Antiretroviral Drug Resistance in a Respondent-Driven Sample of HIV-Infected Men Who Have Sex With Men in Brazil

Background: There are few studies on HIV subtypes and primary and secondary antiretroviral drug resistance (ADR) in community-recruited samples in Brazil. We analyzed HIV clade diversity and prevalence of mutations associated with ADR in men who have sex with men in all five regions of Brazil. Methods: Using respondent-driven sampling, we recruited 3515 men who have sex with men in nine cities: 299 (9.5%) were HIV-positive; 143 subjects had adequate genotyping and epidemiologic data. Forty-four (30.8%) subjects were antiretroviral therapy-experienced (AE) and 99 (69.2%) antiretroviral therapy-naive (AN). We sequenced the reverse transcriptase and protease regions of the virus and analyzed them for drug resistant mutations using World Health Organization guidelines. Results: The most common subtypes were B (81.8%), C (7.7%), and recombinant forms (6.9%). The overall prevalence of primary ADR resistance was 21.4% (i.e. among the AN) and secondary ADR was 35.8% (i.e. among the AE). The prevalence of resistance to protease inhibitors was 3.9% (AN) and 4.4% (AE); to nucleoside reverse transcriptase inhibitors 15.0% (AN) and 31.0% (AE) and to nonnucleoside reverse transcriptase inhibitors 5.5% (AN) and 13.2% (AE). The most common resistance mutation for nucleoside reverse transcriptase inhibitors was 184V (17 cases) and for nonnucleoside reverse transcriptase inhibitors 103N (16 cases). Conclusions: Our data suggest a high level of both primary and secondary ADR in men who have sex with men in Brazil. Additional studies are needed to identify the correlates and causes of antiretroviral therapy resistance to limit the development of resistance among those in care and the transmission of resistant strains in the wider epidemic.

Genotypic distribution of hepatitis C among hepatitis C and HIV co-infected patients in Brazil

Information on hepatitis C virus (HCV) genotypic distribution among HIV-HCV co-infected patients is lacking in Brazil as well as other Latin American countries. The objective of this study was to evaluate the level of exposure to different risk factors associated with HCV transmission among a group of co-infected patients and to characterize the genotypic distribution of HCV in this cluster. A series of 100 HIV-HCV co-infected patients was analysed. The data to be analysed were collected from specific laboratory tests. Information was collected through a questionnaire. HCV genotyping was carried out by sequencing the 5 ` non-coding region of HCV. Chi-square and Fischer association tests or Kruskal-Wallis test were used to study the association between HCV transmission-related variables and the established genotypes. In conclusion, exposure to multiple risk factors associated with HCV transmission was common among HIV co-infected patients and an association between HCV genotype 3 and intravenous drug user was observed.

Vitamin D intoxication: a cause of hypocalcaemia and acute renal failure in a HIV patient

Hypercalcaemia in patients with HIV infection is usually associated with specific conditions such as lymphoma and granulomatous diseases. We described a case of severe hypercalcaemia consequent to vitamin D intoxication and secondary renal failure in a HIV patient under tenofovir using. Serum creatinine and calcium returned to near normal levels after vitamin D discontinuation, saline and furosemide administration. Some aspects of the drug-induced nephropathy are discussed.

Immunogenicity of 23-valent pneumococcal polysaccharide vaccine in HIV-infected pregnant women and kinetics of passively acquired antibodies in young infants

Whether gestational immunization of HIV-infected mothers with the 23-valent pneumococcal polysaccharide vaccine (PPV) confers maternal and infant early life, passive protection is not known. We evaluated safety, immunogenicity and placental transfer of antibodies in 44 HIV-infected women. Pneumococcal IgG antibodies against serotypes 1, 3, 5, 613, 9V, and 14 were measured in mothers (pre-vaccination and at delivery), and infants (at birth, 1, 2, 3, and 6 months). PPV was safe and immunogenic in mothers. Newborns received 46-72% of maternal antibody titers. Overall, infants had antibody levels lower than protective by 2 months of age. Alternative pneumococcal vaccination of HIV-infected pregnant women should be explored with the aim of prolonging passive protection in their infants. (C) 2009 Elsevier Ltd. All rights reserved.

