PGE2 production at sites of tissue injury promotes an anti-inflammatory neutrophil phenotype and determines the outcome of inflammation resolution in vivo.

Neutrophils are the first immune cells recruited to a site of injury or infection, where they perform many functions. Having completed their role, neutrophils must be removed from the inflammatory site-either by apoptosis and efferocytosis or by reverse migration away from the wound-for restoration of normal tissue homeostasis. Disruption of these tightly controlled physiological processes of neutrophil removal can lead to a range of inflammatory diseases. We used an in vivo zebrafish model to understand the role of lipid mediator production in neutrophil removal. Following tailfin amputation in the absence of macrophages, neutrophillic inflammation does not resolve, due to loss of macrophage-dependent handling of eicosanoid prostaglandin E2 (PGE2) that drives neutrophil removal via promotion of reverse migration. Knockdown of endogenous PGE synthase gene reveals PGE2 as essential for neutrophil inflammation resolution. Furthermore, PGE2 is able to signal through EP4 receptors during injury, causing an increase in Alox12 production and switching toward anti-inflammatory eicosanoid signaling. Our data confirm regulation of neutrophil migration by PGE2 and LXA4 (lipoxin A4) in an in vivo model of inflammation resolution. This pathway may contain therapeutic targets for driving inflammation resolution in chronic inflammatory disease.

The triune of intestinal microbiome, genetics and inflammatory status and its impact on the healing of lower gastrointestinal anastomoses.

Gastrointestinal resections are a common operation and most involve an anastomosis to rejoin the ends of the remaining bowel to restore gastrointestinal (GIT) continuity. While most joins heal uneventfully, in up to 26% of patients healing fails and an anastomotic leak (AL) develops. Despite advances in surgical technology and techniques, the rate of anastomotic leaks has not decreased over the last few decades raising the possibility that perhaps we do not yet fully understand the phenomenon of AL and are thus ill-equipped to prevent it. As in all complex conditions, it is necessary to isolate each different aspect of disease for interrogation of its specific role, but, as we hope to demonstrate in this article, it is a dangerous oversimplification to consider any single aspect as the full answer to the problem. Instead, consideration of important individual observations in parallel could illuminate the way forward towards a possibly simple solution amidst the complexity. This article details three aspects that we believe intertwine, and therefore should be considered together in wound healing within the GIT during postsurgical recovery: the microbiome, the host genetic make-up and their relationship to the perioperative inflammatory status. Each of these, alone or in combination, has been linked with various states of health and disease, and in combining these three aspects in the case of postoperative recovery from bowel resection, we may be nearer an answer to preventing anastomotic leaks than might have been thought just a few years ago.

Zebrafish screens for new colitis treatments - a bottom-up approach.

Many factors interact in the development and progression of inflammatory bowel disease. This complexity demands a combination of methods to disentangle the pathology of this disease. As reported by Oehlers et al. in this issue, the zebrafish drug screen is one simple approach that could enable the elucidation of the pathways involved in IBD and ultimately the discovery of new therapeutics.

Boceprevir plus pegylated interferon/ribavirin to re-treat hepatitis C virus genotype 1 in HIV-HCV co-infected patients: final results of the Spanish BOC HIV-HCV Study.

