DBCollHIV: a database system for collaborative HIV analysis in Brazil

We developed a database system for collaborative HIV analysis (DBCollHIV) in Brazil. The main purpose of our DBCollHIV project was to develop an HIV-integrated database system with analytical bioinformatics tools that would support the needs of Brazilian research groups for data storage and sequence analysis. Whenever authorized by the principal investigator, this system also allows the integration of data from different studies and/or the release of the data to the general public. The development of a database that combines sequences associated with clinical/epidemiological data is difficult without the active support of interdisciplinary investigators. A functional database that securely stores data and helps the investigator to manipulate their sequences before publication would be an attractive tool for investigators depositing their data and collaborating with other groups. DBCollHIV allows investigators to manipulate their own datasets, as well as integrating molecular and clinical HIV data, in an innovative fashion.     

Tuberculosis in patients with human immunodeficiency virus infection. Review of current concepts.

Tuberculosis is a frequent complication of human immunodeficiency virus (HIV)-induced immunosuppression. The diagnosis of extrapulmonary tuberculosis in patients with evidence of HIV infection qualifies as a criterion of the acquired immunodeficiency syndrome. Demographic characteristics of patients with tuberculosis and HIV infection vary by region and reflect the degree to which patients with Mycobacterium tuberculosis infection adopt behaviors that put them at risk for HIV infection. The clinical features of tuberculosis in patients with HIV infection are atypical. Extrapulmonary disease, tuberculin anergy, and unusual findings on chest radiographs occur most frequently when tuberculosis afflicts patients with other clinical evidence of HIV infection at the time tuberculosis is diagnosed. Treatment is effective for tuberculosis in HIV-seropositive patients, and isoniazid prophylaxis is recommended for HIV-infected patients with positive tuberculin skin tests.     

The ‘Antiretrovirals,Sexual Transmission Risk and Attitudes’ (ASTRA) Study. Design,Methods and Participant Characteristics

Life expectancy for people diagnosed with HIV has improved dramatically however the number of new infections in the UK remains high. Understanding patterns of sexual behaviour among people living with diagnosed HIV, and the factors associated with having condom-less sex, is important for informing HIV prevention strategies and clinical care. In addition, in view of the current interest in a policy of early antiretroviral treatment (ART) for all people diagnosed with HIV in the UK, it is of particular importance to assess whether ART use is associated with increased levels of condom-less sex. In this context the ASTRA study was designed to investigate current sexual activity, and attitudes to HIV transmission risk, in a large unselected sample of HIV-infected patients under care in the UK. The study also gathered background information on demographic, socio-economic, lifestyle and disease-related characteristics, and physical and psychological symptoms, in order to identify other key factors impacting on HIV patients and the behaviours which underpin transmission. In this paper we describe the study rationale, design, methods, response rate and the demographic characteristics of the participants. People diagnosed with HIV infection attending 8 UK HIV out-patient clinics in 2011-2012 were invited to participate in the study. Those who agreed to participate completed a confidential, self-administered pen-and-paper questionnaire, and their latest CD4 count and viral load test results were recorded. During the study period, 5112 eligible patients were invited to take part in the study and 3258 completed questionnaires were obtained, representing a response rate of 64% of eligible patients. The study includes 2248 men who have sex with men (MSM), 373 heterosexual men and 637 women. Future results from ASTRA will be a key resource for understanding HIV transmission within the UK, targeting prevention efforts, and informing clinical care of individuals living with HIV.     

In vitro and in vivo effects of HIV protease inhibitors on apoptosis

Development of potent inhibitors of HIV protease has revolutionized the treatment of HIV infection. HIV protease inhibitors (PI) have caused more dramatic improvements in CD4 T-cell numbers than in other therapies that were available previously, prompting investigators to assess whether PI possess intrinsic immunomodulatory effects. An emerging body of data indicates that HIV PIs are antiapoptotic, although the exact molecular target responsible for this antiapoptotic effect remains to be defined in vitro and in vivo. Paradoxically, high-dose PI also may have proapoptotic effects, particularly when assessed in vitro in transformed cell lines and implanted mouse models. Future research will define molecular targets of PI that are responsible for their apoptotis modulatory effects (both pro- and anti-apoptotic). In addition, evaluation of the clinical utility of PI-based therapy in those non-HIV disease states that are characterized by excessive apoptotis will reveal the full clinical potential of this intriguing class of drugs.     

