Antiretroviral Drug-Resistance Mutations on the Gag Gene: Mutation Dynamics during Analytic Treatment Interruption among Individuals Experiencing Virologic Failure.

We describe drug-resistance mutation dynamics of the gag gene among individuals under antiretroviral virologic failure who underwent analytical treatment interruption (ATI). These mutations occur in and around the cleavage sites that form the particles that become the mature HIV-1 virus. The study involved a 12-week interruption in antiretroviral therapy (ART) and sequencing of the gag gene in 38 individuals experiencing virologic failure and harboring triple-class resistant HIV strains. Regions of the gag gene surrounding the NC-p2 and p1-p6 cleavage sites were sequenced at baseline before ATI and after 12 weeks from plasma HIV RNA using population-based Sanger sequencing. Fourteen of the sixteen patients sequenced presented at least one mutation in the gag gene at baseline, with an average of 4.93 mutations per patient. All the mutations had reverted to the wild type by the end of the study. Mutations in the gag gene complement mutations in the pol gene to restore HIV fitness. Those mutations around cleavage sites and within substrates contribute to protease inhibitor resistance and difficulty in re-establishing effective virologic suppression. ART interruption in the presence of antiretroviral resistant HIV strains was used here as a practical measure for more adapted HIV profiles in the absence of ART selective pressure.

Fitness Cost of Antiretroviral Drug Resistance Mutations on the pol Gene during Analytical Antiretroviral Treatment Interruption among Individuals Experiencing Virological Failure.

HIV cure studies require patients to enter an analytical treatment interruption (ATI). Here, we describe previously unanalyzed data that sheds light on ATI dynamics in PLHIV (People Living with HIV). We present drug resistance mutation dynamics on the pol gene among individuals with antiretroviral virological failure who underwent ATI. The study involved a 12-week interruption in antiretroviral therapy (ART), monitoring of viral load, CD4+/CD8+ T cell counts, and sequencing of the pol gene from 38 individuals experiencing virological failure and harboring 3-class resistant HIV strains: nucleoside reverse transcriptase inhibitors (NRTI) non-nucleoside inhibitors (NNRTI), and protease inhibitors (PI). Protease and reverse transcriptase regions of the pol gene were sequenced at baseline before ATI and every four weeks thereafter from PBMCs and at baseline and after 12 weeks from plasma HIV RNA using population-based Sanger sequencing. Average viral load increased 0.559 log10 copies per milliliter. CD4+ T cell count decreased as soon as ART was withdrawn, an average loss of 99.0 cells/mL. Forty-three percent of the mutations associated with antiretroviral resistance in PBMCs disappeared and fifty-seven percent of the mutations in plasma reverted to wild type, which was less than the 100% reversion expected. In PBMC, the PI mutations reverted more slowly than reverse transcriptase mutations. The patients were projected to need an average of 33.7 weeks for PI to revert compared with 20.9 weeks for NRTI and 19.8 weeks for NNRTI. Mutations in the pol gene can cause virological failure and difficulty in re-establishing effective virological suppression.

Association of seasonality and serum albumin concentration with vitamin D deficiency in subjects with chronic hepatitis C infection living in a sunny country.

OBJECTIVE: This study aimed to analyse the relationship between vitamin D deficiency and the season when the blood sample was obtained from subjects with chronic hepatitis C (CHC) infection. DESIGN: A cross-sectional study was conducted on a representative sample. Vitamin D deficiency was defined as a serum 25-hydroxyvitamin D [25(OH)D] concentration <50 nmol/l, based on the values set forth by the Endocrine Society guideline for higher-risk populations. Seasonality was defined according to solstices and equinoxes. The association of seasonality and clinical/laboratory characteristics with vitamin D deficiency was assessed using a multivariate logistic regression analysis. SETTING: NUPAIG Viral Hepatitis Outpatient Clinic of the Universidade Federal de São Paulo - Brazil. PARTICIPANTS: Adult subjects with CHC infection (n 306). RESULTS: The prevalence of vitamin D deficiency was 16 %, whereas the median serum 25(OH)D concentration was 87 (interquartile range, 59; third quartile = 118) nmol/l. Serum concentration was consistently lower in samples collected in spring and winter than in other seasons. In multivariate analysis, vitamin D deficiency was found to be independently associated with male gender, serum albumin concentration and with samples drawn in winter and spring. CONCLUSIONS: The findings show not only the relevance to consider season as a factor influencing 25(OH)D concentration but also the need to actively screen for hypovitaminosis D in all patients with CHC infection, especially in females and those with low albumin concentration.

