Risk of non-AIDS-defining events among HIV-infected patients not yet on antiretroviral therapy.

OBJECTIVES: Certain non-AIDS-related diseases have been associated with immunodeficiency and HIV RNA levels in HIV-infected patients on combination antiretroviral therapy (cART). We aimed to investigate these associations in patients not yet on cART, when potential antiretroviral-drug-related effects are absent and variation in RNA levels is greater. METHODS: Associations between, on the one hand, time-updated CD4 counts and plasma HIV RNA and, on the other hand, a composite non-AIDS-related endpoint, including major cardiovascular diseases, liver fibrosis/cirrhosis, and non-AIDS-related malignancies, were studied with multivariate Poisson regression models in 12 800 patients diagnosed with HIV infection from 1998 onwards while not yet treated with cART. RESULTS: During 18 646 person-years of follow-up, 203 non-AIDS-related events occurred. Compared with a CD4 count ≥ 500 cells/µL, adjusted relative risks (RRs) for the composite endpoint were 4.71 [95% confidence interval (CI) 2.98-7.45] for a CD4 count < 200 cells/µL, 2.06 (95% CI 1.38-3.06) for a CD4 count of 200-349 cells/µL, and 1.19 (95% CI 0.82-1.74) for a CD4 count of 350-499 cells/µL. There was no evidence for an independent association with HIV RNA. Other important covariates were age [RR 1.40 (95% CI 1.31-1.49) per 5 years older], hepatitis B virus coinfection [RR 5.66 (95% CI 3.87-8.28)] and hepatitis C virus coinfection [RR 9.26 (95% CI 6.04-14.2)]. CONCLUSIONS: In persons not yet receiving cART, a more severe degree of immunodeficiency rather than higher HIV RNA levels appears to be associated with an increased risk of our composite non-AIDS-related endpoint. Larger studies are needed to address these associations for individual non-AIDS-related events.

Fever and high lactate dehydrogenase in HIV-positive patients from the Antilles and Surinam: histoplasmosis?

We describe four cases of HIV-positive patients, two from Surinam, one from the Dutch Antilles and one from Nigeria, who presented with a febrile illness and a high lactate dehydrogenase plasma level. In all four, the diagnosis of disseminated histoplasmosis was made, in three of them by liver biopsy. Two patients had retinal abnormalities compatible with a systemic fungal infection. Three patients were treated successfully with antifungal agents. One patient died. Between 2000 and 2006, only 14 patients with HIV have been found to have histoplasmosis in the Netherlands. Although histoplasmosis is not endemic in the Netherlands, physicians are more likely to see cases because of a growing number of HIV -positive immigrants from endemic regions.

[Clinical reasoning and decision-making in practice. A young woman with fever, shortness of breath, and reduced consciousness]. / Klinisch denken en beslissen in de praktijk. Een jonge vrouw met koorts, benauwdheid en een gedaald bewustzijn.

A 23-year-old woman with mild psychomotor retardation presented with fever, coughing, reduced consciousness and a stiff neck. A chest X-ray revealed an infiltrate in the left lower lobe; the cerebrospinal fluid was cloudy with a mild pleocytosis. Ceftriaxone was prescribed and the fever subsided. On the second day of admission she had a seizure, and a paraparesis emerged. Despite changes in the antibiotic regimen, her clinical condition hardly improved. On the fifth day, antibodies against Mycoplasma pneumoniae were found to be strongly positive and the diagnosis was M. pneumoniae infection. This accounted for the pneumonia together with meningoencephalitis and a transverse myelitis. The antibiotics were switched to doxycycline and the clinical condition improved dramatically. Six weeks after discharge, the patient had made a complete recovery. In patients suffering from meningitis with an atypical presentation, uncommon causes of infection should be considered. Together with a pneumonia, M. pneumoniae, Chlamydia pneumoniae, Legionella pneumophila and Listeria monocytogenes should be high on the list of potential causes for bacterial meningitis.

Immune restoration disease in HIV-infected individuals receiving highly active antiretroviral therapy: clinical and immunological characteristics.