Diffuse-regressive alterations and apoptosis of myocytes: Possible causes of myocardial dysfunction in HIV-related cardiomyopathy

Objective: To determine the frequency of cardiac alterations in necropsies of AIDS patients in pre-HAART era and better understand the pathogenesis of HIV-related cardiomyopathy. Design: Retrospective study of 94 complete necropsies. Method: Macroscopic, histopathologic (histochemical,immunohistochemical and in situ hybridization techniques) and ultra structural myocardial evaluation (23 cases). Results: Cardiac alterations were observed in 94.4%; 74% showed variable degrees of cardiac dilation not related to known cardiovascular diseases. Eighty-two percent (81.8%) of patients with biventricular dilation showed diffuse-regressive alterations (thinning and waving cardiomyocytes with increase of lipofuscin pigment granules). Myocarditis was diagnosed in 27 cases (28.7%), 16 (59.3%) of known etiology. The ultra structural study has revealed cardiomyocytes alterations (mitochondriosis, loss of myofibrils, increase in the amount of perinuclear-lipofuscin pigment granules) associated to activation signals of capillary-endothelial cells (enhancement of pseudopodia and transcellular channels). Cardiomyocytes` apoptosis was demonstrated at structural level in 10 (43.5%) patients; tumor necrosis factor alpha (TNF alpha) was detected in 17/18 cases. Conclusions: This pioneer study described the association of histopathological and ultra structural findings (thinning and waving cardiomyocytes with increase of lipofuscin pigment granules, mitochondriosis and loss of myofibrils) with different degrees of cardiac-chamber dilation probably representing a spectrum of alterations that would lead to myocardial dysfunction and development of HIV-related cardiomyopathy. Cardiomyocytes` apoptosis observed at ultra structural level and demonstration of TNF alpha associated to described alterations suggest that this cytokine plays an important role in both negative-inotropic effect and capacity to induce apoptosis through death receptor-controlled pathway. (C) 2008 Published by Elsevier Ireland Ltd.

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.

Presence of tropical spastic paraparesis/human T-cell lymphotropic virus type 1-associated myelopathy (TSP/HAM)-like among HIV-1-infected patients

Human immunodeficiency virus type 1 (HIV-1) and human T-cell lymphotropic virus types 1 and 2 (HTLV-1 and -2) are retroviruses that share similar routes of transmission and some individuals may have a dual infection. These co-infected subjects may be at increased risk for tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM)-like. To study the prevalence of tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM) among coinfected HIV-1/HTLV-1 subjects. Since July 1997, our group has been following a cohort to study the interaction of HTLV with HIV and/or hepatitis C virus (HCV), as well as HTLV-1-only infected asymptomatic carriers or those already presenting with TSP/HAM. During these 9 years, 296 HTLV-1-infected individuals were identified from a total of 538 patients who were referred to our clinic at the Institute of Infectious Diseases ""Emilio Ribas,"" in Sao Paulo, Brazil. All subjects were evaluated by two neurologists, blinded to the HTLV status. TSP/HAM diagnosis was based on Kagoshima diagnostic criteria. Results: A total of 38 HIV-1/HTLV-1 co-infected subjects were identified in this cohort: Twenty-six had already been diagnosed with AIDS and 12 remained asymptomatic. Six of 38 co-infected subjects (18%) were diagnosed as having TSP/HAM and also AIDS, and for 5 of them TSP/HAM was their first illness. One additional incident case was diagnosed after 2 years of follow-up. No modifications on HIV-1 viral load was seen. In contrast, the co-infected with TSP/HAM-like group showed higher HTLV-1 proviral load (505 +/- 380 vs. 97 +/- 149 copies/10(4) PBMC, P= 0.012) than asymptomatic co-infected subjects, respectively. The incidence of myelopathy among HIV-1/HTLV-1 co-infected subjects is probably higher than among patients infected only with HTLV-1, and related to a higher HTLV-1 proviral load. Thus, HTLV-1/2 screening should be done for all HIV-1-infected patients in areas where HTLV-1 infection is endemic.