Chronic alcohol abuse and spontaneous clearance of hepatitis C virus.

Spontaneous clearance of hepatitis C virus (HCV) is an uncommon occurrence in the course of chronic infection. We reported a rare case of a 41-year-old male patient infected with HCV genotype 3a who presented spontaneous viral elimination after increasing his daily consumption of alcoholic beverage. In this short review, we overview how modulation of the hepatic inflammatory response could have a role in the viral elimination process.

Previous hepatitis E virus infection, cirrhosis and insulin resistance in patients with chronic hepatitis C.

BACKGROUND: Hepatitis E virus (HEV) infection in patients with pre-existing liver disease has shown high morbidity and lethality. The consequences of HEV superinfection in patients with chronic hepatitis C virus (HCV) infection are not fully understood. This study aimed to evaluate the association between the presence of anti-HEV antibodies, liver cirrhosis, and insulin resistance. METHODS: A total of 618 patients chronically infected with HCV were included from three reference centers for viral hepatitis in São Paulo, Brazil. Presence of anti-HEV IgG was assessed by enzyme-linked immunosorbent assay (WANTAI HEV-IgG ELISA). RESULTS: The seroprevalence of anti-HEV in patients with cirrhosis was significantly higher than in patients without cirrhosis (13.2% vs 8%, OR=1.74, p=0.04). Seropositivity for anti-HEV, adjusted for sex, age, and HCV genotype showed an association trend with hepatic cirrhosis (aOR=1.75, p=0.059). Presence of HEV antibodies, adjusted for age, body mass index and cirrhosis, was shown to be independently associated with insulin resistance (aOR: 4.39; p=0.045). CONCLUSION: Patients with chronic hepatitis C are under risk of hepatitis E virus superinfection in Brazil. The trend toward association between cirrhosis and previous HEV infection suggests that it may accelerate liver fibrosis in patients with chronic hepatitis C. In addition, previous infection by HEV is independently associated with insulin resistance in the studied population, which may be an extra-hepatic manifestation of hepatitis E that persists after resolution of the active infection, and may contribute to fibrosis progression.

Individual factors associated with time to non-adherence to ART pick-up within HIV care and treatment services in three health facilities of Zambézia Province, Mozambique.

INTRODUCTION: Mozambique has made significant gains in addressing its HIV epidemic, yet adherence to visit schedules remains a challenge. HIV programmatic gains to date could be impaired if adherence and retention to ART remains low. We investigate individual factors associated with non-adherence to ART pick-up in Mozambique. METHODS: This was a retrospective cohort of patients initiating ART between January 2013 and June 2014. Non-adherence to ART pick-up was defined as a delay in pick-up ≥ 15 days. Descriptive statistics were used to calculate socio-demographic and clinical characteristics. Adherence to ART pick-up was assessed using Kaplan Meier estimates. Cox proportional hazards model was used to determine factors associated with non-adherence. RESULTS: 1,413 participants were included (77% female). Median age was 30.4 years. 19% of patients remained adherent to ART pick-up during the evaluation period, while 81% of patients were non-adherent to ART pick-up. Probability of being non-adherent to ART pick-up by 166 days following initiation was 50%. In univariate analysis, being widowed was associated with higher adherence to ART pick-up than other marital status groups (p = 0.01). After adjusting, being ≥35 years (aHR: 0.843, 95% CI: 0.738-0.964, p = 0.012); receiving efavirenz (aHR: 0.932, 95% CI: 0.875-0.992, p = 0.026); and being urban (aHR: 0.754, 95% CI: 0.661-0.861, p<0.0001) were associated with improved adherence. Non-participation in a Community ART Support Group (CASG) was associated with a 43% increased hazard of non-adherence to ART pick-up (aHR 1.431, 1.192-1.717, p<0.0001). CONCLUSIONS: Interventions should focus on the first 6 months following ARV initiation for improvements. Younger persons and widows are two target groups for better understanding facilitators and barriers to visit schedule adherence. Future strategies should explore the benefits of joining CASGs earlier in one´s treatment course. Finally, greater efforts should be made to accelerate the scale-up of viral load capacity and HIV resistance monitoring.

