Evaluation of Epstein-Barr Virus Salivary Shedding in HIV/AIDS Patients and HAART Use: A Retrospective Cohort Study

Little data is available on the evaluation of the occurrence rates of Epstein-Barr virus(EBV) in saliva and relationship with highly active antiretroviral therapy(HAART) use in HIV/AIDS patients in China. We conducted a retrospective cohort study of EBV serological tests for HIV/AIDS patients who were treated in the hospitals for infectious diseases in Wuxi and Shanghai, China from May 2016 to April 2017. The EBV-seropositive samples were identified by ELISA. EBV-specific primers and probes were used for the quantitative detection of viral DNA from saliva via quantitative real-time polymerase chain reaction. CD4 cell counts of the HIV/AIDS patients were detected by a flow cytometry. A total of 372 HIV/AIDS patients were ultimately selected and categorized for this retrospective cohort study. For EBV IgG and IgM, the HIV/AIDS HAART use(H) and non-HAART use(NH) groups had significantly higher seropositive rates than the HIV-negative control group. The HIV/AIDS(NH) group had the highest seropositive rate(IgG, 94.27%; IgM, 68.98%) and the highest incidence of EBV reactivation or infection. For salivary EBV DNA-positive rates and quantities, the HIV/AIDS(H)(73.69%) and the HIV/AIDS(NH)(100%) groups showed significantly higher values than the HIV-negative control group(35.79%,[ twofold). Further, the salivary EBV DNA-negative population had significantly higher CD4 cell counts than the EBV DNA-positive population in the HIV/AIDS(H) group and the HIV/AIDS(NH) groups. Thus, HAART use is beneficial in decreasing the EBV salivary shedding in HIV/AIDS patients and indirectly decreases EBV transmission risk.     

Alterations in the gut microbiota of patients with acquired immune deficiency syndrome

Acquired immune deficiency syndrome (AIDS), caused by infection with human immunodeficiency virus (HIV), is associated with gastrointestinal disease, systemic immune activation and changes in the gut microbiota. Here, we aim to investigate the gut microbiota patterns of HIV‐infected individuals and HIV‐uninfected individuals in populations from South China. We enrolled 33 patients with HIV (14 participants treated with highly active antiretroviral therapy [HAART] for more than 3 months; the remaining 19 individuals had not received treatment) and 35 healthy controls (HC) for a cross‐sectional comparison of gut microbiota using stool samples. Gut microbial communities were profiled by sequencing the bacterial 16S rRNA genes. Dysbiosis was more common among patients with AIDS compared with healthy individuals. Dysbiosis was characterized by decreased α‐diversity, low mean counts of Bacteroidetes, Faecalibacterium, Prevotella, Bacteroides vulgatus, Dialister and Roseburia inulnivorans, and high mean counts of Proteobacteria, Enterococcus, Streptococcus, Lactobacillus, Lachnociostridium, Ruminococcus gnavus and Streptococcus vestibularis. Increased abundance of Bacilli was observed in homosexual patients. Proteobacteria were higher among heterosexual patients with HIV infections. Tenericutes were higher among patients with history of intravenous drug abuse. Restoration of gut microbiota diversity and a significant increase in abundance of Faecalibacterium, Blautia and Bacteroides were found in patients receiving HAART compared to those who did not receive. HIV infection‐associated dysbiosis is characterized by decreased levels of α‐diversity and Bacteroidetes, increased levels of Proteobacteria and the alterations of gut microbiota correlate with the route of HIV transmission. The imbalanced faecal microbiota of HIV infection is partially restored after therapy.     

Tracking the evolution of HIV/AIDS in China from 1989-2009 to inform future prevention and control efforts

Background

To determine policy implications, this analysis tracks the evolution of HIV/AIDS infection across China to understand current trends and potential risk factors.

