HIV-1 infection in injection drug users

Injection drug use is an efficient and ongoing means of HIV transmission and is the principal mode of transmission in some parts of the world. In the United States, approximately 10,000 injection drug users are believed to acquire HIV each year. The US Public Health Service hopes to decrease all HIV transmission in the United States by 50% in the next 5 years, by promoting care and prevention services to infected persons. Subtle differences in the virology and immunopathogenesis of HIV between injection drug users and other groups at risk are still being investigated. So far such differences have no practical implication. Comparison of progression rates and survival with HIV across risk groups has been difficult because of the many competing causes of death unrelated to HIV among injection drug users, but overall HIV disease progression rates are similar across risk groups, after adjusting for age. Some AIDS-related opportunistic infections are more common (such as tuberculosis) or less common (such as Kaposi's sarcoma) among injection drug users, based on rates of exposure and latent infection. Other comorbidities, including chronic psychiatric disorders and hepatitis C disease, are more common among injection drug users than among others with HIV infection. Highly active antiretroviral treatment seems to be as effective in persons with a history of injected drug use as in others. Increasing the numbers of HIV-infected injection drug users who know their diagnosis, increasing their access to care and prevention services, and increasing their adherence to a therapeutic regimen are the current challenges in confronting the HIV-epidemic among injection drug users. To overcome these obstacles, clinicians must have both technical knowledge and skill in assisting patients with behavior change.     

Alcohol and viral hepatitis: A mini-review

Due to their high prevalence in the general population, alcohol use and abuse can be associated with hepatitis B and C virus infections and it has been demonstrated that alcohol plays a role as a co-morbid factor in the development of liver disease. There is evidence that alcohol abuse accelerates the progression of liver fibrosis and affects the survival of patients with chronic hepatitis C. The mechanism by which alcohol worsens hepatitis C virus-related liver disease has not been fully clarified, but enhanced viral replication, increased oxidative stress, cytotoxicity and impairment of immune response could play a relevant role. Alcohol abuse also seems to reduce both sensitivity to interferon and adherence to treatment. It sounds reasonable to presume that the mechanisms enhancing liver damage in patients affected by hepatitis B are similar to those involved in hepatitis C virus infection. However, more studies are warranted to improve our knowledge about the interaction between alcohol intake and hepatitis B virus infection. In conclusion alcohol abuse is associated with an accelerated progression of liver injury, leading to an earlier development of cirrhosis, higher incidence of hepatocellular carcinoma, and higher mortality. Abstinence could reverse some of these deleterious effects.     

Primary HIV-1 infection: diagnosis and prognostic impact

Acute infection with HIV is symptomatic in approximately two thirds to three-fourths of patients. This stage is defined as primary HIV infection or acute HIV illness. The diagnosis is crucial for public health because counseling can be provided to reduce the risk of transmission and for individual because early antiretroviral treatment could improve the prognosis, slowing the rate of disease progression. Physicians should be aware of the broad clinical spectrum representative of primary HIV infection, which ranges from mild symptoms resembling classic mononucleosis infection to highly severe presentations. Progression to AIDS and to death has been associated with the severity of the acute HIV infection. Clinical trials with combined antiretroviral drugs are needed to identify the best drug combinations as well as the optimal duration of treatment.     

HCV chronic hepatitis in patients with HIV: clinical management issues

HIV-hepatitis C virus (HCV) coinfection is common and affects more than one-third of all HIV infected persons worldwide. Prevalence among risk categories varies according to shared risk factors for transmission, mainly intravenous drug use (IDU) and hemophiliacs. Chronic HCV infection seems to accelerate the course of HIV disease, resulting in a worsened clinical and immunological progression. At the same time, several studies suggest that HIV disease modifies the natural history of HCV infection, leading to a faster course of progression from active hepatitis to cirrhosis, to end stage liver disease and death. HCV infection mimics opportunistic diseases because its natural history is significantly accelerated in HIV patients. Since highly active antiretroviral therapy (HAART) has slowed the progression of HIV disease and decreased the rate of HIV associated mortality, the prognosis of HIV disease has been modified, and the need to treat HCV coinfection become a significant issue. Because of the poor response rate obtained by either interferon alone or interferon thrice weekly plus ribavirin, the combination of pegylated interferon and ribavirin will probably become the standard of care, although the clinicians should be aware of the overlapping toxicity of nucleoside analogues and ribavirin. Many selected categories of patients pose particular challenges to physicians treating HCV infection: nonresponders to interferon, cirrhotic patients, and patients infected with both HCV and HBV. Liver transplantation in HIV patients is currently under evaluation, but should become the rescue therapy for HIV patients with end stage liver disease.     

