Acquired Immunodeficiency Syndrome: Gatell JM

Iribarren JA, Labarga P, Rubio R, Berenguer J, Miró JM, Antela A, González J, Moreno S, Arrizabalaga J, Chamorro L, Clotet B, Gatell JM, López-Aldeguer J, Martínez E, Polo R, Tuset M, Viciana P, Santamaría JM, Kindelán JM, Ribera E, Segura F, Anonymous00086, Anonymous00087. · Hospital Donostia, San Sebastián, Spain. · Enferm Infecc Microbiol Clin. · Pubmed #15596051 links to  free full text

Abstract: OBJECTIVE: This consensus document is an update of antiretroviral therapy (ART) recommendations for adult patients infected with the human immunodeficiency virus (HIV). METHODS: To formulate these recommendations, a panel composed of members of the Grupo de Estudio de Sida (GESIDA; AIDS Study Group) and the Plan Nacional sobre el Sida (PNS; Spanish AIDS Plan) reviewed the advances in current understanding of the pathophysiology of HIV, the safety and efficacy findings from clinical trials, and the results from cohort and pharmacokinetic studies published in biomedical journals or presented at scientific meetings over the last years. Three levels of evidence were defined according to the source of the data: randomized studies (level A), cohort or case-control studies (level B), and expert opinion (level C). The decision to recommend, consider or not recommend ART was established in each of these situations. RESULTS: ART consisting of at least three drugs is currently the initial treatment of choice for chronic HIV infection. These regimens should include 2 NRTI + 1 NNRTI or 2 NRTI + 1 PI. Initiation of ART is recommended in patients with symptomatic HIV infection. In asymptomatic patients, initiation of ART is recommended on the basis of CD4+ lymphocyte counts per L and plasma viral load, as follows: 1) Therapy should be started in patients with CD4+ counts of < 200 cells/microL; 2) Therapy should be started in most patients with CD4+ counts of 200-350 cells/microL, although it can be delayed when CD4+ count persists at around 350 cells/microL and viral load is low; and 3) Initiation of therapy can be delayed in patients with CD4+ counts of > 350 cells/microL. The initial objective of ART is to achieve an undetectable viral load. Adherence to therapy plays an essential role in maintaining the antiviral response. Because of the development of cross resistance, therapeutic options are limited when ART fails. Genotype studies are useful in these cases. Toxicity is a limiting factor in the use of ART, although the benefits outweigh the risks. In addition, the criteria for the use of ART are discussed in situations of acute infection, pregnancy, and post-exposure prophylaxis, and in the management of co-infection of HIV with HCV or HBV. CONCLUSIONS: CD4+ lymphocyte count is the most important reference factor for initiating ART in asymptomatic patients. The large number of available drugs, the increased sensitivity of tests to monitor viral load, and the possibility to determine viral resistance is leading to a more individualized approach to therapy.

Yeni PG, Hammer SM, Carpenter CC, Cooper DA, Fischl MA, Gatell JM, Gazzard BG, Hirsch MS, Jacobsen DM, Katzenstein DA, Montaner JS, Richman DD, Saag MS, Schechter M, Schooley RT, Thompson MA, Vella S, Volberding PA. · Hôpital Bichat-Claude Bernard, Department of Infectious Diseases, 46 Rue Henri-Huchard, Paris, Cedex 18 France 75877. · JAMA. · Pubmed #12095387 No free full text.

Abstract: OBJECTIVE: New information warrants updated recommendations for the 4 central issues in antiretroviral therapy: when to start, what drugs to start with, when to change, and what to change to. These updated recommendations are intended to guide practicing physicians actively involved in human immunodeficiency virus (HIV)- and acquired immunodeficiency syndrome (AIDS)-related care. PARTICIPANTS: In 1995, physicians with specific expertise in HIV-related basic science and clinical research, antiretroviral therapy, and HIV patient care were invited by the International AIDS Society-USA to serve on a volunteer panel. In 1999, others were invited to broaden international representation. The 17-member panel met regularly in closed meetings between its last report in 2000 and April 2002 to review current data. The effort was sponsored and funded by the International AIDS Society-USA, a not-for-profit physician education organization. EVIDENCE AND CONSENSUS PROCESS: The full panel was convened in late 2000 and assigned 7 section committees. A section writer and 3 to 5 section committee members (each panel member served on numerous sections) identified relevant evidence and prepared draft recommendations. Basic science, clinical research, and epidemiologic data from the published literature and abstracts from recent (within 2 years) scientific conferences were considered by strength of evidence. Extrapolations from basic science data and expert opinion of the panel members were included as evidence. Draft sections were combined and circulated to the entire panel and discussed in a series of full-panel conference calls until consensus was reached. Final recommendations represent full consensus agreement of the panel. CONCLUSIONS: Because of increased awareness of the activity and toxicity of current drugs, the threshold for initiation of therapy has shifted to a later time in the course of HIV disease. However, the optimal time to initiate therapy remains imprecisely defined. Availability of new drugs has broadened options for therapy initiation and management of treatment failure, which remains a difficult challenge.