Previous hepatitis E virus infection, cirrhosis and insulin resistance in patients with chronic hepatitis C

ABSTRACT Background: Hepatitis E virus (HEV) infection in patients with pre-existing liver disease has shown high morbidity and lethality. The consequences of HEV superinfection in patients with chronic hepatitis C virus (HCV) infection are not fully understood. This study aimed to evaluate the association between the presence of anti-HEV antibodies, liver cirrhosis, and insulin resistance. Methods: A total of 618 patients chronically infected with HCV were included from three reference centers for viral hepatitis in São Paulo, Brazil. Presence of anti-HEV IgG was assessed by enzyme-linked immunosorbent assay (WANTAI HEV-IgG ELISA). Results: The seroprevalence of anti-HEV in patients with cirrhosis was significantly higher than in patients without cirrhosis (13.2% vs 8%, OR = 1.74, p = 0.04). Seropositivity for anti-HEV, adjusted for sex, age, and HCV genotype showed an association trend with hepatic cirrhosis (aOR = 1.75, p = 0.059). Presence of HEV antibodies, adjusted for age, body mass index and cirrhosis, was shown to be independently associated with insulin resistance (aOR: 4.39; p = 0.045). Conclusion: Patients with chronic hepatitis C are under risk of hepatitis E virus superinfection in Brazil. The trend toward association between cirrhosis and previous HEV infection suggests that it may accelerate liver fibrosis in patients with chronic hepatitis C. In addition, previous infection by HEV is independently associated with insulin resistance in the studied population, which may be an extra-hepatic manifestation of hepatitis E that persists after resolution of the active infection, and may contribute to fibrosis progression.

Hepatite C no sistema público de saúde brasileiro: impacto da doença / Hepatitis c in the brazilian public health care system: burden of disease

ABSTRACT BACKGROUND: Infection by hepatitis C virus is one of the leading causes of chronic hepatitis C and cause severe burden for patients, families and the health care system. OBJECTIVE: The aims of this research were to assess the severity of liver fibrosis, comorbidities and complications of hepatitis C virus; to examine health-related quality of life (HRQoL), productivity loss and resource use and costs in a sample of Brazilian chronic hepatitis C, genotype 1, patients. METHODS: This was a cross-sectional multicenter study performed in genotype-1 chronic hepatitis C patients to assess disease burden in the Brazilian public health care system between November 2014 and March 2015. Patients were submitted to a liver transient elastography (FibroScan) to assess liver fibrosis and answered an interview composed by a questionnaire specifically developed for the study and three standardized questionnaires: EQ-5D-3L, HCV-PRO and WPAI:HepC. RESULTS: There were 313 subjects enrolled, with predominance of women (50.8%), caucasian/white (55.9%) and employed individuals (39.9%). Mean age was 56 (SD=10.4) years old. Moreover, 42.8% of patients who underwent FibroScan were cirrhotic; the most frequent comorbidity was cardiovascular disease (62.6%) and the most frequent complication was esophageal varices (54.5%). The results also showed that "pain and discomfort" was the most affected HRQoL dimension (55.0% of patients reported some problems) and that the mean HCV-PRO overall score was 69.1 (SD=24.2). Regarding productivity loss, the most affected WPAI:HepC component was daily activity (23.5%) and among employed patients, presenteeism was more frequent than absenteeism (18.5% vs 6.5%). The direct medical costs in this chronic hepatitis C sample was 12,305.72USD per patient in the 2 years study period; drug treatment costs represented 95.9% of this total. CONCLUSION: This study showed that most patients are cirrhotic, present high prevalence of cardiometabolic diseases and esophageal varices, reduced HRQoL mainly in terms of pain/discomfort, and work productivity impairment, especially presenteeism. Additionally, we demonstrated that hepatitis C virus imposes an economic burden on Brazilian Health Care System and that most of this cost is due to drug treatment.

