follow up. Only 69.6% normalized their CD4 cell count within a median of 6.5 (IQR: 3.0–10.5) years. In addition, only 15.9% of the cohort were able to achieve the median reference CD4+ T-cell threshold count in Ethiopians (≈760 cells/μL). CD8+ T-cell counts increased initially until year 1, after which continuous decrease was ascertained. CD4/CD8 ratio trend revealed continuous increase throughout the course of ART, and increased from a median baseline of 0.14 (IQR: 0.09–0.22) to a median of 0.70 (IQR: 0.42–0.95). However, only 12.3% normalized their ratio (≥ 1.0) after a median of 11.5 years. In addition, only 8.8% of the cohort were able to achieve the median reference ratio of healthy Ethiopians.ConclusionDetermination of both CD4+ and CD8+ T-cells, along with CD4/CD8 ratio is highly relevant in long-term follow-up of patients to assess immune recovery. Monitoring ratio levels may serve as a better biomarker risk for disease progression among patients on long-term ART. In addition, the findings emphasize the relevance of initiation of ART at the early stage of HIV-1 infection.

Role of CD4/CD8 ratio on the incidence of tuberculosis in HIV-infected patients on antiretroviral therapy followed up for more than a decade.

The role of CD4/CD8 ratio on the incidence of tuberculosis (TB) in patients on antiretroviral therapy (ART) is unknown. Thus, we sought to determine whether the CD4/CD8 ratio was associated with development of TB in a cohort of HIV infected individuals on ART followed up for more than a decade in the setting of sub-Saharan Africa (SSA). The cohort comprised adult patients who started ART between 2001 and 2007 and followed for up to 15 years. Clinical data were collected in retrospective manner. Patients with an AIDS defining illness or a CD4 count <200 cell/μL were started with a combination of ART. The participants have clinic visits every 6 months and/or as needed. Poisson regression models were used to identify factors associated with development of incident TB. Kaplan-Meier curves were used to estimate the probability of incident TB while on ART. A total of 347 patients with a median duration of follow-up on ART of 11.5 (IQR: 10.0-12.5) years were included. Incident TB developed in 47 patients during the 3259 person-years of follow-up, the majority (76.6%) occurred within five year of ART initiation. On univariate analysis, poor ART adherence (RR:2.57, 95% CI: 1.28-5.17), time-updated CD4 cell count of lower than 200 (RR: 4.86, 95%CI 2.33-10.15), or CD4 cell count between 200 and 500 (RR: 4.68, 95% CI: 2.17-10.09), time-updated CD8 cell count lower than 500 (RR: 2.83 95% CI 1.31-6.10), or CD8 cell count over 1000 (RR: 2.23, 95% CI: 1.12-4.45), time-updated CD4/CD8 ratio of less than 0.30 (RR: 6.00, 95% CI: 2.96-12.14), lack of normalization of CD4 T-cell count (RR: 6.13, 95% CI: 2.20-17.07), and virological failure (RR: 2.35 (95% CI: 1.17-4.71) were all associated with increased risk of incident TB. In multivariate analysis, however, time-updated CD4/CD8 ratio of less than 0.30 (adjusted RR: 4.08, 95% CI: 1.31-12.68) was the only factor associated with increased risk of developing incident TB (p = 0.015). Similar results were obtained in a sensitivity analysis by including only those virally suppressed patients (n = 233, 69% of all patients). In this group, CD4/CD8 ratio of less than 0.30 was associated with development of incident TB (adjusted RR: 4.02, 95% CI: 1.14-14.19, p = 0.031). Overall, the incidence rate of TB in patients with an updated CD4/CD8 ratio of less than 0.30 was more than 5-fold higher when compared with those with a ratio more than 0.45. Low CD4/CD8 ratio is independently associated with an increased risk of incident TB despite viral suppression. CD4/CD8 ratio may serve as a biomarker for identifying patients at risk of TB in patients on ART in the setting of SSA.