Rubio R, Berenguer J, Miró JM, Antela A, Iribarren JA, González J, Guerra L, Moreno S, Arrizabalaga J, Clotet B, Gatell JM, Laguna F, Martínez E, Parras F, Santamaría JM, Tuset M, Viciana P. · Hospital 12 Octubre, Madrid, Spain. · Enferm Infecc Microbiol Clin. · Pubmed #12084354 links to  free full text

Abstract: OBJECTIVE: To provide an update of recommendation on antiretroviral treatment (ART) in HIV-infected adults.Methods. These recommendations have been agreed by consensus by a committee of the spanish AIDS Study Group (GESIDA) and the National AIDS Plan. To do so, advances in the physiopathology of AIDS and the results on efficacy and safety in clinical trials, cohort and pharmacokinetics studies published in biomedical journals or presented at congresses in the last few years have been reviewed. Three levels of evidence have been defined according to the data source: randomized studies (level A), case-control or cohort studies (level B) and expert opinion (level C). Whether to recommend, consider, or not to recommend ART has been established for each situation. RESULTS: Currently, ART with combinations of at least three drugs constitutes the treatment of choice in chronic HIV infection. In patients with symptomatic HIV infection, initiation of ART is recommended. In asymptomatic patients initiation of ART should be based on the CD41/mL lymphocyte count and on the plasma viral load (PVL): a) in patients with CD41 lymphocytes < 200 cells/mL, initiation of ART is recommended; b) in patients with CD41 lymphocytes between 200 and 300 cells/mL, initiation of ART should, in most cases, be recommended; however, it could be delayed when the CD41 lymphocyte count remains close to 350 cells/mL and the PVL is low, and c) in patients with CD41 lymphocytes > 350 cells/mL, initiation of ART can be delayed. The aim of ART is to achieve an undetectable PVL. Adherence to ART plays a role in the durability of the antiviral response. Because of the development of cross-resistance, the therapeutic options in treatment failure are limited. In these cases, genotypic analysis is useful. Toxicity limits ART. The criteria for ART in acute infection, pregnancy and postexposure prophylaxis and in the management of coinfection with HIV and hepatitis C and B virus are controversial. CONCLUSIONS: The current approach to initiating ART is more conservative than in previous recommendations. In asymptomatic patients, the CD41 lymphocyte count is the most important reference factor for initiating ART. Because of the considerable number of drugs available, more sensitive monitoring methods (PVL) and the possibility of determining resistance, therapeutic strategies have become much more individualized.

Miró JM, Antela A, Arrizabalaga J, Clotet B, Gatell JM, Guerra L, Antonio Iribarren J, Laguna F, Moreno S, Parras F, Rubio R, Santamaría JM, Viciana P, Anonymous00076. · Hospital Clínic Universitari, Barcelona. · Enferm Infecc Microbiol Clin. · Pubmed #11153204 links to  free full text

Abstract: OBJECTIVE: To update the recommendations for antiretroviral therapy (ART) in adult HIV-infected persons according to the new scientific advances and the existence of new antiretroviral drugs in the last two years. METHODS: The ART recommendations have been condensed by a panel of experts from the Spanish AIDS Study Group (Grupo de Estudio de Sida-GESIDA) of the Spanish Infectious Diseases and Clinical Microbiology Society (SEIMC) and from the Clinical Advisory Panel (CAP) of the Secretariat of the Spanish National Plan on AIDS (SPNS) of the Ministry of Health. Three levels of evidence have been established depending if the data came from randomized and controlled studies, from cohort or case-control studies or from descriptive studies and expert opinions, for that purpose we have reviewed the advanced in HIV pathophysiology and results of efficacy (clinical, virologic and immunologic) and security (toxicity) from clinical trials involving ART lasting at least 12 months, from cohort studies and pharmacokinetic and security data of antoiretrovírico drugs, presented in international conferences or published in biomedical journals in the last two years. In each situation we have established either to recommend or to consider or not recommend ART. RESULTS: Nowadays, ART consistent of at least three drugs constitutes the election therapy for chronic HIV infection, since it delays clinical progression, increases significantly the survival and diminishes hospital admissions and associated costs. The decision to start ART must be based upon three elements: presence or absence of symptoms, plasma vírica load and CD4+ cells counts. Thus, in asymptomatic cases with a high CD4+ cells count (> 500/microliter) and low vírica load (< 10,000 copies/ml by branched DNA bDNA or < 20,000 copies/ml by reverse-transcription polymerase chain reaction [RT-PCR] or nucleic acid sequence based amplification [NASBA]) we recommend to delay ART. In symptomatic patients we recommend to start it, and in asymptomatic patients, we could recommend or consider ART initiation depending on the risk of progression, established by the vírica load and the CD4+ cells count. In any case, if therapy is started, the objective must be to reach an indetectable vírica load (< 50 copies/ml). The adherence to ART plays a key role for its initial moment and for the duration of the antiviral response. ART can achieve a restoration of cellular immunity inb the advanced patients. There are few therapeutic options in failing patients due to cross-resistance. Resistance studies can be useful in this setting. The toxicity (lypodistrophy) is a new and limiting factor of ART which requires to look for new therapeutic options. ART criteria for acute infection, pregnancy, post-exposure prophylaxis and when to use resistance testing are discussed. CONCLUSIONS: In this moment, there is a more conservative attitude towards starting ART than in previous recommendations in which a virus eradication was considered. On the other hand, the high number of disposable drugs, the more sensitive monitorization methods (plasma vírica load) and the possibility of performing resistance studies make therapeutic strategies more dynamic and individualized for each patient and situation. In any case, it is mandatory to ensure a perfect adherence to ART from the patients.

