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Background CD4+ T-cell recovery in patients with continuous suppression of plasma HIV-1 viral load (VL) is highly variable. This study aimed to identify predictive factors for long-term CD4+ T-cell increase in treatment-naive patients starting combination antiretroviral therapy (cART). Methods Treatment-naive patients in the Swiss HIV Cohort Study reaching two VL measurements 3 months apart during the 1st year of cART were included ( n=1,816 patients). We studied CD4+ T-cell dynamics until the end of suppression or up to 5 years, subdivided into three periods: 1st year, years 2–3 and years 4–5 of suppression. Multiple median regression adjusted for repeated CD4+T-cell measurements was used to study the dependence of CD4+ T-cell slopes on clinical covariates and drug classes. Results Median CD4+ T-cell increases following VL suppression were 87, 52 and 19 cells/μl per year in the three periods. In the multiple regression model, median CD4+ T-cell increases over all three periods were significantly higher for female gender, lower age, higher VL at cART start, CD4+ T-cell + T-cell increase in the previous period. Patients on tenofovir showed significantly lower CD4+T-cell increases compared with stavudine. Conclusions In our observational study, long-term CD4+ T-cell increase in drug-naive patients with suppressed VL was higher in regimens without tenofovir. The clinical relevance of these findings must be confirmed in, ideally, clinical trials or large, collaborative cohort projects but could influence treatment of older patients and those starting cART at low CD4+ T-cell levels.

Potent antiretroviral therapy has dramatically improved the prognosis of patients infected with HIV-1. Primary and secondary prophylaxis against Pneumocystis carinii, Mycobacterium avium, cytomegalovirus, and other pathogens can be discontinued safely once CD4 cell counts have increased beyond pathogen-specific thresholds. Approximately one-third of individuals receiving antiretroviral therapy will not reach CD4 cell counts above 500 cells per muL after 5 years despite continuous suppression of plasma HIV-1 RNA. Whether this failure represents a risk factor for the long-term incidence of opportunistic diseases--eg, tuberculosis or malignancies--remains uncertain. We describe the time course of CD4 cell concentrations in patients whose plasma HIV-1 RNA is durably suppressed by antiretroviral therapy, in patients with incomplete suppression of plasma HIV-1 RNA, and during treatment interruptions. In addition, immune reconstitution disease, an inflammatory syndrome associated with immunological recovery occurring days to weeks after the start of antiretroviral therapy, is briefly described.

The prognosis of patients infected with human immunodeficiency virus (HIV) type 1 has dramatically improved since the advent of potent antiretroviral therapies (ARTs), which have enabled sustained suppression of HIV replication and recovery of CD4 T cell counts. Knowledge of the function of CD4 T cells in immune reconstitution was derived from large clinical studies demonstrating that primary and secondary prophylaxis against infectious agents, such as Pneumocystis jirovecii (Pneumocystis carinii), Mycobacterium avium complex, cytomegalovirus, and other pathogens, can be discontinued safely once CD4 T cell counts have increased beyond pathogen-specific threshold levels (usually >200 CD4 T cells/mm3) for 3-6 months. The downside of immune reconstitution is an inflammatory syndrome occurring days to months after the start of ART, with outcomes ranging from minimal morbidity to fatal progression. This syndrome can be elicited by infectious and noninfectious antigens. Microbiologically, the possible pathogenic pathways involve recognition of antigens associated with ongoing infection or recognition of persisting antigens associated with past (nonreplicating) infection. Specific antimicrobial therapy, nonsteroidal anti-inflammatory drugs, and/or steroids for managing immune reconstitution syndrome should be considered.

Objective Information about the virological response to sequential highly active antiretroviral therapy (HAART) for HIV infection is limited. The virological response to four consecutive therapies was evaluated in the Swiss HIV Cohort. Design Retrospective analysis in an observational cohort. Methods 1140 individuals receiving uninterrupted HAART for 4.8 ±0.6 years were included. The virological response was classified as success (5000 copies/ml). Potential determinants of the virological response, including patient demographics, treatment history and virological response to previous HAART regimens were analysed using survival and logistic regression analyses. Results 40.1% failed virologically on the first (22.0% LF; 18.1% HF), 35.1% on the second (14.2% LF; 20.9% HF), 34.2% on the third (9.9% LF; 24.3% HF) and 32.7% on the fourth HAART regimen (9% LF; 23.7% HF). Nucleoside pre-treatment (OR: 2.34; 95% CI: 1.67–3.29) and low baseline CD4 T-cell count (OR: 0.79/100 cells rise; 95% CI: 0.72–0.88) increased the risk of HF on the first HAART. Virological failure on HAART with HIV-1 RNA levels exceeding 1000 copies/ml predicted a poor virological response to subsequent HAART regimens. A switch from a protease inhibitor- to a non-nucleoside reverse transcriptase inhibitor-containing regimen significantly reduced the risk of HF. Multiple switches of HAART did not affect the recovery of CD4 T lymphocytes. Conclusion Multiple sequential HAART regimens do not per se reduce the likelihood of long-term virological suppression and immunological recovery. However, early virological failure increases significantly the risk of subsequent unfavourable virological responses. The choice of a potent initial antiretroviral drug regimen is therefore critical. This study has been presented in part at the 10th Conference on Retroviruses & Opportunistic Infections. Boston, Mass., USA, 2003. Abstract #571.