BACKGROUND: HIV-infected patients responding to HAART can show a diverse spectrum of symptoms caused by inflammatory reaction. The pathogenesis of this phenomenon, called immune restoration disease (IRD), is unclear. This study describes the spectrum of IRD and analyses the immunological and clinical parameters that could be related to its development. METHODS: In a retrospective, matched case-control study, 17 HIV-infected individuals who developed inflammatory symptoms < 12 months after initiation of HAART were included. HIV-infected controls were matched for age, gender and CDC classification. Factors included in the analysis were: CD4+ and CD8+ cell counts, deltaCD4+ and deltaCD8+, CD4/CD8 ratios, HIV-1-RNA load (VL), AVL and the number of CDC events prior to HAART. RESULTS: The median time after initiation of HAART and developing IRD (n = 17) was 72 days (range 2-319). In nine cases (53%) a mycobacterial infection was identified as the underlying cause. HAART was started at a mean CD4+ count (+/- SD) of 55 x 10(6) /l (+/- 59) and 85 x 10(6) /l (+/- 78.0) for cases and controls, respectively (p = 0.13). After initiation of HAART, the CD4+ count showed a 10.6 fold increase at the onset of IRD in the cases and a 2.7 fold increase in the controls in an equal period of time (p = 0.020). The other parameters analysed did not differ significantly between cases and controls. CONCLUSION: We conclude that the risk of developing IRD is associated with a high-fold increase in CD4+ lymphocytes. In this study, mycobacteria are the pathogens most frequently associated with IRD.

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.

Overlapping activators and repressors delimit transcriptional response to receptor tyrosine kinase signals in the Drosophila eye.

Regulated transcription of the prospero gene in the Drosophila eye provides a model for how gene expression is specifically controlled by signals from receptor tyrosine kinases. We show that prospero is controlled by signals from the EGF receptor DER and the Sevenless receptor. A direct link is established between DER activation of a transcription enhancer in prospero and binding of two transcription factors that are targets of DER signaling. Binding of the cell-specific Lozenge protein is also required for activation, and overlapping Lozenge protein distribution and DER signaling establishes expression in a subset of equivalent cells competent to respond to Sevenless. We show that Sevenless activates prospero independent of the enhancer and involves targeted degradation of Tramtrack, a transcription repressor.

[Authorship in manuscripts published in biomedical journals]. / La autoría en los manuscritos publicados en revistas biomédicas.

Multiauthorship shows an increasing trend in biomedical and other scientific journals. A main concern for editors, reviewers and readers is to find out whether all individuals enlisted as authors actually fulfill criteria for authorship as defined in the document "Uniform Requirements for Manuscripts Submitted to Biomedical Journals". Revista Médica de Chile is addressing this relevant topic with a combined strategy: (1) A retrospective analysis of the manuscripts published in the recent decades in the Revista will quantify and illustrate the local trend in multiauthorship; (2) A "Statement of accountability": signed by all authors in manuscripts submitted to the Revista, is in use since 1997; and (3) A new form of this "Statement of accountability" requests all authors to identify their personal involvement in the work represented by the manuscript. This information will be available to every person participating in the editorial assessment of the manuscript (editors and external reviewers) but during a trial period of six months authors will be allowed to object the publication of this data, stating the reasons for this objection. After six months the editors will evaluate the information collected and the self-declared role of every author enlisted. The terms "Author" and "Main author" will continue being used to designate participants because "contributor" (replacement alternative proposed by Rennie et al., currently in use by several leading general medical journals) has a different main meaning in Spanish than in English and it might have a negative effect.

[Acute coronary syndrome associated with Chlamydia pneumoniae pneumonia in two cases]. / Síndrome coronario agudo asociado a neumonía por Chlamydia pneumoniae, en dos casos.

Epidemiological and clinical studies attribute to Chlamydia pneumoniae infections a pathogenetic role in atherosclerotic vascular lesions. We report two patients in whom this infection was followed by acute coronary events. A 51 years old male presented with a right lower lobe pneumonia and a positive immunofluorescence serology for Chlamydia pneumoniae, with a IgM titer of 1/64. On the second day of evolution, he experienced an acute myocardial infarction. A coronary arteriography demonstrated a 80% obstruction of anterior coronary artery and an angioplasty was performed. A 84 years old male was admitted with a right lower lobe pneumonia and a positive serology for Chlamydia pneumoniae, with an IgM titer of 1/32. On the fourth day of evolution, he developed unstable angina with electrocardiographic changes. A coronary arteriography demonstrated a three vessel disease. In both cases, a tight chronological association was observed between Chlamydia pneumoniae infection and acute coronary events.

Immune reconstitution after 2 years of successful potent antiretroviral therapy in previously untreated human immunodeficiency virus type 1-infected adults.

