A randomized controlled trial of single-class maintenance therapy with abacavir/lamivudine/zidovudine after standard triple antiretroviral induction therapy: final 96-week results from the FREE study.

OBJECTIVES: The aim of the study was to test the antiviral efficacy of a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen, with potential beneficial metabolic effects, as maintenance therapy after induction with dual NRTIs and a boosted protease inhibitor (PI). METHODS: An open-label, noninferiority study was carried out. Antiretroviral therapy (ART)-naïve patients with CD4 count ≤ 350 cells/µL and HIV-1 RNA >30000 copies/mL (n=207) were treated with zidovudine/lamivudine and lopinavir/ritonavir. After achieving HIV-1 RNA <50 copies/mL on two consecutive occasions between weeks 12 and 24 after baseline, 120 patients (baseline: median HIV-1 RNA 5.19 log10 copies/mL; median CD4 count 180 cells/µL) were randomized to receive abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) (n=61) or to continue the PI-based ART (n=59). RESULTS: For the proportions of patients (intention-to-treat; missing=failure) with HIV-1 RNA <400 copies/mL (PI group, 66%; ABC/3TC/ZDV group, 71%) and <50 copies/mL (PI group, 63%; ABC/3TC/ZDV group, 62%) at 96 weeks, switching to ABC/3TC/ZDV was noninferior compared with continuing the PI regimen; the difference in failure rate (ABC/3TC/ZDV minus PI) was -4.4 percentage points [95% confidence interval (CI) -21.0 to +12.3 percentage points] and +0.4 percentage points (95% CI -16.9 to +17.7 percentage points), respectively. In the per protocol analysis, the difference in virological failure for HIV-1 RNA >400 copies/mL (0 of 39 patients in the PI group and two of 45 patients in the NRTI group) and for HIV-1 RNA >50 copies/mL (two of 39 and three of 45 patients, respectively) was +4.4 percentage points (95% CI -2.1 to +11.0 percentage points) and +1.5 percentage points (95% CI -8.6 to +11.7 percentage points), respectively, also showing noninferiority. Serum lipids significantly improved in the NRTI group, but not in the PI arm. CONCLUSIONS: A single-class NRTI regimen after successful induction with standard ART had similar antiviral efficacy compared to continuation of a PI-based regimen at 96 weeks after baseline, with improved serum lipids.

A simplified combination antiretroviral therapy regimen enhances adherence, treatment satisfaction and quality of life: results of a randomized clinical trial.

OBJECTIVES: The aim of the study was to investigate the effect of a simplified regimen, in terms of reducing pill burden, dietary requirements and possible adverse effects, on patients' adherence, treatment satisfaction and quality of life (QoL). METHODS: Antiretroviral-naïve patients who achieved a viral load < 50 HIV-1 RNA copies/ml after induction therapy with twice-daily (bid) lopinavir/ritonavir (LPV/r) and fixed-dose zidovudine (ZDV)/lamivudine (3TC) (CBV) were randomly assigned to continue CBV/LPV/r or switch to fixed-dose ZDV/3TC/abacavir (TZV). Patients completed standardized questionnaires on adherence, treatment satisfaction and QoL at randomization (between weeks 12 and 24) and at weeks 48, 72 and 96. RESULTS: Patients on CBV/LPV/r were more likely to have skipped medicines in the last week (P = 0.035) and during the preceding weekend (P = 0.027) than patients on TZV. Patients on CBV/LPV/r were significantly less satisfied with the convenience of their treatment (P = 0.004) and tended to be less satisfied with the side effects of their treatment (P = 0.091) and continuation of their present treatment (P = 0.056) than patients on TZV. Patients on CBV/LPV/r reported significantly lower levels of role functioning (P = 0.013) than patients on TZV. CONCLUSIONS: In this randomized controlled trial, simplification of therapy to fixed-dose TZV among patients with suppressed HIV RNA was perceived to be more convenient, and resulted in improved adherence and better role functioning, than continuing treatment with CBV/LPV/r.

So close and yet so far - Molecular Microbiology of Campylobacter fetus subspecies.

