Resistance to first-line antituberculosis drugs in Spain, 2010-2011. RETUBES Study.

INTRODUCTION: The magnitude of current resistance to antituberculosis drugs in Spain is unknown. The objective of this study is to describe resistance to first-line antituberculosis drugs and determine the associated factors. METHODS: Prospective multicenter study of adult tuberculosis patients with positive Mycobacterium tuberculosis culture and antibiogram including first-line drugs in 32 hospitals and one out-patient center of the Spanish Health System between 2010 and 2011. RESULTS: A total of 519 patients, 342 Spanish nationals and 177 (34.1%) foreigners were studied. Drug resistance was found in 48 (9.2%), of which 35 (6.7%) were isoniazid-resistant. There were 10 (1.9%) multiresistant cases and no strain was extremely resistant. Initial isoniazid resistance was detected in 28 of the 487 (5.7%) antituberulosis-naïve patients, most of whom were foreigners (P<.01). Acquired resistance was seen in 7 (22.6%) previously treated cases. Multiresistance was initial in 6 cases (1.2%) and acquired in another 4 (12.9%). Factors associated with initial isoniazid resistance were immigrant status and group cohabitation OR=2.3; 95%CI: .98-5.67 and OR=2.2; 95%CI: 1.05-7.07 respectively). The factor associated with acquired resistance to isoniazid was age below 50 years (P=.03). CONCLUSIONS: The rate of initial isoniazid resistance is greater than estimated, probably due to the increase in immigration during recent years, suggesting that systematic national monitoring is required. Immigrants and those who cohabit in groups have a higher risk of isoniazid resistance.

[Consensus statement on the clinical management of non-AIDS defining malignancies. GeSIDA expert panel]. / Guía de práctica clínica sobre los tumores no definitorios de sida e infección por el virus de la inmunodeficiencia humana.

This consensus document has been prepared by a panel of experts appointed by GeSIDA. This paper reviews the recommendations on the most important non-AIDS defining malignancies that can affect patients living with AIDS. Lung cancer, hepatocellular carcinoma, anal carcinoma and other less frequent malignancies such as breast, prostate, vagina or colon cancers are reviewed. The aim of the recommendations is to make clinicians who attend to this patients aware of how to prevent, diagnose and treat this diseases. The recommendations for the use of antiretroviral therapy when the patient develops a malignancy are also presented. In support of the recommendations we have used the modified criteria of the Infectious Diseases Society of America.

Prevalence and risk factors associated with pulmonary hypertension in HIV-infected patients on regular follow-up.

BACKGROUND: Pulmonary arterial hypertension (PAH) is uncommon among HIV-positive patients. However, it is a potentially life-threatening condition. Transthoracic echocardiography (TTE) is a noninvasive tool validated for PAH screening. The aim of our study was to establish the prevalence and factors associated with PAH in HIV-infected patients. METHODS: Consecutive HIV-infected individuals attended at one HIV reference clinic in Madrid, Spain, during year 2011 were examined. Demographics and clinical data were recorded and a Doppler echocardiography was performed in all individuals. PAH was considered when right ventricular pressure was more than 35 mmHg (mild if <40 mmHg, moderate if 40-65 mmHg, and severe if >65 mmHg). RESULTS: Three hundred and ninety-two individuals were examined (83.4% men, median age 47 years, 53% were men who have sex with men and 53% former intravenous drug addicts). Overall, 84% were on HAART, 76% had undetectable HIV viral load and median CD4 cell counts were 577 cells/µl. Cardiovascular risk factors were smoking 50%, arterial hypertension 16% and diabetes mellitus 9%. A total of 28.5 and 4.8% had chronic hepatitis C (CHC) and 4.8% chronic hepatitis B, respectively. PAH was diagnosed in 9.9% of patients (6.4% mild, 2.8% moderate and 0.8% severe). Multivariate logistic regression analysis [odds ratio (OR), 95% confidence interval (CI)] showed that detectable plasma HIV-RNA [OR, 3.3; 95% CI, 1.04-10], CHC [OR, 3.1; 95% CI 1.2-8.2] and female sex [OR, 2.9; 95% CI, 1.04-8.3] were independently associated with PAH. CONCLUSION: The prevalence of PAH HIV-infected patients on regular follow-up approaches 10%, being moderate-severe in nearly 4% of cases. Patients with CHC and/or uncontrolled HIV replication exhibit a higher risk of PAH.