Today's antiretroviral combination regimens can induce significant and sustained decreases in human immunodeficiency virus (HIV)-RNA levels, allowing the immune system to recover. To what extent immune reconstitution is possible and what factors determine the outcome have thus far not been resolved. We studied 19 subjects, treated for 2 years with protease inhibitor-containing triple therapy, who had a strong suppression of HIV-RNA levels. CD4+ T-cell numbers increased from medians of 170 to 420x106 cells/L, but in a number of subjects T-cell numbers did not further increase after week 72, without having reached normal values. Long-term CD4+ T-cell change was mainly caused by a slow but continuous increase in naive CD4+ T cells (CD45RA+CD62L+) and was predicted by the baseline number of these cells. Our data indicate that long-term immunological recovery is gradual, even during strong suppression of viral replication, not always complete, and dependent on the preexisting level of naive CD4+ T cells.

Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy. INCAS Study Group.

BACKGROUND: Current antiretroviral treatment can induce significant and sustained virological and immunological responses in HIV-1-infected persons over at least the short- to mid-term. OBJECTIVES: In this study, long-term immune reconstitution was investigated during highly active antiretroviral therapy. METHODS: Patients enrolled in the INCAS study in The Netherlands were treated for 102 weeks (range 52-144 weeks) with nevirapine (NVP) + zidovudine (ZDV) (n = 9), didanosine (ddl) + ZDV (n = 10), or NVP + ddl + ZDV (n = 10). Memory and naïve CD4+ and CD8+ T cells were measured using CD45RA and CD27 monoclonal antibodies (mAb), T-cell function was assayed by CD3 + CD28 mAb stimulation, and plasma HIV-1 RNA load was measured by ultra-direct assay (cut-off < 20 copies/ml). RESULTS: Compared to both double combination regimens the triple combination regimen resulted in the most sustained increase in CD4+ T cells (change in CD4+, + 253 x 10(6) cells/l; standard error, 79 x 10(6) cells/l) and reduction of plasma HIV-1 RNA. In nine patients (31%) (ddl + ZDV, n = 2; NVP + ddl + ZDV, n = 7) plasma HIV-1 RNA levels remained below cut-off for at least 2 years. On average, these long-term virological responders demonstrated a significantly higher increase of naïve and memory CD4+ T cells (P = 0.01 and 0.02, respectively) as compared with patients with a virological failure, and showed improved T-cell function and normalization of the naïve; memory CD8+ T-cell ratio. However, individual virological success or failure did not predict the degree of immunological response. T-cell patterns were independent of baseline CD4+ T-cell count, T-cell function, HIV-1 RNA load or age. Low numbers of naïve CD4+ T cells at baseline resulted in modest long-term naïve T-cell recovery. CONCLUSIONS: Patients with prolonged undetectable plasma HIV-1 RNA levels during antiretroviral therapy do not invariably show immune restoration. Naïve T-cell recovery in the setting of complete viral suppression is a gradual process, similar to that reported for immune recovery in adults after chemotherapy and bone marrow transplantation.

[Acute myocardial infarction: the evolving knowledge about the disease]. / Infarto agudo del miocardio: una enfermedad en plena evolución de conocimientos.

Important advances in the knowledge of pathophysiology and management of acute myocardial infarction have occurred lately. The results of large multicentric randomized trials allowed the introduction of new diagnostic techniques, patient stratification tools, drugs and treatment strategies to clinical practice. As a result, a significant reduction in mortality has been achieved. However there is a great variation in the adoption of the new diagnostic and therapeutic recommendations in different countries. In this issue of Revista Médica de Chile, a registry of patients with acute myocardial infarction treated in Chile between 1993 and 1995, is reported. The mean age of patients (62 +/- 12 years old), the proportion of males (74%) and the prevalence of risk factors is similar to that reported in series from developed countries. Similarly, 33% of patients received thrombolytic therapy, and the pattern of drug use was comparable. The 13.4% global mortality can be improved. An early consultation to health services when an acute myocardial infarction is suspected should be encouraged in the population. Likewise, treatment norms for health institutions should be devised.

[Coronary angioplasty and stent placement through the radial artery. Report of a case]. / Angioplastia coronaria e implante de stent a través de la arteria radial. Caso clínico.

