Drugs of abuse and HIV infection/replication: implications for mother-fetus transmission

Human immunodeficiency virus (HIV) infection and progression of acquired immunodeficiency syndrome (AIDS) can be modulated by a number of cofactors, including drugs of abuse. Opioids, cocaine, cannabinoids, methamphetamine (METH), alcohol, and other substances of abuse have been implicated as risk factors for HIV infection, as they all have the potential to compromise host immunity and facilitate viral replication. Although epidemiologic evidence regarding the impact of drugs of abuse on HIV disease progression is mixed, in vitro studies as well as studies using in vivo animal models have indicated that drugs of abuse have the ability to enhance HIV infection/replication. Drugs of abuse may also be a risk factor for perinatal transmission of HIV. Because high levels of viral load in maternal blood are associated with increased risk of HIV vertical transmission, it is likely that drugs of abuse play an important role in promoting mother-fetus transmission. Furthermore, because the neonatal immune system differs qualitatively from the adult system, it is possible that maternal exposure to drugs of abuse would exacerbate neonatal immunity defects, facilitating HIV infection of neonate immune cells and promoting HIV vertical transmission. The availability and use of antiretroviral therapy for women infected with HIV increase, there is an increasing interest in determining the impact of drug abuse on efficacy of AIDS Clinical Trials Group (ACTG)-standardized treatment regimens for woman infected with HIV in the context of HIV vertical transmission.     

Speed, Sex, Gay Men, and HIV: Ecological and Community Perspectives

Fifteen years into the HIV/AIDS epidemic, a great deal is now known about the different populations impacted by the disease, including those affected directly or indirectly by drug use. Anthropology has played a critical role in assisting with this task by identifying hidden populations, developing new methodological approaches, and targeting outreach efforts. In spite of this considerable body of ethnographic knowledge, men who have sex with other men (i.e., MSM, or gay and bisexual men) who use drugs have not received the same research attention as other drug users, despite the fact that they represent nearly one-fifth of AIDS cases in the U.S. with injection drug histories. In response to the alarming increase in HIV seroprevalence among this population, this ethnographic project provides preliminary data about those who are at dual risk for HIV through both homosexual behavior and injection drug use.     

Drug abuse,psychiatric disorders,and AIDS. Dual and triple diagnosis.

Substance abuse and psychiatric disorders commonly occur together. This form of dual diagnosis is notable because it complicates assessment and makes treatment more difficult for both psychiatric and drug abuse problems. Drugs can cause psychiatric disorders and can also be used as an attempt to "cure" them by self-medication. The spread of the human immunodeficiency virus (HIV) among drug users has added a third potential clinical problem, that of the acquired immunodeficiency syndrome, to the difficulties already presented by drug abuse and psychiatric disorders. Patients with this triple diagnosis pose challenges to primary care physicians as well as addiction medicine specialists or psychiatrists. Assessment should include a drug abuse history, preferably corroborated by others, evaluation of the mental state, and examination focusing on signs of drug abuse and HIV infection. Treatment should include the management of HIV disease, abstinence from drug abuse, and access to psychiatric care. New systems of health care service, including interdisciplinary case management, may be needed to manage patients with a triple diagnosis.     

HDAC inhibitors in parasitic diseases

Parasitic diseases cause significant global morbidity and mortality, particularly in underdeveloped regions of the world. Malaria alone causes ~800000 deaths each year, with children and pregnant women being at highest risk. There is no licensed vaccine available for any human parasitic disease and drug resistance is compromising the efficacy of many available anti-parasitic drugs. This is driving drug discovery research on new agents with novel modes of action. Histone deacetylase (HDAC) inhibitors are being investigated as drugs for a range of diseases, including cancers and infectious diseases such as HIV/AIDS, and several parasitic diseases. This review focuses on the current state of knowledge of HDAC inhibitors targeted to the major human parasitic diseases malaria, schistosomiasis, trypanosomiasis, toxoplasmosis and leishmaniasis. Insights are provided into the unique challenges that will need to be considered if HDAC inhibitors are to be progressed towards clinical development as potential new anti-parasitic drugs.     

