Double invasive fungal infection due to dematiaceous moulds in a renal transplant patient.

Alternaria and Verruconis are two dematiaceous moulds that occasionally cause disease in immunocompromised hosts. We present the case of a 58-year-old man with history of deceased donor renal transplantation 14 months prior, who presented with fevers and cough. He was found to have right upper lobe pneumonia and a non-healing eschar of his right knee. Dematiaceous fungi grew from bronchoalveolar lavage (BAL) and was sent to reference lab for identification. Meanwhile, the eschar on his right knee was biopsied and grew Alternaria spp. Pathology was consistent with invasive mould infection and he was treated as having disseminated Alternaria infection with voriconazole and amphotericin B lipid complex. Later on, the dematiaceous mould from a BAL specimen was identified as Verruconis gallopava The patient was discharged on voriconazole awaiting minimal inhibitory concentrations for V. gallopava but was readmitted 2 days later with high fevers and died from acute respiratory failure.

Trastorno del desarrollo sexual 46, XY tipo ovotesticular por síndrome de Frasier: Caso clínico

Objetivo: Se presenta el caso clínico de una paciente femenina de 27 años con enfermedad renal crónica estadio V a los 19 años, en condición pos trasplante renal quien es referida a la consulta de Endocrinología por amenorrea primaria. Presentación del caso: Al examen físico se evidencia: fenotipo femenino armónico, talla normal, vello púbico Tanner IV y axilar presente, mamas Tanner I, cardiopulmonar: sin alteraciones. Abdomen: lesión ocupante de espacio en fosa ilíaca derecha, no doloroso, compatible con riñón intrapélvico y lesión ocupante de espacio en canal inguinal derecho <1cm, no doloroso, móvil, sin hernias inguinales ni lesión ocupante de espacio en hipogastrio. Genitales externos: labios mayores de aspecto y configuración normal, Prader 1, no se palpan tumoraciones. Ecosonograma inguinal y pélvico: Riñón intrapélvico, no se observó útero ni gónadas. Cariotipo 46,XY. Estudio genético: Amplificación por PCR del ADN del gen WT1: sustitución de aminoácido C> T IVS9 + 4. Se realiza gonadectomía bilateral, cuya biopsia reportó: ovotestis bilateral sin gonadoblastoma. Conclusiones: La presencia de trastornos de la diferenciación sexual tipo ovotesticular sin gonadoblastoma, es el primer caso reportado en la literatura venezolana.

Objective: Case report of female patient 27 years old, with stage V chronic kidney disease, and received a living donor kidney transplant at 19 age, who is referred to Endocrine Unit for primary amenorrhea. Case report: Physical examination evidenced: Harmonic female phenotype, normal height, Tanner IV pubic hair and axillary hair present, breast Tanner I, cardiopulmonary: unchanged. Abdomen: Space-occupying lesion in the right iliac fossa, painless, compatible with intrapelvic kidney and space-occupying lesion in the right inguinal canal <1 cm, painless, mobile, without inguinal hernia or space-occupying lesion in lower abdomen. External genitalia: Majora labia with appearance and normal configuration, Prader 1, no palpable tumors. Inguinal and pelvic sonography: intrapelvic kidney, uterus and gonads were not observed. 46, XY karyotype. Genetic study: PCR Amplification DNA of WT1 gene: Amino acid substitution C> T + 4. IVS9. Bilateral gonadectomy was performed, the biopsy reported: Bilateral ovotestis without gonadoblastoma. Conclusion: The presence of disorder of sexual development and ovotestis without gonadoblastoma and germ cell tumor are unusual presentations of this syndrome, is the first case reported in literature.

Outcomes in HIV/HBV-Coinfected Patients in the Tenofovir Era Are Greatly Affected by Immune Suppression.