Features of the course of non-alcoholic fatty liver disease in HIV-infected individuals

This article reflects the course of non-alcoholic fatty liver disease (NAFLD) in HIV-infected individuals. It is noted that long-term antiretroviral therapy and the use of D-drugs can explain the high prevalence of steatosis in this category of patients. The results of experimental studies that demonstrate the direct effect of HIV on liver steatosis by infection of stellate liver cells, stimulation of abnormal expression of SREBP-1 and PPARγ are considered. The role of HIV-mediated microbial translocation as one of the triggers for the development of non-alcoholic steatohepatitis (NASH), which contributes to chronic inflammation due to an increase in the permeability of the intestinal barrier to bacterial products and endotoxins, is noted. Data are presented confirming the high prevalence of the abnormal distribution of fat and visceral obesity (components of lipodystrophy syndrome) in a cohort of HIV-infected individuals. There was a high prevalence of steatosis and steatohepatitis in HIV-infected patients with lipodystrophy as compared with HIV-infected patients without lipodystrophy. Data showing the high prevalence of NASH in HIV-infected individuals are presented. A high rate of progression of NAFLD in a cohort of HIV-infected individuals was observed, regardless of the presence/absence of a combined viral infection (chronic hepatitis C). It has been established that the classic risk factors for NAFLD (high body mass index, dyslipidemia, metabolic syndrome) can contribute to the rapid progression of the disease in people living with HIV, compared with representatives of the general population.

Causative factors of liver fibrosis in HIV-infected patients. A single center study

BackgroundLiver disease is a leading cause of morbidity and mortality among Human Immunodeficiency virus (HIV) infected patients; however no consensus exists on HIV-related risk factors for it. The aim of this study was to identify risk factors for liver fibrosis/cirrhosis in a cohort of Greek HIV-infected patients.MethodsPatients attending the HIV outpatient clinic of Pathophysiology Department at «Laiko» General Hospital in Athens, Greece, between December 2014 and December 2017 were eligible for inclusion. Inclusion criteria were confirmed HIV infection and age > 18 years. Exclusion criteria were Body-Mass index (BMI) > 40, liver metastases of malignant diseases and concurrent or previous chemotherapy.Liver stiffness (LS) was measured using Vibration Controlled Transient Elastography (TE) and laboratory tests were acquired in all patients. Patients were classified in 2 groups: those with mild or no fibrosis (equivalent to Metavir score F0-F2) and those with significant fibrosis (equivalent to Metavir score F3-F4).ResultsA total of 187 consecutive patients were included in this study. Median TE value was 5.1 kilopascals (KPa) (range 2.8–26.3), with 92.5% (173/187) of the patients having no/mild fibrosis and 7.4% (14/187) significant fibrosis.On multivariate logistic regression analysis older patient’s age, abnormal serum aspartate aminotransferase (AST) value, Hepatitis C virus (HCV) infection, alcohol abuse, CD4/CD8 ratio and an increased number of liver related events (LREs) were significantly correlated with liver fibrosis/cirrhosis.ConclusionsIn our cohort of HIV-infected individuals HCV/HIV co-infection, older age, alcohol abuse and CD4/CD8 ratio seem to correlate with fibrogenesis in the liver.

Nonparametric estimation of the cumulative incidence function under outcome misclassification using external validation data.

Misclassification of outcomes or event types is common in health sciences research and can lead to serious bias when estimating the cumulative incidence functions in settings with competing risks. Recent work has shown how to estimate nonparametric cumulative incidence functions in the presence of nondifferential outcome misclassification when the misclassification probabilities are known. Here, we extend this approach to account for misclassification that is differential with respect to important predictors of the outcome using misclassification probabilities estimated from external validation data. Moreover, we propose a bootstrap approach in which the observations from both the main study data and the external validation study are resampled to allow the uncertainty in the misclassification probabilities to propagate through the analysis into the final confidence intervals, ensuring appropriate confidence interval coverage probabilities. The proposed estimator is shown to be uniformly consistent and simulation studies indicate that both the estimator and the standard error estimation approach perform well in finite samples. The methodology is applied to estimate the cumulative incidence of death and disengagement from HIV care in a large cohort of HIV infected individuals in sub-Saharan Africa, where a significant death underreporting issue leads to outcome misclassification. This analysis uses external validation data from a separate study conducted in the same country.

