Responses In HIV Patients Research Articles

Occurrence of extended-spectrum β-lactamase, AmpC, and carbapenemase-producing genes in gram-negative bacterial isolates from human immunodeficiency virus infected patients

BackgroundProgressive decline of immune response in HIV patients makes them susceptible to frequent bacterial infections. High usage of antibiotics influences the emergence of multidrug-resistant bacteria and worsens the clinical outcomes. In this study, the occurrence of drug-resistant genes in Gram-negative bacterial isolates from HIV patients in South India was analyzed. MethodsA total of 173 Gram-negative bacterial (GNB) isolates from HIV patients were screened for antibiotic susceptibility profile using the Kirby-Bauer diskdiffusion method. Positivity of drug-resistant genes was analyzed using polymerase chain reaction method. ResultsIn this study, 72.8% of bacterial isolates were obtained from urine specimens, and Escherichia coli (47.4%) was the predominantly isolated bacterium. Overall, 87.3% and 83.2% of GNB were resistant to 3rd generation cephalosporin antibiotics such as cefotaxime and ceftazidime, respectively, 56.6% were resistant to cephamycin (cefoxitin) and 43% to carbapenem (imipenem) antibiotics. Extended-spectrum β-lactamases (ESBL) production was noted among 79.5% of GNB isolates, followed by AmpC (57.1%) and Metallo β-lactamases (37.3%). Molecular analysis revealed that ESBL genes such as blaTEM (94.1%), blaCTX-M (89.2%), and blaSHV (24.2%) were detected at higher levels among GNB isolates. Carbapenemase-producing genes such as blaOXA-48 (20%), blaOXA-23 (2.6%), and both blaOXA-23 and blaOXA-51 like genes (2.6%) and AmpC producing genes such as blaCIT (26.7%), blaDHA (3.6%), and blaACC (1.8%) were detected at low-level. ConclusionsThis study concludes that ESBL producing genes are detected at high level among gram-negative bacterial isolates from HIV patients in South India.

Does gender affect immune response in HIV patients?

Gender differences affect the frequency and course of many diseases. This study aimed to determine the gender distribution in HIV-infected patients and investigate the relationship between gender and immune response. The study included HIV-infected patients who followed up in our hospital in 2018. The patients were divided into HIV RNA negative patients (Group 1) and HIV RNA positive patients (Group 2). Patients with diseases that may affect the immune system and those using drugs that affect the immune system were excluded from the study. The evaluation was made of 549 patients, as 305 patients (45 females 14.75%) in Group 1 and 224 patients (23 females, 9.43%) in Group 2. When the CD4/CD8 ratio of male and female patients was compared in both groups, a lower rate was determined in females (0.71-0.58) than males (0.82-0.93). A negative correlation was determined between HIV RNA and the CD4/CD8 ratio in premenopausal females (p=0.045) and males (≤45 years p=0.0001). Clinical studies of HIV infection have demonstrated better initial viremia control in females with primary infection, faster disease progression, and stronger immune activation than males for the same level of viral replication.

Hepatitis B and C infections in HIV-1 patients on combination antiretroviral therapy (cART) in Ghana: implications for immunologic recovery, clinical response to treatment, and hepatotoxicity

BackgroundViral hepatitis could have an impact on the treatment response in HIV patients. In this study, we sought to determine the prevalence of hepatitis B and C infections and examine the effect on the treatment response in HIV-1 patients attending antiretroviral therapy (ART) centers in the Volta and Oti Regions of Ghana. MethodA longitudinal study design was employed. A cohort of 200 newly diagnosed HIV-1 positive adults who met the inclusion criteria (CD4 count ≤350 cells/μl) were enrolled at three ART Centers and initiated on the combination Antiretroviral Therapy (cART) from January 2014 to December 2015. Blood samples obtained from each participant were subsequently screened for the presence of hepatitis B surface antigen (HBsAg) and hepatitis C antibody. Out of the 200 study respondents recruited, 93 HIV mono-infected were randomly selected plus all 17 HIV co-infected were prospectively followed for twelve months. Using standard methods, three consecutive measurements of CD4 cells, haemoglobin, and liver enzymes [(aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP)] as well as weight measurements were performed at baseline, six months and twelve months, respectively, after treatment initiation. ResultThe overall HIV-viral hepatitis sero-positivity was 8.5%. HBV and HCV co-infections were 7.0% and 1.5% respectively. Among HIV mono-infected CD4 cell count, haemoglobin, and weight significantly increased from baseline to the twelfth month while levels remained statistically comparable in the HIV co-infected patients. The levels of AST, ALT, and ALP were more pronounced (hepatotoxicity) in the HIV co-infected compared to the HIV mono-infected at various time points within the twelve month. ConclusionThe frequency of HIV-hepatitis co-infection was high. This correlates with poor immunological outcome, clinical response to treatment and pronounced hepatotoxicity. The findings, therefore, underscore the need for regular screening of HIV patients for early detection and appropriate management.

