Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients responding to highly active antiretroviral therapy.
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AIDS-Related Opportunistic Infections↗
Biomedical subjects
J Mallolas
Publications and source records attributed to J Mallolas.
Impact of switching from human immunodeficiency virus type 1 protease inhibitors to efavirenz in successfully treated adults with lipodystrophy.
We prospectively followed 20 consecutive patients with human immunodeficiency virus type 1 (HIV-1) with viral loads of <200 RNA copies/mL. These patients had been treated with 2 nucleoside reverse transcriptase inhibitors and > or =1 HIV-1 protease inhibitor for > or =3 months; they developed body changes consistent with lipodystrophy and requested they be switched from protease inhibitor to efavirenz. At baseline and every 3 months, we assessed the following: body mass index, waist-to-hip ratio, regional fat thickness (assessed by sonography), fasting total and high-density lipoprotein cholesterol, triglycerides, glucose, insulin, CD4(+) cells, and viral load. At baseline, hypertriglyceridemia (> or =200 mg/dL) was present in 17 (85%) patients, hypercholesterolemia (> or =200 mg/dL) in 14 (70%), and impaired fasting glucose (> or =110 mg/dL) in 8 (40%); CD4(+) T cells were 280x10(6) cells/L (range, 64-942x10(6) cells/L). HIV-1 RNA had been at <200 copies/mL for a median of 14 months (range, 3-24 months). Six months after switching to efavirenz, there was a reduction in triglyceride levels (a decrease of 31%; P=.03) and fasting insulin resistance index (a decrease of 28%; P=.03), but total and high-density lipoprotein cholesterol and glucose did not change. Waist-to-hip ratio decreased from 0.92 to 0.87 (P=.06). Subcutaneous fat thickness did not change. CD4(+) cells remained stable (363x10(6) cells/L; range, 102-741x10(6) cells/L; P=.65). Nineteen patients (95%) had HIV-1 RNA levels that remained at <200 copies/mL. Although CD4(+) response and viral suppression remained preserved after 6 months of switching from protease inhibitor to efavirenz, the benefits of this approach on the evolution of lipodystrophy were limited, and our findings do not support its routine recommendation to treat lipodystrophy.
Adipose Tissue↗
Dose-finding study of once-daily indinavir/ritonavir plus zidovudine and lamivudine in HIV-infected patients.
BACKGROUND: Strategies for treatment of HIV need to be considered in terms of combining potency, safety, and convenience of dosage. However, regimens including once-daily protease inhibitors are not yet available. We have performed a pilot study to determine an indinavir/ritonavir (IND/RTV) regimen for once-daily dosing, by monitoring plasma levels. METHODS: Antiretroviral-naive HIV-infected adults were eligible. Therapy was zidovudine/lamivudine 1 pill twice daily plus IND/RIT (liquid formulation) 800/100 mg twice daily with food. At 4-week intervals, plasma levels were measured and dosage of IND/RIT switched to 1000/100 mg daily and then 800/200 mg daily. If 12-hour minimum concentrations (Cmin12h) of IND were too low (<0.1 microg/ml) with IND/RIT 1000/100 mg once daily in the first half of the patients, it was planned to switch directly to 800/200 mg once daily in the other half. RESULTS: In all, 27 patients were recruited. Mean baseline CD4+ lymphocyte count was 107 x 106/L (range, 4-623 x 106/L). Eleven patients (40%) discontinued the study medication within the first 4 weeks due to clinical progression (n = 3) or grade 1-2 RTV related side effects (n = 8). Nine patients (group A) switched from 800/100 mg twice daily to 1000/100 mg once daily and then to 800/200 mg once daily. Seven patients (group B) switched directly to 800/200 mg once daily. At week 32, viral load was <5 copies/ml in 15 of 16 patients (94%). RTV levels were always <2.1 microg/ml. The mean and 95% confidence interval for IND Cmin and Cmax in microg/ml was: using IND/RTV 800/100 mg twice daily (n = 16) 1.4 (0.5-2.3) and 6.7 (4.4-9.1), respectively; using IND/RTV 1000/100 mg once daily (n = 9) 0.18 (0-0.41) and 8.6 (3.3-14), respectively; and using 800/200 mg once daily (n = 16) 0.38 (0-0.9), and 7.5 (0.8-14.8). For all 16 patients who received IND/RTV 800/100 mg twice daily, the Cmin value for IND was >/=0.1 microg/ml. Conversely, IND Cmin was <0.1 microg/ml in 4 of 9 receiving 1000/100 mg once daily but in only 1 of 16 receiving 800/200 mg once daily. CONCLUSION: Once-daily regimen of IND/RIT is feasible and deserves further evaluation in larger randomized trials. Liquid formulation of RIT was not well tolerated by our antiretroviral-naive patients despite lower than suggested doses.
