Lamivudine salts with improved solubilities

To optimize solubility of drugs, current strategies mainly focus on engineering and screening of smart crystal phases. Two salts of the anti-human immunodeficiency virus (HIV) drug lamivudinenamely, lamivudine hydrochloride and lamivudine hydrochloride monohydrate, were prepared in the course of screening the crystallization conditions of lamivudine duplex, an uncommon DNA-mimic, double-stranded helical structure made up of partially protonated drug pairs. Here, water solubilities of lamivudine hydrochloride, lamivudine hydrochloride monohydrate, and lamivudine duplex are reported. The aqueous solubility of this anti-HIV drug was significantly increased in both salts and also in lamivudine duplex in relation to the water solubility of lamivudine form II. In comparison with the lamivudine form II incorporated into therapeutic formulations, the drug solubility was increased at a temperature of 299 +/- 2 K by factors of 1.2, 3.3, and 4.5 in lamivudine hydrochloride, lamivudine hydrochloride monohydrate, and lamivudine duplex, respectively, demonstrating that this solid-state property of lamivudine can be improved by crystal engineering strategies. Solubility profiles were understood on the basis of structural and solventsolute interaction approaches. At last, correlations between solubility and crystal structures allowed for a rational approach to understand how this physicochemical feature could be enhanced by engineering new salts of the drug. (C) 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:21432154, 2012

Number of recent sexual partners among blood donors in Brazil: associations with donor demographics, donation characteristics, and infectious disease markers

BACKGROUND: Brazilian blood centers ask candidate blood donors about the number of sexual partners in the past 12 months. Candidates who report a number over the limit are deferred. We studied the implications of this practice on blood safety. STUDY DESIGN AND METHODS: We analyzed demographic characteristics, number of heterosexual partners, and disease marker rates among 689,868 donations from three Brazilian centers between July 2007 and December 2009. Donors were grouped based on maximum number of partners allowed in the past 12 months for each center. Chi-square and logistic regression analysis were conducted to examine associations between demographic characteristics, number of sex partners, and individual and overall positive markers rates for human immunodeficiency virus (HIV), human T-lymphotropic virus Types 1 and 2, hepatitis B virus, hepatitis C virus, and syphilis. RESULTS: First-time, younger, and more educated donors were associated with a higher number of recent sexual partners, as was male sex in Sao Paulo and Recife (p < 0.001). Serologic markers for HIV and syphilis and overall were associated with multiple partners in Sao Paulo and Recife (p < 0.001), but not in Belo Horizonte (p = 0.05, p = 0.94, and p = 0.75, respectively). In logistic regression analysis, number of recent sexual partners was associated with positive serologic markers (adjusted odds ratio [AOR], 1.2-1.5), especially HIV (AOR, 1.9-4.4). CONCLUSIONS: Number of recent heterosexual partners was associated with HIV positivity and overall rates of serologic markers of sexually transmitted infections. The association was not consistent across centers, making it difficult to define the best cutoff value. These findings suggest the use of recent heterosexual contacts as a potentially important deferral criterion to improve blood safety in Brazil.

A Randomized Trial of Noninvasive Positive End Expiratory Pressure in Patients With Acquired Immune Deficiency Syndrome and Hypoxemic Respiratory Failure