Drug interactions associated with methadone, buprenorphine, cocaine, and HIV medications: implications for pregnant women

Pregnancy in substance-abusing women with HIV/AIDS presents a complex clinical challenge. Opioid-dependent women need treatment with opioid therapy during pregnancy to protect the health of mother and developing fetus. However, opioid therapies, methadone and buprenorphine, may have drug interactions with some HIV medications that can have adverse effects leading to suboptimal clinical outcomes. Further, many opioid-dependent individuals have problems with other forms of substance abuse, for example, cocaine abuse, that could also contribute to poor clinical outcomes in a pregnant woman. Physiological changes, including increased plasma volume and increased hepatic and renal blood flow, occur in the pregnant woman as the pregnancy progresses and may alter medication needs with the potential to exacerbate drug interactions, although there is sparse literature on this issue. Knowledge of possible drug interactions between opioids, other abused substances such as cocaine, HIV therapeutics, and other frequently required medications such as antibiotics and anticonvulsants is important to assuring the best possible outcomes in the pregnant woman with opioid dependence and HIV/AIDS.     

The value of primate models for studying human immunodeficiency virus pathogenesis

Abstract: Research on human immunodeficiency virus (HIV) infection is compromised by the obvious limitation in having for study only virus-infected individuals or those exposed to the virus. Steps involved in transmission or pathogenesis require planned experimentation. The identification of animal models of acquired immunodeficiency syndrome (AIDS) has therefore been helpful for evaluating phases of HIV pathogenesis. Of the seven subgenera of lentiviruses now recognized, two share the characteristics with HIV of a T cell tropism and the associated loss of CD4+ cells in the host associated with disease: the feline immunodeficiency virus (FIV) and the simian immunodeficiency virus (SIV) (Table 1). The other animal lentiviruses grow best in macrophages and their infection generally reflects clinical sequellae of infection of this cell type. This review addresses those features of SIV, HIV, and SHIV infections of non-human primates that illustrate the importance of the animal models of AIDS.     

AIDS awareness among rural Utah physicians.

Studies of physicians'' attitudes and knowledge of the acquired immunodeficiency syndrome (AIDS) and the clinical precautions they take against exposure to the human immunodeficiency virus (HIV) have focused on urban physicians. To determine rural physicians'' knowledge and attitudes about AIDS, a questionnaire was mailed to 321 physicians practicing in rural Utah. Of the 169 physicians who completed questionnaires, 96% thought that their community or area of service had only a minor or no problem with AIDS; 89%, however, thought that their chance of seeing a patient who was HIV-positive was fair to moderate. Of the 169 respondents, 3% were not sure whether they would even treat a patient who had AIDS, 67% said they would, and 30% said they would not. Although all physicians are at risk of seeing a patient who has had exposure to HIV and other blood-borne diseases such as hepatitis B, only 55% of the respondents felt a need to take clinical precautions to prevent their exposure to the virus. Our study shows the need for all rural Utah physicians to reevaluate their risk of exposure to HIV, to increase precautionary measures for their own protection, to consider the ethical responsibility of treating AIDS patients, and to take a more active role in teaching their patients how to protect themselves from exposure to the virus.     

Immunopathogenesis of HIV infection.

The ultimate consequence of infection with HIV is profound immunosuppression that is the result of both quantitative and qualitative abnormalities of the helper/inducer subset of T lymphocytes. The initial pathogenic event in HIV infection is binding of the envelope glycoprotein of HIV to the CD4 receptor molecule present on the surface of CD4+ T lymphocytes and monocyte/macrophages. In vivo the reservoir for HIV infection in the peripheral blood is the CD4+ T cell, whereas in other tissues the monocyte/macrophage may play a substantial role. As disease progresses in HIV-infected individuals, the viral burden in the peripheral blood CD4+ T cells increases. An understanding of the mechanisms involved in the transition from an initially low viral burden during the asymptomatic phase of HIV infection to the higher levels of virus expression detected in late stage disease is being investigated intensively. A number of potential agents that may influence regulation of HIV expression have been identified including mitogens, antigens, heterologous viruses, cytokines, and physical factors. The pathogenic mechanisms of HIV-induced neurologic abnormalities and the potential role of HIV in a number of other clinical manifestations of HIV infection are also discussed.     