Mucosal and systemic anti-GAG immunity induced by neonatal immunization with HIV LAMP/gag DNA vaccine in mice

Vaccines capable of inducing mucosal immunity in early postnatal life until adulthood, protecting early sexual initiation, should be considered as strategies to vaccination against HIV. The HIV-1 GAG protein as a chimera with the lysosome-associated membrane protein (LAMP/gag), encoded by a DNA vaccine, is targeted to the endosomal/lysosomal compartment that contains class II MHC molecules and has been shown to be immunogenic in adult mice. Assuming that one such strategy could help to overcome the immunological immaturity in the early postnatal period, we have evaluated the systemic and mucosal immunogenicity of LAMP/gag immunization in neonatal mice. Intranasal immunization with LAMP/gag vaccine induced higher levels of sIgA and IgG anti-GAG antibodies in intestinal washes than did the gag vaccine. The combination of ID injections and the IN protocol with the chimeric vaccine promoted the increase of Ab levels in sera. Both vaccines induced splenic IFN-gamma- secreting cells against GAG peptide pools, as well as in vivo cytotoxic T lymphocyte (CTL) function, and increased the percentage of CD8+ T cells to the immunodominant class I peptide in gut and spleen. However, only the chimeric vaccine was able to enhance Th1/Th2 cytokine secretion in response to class II GAG peptide and to enhance IL-4-secreting cells against GAG peptides and p24 protein stimuli. Long-lasting humoral and cellular responses were detected until adult age, following neonatal immunization with the chimeric vaccine. The LAMP/gag vaccination was able to induce potent GAG-specific T and B cell immune responses in early life which are essential to elicit sustained and long-lasting mucosal and systemic humoral response. (C) 2010 Elsevier GmbH. All rights reserved.

PLUNC protein expression in major salivary glands of HIV-infected patients

Objective: To analyse and compare the expression of Palate, Lung, and Nasal Epithelium Clone (PLUNC) proteins in salivary glands from patients with and without AIDS (control group) using autopsy material. Methods: We analysed the expression of PLUNCs using immunohistochemistry in parotid (n = 45), submandibular (n = 47) and sublingual gland (n = 37) samples of AIDS patients [30 with normal histology, 21 with mycobacteriosis, 14 with cytomegalovirus (CMV) infection, 30 with chronic non-specific sialadenitis, and 30 HIV-negative controls. In situ hybridization (ISH) for SPLUNC 2 in the HIV-negative group was performed. Results: SPLUNC 1 expression was detected in the mucous acini of submandibular and sublingual glands, and SPLUNC 2 were seen in the serous cells. LPLUNC 1 expression was only positive in the salivary ducts. There was a higher expression of SPLUNC 2 in AIDS patients with CMV infection and mycobacteriosis when compared with all other groups. The intensity of staining for SPLUNC 2 was greater around the lesions than the peripheral ones. ISH for SPLUNC 2 showed perinuclear positivity in the serous cells in all HIV-negative cases. Conclusions: SPLUNC 1 and LPLUNC 1 proteins were similarly expressed in the salivary glands of AIDS patients and non-HIV patients. CMV infection and mycobacteriosis increase SPLUNC 2 expression in serous cells in the salivary gland of AIDS patients.

Immunization of neonatal mice with LAMP/p55 HIV gag DNA elicits robust immune responses that last to adulthood

Successful T cell priming in early postnatal life that can generate effective long-lasting responses until adulthood is critical in HIV vaccination strategies because it prevents early sexual initiation and breastfeeding transmission of HIV. A chimeric DNA vaccine encoding p55 HIV gag associated with lysosome-associated membrane protein 1 (LAMP-1; which drives the antigen to the MIIC compartment), has been used to enhance cellular and humoral antigen-specific responses in adult mice and macaques. Herein, we investigated LAMP-1/gag vaccine immunogenicity in the neonatal period in mice and its ability to generate long-lasting effects. Neonatal vaccination with chimeric LAMP/gag generated stronger Gag-specific immune responses, as measured by the breadth of the Gag peptide-specific IFN-gamma, proliferative responsiveness, cytokine production and antibody production, all of which revealed activation of CD4+ T cells as well as the generation of a more robust CTL response compared to gag vaccine alone. To induce long-lived T and B cell memory responses, it was necessary to immunize neonates with the chimeric IAMP/gag DNA vaccine. The LAMP/gag DNA vaccine strategy could be particularly useful for generating an anti-HIV immune response in the early postnatal period capable of inducing long-term immunological memory. (C) 2010 Elsevier Inc. All rights reserved.