Highly dampened blood transcriptome response in HIV patients after respiratory infection

Respiratory viral (RV) infections represent a major threat for human health worldwide. Persons with HIV (PWH) have a compromised immune response and are thought to be at higher risk for severe RV disease. However, very little is known about the host immune response to RV infection in PWH. Here, we investigated gene expression changes in the peripheral blood of PWH co-infected with RV. Only very few differentially expressed genes could be detected between PWH with and without RV infection, suggesting that the immune response to RV in PWH is strongly dampened. Our data provides important insights into the host response to RV infections in HIV patients.

Influenza vaccination in immunocompromised populations: Strategies to improve immunogenicity

Immunocompromised individuals are at high risk of severe illness and complications from influenza infection. For this reason, immunization using inactivated influenza vaccines is recommended for transplant patients, individuals receiving immunosuppressant treatments, and other persons with immunodeficiency. However, these immunocompromised populations are more likely to have lower and non-protective responses to annual vaccination with a standard influenza vaccine. Here, we review strategies aimed to improve the immunogenicity of influenza vaccines in immunocompromised populations. The different strategies employed have included adjuvanted vaccines, high-dose vaccines, booster doses, intradermal vaccination, and temporary discontinuation of immunosuppressant treatment regimens. High-dose trivalent, inactivated, split-virus influenza vaccine (IIV3-HD) is so far one of the leading strategies for improving vaccine responses in HIV patients, transplant patients, and persons receiving immunosuppressant therapies for inflammatory diseases. Several studies in these populations have shown stronger humoral responses with IIV3-HD than existing standard-dose trivalent vaccine, and comparable safety. Accordingly, some scientific societies have stated that high-dose influenza vaccine could be a preferred option for immunocompromised patients. However, larger randomized controlled studies are needed to validate relative immunogenicity and safety of IIV3-HD and other enhanced vaccines and vaccination strategies in immunocompromised individuals.

525. Characteristics of HIV SARS-COV-2 Coinfection in a Highly HIV Seropositive Population in New York City

BackgroundThe HIV and COVID-19 co-infection prevalence has not been described extensively. Given the high prevalence of HIV positive patients in our population-our Designated AIDS Center (DAC) caters to approximately 600 patients-of which 68% are virally suppressed, this relationship is of great interest. The objectives of this analysis are to report the characteristics of HIV and COVID-19 patients, and to evaluate for any associations of HIV with COVID-19 outcomes.MethodsRetrospective chart review of all patients admitted with both HIV and confirmed COVID-19. Collected demographics, past medical history, HIV history including therapy, compliance, viral loads, and CD4 counts, and COVID-19 disease course. Evaluate baseline clinical status utilizing the World Health Organization’s Ordinal Scale for Clinical Improvement, and note disease outcomes. Analyzed mortality and disease severity as compared to the general COVID-19 patient population.Results39 patients were identified with HIV and COVID-19 from March 15th –June 18th 2020. Baseline characteristics of these patients are listed in Figure 1. Of the available labs, 60% of patients were virally suppressed, and 87% had CD4+ counts above 200/µL. On admission, most patients either did not require oxygen support, or received support through noninvasive methods. In Figure 2 we see the final outcome of the patients, with 77% of the patients discharged, and a mortality rate of 18%. Of note, the only baseline characteristic that had a significant correlation with mortality among our patients was age > 60 (p = 0.03).Baseline Characteristics of HIV COVID-19 Patients and Pertinent COVID-19 Admission Statistics COVID-19 Outcomes ConclusionMortality in our HIV COVID-19 population was 18%, significantly lower than the 33% in COVID-19 patients overall at our institution. 39 patients with HIV were admitted for confirmed COVID-19 infections, which only amounts to 6.5% of the DAC population, although it is possible that our patients were admitted to other facilities for COVID-19. In our patients, compliance, viral suppression, and CD4+ counts did not correlate with outcomes. Although our mortality was significantly lower than the overall hospital mortality, larger studies are needed to fully evaluate the mortality relationship and determine the protective effects of antiviral therapy and/or decreased immune response in HIV patients with COVID-19.Disclosures All Authors: No reported disclosures