INTRODUCTION: Boceprevir (BOC) was one of the first oral inhibitors of hepatitis C virus (HCV) NS3 protease to be developed. This study assessed the safety and efficacy of BOC+pegylated interferon-α2a/ribavirin (PEG-IFN/RBV) in the retreatment of HIV-HCV co-infected patients with HCV genotype 1. METHODS: This was a phase III prospective trial. HIV-HCV (genotype 1) co-infected patients from 16 hospitals in Spain were included. These patients received 4 weeks of PEG-IFN/RBV (lead-in), followed by response-guided therapy with PEG-IFN/RBV plus BOC (a fixed 44 weeks was indicated in the case of cirrhosis). The primary endpoint was the sustained virological response (SVR) rate at 24 weeks post-treatment. Efficacy and safety were evaluated in all patients who received at least one dose of the study drug. RESULTS: From June 2013 to April 2014, 102 patients were enrolled, 98 of whom received at least one treatment dose. Seventy-three percent were male, 34% were cirrhotic, 23% had IL28b CC, 65% had genotype 1a, and 41% were previous null responders. The overall SVR rate was 67%. Previous null-responders and cirrhotic patients had lower SVR rates (57% and 51%, respectively). Seventy-six patients (78%) completed the therapy scheme; the most common reasons for discontinuation were lack of response at week 12 (12 patients) and adverse events (six patients). CONCLUSIONS: Response-guided therapy with BOC in combination with PEG-IFN/RBV led to an overall SVR rate of 67%, but an SVR rate of only 51% in patients with cirrhosis. The therapy was generally well tolerated. Although the current standards of care do not include BOC+PEG-IFN/RBV, the authors believe that this combination can be beneficial in situations where new HCV direct antiviral agent interferon-free therapies are not available yet.

Fibrin Association at Hybrid Biointerfaces Made of Clot-Binding Peptides and Polythiophene.

The properties as biointerfaces of electroactive conducting polymer-peptide biocomposites formed by poly(3,4-ethylenedioxythiophene) (PEDOT) and CREKA or CR(NMe)EKA peptide sequences (where Glu has been replaced by N-methyl-Glu in the latter) have been compared. CREKA is a linear pentapeptide that recognizes clotted plasma proteins and selectively homes to tumors, while CR(NMe)EKA is an engineer to improve such properties by altering peptide-fibrin interactions. Differences between PEDOT-CREKA and PEDOT-CR(NMe)EKA reflect dissemblance in the organization of the peptides into the polymeric matrix. Both peptides affect fibrinogen thrombin-catalyzed polymerization causing the immediate formation of fibrin, whereas in the absence of thrombin this phenomenon is only observed for CR(NMe)EKA. Consistently, the fibrin-adsorption capacity is higher for PEDOT-CR(NMe)EKA than for PEDOT-CREKA, even though in both cases adsorbed fibrin exhibits round-like morphologies rather than the characteristic fibrous structure. PEDOT-peptide films coated with fibrin are selective in terms of cell adhesion, promoting the attachment of metastatic cells with respect to normal cells.

Safe Reduction in CD4 Cell Count Monitoring in Stable, Virally Suppressed Patients With HIV Infection or HIV/Hepatitis C Virus Coinfection.

BACKGROUND: It has been suggested that routine CD4 cell count monitoring in human immunodeficiency virus (HIV)-monoinfected patients with suppressed viral loads and CD4 cell counts >300 cell/µL could be reduced to annual. HIV/hepatitis C virus (HCV) coinfection is frequent, but evidence supporting similar reductions in CD4 cell count monitoring is lacking for this population. We determined whether CD4 cell count monitoring could be reduced in monoinfected and coinfected patients by estimating the probability of maintaining CD4 cell counts ≥200 cells/µL during continuous HIV suppression. METHODS: The PISCIS Cohort study included data from 14 539 patients aged ≥16 years from 10 hospitals in Catalonia and 2 in the Balearic Islands (Spain) since January 1998. All patients who had at least one period of 6 months of continuous HIV suppression were included in this analysis. Cumulative probabilities with 95% confidence intervals were calculated using the Kaplan-Meier estimator stratified by the initial CD4 cell count at the period of continuous suppression initiation. RESULTS: A total of 8695 patients were included. CD4 cell counts fell to <200 cells/µL in 7.4% patients, and the proportion was lower in patients with an initial count >350 cells/µL (1.8%) and higher in those with an initial count of 200-249 cells/µL (23.1%). CD4 cell counts fell to <200 cells/µL in 5.7% of monoinfected and 11.1% of coinfected patients. Of monoinfected patients with an initial CD4 cell count of 300-349 cells/µL, 95.6% maintained counts ≥200 cells/µL. In the coinfected group with the same initial count, this rate was lower, but 97.6% of coinfected patients with initial counts >350 cells/µL maintained counts ≥200 cells/µL. CONCLUSIONS: From our data, it can be inferred that CD4 cell count monitoring can be safely performed annually in HIV-monoinfected patients with CD4 cell counts >300 cells/µL and HIV/HCV-coinfected patients with counts >350 cells/µL.