OBJECTIVES: HIV-infected patients have higher mortality when coinfected with hepatitis B virus (HBV). With potent highly active antiretroviral therapy (HAART) and the use of tenofovir (TDF), outcomes may improve. Our objective was to determine the clinical and virological outcomes of a HIV/HBV-Coinfected cohort at our center since TDF became available. METHODS: We retrospectively studied all HIV/HBV-Coinfected adults followed between 2002 and 2012 for ≥3 months. Outcome measurements included HBV DNA suppression, HBV e-antigen (HBeAg) and HBV surface antigen (HBsAg) clearance, cirrhosis diagnosis, development of liver complications, and overall and liver-related mortality. Predicting factors were assessed with log-rank test and logistic regression. RESULTS: Median time to follow-up of the 99 patients included was 5 years. Undetectable HBV DNA and HBsAg loss were achieved by 65% and 18%, respectively. Overall and liver-related mortality rates were 4.58 and 0.91 per 100 person-years, respectively. Most patients died of causes unrelated to the liver. Four patients died from hepatocellular carcinoma (HCC) and one, hepatitis C virus (HCV) coinfected, from liver failure. Higher CD4 counts at last follow-up were associated with HBV suppression (odds ratio [OR] 1.004, 95% confidence interval [CI] 1.001-1.006, P=.007), HBeAg loss (OR 1.003, 95% CI 1-1.005, P=.02), HBsAg loss (CD4 count>700 cells/mm3, OR 3.80, 95% CI 1.06-13.58, P=.04), and survival (OR .994, 95% CI 0.990-0.997, P<.0001). HCV coinfection was associated with higher overall mortality (OR 7.74, 95% CI 1.47-40.81, P=.02). CONCLUSION: Mortality was high and most often unrelated to liver disease in this HIV/HBV-Coinfected cohort treated predominantly with TDF-containing HAART. Optimal CD4 counts predicted survival and the achievement of HBV virological end points. Tenofovir prevented liver decompensation but not HCC, which was the predominant cause of liver death.

Nesidioblastosis en adolescentes: A propósito de un caso

Objetivos: Describir la presentación de un caso clínico de nesidioblastosis en una paciente adolescente. Caso clínico: Adolescente femenina de 14 años de edad, con inicio de enfermedad actual en Febrero/2013, caracterizada por cefalea de moderada intensidad, concomitantemente diaforesis y mareos; en Marzo/2013 presenta movimientos tónico-clónicos generalizados, retroversión ocular con pérdida del estado de conciencia (en 2 oportunidades), es trasladada a centro médico donde evidencian glucemia en 48 mg/dl y 40 mg/dl respectivamente, colocan solución dextrosa con mejoría. Estudios complementarios revelan: hipoglucemia en ayunas: glucemia 40 mg/dl, para vun valor de insulina de 46,7 μUI/ml; es ingresada realizándose prueba de ayuno de 72 horas, a las 10 horas del inicio de la misma se evidencia triada de Whipple, y las muestras confirmaron hipoglucemia por hiperinsulinismo endógeno; se realizan estudios de localización sin evidencia de lesión. El 24/07/13 se realiza laparotomía abierta. Biopsia post-operatoria reportó: hiperplasia de las células de los islotes de Langerhans. En su post-operatorio tardío presenta síntomas de hipoglucemia. Se sugiere completar la cirugía, se inicia manejo farmacológico con Verapamilo a dosis de 40 mg cada 8 horas, con respuesta satisfactoria. Conclusión: La nesidioblastosis en una causa rara de hipoglucemia por hiperinsulinismo endógeno en el adulto, sin casos reportados en adolescentes, clínicamente es indistinguible del insulinoma; bioquímicamente es necesario documentar la hipoglucemia hiperinsulinémica mediante una prueba de ayuno de 72 horas, los estudios de extensión no aportan datos específicos, el tratamiento de elección es la cirugía, el tratamiento médico está reservado principalmente para casos con alto riesgo quirúrgico y recidivas.

