Subclinical cardiovascular disease in patients starting contemporary protease inhibitors.

OBJECTIVES: The aim of the study was to assess changes in and factors associated with anatomical [carotid artery intima-media thickness (CIMT)] and functional (arterial stiffness) markers of subclinical cardiovascular disease progression in antiretroviral-naïve patients starting triple combination antiretroviral therapy containing contemporary protease inhibitors. METHODS: This was a planned substudy of the ATADAR (Metabolic Effects of Atazanavir/Ritonavir Versus Darunavir/Ritonavir in Combination With Tenofovir/Emtricitabine in naïve HIV-1 Infected Patients) clinical trial (ClinicalTrials.gov identifier NCT01274780). ATADAR is a multicentre, randomized, open-label clinical trial comparing the effects of ritonavir-boosted atazanavir and darunavir, both with tenofovir/emtricitabine, in antiretroviral-naïve HIV-infected patients. Common CIMT and aortic augmentation index (AIx@75) were measured at baseline and after 12 months of follow-up. Antiretroviral treatment, traditional cardiovascular risk factors and HIV-related factors were assessed as potential predictors of CIMT and Aix@75 changes using linear regression analysis. RESULTS: Thirty-three patients were included in this pilot study. While CIMT significantly increased in the pooled population [median (interquartile range (IQR)) 68 (-13, 128) µm; P = 0.0511], AIx@75 did not [median (IQR) 1 (-6, 5)%; P = 0.8964]. Patients on darunavir showed a trend to faster CIMT progression than those on atazanavir [median change (IQR) 117 (-2, 143) vs. -6 (-58, 89) µm, respectively; P = 0.0917]. However, after adjustment in the multivariate analysis, a higher baseline Framingham score was the only factor associated with CIMT progression (coefficient 16.02; 95% confidence interval -1.04, 33.08; P = 0.064). AIx@75 change was not associated with any baseline factor. CONCLUSIONS: CIMT was a more sensitive marker of subclinical vascular disease progression than arterial stiffness in antiretroviral-naïve patients starting antiretroviral therapy with contemporary protease inhibitors. Classical risk factors but not antiretroviral therapy were associated with faster CIMT progression.

Improvement of lipoatrophy by switching from efavirenz to lopinavir/ritonavir.

OBJECTIVE: To assess whether changes in antiretroviral drugs other than thymidine nucleoside reverse transcriptase inhibitors (NRTI) may have a body fat impact in HIV-infected patients with lipoatrophy. METHODS: Ninety-six-week phase IV, open-label, multicentre, pilot randomized trial. HIV-infected patients with moderate/severe lipoatrophy at one or more body sites despite long-term thymidine NRTI-free therapy were randomized to continue their efavirenz (EFV)-based antiretroviral regimen or to switch from EFV to lopinavir/ritonavir (LPV/r). The primary endpoint was the absolute change in limb fat mass measured by dual X-ray absorptiometry from baseline to 96 weeks. Changes in other body fat measurements, subjective perception of lipoatrophy, subcutaneous fat gene expression and plasma lipids were also assessed. RESULTS: Thirty-three patients (73% men, median age 52 years) were recruited. At 96 weeks, absolute limb fat mass increased in the LPV/r arm vs. the EFV arm (estimated difference +1082.1 g; 95% CI +63.7 to +2103.5; P = 0.04); this difference remained significant after adjustment by gender, age, fat mass, body mass index and CD4 cell count at baseline. Subjective lipoatrophy perception scores also improved in the LPV/r arm relative to the EFV arm. Adipogenesis, glucose and lipid metabolism, and mitochondrial gene expression increased in the LPV/r arm compared with the EFV arm at 96 weeks. HDL cholesterol decreased in the LPV/r arm relative to the EFV arm. CONCLUSIONS: Switching from EFV to LPV/r in HIV-infected patients with lipoatrophy may offer further limb fat gain beyond thymidine NRTI discontinuation, although this strategy decreased plasma HDL cholesterol and caused changes in subcutaneous fat gene expression that may be associated with increased insulin resistance.