Defining Kinetic Properties of HIV-Specific CD8⁺ T-Cell Responses in Acute Infection.

Multiple lines of evidence indicate that CD8 T cells are important in the control of HIV-1 (HIV) replication. However, CD8 T cells induced by natural infection cannot eliminate the virus or reduce viral loads to acceptably low levels in most infected individuals. Understanding the basic quantitative features of CD8 T-cell responses induced during HIV infection may therefore inform us about the limits that HIV vaccines, which aim to induce protective CD8 T-cell responses, must exceed. Using previously published experimental data from a cohort of HIV-infected individuals with sampling times from acute to chronic infection we defined the quantitative properties of CD8 T-cell responses to the whole HIV proteome. In contrast with a commonly held view, we found that the relative number of HIV-specific CD8 T-cell responses (response breadth) changed little over the course of infection (first 400 days post-infection), with moderate but statistically significant changes occurring only during the first 35 symptomatic days. This challenges the idea that a change in the T-cell response breadth over time is responsible for the slow speed of viral escape from CD8 T cells in the chronic infection. The breadth of HIV-specific CD8 T-cell responses was not correlated with the average viral load for our small cohort of patients. Metrics of relative immunodominance of HIV-specific CD8 T-cell responses such as Shannon entropy or the Evenness index were also not significantly correlated with the average viral load. Our mathematical-model-driven analysis suggested extremely slow expansion kinetics for the majority of HIV-specific CD8 T-cell responses and the presence of intra- and interclonal competition between multiple CD8 T-cell responses; such competition may limit the magnitude of CD8 T-cell responses, specific to different epitopes, and the overall number of T-cell responses induced by vaccination. Further understanding of mechanisms underlying interactions between the virus and virus-specific CD8 T-cell response will be instrumental in determining which T-cell-based vaccines will induce T-cell responses providing durable protection against HIV infection.

Gut check for a promising HIV treatment

HIV Eradicating HIV in infected patients likely requires disrupting the reservoir of infected T cells in the gastrointestinal tract. One approach may be targeting cells expressing the integrin α4β7, which has been tested in simian immunodeficiency virus models and is an approved therapy for inflammatory bowel disease. Uzzan et al. studied a small cohort of HIV-infected individuals on antiretroviral therapy who began receiving an antibody against α4β7 as a treatment for their mild inflammatory bowel disease. Longitudinal colonoscopies revealed that the anti-α4β7 therapy disrupted local lymphoid aggregates. The treatment was well tolerated, but long-term effects on the HIV reservoir remain to be determined. Sci. Transl. Med. 10 , eaau4711 (2018).

Prevalence and clinical characteristics of CMV coinfection among HIV infected individuals in Guinea-Bissau: a cross-sectional study.

To describe the prevalence of CMV in a cohort of HIV infected individuals in Guinea-Bissau, West Africa and to evaluate differences in patients' clinical characteristics associated with their CMV status. Newly diagnosed HIV infected adults were invited to participate in this cross-sectional study, from May until December 2015. Enrolled patients were interviewed and underwent a full physical examination focusing on CMV disease manifestations. Blood samples were analysed for CMV serology, QuantiFERON-CMV response and CMV DNA. Mortality follow-up were registered for one year after inclusion. In total, 180 patients were enrolled. Anti-CMV IgG positivity was found in 100% (138/138) and 2.8% (4/138) were anti-CMV IgM positive. A positive QuantiFERON-CMV response was found in 85.7% (60/70) of the patients and 60.6% (83/137) had CMV viraemia. QuantiFERON-CMV response and detectable CMV DNA were associated with lower CD4 cell count, older age and upper gastrointestinal complaints. During one year of follow-up, the IRR for death among CMV DNA positive patients was 1.5 (P = 0.5). CMV coinfection was detected among all enrolled patients and CMV viraemia was highly prevalent. Only age and upper gastrointestinal complaints were associated with the patients' CMV status.