Progression of liver fibrosis in HIV/hepatitis C virus-coinfected individuals on antiretroviral therapy with early stages of liver fibrosis at baseline.

OBJECTIVES: The aim of the study was to assess the progression of liver fibrosis in HIV/hepatitis C virus (HCV)-coinfected patients with no or mild-to-moderate fibrosis (stages F0-F2). METHODS: Liver fibrosis was reassessed by transient elastometry (TE) between January 2009 and November 2011 in HIV/HCV-coinfected patients with stage F0-F2 fibrosis in a liver biopsy performed between January 1997 and December 2007. Patients with liver stiffness at the end of follow-up < 7.1 kPa were defined as nonprogressors, and those with values ≥ 9.5 kPa or who died from liver disease were defined as progressors. Cirrhosis was defined as a cut-off of 14.6 kPa. The follow-up period was the time between liver biopsy and TE. Cox regression models adjusted for age, gender and liver fibrosis stage at baseline were applied. RESULTS: The median follow-up time was 7.8 years [interquartile range (IQR) 5.5-10 years]. The study population comprised 162 patients [115 (71%) nonprogressors and 47 (29%) progressors; 19 patients (11.7%) had cirrhosis]. The median time from the diagnosis of HCV infection to the end of follow-up was 20 years (IQR 16.3-23.1 years). Three progressors died from liver disease (1.8%). The variables associated with a lower risk of progression were age ≤ 38 years (hazard ratio (HR) 0.32; 95% confidence interval (CI) 0.16-0.62; P = 0.001], having received interferon (HR 2.18; 95% CI 1.14-4.15; P = 0.017), being hepatitis B virus surface antigen (HBsAg) negative (HR 0.20; 95% CI 0.04-0.92; P = 0.039), and baseline F0-F1 (HR 0.43; 95% CI 0.28-0.86; P = 0.017). CONCLUSIONS: A high proportion of patients with stage F0-F2 fibrosis progress to advanced liver fibrosis. Advanced liver fibrosis must be included in the list of diseases associated with aging. Our results support the recommendation to offer HCV antiviral therapy to HIV/HCV-coinfected patients at early stages of liver fibrosis.

[Oesophageal leiomyoma: VATS (video-assisted thoracic surgery) resection]. / Leiomioma esofágico: resección por videotoracoscopia. A propósito de un caso.

Leiomyomas are the most common benign tumours of the oesophagus. The most frequent symptoms are dysphagia and epigastric pain, although 50% of patients remain asymptomatic and the tumour is sometimes discovered incidentally. We report a case of oesophageal leiomyoma with emphasis on the operative management by VATS. Traditionally, operative management by transthoracic enucleation is the procedure of choice. In this study we present our experience using a minimally invasive approach.

Leiomioma esofágico: resección por videotoracoscopia. A propósito de un caso / Oesophageal leiomyoma: VATS (Video-assisted Thoracic Surgery) resection. A case report

Los leiomiomas son los tumores benignos más frecuentes del esófago. Los síntomas más frecuentes son la disfagia y el dolor epigástrico, aunque un 50% de los pacientes permanecen asintomáticos y el tumor a veces se descubre por casualidad. Se presenta un caso de leiomioma esofágico con énfasis en el procedimiento quirúrgico por videotoracoscopia. Tradicionalmente, el tratamiento de elección es la enucleación transtorácica. En este estudio presentamos nuestra experiencia con un abordaje mínimamente invasivo(AU)