Adult↗
Molecular study of the PAK3 and GDI1 genes in nonsyndromic X-linked mental retardation spanish patients.
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Base Sequence↗
Rare variants in the promoter of the fragile X syndrome gene (FMR1).
Fragile X syndrome, the most common form of familial mental retardation, is mainly caused by the expansion of an unstable region of CGG repeats in the 5' untranslated region of the FMR1 (Fragile X Mental Retardation-1) gene. Molecular tools to detect an abnormal CGG expansion in FMR1 include Southern blot hybridization and PCR amplification. Southern blotting with the StB12.3 probe and Eco RI/Eag I double digestion is widely used as a routine test for fragile X syndrome diagnosis in laboratories around the world. A patient with mental retardation of unknown origin showed absence of digestion for Eag I due to a -149C-->G substitution in the CpG island of the FMR1 gene, which destroys that restriction enzyme site. Screening for other changes around that region also detected a -154insGGC in a patient with a phenotype highly suggestive of fragile X syndrome but without CGG expansion. Expression studies did not show any abnormal changes in FMR1 function. In summary, we have identified two different changes (a C to G substitution at -149 and a GGC insertion at -154) in the promoter of the FMR1 gene. These are the first variants described in the promoter of the FMR1 gene.
Adolescent↗
Detection of the fragile X syndrome protein for the evaluation of FMR1 intermediate alleles.
Molecular screening programs in mentally retarded individuals have been performed in several populations worldwide. One finding has been an excess of FMR1 intermediate alleles in a population with learning difficulties. However, other published reports with similar characteristics did not corroborate those previous results. In order to contribute additional data from our population, we studied 563 patients affected with nonspecific mental retardation (MRX) that did not present a CGG expansion in the FMR1 gene and 208 individuals as a control population. Forty MRX patients presented alleles within the intermediate range. Among them, one case showed a pattern of expression of the FMR1 protein (FMRP) concordant with a fragile X syndrome case with an intermediate allele/full mutation mosaicism, although it was not detected by Southern blot analysis. Statistical analysis was performed again showing no statistically significant difference regarding the intermediate allele frequency in the MRX and control populations. This finding is in agreement with the hypothesis that the incidence of intermediate FMR1 alleles in MRX populations does not seem to be higher than in control populations, and it emphasizes the importance of FMRP detection as a diagnostic tool for fragile X syndrome.
Alleles↗
Loss of heterozygosity in renal and hepatic epithelial cystic cells from ADPKD1 patients.
Autosomal dominant polycystic kidney disease (ADPKD) is one of the commonest genetic diseases in man, affecting 1:1000 individuals in the Caucasian population. It is caused by mutations in the PKD1 or PKD2 genes. Recently, controversial data regarding the mutational mechanism underlying cyst initiation have been reported: genetic analyses have shown that second somatic mutations may lead to cyst formation (detected as microsatellite loss of heterozygosity, LOH, and point mutations), but immunohistochemical studies show strong immunoreactivity for polycystin in some cysts. In order to further characterise this matter we have analysed 211 cysts from seven different patients for LOH, we have detected a 13.3% LOH for PKD1. This loss was specific to PKD1 as no LOH was detected when other chromosomal regions were studied. Whenever linkage analysis has been possible, it has been proved that the lost allele corresponded to the wild-type. Our data supports previous results in the two-hit theory for ADPKD due to the large number of cysts studied. ADPKD would occur through a recessive cellular mechanism. The probability of cyst development would depend on the probability of mutation in the second allele. The different phenotypical expression of the same mutation reported in ADPKD could be due to the different tendency of inactivation in the second allele in each individual.