BACKGROUND: Acquired immunodeficiency syndrome (AIDS) is a pandemic disease commonly associated with respiratory infections, hypoxemia, and death. Noninvasive PEEP has been shown to improve hypoxemia. In this study, we evaluated the physiologic effects of different levels of noninvasive PEEP in hypoxemic AIDS patients. METHODS: Thirty AIDS patients with acute hypoxemic respiratory failure received a randomized sequence of noninvasive PEEP (5, 10, or 15 cm H2O) for 20 min. PEEP was provided through a facial mask with pressure-support ventilation (PSV) of 5 cm H2O and an F-IO2, of 1. Patients were allowed to breathe spontaneously for a 20-min washout period in between each PEEP trial. Arterial blood gases and clinical variables were recorded after each PEEP treatment. RESULTS: The results indicate that oxygenation improves linearly with increasing levels of PEEP. However, oxygenation levels were similar regardless of the first PEEP level administered (5, 10, or 15 cm H2O), and only the subgroup that received an initial treatment of the lowest level of PEEP (ie, 5 cm H2O) showed further improvements in oxygenation when higher PEEP levels were subsequently applied. The P-aCO2, also increased in response to PEEP elevation, especially with the highest level of PEEP (ie, 15 cm H2O). PSV of 5 cm H2O use was associated with significant and consistent improvements in the subjective sensations of dyspnea and respiratory rate reported by patients treated with any level of PEEP (from 0 to 15 cm H2O). CONCLUSIONS: AIDS patients with hypoxemic respiratory failure improve oxygenation in response to a progressive sequential elevation of PEEP (up to 15 cm H2O). However, corresponding elevations in P-aCO2, limit the recommended level of PEEP to 10 cm H2O. At a level of 5 cm H2O, PSV promotes an improvement in the subjective sensation of dyspnea regardless of the PEEP level employed.

Three Postpartum Antiretroviral Regimens to Prevent Intrapartum HIV Infection

BACKGROUND The safety and efficacy of adding antiretroviral drugs to standard zidovudine prophylaxis in infants of mothers with human immunodeficiency virus (HIV) infection who did not receive antenatal antiretroviral therapy (ART) because of late identification are unclear. We evaluated three ART regimens in such infants. METHODS Within 48 hours after their birth, we randomly assigned formula-fed infants born to women with a peripartum diagnosis of HIV type 1 (HIV-1) infection to one of three regimens: zidovudine for 6 weeks (zidovudine-alone group), zidovudine for 6 weeks plus three doses of nevirapine during the first 8 days of life (two-drug group), or zidovudine for 6 weeks plus nelfinavir and lamivudine for 2 weeks (three-drug group). The primary outcome was HIV-1 infection at 3 months in infants uninfected at birth. RESULTS A total of 1684 infants were enrolled in the Americas and South Africa (566 in the zidovudine-alone group, 562 in the two-drug group, and 556 in the three-drug group). The overall rate of in utero transmission of HIV-1 on the basis of Kaplan-Meier estimates was 5.7% (93 infants), with no significant differences among the groups. Intrapartum transmission occurred in 24 infants in the zidovudine-alone group (4.8%; 95% confidence interval [CI], 3.2 to 7.1), as compared with 11 infants in the two-drug group (2.2%; 95% CI, 1.2 to 3.9; P=0.046) and 12 in the three-drug group (2.4%; 95% CI, 1.4 to 4.3; P=0.046). The overall transmission rate was 8.5% (140 infants), with an increased rate in the zidovudine-alone group (P=0.03 for the comparisons with the two-and three-drug groups). On multivariate analysis, zidovudine monotherapy, a higher maternal viral load, and maternal use of illegal substances were significantly associated with transmission. The rate of neutropenia was significantly increased in the three-drug group (P < 0.001 for both comparisons with the other groups). CONCLUSIONS In neonates whose mothers did not receive ART during pregnancy, prophylaxis with a two-or three-drug ART regimen is superior to zidovudine alone for the prevention of intrapartum HIV transmission; the two-drug regimen has less toxicity than the three-drug regimen. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHD] and others; ClinicalTrials.gov number, NCT00099359.)

HIV-1 tropism and CD4 T lymphocyte recovery in a prospective cohort of patients initiating HAART in Ribeirao Preto, Brazil