A Complex Systems Approach to Evaluate HIV Prevention in Metropolitan Areas: Preliminary Implications for Combination Intervention Strategies

Background

HIV transmission among injecting and non-injecting drug users (IDU, NIDU) is a significant public health problem. Continuing propagation in endemic settings and emerging regional outbreaks have indicated the need for comprehensive and coordinated HIV prevention. We describe the development of a conceptual framework and calibration of an agent-based model (ABM) to examine how combinations of interventions may reduce and potentially eliminate HIV transmission among drug-using populations.

Methodology/Principal Findings

A multidisciplinary team of researchers from epidemiology, sociology, geography, and mathematics developed a conceptual framework based on prior ethnographic and epidemiologic research. An ABM was constructed and calibrated through an iterative design and verification process. In the model, “agents” represent IDU, NIDU, and non-drug users who interact with each other and within risk networks, engaging in sexual and, for IDUs, injection-related risk behavior over time. Agents also interact with simulated HIV prevention interventions (e.g., syringe exchange programs, substance abuse treatment, HIV testing) and initiate antiretroviral treatment (ART) in a stochastic manner. The model was constructed to represent the New York metropolitan statistical area (MSA) population, and calibrated by comparing output trajectories for various outcomes (e.g., IDU/NIDU prevalence, HIV prevalence and incidence) against previously validated MSA-level data. The model closely approximated HIV trajectories in IDU and NIDU observed in New York City between 1992 and 2002, including a linear decrease in HIV prevalence among IDUs. Exploratory results are consistent with empirical studies demonstrating that the effectiveness of a combination of interventions, including syringe exchange expansion and ART provision, dramatically reduced HIV prevalence among IDUs during this time period.

Conclusions/Significance

Complex systems models of adaptive HIV transmission dynamics can be used to identify potential collective benefits of hypothetical combination prevention interventions. Future work will seek to inform novel strategies that may lead to more effective and equitable HIV prevention strategies for drug-using populations.     

HIV prevalence in blood donors in urban and in rural areas of the Federal Republic of Germany

HIV infection rates in blood donors from the FRG were compared with the prevalence in donors from Berlin to obtain information on the HIV infections in donors of rural versus urban origin. The HIV prevalences decrease similarly in the first years of testing, although on different levels. They are lower in rural areas by a factor of 15 in the first year and of 10 thereafter. The modes of infectivity in both groups are similar although drug abuse seems to be more frequent amongst infected donors of urban areas. Ninety percent of the infected donors are either persons at risk or sexual partners of risk persons. During the observed time period there seems to be a trend from homo-/bisexuality and i.v. drug abuse to heterosexual contacts with persons at risk as the mode of infection. In conjunction with the stabile low and constant rates of infection for the last two years, these data indicate that the risk of HIV infection by blood transfusion is reduced to an acceptable minimum even in urban areas.     

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.     

Global assessment of existing HIV and key population stigma indicators: A data mapping exercise to inform country-level stigma measurement

BackgroundStigma is an established barrier to the provision and uptake of HIV prevention, diagnostic, and treatment services. Despite consensus on the importance of addressing stigma, there are currently no country-level summary measures to characterize stigma and track progress in reducing stigma around the globe. This data mapping exercise aimed to assess the potential for existing data to be used to summarize and track stigma, including discrimination, related to HIV status, or key population membership at the country level.Methods and findingsThis study assessed existing indicators of stigma related to living with HIV or belonging to 1 of 4 key populations including gay men and other men who have sex with men, sex workers, people who use drugs, and transgender persons. UNAIDS Strategic Information Department led an initial drafting of possible domains, subdomains, and indicators, and a 3-week e-consultation was held to provide feedback. From the e-consultation, 44 indicators were proposed for HIV stigma; 14 for sexual minority stigma (including sexual behavior or orientation) related to men who have sex with men; 12 for sex work stigma; 10 for drug use stigma; and 17 for gender identity stigma related to transgender persons. We conducted a global data mapping exercise to identify and describe the availability and quality of stigma data across countries with the following sources: UNAIDS National Commitments and Policies Instrument (NCPI) database; Multiple Indicator Cluster Surveys (MICS); Demographic and Health Surveys (DHS); People Living with HIV Stigma Index surveys; HIV Key Populations Data Repository; Integrated Biological and Behavioral Surveys (IBBS); and network databases. Data extraction was conducted between August and November 2020. Indicators were evaluated based on the following: if an existing data source could be identified; the number of countries for which data were available for the indicator at present and in the future; variation in the indicator across countries; and considerations of data quality or accuracy. This mapping exercise resulted in the identification of 24 HIV stigma indicators and 10 key population indicators as having potential to be used at present in the creation of valid summary measures of stigma at the country level. These indicators may allow assessment of legal, societal, and behavioral manifestations of stigma across population groups and settings. Study limitations include potential selection bias due to available data sources to the research team and other biases due to the exploratory nature of this data mapping process.ConclusionsBased on the current state of data available, several indicators have the potential to characterize the level and nature of stigma affecting people living with HIV and key populations across countries and across time. This exercise revealed challenges for an empirical process reliant on existing data to determine how to weight and best combine indicators into indices. However, results for this study can be combined with participatory processes to inform summary measure development and set data collection priorities going forward.