Methods and Principal Findings

A retrospective study with spatial analytical model and multilevel spatial models was conducted among 326,157 HIV/AIDS cases reported from 1989–2009. The results indicate that the distribution of HIV/AIDS was clustered at the county level with different directional distributions across China from 2003 to 2009. Compared to 2003, by 2009 there was a 122% increase in HIV cases among rural residents, 294% increase among urban residents, 211% increase among migrants, and 237% increase among permanent residents. The overall proportion of HIV by different routes of transmission showed dramatic changes with a 504% increase in sexual transmission of HIV, 90% decrease in blood/plasma transmission, and 35% decrease in injecting drug user transmission. Sexual transmission was the major transmission route among women (44%) and the elderly (59% in men, 44% in women) as well as among permanent (36%) and urban residents (33%). Among those <65 years old, women increased more than men, but among those ≥65 years, men increased more than women. Migrants contributed to the variance of HIV infection between counties but not within counties. The length of highway and urbanization combined with illiteracy were risk factors for HIV/AIDS.

Conclusions/Significance

Rates of HIV/AIDS among permanent urban residents, particularly women and elderly men, have increased significantly in recent years. To prevent HIV from spreading further among the general population, additional attention should be paid to these populations as well as to migrants.     

Efflux transporters- and cytochrome P-450-mediated interactions between drugs of abuse and antiretrovirals

Multidrug regimens and corresponding drug interactions cause many adverse reactions and treatment failures. Drug efflux transporters: P-gp, MRP, BCRP in conjunction with metabolizing enzymes (CYPs) are major factors in such interactions. Most effective combination antiretrovirals (ARV) therapy includes a PI or a NNRTI or two NRTI. Coadministration of such ARV may induce efflux transporters and/or CYP3A4 resulting in sub-therapeutic blood levels and therapeutic failure due to reduced absorption and/or increased metabolism. A similar prognosis is true for ARV-compounds and drugs of abuse combinations. Morphine and nicotine enhance CYP3A4 and MDR1 expression in vitro. A 2.5 fold rise of cortisol metabolite was evident in smokers relative to nonsmokers. Altered functions of efflux transporters and CYPs in response to ARV and drugs of abuse may result in altered drug absorption and metabolism. Appropriate in vitro models can be employed to predict such interactions. Influence of genetic polymorphism, SNP and inter-individual variation in drug response has been discussed. Complexity underlying the relationship between efflux transporters and CYP makes it difficult to predict the outcome of HAART as such, particularly when HIV patients taking drugs of abuse do not adhere to HAART regimens. HIV(+) pregnant women on HAART medications, indulging in drugs of abuse, may develop higher viral load due to such interactions and lead to increase in mother to child transmission of HIV. A multidisciplinary approach with clear understanding of mechanism of interactions may allow proper selection of regimens so that desired therapeutic outcome of HAART can be reached without any side effects.     

HIV behind Bars: Human Immunodeficiency Virus Cluster Analysis and Drug Resistance in a Reference Correctional Unit from Southern Brazil

People deprived of liberty in prisons are at higher risk of infection by the human immunodeficiency virus (HIV) due to their increased exposure through intravenous drug use, unprotected sexual activity, tattooing in prison and blood exposure in fights and rebellions. Yet, the contribution of intramural HIV transmission to the epidemic is scarcely known, especially in low- and middle-income settings. In this study, we surveyed 1,667 inmates incarcerated at Presídio Central de Porto Alegre, located in southern Brazil, for HIV infection and molecular characterization. The HIV seroprevalence was 6.6% (110/1,667). Further analyses were carried out on 40 HIV-seropositive inmates to assess HIV transmission clusters and drug resistance within the facility with the use of molecular and phylogenetic techniques. The molecular epidemiology of HIV-1 subtypes observed was similar to the one reported for the general population in southern Brazil, with the predominance of HIV-1 subtypes C, B, CRF31_BC and unique BC recombinants. In particular, the high rate (24%) of URF_BC found here may reflect multiple exposures of the population investigated to HIV infection. We failed to find HIV-infected inmates sharing transmission clusters with each other. Importantly, the analysis of HIV-1 pol genomic fragments evidenced high rates of HIV primary and secondary (acquired) drug resistance and an alarming proportion of virologic failure among patients under treatment, unveiling suboptimal access to antiretroviral therapy (ARV), low ARV adherence and dissemination of drug resistant HIV strains in primary infections. Our results call for immediate actions of public authority to implement preventive measures, serological screening and, for HIV-seropositive subjects, clinical and treatment follow-up in order to control HIV infection and limit the spread of drug resistance strains in Brazilian prisons.     