Coronary angiography and percutaneous treatment of stenotic lesions have expanded in the last few years, due to availability of better diagnostic equipment. The femoral technique applied to this aims has prevailed, considering its efficacy, safety and wide acceptance. Since the beginning of this decade, an alternative access has been developed, in relation to miniaturization of the required elements to perform coronary diagnostic and therapeutic procedures. This new radial artery access is supported by multiple reports from many centers around the world that are increasingly using the technique. With this access it is possible to perform all the regular procedures done regularly through the femoral route. This case report illustrates a coronary angiography study through the radial access, followed by a stent implantation, through the same route.

[Subcutaneous heparin during the first trimesters of pregnancy in women with prosthetic heart valves]. / Heparina subcutánea durante el primer trimestre del embarazo en mujeres con prótesis valvulares cardíacas.

BACKGROUND: Oral anticoagulation therapy in pregnant women with prosthetic heart valves is associated with a greater risk of abortion, fetal malformations and thromboembolic complications. AIM: To assess the use of subcutaneous heparin in women with pregnancies of less than 12 weeks as an alternative to oral anticoagulation therapy. MATERIAL AND METHODS: Pregnant women were admitted to the hospital and coumarinics were replaced with not fractionated subcutaneous heparin in a dose of 10,000 IU every 12 hours, aiming at prolonging partial thromboplastin time, 2 or 2 1/2 times. During the hospitalization period, women were taught about the heparin injection technique. Coumarinics were restarted after week 13 of pregnancy until 10 days prior to the delivery date in which women were again admitted to the hospital and intravenous heparin was used until the delivery. RESULTS: Between 1991 and 1997, this protocol was used during ten pregnancies in seven women aged 19 to 36 years old. Five had a Starr-Edwards prosthesis, one had a mitral Björk-Shilley prosthesis and one, a double prosthesis (mitral Starr-Machi and aortic St Jude). Subcutaneous heparin was started in the fifth week of pregnancy in 1 case, in the sixth week in seven and in the seventh week in two. There was no maternal mortality and one transient ischemic attack without sequelae. One non compliant patient had a Björk Shilley prosthetic valve dysfunction that required a valve replacement at the twelfth week of pregnancy and she had a spontaneous abortion at week 15. Other patient had a pneumonia at week 37 and gave birth to a stillbirth. There were no fetal malformations. CONCLUSIONS: This therapeutic protocol can be used among Chilean patients, but must be restricted to compliant women and a strict surveillance must be maintained.

[Serum homocysteine levels in healthy Chilean adults]. / Niveles de homocisteína en adultos sanos chilenos.

BACKGROUND: Hyperhomocysteinemia is a newly recognized cardiovascular risk factor that is present in 10 to 20% of European and North American individuals. AIM: To measure homocysteine levels in healthy adults in Chile. SUBJECTS AND METHODS: Serum homocysteine levels were measured in healthy adults using a fluorimetric HPLC method. Folic acid, vitamin. B12, serum lipids, creatinine and glucose were also assessed. All subjects answered a dietary habits questionnaire. RESULTS: One hundred twenty eight subjects (90 female) aged 22 to 78 years old were studied. Homocysteine levels were 9.7 +/- 6.0 and 7.0 +/- 3.1 mumol/l in men and women respectively (p < 0.001). Folic acid levels were 6.1 +/- 2.7 and 6.1 +/- 2.9 ng/ml in men and women, and 24% of individuals had values below 4 ng/ml. Vitamin B12 levels were 393 +/- 147 and 393 +/- 163 pg/ml in the same groups. There was a negative correlation between homocysteine and folic acid levels and a positive correlation between homocysteine and creatinine levels. CONCLUSIONS: Homocysteine levels in healthy Chilean individuals are similar to those reported abroad. Low folic acid levels were found in 24% of subjects.

[Is the methodology of our original articles essentially inferior to similar papers published in English-speaking journals?]. / Es la metodología de nuestros trabajos de investigación esencialmente inferior a la de estudios similares en revistas que se publican en inglés?

Randomised controlled trials reported in languages other than English are generally excluded from systematic reviews. This exclusion is often based in the biased opinion that the strictness of methodology and the quality of assessment of the results are essentially inferior to similar articles reported in English. A study published in 1996 in The Lancet compared completeness of reporting, design characteristics, and analytical approaches of 229 randomised controlled trials published in English, French, German, Italian or Spanish, between 1989 and 1994. Eight of those trials had been published in Revista Medica de Chile. No significant differences were found in any single item analysed, between trials published in English and in other languages. The peer review system applied by a journal and the editorial selection of original articles to be published are crucial determinants of the overall quality of its publications. The role of local journals that publish in languages other than English is most important for the communities they are intended to serve and their contribution to disseminating scientific and other important aspects of medicine should be acknowledged and considered by readers, authors and editors in English-speaking countries, especially when these local journals belong to the mainstream literature included in the major international indexing services.