Carrie Lyons and co-workers report on population-level indicators of stigma for people with or at risk of HIV infection.     

The potential of plant systems to break the HIV‐TB link

Tuberculosis (TB) and human immunodeficiency virus (HIV) can place a major burden on healthcare systems and constitute the main challenges of diagnostic and therapeutic programmes. Infection with HIV is the most common cause of Mycobacterium tuberculosis (Mtb), which can accelerate the risk of latent TB reactivation by 20‐fold. Similarly, TB is considered the most relevant factor predisposing individuals to HIV infection. Thus, both pathogens can augment one another in a synergetic manner, accelerating the failure of immunological functions and resulting in subsequent death in the absence of treatment. Synergistic approaches involving the treatment of HIV as a tool to combat TB and vice versa are thus required in regions with a high burden of HIV and TB infection. In this context, plant systems are considered a promising approach for combatting HIV and TB in a resource‐limited setting because plant‐made drugs can be produced efficiently and inexpensively in developing countries and could be shared by the available agricultural infrastructure without the expensive requirement needed for cold chain storage and transportation. Moreover, the use of natural products from medicinal plants can eliminate the concerns associated with antiretroviral therapy (ART) and anti‐TB therapy (ATT), including drug interactions, drug‐related toxicity and multidrug resistance. In this review, we highlight the potential of plant system as a promising approach for the production of relevant pharmaceuticals for HIV and TB treatment. However, in the cases of HIV and TB, none of the plant‐made pharmaceuticals have been approved for clinical use. Limitations in reaching these goals are discussed.     

Harm reduction policy related to drug use: the needles exchange programs

In several developed countries, needles exchange programs (NEPs) are a key preventive tool in harm reduction policy related to drug use. Many studies about NEP show it reduces HIV infections related to syringes sharing when part of others preventive actions. NEPs seem to have no impact on HCV transmission. Furthermore, young drug users, who are at high risk for HIV and HCV infections, are not attending NEPs very often. Trying to maintain high accessibility to sterile syringes, efforts must be stressed on hard-to-reach populations such as young injection drug users (IDU), focusing on their social network. Emphasis must also be put on prevention of unsafe sexual intercourse, often related to syringe sharing, which must be more prevented. Finally, design of assessment studies should be improved.     

Mathematical modeling of multi-drugs therapy: a challenge for determining the optimal combinations of antiviral drugs

In the current era of antiviral drug therapy, combining multiple drugs is a primary approach for improving antiviral effects, reducing the doses of individual drugs, relieving the side effects of strong antiviral drugs, and preventing the emergence of drug-resistant viruses. Although a variety of new drugs have been developed for HIV, HCV and influenza virus, the optimal combinations of multiple drugs are incompletely understood. To optimize the benefits of multi-drugs combinations, we must investigate the interactions between the combined drugs and their target viruses. Mathematical models of viral infection dynamics provide an ideal tool for this purpose. Additionally, whether drug combinations computed by these models are synergistic can be assessed by two prominent drug combination theories, Loewe additivity and Bliss independence. By combining the mathematical modeling of virus dynamics with drug combination theories, we could show the principles by which drug combinations yield a synergistic effect. Here, we describe the theoretical aspects of multi-drugs therapy and discuss their application to antiviral research.     

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.     