Patient-reported outcomes in daily clinical practise in HIV outpatient care

IntroductionThe use of patient-reported outcomes (PROs) in outpatient care holds promise as a tool to enhance the quality of care. The management of chronic HIV infection is multidimensional, and clinical assessment includes broad screening to identify complications. With growing constraints on time and resources, the use of PROs may provide a much-needed tool to ensure optimal HIV care. The aim of this study was to evaluate the clinical implementation and use of a Web-based tool to collect PROs in a cohort of HIV-infected individuals. MethodsIn December 2015, the PRO system AmbuFlex, a Web-based tool for self-reporting of clinical symptoms, was implemented in HIV outpatient care at Aarhus University Hospital. The HIV-specific questionnaire was designed to cover items in the European AIDS Clinical Society guidelines. Patients responded through a Web-based system from home. Based on an HIV-specific algorithm, responses were automatically assigned a green, yellow, or red colour code reflecting the severity of the symptom. HIV-related data from the electronic hospital management system were used to compare respondents and non-respondents. For cognitive and red symptoms, patient records were accessed to address whether PRO provided new information. Furthermore, it was sought to determine whether implementing PROs in clinical care can help focus the consultation on current needs. This was done by checking if a flagged symptom was assessed clinically at the following consultation. ResultsFive hundred and five HIV patients were invited to participate and 277 (55%) accepted the invitation. Compared to respondents, non-respondents were significantly younger and more often female, born outside Denmark, newly diagnosed, and with a plasma viral load >50 copies/ml. Among the 262 correctly received PRO questionnaires, 104 (39%) had solely green colour-coded responses, whereas 59 (23%) had one or more red colour-coded responses. Of 69 red symptoms, 28 (41%) led to a specific clinical assessment. In many cases, PROs appeared to provide new information on cognitive (76%) and red-coded symptoms (42%). ConclusionsThe use of PROs identified several cases where physical or cognitive symptoms appeared to have been unnoticed. A substantial proportion of patients reported no symptoms requiring medical attention, suggesting a potential to individualize outpatient care and redistribute resource utilization.

Effects of Counselling on Adherence to Antiretroviral Treatment Among People with HIV in Estonia: A Randomized Controlled Trial.

To assess the efficacy of an education- and strengths-based counselling programme to promote antiretroviral therapy (ART) adherence in a cohort of HIV-infected individuals with high prevalence of injection drug use in Estonia. Parallel-group randomized (1:1) controlled trial (RCT). Adults receiving ART in two clinics were followed for 12months. The trial compared: (i) an intervention (three sessions) incorporated into routine clinic visits, providing education about HIV, ART, the role of adherence, and tailoring regimen to daily routines using problem-solving skills to address adherence barriers versus (ii) usual care (control). Primary and secondary outcomes were self-reported ART adherence (3-day recall) and viral load (respectively). 519 patients were randomized and 82% completed the study. Recent optimal ART adherence (3-day recall ≥95%) was reported by 75.6% in the intervention group and 72.9% of controls at baseline and 76.7% and 67.5%, respectively, at 12months (RR 1.14, 95% CI 1.00-1.28; adjusted RR 1.13, 95% CI 1.00-1.27). There was no difference in the proportion of patients with undetectable viral load. At 12months the intervention group reported significantly higher perceptions of ART necessity versus ART concerns [mean ART necessity-concerns differential: intervention group 1.32 (SD 1.22) vs control group 1.08 (SD 1.12); p=0.048]. All-cause mortality among study participants was 27.7 per 1000 person years (95% CI 15.6-44.8). A brief, clinic-based adherence intervention alone may assist with adherence but lacks impact on viral load at 12months.

No Evidence for Association of β-Defensin Genomic Copy Number with HIV Susceptibility, HIV Load during Clinical Latency, or Progression to AIDS.