Analysing T-cell receptor excision circle numbers in healthy individuals we find a marked change in the source of naive T cells before and after 20 years of age. The bulk of the naive T cell pool is sustained primarily from thymic output for individuals younger than 20 years of age whereas proliferation within the naive phenotype is dominant for older individuals. Over 90% of phenotypically naive T cells in middle age are not of direct thymic origin. Moreover, this change in source of naive T cells is accompanied either by an increased death rate of T cells from the thymus or reduced thymic export. Modelling of these processes shows that new naive T cells of a thymic origin have a half-life of approximately 50 days before this change occurs, and that either the life-span of recent thymic emigrants (but not necessarily of all naive cells) decreases approximately threefold in middle age, or thymic production drops by this same amount. The decay rate of T-cell receptor excision circle levels for individuals over 20 years of age is consistent with the decay rate of the productive thymus. Our modelling suggests that at age 25, thymic export is responsible for 20% of naive T-cell production and that this percentage decreases with the 15.7 year half-life of the productive thymus so that by age 55 only 5% of naive production arises from thymic export.

In a prospective open-label study, 41 male subjects received nelfinavir, zidovudine, and lamivudine stratified as either: early stage (ES; negative/indeterminate Western blot; n = 19) or late stage (LS; positive Western blot; n = 22) primary HIV-1 infection. Despite higher median baseline HIV-1 RNA levels and lower CD4(+) cell numbers in the ES subjects, a significantly greater decline in viral load (-3.46 vs. -2.83 log(10) copies/ml; p = 0.023) and increase in CD4(+) cell number (+85 vs. +41 cells/month increase, p = 0.01) were observed over the first 3 months of therapy such that both groups had comparable results at 1 year. The proportion with HIV-1 RNA50 copies/mL at 1 year was similar (9 of 19 ES subjects and 11 of 22 LS subjects by intention-to-treat analysis). Memory CD4(+) cell numbers, and activated CD4(+) percentages, were also significantly improved in ES subjects. Despite poorer prognostic markers at baseline ES subjects achieved responses similar to those of LS subjects after 1 year of treatment.

In industrialised countries, highly active antiretroviral therapy (HAART) has drastically reduced HIV mortality. Only few developing countries have introduced HAART on a large scale, leaving millions of HIV-infected individuals without life-saving therapy. Although HAART appears to be economically viable for middle income countries, it remains unaffordable for many of the poorest and worst affected nations. In response, significant discounts for antiretrovirals and debt relief have been granted. Apart from economic problems, other important issues need to be addressed before antiretroviral therapy can be optimally utilised, including the logistics of drug supply, HIV education for hospital staff and patients, and laboratory facilities that allow clinicians to assess the efficacy of HAART.

A novel deletion of residue 69 of the HIV-1 reverse transcriptase (RT) gene was detected in combination with mutations V75I/V and F77L/F in a patient with partial virological response to several antiretroviral drug regimens, including stavudine (D4T), didanosine (DDI), lamivudine (3TC), saquinavir (SQV), and nevirapine (NVP). Longitudinal analysis of samples revealed that this deletion emerged upon reinitiation DDI/D4T therapy following a toxicity-induced short discontinuation of all antiretrovirals. Analysis of the resistance phenotype showed a greater than 62-fold increase of the IC50 of NVP, but no significant change in sensitivity to other single nonnucleoside reverse transcriptase inhibitors (NNRTIs). The mutated virus showed only a moderately reduced sensitivity to DDI (6.7-fold) and D4T (4.8 fold). In a subsequent sample 3 months later additional RT mutations were found, including A62V, Y188L, and Q151M, conferring high-level cross-resistance to multiple nucleoside analogs. Our findings provide evidence that the deletion of RT residue 69 selectively confers high-level NVP resistance.

A major goal of antiretroviral HIV-1 therapy is the reversal of HIV-1-associated immunological dysfunction. However, the pathogenetic mechanisms involved and their significance are largely unknown. On the basis of the life cycle of naive, activated, and memory CD4(+) T cell subsets, a mathematical model of immune reconstitution was developed and applied to data for T cell subsets in individuals with acute or chronic HIV-1 infection receiving antiretroviral therapy. The final model that most accurately fitted the data, and resulted in realistic estimates for CD4(+) T cell turnover, considered three pathways of immune reconstitution for naive cells, including thymic production, peripheral expansion, and redistribution of naive cells from lymphoid tissue. The reconstitution of the memory compartment was fitted through differentiation and expansion of naive cells and peripheral expansion of memory cells as well as redistribution of memory cells trapped in the lymphoid tissue. Estimated median half-lives for naive and memory CD4(+) T cells were 114 and 21 days, while total production rates were 9.1 x 10(7) and 2.4 x 10(9) cells/day, respectively. Peripheral expansion and thymic production contributed equally to the regeneration of naive cells, but peripheral expansion of memory cells was larger than production of these cells by differentiation of naive cells. A comparison of immune reconstitution in acute and chronic HIV-1 infection revealed that, after adjustment for age, the main difference was the more rapid release of a larger number of naive cells in treated acute HIV-1 infection. Thymic function and peripheral expansion rates, however, were similar in both cohorts.

Objective To determine the long-term T-lymphocyte response to highly active antiretroviral therapy (HAART) and to define predictors of the immunological response. Design Cohort study, including 135 HIV-1-infected subjects at a city general practice who commenced HAART between 1996 and 1998. Methods Collection of plasma HIV-1 RNA, CD4+ and CD8+ T-lymphocyte data at 3-6 monthly time intervals over 2 years. Results Seventy-three subjects (54%) achieved suppression of plasma HIV-1 RNA to levels below 400 copies/ml during the observation period, 31 individuals (23%) had detectable plasma HIV-1 RNA below 10,000 copies/ml and 31 subjects (23%) had virological failures with viral loads above 10,000 copies/mL. Median CD4+ T lymphocytes increased from 246 to 463 x 10(6) cells/l, showing a median rise of 20 x 10(6) cells/l per month in the first 3 months and 7 x 10(6) cells/l per month thereafter. The proportion of individuals who reached CD4+ cell counts above 500 x 10(6) cells/l increased from 8% at baseline to 54% at 2 years. Treatment-naive individuals, subjects with a large reduction of HIV-1 RNA or a large early CD8+ increase had better early CD4+ responses. Long-term CD4+ T-cell increases were inversely correlated with mean plasma HIV-1 RNA levels. Baseline CD4+ T-cell count was the most important determinant of reaching CD4+ cell counts above 500 x 10(6) cells/l. Nineteen per cent of subjects had no further CD4+ T-cell increases in the second year of therapy despite undetectable viral load. Conclusions Immune reconstitution is a slow process, showing a large individual variability. The virological response to HAART was the most important determinant of the immunological short- and long-term response.