Outcomes in HIV-infected patients admitted due to pandemic influenza.

PURPOSE: To determine the clinical, epidemiological and prognostic factors of HIV-infected patients with influenza A H1N1 admitted to hospital. METHODS: The study population was HIV infected patients with confirmed influenza infection admitted to hospital in a multicenter cohort. We analyzed demographic data, comorbid conditions, severe events (bronchopneumonia, respiratory insufficiency, respiratory distress, sepsis, admission to intensive care unit, death) and outcome. Data were analyzed using descriptive statistics. Proportions were compared using the χ(2) test or Fisher exact test, when applicable. Quantitative variables were compared using the Student t test or Mann-Whitney test. Prognostic impact was analyzed using logistic regression. RESULTS: A total of 43 patients, of whom 62.8% were male, were included from 22 hospitals. The mean age was 43.3 years (interquartile range [IQR], 38.4-48.4). HIV was diagnosed for a mean of 14.5 years (IQR, 8.4-20.3). CD4 lymphocyte was <200 cells/µL in 38%; 85.7% were on antiretroviral therapy, and 66.7% virologically suppressed. Comorbid conditions were hepatitis B or C (74.4%), smoking (67.4%), chronic obstructive pulmonary disease (30.2%), asthma (14%), and obesity (8.6%). Seven patients had received seasonal influenza vaccination, and 2 the H1N1 vaccine. Cough (100%), fever (93%), gastrointestinal disorders (27.9%) or general--myalgia, general malaise--(67.4%) were the presenting symptoms. These were severe in 24 (55.8%) with 7 (16.3%) requiring intensive care. Two patients died. A lower CD4 lymphocyte count was associated with bacterial infection (P=.063) and longer hospital stay (P=.007). Early oseltamivir reduced severe cases (OR, 4.5; 1.1-18.3; P=.035). CONCLUSIONS: HIV-infected patients admitted to hospital due to influenza A H1N1 had severe morbidity. Low CD4 lymphocytes correlated with longer hospitalization and bacterial infections. Early oseltamivir treatment reduced severe symptoms.

Comparison of CHOP treatment with specific short-intensive chemotherapy in AIDS-related Burkitt's lymphoma or leukemia.

BACKGROUND AND OBJECTIVE: AIDS-related Burkitt's lymphoma or leukemia (BLL) is increasingly treated with specific and intensive multiagent schedules. This retrospective study aimed to compare the results of CHOP with those from two protocols (PETHEMA-LAL3/97 and BURKIMAB) of specific therapy in Spain. PATIENTS AND METHODS: Patients from Group A (n=31) received 6 standard CHOP cycles every 3 weeks. Patients from group B (n=44) received six multiagent cycles including high-dose methotrexate and high-dose cytarabine. The response to therapy, disease-free survival and overall survival (OS) were compared in the two groups. RESULTS: Both groups were comparable for the main clinical and biological parameters at diagnosis except for risk activity, previous HAART, bone marrow involvement, bulky disease and extranodal involved sites. Complete remission (CR) was achieved in 10 out of 31 (32%) patients in group A and 28 out of 44 (67%) patients in group B (P=.005). After a median (range) follow-up of 70 (26-139) and 17 (1-134) months, the 5-year (95% CI) DFS probability was 87% (64%-100%) for group A and 70% (51%-89%) for group B (P=.374), and the 5-year (95% CI) OS was 27% (10%-43%) for Group A and 57% (40%-74%) for group B (P=.028). Multivariate analyses showed that specific therapy was associated with an improved CR and OS. CONCLUSIONS: In AIDS-related BLL short intensive specific chemotherapy is feasible, with higher remission rate and improved survival than that obtained with CHOP-based regimens.

HIV rebound after discontinuation of antiretroviral therapy increases and expands HIV-specific CD8+ responses but has no impact on its functionality.