Cells, Cultured↗
Intravenous cidofovir for compassionate use in AIDS patients with cytomegalovirus retinitis. Spanish Cidofovir Study Group.
We report the compassionate use of intravenous cidofovir for the treatment of cytomegalovirus retinitis in 51 patients with AIDS who were receiving highly active antiretroviral therapy (HAART). After a median of 9 doses, 49 patients showed no retinitis activity. However, treatment was stopped in 17 patients because of adverse reactions and in 5 patients for other reasons. Two deaths were considered related to the drug. Iritis developed in 21 patients (41.2%), a frequency higher than that reported during the pre-HAART era. Patients with iritis had median CD4 cell counts-both at nadir and at the initiation of cidofovir therapy-approximately 3 times higher than those for patients without iritis (P=.003 and P=.05, respectively). Our study confirms the efficacy of cidofovir therapy for AIDS-associated cytomegalovirus retinitis. Our data suggest that the risk of iritis may be higher for patients with better immunological status, probably because of their enhanced ability to mount an inflammatory response.
AIDS-Related Opportunistic Infections↗
Antineutrophil antibodies associated with ulcerative colitis interact with the antigen(s) during the process of apoptosis.
BACKGROUND: Cell death by apoptosis seems to be an important mechanism for translocation to the cell surface of a variety of intracellular components capable of inducing autoantibody production. AIMS: To identify the cellular location of antigen (Ag)-antineutrophil cytoplasmic antibodies (ANCA) in non-apoptotic human neutrophils, and to assess if ANCA associated with ulcerative colitis reacts with neutrophil antigen(s) during neutrophil apoptosis. The cellular distribution of Ag-ANCA in apoptotic neutrophils was also investigated. METHODS: Sera from 18 ulcerative colitis patients known to be positive for perinuclear IgG-ANCA (titre > or =1/320), as assessed by indirect immunofluorescence (IIF), were analysed by immunofluorescent confocal laser scanning microscopy. ANCA were identified with fluorescein isothiocyanate (FITC) and tetramethylrhodamine isothiocyanate (TRITC) in non-apoptotic and apoptotic neutrophils, respectively. Apoptotic and non-apoptotic DNA was labelled with FITC and propidium iodide, respectively. Cycloheximide was added to polymorphonuclear leucocyte culture to induce apoptosis. RESULTS: Three patterns of scanning laser immunofluorescence microscopy in non-apoptotic neutrophils were observed with respect to cellular ulcerative colitis associated ANCA distribution: (1) diffuse nuclear localisation (16.7%); (2) nuclear localisation in the nuclear periphery (50%); and (3) mixed nuclear and cytoplasmic localisation (33.4%). In all sera ANCA fluorescence colocalised almost completely with apoptotic DNA, with persistence of a diffuse and intense fluorescence. No significant changes in ANCA titres were found in non-apoptotic neutrophils. CONCLUSIONS: The antigen(s) of ANCA associated with ulcerative colitis seems to be localised in most cases in the neutrophil nucleus. The almost identical colocalisation of ANCA and apoptotic cleaved DNA suggests that intracellular DNA redistribution during neutrophil apoptosis may play a role in antigen exposure to the immune system and ANCA production in ulcerative colitis.
Antibodies, Antineutrophil Cytoplasmic↗
Single-strand conformation polymorphism analysis in the FMR1 gene.