BACKGROUND The prevalence and severity of lipodystrophy syndrome with long-term therapy for HIV-1 infection that includes a protease inhibitor is unknown. We studied the natural course of the syndrome to develop diagnostic criteria and identifying markers that predict its severity. METHODS We assessed 113 patients who were receiving HIV-1 protease inhibitors (mean 21 months) and 45 HIV-1-infected patients (28 with follow-up) never treated with a protease inhibitor. Lipodystrophy was assessed by questionnaire (including patients' rating of severity), physical examination, and dual-energy x-ray absorptiometry. Body composition and fasting lipid and glycaemic variables were compared with data obtained 8 months previously. Oral glucose tolerance was investigated. FINDINGS There was 98% concordance between patients' reports of the presence or absence of lipodystrophy (reported by 83% of protease-inhibitor recipients and 4% of treatment-naive patients; p=0.0001) and physical examination. Patients' ratings of lipodystrophy were significantly associated with declining total body fat (p=0.02). Lower body fat was independently associated with longer duration of protease-inhibitor therapy and lower bodyweight before therapy, and more severe lipodystrophy was associated with higher previous (p < 0.03) and current (p < or = 0.01) triglyceride and C-peptide concentrations, and less peripheral and greater central fat (p=0.005 and 0.09, respectively). Body fat declined a mean 1.2 kg over 8 months in protease-inhibitor recipients (p=0.05). The prevalence of hyperlipidaemia remained stable over time (74% of treated patients vs 28% of naive patients; p=0.0001). Impaired glucose tolerance occurred in 16% of protease-inhibitor recipients and diabetes mellitus in 7%; in all but three patients these abnormalities were detected on 2 h post-glucose load values. INTERPRETATION Diagnosis and rating severity of lipodystrophy is aided by the combination of physical examination, patient's rating, and measurement of body fat, fasting triglycerides, and C-peptide. Weight before therapy, fasting triglyceride, and C-peptide concentrations early in therapy, and therapy duration seem to predict lipodystrophy severity. Lipodystrophy was common and progressive after almost 2 years of protease inhibitor therapy, but was not usually severe. Hyperlipidaemia and impaired glucose tolerance were also common.

This study used curve-fitting techniques to detail the dynamics of human immunodeficiency virus (HIV)-1 and its relationship to circulating T lymphocyte changes in a cohort of 41 male patients (mean age 36+/-7 years) infected with HIV-1. The following characteristics of viral kinetics were obtained: virus load peak, 6. 35+/-0.71 log10 RNA copies/mL at 12.2+/-7.1 days; virus load drop from peak, 2.02+/-0.93 log10 copies/mL; viral decay rate from peak, 0.071+/-0.042 log10 RNA copies/mL/day; and steady state virus load, 4.57+/-0.68 log10 copies/mL at 135+/-81 days. Analysis of individual virus load curves revealed highly variable viral kinetics. Although these could be grouped into three distinct patterns, virus load and CD4 lymphocyte counts were similar in all patterns at 12 months, but the interval from infection to achievement of steady state virus load varied significantly.

In the past few years, major advances have been made in the field of primary HIV-1 infection. Several studies have reevaluated the clinical syndrome. The emergence of new molecular laboratory techniques has permitted a detailed analysis of viral dynamics and subsequent immunologic changes. Measurements of subsets of T-lymphocytes have allowed greater insight into the early pathogenesis of HIV-1 disease. There is now evidence that HIV-1-specific cytotoxic T-lymphocytes occur early during primary HIV-1 infection and are probably the most important immune defense against HIV-1. However, HIV-1 immune escape mutants have been identified during primary infection, which may be one reason for the failure of the immune system to completely eradicate the virus. Cytokines have been shown to play a role in primary HIV-1 infection, and the therapy of primary infection has gained more interest due to the introduction of potent triple combinations, including protease inhibitors.

The predictive value of a two-compartment Bayesian feedback program for tobramycin dose optimization was retrospectively evaluated in 199 hospitalized patients and compared with that of a simple non-Bayesian one-compartment model. Before dose adjustment, 64% of the patients were underdosed indicating that tobramycin monitoring is still necessary to avoid ineffective antibiotic therapy. When physicians adhered to the dose instructions calculated with the Bayesian method, 90% of the patients had optimal concentration-time profiles as opposed to only 53% of the 43 patients in whom dose recommendations were not followed. In young patients with normal renal function, precision and accuracy of the Bayesian feedback and the one-compartment method were well correlated, whereas in elderly patients (> 60 years) and patients with impaired renal function (estimated creatinine clearance < 60 ml/minute), the Bayesian method was significantly more precise. Multiple regression analysis revealed that renal function was the only independent variable predicting the performance of the Bayesian program. The results of this study indicate that the Bayesian feedback method is a reliable method for the therapeutic tobramycin monitoring under clinical conditions and in particular, elderly patients in whom renal impairment is frequent.