Reactive Oxygen Species (ROS), Oxidative Stress and its role In HIV Infection

Throughout several regular cell cycles, reactive oxygen species (ROS) play a critical role. When ROS values are high, and when the defence mechanism (antioxidants) cannot neutralise, they harm and modify the part of biological molecules. They also act as signalling molecules which generate a spectrum of disease.In this study, we reviewed existing oxidants, oxidative stress, and their relationship with infection by human immunodeficiency virus in patients, and the effects of oxidative stress in patients with HIV.Our prospect is to do a clinical study on HIV patients and estimate oxidative parameters like nitric oxide, total antioxidant level and correlate them with CD4 count and viral load which may be helpful during monitoring and giving efficient ART to the HIV patients. And also the importance of ROS in infection has been established through clinical and in vitro studies. Here we review the role of oxidative stress in HIV pathogenesis, the impact of ROS on immune responses in HIV patients, and ROS-mediated regulation of HIV infection. Future studies on the interplay between ROS and HIV infection may offer a new strategy for prevention and treatment.

Candida spp. Determination and Th1/Th2 Mixed Cytokine Profile in Oral Samples From HIV+ Patients With Chronic Periodontitis.

Background: Chronic periodontitis (CP), caused by bacteria and fungi, appears in up to 66% of HIV-patients. The impact and association of HIV-treatment (HAART) and Candida itself has not been properly evaluated in the development and progression of CP. The immunopathogenesis is characterized by CD4+ T-cells activation and the balance between the T-helper 1 (Th1) and T-helper 2 (Th2) or a mixed cytokine profile. Currently, the associated causes of an immune response in HIV-patients with CP is controversial. Our aims were the determination of Candida spp. and cytokine profile in oral samples from HIV-positive patients with CP, considering the CD4+ T cells levels and HAART use.Methods: From 500 HIV-positive patients evaluated, 228 patients were enrolled. Patients were separated in groups: (A) n = 53 (≤200 CD4+ T-cells on HAART); (B) n = 57 (≤200 CD4+ T-cells without HAART); (C) n = 50 (>200 CD4+ T-cells without HAART); (D) n = 68 (>200 CD4+ T-cells on HAART). Candida spp. were isolated from the oral biofilm and crevicular fluid in CHROMagar and confirmed by endpoint PCR. Cytokine levels were measured by beads-based immunoassay in saliva by flow cytometry.Results: 147 patients (64.5%) were positive to Candida spp. and 204 strains were isolated; 138 (67.6%) were C. albicans and the remaining C. non-albicans species (C. glabrata>C. tropicalis>C. krusei>C. dubliniensis). In this study, CHROMagar showed good sensitivity (95%) but poor specificity (68%); since of the 152 samples identified as C. albicans, only 131 were confirmed by PCR; from the 10 samples identified as C. glabrata, only six were confirmed. Finally, of the 42 samples detected as C. tropicalis, only five were confirmed. When evaluating Candida spp. presence, group A and D had higher isolation, while group B had the highest species diversity. Whereas, group C had a significant reduction of Candida spp. Despite the presence of Candida and HAART, we found a Th1/Th2 hybrid profile in the saliva of patients with low CD4+ T-cell count (group A).Conclusion: Abundance and diversity of the Candida spp. detected in HIV-patients with CP could be related to HAART and low CD4+ T-cells levels. Also, the immunosuppression might promote a local Th1/Th2 hybrid cytokine profile.