Understanding Barriers to Routine HIV Screening: Knowledge, Attitudes, and Practices of Healthcare Providers in King County, Washington

Objective

In 2006, the Centers for Disease Control and Prevention (CDC) recommended routine HIV screening in healthcare settings for persons between 13 and 64 years old. In 2010, the Washington Administrative Code (WAC) was changed to align testing rules with these recommendations. We designed this survey to ascertain the current state of HIV testing and barriers to routine screening in King County, Washington.

Methods

Between March 23 and April 16, 2010, a convenience sample of healthcare providers completed an online survey. Providers answered true-false and multiple choice questions about national recommendations and the WAC, policies in their primary clinical settings, and their personal HIV testing practices. Providers were asked to agree or disagree whether commonly reported barriers limited their implementation of routine HIV screening.

Results

Although 76% of the 221 respondents knew that the CDC recommended routine HIV screening for persons regardless of their risk, 99 (45%) providers reported that their primary clinical setting had a policy to target testing based on patient risk factors. Forty-four (20%) providers reported that their primary clinical setting had a policy of routine HIV screening, 54 (25%) reported no official policy, and 15 (7%) did not know whether a policy existed. Only 11 (5%) providers offer HIV testing to all patients at initial visits. When asked about barriers to routine screening, 57% of providers agreed that perception that their patient population is low risk limits the number of HIV tests they perform. Only 26 (13%) providers agreed that concern about reimbursement posed a barrier to testing.

Conclusions

Most providers participating in this survey continue to target HIV testing, despite knowledge of national recommendations. Efforts are still needed to educate providers and policymakers, clarify the recent WAC revisions, and implement structural changes in order to increase HIV testing in Washington State.     

The usefulness of defined clinical features in the diagnosis of HIV/AIDS infection in Sierra Leone.

Sierra Leone ranks at the bottom of the global World Bank Development Index based on multiple health and economic indices and lacks the resources to purchase HIV diagnostic kits. Our study has defined some common clinical features presenting HIV infection that could form clinical algorithms for the diagnosis and recognition of HIV infection by health workers in Sierra Leone. In a private clinic in Freetown, Sierra Leone, West Africa, 106 out of a total of 124 patients presenting with various symptoms and strong clinical suspicion of HIV infection within a two-year period (1999 and 2000), were deemed positive by two different ELISA tests. The prevalence of HIV infection seen in this private clinic in Freetown in 2000 was 14.89% as compared to 9.25% in 1999. The positive predictive value of our clinical diagnosis of HIV/AIDS infection was 85.5%. The male:female ratio of the patients in our series was 1:1.9, with a mean age of 39 years for males and 28 years for females. HIV infection was found in a cross-section of the population that we examined. Heterosexual contact appeared to be the major mode of transmission amongst our patients and there seemed to be a significant epidemiological risk of HIV infection amongst those who traveled to other countries in the West African sub region. Common clinical features in decreasing frequency were fever (92.5%), weight loss (84.1%), lymphadenopathy (78.3%), cough (48.1%), diarrhea (37.7%), candidiasis (32.1%) and body aches (30.1%).     

Psychosocial aspects of human immunodeficiency virus infection

Infection with the human immunodeficiency virus (HIV) affects not only the physiological integrity of an individual but their psychological as well. The psychosocial aspects of HIV infection are varied and may be manifested in different behaviors and emotions specific to the stage of infection. These psychosocial aspects of HIV infection are explored using its chronology as a conceptual framework. An overview of issues pertinent to the asymptomatic, acquired immunodeficiency syndrome (AIDS)-related complex and AIDS client is given with suggestions for clinical management.     