Hepatitis C virus infections in dialysis centers in The Netherlands: a national survey by serological and molecular methods.

A national survey of hepatitis C virus (HCV) infections among dialysis patients in The Netherlands was performed. The study involved 2,653 patients (2,108 hemodialysis patients and 545 chronic ambulatory peritoneal dialysis [CAPD] patients) from 39 of the 49 dialysis centers in the country. Patient sera were analyzed by both serological and molecular methods. Screening by a third-generation enzyme immunoassay (EIA) yielded 79 reactive sera. The presence of anti-HCV antibodies was confirmed in 70 patients by a line immunoassay. All seropositive samples were tested by reverse transcriptase PCR, and 57 samples were found to contain HCV RNA. Of the nine EIA-positive and line immunoassay-negative or indeterminate samples, four were HCV RNA positive. All seronegative samples were screened for the presence of HCV RNA in pools of five sera. Of 2,576 antibody-negative samples, 6 contained HCV RNA. All antibody-positive and RNA-positive samples were also tested by a second serological assay. The prevalence of HCV infections among Dutch dialysis patients as determined by serology or the presence of HCV RNA was 3% (80 of 2,653), i.e., 3.5% (73 of 2,108) in patients treated on hemodialysis and 1.3% (7 of 545) in patients on CAPD. Of these 80 HCV-infected dialysis patients, 67 (84%) were HCV RNA positive. Serological screening alone would have diagnosed only 70 infected patients. Therefore, antibody screening combined with detection of HCV RNA should be considered as the "gold standard" for diagnosing HCV infection in dialysis patients. The prevalence of HCV-infected patients in Dutch dialysis centers ranged from 0 to 8%, suggesting the existence of local risk factors for acquiring HCV infection. Genotyping analysis by reverse hybridization line probe assay revealed the presence of genotypes la (23%), 1b (46%), 2 (3%), 2a (13%), 2b (1%), 3a (7%), and 4a (4%). In four (6%) samples multiple genotypes were detected. The genotype distribution of HCV isolates among Dutch dialysis patients was similar to the distribution among nondialysis patients from the Benelux, except for subtype 1a, which was significantly more prevalent among dialysis patients. In only one center, a high prevalence of an uncommon genotype was suggestive of infection from a common source.

Decrease of HIV-1 RNA levels in lymphoid tissue and peripheral blood during treatment with ritonavir, lamivudine and zidovudine. Ritonavir/3TC/ZDV Study Group.

OBJECTIVES: Triple combination treatment of HIV-1 infection using two reverse transcriptase inhibitors and a protease inhibitor can result in significant and sustained decreases in the quantity of viral RNA in peripheral blood. Lymphoid tissue, however, constitutes the major reservoir of HIV in infected patients. Study of the viral burden in these tissues has provided additional insight in the efficacy of antiretroviral treatment. DESIGN: Patients were randomized into two groups in order to study differences in the development of resistance to reverse transcriptase inhibitors. Group I started treatment with all three drugs simultaneously. Group II started with ritonavir monotherapy, aiming at initial reduction in virus production before the addition of lamivudine and zidovudine 3 weeks later. METHODS: Changes in the amount of HIV in plasma and tonsillar lymphoid tissue during 24 weeks of treatment with ritonavir, lamivudine and zidovudine were studied by reverse transcriptase polymerase chain reaction. RESULTS: Thirty-three antiretroviral-naive HIV-infected patients were included for analysis. After 24 weeks, median CD4+ cell count increased by 152 x 10(6)/l and median plasma viral RNA levels decreased by at least 2.87 log10 copies/ml. In 88% of the patients remaining on treatment, plasma RNA levels were below the quantification limit of the assay used (mean, 2.4 log10 copies/ml). The lymphoid tissue viral burden, ranging from 9.16 to 8.52 log10 copies/g at baseline, was markedly reduced with at least 2.1 log10 copies/g by week 24 in the five patients analysed. Eight patients (24%) withdrew because of side-effects. In one patient in group II, ritonavir and lamivudine resistance-associated mutations developed. CONCLUSIONS: Treatment with this triple antiretroviral drug combination produced a durable and strong decrease of HIV-1 RNA burden in both plasma and lymphoid tissue.