Evaluation of Adherence, Virology and Imunology Response in HIV Patients Treated with a Once Daily Fixed Dose Combination (FDC) and a Free Combination of Antiretroviral

A once daily FDC is a treatment strategy to reduce both the pill burden and the dosing frequency. This study to evaluate the adherence, virology and immunology response in patients treated with a once daily FDC (single pill) and free combination of antiretroviral (more than one pill). A cross sectional study on adults HIV–infected (aged >18 years old) in Sulianti Saroso Hospital, ARV–naïve patients for 12 months of treatment, receiving the first line ARV bases on Tenovofir and Efavirenz in the form of once daily FDC and a free combination of ARV. Ninety eight patients (a once daily FDC group consist of 78 patients and a free combination group consist of 20 patients) were recruited during the period of July to October 2017. The proportion of patients with good adherence (≥95%) after 12 months of once daily FDC treatment group was 98,7%, and a free combination group was 100%. The proportion of patients with an undetectable viral load to a once daily FDC treatment group was 80%, and a free combination group was 85,5%. The viral load and adherence were not significantly different statistically in two groups (Fisher Exact, p value >0,05) at 12 months of treatment and there was no significant difference in the increase in CD4 cell count at 6 months between those 2 groups at 6 months of treatment (Chi-Square p = 0,723). A once daily FDC treatment strategy and a free combination of ARV have the same benefits toward adherence, immunology response at 6 months therapy and virology response in HIV patients during 12 months of therapy. Confirmatory studies with similar proportion of patients between the two groups are needed to clarify the benefits of adherence, immunology and virology response.

Assessing non-classical antigen presentation in HIV-infected CD4+ T cells.

Abstract CD4+T cells recognize peptides presented by MHC Class II (MHC-II) molecules on B cells, dendritic cells, and macrophages. Interestingly, in humans, activated CD4+ T cells themselves express MHC-II molecules (HLA-DR, -DP, -DQ), but their potential role as antigen processing cells has not been well characterized. Recent promising data in a simian immunodeficiency (SIV) model suggest that antigen presentation by CD4+ T cells may be important in immunity. In these studies, a vaccine incorporating SIV antigens into a cytomegalovirus vector induced MHC-II restricted CD8+ T cells in macaques. Notably, these non-canonical cells were also observed in HIV patients. Clones generated from these MHC-II restricted CD8+ T cells killed autologous HIV-infected CD4+ T cells, suggesting that HIV is processed and presented on MHC-II on CD4+ T cells. To investigate this potentially novel form of antigen presentation, we eluted peptides from HLA-DR on activated CD4+T cells and sequenced them by LC-MS/MS. We show for the first time that human primary CD4+ T cells indeed process and present peptides on HLA-DR. We are currently applying this approach to HIV-infected cells to detect HIV peptides. Given the low sensitivity of untargeted MS for rare viral peptides, we are also generating a library of MHC-II HIV epitopes presented on HLA-DR to help guide more targeted MS analysis. To create this library, we are using a MHC-II cell-free processing system. We have already identified several epitopes from HIV Gag, Pol, Env, Vif, Rev, and Tat, some of which we show elicit memory responses in HIV patients. Our studies reveal a novel role for CD4+ T cells in antigen presentation and show that a cell-free processing system can predict HIV epitopes that may be presented on these cells.

CD 4 Response in HIV Patients on Long Term First Line ART – A Cross Sectional Study from South India

CD 4 Response in HIV Patients on Long Term First Line ART – A Cross Sectional Study from South India

Management algorithm for HIV-associated parotid lymphoepithelial cysts.

We report an evidence-based management algorithm for benign lymphoepithelial cysts (BLEC) of the parotid glands in HIV patients based on long-term outcomes after radiation therapy. From 1987 to 2013, 72 HIV-positive patients with BLEC of the parotid glands treated at our institutions were identified and their medical records were reviewed and analyzed. The primary endpoint of our study was to determine a dose response in HIV patients with BLEC. In group A (≤18Gy), which received a median dose of 10Gy (8-18), overall response (OvR), complete response (CR), partial response (PR), and local failure (LF) was experienced by 7, 7, 0, and 93%, respectively. In group B (≥22.5Gy), which received a median dose of 24Gy (22.5-30), OvR, CR, PR, and LF was experienced by 88, 65, 23, and 12%. Logistic regression revealed that higher dose (≥22.5Gy) predicted for cosmetic control (p=0.0003). Multiple regression analysis revealed higher dose predicted for cosmetic control (p=0.0001) after adjusting for confounding variables (age, gender, race, HAART use, BLEC duration, and fractionation size). No patients in either group experienced RTOG grade ≥3 toxicities. A radiation dose of 24Gy delivered in 12-16 fractions of 1.5-2Gy per fraction provides long-term cosmetic control in HIV-positive patients with BLEC of the parotid glands.