A higher functionality of CD8(+) T cells might contribute to low-level HIV replication in long-term nonprogressors (LTNPs). However, the contrary could also be true, being the function of CD8(+) T cells modulated by HIV replication. We tested whether enhanced HIV replication following antiretroviral therapy interruption could modify the functional profile of HIV-specific CD8(+) responses. Production of MIP-1beta, IL-2, TNF-alpha, and CD107 expression by CD8(+) T cells in response to Gag and Nef optimal peptide pools was analyzed using polychromatic flow cytometry in nine HIV-infected individuals followed for 12 months after discontinuation of antiretroviral therapy. At baseline, CD8(+) T cell subsets with the greatest contribution to response were MIP-beta(+)TNF-alpha(-)IL-2(-)CD107(+) and MIP-beta(+)TNF-alpha(-)IL-2(-)CD107. Most responses were mediated by subsets expressing only one or two molecules. After 12 months of discontinuing antiretroviral therapy, no significant differences were observed in the functional profile of Gag- and Nef-specific CD8(+) responses. However, viral rebound induced a significant increase in the heterogeneity of Gag-specific CD8(+) responses. In summary, viral replication following discontinuation of antiretroviral therapy has no significant impact on qualitative aspects of HIV-specific CD8(+) responses. Thus, a higher functionality of CD8(+) responses does not seem to be the consequence of low-level virus replication.

Characteristics and outcome of AIDS-related Hodgkin lymphoma before and after the introduction of highly active antiretroviral therapy.

OBJECTIVES: We analyzed survival, therapeutic response, and prognostic factors in patients with HIV-related Hodgkin lymphoma (HL) treated or not with highly active antiretroviral therapy (HAART). METHODS: This study included 104 patients with HL, treated (n = 83) or not (n = 21) with HAART. Outcomes and prognostic factors of complete remission (CR), overall survival (OS), and disease-free survival (DFS) were assessed by an intention-to-treat analysis of all patients who received at least 1 chemotherapy course. RESULTS: No differences were found between groups at baseline in the specific characteristics of HIV and HL. The proportion of patients receiving appropriate-for-stage therapy for HL was similar for both groups. The CR rates in the HAART (-) and HAART (+) groups were 14 (70%) of 20 versus 71 (91%) of 78 (P = 0.023). The median OS in the HAART (-) group was 39 months (95% confidence interval [CI]: 0 to 89) and was not reached in the HAART (+) group (P = 0.0089). The median DFS in the HAART (-) group was 85 months (95% CI: 73 to 97) and was not reached in the HAART (+) group (P = 0.129). Factors independently associated with CR by logistic regression analysis were appropriate-for-stage therapy of HL, HAART, and baseline CD4 count > or =100 cells/microL. CR was the only factor independently associated with OS by Cox regression analysis. CONCLUSIONS: The achievement of CR was independently associated with appropriate-for-stage therapy for HL, with HAART, and with a baseline CD4 count > or =100 cells/microL. The only variable independently associated with OS was the achievement of CR.

Prognosis of AIDS-related systemic non-Hodgkin lymphoma treated with chemotherapy and highly active antiretroviral therapy depends exclusively on tumor-related factors.

OBJECTIVES: To assess complete remission (CR) and survival in patients with systemic AIDS-related non-Hodgkin lymphoma (ARL) receiving highly active antiretroviral therapy (HAART). METHODS: We analyzed the Grupo de Estudio del SIDA register of systemic ARL, which started in Jan 1994, to collect cases diagnosed at 15 institutions prospectively and with active follow-up every 6 months. The date of censorship for this study was March 2005. RESULTS: During the study period, 210 consecutive patients were diagnosed with ARL, with a median age 39 of years, 75.7% of whom were male, and with a median baseline CD4 count of 160 cells/microL. Histologic subtypes were diffuse large B-cell lymphoma (DLCL; n = 153 [72.9%]), Burkitt and atypical Burkitt/Burkitt-like lymphoma (BL; n = 40 [19.0%]), T-cell lymphoma (TC; n = 8 [3.8%]), and miscellaneous (n = 9 [4.3%]). Chemotherapy with or without other modalities was administered to 186 (88.6%) patients. In an intent-to-treat analysis of 184 patients who received at least 1 chemotherapy course with adequate follow-up to assess their response, 119 (64.7%) achieved CR, and the median length of survival (Kaplan-Meier analysis) was 52 months (95% confidence interval [CI]: 23 to 82 months). Factors independently associated with CR were histologic subtype and International Prognostic Index (IPI) score. Factors independently associated with improved overall length of survival (OS) were CR, low IPI score, and histologic subtype. The single factor independently associated with disease-free survival was Ann Arbor stage. CONCLUSIONS: In patients with ARL treated with HAART, CR was associated exclusively with tumor-related factors. The CR rate was poorer in patients with BL and TC subtypes and was inversely correlated with IPI score. OS was independently associated with CR, IPI score, and the histologic subtype.