Objectives: To describe a clinical case of nesidioblastosis in a teenage patient. Clinical case: This is a fourteen-year-old female teenage patient, with current illness starting on February/2013 characterized by headache of moderate intensity, concomitantly diaphoresis and dizziness. In March/2013 she presents generalized tonic-clonic movements, ocular retroversion with loss of consciousness (2 opportunities) and is referred to a medical center where they find a glycemia of 48 mg/dl and 40 mg/dl respectively, improving with glucose solution. Since complementary studies revealed fasting hypoglycemia: glycemia 40 mg/dl for insulin value 46.7 μUI/ml, the patient is hospitalized for a 72 hours fasting test, and at 10 hours from the start, a Whipple triad is evidenced, and blood tests confirmed hypoglycemia due to endogenous hyperinsulinism. Localization studies are performed with no evidence of a lesion. On 07/24/2013 an open laparotomy is carried out. Postoperatory biopsy reported: Langerhans islet cell hyperplasia. During late postoperative period, hypoglycemic symptoms reappear. It is suggested to complete surgery and pharmacological management with Verapamil at 40 mg every 8 hours is started, with a satisfactory response. Conclusion: Nesidioblastosis is a rare cause of hypoglycemia by endogenous hyperinsulinism in adults, with no case reports in teenagers. It is clinically indistinguishable from insulinoma and it is necessary to biochemically demonstrate hyperinsulinemic hypoglycemia with a 72 hour fasting test. Imaging studies don’t provide specific data. Surgical treatment is first choice and pharmacological treatment is reserved mainly for high-risk surgical patients and recurrence.

JC polyoma virus interacts with APOL1 in African Americans with nondiabetic nephropathy.

Individuals with HIV infection and two apolipoprotein L1 gene (APOL1) risk variants frequently develop nephropathy. Here we tested whether non-HIV viral infections influence nephropathy risk via interactions with APOL1 by assessing APOL1 genotypes and presence of urine JC and BK polyoma virus and plasma HHV6 and CMV by quantitative polymerase chain reaction. We analyzed 300 samples from unrelated and related first-degree relatives of African Americans with nondiabetic nephropathy using linear and nonlinear mixed models to account for familial relationships. The four groups evaluated were APOL1 zero/one versus two risk alleles, with or without nephropathy. Urine JCV and BKV were detected in 90 and 29 patients, respectively, whereas HHV6 and CMV were rare. Adjusting for family age at nephropathy, gender, and ancestry, presence of JCV genomic DNA in urine and APOL1 risk alleles were significantly negatively associated with elevated serum cystatin C, albuminuria (albumin-to-creatinine ratio over 30 mg/g), and kidney disease defined as an eGFR under 60 ml/min per 1.73 m(2) and/or albuminuria in an additive (APOL1 plus JCV) model. BK viruria was not associated with kidney disease. Thus, African Americans at increased risk for APOL1-associated nephropathy (two APOL1 risk variants) with JC viruria had a lower prevalence of kidney disease, suggesting that JCV interaction with APOL1 genotype may influence kidney disease risk.

Aprendizaje-servicio como metodología para el desarrollo del pensamiento crítico en educación superior / Learning plus service as a methodology for the development of the critical thinking in the higher education

Aprendizaje-servicio (A+S) es una metodología que nace en Estados Unidos en el año 1903 como un movimiento de educación cooperativa, que integra trabajo, servicio y aprendizaje. Esta revisión tiene por objetivo conocer el estado del arte del uso de esta metodología en diversos planes de estudio en profesiones de servicio. Se realizó una búsqueda en las bases de datos disponibles en el Sistema de Bibliotecas de la Pontificia Universidad Católica de Chile durante noviembre del 2011. Los resultados hacen referencia a la conceptualización de aprendizaje-servicio y pensamiento crítico en la educación superior, su interrelación y modelos de implementación de A+S. Se concluye que su incorporación en la educación superior tiene impacto, debido a que otorga beneficios de las actividades de reflexión, tanto académicas (habilidades de pensamiento complejo y solución de problemas), como de desarrollo personal (clarificación de valores, autoconocimiento) y curricular...

Learning plus service is a type of methodology that emerged in the United States in 1903 as a cooperative educational movement comprising work, service and learning. The present review has the objective of finding out the state of the art of the use of this methodology in several curricula of professions for service. A search was made in the databases available in the library system of the Pontificia Universidad Catolica de Chile on November, 2011. The results referred to the conceptualization of the service learning, and the critical thinking at the higher education, their interrelationship, and the models of the service learning implementation. It was concluded that the incorporation of this methodology in the higher education has an impact, since it brings the benefits of the reflection activities, including academic (abilities for the complex thinking and the resolution of problems), personal development (clarification of values, self-knowledge) and curricular...

Liver toxicity of antiretroviral drugs.