Campylobacter fetus comprises two subspecies, C. fetus subsp. fetus and C. fetus subsp. venerealis, which are considered emerging pathogens in humans and animals. Comparisons at the genome level have revealed modest subspecies-specific variation; nevertheless, these two subspecies show distinct host and niche preferences. C. fetus subsp. fetus is a commensal and pathogen of domesticated animals that can be transmitted to humans via contaminated food. The clinical features of human infection can be severe, especially in impaired hosts. In contrast, C. fetus subsp. venerealis is a sexually transmitted pathogen essentially restricted to cattle. Infections leading to bovine venereal campylobacteriosis cause substantial economic losses due to abortion and infertility. Recent genome sequencing of the two subspecies has advanced our understanding of C. fetus adaptations through comparative genomics and the identification of subspecies-specific gene regions predicted to be involved in pathogenesis. The most striking difference between the subspecies is the highly subspecies-specific association of a pathogenicity island in the C. fetus subsp. venerealis chromosome. The inserted region encodes a Type 4 secretion system, which contributes to virulence properties of this organism in vitro. This review describes the main differences in epidemiological, phenotypic, and molecular characteristics of the two subspecies and summarizes recent advances towards understanding the molecular mechanisms of C. fetus pathogenesis.

Relationship between cytomegalovirus infection and procoagulant changes in human immunodeficiency virus-infected patients.

Cytomegalovirus is associated with hypercoagulability, and is reported to increase the risk of venous thrombosis in human immunodeficiency virus (HIV)-infected patients. Progression to AIDS, however, is also associated with hypercoagulability and venous thrombosis, and may result in more comorbidities, such as reactivation of cytomegalovirus. It is therefore unknown whether active cytomegalovirus in HIV infection results in a procoagulant state or whether hypercoagulability is the result of HIV infection itself. In this cross-sectional study of 104 consecutive HIV-infected patients, active cytomegalovirus infection was associated with hypercoagulability independently of stage of HIV disease. This finding may deserve attention in preventative recommendations for use of thromboprophylaxis in HIV-infected patients.

Immune response to hepatitis B vaccine in HIV-infected subjects using granulocyte-macrophage colony-stimulating factor (GM-CSF) as a vaccine adjuvant: ACTG study 5220.

HIV-infected persons are at risk for HBV co-infection which is associated with increased morbidity and mortality. Unfortunately, protective immunity following HBV vaccination in HIV-infected persons is poor. This randomized, phase II, open-label study aimed to evaluate efficacy and safety of 40 mcg HBV vaccine with or without 250 mcg GM-CSF administered at day 0, weeks 4 and 12. HIV-infected individuals >or=18 years of age, CD4 count >or=200 cells/mm(3), seronegative for HBV and HCV, and naïve to HBV vaccination were eligible. Primary endpoints were quantitative HBsAb titers and adverse events. The study enrolled 48 subjects. Median age and baseline CD4 were 41 years and 446 cells/mm(3), 37 were on ART, and 26 subjects had undetectable VL. Vaccination was well tolerated. Seven subjects in the GM-CSF arm reported transient grade >or=2 signs/symptoms (six grade 2, one grade 3), mostly aches and nausea. GM-CSF had no significant effect on VL or CD4. Four weeks after vaccination, 26 subjects (59%) developed a protective antibody response (HBsAb >or=10 mIU/mL; 52% in the GM-CSF arm and 65% in the control arm) without improved Ab titer in the GM-CSF vs. control arm (median 11 mIU/mL vs. 92 mIU/mL, respectively). Response was more frequent in those with CD4 >or=350 cells/mm(3) (64%) than with CD4 <350 cells/mm(3) (50%), though not statistically significant. GM-CSF as an adjuvant did not improve the Ab titer or the development of protective immunity to HBV vaccination in those receiving an accelerated vaccine schedule. Given the common routes of transmission for HIV and HBV, additional HBV vaccine research is warranted.

Abacavir pharmacokinetics during chronic therapy in HIV-1-infected adolescents and young adults.