Miró JM, Antela A, Arrizabalaga J, Clotet B, Gatell JM, Guerra L, Iribarren JA, Laguna F, Moreno S, Parras F, Rubio R, Santamaría JM, Viciana P. · Hospital Clínic Universitari, Barcelona. · Enferm Infecc Microbiol Clin. · Pubmed #11109725 links to  free full text

Abstract: OBJECTIVE: To update the recommendations for antiretroviral therapy in adult HIV-infected persons according to the new scientific advances and the existence of new antiretroviral drugs in the last two years. METHODS: The antiretroviral therapy recommendations have been condensed by a panel of experts from the Spanish AIDS Study Group (Grupo de Estudio de sida-GESIDA) of the Spanish Infectious Diseases and Clinical Microbiology Society (SEIMC) and from the Clinical Advisory Panel of the Secretariat of the Spanish National Plan on AIDS (SPNS) of the Ministry of Health. Three levels of evidence have been established depending if the data came from randomised and controlled studies, from cohort or case-control studies or from descriptive studies and expert opinions. For that purpose we have reviewed the advances in HIV pathophysiology and results of efficacy (clinical, virologic and immunologic) and security (toxicity) from clinical trials involving antiretroviral therapy lasting at least 12 months, from cohort studies and pharmacokinetic and security data of antiretroviral drugs, presented in international conferences or published in biomedical journals in the last two years. In each situation we have established either to recommend or to consider or not recommend antiretroviral therapy. RESULTS: Nowadays, antiretroviral therapy consisting of at least three drugs constitutes the election therapy for chronic HIV infection, since it delays clinical progression, increases significantly the survival and diminishes hospital admissions and associated costs. The decision to start antiretroviral therapy must be based upon three elements: presence or absence of symptoms, plasma viral load and CD4+ cells counts. Thus, in asymptomatic cases with a high CD4+ cells count (> 500/microL) and low viral load (< 10,000 copies/ml by branched DNA [bDNA] or < 20,000 copies/ml by reverse-transcription polymerase chain reaction [RT-PCR] or nucleic acid sequence based amplification [NASBA]) we recommend to delay antiretroviral therapy. In symptomatic patients we recommend to start it, and in asymptomatic patients, we could recommend or consider antiretroviral therapy initiation depending on the risk of progression, established by the viral load and the CD4+ cells count. In any case, if therapy is started, the objective must be to reach an undetectable viral load (< 50 copies/ml). The adherence to antiretroviral therapy plays a key role for its initial moment and for the duration of the antiviral response, antiretroviral therapy can achieve a restoration of cellular immunity in the advanced patients. There are few therapeutic options in failing patients due to cross-resistance. Resistance studies can be useful in this setting. The toxicity is a new and limiting factor of antiretroviral therapy which requires to look for new therapeutic options. Antiretroviral therapy criteria for acute infection, pregnancy, post-exposure prophylaxis and when to use resistance testing are discussed. CONCLUSIONS: In this moment, there is a more conservative attitude towards starting antiretroviral therapy than in previous recommendations in which a virus eradication was considered. On the other hand, the high number of disposable drugs, the more sensitive monitorization methods (plasma viral load) and the possibility of performing resistance studies make therapeutic strategies more dynamic and individualised for each patient and situation. In any case, it is mandatory to ensure a perfect adherence to antiretroviral therapy from the patients.

Martínez E, Gatell JM. · No affiliation provided · Rev Clin Esp. · Pubmed #10522426 No free full text.

This publication has no abstract.

Franco R, Pacheco R, Gatell JM, Gallart T, Lluis C. · Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Spain. · Crit Rev Immunol. · Pubmed #18197796 No free full text.

Abstract: Adenosine deaminase 1 (ADA1) is an enzyme of the purine metabolism whose congenital defect leads to severe combined immunodeficiency (SCID). Although classically considered a cytosolic enzyme, early evidence from work in brain synaptosomes suggested that the enzyme could be an ectoenzyme. In lymphoid cells, ectoenzymatic activity of ADA1 was also found. The obvious role of this enzyme located on the cell surface of lymphocytes and monocytes was to deaminate adenosine, making it less available for uptaking and metabolism, and also for adenosine-receptor activation. Quite unexpectedly, ADA1 was shown to act extraenzymatically. In addition, cell surface ADA1-binding proteins have been identified. Interestingly, the interaction of ADA1 with these anchoring proteins leads to costimulation of T-cell activation. Recent studies performed with professional antigen-presenting cells and T lymphocytes have shown that ADA1 can bridge the two cell types together by a cross-linking established between different anchoring molecules in each cell. Some aspects of ADA action are similar to that of growth factors. In fact, ADA1 is a member of the adenosine deaminase growth factor (ADGF) family. Some molecular mechanisms that occur in ADA-related SCID and the role ADA1 may play in acquired immunodeficiency are also reviewed here.

Millán O, Brunet M, Martorell J, García F, Vidal E, Rojo I, Plana M, Gallart T, Pumarola T, Miró JM, Gatell JM. · Servei Immunologia, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain. · Clin Pharmacokinet. · Pubmed #15871638 No free full text.