Leiomyomas are the most common benign tumours of the oesophagus. The most frequent symptoms are dysphagia and epigastric pain, although 50% of patients remain asymptomatic and the tumour is sometimes discovered incidentally. We report a case of oesophageal leiomyoma with emphasis on the operative management by VATS. Traditionally, operative management by transthoracic enucleation is the procedure of choice. In this study we present our experience using a minimally invasive approach(AU)

Therapeutic immunization with an inactivated HIV-1 Immunogen plus antiretrovirals versus antiretroviral therapy alone in asymptomatic HIV-infected subjects.

To determine whether the addition of an inactivated-gp120-depleted HIV-1 Immunogen to antiretrovirals (ARTs) conferred a beneficial effect on delaying time to virologic failure relative to that obtained by ARTs alone, a phase II clinical trial was performed in 243 asymptomatic, ART naïve, HIV-1 seropositive adults. The Cox model showed that HIV-1 Immunogen treatment was associated with a 34% decrease in the risk of virologic failure (P = 0.056). When the analysis incorporated baseline HIV-RNA stratification the risk of virologic failure in the HIV-1 Immunogen Arm was significantly reduced a 37% compared to the IFA placebo Arm (P = 0.034). The data suggest that therapeutic immunization plus ARTs could influence virologic control.

Prospective randomized two-Arm controlled study to determine the efficacy of a specific intervention to improve long-term adherence to highly active antiretroviral therapy.

BACKGROUND: Nearly perfect compliance seems to be indispensable to obtain the maximum benefit from highly active antiretroviral therapy (HAART). Interventions to ensure a high level of adherence during a relatively long-term period of therapy are necessary. METHODS: This is a prospective, randomized, two-arm controlled study including patients starting their first-or second-line HAART who were randomized to receive psychoeducative intervention to implement adherence (experimental group [EG]) or a usual medical follow-up (control group [CG]). We aimed to study the efficacy of a psychoeducative intervention to ensure long-term adherence to HAART, its relation with the virologic efficacy of treatment, and to determine the variables related to long-term adherence. Visits were made at weeks 0, 4, 24, and 48 for data collection. Self-reported adherence was registered at each visit and its veracity was tested by randomized blood analyses performed without previous warning to 40% of patients. Appropriate adherence was defined as the consumption of >/=95% of medication prescribed. Statistical analyses were performed both by the as treated (AT) and the intention to treat missing = failure (ITT) methods. RESULTS: In all, 116 patients were included. At week 48, 94% of patients in the EG versus 69% controls achieved adherence >/=95% (p =.008); 89% of patients in the EG versus 66% controls had HIV-1 RNA levels <400 copies/ml (p =.026). Overall, 85% of patients with adherence >/=95% but only 45% of those with adherence <95% had viral load (VL) <400 copies/ml (p =. 008). In multivariate analysis, variables significantly related to adherence were having received a psychoeducative intervention (odds ratio [OR], 6.58; p =.04), poor effort to take medication (OR, 5.38; p =.03), and high self-perceived capacity to follow the regimen (OR, 13.76; p =.04). Self-reported adherence and drug plasma levels coincided in 93% of cases. However, differences in adherence did not reach statistical significance in the ITT analysis although a clear tendency toward benefit was observed in EG. CONCLUSIONS: Specific and maintained psychoeducative interventions based on excellence on clinical practice are useful to keep high levels of adherence as well as high levels of viral suppression. There is a clear relation between high adherence levels and virologic success. Assessment of certain specific variables related to adherence may be helpful to monitor patient's compliance in the clinical setting.