Risk of intrauterine growth restriction among HIV-infected pregnant women: a cohort study.

The purpose of this investigation was to study the risk of intrauterine growth restriction in human immunodeficiency virus (HIV)-infected women and to describe the associated risk factors. A cohort study was performed among HIV-infected women who delivered in a single tertiary centre in Barcelona, Spain, from January 2006 to December 2011. Consecutive singleton pregnancies delivered beyond 22 weeks of pregnancy were included. Intrauterine growth restriction (IUGR) was defined as a birth weight below the 10th customised centile for gestational age and IUGR babies were compared to non-IUGR newborns. Intrauterine Doppler findings were described among IUGR foetuses. Baseline characteristics, HIV infection data and perinatal outcome were compared between groups. The results were adjusted for potential confounders. A total of 156 singleton pregnancies were included. IUGR occurred in 23.4 % of cases (38/156). In two-thirds of the cases detected before birth, Doppler abnormalities compatible with placental insufficiency were observed. IUGR pregnancies presented a worse perinatal outcome, mainly due to a higher risk of iatrogenic preterm delivery [adjusted odds ratio 6.9, 95 % confidence interval (CI) 1.4-33.5]. IUGR foetuses also had a higher risk of emergent Caesarean section and neonatal intensive care unit admission. No cases of intrauterine foetal death occurred. A high rate of IUGR was observed among HIV pregnancies, and it was associated with adverse perinatal outcomes, mainly iatrogenic preterm and very preterm birth due to placental insufficiency. Our results support that ultrasound detection and follow-up of IUGR foetuses should be part of routine antenatal care in this high-risk population to improve antenatal management.

Differential subcutaneous adipose tissue gene expression patterns in a randomized clinical trial of efavirenz or lopinavir-ritonavir in antiretroviral-naive patients.

Gene expression studies of subcutaneous adipose tissue may help to better understand the mechanisms behind body fat changes in HIV-infected patients who initiate antiretroviral therapy (ART). Here, we evaluated early changes in adipose tissue gene expression and their relationship to fat changes in ART-naive HIV-infected patients randomly assigned to initiate therapy with emtricitabine/tenofovir plus efavirenz (EFV) or ritonavir-boosted lopinavir (LPV/r). Patients had abdominal subcutaneous adipose tissue biopsies at baseline and week 16 and dual-energy-X-ray absorptiometry at baseline and weeks 16 and 48. mRNA changes of 11 genes involved in adipogenesis, lipid and glucose metabolism, mitochondrial energy, and inflammation were assessed through reverse transcription-quantitative PCR (RT-qPCR). Additionally, correlations between gene expression changes and fat changes were evaluated. Fat increased preferentially in the trunk with EFV and in the limbs with LPV/r (P < 0.05). After 16 weeks of exposure to the drug regimen, transcripts of CEBP/A, ADIPOQ, GLUT4, LPL, and COXIV were significantly down-regulated in the EFV arm compared to the LPV/r arm (P < 0.05). Significant correlations were observed between LPL expression change and trunk fat change at week 16 in both arms and between CEBP/A or COXIV change and trunk fat change at the same time point only in the EFV arm and not in the LPV/r arm. When combined with emtricitabine/tenofovir as standard backbone therapy, EFV and LPV/r induced differential early expression of genes involved in adipogenesis and energy metabolism. Moreover, these mRNA expression changes correlated with trunk fat change in the EFV arm. (This was a substudy of a randomized clinical trial [LIPOTAR study] registered at ClinicalTrials.gov under identifier NCT00759070.).

Impact of steady-state lopinavir plasma levels on plasma lipids and body composition after 24 weeks of lopinavir/ritonavir-containing therapy free of thymidine analogues.