Drug-induced liver injury (DILI) associated with antiretroviral treatment has represented an important side effect since the beginning of the HAART era. The lack of standard definition and specific markers makes assessment of DILI very challenging. Several clinical syndromes of DILI have been described over the years; the pathogenic mechanisms are not fully understood. Better knowledge of DILI, identification of high-risk patients using pharmacogenetics, and the availability of antiretroviral agents with improved safety profile have all contributed to decrease the incidence of DILI and to ameliorate its effects. Nevertheless, with an aging human immunodeficiency virus- (HIV-) infected population and increased survival, DILI will probably continue to represent a relevant entity in e HIV therapeutic management.

Association of APOL1 variants with mild kidney disease in the first-degree relatives of African American patients with non-diabetic end-stage renal disease.

Familial aggregation of non-diabetic end-stage renal disease (ESRD) is found in African Americans and variants in the apolipoprotein L1 gene (APOL1) contribute to this risk. To detect genetic associations with milder forms of nephropathy in the high-risk families, analyses were performed using generalized estimating equations to assess relationships between kidney disease phenotypes and APOL1 variants in 786 relatives of 470 families. Adjusting for familial correlations, 23.1, 46.7, and 30.2% of genotyped relatives possessed two, one, or no APOL1 risk variants, respectively. Relatives with two compared with one or no risk variants had statistically indistinguishable median systolic blood pressure, urine albumin to creatinine ratio, estimated glomerular filtration rate (GFR; MDRD equation), and serum cystatin C levels. After adjusting for age, gender, age at ESRD in families, and African ancestry, significant associations were detected between APOL1 with overt proteinuria and estimated GFR (CKD-EPI equation), with a trend toward significance for quantitative albuminuria. Thus, relatives of African Americans with non-diabetic ESRD are enriched for APOL1 risk variants. After adjustment, two APOL1 risk variants weakly predict mild forms of kidney disease. Second hits appear necessary for the initiation of APOL1-associated nephropathy.

Virological rather than host factors are associated with transaminase levels among HIV/HCV-coinfected patients.

Alanine aminotransferase (ALT) is a routine parameter in the assessment and monitoring of chronic hepatitis C viral (HCV) infection. Hepatitis C virus-infected African Americans (AAs) have been reported to have lower ALT levels. In this retrospective, cross-sectional, multicenter study, host and virological factors possibly associated with ALT levels were analyzed by multivariate regression analyses among HIV/HCV-coinfected patients. Of the 289 patients included, 142 were African Americans and 144 Caucasians. In multivariate analysis, only HCV genotype 3 (B 0.2 [95% CI 13.39-52.33]; P = .001) and HCV RNA >500 000 IU/mL (B 3.1 [95% CI 7.67-34.75]; P = .002) were independent predictors of higher ALT levels. Per the American Association for the Study of Liver Disease (AASLD) definition, 18.2% had ALT levels within normal limits. Male sex and HCV RNA <500 000 IU/mL predicted ALT within normal limits. Hepatitis C viral factors rather than race were associated with ALT levels in this HIV/HCV-coinfected population. ALT were within normal limits in 18% of patients, who more often were male and had lower Hepatitis C viral load.

Undetectable hepatitis C virus RNA at week 4 as predictor of sustained virological response in HIV patients with chronic hepatitis C.