Objectives To evaluate the prevalence of slow acetylation of hepatic N-acetyltransferase 2 (NAT2) in patients with different stages of human immunodeficiency virus (HIV) infection, to assess the relationship between acetylation capacity and the degree of immunosuppression, and to study the concordance between NAT2 phenotype and genotype. Methods This prospective study in a consecutive sample of HIV-infected patients was performed in the outpatient department of a university hospital that provides primary and tertiary care. The NAT2 genotype was assessed by polymerase chain reaction and restriction fragment length polymorphism, the NAT2 phenotype was determined by caffeine test (urinary metabolic ratio of the caffeine metabolites 5-acetylamino-6-formylamino-3-methyluracil and 1-methylxanthine). Results Fifty patients with Centers for Disease Control HIV infection stages A (10 patients), B (20 patients), and C (20 patients) were included in the study after each gave informed consent. According to genotyping and phenotyping, 32 (64%) patients were slow acetylators, with a concordance of the two methods of 96%. The overall distribution was similar to distributions reported in other white populations. The slow acetylator phenotype was found in seven, 16, and nine patients with stage A, B, and C, respectively. Eight of the 10 patients with previous adverse reactions to sulfonamides had slow acetylator phenotypes. Acetylation capacity was independent of CD4 cell counts. Conclusions This study revealed an excellent agreement between genotypes and phenotypes of NAT2 in patients with HIV infection. There was no increase in prevalence of slow acetylation in patients with advanced stages of the disease. This apparent discrepancy to an earlier study may be the result of differences in co-medication of the patients studied and may point to the relevance of drug interactions in the treatment of patients with HIV infection. Clinical Pharmacology & Therapeutics (1996) 60, 62–67; doi

Background Current guidelines for a check-up recommend routine screening not triggered by specific symptoms for some known risk factors and diseases in the general population. Patients' perceptions and expectations regarding a check-up exam may differ from these principles. However, quantitative and qualitative data about the discrepancy between patient- and provider expectations for this type of clinic consultation is lacking. Methods For a year, we prospectively enrolled 66 patients who explicitly requested a "check-up" at our medical outpatient division. All patients actively denied upon prompting having any symptoms or specific health concerns at the time they made their appointment. All consultations were videotaped and analysed for information about spontaneously mentioned symptoms and reasons for the clinic consultation ("open agendas") and for cues to hidden patient agendas using the Roter interaction analysis system (RIAS). Results All patients initially declared to be asymptomatic but this was ultimately the case in only 7 out of 66 patients. The remaining 59 patients spontaneously mentioned a mean of 4.2 ± 3.3 symptoms during their first consultation. In 23 patients a total of 31 hidden agendas were revealed. The primary categories for hidden agendas were health concerns, psychosocial concerns and the patient's concept of disease. Conclusions The majority of patients requesting a general check-up tend to be motivated by specific symptoms and health concerns and are not "asymptomatic" patients who primarily come for preventive issues. Furthermore, physicians must be alert for possible hidden agendas, as one in three patients have one or more hidden reasons for requesting a check-up.

A major goal of antiretroviral therapy (ART) for HIV-1-infected persons is the recovery of CD4 T lymphocytes, resulting in thorough protection against opportunistic complications. Interruptions of ART are still frequent. The long-term effect on CD4 T-cell recovery and clinical events remains unknown.Immunological and clinical endpoints were evaluated in 2491 participants of the Swiss HIV Cohort Study initiating ART during a mean follow-up of 7.1 years. Data were analysed in persons with treatment interruptions (n = 1271; group A), continuous ART, but intermittent HIV-1 RNA at least 1000 copies/ml (n = 469; group B) and continuous ART and HIV-1 RNA constantly less than 1000 copies/ml (n = 751; group C). Risk factors for low CD4 T-cell counts and clinical events were analysed using Cox proportional hazards models.In groups A-C, CD4 T lymphocytes increased to a median of 427, 525 and 645 cells/μl at 8 years. In group A, 63.0 and 37.2% reached above 350 and 500 CD4 T cells/μl, whereas in group B 76.3 and 55.8% and in group C 87.3 and 68.0% reached these thresholds (P0.001). CD4 T-cell recovery directly depended on the cumulative duration of treatment interruptions. In addition, participants of group A had more Centers for Disease Control and Prevention B/C events, resulting in an increased risk of death. Major risk factors for not reaching CD4 T cells above 500 cells/μl included lower baseline CD4 T-cell count, higher age and hepatitis C virus co-infection.In persons receiving continuous ART larger CD4 T-cell recovery and a reduced risk for opportunistic complications and death was observed. CD4 T-cell recovery was smaller in persons with treatment interruptions more than 6 months.

Four of 107 samples obtained from hepatitis C virus (HCV) carriers showed lower HCV core antigen levels in a fluorescence enzyme immunoassay (FEIA) than expected from corresponding HCV RNA levels. Nucleotide sequencing revealed a mutation in the HCV core region (Thr49Pro) that appears to have reduced the FEIA sensitivity.

BACKGROUND: CD4+ T cell depletion and destruction and the involution of the lymphoid tissue are hallmarks of HIV infection. Although the underlying mechanisms are still unclear, apoptosis appears to play a central role. The objective of this study was to investigate the effect of antiretroviral therapy on the lymph node tissue, particularly with respect to morphology and apoptosis. PATIENTS AND METHODS: Between 1997 and 1999, two inguinal lymph nodes were excised from 31 previously untreated individuals who were in an early stage of HIV infection, the first one prior to treatment and the second after 16 to 20 months of treatment. Paraffin sections were investigated for lymph node architecture, distribution of cellular and viral markers, apoptosis, and expression of apoptotic key molecules which indirectly reflect apoptotic processes. RESULTS: After 16-20 months of antiretroviral therapy, a significant decrease in highly activated HIV-driven immune response was observed in the lymph node tissue as a marked reduction in follicular hyperplasia, a normalization of the follicular dendritic cell network, a significant increase in the number of CD4+ T cells, and a significant decrease in the number of CD8+ T cells. The expression of several proapoptotic (Fas, TRAIL, and active caspase 3) and antiapoptotic (Bcl-2 and IL-7Ralpha) molecules that were reconstituted in the tissues during therapy resembled their expression in lymph nodes of HIV-negative individuals. Limitations of the study are (a) the lack of untreated patients in the late stages, (b) for ethical reasons, the lack of a control group with untreated patients, and (c) for methodological reasons, the restriction of sequential measurements of apotpotic markers to one-third of the patients. CONCLUSION: Antiretroviral therapy initiated in the early stages in HIV infection may halt the irreversible destruction of the lymph node tissue and may partially normalize apoptotic processes.