While human immunodeficiency virus (HIV)-1 chemokine co-receptors 5 tropism and the GWGR motif in the envelope third variable region (V3 loop) have been associated with a slower disease progression, their influence on antiretroviral response remains unclear. The impact of baseline V3 characteristics on treatment response was evaluated in a randomised, double blind, prospective cohort study with patients initiating highly active antiretroviral therapy with lopinavir or efavirenz plus azithothymidine/3TC (1:1) over 48 weeks. Similar virological and immunological responses were observed for both treatment regimens. The 43 individuals had a mean baseline CD4 T cell count of 119 cells/mm(3) [standard deviation (SD) = 99] and a mean viral load of 5.09 log(10) copies/mL (SD = 0.49). The GWGR motif was not associated with a CD4 T cell response, but predicted R5 tropism by the geno2pheno([clinical20%]) algorithm correlated with higher CD4 T cell levels at all monitoring points (p < 0.05). Moreover, higher false-positive rates (FPR) values from this analysis revealed a strong correlation with CD4 T cell recovery (p < 0.0001). Transmitted drug resistance mutations, documented in 3/41 (7.3%) cases, were unrelated to the assigned antiretroviral regimen and had no impact on patient outcomes. In conclusion, naive HIV-1 R5 infected patients exhibited higher CD4 T cell counts at baseline; this difference was sustained throughout therapy. The geno2pheno[clinical] option FPR positively correlated with CD4 T cell gain and may be useful in predicting CD4 T cell recovery.

Immunogenicity of a meningococcal serogroup C conjugate vaccine in HIV-infected children, adolescents, and young adults

Children and adolescents infected with HIV typically have a lower response to immunization than do those in the general population. In most developed countries, meningococcal serogroup C conjugate vaccine is one of the recommended vaccines for such individuals. However, there have been no studies evaluating the antibody response to this vaccine in HIV-infected children, adolescents or young adults. In this study, we evaluated that response using serum bactericidal antibody (SBA) and enzyme-linked immunosorbent assay, comparing HIV-infected with non-HIV-infected patients, as well as analysing the occurrence of side effects. In non-responders, we assessed the antibody response to revaccination. This clinical trial involved 92 patients between 10 and 20 years of age: 43 HIV-infected patients (HIV+ group) and 49 non-HIV-infected patients (HIV- group). After one dose of the vaccine, 72.1% of the HIV+ group patients and 100% of the HIV- group patients were considered protected. Of the HIV+ group patients who received a second dose of the vaccine, only 40% acquired protection. Overall, 81.4% of the HIV+ group patients acquired protection (after one or two doses of the vaccine). Side effects occurred in 16.3% and 44% of the HIV+ group and HIV- group patients, respectively. Therefore, the meningococcal serogroup C conjugate vaccine proved to be safe and effective for use in HIV-infected children, adolescents, and young adults, although their antibody response was weaker than that shown by non-HIV-infected patients. This indicates the need to discuss changes to the immunization schedule for children, adolescents, and young adults infected with HIV, in order to ensure more effective protection against meningococcal disease. (c) 2012 Elsevier Ltd. All rights reserved.

Transplant-Associated and Blood Transfusion-Associated Tropical and Parasitic Infections

Blood transfusion and transplantation may represent efficient mechanisms of spreading infectious agents to naive populations. In the developed countries, as a consequence of globalization, several factors such as international commerce, tourism, and immigration have acted as important features for the emergence or reemergence of infectious diseases previously referred to as tropical. This article reviews the relevant bacterial, protozoan and viral infections that are more frequently associated with blood transfusion and/or solid organ or marrow transplantation and may affect susceptible populations worldwide.

Motor Neuron Disease and Acquired Axonal Neuropathy Association in HIV Infection: Case Report and Update

Background: A possible viral etiology has been documented in the genesis of motor neuron disorders and acquired peripheral neuropathies, mainly due to the vulnerability of peripheral nerves and the anterior horn to certain viruses. In recent years, several reports show association of HIV infection with Amyotrophic Lateral Sclerosis Syndrome, Motor Neuron Diseases and peripheral neuropathies. Objective: To report a case of an association between Motor Neuron Disease and Acquired Axonal neuropathy in HIV infection, and describe the findings of neurological examination, cerebrospinal fluid, neuroimaging and electrophysiology. Methods: The patient underwent neurological examination. General medical examinations were performed, including, specific neuromuscular tests, analysis of cerebrospinal fluid, muscle biopsy and imaging studies. Results and Discussion: The initial clinical presentation of our case was marked by cramps and fasciculations with posterior distal paresis and atrophy in the left arm. We found electromyography tracings with deficits in the anterior horn of the spinal cord and peripheral nerves. Dysphagia and release of primitive reflexes were also identified. At the same time, the patient was informed to be HIV positive with high viral load. He received antiretroviral therapy, with load control but with no clinical remission. Conclusion: Motor Neuron disorders and peripheral neuropathy may occur in association with HIV infection. However, a causal relationship remains uncertain. It is noteworthy that the antiretroviral regimen may be implicated in some cases.