OBJECTIVES: To study the impact of lopinavir/ritonavir-containing therapy on plasma lipids and body fat of HIV-infected adults and to assess whether lopinavir plasma levels at steady state are correlated with plasma lipids and body fat after 24 weeks. METHODS: Patients had their antiretroviral therapy switched to an antiretroviral regimen containing lopinavir/ritonavir plus one or two non-thymidine analogues. Body composition was assessed by dual energy X-ray absorptiometry at baseline and at week 24 and an intensive pharmacokinetic (PK) 12 h profile was performed at week 2. RESULTS: Twenty-six patients were included. Plasma triglycerides (from 206 mg/dL to 261 mg/dL, P = 0.09) and total cholesterol (from 201 to 206 mg/dL, P = 0.03) increased from baseline to week 24. There was a significant rise in total fat (from 10.9 to 11.9 kg, P = 0.02) and limb fat (from 3.8 to 4.4 kg, P = 0.02) from baseline to week 24. We did not find any correlation between PK lopinavir levels and changes over time for triglycerides, cholesterol or body fat composition. CONCLUSIONS: There was an increase in plasma triglycerides and total cholesterol levels and a gain in both total and limb fat at 24 weeks, but these changes were not correlated with lopinavir plasma levels.

Fertility assessment in non-infertile HIV-infected women and their partners.

The objective of the study was to assess the fertility of non-infertile couples seeking pregnancy in whom the woman was HIV infected. Therefore, a cross-sectional study was conducted between January 1998 and March 2005. A standardized fertility assessment was performed in all the included couples. A total of 130 women and 121 men were evaluated. Their median age was 34 years (range 22-43). Only 7.2% of the women were severely immunocompromised. The majority of women had regular cycles. Only one woman had an active sexually transmitted disease at the time of evaluation. A tubal occlusion on hysterosalpingogram was present in 27.8% of the women with no proven fertility. In 50.5% of the women, hepatitis C virus co-infection was present. One-third of the male partners (38/121) was infected with HIV. Abnormal semen parameters were observed in 83.4% of HIV-infected and 41.7% of HIV-uninfected partners (OR = 7; 95% CI = 2.1-23). It is concluded that the great majority of the HIV-infected women seeking pregnancy had a good infection status. Because in many of the couples, the women presented unexplained tubal occlusions and the men presented semen alterations, a hysterosalpingography and semen analysis should be part of the preconceptional investigations.

Incidence and causes of death in HIV-infected persons receiving highly active antiretroviral therapy compared with estimates for the general population of similar age and from the same geographical area.

BACKGROUND: Since the introduction of highly active antiretroviral therapy (HAART), the incidence of death in HIV-infected patients has dramatically decreased, and causes of death other than those related to HIV infection have increased, although it is unclear how these parameters compare with those in the age-matched general population living in the same geographical region. METHODS: Consecutive HIV-infected adults who were prescribed HAART in our hospital were prospectively followed from January 1997 to December 2004 or until death, loss to follow-up or discontinuation of HAART. Estimations of the annual incidence and causes of death in the general population of similar age in Catalonia per calendar year in the study period were obtained and compared with those in the HIV-infected cohort. RESULTS: There were 235 deaths among the 4471 patients on HAART (5%). The incidence of mortality decreased over time in HIV-infected patients (P<0.001; chi(2) test for trend), although it has remained approximately five times higher than that for the age-matched general population. AIDS-related events were the most common cause of death (n=95; 40%), although they significantly decreased over time (P<0.001; chi(2) test for trend), whereas liver diseases (P<0.001; chi(2) test for trend) and non-AIDS-defining infections (P=0.008; chi(2) test for trend) significantly increased over time. Infections in general (33 times higher), liver diseases (11 times higher) and non-Hodgkin lymphoma (5 times higher) were overrepresented as causes of death in the HIV-infected cohort compared with the age-matched general population. CONCLUSIONS: Non-AIDS-defining infectious diseases, liver diseases, and non-Hodgkin lymphoma represent specific targets for efforts to further decrease mortality in HIV-infected patients receiving HAART.

Intrathoracic fat in HIV-infected patients.