BACKGROUND: In recent years, treatment options for human immunodeficiency virus type 1 (HIV-1) infection have changed from nonboosted protease inhibitors (PIs) to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) and boosted PI-based antiretroviral drug regimens, but the impact on immunological recovery remains uncertain. METHODS: During January 1996 through December 2004 [corrected] all patients in the Swiss HIV Cohort were included if they received the first combination antiretroviral therapy (cART) and had known baseline CD4(+) T cell counts and HIV-1 RNA values (n = 3293). For follow-up, we used the Swiss HIV Cohort Study database update of May 2007 [corrected] The mean (+/-SD) duration of follow-up was 26.8 +/- 20.5 months. The follow-up time was limited to the duration of the first cART. CD4(+) T cell recovery was analyzed in 3 different treatment groups: nonboosted PI, NNRTI, or boosted PI. The end point was the absolute increase of CD4(+) T cell count in the 3 treatment groups after the initiation of cART. RESULTS: Two thousand five hundred ninety individuals (78.7%) initiated a nonboosted-PI regimen, 452 (13.7%) initiated an NNRTI regimen, and 251 (7.6%) initiated a boosted-PI regimen. Absolute CD4(+) T cell count increases at 48 months were as follows: in the nonboosted-PI group, from 210 to 520 cells/muL; in the NNRTI group, from 220 to 475 cells/muL; and in the boosted-PI group, from 168 to 511 cells/muL. In a multivariate analysis, the treatment group did not affect the response of CD4(+) T cells; however, increased age, pretreatment with nucleoside reverse-transcriptase inhibitors, serological tests positive for hepatitis C virus, Centers for Disease Control and Prevention stage C infection, lower baseline CD4(+) T cell count, and lower baseline HIV-1 RNA level were risk factors for smaller increases in CD4(+) T cell count. CONCLUSION: CD4(+) T cell recovery was similar in patients receiving nonboosted PI-, NNRTI-, and boosted PI-based cART.

OBJECTIVE Zidovudine-containing antiretroviral therapy has been associated with a lower rise in absolute CD4 cell counts in several randomized trials. We examined the predictive factors for this phenomenon and assessed its impact on clinical progression during treatment in a large patient cohort. DESIGN An analysis of data from the Swiss HIV Cohort Study. METHODS All 2177 treatment-naive adults who began potent antiretroviral therapy (ART) between September 1995 and September 2004 were included. Exclusion criteria were previous ART and treatment duration of less than 3 months. Follow-up was censored in the case of a treatment switch or stop. RESULTS A total of 1312 patients initiated zidovudine-containing ART and 865 started ART without zidovudine. Except for slightly higher absolute CD4 cell counts in the zidovudine group, prognostic characteristics at baseline and viral suppression during treatment did not differ. During an observation time of 2343 and 1486 patient-years, the CD4 cell count increased by a median of 221 versus 286 cells/microl at 2 years and 290 versus 379 cells/microl at 4 years in the zidovudine versus no zidovudine group; however, the rise in the percentage of CD4 cells was similar in both groups. The zidovudine group had a significantly slower rise in total lymphocytes and haemoglobin. In multivariable Cox models, the hazard for new HIV-associated clinical events was not affected by zidovudine-containing ART. CONCLUSION Over 4 years, zidovudine led to a smaller increase in absolute, but not percentage, CD4 cell counts. The effect can be explained as a slower rise in total lymphocytes and has no impact on clinical efficacy.

CD4 T-cell depletion in HIV-1 infection is partly the result of T-cell apoptosis. Spontaneous apoptosis (SA) and apoptosis markers Fas-associated death-domain-like IL-1 beta converting enzyme (FLICE)-like inhibitory protein (FLIP), Bcl-2, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), TRAIL receptor 1, and Fas were determined in 55 HIV-1 infected persons treated with highly active antiretroviral therapy (HAART) for 48 months. Despite suppressive HAART, SA remained elevated. Increased SA of peripheral blood mononuclear cells (PBMCs) and CD8 T lymphocytes and increased TRAIL receptor 1 expression strongly predicted a poorer recovery of CD4 T-cell count. HAART did not significantly alter anti-or proapoptotic markers in cultured PBMCs and T lymphocytes. The significant relationship between residual T-lymphocyte apoptosis and CD4 T-cell recovery suggests that persistent apoptosis may impede immune restoration.