Common single-nucleotide variation in the host accounts for 25% of the variability in the plasma levels of HIV during the clinical latency stage (viral load set point). However, the role of rare variants and copy number variants remains relatively unexplored. Previous work has suggested copy number variation of a cluster of β-defensin genes affects HIV load in treatment-naïve sub-Saharan Africans and rate of response to antiretroviral treatment. Here we analyse a total of 1827 individuals from two cohorts of HIV-infected individuals from Europe and sub-Saharan Africa to investigate the role of β-defensin copy number variation on HIV load at set point. We find no evidence for association of copy number with viral load. We also compare distribution of β-defensin copy number between European cases and controls and find no differences, arguing against a role of β-defensin copy number in HIV acquisition. Taken together, our data argue against an effect of copy number variation of the β-defensin region in the spontaneous control of HIV infection.

Plasma Soluble CD163 Level Independently Predicts All-Cause Mortality in HIV-1-Infected Individuals.

CD163, a monocyte- and macrophage-specific scavenger receptor, is shed as soluble CD163 (sCD163) during the proinflammatory response. Here, we assessed the association between plasma sCD163 levels and progression to AIDS and all-cause mortality among individuals infected with human immunodeficiency virus type 1 (HIV). Plasma sCD163 levels were measured in 933 HIV-infected individuals. Hazard ratios (HRs) with 95% confidence intervals (CIs) associated with mortality were computed by Cox proportional hazards regression. At baseline, 86% were receiving antiretroviral treatment, 73% had plasma a HIV RNA level of <50 copies/mL, and the median CD4(+) T-cell count was 503 cells/µL. During 10.5 years of follow-up, 167 (17.9%) died. Plasma sCD163 levels were higher in nonsurvivors than in survivors (4.92 mg/L [interquartile range {IQR}, 3.29-8.65 mg/L] vs 3.16 mg/L [IQR, 2.16-4.64 mg/L]; P = .0001). The cumulative incidence of death increased with increasing plasma sCD163 levels, corresponding to a 6% or 35% increased risk of death for each milligram per liter or quartile increase, respectively, in baseline plasma sCD163 level (adjusted HR, 1.06 [95% CI, 1.03-1.09] and 1.35 [95% CI, 1.13-1.63], respectively). Plasma sCD163 was an independent marker of all-cause mortality in a cohort of HIV-infected individuals, suggesting that monocyte/macrophage activation may play a role in HIV pathogenesis and be a target of intervention.

HIV Vaccine Development: Current Scenario and Future Prospects

The search for a preventive vaccine that can halt the global pandemic is the ultimate goal of HIV research. Development of a vaccine against HIV-1 has been plagued by many insurmountable challenges. Different vaccine concepts have been tested to overcome these challenges. Experimental vaccines that showed promise in preclinical studies were advanced into clinical trials. Yet, human trials proved to be a huge disappointment until the results of the RV144 trial in Thailand. This trial not only provided the first evidence of a modest efficacy, but also valuable insights on the possible immunologic correlates of vaccine protection. Currently, the HIV vaccine research landscape has been rejuvenated by two major developments. On one hand, there has been a resurgence of interest in T cell-based vaccines with the promising results obtained using a recombinant cytomegalovirus vector vaccine. On the other hand, the discovery of more than a hundred broadly neutralizing antibodies from cohorts of HIV-infected individuals has led to the development of antibody-based preventive vaccines. Innovations in the design of vaccines, vaccination strategies and clinical trial programs will be necessary to accelerate the search for a prophylactic HIV vaccine. This article reviews the current status of HIV vaccine research and provides a roadmap to future efforts in vaccine development.

Factors associated with abnormal spirometry among HIV-infected individuals.