Mother-to-child transmission of HIV-1 in the era prior to the availability of combination antiretroviral therapy: the role of drugs of abuse

Since the use of combination antiretroviral therapy (HAART) to treat pregnant women, the rate of mother-to-child transmission (MTCT) of HIV in the United States has dropped dramatically to less than 2%. With this, the principal determinants of the risk of transmission are the maternal viral load and her use of antiretroviral therapy (ART). However, in the pre-HAART era, the MTCT ranged from 12 to 45% and was influenced by a variety of risk factors for transmission including no ART during pregnancy or delivery, advanced maternal HIV infection (high viral load, low CD4 count, and AIDS diagnosis), prolonged rupture of membranes, first-born of twins, prematurity/low birth weight, chorioamnionitis, vaginal delivery or non-elective Cesarean section, and maternal drug use. Several studies in the pre-HAART era found maternal illicit drug use to be an independent predictor of MTCT. Reasons for this association may be both behavioral and biological. Drug use is associated with poor adherence to ART and medical care. Opioids enhance infection of macrophages by HIV.     

Injection drug use and HIV/AIDS transmission in China

After nearly three decades of being virtually drug free, use of heroin and other illicit drugs has re-emerged in China as a major public health problem. One result is that drug abuse, particularly heroin injection, has come to play a predominant role in fueling China's AIDS epidemic. The first outbreak of HIV among China's IDUs was reported in the border area of Yunnan province between China and Myanmar where drug trafficking is heavy. Since then drug-related HIV has spread to all 31 provinces, autonomous regions and municipalities. This paper provides an overview to HIV/AIDS transmission through injection drug use in China. It begins with a brief history of the illicit drug trade in China, followed by a discussion of the emergence of drug related AIDS, and a profile of drug users and their sexual partners who have contracted the virus or who are vulnerable to infection. It ends by summarizing three national strategies being used by China to address both drug use and AIDS as major health threats.     

Characterisation of AIDS presenters and their response to antiretroviral therapy at legnano general hospital (Italy) during the period 2000-2008

The aim of this study was to characterise the AIDS presenters diagnosed between 2000 and 2008 in Legnano (Italy), and describe their initial response to highly active antiretroviral therapy (HAART) and trends over time. Seventy-six (48.7%) of 156 patients diagnosed as having AIDS in the period 2000-2008 were AIDS presenters. The proportion of AIDS presenters increased from 23.8% in 2000 to 70.6% in 2008 (p = 0.009). The major risk factors were heterosexual transmission and a foreign place of birth, and did not significantly change over time. The median CD4+ cell count at diagnosis was 30 cells/microl and the median level of HIV RNA was 5.38 log copies/ml, with no differences between the transmission risk groups. Fifteen AIDS presenters died of AIDS-defining diseases; the others started HAART (72% with 2 NRTIs + boosted PI), and 40% after a drug resistance test. The median duration of the initial HAART was 107 days. After three months, 34% of the patients had undetectable HIV-RNA levels and the median CD4+ cell count was 140 cells/microl; the corresponding figures after 12, 24 and 48 months were respectively 84%, 82.3% and 94.1%, and 310, 370 and 380 cells/microl. In conclusion, the AIDS presenters were mainly heterosexual men and immigrants. Their proportion increased significantly over time, and a substantial proportion maintained an immunovirological response to HAART.     