In HIV-infected patients, reduced ability to work may be an important component of the societal costs of this disease. Few data about productivity costs in HIV-infected patients are available.The goals of this study were to estimate productivity costs in the HIV-infected population in Switzerland and to identify characteristics that may influence patient productivity.This cross-sectional study included all patients younger than retirement age (65 years for men and 62 years for women) who were enrolled in the Swiss HIV Cohort Study in 2002. Measures of productivity losses in this population were based on patients' ability to work and the median monthly wage rates adjusted for age, sex, and educational level in Switzerland. Factors associated with ability to work were analyzed in a multivariate ordinary logistic regression (proportional odds) model. As of July 1, 2002, the exchange rate for US dollars to Swiss francs (CHF) was US $1.00 approximately equal to CHF 1.48.A total of 5319 HIV-infected patients (3665 men [68.9%] and 1655 women [31.1%]; mean [SD] age, 40.6 [8.4] years; range, 17-64 years) were included in the study. The mean annual productivity loss per patient was estimated at CHF 22,910 (95% CI, CHF 22,064-CHF 23, 756). Ability to work was independently associated with the following (P0.001 for all): age (10-year increase: odds ratio [OR], 0.60 [95% CI, 0.54-0.62]), sex (female/male: OR, 0.73 [95% CI, 0.63-0.84]), history of IV drug use (OR, 0.22 [95% CI, 0.19-0.26]), time since first positive HIV test (10 years vsor = 10 years: OR, 0.66 [95% CI, 0.58-0.76]), CD4 cell count (201-500 vs 0-200 cells/microL: OR, 1.68 [95% CI, 1.38-2.46];or =501 vs 0-200 cells/microL: OR, 2.01 [95%, CI, 1.64-2.46]), history of AIDS-indicator disease (OR, 0.47 [95% CI, 0.41-0.55]), stable partnership during the last 6 months (OR, 1.63 [95% CI, 1.43-1.86]), and educational level (higher vs basic: OR, 1.68 [95% CI, 1.45-1.95]).Productivity losses to society for the HIV-infected population appeared to be substantial in this analysis. Given a patient's clinical health status, a higher education level and a stable partnership were associated with greater ability to work. Socioeconomic characteristics may influence the cost-effectiveness of health care interventions in HIV-infected patients.

BACKGROUND: Highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV)-1 infection allows recovery of CD4 T lymphocytes. Few studies have explored the long-term T-lymphocyte responses to HAART. 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 T-lymphocyte count increase, the percentage of individuals with a CD4 T-lymphocyte count of 500/microL or greater and less than 200/microL, and the determinants of CD4 T-lymphocyte recovery were evaluated in individuals treated with continuous (CONT; n = 985) and discontinuous (DISCONT; n = 1250) HAART. RESULTS: At 4 years, 69.5% of subjects (CONT, 84.5%; DISCONT, 53.6%; P

We quantified T cell proliferation and thymic function in primary HIV infection (PHI; n = 19) and chronic HIV infection (CHI; n = 14) by measuring Ki67 staining and TCR excision circle (TREC) number. After antiretroviral therapy of PHI there is a profound decrease in the number and percentage of Ki67+ T cells (

Objective To study the long-term immunological recovery in HIV-1-infected individuals receiving potent antiretroviral therapy (ART). Design Prospective, observational study. Methods Plasma HIV-1 RNA, CD4 and CD8 T lymphocyte counts were determined at 3-6 monthly intervals in 95 HIV-1-infected subjects receiving ART who suppressed plasma HIV-1 RNA to levels below 400 copies/ml during a median observation period of 45 months. Results The median CD4 cell count rose from 325 to 624 cells/microl at 48 months, increasing by 22.6 cells/microl per month in the first 3 months, 8.1 cells/microl per month from months 3 to 12, 6.8 cells/microl per month in the second year, 3.3 cells/microl per month in the third, and 1.7 cells/microl per month in the fourth year. At 48 months, 98% of subjects reached CD4 cell counts > 200 cells/microl, 86% > 350 cells/microl, and 74% > 500 cells/microl. A higher nadir CD4 cell count and younger age were independently associated with greater increases in CD4 cell counts, and higher absolute CD4 cell counts at 48 months. Poor immunological responders who did not reach 500 CD4 lymphocytes/microl at 48 months showed lower nadir and baseline CD4 cell counts than good responders (99 versus 300 cells/microl and 160 versus 373 cells/microl, respectively). Conclusion The recovery of CD4 T lymphocytes occurs mainly in the first 2 years after the initiation of ART, and is associated with age and the pre-existing degree of HIV-1-related immunodeficiency, suggesting that the long-term exposure to HIV-1 infection has caused damage to the immune system that is difficult to correct.

Genotype alterations of HIV-1 protease, reverse transcriptase, cleavage sites p7/p1 and p1/p6, as well as p6(gag) and transframe protein p6* were studied in an observational cohort of 42 individuals who received antiretroviral therapy consisting of saquinavir, ritonavir, and two nucleoside analogs. In a multivariate logistic regression analysis, the prior protease inhibitor experience (odds ratio, 6.20; 95% CI, 1.22-31.38) and the presence of primary protease mutations (odds ratio, 9.99; 95% CI, 1.05-94.72) were independently associated with virological failure. Moreover, a trend was observed in that individuals with N-terminal amino acid insertions in the proline-rich motif of the p6(gag) protein were less likely to experience virological failure (OR, 0.17; 95% CI, 0.02-1.35; p = 0.09). In contrast, the presence of secondary protease, reverse transcriptase, or cleavage site mutations was not independently associated with treatment failure. However, mutations at cleavage site p7/p1 (p = 0.01) and C-terminal p6* mutations (p = 0.02) were both associated with primary protease mutations. In conclusion, the presence of primary protease mutations was the most important predictor of the subsequent virological response. Moreover, there is some evidence that insertions in the proline-rich area of the p6(gag) protein may affect the virological response. The relationship between mutations of cleavage sites or C-terminal p6* residues and protease mutations suggests that these alterations may serve a compensatory role, increasing viral fitness.