Abstract: BACKGROUND: The use of mycophenolate mofetil in combination with highly active antiretroviral therapy (HAART) has been proposed in order to inhibit HIV replication. Due to the low doses involved, pharmacokinetic-pharmacodynamic monitoring is recommended. OBJECTIVE: The aim of this study was to characterise the pharmacokinetic and pharmacodynamic monitoring of low doses of mycophenolate mofetil (0.25 g twice daily) in HIV-infected patients treated with HAART and after programmed discontinuation of HAART, in order to assess whether low doses of this immunosuppressive agent provide a biological effect. METHODS: Mycophenolic acid (MPA) plasma levels (assessed by high-performance liquid chromatography) and the capacity of patients' sera to inhibit CEM cell line proliferation (assessed by (3)H-thymidine uptake) were measured post-dose at 0, 20, 40 minutes and 1, 2, 4, 6, 8, 10 and 12 hours in nine HIV-infected patients treated with a combination of abacavir, nelfinavir and efavirenz (HAART) and mycophenolate mofetil 0.25 g twice daily at days 7, 28, 120 and 150 (30 days without HAART) after the treatment initiation. A control group of eight patients was treated with HAART alone. RESULTS: In the 35 post-dose curves analysed, no differences were found in MPA levels between days 7, 28, 120 and 150: area under the plasma concentration-time curve - mean value 15.3 mg . h/L, range 10.4-24.4 mg . h/L; minimum plasma concentration - mean value 0.60 mg/L, range 0.20-4.67 mg/L; maximum plasma concentration mean value 2.60 mg/L, range 0.94-7.98 mg/L. Pretreatment patients' sera did not inhibit CEM proliferation. Post-treatment patients' sera inhibited CEM proliferation to <40% in 25 of 35 curves at 0 hours (six of nine patients), in 34 of 35 curves at 1 hour, in 32 of 35 curves at 2 hours, in 22 of 35 curves at 4 hours, and in 8 of 35 curves at 12 hours. The MPA level versus CEM proliferation inhibition had a concentration that produces 50% of the maximum drug effect (EC(50)) of 0.33 mg/L. Viral load at day 150 was >200 copies/mL in all control patients and in three of nine patients receiving mycophenolate mofetil. These three patients were the only ones repeatedly unable to inhibit pre-dose CEM proliferation to <40%. CONCLUSIONS: Mycophenolate mofetil pharmacokinetic profiles in HIV patients under HAART are not significantly different from those found in transplant patients. Sera from the majority of patients receiving low doses of mycophenolate mofetil inhibited lymphocyte proliferation during most of the inter-dose interval, despite low MPA plasma levels. For some patients, higher doses may be necessary: the capacity of sera to inhibit CEM proliferation may help to identify these patients.

Martínez E, Arnaiz JA, Podzamczer D, Dalmau D, Ribera E, Domingo P, Knobel H, Riera M, Pedrol E, Force L, Llibre JM, Segura F, Richart C, Cortés C, Javaloyas M, Aranda M, Cruceta A, de Lazzari E, Gatell JM, Anonymous00159. · Infectious Diseases Unit, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain. · N Engl J Med. · Pubmed #12968087 links to  free full text

Abstract: BACKGROUND: We assessed the strategy of substituting nevirapine, efavirenz, or abacavir for a protease inhibitor in patients infected with human immunodeficiency virus type 1 (HIV-1) in whom virologic suppression had been achieved. METHODS: We randomly assigned 460 adults who were taking two nucleoside reverse-transcriptase inhibitors and at least one protease inhibitor and whose plasma HIV-1 RNA levels had been less than 200 copies per milliliter for at least the previous six months to switch from the protease inhibitor to nevirapine (155 patients), efavirenz (156), or abacavir (149). The primary end point was death, progression to the acquired immunodeficiency syndrome, or an increase in HIV-1 RNA levels to 200 copies or more per milliliter. RESULTS: At 12 months, the Kaplan-Meier estimates of the likelihood of reaching the end point were 10 percent in the nevirapine group, 6 percent in the efavirenz group, and 13 percent in the abacavir group (P=0.10 according to an intention-to-treat analysis). HIV-1 RNA could be amplified in 21 of the 29 patients in whom virologic failure developed during treatment with study medication (72 percent), and resistance mutations to the study medication and to at least one of the nucleoside reverse-transcriptase inhibitors in the regimen that failed were detected in all but 1 of the 21 patients. Twenty-three of the 29 patients with virologic failure during treatment with study medication had received prior suboptimal therapy with nucleoside reverse-transcriptase inhibitors. Fewer patients in the abacavir group (6 percent) than in the nevirapine group (17 percent) or the efavirenz group (17 percent) discontinued the study medication because of adverse events (P=0.01). The proportion of patients with fasting lipid levels warranting therapeutic intervention decreased significantly in the abacavir group, but the prevalence of clinical lipodystrophy did not change significantly in the three groups. CONCLUSIONS: When therapy was switched from a protease inhibitor to nevirapine, efavirenz, or abacavir in patients with virologic suppression, there was a trend toward a higher rate of virologic failure among those given abacavir.

Vidal C, Arnedo M, Garcia F, Mestre G, Plana M, Cruceta A, Capon A, Gallart T, Miro JM, Pumarola T, Gatell JM. · Microbiology Laboratory, Institut Clínic de Infeccions i Immunologia, Institut d'Investigacions Biomèdiques August Pi I Sunyer, Hospital Clinic, Faculty of Medicine, University of Barcelona, Spain. · Antivir Ther. · Pubmed #12553483 No free full text.

Abstract: The objectives of this study were to determine the genotypic and phenotypic patterns of resistance in a group of early-stage antiretroviral-naive patients failing initial therapy with didanosine, stavudine and nevirapine. These patterns of resistance were determined at baseline and at time of virological failure in 89 antiretroviral-naive patients with CD4 cells >500 cells/ml and viral load >5000 copies/ml who received initial antiretroviral therapy with didanosine plus stavudine and nevirapine as part of the SCAN study, and who failed after having reached undetectable plasma levels (<200 copies/ml). Of the 89 patients recruited in the SCAN study, 14 (16%) developed a virological failure after reaching a viral load below 200 copies/ml after a median of 20 months of follow-up. At baseline, none of these 14 patients had genotypic resistance. At time of failure, six out of 14 (43%) failing patients had wild-type genotype and no phenotypic resistance. Suboptimal compliance could be documented in four of these six patients. Seven patients (50%) had nevirapine resistance mutations (mainly K103N [4/7], Y181C/I [2/7], G190A/S [2/7] and V108I [1/7]) associated with phenotypic high-level resistance to nevirapine, delavirdine and efavirenz (nevirapine >47.4- to 58.1-fold, delavirdine >74.4- to 168.9-fold and efavirenz >56.0- to 347.2-fold). Four of these seven patients also had thymidine analogue-associated mutations (TAM) (T215Y/F [2/4], M41L [1/4], D67N [2/4] and K70R [1/4]). Finally, one patient (7%) had exclusively TAM mutations (M41L). None of the patients developed mutations associated with didanosine resistance or phenotypic resistance to didanosine or stavudine. Suboptimal compliance or selection of nevirapine resistance often with TAM mutations was frequently associated with virological failure in a cohort of early-stage chronic HIV-1-infected patients treated with a protease inhibitor-sparing regimen.