HIV-infected individuals are susceptible to development of chronic lung diseases, but little is known regarding the prevalence and risk factors associated with different spirometric abnormalities in this population. We sought to determine the prevalence, risk factors and performance characteristics of risk factors for spirometric abnormalities among HIV-infected individuals. Cross-sectional cohort study. We analyzed cross-sectional US data from the NHLBI-funded Lung-HIV consortium - a multicenter observational study of heterogeneous groups of HIV-infected participants in diverse geographic sites. Logistic regression analysis was performed to determine factors statistically significantly associated with spirometry patterns. A total of 908 HIV-infected individuals were included. The median age of the cohort was 50 years, 78% were men and 68% current smokers. An abnormal spirometry pattern was present in 37% of the cohort: 27% had obstructed and 10% had restricted spirometry patterns. Overall, age, smoking status and intensity, history of Pneumocystis infection, asthma diagnosis and presence of respiratory symptoms were independently associated with an abnormal spirometry pattern. Regardless of the presence of respiratory symptoms, five HIV-infected participants would need to be screened with spirometry to diagnose two individuals with any abnormal spirometry pattern. Nearly 40% of a diverse US cohort of HIV-infected individuals had an abnormal spirometry pattern. Specific characteristics including age, smoking status, respiratory infection history and respiratory symptoms can identify those at risk for abnormal spirometry. The high prevalence of abnormal spirometry and the poor predictive capability of respiratory symptoms to identify abnormal spirometry should prompt clinicians to consider screening spirometry in HIV-infected populations.

Altered metabolism of gut microbiota contributes to chronic immune activation in HIV-infected individuals.

Altered interplay between gut mucosa and microbiota during treated HIV infection may possibly contribute to increased bacterial translocation and chronic immune activation, both of which are predictors of morbidity and mortality. Although a dysbiotic gut microbiota has recently been reported in HIV+ individuals, the metagenome gene pool associated with HIV infection remains unknown. The aim of this study is to characterize the functional gene content of gut microbiota in HIV+ patients and to define the metabolic pathways of this bacterial community, which is potentially associated with immune dysfunction. We determined systemic markers of innate and adaptive immunity in a cohort of HIV-infected individuals on successful antiretroviral therapy without comorbidities and in healthy non-HIV-infected subjects. Metagenome sequencing revealed an altered functional profile, with enrichment of the genes involved in various pathogenic processes, lipopolysaccharide biosynthesis, bacterial translocation, and other inflammatory pathways. In contrast, we observed depletion of genes involved in amino acid metabolism and energy processes. Bayesian networks showed significant interactions between the bacterial community, their altered metabolic pathways, and systemic markers of immune dysfunction. This study reveals altered metabolic activity of microbiota and provides novel insight into the potential host-microbiota interactions driving the sustained inflammatory state in successfully treated HIV-infected patients.

Applications and Limitations of Inflammatory Biomarkers for Studies on Neurocognitive Impairment in HIV Infection

Despite reduced prevalence of severe forms of HIV-associated neurocognitive disorders (HAND) on current antiretroviral therapy (ART) regimens, milder forms of neurocognitive impairment (NCI) remain prevalent in HIV-infected populations. These mild forms of HAND consist of subtypes, probably reflecting distinct, though possibly overlapping, pathophysiological mechanisms. Factors associated with HAND in HIV patients with prolonged viral suppression on ART include older age, low nadir CD4, active HCV co-infection, and cardiovascular risk factors, but underlying mechanisms and their relationship to innate immune activation, chronic inflammation, and other features of systemic disease are poorly understood. In this article, we discuss applications and limitations of plasma inflammatory biomarkers for studies on HAND in HIV patients on ART and describe an analysis pipeline to reduce common sources of noise and increase likelihood of identifying relevant inflammatory biomarkers. Clinical covariates and comorbidities that influence inflammatory biomarkers, such as aging, obesity, metabolic abnormalities, HCV co-infection, and substance abuse, are also reviewed. As an example for using this analytic pipeline, we present an exploratory study of 22 plasma inflammatory biomarkers (IFN-α 2b and -γ, 16 cytokines/chemokines, sIL-2R, sCD14, HA, and YKL-40) in a cohort of HIV-infected individuals with advanced disease, frequent HCV co-infection, and viral suppression on ART. The identification of inflammatory biomarkers associated with HAND in HIV+ patients on ART may be useful to distinguish between HAND subtypes with distinct pathophysiology, and is important for achieving a systems-level understanding of the biology of these disorders, developing effective therapies, and evaluating therapeutic outcomes.Electronic supplementary materialThe online version of this article (doi:10.1007/s11481-013-9512-2) contains supplementary material, which is available to authorized users.