Prevalence and distribution of the GBV-C/HGV among HIV-1-infected patients under anti-retroviral therapy

Infection with GB virus C (GBV-C) or hepatitis G virus (HGV) is highly prevalent among HIV/AIDS patients. GBV-C/HGV viremia has not been associated with liver disease and seems to slow HIV disease progression. To study the GBV-C/HGV genotypes prevalence among HIV/AIDS patients and its association with HIV viral load (VL) and CD4+ lymphocyte counts. From February 2003 to February 2004, we analyzed 210 HIV-1-infected subjects who were on anti-retroviral therapy (ART). For 63 of them a PCR-nested to the non-coding 5` (5`NCR) region of the GBV-C/HGV was done, and for 49 a DNA direct sequencing was done. A phylogenetic analysis was performed by PHYLIP program. 63(30%) of the HIV-1-infected patients were co-infected with GBV-C/HGV. The phylogenetic analysis revealed the following genotypes (and respective relative frequencies): 1(10%), 2a (41%), 2b (43%), and 3 (6%). Co-infected patients presented lower HIV-1 VL and higher T CD4+ lymphocyte cells counts as compared with patients negative for GBV-C/HGV sequences (log = 4.52 vs. 4.71, p = 0.036), and T CD4+ lymphocyte counts (cells/mm(3) = 322.6 vs. 273.5, p = 0.081, respectively). T CD4+ cells counts equal to, or higher than, 200/mm(3) were significantly more common among co-infected patients than among HIV-infected-only patients (p = 0.042). The lowest T CD4+ cells counts were associated with genotype 1 and the highest with genotype 2b (p = 0.05). The GBV-C/HGV infection prevalence was 30% among HIV-1-infected subjects, and was associated with lower VL and higher CD4+ lymphocyte counts. GBV-C/HGV genotype 2b may be associated with better immunological response. Published by Elsevier B.V.

Giant multilocular thymic cyst in an HIV-infected adolescent

A girl with vertically acquired HIV infection presented with a 6-month history of dyspnea and chest pain. Computed tomography of the thorax showed a heterogenous mass measuring 13 x 9 x 17 cm located in the anterior mediastinum. Complete surgical resection was accomplished with no complications. The final diagnosis was multilocular thymic cyst, a distinct pathologic entity that is morphologically distinguishable and unrelated to congenital thymic cyst. (C) 2011 Elsevier Inc. All rights reserved.

Persistence and Clearance of HPV From the Penis of Men Infected and Non-Infected With HIV

Due to high rates of human papillomavirus (HPV) infection, the incidence of intraepithelial neoplasia and anal cancer, most studies concerning HPV in men seropositive for HIV have focused on the anal canal. Few studies have targeted the penile region in HIV-infected men. A total of 72 men seropositive for HIV and 72 men seronegative for HIV were followed-up for 6 months, and their penile exfoliated cells were tested for HPV DNA. There were no significant differences between the HIV-positive and HIV-negative men in persistence (respectively, 69.5% vs. 66.9%), clearance (respectively, 15.3% vs. 23.1%), and those men never infected with HPV during the four follow-up visits (15.2% for HIV-positive vs. 20% for HIV-negative). High-risk HPV types were detected more frequently in penile smears from men infected with HIV, while, in HIV-seronegative men, the low-risk HPV types were more abundant (P=0.001). Multiple infections with both high- and low-risk HPV types were significantly more frequent in HIV-seropositive compared to those who were HIV-seronegative (P=0.0004). The attendance rates at follow-up visits were 86%, 78%, and 58% in months 1, 2, and 6, respectively, for men infected with HIV and 93%, 72%, and 60% for the HIV-negative group. It is concluded that HIV infection can be considered a risk factor for clearance and persistence of HPV. Multiple infections with different types of HPV including high-risk HPVs are frequent in men who are infected with HIV. J. Med. Virol. 83:127-131, 2011. (C) 2010 Wiley-Liss, Inc.

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.