Efficacy of low-dose subcutaneous interleukin-2 to treat advanced human immunodeficiency virus type 1 in persons with

The immunologic efficacy of low-dose recombinant interleukin-2 (rIL-2) administered subcutaneously (sc) once a day in combination with highly active antiretroviral therapy (HAART) was assessed in a pilot study in patients with advanced human immunodeficiency virus (HIV) disease. Twenty-five persons with 24 weeks were randomly assigned to receive sc rIL-2 (3 x 10(6) IU once a day) with their previous antiretroviral regimen (n=13) or to continue with the same treatment (n=12). The level of CD4 T cells was significantly higher in the IL-2 group at week 24 (105+/-65/microL; P<.05) but not in the control group (30+/-78/microL). Memory T cells initially contributed to the CD4 T cell increase at week 4 (P<.05). Naive T cell increases (99+/-58/microL) in the IL-2 group became statistically significant at week 24 compared with the control group (28+/-27/microL; P<.05). Subcutaneous rIL-2 once a day in combination with HAART was well tolerated and improved immunologic surface markers in patients with advanced HIV infection.

Chemokine and chemokine receptor expression after combined anti-HIV-1 interleukin-2 therapy.

OBJECTIVE: To evaluate changes in serum levels of chemokines, chemokine production, and chemokine receptor expression by peripheral blood mononuclear cells (PBMC), after treatment of HIV-1-infected individuals with interleukin (IL)-2. METHODS: We determined CC-chemokine levels by enzyme-linked immunosorbent assay and chemokine receptor expression using FACS analysis or reverse transcriptase polymerase chain reaction in samples from patients receiving highly active antiretroviral therapy (HAART) supplemented with low doses of recombinant IL-2. Results were compared with a control group of patients receiving HAART. RESULTS: Serum levels of RANTES, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, and the production of these chemokines by unstimulated and stimulated PBMC, were not modified by IL-2 administration. In contrast, the IL-2-treated group showed increased expression of CXC-chemokine receptor (CXCR)-4 in the CD4 T-cell subset after 24 weeks of treatment, which was associated with increased mRNA levels. A lower increase was observed in CC-chemokine receptor (CCR)-5 expression by CD4 T cells. No modifications in the expression of these receptors were observed in monocytes and no general increases were observed in mRNA levels of chemokine receptors CCR-1, CCR-2b and CCR-3 in IL-2-treated patients. CONCLUSIONS: IL-2 at doses that significantly increase CD4 cell counts does not induce dramatic modifications in the chemokine/chemokine receptor system. Only expression of CXCR-4 appears to increase, due in part to lymphocyte activation. Therefore, the efficacy of IL-2 treatment in HIV-1 infection has to be evaluated by its ability to activate and induce faster regeneration of the immune system.

High-dose saquinavir plus ritonavir: long-term efficacy in HIV-positive protease inhibitor-experienced patients and predictors of virologic response.

The year-long antiviral efficacy of a high-dose salvage regimen consisting of saquinavir (800 mg twice daily) plus ritonavir (400 mg twice daily) was evaluated in 58 HIV-positive patients who had seen no improvement under first-line protease inhibitor-containing regimens, nor in baseline predictors of virologic response. The efficacy of therapy was determined by CD4+/CD8+ and HIV-1 RNA values. The primary endpoint of our study was the percentage of patients with HIV-1 RNA levels <200 copies/ml (virologic success) at 6 and 12 months of of follow-up. Secondary endpoints were log10 reduction in HIV-1 RNA levels and CD4+ increases through follow-up. Surrogate markers related with a lower HIV-1 RNA area under the curve were identified at baseline. Kaplan-Meier analysis and Cox proportional hazards models were applied to identify baseline predictors of achieving viral suppression at <200 copies/ml. All analyses were intention to treat-last observation carried forward. Patients achieved a median HIV-1 RNA level reduction of >0.5 log through 1 year (-0.59 log10 at 12 months), as well as CD4+ counts increased significantly (89 cells/mm3 at 12 months). Overall, 53% of patients were likely to achieve HIV-1 RNA levels <200 copies/ml at 6 months. Seventy-six percent of patients who started therapy at HIV-1 RNA levels <5000 copies/ml but only 42% with baseline viral load of 5000 to 30,000 copies/ml and 18.7% with baseline viral load >30,000 copies/ml were likely to achieve viral suppression at 6 months (p < .001, log-rank test). Patients with baseline HIV-1 RNA levels between 5000 and 30,000 copies/ml (relative hazard [RH], 0.39; 95% confidence interval [CI], 0.01 to 0.98; p = .0396) and patients with baseline HIV-1 RNA levels >30,000 copies/ml (RH, 0.20; 95% CI, 0.07-0.61; p = .0040) were less likely to reach undetectable HIV-1 RNA levels than those with baseline HIV-1 RNA levels <5000 copies/ml. Salvage highly active antiretroviral therapy (HAART) strategies including saquinavir (SQV) at high doses plus ritonavir (RTV) exert a significant long-term efficacy in more than half of PI-experienced patients without significant additional toxicity. This therapeutic efficacy is strongly implemented by a switch at the lower HIV-1 RNA levels.