RESUMO CONTEXTO: A infecção pelo vírus da hepatite C (HCV) é uma das principais causas de hepatite C crônica e provoca implicações graves para pacientes, familiares e sistema de saúde. OBJETIVO: Os objetivos deste estudo foram: analisar a gravidade da fibrose hepática, comorbidades e complicações da hepatite C; examinar a qualidade de vida relacionada à saúde (QVRS), a perda de produtividade e o uso de recursos e custos no sistema público por pacientes brasileiros com hepatite C crônica, genótipo tipo 1. MÉTODOS: Foi realizado um estudo transversal, multicêntrico em pacientes com hepatite C crônica genótipo-1 para avaliar a carga da doença no sistema público de saúde brasileiro entre novembro de 2014 e março de 2015. Os pacientes foram submetidos a uma elastografia hepática transitória (FibroScan) para avaliar a fibrose e a uma entrevista composta por um questionário desenvolvido para o estudo e cinco questionários padronizados: EQ-5D-3L, HCV-PRO, e WPAI:HepC. RESULTADOS: Foram recrutados 313 pacientes. A amostra foi composta predominantemente por mulheres (50,8%), caucasianos/brancos (55,9%) e indivíduos empregados (39,9%). A média de idade foi 56 (DP=10,4) anos. Em média, os pacientes com HCV esperaram 40,6 (DP=49,6) meses entre o diagnóstico e o primeiro tratamento. Ademais, 42,8% dos pacientes que realizaram o FibroScan tinham cirrose; a comorbidade mais frequente foi doença cardiovascular (62,6%) e a complicação mais comum as varizes esofágicas (54,5%). Os resultados também mostraram que "dor e desconforto" foi a dimensão de QVRS mais afetada (55,0% dos pacientes relataram alguns problemas) e que a média do escore do HCV-PRO foi 69,1 (DP=24,2). Em relação à perda de produtividade, o componente do WPAI:HepC mais afetado foi atividade diária (23,5%) e entre os pacientes empregados, presenteísmo foi mais frequente do que absenteísmo (18,5% vs 6,5%). Os custos diretos médicos totais com essa amostra foi de 12.305,72USD por paciente em um período de dois anos; o tratamento medicamentoso representou 95% desse total. CONCLUSÃO Esse estudo mostrou a maioria dos pacientes possui cirrose, apresenta alta prevalência de doenças cardiometabolicas e varizes esofágicas, QVRS reduzida principalmente em termos de dor/desconforto e dano na produtividade, especialmente presenteísmo. Adicionalmente, nós demonstramos que o HCV impõe uma carga econômica no sistema de saúde brasileiro e que os medicamentos correspondem à maioria dos custos.

Seroprevalence of hepatitis E virus in chronic hepatitis C in Brazil.

BACKGROUND AND AIMS: Hepatitis E virus infection in patients with underlying chronic liver disease is associated with liver decompensation and increased lethality. The seroprevalence of hepatitis E virus in patients with chronic hepatitis C in Brazil is unknown. This study aims to estimate the seroprevalence of hepatitis E virus in patients with chronic hepatitis C and to describe associated risk factors. METHODS: A total of 618 patients chronically infected with hepatitis C virus from three reference centers of São Paulo, Brazil were included. Presence of anti-HEV IgG was assessed by enzyme-linked immunosorbent assay (WANTAI HEV-IgG ELISA). RESULTS: Out of the 618 patients tested, 10.2% turned out positive for anti-HEV IgG (95% CI 8.0-12.8%). Higher seroprevalence was found independently associated with age over 60 years (OR=2.04; p=0.02) and previous contact with pigs (OR=1.99; p=0.03). CONCLUSIONS: Patients with chronic hepatitis C are under risk of hepatitis E virus superinfection in São Paulo. Contact with pigs is a risk factor for the infection, suggesting a possible zoonosis with oral transmission.

Mother-to-child transmission of hepatitis C virus.

Hepatitis C virus (HCV) infection is a worldwide health problem. Based on results of a serosurvey, global prevalence is estimated to be 2,5%, and women account for about 35.8% of the cases. For pregnant women the prevalence is lower and showed a range between 0.24% to 4.3%. Sinse mechanisms and timing of mother to child transmission are not fully understood, efforts are made to assess and understand its risk factors. The purpose of this review was to synthesize the evidence about the mother-to-child transmission of hepatitis C virus and review its risk factors.