Blanch J, Rousaud A, Martínez E, De Lazzari E, Peri JM, Milinkovic A, Perez-Cuevas JB, Blanco JL, Gatell JM. · Clinical Institute of Psychiatry and Psychology, Hospital Clínic Universitari de Barcelona, Barcelona, Spain. · J Acquir Immune Defic Syndr. · Pubmed #12447011 No free full text.

Abstract: INTRODUCTION: Lipodystrophy (LD) represents an important problem for HIV-1-infected patients receiving highly active antiretroviral therapy (HAART), although its impact on quality of life (QoL) has not been properly studied. DESIGN: Cross-sectional, nonrandomized, observational study performed on consecutive, clinically stable outpatients taking HAART for more than 1 year. METHODS: Data on patients' characteristics, HIV-1 infection, treatment adherence and adverse effects, overall QoL measured by the Profil der Lebensqualität Chronischkranker (PLC), and the presence of LD defined by clinical criteria were assessed. RESULTS: Eighty-four (56%) of 150 interviewed patients fulfilled criteria for LD. Patients with LD were older, had been taking antiretroviral treatment longer, and reported a poorer physical status than patients without LD. Surprisingly, LD itself was not found to influence overall QoL. However, homosexual patients, unemployed patients, and those patients undergoing current psychiatric treatment showed greater impairment on some of the QoL subscales related to psychological well-being if they suffered from LD. CONCLUSION: The impact of HIV-related LD on QoL depends on certain patient characteristics, rather than on the presence of LD itself.

Arribas JR, Pulido F, Miró JM, Costa MA, González J, Rubio R, Peña JM, Torralba M, Lonca M, Lorenzo A, Del Palacio A, Vázquez JJ, Gatell JM, Anonymous00224. · Internal Medicine Service, La paz Hospital, Autónoma University School of Medicine, Madrid, Spain. · AIDS. · Pubmed #12131195 No free full text.

Abstract: We evaluated the therapeutic outcomes of all antiretroviral-naive HIV-1-infected patients with fewer than 100 CD4 cells/microl, who received efavirenz-based highly active antiretroviral therapy (HAART). Sixty-one percent suffered AIDS-defining diseases, and after a median follow-up of 45 weeks there were three deaths and five AIDS-related conditions (two relapses, three new). Efavirenz-based HAART was found to be effective in profoundly immunosuppressed HIV-1-infected patients.

Podzamczer D, Olmo M, Sanz J, Boix V, Negredo E, Knobel H, Domingo P, Pineda JA, Vilades C, Quero JH, Force L, Lahoz JG, Muñoz P, Llibre JM, Mariño A, Ortega E, Dalmau D, Gatell JM, Antón E, Sola J, Galindo MJ, Pedrol E, Sanz J, Lima JT, Flores J, Anonymous00075. · Hospital Universitari de Bellvitge, L'Hospitalet, Barcelona, Spain. · J Acquir Immune Defic Syndr. · Pubmed #19214120 No free full text.

Abstract: BACKGROUND: The strategy of switching nevirapine (NVP) twice daily to once daily was evaluated. METHODS: Forty-eight-week randomized, open, multicenter trial. Stable HIV-infected patients on NVP twice daily for >12-18 weeks with alanine aminotransferase (ALT) <2.5, the upper normal limit were randomized to continue their regimen or switch to NVP 400 mg once daily. Primary end point was the proportion of ALT/aspartate transaminase (AST) > or =grade 3. RESULTS: Two hundred eighty-nine patients were included, mean CD4 620 cells per microliter. Noninferiority was demonstrated in the per protocol analysis, with 97.9% (once daily) and 99.3% (twice daily) of patients event free (difference, 1.4%; 95% confidence interval, -1.95% to 5.4%), whereas 81.8% vs. 93.8% were event free by intent-to-treat switch = toxicity analysis (difference, 12%; 95% confidence interval, 4.6% to 19.4%). Only 4 patients (3 once daily, 1 twice daily) had NVP-related grade 3/4 ALT/AST increases, but in 2 of them (once daily), transaminases decreased despite continuation with NVP. Two other once daily patients presented grade 3/4 ALT/AST increase due to well-documented acute hepatitis A virus or hepatitis C virus infection. Grade 2 ALT/AST increases occurred in 11.2% (once daily) vs. 10.3% (twice daily) of patients (P = 0.80). A larger number of once daily patients were lost to follow-up/violated protocol (15% vs. 5%). CONCLUSIONS: In patients on standard twice daily NVP-containing regimens for at least 12-18 weeks, per protocol analysis showed that switching to once daily NVP was not inferior to continued twice daily NVP in terms of the predefined noninferiority margin of 10% for hepatotoxicity.

Soriano A, Lozano F, Oliva H, García F, Nomdedéu M, De Lazzari E, Rodríguez C, Barrasa A, Lorenzo JI, Del Romero J, Plana M, Miró JM, Gatell JM, Vives J, Gallart T. · Service of Infectious Diseases and AIDS Unit, Hospital Clínic de Barcelona, Villarroel, 170, 08036, Barcelona, Spain. · Immunogenetics. · Pubmed #16189667 No free full text.