Benefit of switching from a protease inhibitor (PI) to nevirapine in PI-experienced patients suffering acquired HIV-related lipodystrophy syndrome (AHL): interim analysis at 3 months of follow-up.

This multicentre, randomized, open-label, prospective trial is evaluating the effects of switching treatment from a protease inhibitor (PI)-containing regimen to one containing the non-nucleoside reverse transcriptase (RT) inhibitor nevirapine in human immunodeficiency virus (HIV)-infected patients with durable viral suppression but suffering from lipodystrophy. Objectives of this ongoing study are to evaluate the effects of this switch on changes in body shape and metabolic abnormalities associated with acquired HIV-related lipodystrophy syndrome (AHL), as well as on maintenance of viral suppression and immunological and psychological effects. Preliminary data involving 57 patients with 3 months of follow-up show an initial improvement of AHL in two regions, the face and arms. There is also a tendency toward improved cholesterol and triglyceride levels and improved quality of life among patients receiving the nevirapine-containing regimen. Maintenance of viral suppression was equivalent in both treatment groups. Additional data with longer follow-up are needed to confirm these results.

Long-lasting remission of cytomegalovirus retinitis without maintenance therapy in human immunodeficiency virus-infected patients.

Seven AIDS patients who were receiving suppressive therapy for previously diagnosed cytomegalovirus (CMV) retinitis were offered treatment with protease inhibitors (PIs). Secondary prophylaxis for CMV was discontinued after 3 months of therapy with PIs if patients had >150 CD4 cells/mm3 and a human immunodeficiency virus (HIV) load of <200 copies/mL and if they were negative for CMV as determined by qualitative CMV polymerase chain reaction (PCR). Ophthalmologic exams were done periodically. After a median follow-up of 9 months (range, 9-12), no new episodes of CMV retinitis were observed. CD4 cell counts were >150 cells/mm3 in all cases, HIV loads were <200 copies/mL, and results for qualitative CMV PCRs remained negative. These observations suggest that for selected patients with healed CMV retinitis who have immunologic and virologic evidence of a clinical response to potent combination antiretroviral therapy, temporary discontinuation of a chronic anti-CMV suppressive therapy may not result in further retinal necrosis. However, the long-term immunologic benefit of PIs and hence the safety of prolonged withdrawal of anti-CMV therapy is unknown.

Filgrastim to treat neutropenia and support myelosuppressive medication dosing in HIV infection. G-CSF 92105 Study Group.