Seroprevalence of hepatitis E virus in chronic hepatitis C in Brazil

ABSTRACT Background and aims: Hepatitis E virus infection in patients with underlying chronic liver disease is associated with liver decompensation and increased lethality. The seroprevalence of hepatitis E virus in patients with chronic hepatitis C in Brazil is unknown. This study aims to estimate the seroprevalence of hepatitis E virus in patients with chronic hepatitis C and to describe associated risk factors. Methods: A total of 618 patients chronically infected with hepatitis C virus from three reference centers of São Paulo, Brazil were included. Presence of anti-HEV IgG was assessed by enzyme-linked immunosorbent assay (WANTAI HEV-IgG ELISA). Results: Out of the 618 patients tested, 10.2% turned out positive for anti-HEV IgG (95% CI 8.0-12.8%). Higher seroprevalence was found independently associated with age over 60 years (OR = 2.04; p = 0.02) and previous contact with pigs (OR = 1.99; p = 0.03). Conclusions: Patients with chronic hepatitis C are under risk of hepatitis E virus superinfection in São Paulo. Contact with pigs is a risk factor for the infection, suggesting a possible zoonosis with oral transmission.

HEPATITIS C IN THE BRAZILIAN PUBLIC HEALTH CARE SYSTEM: BURDEN OF DISEASE.

BACKGROUND: Infection by hepatitis C virus is one of the leading causes of chronic hepatitis C and cause severe burden for patients, families and the health care system. OBJECTIVE: The aims of this research were to assess the severity of liver fibrosis, comorbidities and complications of hepatitis C virus; to examine health-related quality of life (HRQoL), productivity loss and resource use and costs in a sample of Brazilian chronic hepatitis C, genotype 1, patients. METHODS: This was a cross-sectional multicenter study performed in genotype-1 chronic hepatitis C patients to assess disease burden in the Brazilian public health care system between November 2014 and March 2015. Patients were submitted to a liver transient elastography (FibroScan) to assess liver fibrosis and answered an interview composed by a questionnaire specifically developed for the study and three standardized questionnaires: EQ-5D-3L, HCV-PRO and WPAI:HepC. RESULTS: There were 313 subjects enrolled, with predominance of women (50.8%), caucasian/white (55.9%) and employed individuals (39.9%). Mean age was 56 (SD=10.4) years old. Moreover, 42.8% of patients who underwent FibroScan were cirrhotic; the most frequent comorbidity was cardiovascular disease (62.6%) and the most frequent complication was esophageal varices (54.5%). The results also showed that "pain and discomfort" was the most affected HRQoL dimension (55.0% of patients reported some problems) and that the mean HCV-PRO overall score was 69.1 (SD=24.2). Regarding productivity loss, the most affected WPAI:HepC component was daily activity (23.5%) and among employed patients, presenteeism was more frequent than absenteeism (18.5% vs 6.5%). The direct medical costs in this chronic hepatitis C sample was 12,305.72USD per patient in the 2 years study period; drug treatment costs represented 95.9% of this total. CONCLUSION: This study showed that most patients are cirrhotic, present high prevalence of cardiometabolic diseases and esophageal varices, reduced HRQoL mainly in terms of pain/discomfort, and work productivity impairment, especially presenteeism. Additionally, we demonstrated that hepatitis C virus imposes an economic burden on Brazilian Health Care System and that most of this cost is due to drug treatment.

Prevalence of IFNL3 gene polymorphism among blood donors and its relation to genomic profile of ancestry in Brazil.

The recent development of interferon-free regimens based on direct-acting antivirals for the treatment of chronic hepatitis C virus infection has benefited many but not all patients. Some patients still experience treatment failure, possibly attributed to unknown host and viral factors, such as IFNL3 gene polymorphism. The present study assessed the prevalence of rs12979860-CC, rs12979860-CT, and rs12979860-TT genotypes of the IFNL3 gene, and its relationship with ancestry informative markers in 949 adult Brazilian healthy blood donors. Race was analyzed using ancestry informative markers as a surrogate for ancestry. IFNL3 gene was genotyped using the ABI TaqMan single nucleotide polymorphisms genotyping assays. The overall frequency of rs12979860-CC genotype was 36.9%. The contribution of African ancestry was significantly higher among donors from the northeast region in relation to southeast donors, whereas the influence of European ancestry was significantly higher in southeast donors. Donors with rs12979860-CC and rs12979860-CT genotypes had similar ancestry background. The contribution of African ancestry was higher among rs12979860-TT genotype donors in comparison to both rs12979860-CC and rs12979860-CT genotypes. The prevalence of rs12979860-CC genotype is similar to that found in the US, despite the Brazilian ancestry informative markers admixture. However, in terms of ancestry, rs12979860-CT genotype was much closer to rs12979860-CC individuals than to rs12979860-TT.