Using Behavioral Research to Address Drug Abuse and AIDS

Drug abuse and the spread of HIV/AIDS are intertwined public health problems that require many and multifaceted solutions. Behavioral and social science research plays an important role in helping us to understand and develop solutions to these related epidemics. Behavioral research supported by the National Institute on Drug Abuse (NIDA) has demonstrated that drug users are amenable to behavior change strategies. Drug abuse treatment, prevention and community-based outreach programs have all been found to be effective in reducing drug use, needle-sharing practices, unsafe sex behaviors, as well as risk for HIV infection.     

Drugs of Abuse and Their Impact on Viral Pathogenesis

Commonly misused substances such as alcohol, cocaine, heroin, methamphetamine, and opioids suppress immune responses and may impact viral pathogenesis. In recent years, illicit use of opioids has fueled outbreaks of several viral pathogens, including the human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV). This review focuses on the myriad of mechanisms by which drugs of abuse impact viral replication and disease progression. Virus–drug interactions can accelerate viral disease progression and lead to increased risk of virus transmission.     

Is autoimmunity a component of natural immunity to HIV?

Antibody neutralization would be a major way to prevent HIV infection and disease progression, but the complex relationship between host and pathogen makes tough to achieve this target through immunogens based on viral envelope proteins. Autoimmunity has been associated to bacterial and viral diseases, as a consequence of inflammatory response to pathogens; it may eventually lead to harm host cells and organs. However, autoimmune-like responses have also been observed in HIV-infected patients, raising many questions about their clinical significance. Recent studies have elucidated both similarities and differences between anti-self responses in HIV infection and autoimmune diseases, identifying new molecular players that might enhance immune protection to HIV and/or modulate the clinical progression of the established infection. This paper will present the current knowledge on auto-antibodies observed in HIV infection, their putative mechanisms of generation and their possible implications for immune therapy.     

A Comparison of Risk Factors for HCV-mono-infection,HIV-mono-infection,and HCV/HIV-co-infection in a Community Setting

The prevalence of HIV infection in HCV patients is much lower than the prevalence of HCV infection in HIV patients. Whereas the higher prevalence of HCV infection in HIV is clearly related to drug abuse, the reasons for the lower prevalence of HIV infection in HCV patients has not been reported. The prevalence of non-sexual and sexual risk factors associated with acquisition of hepatitis C and HIV were studied in HIV-mono-infected, HCV-mono-infected, and HCV/HIV-co-infected individuals. None of the 114 HCV-mono-infected patients tested positive for HIV and this finding was associated with a significantly lower number of men who have sex with men (MSM) among the HCV-mono-infected subjects than among either the HIV-mono-infected or HCV/HIV-co-infected individuals. Unprotected anal intercourse and sex for money or drugs were reported less often by HCV-mono-infected individuals than by HIV-mono-infected and HCV/HIV-co-infected subjects. Having sex with an intravenous-drug user (IVDU) was reported more frequently by both HCV-mono-infected and HCV/HIV-co-infected individuals than by HIV-mono-infected individuals. Sub-analysis of the group of MSM revealed that IVDU differentiated between HIV-mono-infected and HCV/HIV-co-infected subjects. These results reveal that the lower prevalence of HIV in HCV patients is related to a lower number of MSM in this group and that sex with an IVDU is a surrogate marker for drug abuse related to acquiring HCV but not HIV. The guidelines should include strategies for testing for HCV and HIV in patients with these infections.     

The effects of the 32-bp CCR-5 deletion on HIV transmission and HIV disease progression in individuals with haemophilia

The chemokine receptor CCR5 is an important co-receptor for cell fusion. A 32-bp deletion of the CCR5 gene, leading to complete absence of functional CCR5 expression, has been associated with resistance to human immunodeficiency virus (HIV) infection in homozygotes and slower HIV disease progression in heterozygotes. The objectives of this study were to assess the effects of this 32-bp deletion on transmission of HIV infection and on HIV disease progression in haemophilic individuals. Six HIV-negative patients from our centre, known to have been exposed to infectious factor VIII concentrates, have been analysed. Three of these patients possess the CCR5 32-bp deletion, two patients being homozygous. The presence of the CCR5 32-bp gene deletion has also been analysed in 71 HIV-positive patients. In this group of patients, there was a lower than expected incidence of the 32-bp deletion. Those who possess the 32-bp deletion progress to AIDS more slowly than those who do not (P = 0.05, log-rank test). Rates of CD4 loss were slower in those heterozygous for the gene deletion. We confirm that heterozygosity for the 32-bp gene deletion in CCR5 is partially protective against initial infection with HIV. In those heterozygous patients who became infected with HIV, disease progression was slower.     