CD4+ T cell-derived IL-21 and deprivation of CD40 signaling favor the in vivo development of granzyme B-expressing regulatory B cells in HIV patients.

IL-21 can induce both plasma cells and regulatory B cells. In this article, we demonstrate that untreated HIV patients display CD4(+) T cells with enhanced IL-21 expression and high in vivo frequencies of regulatory B cells overexpressing the serine protease granzyme B. Granzyme B-expressing regulatory B cells (GraB cells) cells from HIV patients exhibit increased expression of CD5, CD43, CD86, and CD147 but do not produce IL-10. The main functional characteristic of their regulatory activity is direct granzyme B-dependent degradation of the TCR-ζ-chain, resulting in significantly decreased proliferative T cell responses. Although Th cells from HIV patients secrete IL-21 in a Nef-dependent manner, they barely express CD40L. When culturing such IL-21(+)CD40L(-) Th cells with B cells, the former directly induce B cell differentiation into GraB cells. In contrast, the addition of soluble CD40L multimers to T cell/B cell cultures redirects B cell differentiation toward plasma cells, indicating that CD40L determines the direction of IL-21-dependent B cell differentiation. As proof of principle, we confirmed this mechanism in a patient lacking intact CD40 signaling due to a NEMO mutation. The majority of peripheral B cells from this patient were GraB cells and strongly suppressed T cell proliferation. In conclusion, GraB cells represent potent regulatory B cells in humans that are phenotypically and functionally distinct from B10 cells and occur in early HIV infection. GraB cells may contribute significantly to immune dysfunction in HIV patients, and may also explain ineffective Ab responses after vaccination. The use of soluble CD40L multimers may help to improve vaccination responses in HIV patients.

CD11c+CD123Low dendritic cell subset and the triad TNF-α/IL-17A/IFN-γ integrate mucosal and peripheral cellular responses in HIV patients with high-grade anal intraepithelial neoplasia: a systems biology approach.

The incidence of anal cancer has increased over the past 25 years, and HIV/HPV coinfection is the most important risk factor for anal squamous cell carcinoma. In this study, we demonstrated that the evaluation of systemic and compartmentalized anal mucosa immune response is relevant to differentiating HIV(+) patients at risk of anal intraepithelial neoplasia (AIN). A systems biology approach was used to integrate different immunological parameters from anal mucosal tissue and peripheral blood assessed by phenotypic and intracytoplasmic analysis of lymphocytes and dendritic cell subsets. Our data demonstrated that anal mucosal mononuclear cells from AIN(+)HIV(+) patients showed a robust capacity in producing proinflammatory/regulatory cytokines, mainly mTNF-α > IL-4 > IL-10 > IL-6 = IL-17A. Mucosal TNF-α/IFN-γ/IL-17A are selective high-grade squamous intraepithelial lesion (HSIL)-related biomarkers. Higher levels of circulating CD11cCD123cells and CD1a cells along with elevated levels of IFN-γCD4 T cells are major features associated with HSIL in AIN(+)HIV(+) patients. Regardless of the presence of AIN, HIV(+) patients presented a complex biomarker network, rich in negative connections. Among those patients, however, HSIL+ patients displayed stronger positive links between peripheral blood and anal mucosa environments, exemplified by the subnet of IL-17A/TNF-α/CD4IFN-γ/CD11cCD123 cells. The significant association between HSIL and the levels of TNF-α/IL-17A/IFN-γ along with the different subsets of DCs present in the anal mucosa milieu should be studied in more detail as a way to identify and categorize HIV(+) patients vis à vis the high risk of anal cancer outcome.