BACKGROUND: Low baseline serum hepatitis C virus (HCV)-RNA and clearance of viraemia at week 4 with pegylated interferon (pegIFN) plus ribavirin therapy predict sustained virological response (SVR) and enable a shorter duration of therapy in patients with chronic hepatitis C. It is unclear whether this applies to HIV/HCV-co-infected patients. PATIENTS AND METHODS: In the Peginterferon Ribavirin ESpaña COinfection (PRESCO) trial, 389 co-infected patients received pegIFN-alpha2a 180 microg/week plus ribavirin 1000-1200 mg/day. Patients with HCV-2/3 were treated for 6 or 12 months, whereas patients with HCV-1/4 were treated for 12 or 18 months. For each genotype, baseline HCV-RNA and rapid virological response (RVR), defined as under 50 IU/ml HCV-RNA at week 4, were evaluated as predictors of SVR in an 'on-treatment' analysis. RESULTS: Overall, SVR was achieved by 193 patients (49.6%), 68/191 (35.6%) with genotype 1, 110/152 (72.4%) with genotypes 2/3 and 15/46 (32.6%) with genotype 4. RVR was the best predictor of SVR regardless of HCV genotype. Only for HCV-1 patients, baseline HCV-RNA less than 500 000 IU/ml was also associated with SVR. In HCV-3 patients RVR had a positive predictive value (PPV) for SVR of 90%, with treatment for 24 or 48 weeks. The PPV of SVR for patients with RVR was 69% for HCV-1 and 83% for HCV-4. CONCLUSION: Undetectable HCV-RNA at week 4 is the best predictor of curing chronic hepatitis C in HCV/HIV-co-infected patients. In HCV-1 patients, baseline HCV-RNA also predicts response. HIV patients with HCV-3 and RVR may permit shortening therapy duration to only 24 weeks of pegIFN plus 1000-1200 mg ribavirin.

Role of weight-based ribavirin dosing and extended duration of therapy in chronic hepatitis C in HIV-infected patients: the PRESCO trial.

The response to pegylated interferon (pegIFN) plus ribavirin (RBV) as treatment of chronic hepatitis C virus (HCV) infection is lower in HIV-coinfected than in HCV-monoinfected patients and could be due to suboptimal RBV dosing and/or insufficient duration of therapy in prior trials. In a prospective, multicenter, open, comparative trial, HCV/HIV-coinfected patients received pegIFN plus weight-based RBV for 48 or 72 weeks (HCV genotypes 1 and 4) and 24 or 48 weeks (HCV genotypes 2 and 3). Use of didanosine was not allowed. Out of 389 patients included in the trial, 61% were infected by HCV-1/4 and 67% had serum HCV-RNA >500,000 IU/ml. Sustained virological response (SVR) was achieved by 49.6%, significantly higher in HCV-2/3 than HCV-1/4 (72.4% vs. 35%; p < 0.0001). A high drop-out rate in the longer treatment arms precluded obtaining definitive conclusions about the efficacy of prolonging therapy. Premature treatment discontinuations due to serious adverse events occurred in 8.2%. Infection with HCV-2/3, lower baseline HCV-RNA, and negative HCV-RNA at week 12 were all independent predictors of SVR in the multivariate analysis. The use of RBV 1000-1200 mg/day plus pegIFN is relatively safe and provides SVR in nearly half of coinfected patients, twice as high in HCV-2/3 than HCV-1/4.

Influence of HCV genotype and co-infection with human immunodeficiency virus on CD4(+) and CD8(+) T-cell responses to hepatitis C virus.

The role of T-cells in clearance of hepatitis C virus (HCV) during acute infection is critical. The relevance of the immunological response in the control of HCV replication is less clear in chronic HCV infection. HCV-specific T-cell responses were examined in 92 interferon-naive individuals with chronic hepatitis C. A panel of 441 overlapping peptides spanning all expressed HCV proteins was used to measure HCV-specific T-cell responses, using flow cytometry after stimulating peripheral blood mononuclear cells (PBMCs) with different pools of these peptides. Most patients showed responses to at least one HCV protein, with NS5B for CD8(+) responses and E2 for CD4(+) responses identified most frequently. Both the prevalence and breadth of CD4(+) and CD8(+) responses were lower in co-infected patients, independently of the HCV genotype.

Liver fibrosis in HIV-infected patients with chronic hepatitis B extensively exposed to antiretroviral therapy with anti-HBV activity.

PURPOSE: The extent and predictors of liver fibrosis were examined in a HIV/HBVcoinfected cohort with extensive exposure to anti-HBV active HAART. METHOD: Liver fibrosis was measured using transient elastography. RESULTS: Thirty-seven patients of a median age of 43 were included in the study. All but 2 patients had received anti-HBV drugs for a median time of 40 months in the context of HAART. F0-F1 METAVIR fibrosis scores (minimal or no fibrosis) as measured by elastography were found in 21 (57%) patients. AST levels were significantly lower among F0-F1 patients (33 IU/L) compared to F2-F4 patients (48 IU/L) (p = .01). ALT levels were also lower in F0-F1 patients (38 IU/L) than in F2-F4 patients (54 IU/L) (p = .05). CONCLUSION: In this HIV/HBV-coinfected cohort, with extensive HAART exposure including anti-HBV agents, more than half of the patients had no or minimal liver fibrosis. Higher transaminase levels were recognized in patients with higher degree of fibrosis.

Chronic hepatitis C in HIV-infected patients: those who more need therapy are those who respond less.

One third of HIV-infected individuals worldwide suffer from chronic hepatitis C virus (HCV) infection. Two main reasons justify considering HCV therapy as a priority in HIV-coinfected patients. First, these patients have more rapid liver disease progression, and second, they have a higher risk of developing hepatotoxicity following the initiation of antiretroviral therapy. Unfortunately, HCV therapy is associated with lower response rates and higher rate of side effects in HIV-coinfected patients. However, recent evidence suggests that when HCV therapy is administered adequately (to optimal candidates; using full doses of ribavirin; at least for 12 months irrespective of the HCV genotype; and with satisfactory drug adherence), treatment responses may not differ much from those seen in HCV-monoinfected individuals. Treatment should be considered up front in antiretroviral-naive subjects with stable HIV infection. In patients already on antiretroviral therapy, HCV therapy should not be administered before replacing didanosine by another antiretroviral, given the increased risk of mitochondrial toxicities. If possible, zidovudine should be avoided as well, given the high risk of anemia. The histological information provided by either non-invasive procedures (FibroScan, Fibro-test, etc.) or liver biopsy is useful but should not be considered as mandatory before prescribing HCV therapy. In summary, liver disease associated to HCV is a growing problem among HIV-positive individuals. The relatively low efficacy of current anti-HCV medications and their low tolerability clearly indicated the need for new drugs with more potent and direct antiviral activity against HCV.

Severe liver disease associated with prolonged exposure to antiretroviral drugs.

BACKGROUND: Liver damage is frequently seen in HIV-positive subjects, often resulting from coinfection with hepatitis B and/or C viruses (HCV), alcohol abuse, etc. However, the etiology of liver disease still remains unknown for a small subset of individuals. METHODS: Cryptogenic liver disease (CLD) was defined as persistently elevated aminotransferases levels in the absence of hepatitis C and/or B viruses replication and of other common causes of liver disease (alcohol, medications, etc). We identified cases initially meeting this definition by examining all HIV-positive subjects attended during the year 2004 in 2 large HIV clinics in Spain. Their clinical charts were retrospectively reviewed, and their assessment completed when needed to rule out other less frequent causes of liver disease. The stage of liver fibrosis was assessed by liver biopsy and/or elastography. To assess which factors could be associated with CLD, HIV-positive controls were chosen and matched by age, gender, and CD4 status. RESULTS: CLD was diagnosed in 17 (0.5%) out of 3200 HIV-positive patients. Their mean age was 43 years, 82.4% were male, and 76% had acquired HIV through homosexual relationships. The mean time from HIV diagnosis was >15 years, and all patients had been exposed to antiretroviral therapy. Nevirapine, stavudine, and didanosine were the drugs more frequently used by this subset of patients. None of them had liver function test abnormalities before initiating antiretroviral therapy. Advanced liver fibrosis (F3-F4 Metavir scores) was recognized in 10 (58.8%) individuals, and 9 (52.9%) had developed symptomatic liver complications, including ascites (8), portal thrombosis (6), variceal bleeding (5), and encephalopathy (2). In the case-control analysis, prolonged didanosine exposure was the only independent predictor of developing CLD in this population. CONCLUSIONS: CLD is an uncommon condition in HIV-positive individuals and might be associated with prolonged didanosine exposure. It may evolve causing severe liver complications, with variceal bleeding and portal thrombosis being particularly frequent.

Management of chronic hepatitis B and C in HIV-coinfected patients.