BACKGROUND: The impact of HIV infection or antiretroviral therapy on the intrathoracic fat compartment is unknown. METHODS: Consecutive clinically stable HIV-infected adult patients, irrespective of exposure to antiretroviral therapy, and non-HIV-infected healthy volunteers, both without clinical evidence of body fat changes consistent with lipodystrophy and adjusted for age, gender and body mass index, were recruited for this study. Thoracic and abdominal fat was assessed by computed tomography and compared between patients and controls. RESULTS: There were nine women (33%) and 18 men (67%) in each group. Nineteen patients (70%) had been taking antiretrovirals for a median of 8 months (interquartile range: 6-11). Among the HIV-infected patients, intrathoracic fat (median; interquartile range) did not differ significantly between treated (6.7 cm(2); 4.5-8.3 cm(2)) and untreated (6.9 cm(2); 5.7-10.9 cm(2)) individuals (P=0.288). However, intrathoracic fat content (median; interquartile range) was higher in HIV-infected patients (6.8 cm(2); 5.6-10.5 cm(2)) than in controls (5.6 cm(2); 3.9-6.7 cm(2)) (P=0.025). Intrathoracic fat was positively correlated with intra-abdominal fat both in patients (rho=0.6, P=0.002) and in controls (rho=0.7, P=0.004). CONCLUSION: In HIV-infected adults without clinical evidence of lipodystrophy, intrathoracic fat content was higher than in healthy persons and positively correlated with intra-abdominal fat content.

Estrategias para el manejo de la infección por el virus de la hepatitis C / Management strategies for HVC infections

El objetivo de esta revisión del manejo de la infección por el virus C de la hepatitis, es repasar su epidemiología, diagnóstico, razones para hacer pruebas complementarias como la biopsia hepática o para administrar los últimos tratamientos como la Rivabirina o el Interferón Pegilado (AU)

Estudio multicéntrico penitenciario sobre adherencia a corto plazo de una pauta antirretroviral con Nelfinavir y/o Saquinavir / Study in several prisons of short term adherence to antiretroviral protocol with Nelfinavir and/or Saquinavir

Objetivo: Estudiar la adherencia a una pauta que incluye inhibidores de la proteasa y la importancia del cumplimiento en la eficacia de la terapia. Material y Métodos: Estudio observacional, prospectivo y multicéntrico realizado en 3 prisiones de Barcelona. Se estudia a las 12 y 24 semanas la adherencia y eficacia según cumplimiento de una pauta con nelfinavir y/o saquinavir. Se utiliza la >=2 con la corrección de Yates y la prueba de Mantel-Haenzel en los casos pertinentes. Se calcula la odds ratio con IC del 95 por ciento mediante el método de la proximación mediática de Fleiss. Resultados: Se estudian 98 casos, 96 por ciento hombre y 98 por ciento UDVPs. Se efectuó seguimiento al 85 por ciento a las 12 semanas y al 32 por ciento a las 24 con adherencias del 80,7 por ciento y 60,4 por ciento, respectivamente. Sólo el 50 por ciento realizaba un cumplimiento theta 95 por ciento a las 12 semanas. Fueron causas de incumplimiento los olvidos y la concesión de permisos. El cumplimiento se asoció a la eficacia, observándose que los de cumplimiento theta 95 por ciento presentaban mayor porcentaje de CV indetectable (81,8 por ciento frente a 38,2 por ciento a las 12 semanas y 83,3 por ciento frente a 27,3 por ciento a las 24 semanas) con diferencias estadísticamente significativas (p= 0,0007 y p=0,005, respectivamente). Discusión: La adherencia al TAR en los internos es similar a la citada en otros estudios extrapenitenciarios, pero son escasos los cumplimientos theta 95 por ciento. Se recomienda cuantificar correctamente la adherencia y diseñar estrategias que mejoren el cumplimiento en situaciones como los olvidos o las excarcelaciones temporales (AU)

[Prophylaxis secondary to retinitis by CMV in patients with AIDS: the efficacy of an intermittent schedule of 3 days/week]. / Profilaxis secundaria de la retinitis por citomegalovirus en pacientes con sida: eficacia de una pauta intermitente de 3 días por semana.