Poor CD4 response despite viral suppression is associated with increased non-AIDS-related mortality among HIV patients and their parents

Poor CD4 response to antiretroviral treatment (HAART) is associated with increased mortality. We analyzed the impact of CD4 increase on non-AIDS-related morbidity and on mortality in HIV patients and their parents. Mortality rates were estimated among 1758 virally suppressed patients in the Danish HIV Cohort Study after 2 years on HAART and among their parents (n = 1603). Analyses were stratified by pre-HAART CD4 count and CD4 increase. Incidence rate ratios (IRRs) of non-AIDS-related morbidity and mortality rate ratios (MRR) were analyzed using Poisson regression. CD4 increases less than 25 vs. more than 100 cells/μl was associated with increased mortality [MRR 3.5 (95% confidence interval (CI) 1.8-6.8)] even in individuals with pre-HAART CD4 cell count more than 250 cells/μl (MRR 3.2 (95%CI, 1.3-7.8). Mortality of parents of patients with poor CD4 response was also increased [MRR 1.5 (95%CI, 1.1-2.1)]. There was a trend towards association between poor CD4 response and increased risk of cardiovascular disease and cancer [IRR 1.6 (95%CI, 0.8-3.2) and 1.6 (95%CI, 0.6-4.8)]. Poor CD4 increase post-HAART is associated with adverse prognosis even in absence of severe immunosuppression. CD4 response in HIV patients is associated with mortality among their parents, thus poor CD4 response may be caused by genetic factors, which might also affect morbidity and mortality in the HIV-negative population.

Immunosenescent CD57+CD4+ T-cells accumulate and contribute to interferon-γ responses in HIV patients responding stably to ART.

HIV-infected individuals responding to antiretroviral therapy (ART) after severe CD4+ T-cell depletion may retain low responses to recall antigens [eg: cytomegalovirus (CMV)] and altered expression of T-cell co-stimulatory molecules consistent with immunosenescence. We investigated the capacity of phenotypically senescent cells to generate cytokines in HIV patients receiving long-term ART (n = 18) and in healthy controls (n = 10). Memory T-cells were assessed by interferon (IFN)-γ ELISpot assay and flow cytometrically via IFN-γ or IL-2. Proportions of CD57brightCD28null CD4+ T-cells correlated with IFN-γ responses to CMV (p = 0.009) and anti-CD3 (p = 0.002) in HIV patients only. Proportions of CD57brightCD28null CD8+ T-cells and CD8+ T-cell IFN-γ responses to CMV peptides correlated in controls but not HIV patients. IL-2 was predominantly produced by CD28+T-cells from all donors, whereas IFN-γ was mostly produced by CD57+ T-cells. The findings provide evidence of an accumulation of immunosenescent T-cells able to make IFN-γ. This may influence the pathogenesis of secondary viral infections in HIV patients receiving ART.

Preemptive Erythropoietin Plus High Ribavirin Doses to Increase Rapid Virological Responses in HIV Patients Treated for Chronic Hepatitis C

Chronic hepatitis C affects one-third of HIV(+) patients worldwide. High ribavirin (RBV) exposure is crucial to maximize the response to hepatitis C therapy in this population, although it may increase the risk for hemolytic anemia. PERICO is a prospective multicenter trial in which HIV/HCV-coinfected patients are randomized to receive peginterferon (pegIFN) alfa-2a 180 microg/week plus either weight-based RBV (1000-1200 mg/day) or RBV 2000 mg/day, the latest along with erythropoietin alfa (EPO) 30,000 IU/week from the first day until week 4. A total of 149 patients were assessed in a planned interim analysis at week 4. In both arms, 22% of patients achieved negative HCV-RNA (rapid virological response, RVR). Multivariate analysis [OR (IC 95%), p] showed that factors associated with RVR were HCV genotypes 2/3 vs. 1/4 [20 (5-100), <0.01] and baseline HCV-RNA [0.16 (0.07-0.37) per log IU/ml, <0.01]. The occurrence of severe anemia (hemoglobin <10 g/dl) did not differ when comparing RBV vs. high RBV + EPO (7% vs. 3%; p = 0.4). Moreover, RBV plasma trough levels were comparable at week 4 (1.9 vs. 2.4 microg/ml; p = 0.2). Use of high RBV doses with preemptive EPO during the first 4 weeks of hepatitis C therapy is safe, but fails to enhance significantly RBV plasma exposure and RVR rates. Extensive intraerythrocyte accumulation of RBV following boosted production of red blood cells by EPO could explain these findings.