The relationship between virologic and immunologic responses in AIDS clinical research using mixed-effects varying-coefficient models with measurement error

In this article we study the relationship between virologic and immunologic responses in AIDS clinical trials. Since plasma HIV RNA copies (viral load) and CD4+ cell counts are crucial virologic and immunologic markers for HIV infection, it is important to study their relationship during HIV/AIDS treatment. We propose a mixed-effects varying-coefficient model based on an exploratory analysis of data from a clinical trial. Since both viral load and CD4+ cell counts are subject to measurement error, we also consider the measurement error problem in covariates in our model. The regression spline method is proposed for inference for parameters in the proposed model. The regression spline method transforms the unknown nonparametric components into parametric functions. It is relatively simple to implement using readily available software, and parameter inference can be developed from standard parametric models. We apply the proposed models and methods to an AIDS clinical study. From this study, we find an interesting relationship between viral load and CD4+ cell counts during antiviral treatments. Biological interpretations and clinical implications are discussed.     

Development of V2-deleted trimeric envelope vaccine candidates from human immunodeficiency virus type 1 (HIV-1) subtypes B and C

The urgent need for a vaccine against HIV/AIDS requires that multiple strategies be employed and evaluated in a clinical setting. V2-loop deleted trimeric envelope (Env) immunogens (protein and DNA) from subtypes B and C human immunodeficiency virus type 1 (HIV-1) strains were produced for ongoing and future clinical evaluations with other HIV antigens, adjuvants and deliveries.     

Neuromuscular diseases of AIDS

Neuromuscular diseases are common in acquired immune deficiency syndrome (AIDS). Although the clinical incidence of peripheral neuropathy has not been systematically studied, various reports suggest that up to 40% of AIDS patients have clinical symptoms. Biopsy and autopsy studies have shown an inflammatory neuropathy with a variable component of demyelination and axonal loss. Evidence of direct involvement by the human immunodeficiency virus (HIV) is scant. Immunosuppression followed by cytomegalovirus (CMV) infection appears to be a direct cause of polyradiculoneuropathy and perhaps other forms of peripheral neuropathy in AIDS. The clinical incidence of myopathy in AIDS is less clear, and clinically less appreciated than the neuropathy. Scattered reports have identified an inflammatory myopathy that does not appear to be due to direct HIV infection, but could be mediated by another human retrovirus. HIV seropositive patients being treated with antiviral drugs develop a unique set of neuromuscular diseases that must be distinguished from the non-drug-related conditions.     

A comparison study of models and fitting procedures for biphasic viral dynamics in HIV-1 infected patients treated with antiviral therapies

The study of HIV dynamics is one of the most important developments in recent AIDS research. It has led to a new understanding of the pathogenesis of HIV infection. But, although important findings in HIV dynamics have been published in prestigious scientific journals in the last 5 years, the model-fitting procedures used in these publications have not been studied in any detail. In this paper, we evaluate the performance of four model-fitting procedures proposed and used in biphasic HIV dynamic data analysis via extensive Monte Carlo simulations. We propose some guidelines for practitioners to select an appropriate method for their own data analysis. Real data examples from an AIDS clinical trial are provided as illustrations.     

Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing

Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the ability of romidepsin (RMD), a histone deacetylase inhibitor approved for the treatment of T-cell lymphomas, to activate the expression of latent HIV. In an in vitro T-cell model of HIV latency, RMD was the most potent inducer of HIV (EC₅₀ = 4.5 nM) compared with vorinostat (VOR; EC₅₀ = 3,950 nM) and other histone deacetylase (HDAC) inhibitors in clinical development including panobinostat (PNB; EC₅₀ = 10 nM). The HIV induction potencies of RMD, VOR, and PNB paralleled their inhibitory activities against multiple human HDAC isoenzymes. In both resting and memory CD4 T cells isolated from HIV-infected patients on suppressive combination antiretroviral therapy (cART), a 4-hour exposure to 40 nM RMD induced a mean 6-fold increase in intracellular HIV RNA levels, whereas a 24-hour treatment with 1 µM VOR resulted in 2- to 3-fold increases. RMD-induced intracellular HIV RNA expression persisted for 48 hours and correlated with sustained inhibition of cell-associated HDAC activity. By comparison, the induction of HIV RNA by VOR and PNB was transient and diminished after 24 hours. RMD also increased levels of extracellular HIV RNA and virions from both memory and resting CD4 T-cell cultures. The activation of HIV expression was observed at RMD concentrations below the drug plasma levels achieved by doses used in patients treated for T-cell lymphomas. In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART.