Efficacy and safety of entecavir for chronic HBV in HIV/HBV coinfected patients receiving lamivudine as part of antiretroviral therapy

Background: Prolonged use of lamivudine in patients coinfected with HIV and hepatitis B virus (HBV) leads to an increasing risk of lamivudine resistance in both diseases. We investigated the addition of entecavir, a potent inhibitor of HBV polymerase, to lamivudine-containing highly active antiretroviral therapy (HAART) in patients who experienced rebound in HBV viremia while maintaining Suppression of plasma HIV RNA less than 400 copies/ml. Methods: Sixty-eight patients were randomized to entecavir 1 mg (n = 51) or placebo (n = 17) once daily for 24 weeks; 65 patients continued the study with entecavir for an additional 24 weeks. Lamivudine-containing HAART was continued throughout. Results: At week 24, the mean HBV DNA in entecavir-treated patients was 5.52 log(10) - copies/ml versus 9.27 log(10) copies/ml for placebo, and at week 48, it was 4.79log(10) copies/ml versus 5.63log(10) copies/ml, respectively. The mean HBV DNA change from baseline for entecavir was -3.65 log(10) copies/ml (versus + 0.11 for placebo, P < 0.0001) and alanine aminotransferase normalization in 34%. of patients (versus 8% for placebo, P=0.08)At 48 weeks, mean change in HBV DNA reached -4.20log(10) copies/ml inpatients who received entecavir for the entire 48 weeks. The frequency of adverse events with entecavir and placebo was comparable. Through 48 weeks, no clinically relevant changes in HIV viremia or CD4 cell Counts were identified. Conclusion: In this study, entecavir was associated with rapid, clinically significant reductions in HBV DNA, with maintenance of HIV viremia suppression, in HIV/HBV coinfected patients with HBV viremia while on lamivudine treatment. (C) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Tuberculosis-Associated Collapsing Glomerulopathy: Remission after Treatment

Collapsing glomerulopathy (CG) is a severe form of nephrotic syndrome and has been mostly associated with human immunodeficiency virus (HIV) infection. Treatment response is poor, and the disease frequently leads to end-stage renal disease. More recently, CG has been described in association with other conditions, such as drug exposure and other infections, but renal prognosis remains unfavorable. This paper reports an interesting case of an HIV-negative patient with tuberculosis-related CG who needed dialysis for five months but presented full renal recovery after tuberculosis (TB) treatment and corticotherapy.

Very early prediction of response to HCV treatment with PEG-IFN-alfa-2a and ribavirin in HIV/HCV-coinfected patients

The objective of this study was to find very early viral kinetic markers to predict nonresponse to hepatitis C virus (HCV) therapy in a group of human immunodeficiency virus (HIV)/HCV-coinfected patients. Twenty-six patients (15 HCV genotype-1 and 11 genotype-3) were treated with a 48-week regimen of peginterferon-alfa-2a (PEG-IFN) (180 mu g/week) and weight-based ribavirin (11 mg/kg/day). Samples were collected at baseline; 4, 8, 12, 18, 24, 30, 36 and 42 h; days 2, 3, 4, 7, 8, 15, 22, 29, 43 and 57 then weekly and monthly. Five patients discontinued treatment. Seven patients (27%) achieved a sustained virological response (SVR). Nadir HCV RNA levels were observed 1.6 +/- 0.3 days after initiation of therapy, followed by a 0.3- to 12.9-fold viral rebound until the administration of the second dose of PEG-IFN, which were not associated with SVR or HCV genotype. A viral decline < 1.19 log for genotype-1 and < 0.97 log for genotype-3, 2 days after starting therapy, had a negative predictive value (NPV) of 100% for SVR. The day 2 virological response had a similar positive predictive value for SVR as a rapid virological response at week 4. In addition, a second-phase viral decline slope (i.e., measured from day 2 to 29) < 0.3 log/week had a NPV = 100% for SVR. We conclude that first-phase viral decline at day 2 and second-phase viral decline slope (< 0.3 log/week) are excellent predictors of nonresponse. Further studies are needed to validate these viral kinetic parameters as early on-treatment prognosticators of nonresponse in patients with HCV and HIV.

Distinct resistance mutation and polymorphism acquisition in HIV-1 protease of subtypes B and F1 from children and adult patients under virological failure

The goal of this work was to compare the differences between human immunodeficiency Virus type 1 (HIV-1) of B and F1 Subtypes in the acquisition of major and rninot- protease inhibitor (P1)-associated resistance mutations and of other polymorphisms at the protease (PR) gene, through a cross sectional Study. PR sequences from subtypes B and F1 isolates matched according to P1 exposure time from Brazilian patients were included in this study. Sequences were separated in four groups: 24 and 90 from children and 141 and 99 from adults infected with isolates of subtypes F1 and B, respectively. For comparison, 211 subype B and 79 subtype F1 PR sequences from drug-naive individuals Were included. Demographic and clinical data were similar among B- and F1-infected patients. In untreated patients, Mutations L1OV, K20R, and M361 were more frequent in subtype F1, while L63P, A7IT, and V771 were more prevalent in Subtype B. In treated patients, K20M, D30N, G73S, 184V, and L90M, were More prevalent in subtype B, and K20T and N88S Were more prevalent in Subtype F1. A higher proportion of subtype F1 than Of subtype B Strains Containing other polymorphisms was observed. V82L mutation was Present With increased frequency in isolates from children compared to isolates from adults infected with both subtypes. We could observe a faster resistance emergence in children than in adults, during treatment with protease inhibitors. This data provided evidence that, although rates of overall drug resistance do not differ between subtypes B and F1, the former accumulates resistance at higher proportion in specific amino acid positions of protease when compared to the latter. (c) 2008 Elsevier B.V. All rights reserved.

Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men.

Background: Antiretroviral chemoprophylaxis before exposure is a promising approach for the prevention of human immunodeficiency virus (HIV) acquisition. Methods: We randomly assigned 2499 HIV-seronegative men or transgender women who have sex with men to receive a combination of two oral antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate (FTC-TDF), or placebo once daily. All subjects received HIV testing, risk-reduction counseling, condoms, and management of sexually transmitted infections. Results: The study subjects were followed for 3324 person-years (median, 1.2 years; maximum, 2.8 years). Of these subjects, 10 were found to have been infected with HIV at enrollment, and 100 became infected during follow-up (36 in the FTC-TDF group and 64 in the placebo group), indicating a 44% reduction in the incidence of HIV (95% confidence interval, 15 to 63; P=0.005). In the FTC-TDF group, the study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001). Nausea was reported more frequently during the first 4 weeks in the FTC-TDF group than in the placebo group (P<0.001). The two groups had similar rates of serious adverse events (P=0.57). Conclusions: Oral FTC-TDF provided protection against the acquisition of HIV infection among the subjects. Detectable blood levels strongly correlated with the prophylactic effect. (Funded by the National Institutes of Health and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT00458393.) N Engl J Med 2010;363:2587-99.

A Sustained Virologic Response Is Durable in Patients With Chronic Hepatitis C Treated With Peginterferon Alfa-2a and Ribavirin

BACKGROUND & AIMS: A sustained virologic response (SVR) to therapy for hepatitis C virus (HCV) infection is defined as the inability to detect HCV RNA 24 weeks after completion of treatment. Although small studies have reported that the SVR is durable and lasts for long periods, it has not been conclusively shown. METHODS: The durability of treatment responses was examined in patients originally enrolled in one of 9 randomized multicenter trials (n = 1343). The study included patients who received pegylated interferon (peginterferon) alfa-2a alone (n = 166) or in combination with ribavirin (n = 1077, including 79 patients with normal alanine aminotransferase levels and 100 patients who were coinfected with human immunodeficiency virus and HCV) and whose serum samples were negative for HCV RNA (<50 IU/mL) at their final assessment. Patients were assessed annually, from the date of last treatment, for a mean of 3.9 years (range, 0.8-7.1 years). RESULTS: Most patients (99.1%) who achieved an SVR had undetectable levels of HCV RNA in serum samples throughout the follow-up period. Serum samples from 0.9% of the patients contained HCV RNA a mean of 1.8 years (range, 1.1-2.9 years) after treatment ended. It is not clear if these patients were reinfected or experienced a relapse. CONCLUSIONS: In a large cohort of patients monitored for the durability of an SVR, the SVR was maintained for almost 4 years after treatment with peginterferon alfa-2a alone or in combination with ribavirin. In patients with chronic hepatitis C infection, the SVR is durable and these patients should be considered as cured.

Simultaneous Chlamydia trachomatis and HPV Infection in Pregnant Women

Pregnancy is associated with HPV infection and with Chlamydia trachomatis (CT) infection mostly due to the natural immunosuppression. In addition, pregnancy associated to CT infection can lead to adverse conditions to the woman and fetus, and CT is also believed to be a co-factor in human immunodeficiency virus infection and HPV-induced cervical cancer. The aim of this study was to establish the odds ratios (OR) of CT infection in to HPV-infected pregnant women and vice versa of women stratified by age (<25 years) and marital status. This work is part of a national multicentric transversal study carried out in six Brazilian cities supported by the Ministry of Health of Federal Government of Brazil in 2003. Cervical scrapes of 371 pregnant women were sampled. We performed a hybrid capture-2 technique to diagnose these samples on HPV and CT infection, and the women responded a questionnaire. Significant association was observed between nonstable marital status and hr-HPV infection [OR = 2.61 (1.38-4.97) P = 0.003)], and age <25 years old [OR = 2.26 (1.09-4.71) P = 0.029]. Nonstable marital status was also associated with lr-HPV infection [OR = 2.67 (1.59-4.50) P < 0.001), and age <25 years old [OR = 2.55 (1.51-4.32) P < 0.001). Fifty of the 371 pregnant women were infected with hr-HPV (13.5%) and 111 (30.0%) were infected with lr-HPV. The coinfections of HPV and CT were found in 31 women, that is, 8.36% of the pregnant women (P < 0.001). The high rate of simultaneous CT and HPV infection in pregnant women favors the recommendation to screen pregnant women for both CT and HPV. Diagn. Cytopathol. 2010;38:397-401. (C) 2009 Wiley-Liss, Inc.

Brain abscess due to viridans streptococci in a severely immunosuppressed HIV-infected patient

We report a case of viriclans streptococcus brain abscess in a severely immunosuppressed HIV-infected patient with a history of chronic sinusitis. A 39-year-old homosexual man showed mental confusion and worsening of a frontal brain lesion after two weeks with antitoxoplasma therapy. Empiric treatment for central nervous system tuberculosis and pyogenic brain abscess was started. He underwent surgical drainage and the diagnosis of brain abscess due to viriclans streptococci was confirmed. All empiric treatments were stopped and ceftriaxone was used for eight weeks, showing complete clinical and radiological resolution. Although infrequent, viriclans streptococci, a common pyogenic aetiology of brain abscess in immunocompetent patients, should be considered in the differential diagnosis of brain lesions in AIDS patients.

Nonhuman primate models and the failure of the Merck HIV-1 vaccine in humans

The adenovirus type 5 (Ad5)-based vaccine developed by Merck failed to either prevent HIV-1 infection or suppress viral load in subsequently infected subjects in the STEP human Phase 2b efficacy trial. Analogous vaccines had previously also failed in the simian immunodeficiency virus (SIV) challenge-rhesus macaque model. In contrast, vaccine protection studies that used challenge with a chimeric simian-human immunodeficiency virus (SHIV89.6P) in macaques did not predict the human trial results. Ad5 vector -based vaccines did not protect macaques from infection after SHIV89.6P challenge but did cause a substantial reduction in viral load and a preservation of CD4(+) T cell counts after infection, findings that were not reproduced in the human trials. Although the SIV challenge model is incompletely validated, we propose that its expanded use can help facilitate the prioritization of candidate HIV-1 vaccines, ensuring that resources are focused on the most promising candidates. Vaccine designers must now develop T cell vaccine strategies that reduce viral load after heterologous challenge.

Histoplasma capsulatum Cell Wall beta-Glucan Induces Lipid Body Formation through CD18, TLR2, and Dectin-1 Receptors: Correlation with Leukotriene B(4) Generation and Role in HIV-1 Infection

Histoplasma capsulatum (Hc) is a facultative, intracellular parasite of worldwide significance. Infection with Hc produces a broad spectrum of diseases and may progress to a life-threatening systemic disease, particularly in individuals with HIV infection. Resolution of histoplasmosis is associated with the activation of cell-mediated immunity, and leukotriene B(4) plays an important role in this event. Lipid bodies (LBs) are increasingly being recognized as multifunctional organelles with roles in inflammation and infection. In this study, we investigated LB formation in histoplasmosis and its putative function in innate immunity. LB formation in leukocytes harvested from Hc-infected C57BL/6 mice peaks on day 2 postinfection and correlates with enhanced generation of lipid mediators, including leukotriene B(4) and PGE(2). Pretreatment of leukocytes with platelet-activating factor and BLT1 receptor antagonists showed that both lipid mediators are involved in cell signaling for LB formation. Alveolar leukocytes cultured with live or dead Hc also presented an increase in LB numbers. The yeast alkali-insoluble fraction 1, which contains mainly beta-glucan isolated from the Hc cell wall, induced a dose- and time-dependent increase in LB numbers, indicating that beta-glucan plays a signaling role in LB formation. In agreement with this hypothesis, beta-glucan-elicited LB formation was inhibited in leukocytes from 5-LO(-/-), CD18(low) and TLR2(-/-) mice, as well as in leukocytes pretreated with anti-Dectin-1 Ab. Interestingly, human monocytes from HIV-1-infected patients failed to produce LBs after beta-glucan stimulation. These results demonstrate that Hc induces LB formation, an event correlated with eicosanoid production, and suggest a role for these lipid-enriched organelles in host defense during fungal infection. The Journal of Immunology, 2009, 182: 4025-4035.

Advantages and Pitfalls of the Polymerase Chain Reaction in the Diagnosis of Esophageal Ulcers in AIDS Patients

HIV-1-infected patients frequently have opportunistic esophageal infections which, when associated with severe immunodeficiency, can be attributed to unusual pathogens. The clinical presentation of several esophageal diseases is similar and the best method for a specific diagnosis of these patients has not been well defined. To evaluate the role of the polymerase chain reaction (PCR) in the etiologic definition of esophageal ulcers in HIV-1-infected patients, 96 esophageal biopsies from 79 HIV-1-infected patients were processed by PCR using specific primers for cytomegalovirus (CMV), herpes virus (HSV), human papilloma virus (HPV), HIV-1, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Treponema pallidum, and Haemophilus ducreyi. The PCR results were compared to the histopathologic results. Seventy-nine patients were studied (mean age: 34 years; 62% men; median CD4 + T cell = 103.59 cells/mu l (range 1-795.2 cells/mu l). The most common endoscopic findings were as follows: esophageal candidiasis (37.1%), esophageal ulcers (24.7%), esophagitis (11.2%), and lugol-negative areas (10.1%). The histopathologic findings in the esophageal ulcers (22 biopsies) were non-specific inflammation (31.8%), HSV (36.4%), Candida (13.6%), CMV (13.6%), or HPV disease (4.5%). In the esophageal ulcer biopsies, the PCR results were negative in 27.6% of cases, and positive for HIV (65.5%), CMV (31%), HPV (20.7%), HSV (10.3%), and H. ducreyi (6.9%). The histopathologic examination did not identify a pathogen or identified only Candida in 15 biopsies of esophageal ulcers. PCR was positive in ten (66.7%) and negative in five (33.3%) of these biopsies (idiopathic ulcers). PCR detected: HIV (53.3%), CMV (20%), HPV (13.3%), and H. ducreyi (6,7%). PCR detected more etiologic agents in esophageal ulcers than histopathology and was able to detect unusual pathogens. On the other hand, sometimes more than one pathogen was detected in the esophageal ulcers, making it difficult to reach an accurate diagnosis. This finding indicates the need for more studies to evaluate the benefit of this method in the routine evaluation of esophageal ulcer biopsies in HIV-1-infected patients.