BACKGROUND: An approach of daily or 5 days per week treatment as maintenance therapy is mandatory among HIV patients with CMV retinitis. We evaluate the efficacy and tolerance of thrice weekly maintenance therapy for CMV retinitis in AIDS patients. METHODS: Sixty nine consecutive patients with CMV disease were eligible for a prospective open clinical trial. Thirty three completed the induction treatment of CMV retinitis, agreed on maintenance thrice weekly and were included. Twenty nine received Ganciclovir (10 mg/kg/day) and 4 foscarnet (100 mg/kg/day) thrice weekly. RESULTS: The mean age was 34 years. Twenty nine of the 33 (87%) were males and 13 (39%) drug addicts. Mean CD4+ lymphocyte count at inclusion was 44 cells per relapsed and 22 (66%) died. The median time to relapse, survival free of CMV retinitis and the median survival was 18, 14 and 34 weeks respectively. CONCLUSION: Since the outcome of our patients with thrice weekly maintenance therapy was similar to historical controls our study at least provides the rational for this hypothesis to be tested in a future randomised trial.

Filgrastim to treat neutropenia and support myelosuppressive medication dosing in HIV infection. G-CSF 92105 Study Group.

BACKGROUND: Patients with HIV infection frequently experience disease or treatment-related myelosuppression leading to neutropenia. Neutropenia often leads to dose-reduction or discontinuation of important myelosuppressive therapy. OBJECTIVE: To examine the efficacy and safety of filgrastim for reversing neutropenia and determine the effect of this on use of myelosuppressive medications. DESIGN: Open-label, non-comparative, multicentre study in 200 HIV-positive patients with neutropenia [absolute neutrophil count (ANC) < 1.0 x 10(9)/l]. Filgrastim was started at 1 microgram/kg/day subcutaneously for 28 days. This initial treatment phase was followed by a maintenance phase, using 300 micrograms on 1-7 days/week. In both phases the dose of filgrastim was adjusted to achieve an ANC of 2-5 x 10(9)/l. RESULTS: Filgrastim reversed neutropenia in 98% of patients (ANC > or = 2 x 10(9)/l), with a median time to reversal of 2 days (range 1-16) and a median dose of 1 microgram/kg/day (range 0.5-10). Most patients (96%) achieved reversal of neutropenia with a filgrastim dose of < or = 300 micrograms/day (< or = 1 vial/day). Normal ANCs were then maintained with a median of 1 microgram/kg/day (range 0.22-10.6) during the treatment phase and 3 x 300 micrograms vials/week (range 1-7) during the maintenance phase. Ganciclovir, zidovudine, co-trimoxazole and pyrimethamine were the drugs most frequently considered to be causing neutropenia, and 83% of patients received one or more of these in the study. Filgrastim allowed > 80% of patients to increase or maintain dose-levels of these four medications or add them to their therapy. The number of these four medications received per patient increased by > 20% during filgrastim therapy. Filgrastim was well tolerated. CD4, CD8 and total lymphocyte counts all increased slightly, and there was no difference in HIV-1 p24 antigen levels. CONCLUSION: Filgrastim rapidly reverses neutropenia and maintains normal ANC in patients with HIV infection. This allows greater use of myelosuppressive medications without the potentially life-threatening complications of neutropenia.

Necrotizing external otitis treated with ciprofloxacin. A case report.

Necrotizing (malignant) external otitis is a severe infection caused by Pseudomonas aeruginosa which occurs mainly in elderly diabetics or in immuno-depressed patients (Chandler, 1968). The management of this condition requires the association between an aminoglycoside antibiotic and an antipseudomonal beta-lactamic, given parenterally during a 4 to 6 week period. Sometimes it is necessary to continue the therapy for months until there is no evidence of residual disease (Strauss et al., 1982). Ciprofloxacin is a quinolone with antipseudomonal activity which can be taken orally, and it is a useful alternative to the current treatment. The authors report a case of necrotizing external otitis which was successfully treated with ciprofloxacin.