BACKGROUND: Patients with HIV infection frequently experience disease or treatment-related myelosuppression leading to neutropenia. Neutropenia often leads to dose-reduction or discontinuation of important myelosuppressive therapy. OBJECTIVE: To examine the efficacy and safety of filgrastim for reversing neutropenia and determine the effect of this on use of myelosuppressive medications. DESIGN: Open-label, non-comparative, multicentre study in 200 HIV-positive patients with neutropenia [absolute neutrophil count (ANC) < 1.0 x 10(9)/l]. Filgrastim was started at 1 microgram/kg/day subcutaneously for 28 days. This initial treatment phase was followed by a maintenance phase, using 300 micrograms on 1-7 days/week. In both phases the dose of filgrastim was adjusted to achieve an ANC of 2-5 x 10(9)/l. RESULTS: Filgrastim reversed neutropenia in 98% of patients (ANC > or = 2 x 10(9)/l), with a median time to reversal of 2 days (range 1-16) and a median dose of 1 microgram/kg/day (range 0.5-10). Most patients (96%) achieved reversal of neutropenia with a filgrastim dose of < or = 300 micrograms/day (< or = 1 vial/day). Normal ANCs were then maintained with a median of 1 microgram/kg/day (range 0.22-10.6) during the treatment phase and 3 x 300 micrograms vials/week (range 1-7) during the maintenance phase. Ganciclovir, zidovudine, co-trimoxazole and pyrimethamine were the drugs most frequently considered to be causing neutropenia, and 83% of patients received one or more of these in the study. Filgrastim allowed > 80% of patients to increase or maintain dose-levels of these four medications or add them to their therapy. The number of these four medications received per patient increased by > 20% during filgrastim therapy. Filgrastim was well tolerated. CD4, CD8 and total lymphocyte counts all increased slightly, and there was no difference in HIV-1 p24 antigen levels. CONCLUSION: Filgrastim rapidly reverses neutropenia and maintains normal ANC in patients with HIV infection. This allows greater use of myelosuppressive medications without the potentially life-threatening complications of neutropenia.

Switching from zidovudine to didanosine in patients with symptomatic HIV infection and disease progression. ddI Iberian Study Group.

This study evaluated the efficacy of switching to didanosine in patients who were clinically or immunologically progressing despite zidovudine therapy. This multicenter, open-label study involved 400 patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC), who had tolerated zidovudine for at least 12 weeks and had signs of clinical or immunological disease progression. They were randomly assigned to receive 600 mg/d of zidovudine (n=133), 500 mg/d of didanosine (n=131), or 200 mg/d of didanosine (n=136). The primary end point was a new AIDS-defining event or death. The study was prematurely terminated, after the first interim analysis, mainly owing to results of two controlled studies demonstrating that a change to didanosine was associated with an improved outcome in patients with advanced HIV-1 disease. The median duration of follow-up was 53 weeks. The primary end point rates were 41, 58, and 59 (per 100 person-years) in the didanosine 500 mg, didanosine 200 mg, and zidovudine groups (zidovudine vs. didanosine 500 mg, relative risk 1.28, 95% confidence interval, 0.88-1.86, p = 0.19; didanosine 200 vs. 500 mg, relative risk 1.24, 95% confidence interval, 0.85-1.79, p = 0.26). In subjects with a baseline CD4 count of 100/mm3 or more, the primary end point rates were 8, 29, and 25 (per 100 person-years) in the didanosine 500 mg, didanosine 200 mg, and zidovudine groups, respectively (zidovudine vs. didanosine 500 mg, relative risk 2.96, 95% confidence interval 0.91-9.62, p = 0.07). No difference was seen in survival. In the didanosine 500 mg group, more patients had a 50% increase in CD4 cells (10% vs. 1% in zidovudine group, p = 0.01) and an increase of > or = 2.5 kg in body weight (2% versus 3%). Fatal pancreatitis developed in one patient assigned to didanosine 500 mg and in one to zidovudine. Our data suggest that switching from zidovudine to currently recommended doses of didanosine in subjects with ARC or AIDS who show evidence of clinical and laboratory disease progression can be associated with improvements in clinical outcome as well as in surrogate markers of HIV disease progression. This effect tended to be greater among individuals with higher CD4 counts (>100/mm3).