Clostridium difficile in a HIV-infected cohort

Clostridium difficile is the most commonly reported infectious diarrhoea in HIV-infected patients in the United States. We set out to determine the incidence, risk factors and clinical presentation of C. difficile infections (CDIs) in a cohort of HIV-infected individuals. We performed a nested, case-control analysis with four non-CDI controls randomly selected for each case. We assessed the incidence of CDI in the Johns Hopkins HIV Clinical Cohort between 1 July 2003 and 31 December 2010. Incident cases were defined as first positive C. difficile cytotoxin assay or PCR for toxin B gene. We used conditional logistic regression models to assess risk factors for CDI. We abstracted data on the clinical presentation and outcomes from case chart review. We identified 154 incident CDI cases for an incidence of 8.3 cases per 1000 patient years. No unique clinical features of HIV-associated CDI were identified. In multivariate analysis, risk of CDI was independently increased for CD4 cell count of 50 cells/μl or less [adjusted odds ratio (AOR) 20.7, 95% confidence interval (CI) 2.8-151.4], hospital onset CDI (AOR 26.7, 95% CI 3.1-231.2) and use of clindamycin (AOR 27.6, 95% CI 2.2-339.4), fluoroquinolones (AOR 4.5, 95% CI 1.2-17.5), macrolides (AOR 6.3, 95% CI 1.8-22.1), gastric acid suppressants (AOR 3.1, 95% CI 1.4-6.9) or immunosuppressive agents (AOR 6.8, 95% CI 1.2-39.6). The incidence of CDI in HIV-infected patients was twice that previously reported. Our data show that compromised cellular immunity, as defined by CD4 cell count of 50 cells/μl or less, is a risk factor for CDI. Clinicians should be aware of the increased CDI risk, particularly in those with severe CD4 cell count suppression.

Differential Impact of Magnitude, Polyfunctional Capacity, and Specificity of HIV-Specific CD8 + T Cell Responses on HIV Set Point

Defining the characteristics of HIV-specific CD8(+) T cell responses that lead to viral control is crucial for vaccine development. We evaluated the differential impact of magnitude, polyfunctional capacity, and specificity of the CD8(+) response at approximately 6 months postinfection on the viral set point at 12 months in a cohort of HIV-infected individuals. High frequencies of Gag and Nef responses endowed with four functions were the best predictors of a low viral set point.

Incidence and Determinants of Severe Morbidity among HIV-Infected Patients from Rio De Janeiro, Brazil, 2000–2010

Reliable information on severe morbidity is essential for identifying priorities for case management and to guide resource allocation within the health sector. This study describes overall, AIDS- and non-AIDS-related severe morbidity as well as mortality and its determinants in an urban cohort of HIV-infected individuals from a public healthcare institution, the Evandro Chagas Research Institute (IPEC) of the Oswaldo Cruz Foundation, Rio de Janeiro, Brazil. Severe morbid events were defined as all clinical diagnoses listed in hospitalization discharge records; all diagnoses were checked and validated. Generalized estimating equation models were used to estimate incidence rates while adjusting for within-subject correlation. Between 2000 and 2010, 3,537 patients were followed for a total of 16,960 person-years (PY) of follow-up. Over the years, annual incidence rate of severe morbid events, AIDS-related events, non-AIDS-related events, and deaths significantly decreased from, respectively, 36.6, 12.9, 23.7 and 3.2 per 100 PY in 2000 to 25.3, 7.9, 17.4 and 1.9 per 100 PY in 2010. Patients' immunological profiles significantly improved with time; 84% of the patients used combination antiretroviral therapy (cART) per year. Immunodeficiency was associated with a higher incidence rate of AIDS- and non-AIDS-related events as well as with the incidence rate of specific non-AIDS events (bacterial infections, toxicities, cardiovascular, renal and respiratory diseases). Our results show that in a middle income country with access to cART, non-AIDS-related events represent an important cause of severe morbidity alongside a still high incidence rate of AIDS-related events.