Endocarditis in the setting of HIV infection.

BACKGROUND: Cardiac complications are becoming more important in patients with HIV infection. The most common is infective endocarditis (IE) in patients who are intravenous drug addicts (IVDA). Other less common problems are pulmonary hypertension, cardiotoxicity, pericardial effusion, cardiac neoplasms, etc. PATIENTS AND METHODS: A literature review of published studies on IE was done and the personal experience of the authors is reflected. RESULTS: The clinical pattern of IE has remained unchanged. It is usually due to Staphylococcus aureus and is more commonly localized to the right side of the heart. It is not clearly defined if HIV infection is responsible for the worst evolution in these patients and the treatment is the same as that used in HIV- subjects. CONCLUSIONS: IE is responsible for 5-20% of hospital admissions and for 5-10% of total deaths in IVDA patients with HIV infection, but the clinical outcome of the patients depends on the affected valve and the culture germen rather than the HIV serostatus.

Gynecomastia in HIV-infected patients receiving antiretroviral therapy.

Thirty-four HIV-positive men with gynecomastia were seen in an HIV outclinic during a 20-month period (incidence of 2.4 cases/100 patients receiving HAART per year). It developed mainly in subjects having good immunologic and virologic status, after an average of 3 years of HAART. No hormone abnormalities were found, or association with specific drugs. Although initially unilateral, more than half of cases progressed to bilateral gynecomastia. Spontaneous resolution occurred in most subjects with 12 months without modifying therapy.

Salvage treatment with lopinavir/ritonavir (Kaletra) in HIV-infected patients failing all current antiretroviral drug families.

BACKGROUND: Lopinavir/ritonavir (Kaletra) is the latest available protease inhibitor (PI). It has shown greater potency than the former PIs in phase II/III trials, either in naive or in PI-experienced patients being naive for nonnucleoside reverse transcriptase inhibitors (NNRTIs). METHOD: We analyzed the first 138 patients recruited during the expanded access program in an HIV/AIDS reference center. Only patients who had significant past exposure to all three different antiretroviral drug families and who were failing their current regimens were chosen. RESULTS: A total of 93 and 76 patients completed, respectively, 3 and 6 months of follow-up. Mean plasma HIV RNA log(10) copies/mL before beginning Kaletra was 4.04 +/- 1.1 and mean CD4 count was 285 +/- 197 cells/mL. Overall, 76.3% and 63.2% of patients showed a significant virologic response (defined as >1 log reduction in plasma HIV RNA and/or a reduction to less than 500 HIV RNA copies/mL) at 3 and 6 months, respectively. The mean CD4 increase was +77.3 cells/mL at 6 months. Thirteen individuals did not complete 6 months on therapy: there were 2 deaths (1 was non-AIDS related), 2 patients were lost to follow-up, 7 patients withdrew due to potential drug adverse events, and 2 patients withdrew due to complications of intercurrent illnesses. Triglyceride levels significantly increased 3 months after initiation of Kaletra (+70 mg/dL; p =.04) while cholesterol levels remained stable (+7.7 mg/dL; p =.7). Sequence analysis at baseline showed a median number of PI mutations of 4 (0 to 12). Overall, 45% of patients harbored >/=5 PI mutations. Attainment of plasma HIV RNA <500 copies/mL occurred in 88% of patients with 5 PI mutations (p <.001). Baseline mutations at codons 71 and 82 were associated with a lower response to Kaletra. CONCLUSION: Kaletra is relatively well tolerated and provides potent antiviral activity in heavily pretreated patients. Significant virological responses are seen in more than three quarters of patients at 3 months. Genotyping at the time of initiation of salvage therapy with Kaletra might help to predict which individuals will experience a greater benefit.