Antioxidant status and biomarkers of oxidative stress in bovine leukemia virus-infected dairy cows

Bovine leukemia virus (BLV) is among the most widespread livestock pathogens in many countries. Despite advances in understanding the pathogenesis of this disease, little is known about the involvement of oxidative stress. Therefore, this study examined the antioxidant status and the markers of oxidative stress in BLV-infected dairy cows. BLV infection was associated with an increase in triacylglycerol levels, a decrease in glutathione peroxidase (GSH-Px) activity and a tendency toward lower superoxide dismutase activity in the infected animals. No significant difference was observed in other markers of oxidative stress (i.e., conjugated dienes, hydroperoxides and malondialdehyde) in the infected animals compared to controls. A novel method for the analysis of oxidative stress, Z-scan based on the measurement of the mean-value of 9 in low density lipoprotein indicated that the infected animals had low-density lipoprotein particles that were slightly less modified than those from the healthy group. Thus, we conclude that BLV infection is associated with a selective decrease in GSH-Px activity without any alteration in the common plasma markers of oxidative stress. (C) 2011 Elsevier B.V. All rights reserved.

Genetic diversity of Brazilian isolates of feline immunodeficiency virus

FAPESP (the Sao Paulo State research funding foundation)

Oral manifestations after immune reconstitution in HIV patients on HAART

In order to verify possible association between immune reconstitution inflammatory syndrome (IRIS) and oral manifestations (OMs), we selected AIDS patients who had low CD4 count before the initiation of highly active antiretroviral therapy (HAART) and who returned three months later for therapy evaluation. The oral lesions observed three months after the initiation of HAART were evaluated and associated with the type of antiretroviral therapy (ART), CD4 count and HIV-RNA load levels (before and three months after HAART initiation). A total of 105 patients matched the selected criteria. Immune reconstitution (IR) was identified in 35.2%. Among these patients, the mean CD4 cell count rose from 105.97 to 330.29 and the mean viral load dropped from 168.005 (log 5.22) to 21.852 (log 4.33). There was no significant difference in age (P=0.78), sex (P=0.41) or previous history of ART (P=0.55) between IR and non-IR patients. In the IR group, the most common OM was. parotid enlargement (57.14%) (P=0.619), whereas in the non-IR group candidiasis (46.15%) was the most common OM. The results of our study suggest that the parotid gland enlargement found in the studied population might be an IRIS event, as it was found in patients with IR three months after the initiation of HAART.

The immunology of Epstein-Barr virus infection

Epstein-Barr virus is a classic example of a persistent human virus that has caught the imagination of immunologists, virologists and oncologists because of the juxtaposition of a number of important properties. First, the ability of the virus to immortalize B lymphocytes in vitro has provided an antigen presenting cell in which all the latent antigens: of the virus are displayed and are available for systematic study. Second, the virus presents an ideal system for studying the immune parameters that maintain latency and the consequences of disturbing this cell-virus relationship. Third, this wealth of immunological background has provided a platform for elucidating the role of the immune system in protection from viral-associated malignancies of B cell and epithelial cell origin. Finally attention is now being directed towards the development of vaccine formulations which might have broad application in the control of human malignancies.