The pharmacokinetics of abacavir and its metabolites were investigated in 30 human immunodeficiency virus (HIV)-infected adolescents and young adults 13-25 years of age, equally divided into two groups: <18 years of age and >or=18 years of age. All the subjects received the recommended adult dose of 300 mg twice daily. The area under the plasma concentration-time curve (AUC) and half-life of abacavir did not differ significantly between the age groups or by gender or race, and there were only modest associations of age with apparent abacavir clearance and with volume of distribution. There were no significant correlations of carboxylate or glucuronide metabolite levels with age or gender, although glucuronide AUC was higher in Hispanic subjects than in African-American subjects. Zidovudine and lamivudine concentration profiles were also similar in the two age groups. A novel aspect of the study included an assessment of intracellular carbovir, zidovudine, and lamivudine triphosphate levels, and these were found to be similar in the two age-based groups. Overall, these findings suggest that current recommendations relating to adult dosages are appropriate for adolescents and young adults.

Estimation and prediction of the HIV-AIDS-epidemic under conditions of HAART using mixtures of incubation time distributions.

The estimation of the HIV-AIDS epidemic by means of back-calculation (BC) has been difficult since the introduction of highly active anti-retroviral therapy (HAART) because the incubation time distributions needed for BC were poorly known. Moreover, it has been assumed that if the general public is aware that effective treatments are available then the majority of infected people would be known, and therefore a hidden epidemic was assumed not to exist. Nevertheless, it was suspected that not every infected person would come to the attention of health-care providers, and therefore estimates independent of the patients' registration were necessary. In this paper, the incubation time distributions for HIV treated with the HAART regimen are derived from a cohort study. By using estimates of the proportion treated according to the HAART regimen and the incubation time distributions estimated in the era before the implementation of HAART (pre-HAART), new marginal population incubation time distributions for each of the three risk groups (homosexuals, drug users and others) were constructed. The BC was performed using an empirical Bayesian approach based on the latter incubation time distribution.

Bilateral renal aspergillosis in a patient with AIDS: a case report and review of reported cases.

Renal aspergillosis is an extremely uncommon complication in HIV-infected patients. In general, prognosis is poor and the need for nephrectomy is emphasized. We report the case of a 37-year-old patient with AIDS since April 2003 (CD4 count 10 cells/mm(3), a high viral load, Candida esophagitis, bilateral pneumonia, HIV encephalopathy). Treatment with zidovudine, lamivudine, nevirapine, and lopinavir/ritonavir was started. Adherence to this medication proved to be a problem, but after 18 weeks of HAART the CD4 count was 110 cells/mm(3) and viral load was undetectable. One year later, he presented with hematuria and flank pain. Computed tomography (CT) scan revealed multiple lesions in both kidneys. Cultures of the abscess aspirates yielded Aspergillus fumigatus. Our review of 18 reported cases shows that prognosis of renal aspergillosis is poor if nephrectomy is not performed. However, in the present case a conservative approach was chosen to avoid life-long dialysis. The patient was treated successfully with a combination of voriconazole, percutaneous drainage, and highly active antiretroviral therapy (HAART). Renal function was completely preserved. Reported cases from the literature of renal aspergillosis in HIV-infected patients are summarized in this paper.

[Diagnosis and treatment of HIV-related Kaposi's sarcoma]. / Diagnostiek en behandeling van hiv-gerelateerde kaposisarcomen.

A 42-year-old heterosexual man presented with bluish-purple spots on his skin and in his mouth cavity that had been present for a few months; a 48-year-old homosexual man had painful lymphadenopathy in the groins and left axilla. Both men appeared to have a Kaposi's sarcoma and to be HIV-positive. During highly active antiretroviral therapy (HAART) and radiotherapy or chemotherapy, both the AIDS parameters and the skin lesions improved. Kaposi's sarcoma is AIDS-defining in HIV-seropositive patients. Human herpesvirus-8 infection seems to play a role in the development of Kaposi's sarcoma. The incidence of Kaposi's sarcoma has declined since the introduction of HAART. Nowadays, Kaposi's sarcoma is frequently the presenting symptom of HIV-seropositivity. Patients present with purple cutaneous lesions and/or generalised lymphadenopathy. Visceral lesions are associated with a shorter median survival. The treatment of Kaposi's sarcoma is palliative, whereas immune restitution can lead to regression of the sarcoma.