One-third of HIV-infected individuals worldwide suffer from chronic hepatitis C virus (HCV) infection, but chronic hepatitis C affects more than 75% of HIV-positive subjects infected parenterally, such as haemophiliacs and intravenous drug users. Chronic hepatitis B virus (HBV) infection, on the other hand, occurs in 10% of HIV-infected persons, coinfection being more prevalent in Southeast Asia. There are two main reasons for considering HCV and HBV therapy as a priority in HIV-coinfected patients: first, the more rapid liver disease progression seen in this population, leading to end-stage liver disease complications, including hepatocellular carcinoma, at younger ages; and second, the higher risk of developing hepatotoxicity following the initiation of antiretroviral therapy in subjects with underlying chronic hepatitis than in HIV-monoinfected individuals. As highly active antiretroviral therapy (HAART) has dramatically improved the prognosis of those with HIV disease, the consequences of associated illnesses such as hepatitis B and C, which are currently among the leading causes of hospital admission and death in the HIV-infected population, have become more relevant. Therefore, the adequate management of viral hepatitis should now be considered a priority in HIV-coinfected patients. Several guidelines have recently been released in response to this demand. In this article, we discuss the most critical issues highlighted in these documents.

Selection of hepatitis B virus polymerase mutations in HIV-coinfected patients treated with tenofovir.

BACKGROUND: Tenofovir (TDF) is an adenosine nucleotide analogue that has been approved for the treatment of HIV-1 infection. It also shows activity against hepatitis B virus (HBV) in patients with or without lamivudine (LAM)-associated mutations. Development of clinical or virological HBV breakthrough during TDF therapy has not been reported so far. The aim of this study was to analyse the HBV polymerase (pol) from HIV/HBV-coinfected patients with detectable serum levels of HBV DNA during treatment with TDF for longer than 6 months. METHODS: The HBV pol was sequenced from 43 patient's serum before and during TDF therapy. Phenotypic analyses were performed using HBV replication-competent plasmids carrying unique mutations selected under TDF therapy. RESULTS: Mean exposure to LAM was 35.3 +/- 27.5 months and to TDF 11.2 +/- 6.7 months. Genotypic analyses from 21 of the patients revealed LAM-associated mutations, and a further two patients developed a novel mutation, rtA194T, along with LAM-resistance-associated mutations. Phenotypic analyses revealed that constructs harbouring rtA194T combined with rtL180M and rtM204V displayed an over 10-fold increase in the IC50 for TDF compared with the wild type. CONCLUSION: The selection of HBV mutations in HBV/HIV-coinfected patients failing TDF therapy is an unlikely event within the first 12 months of treatment. However, HBV from two of the 43 patients treated with TDF for more than 12 months was found to contain one novel mutation located distal to the catalytic site of the HBV pol. In vitro, rtA194T conferred a reduced susceptibility to TDF in the presence of LAM-associated mutations.

Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virus suppression taking tenofovir and didanosine.

BACKGROUND: Tenofovir (TDF) and didanosine (ddI) are both adenosine analogues with convenient posology, strong potency and a relatively high genetic barrier for resistance. The popularity of this combination, however, has been questioned due to concerns about pharmacokinetic interactions and increased risk of pancreatitis and hyperglycemia. Less information is available about other possible side effects. PATIENTS AND METHODS: HIV-infected individuals who initiated a protease inhibitor-sparing regimen between September 2002 and June 2003 at five hospitals, and had at least one subsequent visit within the next 12 months, always with complete virus suppression, were retrospectively assessed. Only drug-naive individuals and patients who simplified a prior successful antiretroviral regimen were analysed. RESULTS: Outcomes were analysed in 570 individuals according to treatment modality (98 drug-naive versus 472 simplified); the nucleoside analogue (NA) backbone (298 with TDF + ddI, 88 with ddI, 44 with TDF, and 140 with neither ddI nor TDF); and the third agent used (378 with non-nucleoside analogues versus 192 with NA). Significant CD4+ T-cell declines were seen in patients taking ddI + TDF with respect to all other NA combinations, including ddI or TDF separately. Patients exposed to high ddI doses or taking a third NA showed more pronounced CD4 declines. Plasma levels of ddI correlated with the extent of CD4+ T-cell loss. CONCLUSION: Patients receiving ddI + TDF-based combinations show CD4+ T-cell declines despite achieving complete virus suppression. This effect generally progresses with time. An imbalance in adenosine metabolites within CD4+ T lymphocytes may explain this phenomenon, which resembles the genetic purine nucleoside phosphorylase deficiency syndrome.