Biowaiver monographs for immediate-release solid oral dosage forms: Stavudine

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release (IR) solid oral dosage forms containing stavudine (d4T) are reviewed. According to Biopharmaceutics Classification System (BCS), d4T can be assigned to BCS class I. No problems with BE of IR d4T formulations containing different excipients and produced by different manufacturing methods have been reported and, hence, the risk of bioinequivalence caused by these factors appears to be low. Furthermore, d4T has a wide therapeutic index. It is concluded that a biowaiver is appropriate for IR solid oral dosage forms containing d4T as the single active pharmaceutical ingredient (API) provided that (a) the test product contains only excipients present in the IR d4T drug products that have been approved in a number of countries for the same dosage form, and (b) both test product and its comparator are either very rapidly dissolving or rapidly dissolving with similarity of dissolution profiles demonstrated at pH 1.2, 4.5, and 6.8. (c) 2011 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:1016, 2012

Cutaneous and Mucocutaneous Leishmaniasis

Tegumentary leishmaniases are caused by approximately 15 species of protozoa of the genus Leishmania. They prevail in tropical and subtropical areas of the Old and New World but human mobility also makes them a medical problem in nonendemic areas. Clinical manifestations may comprise cutaneous and mucocutaneous forms that may be localized, disseminated, or diffuse in distribution and may differ in Old and New World leishmaniases. Diagnosis and treatment vary according to the clinical manifestations, geographic area, and Leishmania species involved. This article highlights the diversity and complexity of tegumentary leishmaniases, which are worsened by human immunodeficiency virus/Leishmania coinfection.

Pilot Studies for Development of an HIV Subtype Panel for Surveillance of Global Diversity

The continued global spread and evolution of HIV diversity pose significant challenges to diagnostics and vaccine strategies. NIAID partnered with the FDA, WRAIR, academia, and industry to form a Viral Panel Working Group to design and prepare a panel of well-characterized current and diverse HIV isolates. Plasma samples that had screened positive for HIV infection and had evidence of recently acquired infection were donated by blood centers in North and South America, Europe, and Africa. A total of 80 plasma samples were tested by quantitative nucleic acid tests, p24 antigen, EIA, and Western blot to assign a Fiebig stage indicative of approximate time from initial infection. Evaluation of viral load using FDA-cleared assays showed excellent concordance when subtype B virus was tested, but lower correlations for subtype C. Plasma samples were cocultivated with phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) from normal donors to generate 30 viral isolates (50-80% success rate for samples with viral load >10,000 copies/ml), which were then expanded to 10(7)-10(9) virus copies per ml. Analysis of env sequences showed that sequences derived from cultured PBMCs were not distinguishable from those obtained from the original plasma. The pilot collection includes 30 isolates representing subtypes B, C, B/F, CRF04_cpx, and CRF02_AG. These studies will serve as a basis for the development of a comprehensive panel of highly characterized viral isolates that reflects the current dynamic and complex HIV epidemic, and will be made available through the External Quality Assurance Program Oversight Laboratory (EQAPOL).

Evaluation of HIV-1 resistance to antiretroviral drugs among 150 patients after six months of therapeutic interruption

Most of the antiretroviral (ARV) studies in Brazil have been reported in treatment-experienced and naive patients rather than in the setting of treatment interruption (TI). In this study, we analysed reasons given for TI and resistance mutations occurring in 150 HIV-1-infected patients who underwent TI. Of the patients analysed, 110 (73.3%) experienced TI following medical advice, while the remaining patients stopped antiretroviral therapy (ART) of their own accord. The main justifications for TI were: ARV-related toxicities (38.7%), good laboratory parameters (30%) and poor adherence (20%). DNA sequencing of the partial pol gene was successful in 137 (91.3%) patients, of whom 38 (27.7%) presented mutations conferring ARV resistance. A higher viral load prior to TI correlated with drug resistance (P < 0.05). Our results demonstrate that there are diverse rationales for TI and that detection of resistant strains during TI most likely indicates a fitter virus than the wild type. High viral loads coupled with unprotected sex in this group could increase the likelihood of transmission of drug-resistant virus. Thus, treating physicians should be alerted to this problem when the use of ARVs is interrupted.