[Three patients with orf (ecthyma contagiosum)]. / Drie patiënten met orf (ecthyma contagiosum).

Orf was diagnosed in three patients: a 16-year-old Moroccan girl who had cut her finger in a butcher's shop, a 47-year-old Dutch woman who had allowed a lamb to suck on her finger on a children's farm, and a 50-year-old Dutch farm woman. Orf or ecthyma contagiosum is a well-known viral disease among sheep and goats. Transmission to humans as a zoonosis is rare but can take place via direct contact with infected animals or animal products. The clinical picture is usually characterized by a solitary lesion that develops on the dorsal side of the fingers or hands. This viral condition produces little or no systemic complaints and the lesions usually regress spontaneously without scar formation within 6 weeks (range 4-9 weeks). The correct diagnosis can usually be made on clinical grounds. The diagnosis may be confirmed by demonstration of the virus by electron microscopy or the polymerase chain reaction in fluid obtained from the skin lesions or by conventional histopathology. Early clinical recognition and knowledge of this benign, self-limiting viral condition is vital to avoid unnecessary surgical intervention. Proper information and reassurance of the infected patient are very important. All three patients recovered.

[Frequency distribution of dibucaine numbers in 24,830 patients]. / Verteilungsmuster der Dibucainzahl bei 24.830 Patientinnen und Patienten.

PURPOSE: Atypical cholinesterase prolongs the duration of neuromuscular blocking drugs such as succinylcholine and mivacurium. Measuring the dibucaine number identifies patients who are at risk. This study shows the frequency distribution of dibucaine numbers routinely measured and discusses avoidable clinical problems and economic implications. METHODS: Dibucaine numbers were measured on a Hitachi 917-analyzer and all dibucaine numbers recorded over a period of 4 years were taken into consideration. Repeat observations were excluded. RESULTS: A total of 24,830 dibucaine numbers were analysed and numbers below 30 were found in 0.07% ( n=18) giving an incidence of 1:1,400. Dibucaine numbers from 30 to 70 were found in 1.23% ( n=306). On the basis of identification of the Dibucaine numbers we could avoid the administration of succinylcholine or mivacurium resulting in a cost reduction of 12,280 Euro offset against the total laboratory costs amounting to 10,470 Euro. CONCLUSIONS: An incidence of 1:1,400 of dibucaine numbers below 30 is higher than documented in the literature. Therefore, routine measurement of dibucaine number is a cost-effective method of identifying patients at increased risk of prolonged neuromuscular blockade due to atypical cholinesterase.

[Diagnostic image (105). A woman with painful nodules. Infection with O. volvulus]. / Diagnose in beeld (105). Een vrouw met pijnlijke noduli. Infectie met O. volvulus.

A 17-year-old woman from the Democratic Republic of Congo presented with painful nodules on the legs and malaise. An infection with Onchocerca volvulus was diagnosed.

[Signs of miliary tuberculosis: which diagnostic tests and when to treat?]. / Aanwijzingen voor miliaire tuberclose: welke diagnostiek en wanneer behandelen?

Three patients, men aged 21, 57 and 53 years, presented with variable non-specific symptoms such as general malaise, weight loss, elevated temperature, abdominal pain, cough, pulmonary crepitations and elevated liver enzymes. Diffuse fine nodular infiltration was seen on chest radiography in the last two cases. The first patient refused to be tentatively treated with tuberculostatics and died. Mycobacterium tuberculosis complex grew on Löwenstein medium a week later. The two other patients received tuberculostatic treatment. The second patient recovered, while the third patient suffered a cerebrovascular accident on top of emaciation and respiratory insufficiency and died. In the Netherlands, currently more than one hundred patients with tuberculosis disease die each year. The disease is mostly seen in people from the high-risk groups for tuberculosis such as asylum seekers and immigrants. Even after extensive diagnostic procedures it can be difficult to obtain rapid bacteriological confirmation. When miliary tuberculosis is suspected it is important to carry out the complete range of tests (Ziehl Neelsen microscopy, PCR, Löwenstein cultivation) and to start therapy immediately and not to await the results of the diagnostic tests. However, in many cases this may still be too late, with an estimated mortality of 20%.