Pathogenic interactions between alcohol and hepatitis C

Alcohol is the most commonly abused substance in the United States, and alcohol abuse leads to alcoholic liver disease, a long recognized major public health concern. The high prevalence of chronic hepatitis C virus (HCV) infection, along with the clinical observation that HCV infection is common in alcoholic patients presenting with liver disease, has directed attention to the interaction between alcohol and HCV infection. Clinical studies have identified alcohol use as an independent risk factor for progression of fibrosis in chronic HCV infection. Experimental evidence suggests additive inhibitory effects between HCV and alcohol on antiviral immune responses. In addition, specific pathways have been identified by which HCV core protein and alcohol interact to activate hepatocytes. Nonspecific inflammatory cell recruitment and proinflammatory cytokine activation have also been implicated in both alcohol-and HCV-induced liver diseases. Further investigation of these and other pathways by which alcohol and HCV interact should unravel the mechanisms that accelerate the progression of liver disease.     

Mycobacterium avium complex and other nontuberculous mycobacteria in patients with HIV infection

Nontuberculous mycobacteria (NTM) have been frequently identified as opportunistic pathogens in individuals with advanced human immunodeficiency virus (HIV) infection. The majority of these infections have been caused by members of the Mycobacterium avium-intracellulare complex (MAC). Disseminated MAC infection has generally been diagnosed late in the course of HIV infection, and it is often associated with persistent nonspecific symptoms of fever, generalized weakness, and weight loss. Abdominal pain and/or diarrhea with malabsorption may also occur in some patients. Despite frequent isolation of MAC organisms from respiratory secretions in these patients, significant pulmonary involvement has not been seen commonly with disseminated MAC infection. While MAC can be isolated from a variety of clinical specimens in infected individuals, culturing of blood is the single most useful diagnostic procedure to evaluate for MAC infection. The prognosis for disseminated MAC infection in HIV-infected patients has been poor, with a reported median survival of 7.4 months after diagnosis. The overall contribution of MAC infection to mortality in these patients has not been clearly delineated. Treatment of MAC infection in HIV-infected individuals using a variety of drug regimens has not been effective in clearing mycobacteremia or improving overall survival in the majority of patients. However, initiation of drug therapy for MAC may decrease the severity of disease symptoms in some patients. Several NTM other than MAC have also been reported as causing infection in HIV-infected patients. Many of these organisms are ubiquitous in the environment and are frequent colonizers of biologic specimens. Although many NTM are regarded as relatively avirulent, these organisms need to be recognized as potentially important pathogens in HIV-infected patients with significant immunosuppression.     

Emergence of a novel penicillin-nonsusceptible,invasive serotype 35B clone of Streptococcus pneumoniae within the United States

Opiate abuse has been postulated to be a cofactor in the immunopathogenesis of acquired immunodeficiency syndrome (AIDS). This study evaluated whether methadone, a drug widely prescribed for the treatment of drug abusers with opioid dependence, affects human immunodeficiency virus (HIV) infection of human immune cells. When added to human fetal microglia and blood monocyte-derived macrophage cultures, methadone significantly enhanced HIV infection of these cells. This enhancement was associated with the up-regulation of expression of CCR5, a primary coreceptor for macrophage-tropic HIV entry into macrophages. Most importantly, the addition of methadone to the cultures of latently infected peripheral blood mononuclear cells from HIV-infected patients enhanced viral activation and replication. Although the in vivo relevance of these findings remains to be determined, the data underscore the necessity of further studies to define the role of opioids, including methadone, in the immunopathogenesis of HIV infection and AIDS.     

Hepatitis C antiviral treatment in special populations

Early identification and consideration for antiviral treatment of chronic hepatitis C virus (HCV) is an important component in reducing morbidity and mortality. Although many HCV-infected patients do not meet current criteria for antiviral therapy, increased efforts are needed to overcome barriers to care and improve treatment candidacy. In select patients, clinicians should consider expanding treatment eligibility to reduce disease progression, lifethreatening complications, and future disease burden. Preliminary data suggest that HCV-infected "special populations," including those with substance abuse disorders (ie, injection drug use, alcohol abuse), those coinfected with HIV, and those with cirrhosis but only mild hepatic compromise, can be successfully treated with interferonbased preparations and ribavirin. Larger, controlled clinical studies are needed to validate preliminary results. Collaboration with a multidisciplinary team experienced in managing HCV infection is crucial to improve treatment candidacy, address the complexities involved with treating special populations, and optimize response and ensure safety in those undergoing HCV antiviral therapy.     