The fragile X syndrome is due to an expansion of the CGG trinucleotide repeat in the FMR1 gene and hypermethylation of its 5' upstream CpG island in about 95% of the cases. The remaining 5% of cases correspond to other molecular alterations in FMR1 gene such as partial or complete deletions, or point mutations within the coding sequence. We selected 31 patients with clinical manifestations of fragile X syndrome, scoring 16 or more in Hagerman's checklist, but without the CGG expansion. We performed single-strand conformation polymorphism analysis using a nonradioactive technique (silver staining) and we detected six anomalous migrations that, by sequence analysis, corresponded to six nucleotide changes. We screened two different populations (control and fragile X) for these changes, and concluded that they correspond to five new polymorphisms within the FMR1 gene and to one possible synonymous mutation.
Fragile X Messenger Ribonucleoprotein 1↗
[Disseminated cryptococcosis in patients with AIDS. Prognostic factors of poor outcome].
BACKGROUND: The objectives of this study were to analyze the changes in the incidence of cryptococcal disease in the last 10 years (1987-1997) and to assess the factors of poor prognosis in HIV-1 infected patients. PATIENTS AND METHODS: Clinical records of HIV-1 infected patients diagnosed with cryptococcal infection from June 1987 to December 1997 at Hospital Clinic i Provincial in Barcelona, Spain, were examined. An univariate and multivariate analysis of the predictors of poor outcome was performed. RESULTS: Sixty clinical records were analyzed. The number of cases per 100 exposed patients per year decreased from 1991 to 1993 and, afterwards, decreased again from 1996. Fifty patients had a resolution of clinical symptoms, 17 out of this 50 patients (34%) had a relapse. Factors associated with a higher risk of relapse were a positive blood culture and cryptococcal antigen title in cerebrospinal fluid above 1/1.024. CONCLUSIONS: The decrease in the number of cases of cryptococcal infection coincides with the broad use of triazole antifungal drugs for oral candidiasis (1990-1991) and, afterwards, with the initiation of highly active antiretroviral therapy (1996). The best predictors of relapse are a positive blood cryptococcal culture and a high titter of cryptococcal antigen.
AIDS-Related Opportunistic Infections↗
Isolation of pig mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene promoter: characterization of a peroxisome proliferator-responsive element.
Low expression of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase gene during development correlates with an unusually low hepatic ketogenic capacity and lack of hyperketonaemia in piglets. Here we report the isolation and characterization of the 5' end of the pig mitochondrial HMG-CoA synthase gene. The 581 bp region proximal to the transcription start site permits transcription of a reporter gene, confirming the function of the promoter. The pig mitochondrial HMG-CoA synthase promoter is trans-activated by the peroxisomal proliferator-activated receptor (PPAR), and a functional response element for PPAR (PPRE) has been localized in the promoter region. Pig PPRE is constituted by an imperfect direct repeat (DR-1) and a downstream sequence, both of which are needed to confer PPAR-sensitivity to a thymidine kinase promoter and to form complexes with PPAR.retinoid X receptor heterodimers. A role of PPAR trans-activation in starvation-associated induction of gene expression is suggested.
Amino Acid Sequence↗
Withdrawal of Mycobacterium avium complex suppressive therapy in HIV-1-infected patients on highly active antiretroviral therapy.
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AIDS-Related Opportunistic Infections↗
Biochemical phenotype and its relationship with genotype in hyperphenylalaninemia heterozygotes.
The molecular detection of heterozygotes for hyperphenylalaninemia is difficult due to the large number of mutations in the PAH gene. For this reason, various indexes that measure plasma concentrations of phenylalanine (Phe) and tyrosine (Tyr), as an expression of Phe metabolizing capacity, have been used for the detection of carriers for mutations in the PAH gene. In this study, we contrast the biochemical and the molecular data in order to know if this is an accurate method. Familial genetic analysis of the PAH gene in 93 parents of hyperphenylalaninemia patients allows the study of the biochemical expression of the different mutant alleles. Molecular study was performed by SSCP and DGGE analyses of PAH genes, and plasma amino acid analysis by ion-exchange chromatography. Then the biochemical and molecular data were compared by the Student t test. The results found show a relationship between the severity of PKU/HPA mutations in the PAH gene and their biochemical phenotype (Phe/Tyr, Phe2/Tyr) as an expression of the residual enzymatic activity. The study adds further information about the prevalent Mediterranean allele mutations.