Limited patient adherence to highly active antiretroviral therapy for HIV-1 infection in an observational cohort study.

BACKGROUND: Adherence to highly active antiretroviral therapy (HAART) for human immunodeficiency syndrome type 1 (HIV-1) infection is essential to sustain viral suppression and prevent drug resistance. We investigated adherence to HAART among patients in a clinical cohort study. METHODS: Patients receiving HAART had their plasma concentrations of protease inhibitors or nevirapine measured and completed a questionnaire on adherence. We determined the percentage of patients who reported taking all antiretroviral medication on time and according to dietary instructions in the past week. Drug exposure was compared between patients reporting deviation from their regimen and fully adherent patients. Among patients who received HAART for at least 24 weeks, we assessed the association between adherence and virologic outcome. RESULTS: A total of 224 of 261 eligible patients completed a questionnaire. Forty-seven percent reported taking all antiretroviral medication on time and according to dietary instructions. Patients who reported deviation from their regimen showed lower drug exposure compared with fully adherent patients (median concentration ratio, 0.81 vs 1.07; P =.001). Among those receiving HAART for at least 24 weeks, patients reporting deviation from their regimen were less likely to have plasma HIV-1 RNA levels below 500 copies/mL (adjusted odds ratio, 4.0; 95% confidence interval, 1.4-11.6) compared with fully adherent patients. CONCLUSIONS: Only half of the patients took all antiretroviral medication in accordance with time and dietary instructions in the preceding week. Deviation from the antiretroviral regimen was associated with decreased drug exposure and a decreased likelihood of having suppressed plasma HIV-1 RNA loads. Patient adherence should remain a prime concern in the management of HIV-1 infection.

[Tuberculosis of the pancreas in a HIV-seropositive patient]. / Tuberculose van het pancreas bij een HIV-seropositieve patiënt.

A 34-year-old man from Nigeria who had resided permanently in the Netherlands for five years had experienced fever, upper abdominal pain and weight loss for several months. He did not give the impression of being ill. A CT scan gave cause to suspect pancreatitis. An HIV test gave a positive result. Puncture of the accumulated fluid around the pancreas led to the diagnosis 'tuberculosis' (infection by Mycobacterium tuberculosis). Once the patient had made a good recovery with antituberculosis therapy, antiretroviral therapy was initiated, whereupon the number of CD4+ cells in the blood increased. Extrapulmonal tuberculosis is not unusual in HIV seropositive patients from countries with a high prevalence of tuberculosis. However, in such patients isolated tuberculosis of the pancreas is unusual and has not previously been described in the Netherlands. The diagnosis can be established following a CT guided puncture; tuberculosis is instantly suspected if the Ziehl-Neelsen stains are positive and the diagnosis can then be confirmed by a polymerase chain reaction (PCR) analysis and by culturing. Anti-retroviral therapy is withheld until response to anti-tuberculosis treatment is satisfactory.

Increase of CCR1 and CCR5 expression and enhanced functional response to MIP-1 alpha during differentiation of human monocytes to macrophages.

Chemokines and their receptors regulate migration of leukocytes under normal and inflammatory conditions. In this study, we analyzed the CC chemokine receptor (CCR) expression of monocytes differentiating in vitro to macrophages. We observed a time-dependent change of expression and functional responsiveness of CCR1, CCR2, and CCR5 within 48 h. Whereas freshly harvested monocytes were strongly attracted by monocyte chemotactic protein 1 (MCP-1), a specific ligand for CCR2, only a weak response was observed to macrophage inflammatory protein 1alpha (MIP-1alpha), which binds to CCR1 and CCR5. In striking contrast, differentiated macrophages displayed a strong chemotactic response to MIP-1alpha and only a weak response to MCP-1. These findings were paralleled by intracellular calcium shifts. During the time course of monocyte to macrophage differentiation, mRNA levels and surface expression of CCR2 decreased, whereas that of CCR1 and CCR5 increased. The time-dependent switch from CCR2 on monocytes to CCR1 and CCR5 on mature macrophages reflects a functional change belonging to the differentiation process of monocytes to macrophages and may form the basis for a differential responsiveness of monocytes and macrophages to distinct sets of chemokines.