To compare the effect of highly active antiretroviral therapy on immune reconstitution in subjects with acute and chronic HIV-1 infection.Prospective study including 58 treatment-naive subjects who commenced indinavir or nelfinavir and two nucleosides during primary (PHI; n = 28) or chronic HIV-1 infection (CHI; n = 30).Naive (CD45RA+ 62L+), memory (CD45RA-) and activated (CD38+ HLA-DR+) T cell subsets were quantified at 1-2 monthly time intervals using 4-colour flow cytometry.At 1 year, HIV-1 RNA declined in both cohorts to undetectable levels (50 copies/ml), while median CD4 lymphocyte count increased from 470 to 758 x 10(6) cells/l in PHI and from 204 to 310 x 10(6) cells/l in CHI, reaching500 x 10(6) cells/l in 93% of PHI, but only in 37% of CHI subjects (P0.001). Naive CD4 lymphocytes increased from 106 to 176 x 10(6) cells/l in PHI and from 41 to 44 x 10(6) cells/l in CHI (PHI versus CHI at 12 months: P = 0.003), while memory cells rose from 368 to 573 x 10(6) cells/l in PHI and from 148 to 223 x 10(6) cells/l in CHI (P0.001). Early increases (3 months) of CD4 lymphocytes were larger in subjects with PHI, consisting of naive CD45RA+ CD62L+ as well as memory CD45RA- CD62L+ cells (P = 0.001). CD4 activation declined from 5 to 2% in PHI and from 13 to 6% in CHI (P = 0.001), while CD8 cell activation was reduced from 33 to 15% in PHI and from 42 to 19% in CHI (P = 0.02).Immune reconstitution was more complete, occurred earlier and comprised both naive and memory CD4 T lymphocytes in subjects who commenced antiretroviral therapy during primary HIV-1 infection.

Recently, studies have shown that non-nucleoside reverse transcriptase inhibitors, such as efavirenz or nevirapine, in combination with two nucleoside analogues have an antiretroviral potency comparable to protease inhibitor containing regimens. Triple combination therapy that includes a non-nucleoside reverse transcriptase inhibitor can therefore be regarded as an effective alternative first-line treatment of HIV-1 infection.

CCR5 is the major coreceptor for human immunodeficiency virus (HIV) type 1 during primary infection. CCR5 + CD4 T lymphocytes were studied in subjects with primary HIV-1 infection (PHI) or acute Epstein-Barr virus (EBV) infection and in HIV-uninfected controls. The early decline of CD4 T lymphocytes during PHI resulted from depletion of CCR5 - CD4 T lymphocytes. After antiretroviral therapy, Ki-67 - CCR5 - CD4 T cell counts rapidly increased in the circulation, which suggests that the initial decrease was due to an alteration in trafficking andlor sequestration. In the CCR5 + subset of CD4 T cells, there was an elevation in the proliferative (Ki-67 + ) fraction during PHI, yet their total number remained in the normal range. In contrast, in acute EBV infection, proliferating CCR5 + CD4 T cells accumulated to very high levels, suggesting they have an important role in the early antiviral response, which may be impaired in HIV-1 infection.

The introduction of potent antiretroviral drug regimens contributed to a decline in HIV-1 associated morbidity and mortality. Clinical observations of spontaneous remission of previously untreatable opportunistic infections in subjects on highly active antiretroviral therapy (HAART) reflect the substantial degree of immune reconstitution which can be achieved by those therapies. A biphasic increase of CD4+ T lymphocytes has been reported including naive (CD45RA+) and memory (CD45RO+) cell subsets. Proliferative lymphocyte responses to recall antigens and mitogens are enhanced over time, while T lymphocyte activation is largely reduced and T cell receptor (TCR) repertoires are partly restored. Proliferative lymphocyte responses specific to HIV-1 antigens, in contrast, remain weak. A complete normalisation of HIV-1 associated immunological alterations has not been reported so far, but the observation period of subjects on potent antiretroviral therapies is still relatively short.

The phenotype of circulating CD8+ T lymphocytes and its association with plasma HIV-1 RNA were analyzed in 34 HIV-1-infected subjects, who were treated with saquinavir, ritonavir, and two nucleoside analogs (HAART) for 1 year. Four-color flow cytometry was applied to measure the expression of cell surface antigens CD38, HLA-DR, CD45RA, CD28, and CD62L on CD8+ T lymphocytes. The results were compared with data on 35 HIV-1-seronegative subjects, 18 untreated asymptomatic HIV-1-seropositive individuals, and 24 HIV-1-infected subjects receiving reverse transcriptase inhibitors (RTIs). Subjects receiving HAART showed a significantly elevated number and percentage of CD38- and HLA-DR-positive and CD28-negative CD8+ T lymphocytes as well as a lower percentage of naive (CD45RA+62L+) CD8+ T lymphocytes compared with HIV-1-uninfected controls. Even subjects with undetectable plasma HIV-1 RNA showed a persistent elevation of activated CD8+ T lymphocytes. However, fewer activated CD8+ T lymphocytes were observed in subjects receiving HAART than in untreated individuals and subjects administered RTIs. In individuals receiving RTIs, CD8+ cell activation was not significantly reduced compared with untreated subjects. Of all evaluated activation markers, the percentage of CD8+ T lymphocytes expressing CD38 and the combination of CD38 and HLA-DR showed the best correlation with plasma HIV-1 RNA. The persistence of CD8+ T lymphocyte activation in subjects receiving HAART strongly suggests ongoing viral activity, even in subjects with undetectable plasma HIV-1 RNA. A complete normalization of immunologic changes of CD8+ T lymphocytes would therefore require a more potent drug regimen or a longer duration of therapy.