Female↗
Mutational spectrum of phenylalanine hydroxylase deficiency in the population resident in Catalonia: genotype-phenotype correlation.
Hyperphenylalaninemia (HPA) is a group of diseases characterized by the persistent elevation of phenylalanine levels in tissues and biological fluids. It is an autosomal recessive disorder affecting 1 in 10,000 individuals in Caucasian populations and about 1 in 6,600 in Catalonia. We report the mutational spectrum of phenylalanine hydroxylase deficiency in the population living in Catalonia and the genotype-phenotype correlation. The molecular study was performed in 383 samples corresponding to 115 patients from 99 unrelated families and 268 relatives. We have characterized 90% of the mutant alleles; there were 57 different mutations, 49 of which have previously been described, 8 being novel mutations and two being large deletions. The 57 mutations detected corresponded to: five nonsense, seven frameshift, and eight splice defects, the remainder being missense mutations. These mutations cause 72 different genotypes in the 83 families characterized, confirming the mutational heterogeneity of phenylketonuria (PKU) in the Mediterranean population. According to our biochemical classification, our HPA population is composed of 40 PKU (35%), 36 variant PKU (31%), and 39 non-PKU HPA (34%). Mutations such as IVS 10, A403 V, and E390G correlated as expected with the phenotype and the predicted residual activity in vitro. However, in four cases (165 T, V388 M, R261Q, and Y414 C), the observed metabolic phenotype was not consistent with the predicted genotypic effect. The identification of the mutations in the PAH gene and the genotype-phenotype correlation should facilitate the evaluation of metabolic phenotypes, diagnosis, implementation of optimal dietary therapy, and determination of prognosis in the patients and genetic counselling for the patient's relatives.
Alleles↗
Influence of environmental temperature on incidence of indinavir-related nephrolithiasis.
We analyzed the influence of temperature, humidity, and atmospheric pressure on the 1-year incidence of nephrolithiasis among human immunodeficiency virus type 1-infected patients treated with indinavir. One hundred three patients (13.6%) developed 326 episodes of nephrolithiasis. Eighty-two patients (79.6%) had more than one episode (range, two to seven episodes). The overall incidence ranged from 0 to 10.2 episodes per 100 patients exposed per month. There was a significant correlation between temperature and the overall incidence of nephrolithiasis and the incidence of recurrences but not with the incidence of first episodes. Nephrolithiasis was not related to humidity or atmospheric pressure. Our data support the standard recommendation of drinking at least 1.5 L of water daily to prevent nephrolithiasis in most patients treated with indinavir irrespective of meteorologic factors. However, the risk of nephrolithiasis is higher for a certain subgroup of patients when the environment is hot irrespective of adequate water intake.
Atmospheric Pressure↗
[Evaluation of the efficacy of anti-retroviral treatment. Publication of clinical trials].