Abstract: Interleukin (IL) 4 is a key T helper-2 cytokine that downregulates and upregulates CCR5 and CXCR4, respectively, the main coreceptors for HIV. Our objective is to investigate whether single-nucleotide polymorphisms (SNPs) in the IL-4 receptor alpha chain gene (IL4RA) affect HIV infection and its progression to AIDS. The I50V SNP in exon 5 and the haplotypes of six SNPs in exon 12 (E375A, C406R, S411L, S478P, Q551R, and V554I) were studied by polymerase chain reaction and sequencing in 30 HIV+ long-term nonprogressors (LTNP), 36 HIV+ typical progressors (TP), 55 highly exposed but uninfected individuals (EU), 25 EU-sexuals (EU-Sex; mostly women) and 30 EU-hemophiliacs (EU-Hem; hepatitis C virus+), and 97 healthy controls (HC), all Caucasians and lacking CCR5Delta32 homozygosity. V50 homozygosity was increased in LTNP (44%) compared with the other groups [p = 0.005; relative risk ratio = 3.4, 95% confidence interval (CI) = 1.12-10.6, p = 0.03]. The most common (C) exon 12 haplotype, ECSSQV, predominated in all groups, but uncommon (U) haplotypes were increased in HIV+ individuals (n = 64), especially in those (51 of 64) infected via parenteral exposure (35.3%) compared with HC (20.4%) and EU-Hem (18.4%) [p = 0.01; odds ratio (OR) = 2.14, 95% CI = 1.25-3.67, p = 0.01]. EU-Sex also had an increased frequency of U-haplotypes (34.8%) (OR = 2.10, 95% CI = 1.03-4.21, p = 0.01) as well as an increased frequency of CU + UU genotypes (60.9%) compared with HC (38.2%) and EU-Hem (26.6%) (p = 0.043). Distributions of genotypes fitted Hardy-Weinberg equilibrium. Data suggest that V50 homozygosity associates with slow progression and that exon 12 U-haplotypes might be associated with both susceptibility to infection via parenteral route and resistance to infection via sexual exposure. Further studies are required to confirm these findings.

Antón E, Sala M, Mallolas J, Navarro G, Cervantes M, Gatell JM, Segura F. · Servicio de Medicina Interna, Corporació Parc Taulí, Sabadell, Barcelona, Spain. · Enferm Infecc Microbiol Clin. · Pubmed #15757586 links to  free full text

Abstract: INTRODUCTION: The epidemiology of human immunodeficiency virus (HIV) infection has changed in recent years. Cases in persons over the age of 50 have increased, and the most frequent mode of transmission is sexual contact. The objective of this study is to analyse the epidemiological, clinical and evolution characteristics of a clinical series of HIV-infected patients over 50 years old at the time of diagnosis. METHODS: 165 HIV-infected patients over the age of 50, attended at Hospital Clinic (Barcelona) and Corporació Parc Taulí (Sabadell) during the period of 1985 to 2001, were studied. RESULTS: Among the total, 81% of the patients were men, mean age at the time of diagnosis was 58.5 years, and 81.8% had acquired the disease by sexual contact. The median initial CD4 T cell count was 216 cells/microl. Initial viral load was 1,000-100,000 copies/ml in 45.2% of the patients, whereas 52.3% had > 100,000 copies/ml. At the time of diagnosis, 30.9% had an AIDS-defining disease. The main opportunistic diseases were pulmonary tuberculosis, Kaposi's sarcoma, P. jiroveci (before carinii) pneumonia and non-Hodgkin lymphoma. Mortality due to AIDS was 32.7%. CONCLUSIONS: Subjects over 50 years old diagnosed with HIV-infection were predominantly men, who acquired the infection by sexual contact. A high percentage of patients were diagnosed with the development of an opportunistic disease.

García F, de Lazzari E, Plana M, Castro P, Mestre G, Nomdedeu M, Fumero E, Martínez E, Mallolas J, Blanco JL, Miró JM, Pumarola T, Gallart T, Gatell JM. · Clinic Institute of Infectious Diseases and Immunology, IDIBAPS, Hospital Clínic, Faculty of Medicine, University of Barcelona, Spain. · J Acquir Immune Defic Syndr. · Pubmed #15167289 No free full text.

Abstract: Current treatment guidelines for HIV infection recommend a relatively late initiation of highly active antiretroviral therapy (HAART). Nevertheless, there is still a concern that immune recovery may not be as complete once CD4+ T cells have decreased below a certain threshold. This study addressed the long-term response of CD4+ T-cell counts in patients on HAART and analyzed the influence of baseline CD4+ T-cell counts, baseline viral load, and age. An observational analysis of evolution of CD4+ T cells in 861 antiretroviral therapy-naive chronic HIV-1-infected patients who started treatment consisting of at least 3 drugs in or after 1996 was performed. Patients were classified in 4 groups according to baseline CD4+ T cells: <200 cells/mm3, 200-349 cells/mm3, 350-499 cells/mm3, and >or=500 cells/mm3. The main outcome measures were proportion of patients with CD4+ T cells <200/mm3 and >500/mm3 at last determination and rate of CD4+ T-cell recovery. Patients were followed-up for a median of 173 weeks (interquartile range [IQR], 100-234). There were no differences in follow-up between the 4 groups. CD4+ T cells increased in the whole cohort from a median of 214 cells/mm3 (IQR, 90-355) to 499 cells/mm3 (IQR, 312-733) (P<0.001). Compared with the group with a baseline CD4+ T-cell count of >or=500/mm3, the relative risk of having a last determination of CD4+ T-cell counts >200 cells/mm3 was 0.79 (95% CI, 0.75-0.83), 0.92 (95% CI, 0.89-0.96) and 1 for baseline CD4+ T cells <200 cells/mm3, 200-349 cells/mm3, and 350-499 cells/mm3, respectively. The relative risk of having a last determination of CD4+ T-cell counts >500 cells/mm3 was 0.32 (95% CI, 0.27-0.39, P<0.001), 0.69 (95% CI, 0.60-0.79, P<0.001), and 0.94 (95% CI, 0.83-1.06, P=0.38) for baseline CD4+ T-cell counts <200 cells/mm3, 200-349 cells/mm3, and 350-0499 cells/mm3, respectively, compared with a baseline CD4+ T-cell count of >or=500 cells/mm3. The increase in CD4+ T cells from baseline was statistically significant and was maintained for up to 4 years of follow-up. This increase seemed to slow down after approximately 3 years and reached a plateau after 4-5 years of follow-up even in patients who achieved and maintained viral suppression in plasma. Long-term immune recovery is possible regardless of baseline CD4+ T-cell count. However, patients who start therapy with a CD4+ T-cell count <200 cells/mm3 have poorer immunologic outcome as measured by the proportion of patients with CD4+ T cells <200/mm3 or >500/mm3 at last determination. It seems that the immune recovery slows down after approximately 3 years of HAART and reaches a plateau after 4-5 years of HAART.