Influence of pharmacogenetics on indinavir disposition and short-term response in HIV patients initiating HAART

To assess the relationship between genetic polymorphisms and indinavir pharmacokinetic variability and to study the link between concentrations and short-term response or metabolic safety. Forty protease inhibitor-naive patients initiating highly active antiretroviral therapy (HAART) including indinavir/ritonavir and enrolled in the COPHAR 2-ANRS 111 trial were studied. At week 2, four blood samples were taken before and up to 6 h following drug intake. A population pharmacokinetic analysis was performed using the stochastic approximation expectation maximization (SAEM) algorithm implemented in MONOLIX software. The area under the concentration-time curve (AUC) and maximum (C(max)) and trough concentrations (C(trough)) of indinavir were derived from the population model and tested for their correlation with short-term viral response and safety measurements, while for ritonavir, these same three parameters were tested for their correlation with short-term biochemical safety A one-compartment model with first-order absorption and elimination best described both indinavir and ritonavir concentrations. For indinavir, the estimated clearance and volume of distribution were 22.2 L/h and 97.3 L, respectively. The eight patients with the *1B/*1B genotype for the CYP3A4 gene showed a 70% decrease in absorption compared to those with the *1A/*1B or *1A/*1A genotypes (0.5 vs. 2.1, P = 0.04, likelihood ratio test by permutation). The indinavir AUC and C(trough) were positively correlated with the decrease in human immunodeficiency virus RNA between week 0 and week 2 (r = 0.4, P = 0.03 and r = -0.4, P = 0.03, respectively). Patients with the *1B/*1B genotype also had a significantly lower indinavir C(max) (median 3.6, range 2.1-5.2 ng/mL) than those with the *1A/*1B or *1A/*1A genotypes (median 4.4, range 2.2-8.3 ng/mL) (P = 0.04) and a lower increase in triglycerides during the first 4 weeks of treatment (median 0.1, range -0.7 to 1.4 vs. median 0.6, range -0.5 to 1.7 mmol/L, respectively; P = 0.02). For ritonavir, the estimated clearance and volume of distribution were 8.3 L/h and 60.7 L, respectively, and concentrations were not found to be correlated to biochemical safety. Indinavir and ritonavir absorption rate constants were found to be correlated, as well as their apparent volumes of distribution and clearances, indicating correlated bioavailability of the two drugs. The CYP3A4*1B polymorphism was found to influence the pharmacokinetics of indinavir and, to some extent, the biochemical safety of indinavir.

Nadir CD4 T-Cell Counts Continue to Influence Interferon-γ Responses in HIV Patients Who Began Antiretroviral Treatment With Advanced Immunodeficiency

Nadir CD4 T-Cell Counts Continue to Influence Interferon-γ Responses in HIV Patients Who Began Antiretroviral Treatment With Advanced Immunodeficiency

The number and function of circulating dendritic cells may limit effector memory CD4 + T-cell responses in HIV patients responding to antiretroviral therapy

Some HIV patients who previously experienced severe immunodeficiency retain low pathogen-specific T-cell responses despite a virological response to antiretroviral therapy (ART). To identify correlates with dysfunction in accessory cell populations, HIV patients were stratified into groups maintaining high or low CD4 + T-cell IFN-γ responses to cytomegalovirus (CMV) over 4–8 years on ART. Myeloid dendritic cells (mDC), plasmacytoid (p) DC, M-DC8 + cells and monocytes were enumerated and mRNA of cytokines and activation molecules were quantitated in purified subpopulations. Proportions of pDC were lower ( p = 0.043) and mDC were higher ( p = 0.043) in low responders. TRAIL receptor 2 (DR5) mRNA levels in pDC ( p = 0.0008) and mDC ( p = 0.0062) were lower in high responders compared to controls. Levels of IL-15 mRNA were higher in mDC from high responders ( p = 0.015) and levels of IL-10 mRNA were higher in M-DC8 + cells from low responders ( p = 0.036). Hence CMV-specific CD4 + T-cell IFN-γ responses may be affected by numbers and function of circulating DC.