Randomized trial - oxybutynin for treatment of persistent plantar hyperhidrosis in women after sympathectomy.

OBJECTIVE: Hyperhidrosis is a common disease, and thoracoscopic sympathectomy improves its symptoms in up to 95% of cases. Unfortunately, after surgery, plantar hyperhidrosis may remain in 50% of patients, and compensatory sweating may be observed in 70%. This clinical scenario remains a challenge. Our objective was to evaluate the effectiveness of oxybutynin in the treatment of persistent plantar hyperhidrosis and compensatory sweating and its effects on quality of life in women after thoracoscopic sympathectomy. METHOD: We conducted a prospective, randomized study to compare the effects of oxybutynin at 10 mg daily and placebo in women with persistent plantar hyperhidrosis. The assessment was performed using a quality-of-life questionnaire for hyperhidrosis and sweating measurement with a device for quantifying transepidermal water loss. Clinicaltrials.gov: NCT01328015. RESULTS: Sixteen patients were included in each group (placebo and oxybutynin). There were no significant differences between the groups prior to treatment. After oxybutynin treatment, there was a decrease in symptoms and clinical improvement based on the quality-of-life questionnaire (before treatment, 40.4 vs. after treatment, 17.5; p=0.001). The placebo group showed modest improvement (p=0.09). The outcomes of the transepidermal water loss measurements in the placebo group showed no differences (p=0.95), whereas the oxybutynin group revealed a significant decrease (p=0.001). The most common side effect was dry mouth (100% in the oxybutynin group vs. 43.8% in the placebo group; p=0.001). CONCLUSION: Oxybutynin was effective in the treatment of persistent plantar hyperhidrosis, resulting in a better quality of life in women who had undergone thoracoscopic sympathectomy.

A randomized controlled trial to assess safety, tolerability, and antepartum viral load with increased lopinavir/ritonavir dosage in pregnancy.

HIV mother-to-child transmission (MTCT) is significantly reduced if antepartum viral load (apVL) is<50 copies/mL. Pharmacokinetic studies suggest increasing the dosage of lopinavir/ritonavir (LPV/r) in pregnancy. It is important to assess tolerance, safety, and rate of patients presenting a apVL<50 copies/mL when treating with increased dose of LPV/r during pregnancy. Confirmed HIV-infected pregnant women with a fetus at a gestational age of 14-33 weeks were randomly assigned to receive LPV/r 400/100 or 600/150 mg b.i.d. plus two nucleoside analogues (NRTIs). Treatment was discontinued in the case of alanine transaminase (ALT) of grade III elevation or higher, glucose, or triglycerides. Thirty-two women were randomized to the LPV/r 400/100 mg dose, and 31 women were randomized to the 600/150 mg dose. Overall, 9.4% of the women receiving the conventional dose, and 17.2% receiving the increased dose, discontinued treatment because of adverse events (p=0.29). The rates of gastrointestinal (GI) symptoms, laboratory abnormalities, preterm delivery, and low birth weight were similar in both groups. There were no cases of HIV MTCT. Among the women with a baseline VL>50 copies/mL assigned to the conventional dose group, 45% (95% confidence interval [CI] 62.5-27.5%) had a apVL>50 copies/mL compared with 10.5% (95% CI 21.6-0.6%) of those assigned to the increased dose group (p=0.01). There was no significant difference found for the patients with a baseline VL<50 copies/mL. In pregnant women with a baseline VL>50 copies/mL, it may be warranted to initiate LPV/r dosing at 600/150 mg, whereas the conventional dose is sufficient for pregnant women with a baseline VL<50 copies/mL.

HIV peripheral neuropathy.

Peripheral neuropathies are the most common neurological manifestations occurring in HIV-infected individuals. Distal symmetrical sensory neuropathy is the most common form encountered today and is one of the few that are specific to HIV infection or its treatment. The wide variety of other neuropathies is akin to the neuropathies seen in the general population and should be managed accordingly. In the pre-ART era, neuropathies were categorized according to the CD4 count and HIV viral load. In the early stages of HIV infection when CD4 count is high, the inflammatory demyelinating neuropathies predominate and in the late stages with the decline of CD4 count opportunistic infection-related neuropathies prevail. That scenario has changed with the present almost universal use of ART (antiretroviral therapy). Hence, HIV-associated peripheral neuropathies are better classified according to their clinical presentations: distal symmetrical polyneuropathy, acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), mononeuropathies, mononeuropathies multiplex and cranial neuropathies, autonomic neuropathy, lumbosacral polyradiculomyelopathy, and amyotrophic lateral sclerosis (ALS)-like motor neuropathy. Treated with ART, HIV-infected individuals are living longer and are at a higher risk of metabolic and age-related complications; moreover they are also prone to the potentially neurotoxic effects of ART. There are no epidemiological data regarding the incidence and prevalence of the peripheral neuropathies. In the pre-ART era, most data were from case reports, series of patients, and pooled autopsy data. At that time the histopathological evidence of neuropathies in autopsy series was almost 100%. In large prospective cohorts presently being evaluated, it has been found that 57% of HIV-infected individuals have distal symmetrical sensory neuropathy and 38% have neuropathic pain. It is now clear that distal symmetrical sensory neuropathy is caused predominantly by the ART's neurotoxic effect but may also be caused by the HIV itself. With a sizeable morbidity, the neuropathic pain caused by distal symmetrical sensory neuropathy is very difficult to manage; it is often necessary to change the ART regimen before deciding upon the putative role of HIV infection itself. If the change does not improve the pain, there are few options available; the most common drugs used for neuropathic pain are usually not effective. One is left with cannabis, which cannot be recommended as routine therapy, recombinant human nerve growth factor, which is unavailable, and topical capsaicin with its side-effects. Much has been done to and learned from HIV infection in humans; HIV-infected individuals, treated with ART, are now dying mostly from cardiovascular disease and non-AIDS-related cancers. It hence behooves us to find new approaches to mitigate the residual neurological morbidity that still impacts the quality of life of that population.

The management of HIV-infected pregnant women.

PURPOSE OF REVIEW: The purpose of this article is to update the current practice in the management of HIV-infected pregnant women and present evidence-based recommendations for the reduction of mother-to-child transmission. RECENT FINDINGS: Early and sustained control of HIV viral replication is associated with decreasing residual risk of transmission and favors initiating antiretroviral drugs sufficiently early in naive women to suppress viral replication by the third trimester; however, this potential benefit must be balanced against the unknown long-term outcome of first-trimester drug exposure. Efavirenz should whenever possible be avoided in the first trimester of gestation, but its use seems well tolerated for 39 days after last menstrual period when the neural tube closes. Raltegravir may be considered in special circumstances in pregnancy. SUMMARY: The HIV viral load and the risk factors for prematurity must be considered when deciding when to start antiretroviral treatment in each individual pregnant woman. A ritonavir-boosted protease inhibitor combined with two nucleoside reverse transcriptase inhibitors is currently the most widely used regimen. Among protease inhibitors, lopinavir combined with ritonavir is the most frequently used; however, atazanavir combined with ritonavir is a good alternative. Elective cesarean section is the best delivery mode for pregnant women with viral loads more than 50  copies/ml.

The immunoexpression of heparanase 2 in normal epithelium, intraepithelial, and invasive squamous neoplasia of the cervix.

OBJECTIVE: Heparanase 2 (HPSE2) is expressed in various tissues, including the brain, intestine, prostate, breast, and endometrium. The aim of this study was to investigate the role of HPSE2 in cervical carcinogenesis, which has not been clarified to date. MATERIALS AND METHODS: The immunoexpression of HPSE2 in normal and neoplastic cervical squamous epithelia was determined using a semiquantitative (SQ) method and an index of expression (IE) method, using Image Lab Software. A total of 230 cervical tissue samples were analyzed and segregated into the following diagnostic groups: normal (27.4%), cervical intraepithelial neoplasia 1 (CIN 1, 15.2%), CIN 2 (16.5%), CIN 3 (15.2%), and invasive neoplasia (25.7%). The mean HPSE2 expression in the normal group was significantly lower than that of the other groups individually or combined (p < .001, for all combinations). The immunoexpression via the SQ method was significantly greater in the CIN 3 group compared with that in the CIN 1 group (p = .02). The mean immunoexpression of the high-grade squamous intraepithelial lesion groups was significantly greater than those of the normal and low-grade squamous intraepithelial lesion groups (p < .001) and lower compared with that of the invasive neoplasia group (p < .001). There were no statistically significant differences in the immunoexpression of HPSE2 among the different clinical states within the invasive neoplasia group. CONCLUSIONS: The SQ method produced a greater sensitivity and specificity than did the index of expression method. There was a progressive increase in the mean HPSE2 immunoexpression according to the severity of the cervical lesion from the low-grade squamous intraepithelial lesion group to the invasive neoplasm group, whereas the normal group displayed the lowest level of expression. This is a novel study concerning HPSE2 in the cervix and cervical cancer carcinogenesis.

Current treatment strategies, complications and considerations for the use of HIV antiretroviral therapy during pregnancy.

The global prevalence of HIV infection in the female population presents a significant healthcare burden in terms of mother-to-child transmission (MTCT) of the disease. This review aims to discuss current trends and treatment guidelines for the use of antiretroviral therapy during pregnancy and associated complications in this population. Historically, antiretroviral monotherapy with zidovudine was commonly used for preventing MTCT, and monotherapy with single-dose nevirapine is still used for prevention in resource-limited settings. Evidence suggests that combination therapy with HAART is a more effective treatment option than monotherapy when managing HIV in pregnant women. Current treatment guidelines recommend the use of HAART with a protease inhibitor (PI) or a nonnucleoside reverse transcriptase inhibitor (NNRTI) plus two nucleoside reverse transcriptase inhibitors (NRTI) as first-line therapy for the management of HIV infection in pregnant women and for preventing MTCT. Complications associated with the use of antiretroviral therapy during pregnancy should be taken into consideration when selecting a new antiretroviral regimen, or when continuing certain antiretroviral regimens in HIV-infected women who become pregnant while on therapy. NNRTI have been associated with severe and sometimes fatal hepatoxicity in some pregnant women and potentially teratogenic side effects in the fetus, and their use raises concerns regarding the development of drug- and class-resistant mutations. PI-based HAART has been associated with an increased risk of adverse effects such as premature delivery, low birth weight, dyslipidemia, glucose intolerance, and lipodystrophy. Despite this, initiating antiretroviral therapy with a PI plus two NRTI may become the preferred treatment option in pregnant women. Many of the side effects associated with PI were more prevalent when older PI and PI-based regimens that included those in combination with thymidine analog NRTI were used. An individual's history and baseline clinical and laboratory parameters should also be taken into consideration when choosing the most appropriate antiretroviral regimen during pregnancy.

Absence of the predisposing factors and signs and symptoms usually associated with overreaching and overtraining in physical fitness centers.

OBJECTIVE: The aim of this study was to evaluate the occurrence of the well-known predisposing factors and signs and symptoms usually associated with either overreaching or overtraining syndrome in physical fitness centers in São Paulo City, Brazil. METHOD: A questionnaire consisting of 13 question groups pertaining to either predisposing factors (1-7) or signs and symptoms (8-13) was given to 413 subjects. The general training schedule of the volunteers was characterized by workout sessions of 2.18 ± 0.04 h for a total of 11.0 ± 0.3 h/week for 33 ± 2 months independent of the type of exercise performed (walking, running, spinning, bodybuilding and stretching). A mean score was calculated ranging from 1 (completely absent) to 5 (severe) for each question group. A low occurrence was considered to be a question group score lower than 4, which was observed in all 13 question groups. RESULTS: The psychological evaluation by POMS Mood State Questionnaire indicated a normal non-inverted iceberg. The hematological parameters, creatine kinase activity, cortisol, total testosterone and free testosterone concentrations were within the normal ranges for the majority of the volunteers selected for this analysis (n = 60). CONCLUSION: According to the questionnaire score analysis, no predisposing factors or signs and symptoms usually associated with either overreaching or overtraining were detected among the members of physical fitness centers in São Paulo City, Brazil. This observation was corroborated by the absence of any significant hematological or stress hormone level alterations in blood analyses of the majority of the selected volunteers (n = 60).