Navarrete P, Morente V, García F, Alós L, Arnedo M, Plana M, Gil C, Caballero M, Miró JM, Martínez E, Fumero E, Castro P, Blanco JL, Mallolas J, Blanch JL, Cruceta A, Mestre G, Pumarola T, Gallart T, Gatell JM. · Infectious Diseases Unit, Clinic Institute of Infectious Diseases and Immunology, Faculty of Medicine, University of Barcelona, Barcelona, Spain. · Antivir Ther. · Pubmed #14760898 No free full text.

Abstract: In 81 antiretroviral-navie HIV-1 chronic-infected patients, we found a correlation among tonsillar tissue viral load, and virological and immunological measures in blood at baseline. No correlation was observed after 1 year of antiretroviral therapy. A protease inhibitor-containing regimen was the best predictor of good tonsillar tissue virological response.

Horcajada JP, Pumarola T, Martínez JA, Tapias G, Bayas JM, de la Prada M, García F, Codina C, Gatell JM, Jiménez de Anta MT. · Service of Infectious Diseases, Institut Cĺinic Infeccions i Immunologia, Hospital Clinic Universitari, Institut d'Investigacions Biomèdiques Augusti Pi i Sunyer, Barcelona, Spain. · Eur Respir J. · Pubmed #12608445 links to  free full text

Abstract: The objective of this study was to describe a nosocomial outbreak of influenza during a period without influenza epidemic activity in the community. Outbreak investigation was carried out in an infectious diseases ward of a tertiary hospital. Presence of two or more of the following symptoms were used to define influenza: cough, sore throat, myalgia and fever. Epidemiological survey, direct immunofluorescence, viral culture, polymerase chain reaction, haemagglutination-inhibition test in throat swabs and serology for respiratory viruses were performed. Twenty-nine of 57 healthcare workers (HCW) (51%) and eight of 23 hospitalised patients (34%) fulfilled the case definition. Sixteen HCW (55%) and three inpatients (37%) had a definitive diagnosis of influenza A virus infection (subtype H1N1). Among the symptomatic HCW, 93% had not been vaccinated against influenza that season. Affected inpatients were isolated and admissions in the ward were cancelled for 2 weeks. Symptomatic HCW were sent home for 1 week. On the seventeenth day of the outbreak the last case was declared. The incidence of cases in this outbreak of influenza, which occurred during a period without influenza epidemic activity in the community, was notably high. Epidemiological data suggest transmission from healthcare workers to inpatients. Most healthcare workers were not vaccinated against influenza. Vaccination programmes should be reinforced among healthcare workers.

García de Olalla P, Martínez-González MA, Caylà JA, Jansà JM, Iglesias B, Guerrero R, Marco A, Gatell JM, Ocaña I, Anonymous00283. · Department of Epidemiology, Municipal Institute of Health, Barcelona, Spain. · Int J Tuberc Lung Dis. · Pubmed #12546112 No free full text.

Abstract: OBJECTIVE: To determine factors related to survival in acquired immune-deficiency syndrome (AIDS) patients with extra-pulmonary tuberculosis (EPTB), when this condition is the first AIDS-defining disease. DESIGN: A retrospective cohort-study of 549 AIDS patients with EPTB as the first AIDS-defining disease. Potential candidates to predict survival were sex, human immunodeficiency virus (HIV) exposure, the coexistence of pulmonary and EPTB at diagnosis, tuberculin skin test, directly observed therapy for tuberculosis (DOT), and highly active anti-retroviral therapy (HAART). The Kaplan-Meier method and Cox regression models were used to assess factors associated with survival. RESULTS: Estimated 3-year survival was 47.0% for those diagnosed before 1993, 72.6% for patients with first AIDS diagnosis during 1995-1996 and 84.6% for those diagnosed after 1996. A negative tuberculin test (hazard ratio [HR] = 1.6, 95% CI 1.1-2.3), not being on DOT (HR 2.2; 95% CI 1.3-3.7) and having pulmonary tuberculosis involvement also (HR 1.3; 95% CI 1.1-1.7) were independently associated with poorer survival. The survival of patients significantly improved after the introduction of HAART (HR 0.4; 95% CI 0.2-0.6). CONCLUSION: The survival of HIV patients with EPTB as their first AIDS-defining disease has substantially improved during the last decade. A negative tuberculin skin test and not receiving DOT are associated with poorer survival among HIV-infected patients whose first AIDS-defining disease is EPTB.