Antiretroviral therapy commenced during primary human immunodeficiency virus type 1 (HIV-1) infection (PHI) may limit the extent of viral replication and prevent early loss of HIV-specific CD4 lymphocyte function. We studied the effect of current standard therapy (2 nucleoside analogues and a protease inhibitor) in 16 patients with symptomatic PHI. In the 13 patients who completed 1 year of treatment, plasma HIV RNA was

To evaluate treatment response, durability and tolerance of a four-drug regimen including saquinavir and ritonavir in combination with either zidovudine/lamivudine or stavudine/lamivudine.Observational cohort of HIV-positive individuals.Viral load, CD4+ and CD8+ T lymphocyte counts were assessed at intervals of 1-3 months in subjects commencing therapy between July 1996 and November 1996. Adverse events were evaluated as well as risk factors for therapeutic failures.A group of 56 male patients were included and followed for 48 weeks. Of these, 66% had already taken a protease inhibitor. Viral load dropped by a median 1.98 log10 HIV RNA copies/ml from baseline (interquartile range: 1.49-2.46) and became undetectable (400 copies/ml) in 68% of patients. Response varied: 9% were non-responders (HIV RNA reduction0.5 log10 copies/ml) and 23% were incomplete responders (nadir of HIV RNA400 copies/ml). After 48 weeks, viral load remained undetectable in 49%. Median CD4+ T lymphocyte count increased from 191 x 10(6) to 418 x 10(6) cells/l (range, 241-537 x 10(6) cells/l). Although protease inhibitor and nucleoside pretreatment selected for drug-resistant viral mutants, only the protease inhibitor experience was identified as a risk factor for therapeutic failure. Adverse events occurred in 73% of patients and led to a change of therapy in 9%.Despite advanced HIV disease and pretreatment with multiple antiretroviral drugs, a strong initial treatment response to this drug regimen was observed. However, virological failure occurred in 51% of patients after 48 weeks and frequent adverse events complicated therapy.

Background Highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV)-1 infection allows recovery of CD4 T lymphocytes. Few studies have explored the long-term T-lymphocyte responses to HAART. 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 T-lymphocyte 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 T-lymphocyte recovery were evaluated in individuals treated with continuous (CONT; n = 985) and discontinuous (DISCONT; n = 1250) HAART. Results At 4 years, 69.5% of subjects (CONT, 84.5%; DISCONT, 53.6%; P P P P Conclusions At 4 years, only 39% of individuals treated with HAART reached a CD4 T-lymphocyte count of 500/µL or greater, and 16% with CD4 T-lymphocyte counts less than 200/µL remained susceptible to opportunistic infections. Treatment interruptions, a poor virologic response, and older age were the major factors negatively affecting the recovery of CD4 T lymphocytes.

Plasma HIV-1 RNA and CD4+ T-cell counts after HIV-1 seroconversion are important independent markers that predict the clinical course of HIV-1 infection. The prognostic significance of these parameters during primary HIV-1 infection, however, remains largely unknown. In a cohort of 53 male study subjects (age, 33 +/- 7 years), who consecutively presented with primary HIV-1 infection, we analyzed the relationship between early plasma HIV-1 RNA, CD4+ and CD8+ T-cell counts, beta2-microglobulin, and p24-antigen levels determined in the first 3 months and subsequent plasma HIV-1 RNA levels and CD4+ T-cell counts 6 to 12 months after onset of primary symptoms. Peak, nadir, and median HIV-1 RNA levels in the first 30 days were already significantly associated with HIV-1 RNA levels at 6 to 12 months (p = .02, p < .0001, and p = .01, respectively). Similarly, early nadir and median CD4+ T-lymphocyte counts in the first 30 days showed a significant relationship with CD4+ T-cell counts at 6 to 12 months (p = .009 and p = .0008, respectively). Study subjects with an early decline of CD4+ counts to

Lidocaine is a first line antiarrhythmic agent for treatment and prevention of severe acute ventricular arrhythmias in patients with myocardial infarction. Its efficacy and safety is limited, however, by a large unpredictable between-patient variability in the dose-concentration relationship. We have developed an adaptive microcomputer-based method that helps the physician to choose the optimum dose in an individual patient. The algorithm known in pharmacokinetics as Bayesian feedback uses the concept of nonlinear filtering theory. In this paper the performance of the method is evaluated on the basis of data obtained in 93 patients treated with lidocaine in three clinical studies. With respect to point prediction of future drug levels the performance was excellent. With only one individual feedback measurement of the lidocaine concentration, obtained early in the course of treatment, the serum drug level after 12 hours on continuous intravenous infusion could be predicted with high precision: root mean squared error (RMSE) = 25 %. The estimate of the prediction interval was found to be upwards biased. 86 % of the 93 drug levels lay within the 68 % prediction interval. This was significantly larger than the expected 68 %. On the basis of these results we conclude that, although somewhat inefficient, the method was under realistic routine clinical conditions precise and safe.

The relation between serum concentration of 3-hydroxyquinidine (3-OHQ), a major metabolite of quinidine in humans, and the pharmacologic effect alone and in combination with the parent drug was studied. The heart rate-corrected, computer-averaged QT interval (QTc) was used as the pharmacologic endpoint. In a randomized, double-blind study, 5 healthy subjects received, on 3 separate days 1 week apart, either (1) 300 to 400 mg 3-OHQ orally or (2) 150 mg quinidine base intravenously or (3) a combination in the same doses. Blood samples and electrocardiographic recordings were obtained over the following 10 hours. Serum concentrations of 3-OHQ and quinidine were determined by high-pressure liquid chromatography and the free fraction by ultrafiltration. Peak concentrations of 3-OHQ varied between 1,362 and 3,480 ng/ml after oral 3-OHQ ingestion, but were negligible after intravenous quinidine infusion. The free fraction was 49% +/- 4.8 (mean +/- standard deviation) for 3-OHQ and 20% +/- 4.3 for quinidine. In all 5 subjects a statistically significant correlation was found between serum concentration and QTc prolongation for both quinidine and 3-OHQ (largest p value less than 0.025). The mean slope of the regression line was 0.0184 +/- 0.0128 for 3-OHQ and 0.0297 +/- 0.0111 for quinidine. Multiple linear regression revealed in each subject a significant additive effect of 3-OHQ when administered together with quinidine (largest p value less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Excerpt Phenytoin is used for maintenance therapy and in acute situations, such as the treatment of status epilepticus and seizure prophylaxis after neurosurgery (1, 2). The recommended serum conce...