Evaluation of inadequate anti-retroviral treatment in patients with HIV/AIDS

Introduction: Since the emergence of antiretroviral therapy, the survival of patients infected with human immunodeficiency virus has increased. Non-adherence to this therapy is directly related to treatment failure, which allows the emergence of resistant viral strains. Methods: A retrospective descriptive study of the antiretroviral dispensing records of 229 patients from the Center for Health Care, University Hospital, Federal University of Juiz de Fora, Brazil, was conducted between January and December 2009. Results: The study aimed to evaluate patient compliance and determine if there was an association between non-adherence and the therapy. Among these patients, 63.8% were men with an average age of 44.0 +/- 9.9 years. The most used treatment was a combination of 2 nucleoside reverse transcriptase inhibitors with 1 non-nucleoside reverse transcriptase inhibitor (55.5%) or with 2 protease inhibitors (28.8%). It was found that patients taking lopinavir/ritonavir with zidovudine and lamivudine had a greater frequency of inadequate treatment than those taking atazanavir with zidovudine and lamivudine (85% and 83.3%, respectively). Moreover, when the combination of zidovudine/lamivudine was used, the patients were less compliant (chi(2) = 4.468, 1 degree of freedom, p = 0.035). Conclusions: The majority of patients failed to correctly adhere to their treatment; therefore, it is necessary to implement strategies that lead to improved compliance, thus ensuring therapeutic efficacy and increased patient survival.

An in-depth analysis of the HIV-1/AIDS dynamics by comprehensive mathematical modeling

This work presents major results from a novel dynamic model intended to deterministically represent the complex relation between HIV-1 and the human immune system. The novel structure of the model extends previous work by representing different host anatomic compartments under a more in-depth cellular and molecular immunological phenomenology. Recently identified mechanisms related to HIV-1 infection as well as other well known relevant mechanisms typically ignored in mathematical models of HIV-1 pathogenesis and immunology, such as cell-cell transmission, are also addressed. (C) 2011 Elsevier Ltd. All rights reserved.

Candida albicans Isolation from Buccal Mucosa of Patients with HIV Wearing Removable Dental Prostheses

Purpose: The aim of this study was to evaluate the influence of complete or partial removable dental prostheses (RDPs) on the frequency of Candida albicans isolated from the mouth and the presence of oral candidiasis in human immunodeficiency virus positive (HIV+) patients correlated with CD4 levels. Materials and Methods: One hundred ninety-three HIV+ patients were evaluated; 68 had RDPs and 125 did not. CD4 cell count was obtained after blood sampling and performed on the day of clinical examination. The material was collected from the buccal mucosa for isolation of yeasts with a sterile swab and seeded onto Sabouraud dextrose agar with chloramphenicol. C albicans strains were identified by testing germ tubes and chlamydospore formation and biochemical (zymogram, auxanogram) characteristics. The results were subjected to the Fischer exact test and chi-square tests. Results: C albicans were isolated from 45(66.17%) patients who had RDPs and 48 (38.4%) who did not (P = .0003). The presence of oral candidiasis was observed in 14 patients (7.25%), and 10 of the 14 (71.43%) were RDP users. The absence of candidiasis occurred in 121 (67.59%) nonusers and 58 (32.40%) users of RDPs (P = .0065). The mean CD4 cell count was lower in patients with oral candidiasis regardless of the use of RDPs. Conclusion: The use of RDPs was an important factor in the isolation of C albicans among HIV+ patients, and CD4 level seems to play a role in the presence of oral candidiasis. Int J Prosthodont 2012;25:127-131.