Cocaine-mediated induction of platelet-derived growth factor: implication for increased vascular permeability

Neuroinflammation associated with advanced HIV-1 infection is often exacerbated in cocaine-abusing, HIV-infected patients. The underlying mechanisms could, in part, be attributed to the increased impairment of blood brain barrier integrity in the presence of cocaine. Platelet-derived growth factor (PDGF) has been implicated in several pathologic conditions, specifically attributable to its potent mitogenic effects. Its modulation by drug abuse, however, has received very little attention. In the present study, we demonstrated cocaine-mediated induction of PDGF-BB in human brain microvascular endothelial cells through the binding to its cognate σ receptor. Furthermore, this effect was mediated, with subsequent activation of mitogen-activated protein kinases and Egr-1 pathways, culminating ultimately into increased expression of PDGF-BB. Cocaine exposure resulted in increased permeability of the endothelial barrier, and this effect was abrogated in mice exposed to PDGF-BB neutralizing antibody, thus underscoring its role as a vascular permeant. In vivo relevance of these findings was further corroborated in cocaine-treated mice that were administered neutralizing antibody specific for PDGF-BB as well as in Egr-1(-/-) mice. Understanding the regulation of PDGF-BB expression may provide insights into the development of potential therapeutic targets for neuroinflammation associated with HIV infection and drug abuse.     

Risk of HIV infection in psychiatrically ill patients

The growing spread of HIV infection and AIDS incidence has led the medical milieu to increase efforts in the study of the at-risk population and in the development of prevention programmes. Nevertheless, little attention has been focused on psychiatric patients as a vulnerable and disadvantaged segment of the population with high risk of HIV infection. In fact, several studies in the last years have shown that high-risk behaviour, especially intravenous drug abuse and non-protected at-risk sexual intercourse, is reported by 20-50% of psychiatric patients, particularly those affected by bipolar disorders and schizophrenia. The prevalence of HIV infection has also been found to be higher in psychiatric patients than in the general population. In general, only a proportion (15-50%) of HIV-positive psychiatric patients have knowledge about their serological status, while the others do not know that they have been infected. Preliminary studies show that educational programmes specifically developed for psychiatric patients improved knowledge of HIV infection and reduced the patients' HIV-risk behaviour. Specific intervention strategies should also be known when dealing with mentally ill HIV-positive patients. Open problems and further issues to be addressed by future research are discussed.     

NIH conference. Immunopathogenic mechanisms in human immunodeficiency virus (HIV) infection.

An understanding of the immunopathogenic mechanisms of infection with human immunodeficiency virus (HIV) is fundamental in developing successful approaches to designing effective therapeutic and vaccine strategies. In this regard, we have investigated the mechanisms by which HIV inserts itself into the human immune system and uses the elaborate cytokine network to its own replicative advantage. We have also shown that the burden of HIV in CD4+ T cells is directly associated with a decline in this cell population in vivo and a progression to disease. Mononuclear phagocytes may play a role in the pathogenesis of HIV infection by serving as reservoirs of the virus. Of note is the fact that monocytes in the peripheral blood of HIV-infected individuals are rarely infected in vivo, whereas infected-tissue macrophages may play a role in organ-specific HIV-related pathogenesis. The role of HIV-specific humoral and cell-mediated immunity in HIV infection is not well understood. However, fine specificity of responses against HIV have been delineated in some in-vitro systems. It is unclear why these responses, particularly HIV-specific cytolytic T-cell responses, diminish over the course of infection and are unable to contain progression of infection.     

Renal transplantation in patients with HIV infection

The prevalence of human immunodeficience virus (HIV) infection among patients under renal replacement therapy varies, with estimates of 1% for Europe and 1.5% for the United States. Survival in HIV infected individuals receiving renal replacement therapy has improved since the introduction of high activity antiretroviral therapy (HAART). Current experience in renal transplantation in HIV-infected patients in the United States indicates that the three-year survival rate is similar to that of HIV-negative transplant recipients, with virological and immunological control of the infection by HAART and no increase in the number of opportunistic infections or tumors. The criteria for selecting renal transplantation candidates in this population are the following: no aids-defining events, CD4 cells > 200 cells/.l and undetectable viral load under HAART. In Spain, where most of these patients are former drug abusers, a two-year period of abstinence from cocaine and heroine abuse is also required, although patients can be participating in the methadone program. The main problems in the post-transplantation period have been interactions between HAART and immunosuppressive drugs, management of hepatitis C virus (HCV) coinfection and the high rate of acute rejection. To date, seven such renal transplantations have been performed in Spain, with favorable patient and graft survival and no progression to aids.