广西靖西县1997—2012年HIV/AIDS流行病学特征分析

目的了解广西靖西县1997—2012年HIV/AIDS流行病学状况,分析流行趋势,为制定艾滋病防治措施提供科学依据。方法采用描述流行病学分析方法,对靖西县1997—2012年艾滋病疫情监测资料进行分析。结果靖西县1997—2012年累计报告HIV/AIDS 147例,其中HIV感染者60例,AIDS病人47例,死亡40例;男性95例,女性52例,男女性别比为1.83∶1;以20~49岁青壮年为主,这些年龄组发病率为3.24/10万;传播途径以性接触传播为主,占90.48%;其次为静脉注射毒品传播,占6.80%。结论靖西县艾滋病流行近年呈明显上升趋势,艾滋病已经从高危人群向普通人群扩散传播,性接触传播已经成为艾滋病的主要传播途径,应加强对高危人群性行为的干预,遏制艾滋病传播蔓延。     

AIDS and associated malignancies

AIDS associated malignancies (ARL) is a major complication associated with AIDS patients upon immunosuppression. Chronically immunocompromised patients have a markedly increased risk of developing lymphoproliferative disease. In the era of potent antiretrovirals therapy (ARV), the malignant complications due to HIV-1 infection have decreased in developed nations where ARV is administered, but still poses a major problem in developing countries where HIV-1 incidence is high and ARV is still not yet widely available. Even in ARV treated individuals there is a concern that the prolonged survival of many HIV-1 carriers is likely to eventually result in an increased number of malignancies diagnosed. Malignancies that were found to have high incidence in HIV-infected individuals are Kaposi's sarcoma (KS), Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). The incidence of NHL has increased nearly 200 fold in HIV-positive patients, and accounts for a greater percentage of AIDS defining illness in the US and Europe since the advent of HAART therapy. These AIDS related lymphomas are distinct from their counterparts seen in HIV-1 seronegative patients. For example nearly half of all cases of ARL are associated with the presence of a gamma herpesvirus, Epstein Barr virus (EBV) or human herpesvirus-8 (HHV-8)/ Kaposi's sarcoma associated herpesvirus (KSHV). The pathogenesis of ARLs is complex. B-cell proliferation driven by chronic antigenemia resulting in the induction of polyclonal and ultimately monoclonal lymphoproliferation may occur in the setting of severe immunosuppression.     

Evolution of antiretroviral drug costs in Brazil in the context of free and universal access to AIDS treatment

Background

Little is known about the long-term drug costs associated with treating AIDS in developing countries. Brazil''s AIDS treatment program has been cited widely as the developing world''s largest and most successful AIDS treatment program. The program guarantees free access to highly active antiretroviral therapy (HAART) for all people living with HIV/AIDS in need of treatment. Brazil produces non-patented generic antiretroviral drugs (ARVs), procures many patented ARVs with negotiated price reductions, and recently issued a compulsory license to import one patented ARV. In this study, we investigate the drivers of recent ARV cost trends in Brazil through analysis of drug-specific prices and expenditures between 2001 and 2005.

Methods and Findings

We compared Brazil''s ARV prices to those in other low- and middle-income countries. We analyzed trends in drug expenditures for HAART in Brazil from 2001 to 2005 on the basis of cost data disaggregated by each ARV purchased by the Brazilian program. We decomposed the overall changes in expenditures to compare the relative impacts of changes in drug prices and drug purchase quantities. We also estimated the excess costs attributable to the difference between prices for generics in Brazil and the lowest global prices for these drugs. Finally, we estimated the savings attributable to Brazil''s reduced prices for patented drugs. Negotiated drug prices in Brazil are lowest for patented ARVs for which generic competition is emerging. In recent years, the prices for efavirenz and lopinavir–ritonavir (lopinavir/r) have been lower in Brazil than in other middle-income countries. In contrast, the price of tenofovir is US$200 higher per patient per year than that reported in other middle-income countries. Despite precipitous price declines for four patented ARVs, total Brazilian drug expenditures doubled, to reach US$414 million in 2005. We find that the major driver of cost increases was increased purchase quantities of six specific drugs: patented lopinavir/r, efavirenz, tenofovir, atazanavir, enfuvirtide, and a locally produced generic, fixed-dose combination of zidovudine and lamivudine (AZT/3TC). Because prices declined for many of the patented drugs that constitute the largest share of drug costs, nearly the entire increase in overall drug expenditures between 2001 and 2005 is attributable to increases in drug quantities. Had all drug quantities been held constant from 2001 until 2005 (or for those drugs entering treatment guidelines after 2001, held constant between the year of introduction and 2005), total costs would have increased by only an estimated US$7 million. We estimate that in the absence of price declines for patented drugs, Brazil would have spent a cumulative total of US$2 billion on drugs for HAART between 2001 and 2005, implying a savings of US$1.2 billion from price declines. Finally, in comparing Brazilian prices for locally produced generic ARVs to the lowest international prices meeting global pharmaceutical quality standards, we find that current prices for Brazil''s locally produced generics are generally much higher than corresponding global prices, and note that these prices have risen in Brazil while declining globally. We estimate the excess costs of Brazil''s locally produced generics totaled US$110 million from 2001 to 2005.

Conclusions

Despite Brazil''s more costly generic ARVs, the net result of ARV price changes has been a cost savings of approximately US$1 billion since 2001. HAART costs have nevertheless risen steeply as Brazil has scaled up treatment. These trends may foreshadow future AIDS treatment cost trends in other developing countries as more people start treatment, AIDS patients live longer and move from first-line to second and third-line treatment, AIDS treatment becomes more complex, generic competition emerges, and newer patented drugs become available. The specific application of the Brazilian model to other countries will depend, however, on the strength of their health systems, intellectual property regulations, epidemiological profiles, AIDS treatment guidelines, and differing capacities to produce drugs locally.     

Approaches to antiretroviral therapy in China

INTRODUCTION Advances in antiretroviral therapy (ART) have resulted in dramatic declines in hospitalizations and death rates in the U.S. and Europe, with concomitant steady increases in life expectancy. In China, the government has recog- nized the imminent threat that HIV/AIDS poses to its popu- lation and responded with a national antiretroviral (ARV) treatment program providing ARV drugs free to those most in need [1]. However, given the potentially catastrophic impact of HIV …     

HIV感染者/AIDS病人高迁移率族蛋白1的表达及其临床意义

通过检测74例处于不同病期的HIV感染者/AIDS患者和10例健康对照者PBMCs中HMGB1 mRNA的表达水平及其外周血浆HMGB1、TNF-a和IL-2水平,比较各组之间表达水平的差异及其与CD4＋T淋巴细胞的关系.发现HMGB1 mRNA的表达水平及血浆HMGB1含量在AIDS病人组明显高于感染者组和正常对照组（P〈0.05）;AIDS患者经HAART治疗后疗效差组HMGB1 mRNA的表达水平及血浆HMGB1含量也明显高于疗效好组（P〈0.05）;而经HAART治疗后效果好且免疫功能恢复的患者HMGB1 mRNA的表达及血浆HMGB1含量均较治疗前明显下降（P〈0.05）;当CD4＋T细胞数低于200/μL时,血浆HMGB1含量以及PBMCs中HMGB1 mRNA表达水平与CD4＋T细胞数呈负相关.显示HMGB1在HIV/AIDS发病及病情进展过程中可能起重要作用,HMGB1血浆含量及PBMCs中HMGB1 mRNA的表达水平高低与HIV/AIDS患者病情轻重密切相关.     

HIV+/AIDS related bioethical issues in Japan

Annual and cumulative incidences of HIV+ and AIDS in patients reported by the AIDS Surveillance Committee of the Ministry of Health and Welfare are cited to illustrate some characteristics in Japan: nearly 59% of either HIV+ or AIDS patients were infected through injection of blood products or by blood transfusion. A number of plaintiffs have sued the Japanese government and pharmaceutical companies since 1989, but no judicial decisions have yet been made. The incidence of HIV decreases for each of the following routes of infection: the second highest route of transmission being heterosexual, followed by bisexual and unconfirmed or unknown cases, and less frequently homosexual, drug use and lastly via vertical transmission. The most serious bioethical problems with HIV+ and AIDS patients in Japan is the social segregation of these patients. There are many emotional fears among the general public and medical personnel about AIDS because of their inadequate scientific knowledge of this disease. The Japan Hospital Association is doing The Stop AIDS Campaign and made several surveys. Japan has become increasingly aware of the importance of AIDS education and a great deal of effort is being made to enhance bioethical consideration.     

Hierarchical Bayesian inference for HIV dynamic differential equation models incorporating multiple treatment factors

Studies on HIV dynamics in AIDS research are very important in understanding the pathogenesis of HIV‐1 infection and also in assessing the effectiveness of antiretroviral (ARV) treatment. Viral dynamic models can be formulated through a system of nonlinear ordinary differential equations (ODE), but there has been only limited development of statistical methodologies for inference. This article, motivated by an AIDS clinical study, discusses a hierarchical Bayesian nonlinear mixed‐effects modeling approach to dynamic ODE models without a closed‐form solution. In this model, we fully integrate viral load, medication adherence, drug resistance, pharmacokinetics, baseline covariates and time‐dependent drug efficacy into the data analysis for characterizing long‐term virologic responses. Our method is implemented by a data set from an AIDS clinical study. The results suggest that modeling HIV dynamics and virologic responses with consideration of time‐varying clinical factors as well as baseline characteristics may be important for HIV/AIDS studies in providing quantitative guidance to better understand the virologic responses to ARV treatment and to help the evaluation of clinical trial design in response to existing therapies.     

HIV +/AIDS RELATED BIOETHICAL ISSUES IN JAPAN

Annual and cumulative incidences of HIV + and AIDS in patients reported by the AIDS Surveillance Committee of the Ministry of Health and Welfare are cited to illustrate some characteristics in Japan: nearly 59% of either HIV + or AIDS patients were infected through injection of blood products or by blood transfusion. A number of plaintiffs have sued the Japanese government and pharmaceutical companies since 1989, but no judicial decisions have yet been made. The incidence of HIV decreases for each of the following routes of infection: the second highest route of transmission being heterosexual, followed by bisexual and unconfirmed or unknown cases, and less frequently homosexual, drug use and lastly via vertical transmission. The most serious bioethical problems with HIV + and AIDs patients in Japan is the social segregation of these patients. There are many emotional fears among the general public and medical personnel about AIDS because of their inadequate scientific knowledge of this disease. The Japan Hospital Association is doing The Stop AIDS Campaign and made several surveys. Japan has become increasingly aware of the importance of AIDS education and a great deal of effort is being made to enhance bioethical considerations.     

Penicillium marneffei Infection in Immunocompromised Host

Penicillium marneffei (PM) was first described in 1973, causing human infection in a patient with Hodgkin Lymphoma. In the HIV/AIDS epidemic, it has been described as one of the important opportunistic infection following tuberculosis and cryptococcosis in endemic region of Southeast Asia and Southern China. Immunocompromised patients acquire penicilliosis through inhalation of conidia, resulting in disseminated disease characterized by prolonged fever, pancytopenia, hepatosplenomegaly, and classic cutaneous presentation of umbilicated papular eruption. Nowadays, rare manifestations such as fungemia, pneumonia, enterocolitis, genital ulcers, oral ulcer, and central nervous system infection have been reported. Over the past decade, molecular and genomic studies have revealed more knowledge of PM, and vaccines are under development. Modern era PM has become a serious threat in immunocompromised travelers, rather than HIV/AIDS patient in the endemic area, who receive an effective prophylaxis strategy along with the highly active antiretroviral therapy (HAART) initiation.     

Prevention and control of HIV infection in the Osh region of the Kyrgyz Republic

A total of 178 cases of HIV infection were diagnosed in the Osh region of the Kyrgyz Republic for January 1, 2003, the intensity of the prevalence of HIV infection being 14.5 per 100,000 of the population with this figure for the whole republic being equal to 5.9. In the dynamics of the HIV infection epidemic two periods were detected. During the first 3 years (1998-2000) a few individual imported cases of HIV infection were registered in the region. During the last 2 years (2001-2002) 98.8% of all cases of HIV infection registered in the region, as well as the presence of an epidemic outbreak among injection drug users (IDU), were detected. The risk factors of getting HIV infection were the intravenous use of drugs and a low level of information among young people concerning the routes of transmission of this infection and means of protection from HIV/AIDS: the promotion of healthy life style among young people, the introduction of the programs of "harm reduction" among IDU and the rules of safe sex.