BACKGROUND: Although it is true that the practice of medicine is a combination of both science and art, clinical decisions regarding antiretroviral treatment should be based on scientifically validated recommendations by data obtained from patients in randomized and controlled clinical trials. Moreover, the information that is currently available regarding antiretroviral treatment is enormous and in some cases contradictory. Therefore, it appears reasonable to take into account that, without forgetting recent results from studies presented at congresses, symposia, and other meetings, the most important data when determining recommendations on the treatment of patients infected by HIV should be those published in renowned journals, which are submitted for a strict "peer review" of the publication. Nevertheless, it is also true that this review process may take months, invalidating the results from a "current news" point of view, especially in an area with a rapid turnover of knowledge as is antiretroviral treatment. METHODS: Systematic review of the literature published evaluating antiretroviral treatment. RESULTS: Over the last 10 years, we have witnessed how mono and bitherapies against the HIV have gradually been neglected, although short-term results had been obtained, favoring triple combinations which usually include two nucleoside analogues and a potent protease inhibitor. In general, this therapeutic practice accounts for the impressive decrease in morbi-mortality in patients infected by HIV which has been observed in the Western world. Globally, the most notable results published to this date in terms of antiretroviral efficacy and good tolerability compared to other highly effective alternatives, are possibly those related with indinavir in association with AZT plus 3TC. Despite this fact, on occasions the duration of these long term treatments becomes complicated due to the appearance of adverse effects, although a substitution of same by less potent alternatives is not possible without affecting antiviral efficacy. Finally, it should be noted that all these exceptionally good results are obtained with the treatment with protease inhibitors and triple therapy have set the pace for a substantial immunological improvement allowing for the possibility of discontinuing prophylaxis therapy against different pathogens such as, e.g. primary prophylaxis against P. carinii.
AIDS-Related Opportunistic Infections↗
Predictive factors influencing peak viral load drop in response to nucleoside reverse transcriptase inhibitors in antiretroviral-naive HIV-1-infected patients.
Therapy with two nucleoside reverse transcriptase inhibitors (NRTI), the backbone of triple combinations, is still widely used in early stages of HIV-1 disease. However, factors influencing virologic response need to be further analyzed, to test the hypothesis that the reduction of plasma RNA viremia with NRTI may be greater in patients with higher baseline viral load (BVL) and to analyze the predictive factors of viral load drop below detection (200 HIV RNA copies/ml of plasma). Selected for the study were 169 HIV-1-infected antiretroviral therapy-naive patients with CD4+ T-lymphocyte counts ranging from 6 to 1040/microl coming from three randomized studies comparing the efficacy of monotherapy (zidovudine [ZDV], 250 mg every 12 hours; N=40) versus two-drug therapy consisting of ZDV (250 mg every 12 hours) with dideoxycytidine (ddC, 0.75 mg every 8 hours) or didanosine (ddI, 200 mg every 12 hours; N=129). Viral load was measured at 1, 3, and 6 months by polymerase chain reaction (PCR). A linear regression model was used to analyze the relation between BVL and the peak reduction of plasma RNA viremia. The variables included in a logistic regression model to determine the likelihood of VLs dropping below detection levels were age, gender, risk group for HIV-1 infection, baseline CD4+ lymphocyte count, BVL, clinical status (AIDS versus non-AIDS), HIV-1 phenotype (syncytium-inducing [SI] versus non-syncytium-inducing [NSI]) and type of treatment (monotherapy versus double therapy). The peak reduction of VL was related to baseline level following a linear model in both monotherapy and double-therapy regimens. In the subgroup of patients treated with two NRTIs, the regression line that fitted best with the data was log10 (peak reduction)=1.8-0.36 log10 (BVL) (F=23.5; p < .0001). This indicates that for every increase of 1 log10 of BVL, the peak reduction would be of 0.64 log10 greater. Forty-nine (29%) of the 169 patients dropped to <200 copies/ml. The likelihood of dropping below detection level was significantly greater in those receiving double therapy versus monotherapy (odds ratio [OR]=16.1; 95% confidence interval [CI], 2-128), in those with baseline CD4+ lymphocyte count >350/microl (OR=2.28; 95% CI, 1.1-4.9) and in those with BVL <10,000 HIV-1 RNA copies/ml (OR= 2.25; 95% CI, 1.1-6.1). None of the 13 patients with an SI phenotype at baseline dropped below detection levels. The reduction of VL in response to two NRTIs was greater in those patients with a higher level of BVL. In conclusion, peak reduction below detection in response to NRTI can be predicted and is associated with double therapy, with a baseline CD4+ cell count >350/microl and with a BVL <10,000 RNA copies/ml.
Adult↗