Kirk O, Pedersen C, Cozzi-Lepri A, Antunes F, Miller V, Gatell JM, Katlama C, Lazzarin A, Skinhøj P, Barton SE, Anonymous00094. · EuroSIDA Coordinating Centre, Department of Infectious Diseases, Hvidovre Hospital, Copenhagen, Denmark. · Blood. · Pubmed #11719381 links to  free full text

Abstract: This study was designed to assess the influence of highly active antiretroviral therapy (HAART) on non-Hodgkin lymphoma (NHL) among patients infected with human immunodeficiency virus (HIV). Within EuroSIDA, a multicenter observational cohort of more than 8500 patients from across Europe, the incidences of NHL and subtypes (Burkitt, immunoblastic, primary brain lymphoma [PBL], and other/unknown histology) were determined according to calendar time of follow-up, and for those who initiated HAART (> or =3 drugs) also time on HAART. Potential predictive factors of NHL were evaluated in Cox proportional hazard models. Over 26 764 person-years of prospective follow-up (PYF) from May 1994 to December 2000, the incidence of NHL decreased from 1.99 (95% confidence interval, 1.51-2.47) before September 1995 to 0.30 (0.19-0.42) cases/100 (PYF) after March 1999 (P <.001). The incidence of all subtypes of NHL decreased significantly and most pronouncedly for PBL. Among patients who started HAART, the incidence of NHL decreased from 0.88 (0.60-1.16) within the first 12 months after starting HAART to 0.45 (0.31-0.60) cases/100 PYF after more than 24 months (P =.004). In an adjusted Cox model for patients on HAART, the latest CD4 cell count and plasma viral load were both significantly associated with diagnosis of NHL; the relative hazard was 1.39 (range, 1.14-1.69) per 50% lower CD4 cell count, and 1.51 (range, 1.21-1.88) per 1 log higher plasma viral load. In conclusion, the incidence of NHL among HIV-infected patients has decreased significantly after the introduction of HAART, and the decline was most pronounced for PBL. After starting HAART, patients with insufficient immunologic and virologic responses were at highest risk of NHL.

Alves C, Nicolás JM, Miró JM, Torres A, Agustì C, Gonzalez J, Raño A, Benito N, Moreno A, Garcìa F, Millá J, Gatell JM. · Dept of Infectious Diseases Service, Facultat de Medicina, Universitat de Barcelona, Villarroel, Spain. · Eur Respir J. · Pubmed #11307762 links to  free full text

Abstract: The introduction of highly active antiretroviral therapy with protease inhibitors in 1996 has changed the morbidity and mortality of acquired immune deficiency syndrome patients. Therefore, the aetiologies and prognostic factors of human immunodeficiency virus (HIV)-infected patients with life-threatening respiratory failure requiring intensive care unit (ICU) admission need to be reassessed. From 1993 to 1998, we prospectively evaluated 57 HIV patients (mean+/-SEM age 36.5+/-1.3 yrs) admitted to the ICU showing pulmonary infiltrates and acute respiratory failure. A total of 21 and 30 patients were diagnosed as having Pneumocystis carinii and bacterial pneumonia, respectively, of whom 13 and eight died during their ICU stay (p=0.01). Both groups of patients had similar age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and severity in respiratory failure. The number of cases with bacterial pneumonia admitted to ICU decreased after 1996 (p=0.05). Logistic regression analysis showed that (APACHE) II score >17, serum albumin level <25 g.(-1), and diagnosis of P. carinii pneumonia were the only factors at entry associated with ICU mortality (p=0.02). Patients with bacterial pneumonia are less frequently admitted to the intensive care unit after the introduction of highly active antiretroviral therapy with protease inhibitors in 1996. Compared to the previous series, it was observed that the few Pneumocystis carinii pneumonia patients that need intensive care still have a bad prognosis.

Romeu J, Balagué M, Ruiz L, Marfil S, Gatell JM, Puig T, Arnó A, Tural C, Sirera G, Clotet B. · AIDS Care Unit, Germans Trias i Pujol University Hospital, Badalona, Spain. · Scand J Infect Dis. · Pubmed #10381216 No free full text.

Abstract: The objective of this study was to assess the value of quantitative HIV-1 RNA as a predictor for the short-term risk of developing AIDS-defining events in comparison with CD4 cell counts. A total of 1,028 samples from 324 patients were analysed. Median initial CD4 cell counts and HIV-1 RNA were 249 x 10(6)/l (range 0-1400 x 10(6)/l) and 4.5 log copies/ml (range: 2.3-6.4 log copies/ml). CD4 cell counts and viral load (VL) values obtained the year before a single AIDS-indicator disease were selected to define the risk of developing that event. Cox regression models with CD4 cell counts and VL values treated as time-dependent covariates were performed to analyse the risk for developing certain events. Receiver operating characteristic (ROC) curves were used to compare CD4 cell counts and VL values as predictive markers for progression. During a median follow-up of 870 d (range 30-1381 d), 132 patients developed AIDS. Median log VL values during the year before the event were 3.6 for non-progressors and 5.2 for those who developed AIDS (p < 0.0001). Minimum log VL threshold values for developing diseases were 2.3 for tuberculosis, 3.8 for Candida esophagitis, 4.4 for wasting syndrome, 4.5 for CMV disease and 4.7 for PCP. VL values were not, however, a better predictive marker for developing specific events than were CD4 cell counts. Although we have identified VL thresholds for the risk of developing certain AIDS-indicator diseases, the indication for starting prophylactic regimens may still be based on CD4 cell counts.