Sex differences and ovarian hormones in animal models of drug dependence

Increasing evidence indicates the presence of sex differences in many aspects of drug abuse. Most studies reveal that females exceed males during the initiation, escalation, extinction, and reinstatement (relapse) of drug-seeking behavior, but males are more sensitive than females to the aversive effects of drugs such as drug withdrawal. Findings from human and animal research indicate that circulating levels of ovarian steroid hormones account for these sex differences. Estrogen (E) facilitates drug-seeking behavior, while progesterone (P) and its metabolite, allopregnanalone (ALLO), counteract the effects of E and reduce drug seeking. Estrogen and P influence other behaviors that are affiliated with drug abuse such as drug-induced locomotor sensitization and conditioned place preference. The enhanced vulnerability to drug seeking in females vs. males is also additive with the other risk factors for drug abuse (e.g., adolescence, sweet preference, novelty reactivity, and impulsivity). Finally, treatment studies using behavioral or pharmacological interventions, including P and ALLO, also indicate that females show greater treatment effectiveness during several phases of the addiction process. The neurobiological basis of sex differences in drug abuse appears to be genetic and involves the influence of ovarian hormones and their metabolites, the hypothalamic pituitary adrenal (HPA) axis, dopamine (DA), and gamma-hydroxy-butyric acid (GABA). Overall, sex and hormonal status along with other biological risk factors account for a continuum of addiction-prone and -resistant animal models that are valuable for studying drug abuse prevention and treatment strategies.     

Prevalence and Correlates of HIV and Hepatitis C Virus Infections and Risk Behaviors among Malaysian Fishermen

Fishermen in Southeast Asia have been found to be highly vulnerable to HIV, with research evidence highlighting the role of sexual risk behaviors. This study aims to estimate the rate of HIV as well as hepatitis C virus (HCV) infections among Malaysian fishermen, and the risky sexual and injection drug use behaviors that may contribute to these infections. The study also includes an assessment of socio-demographic, occupational and behavioral correlates of testing positive for HIV or HCV, and socio-demographic and occupational correlates of risk behaviors. The study had a cross-sectional design and recruited 406 fishermen through respondent-driven sampling (RDS). Participants self-completed a questionnaire and provided biological specimens for HIV and HCV testing. We conducted and compared results of analyses of both unweighted data and data weighted with the Respondent-Driven Sampling Analysis Tool (RDSAT). Of the participating fishermen, 12.4% were HIV positive and 48.6% had HCV infection. Contrary to expectations and findings from previous research, most fishermen (77.1%) were not sexually active. More than a third had a history of injection drug use, which often occurred during fishing trips on commercial vessels and during longer stays at sea. Of the fishermen who injected drugs, 42.5% reported unsafe injection practices in the past month. Reporting a history of injection drug use increased the odds of testing HIV positive by more than 6 times (AOR = 6.22, 95% CIs [2.74, 14.13]). Most fishermen who injected drugs tested positive for HCV. HCV infection was significantly associated with injection drug use, being older than 25 years, working on a commercial vessel and spending four or more days at sea per fishing trip. There is an urgent need to strengthen current harm reduction and drug treatment programs for Malaysian fishermen who inject drugs, especially among fishermen who work on commercial vessels and engage in deep-sea fishing.     

Epigenetic Alterations in the Brain Associated with HIV-1 Infection and Methamphetamine Dependence

HIV involvement of the CNS continues to be a significant problem despite successful use of combination antiretroviral therapy (cART). Drugs of abuse can act in concert with HIV proteins to damage glia and neurons, worsening the neurotoxicity caused by HIV alone. Methamphetamine (METH) is a highly addictive psychostimulant drug, abuse of which has reached epidemic proportions and is associated with high-risk sexual behavior, increased HIV transmission, and development of drug resistance. HIV infection and METH dependence can have synergistic pathological effects, with preferential involvement of frontostriatal circuits. At the molecular level, epigenetic alterations have been reported for both HIV-1 infection and drug abuse, but the neuropathological pathways triggered by their combined effects are less known. We investigated epigenetic changes in the brain associated with HIV and METH. We analyzed postmortem frontal cortex tissue from 27 HIV seropositive individuals, 13 of which had a history of METH dependence, in comparison to 14 cases who never used METH. We detected changes in the expression of DNMT1, at mRNA and protein levels, that resulted in the increase of global DNA methylation. Genome-wide profiling of DNA methylation in a subset of cases, showed differential methylation on genes related to neurodegeneration; dopamine metabolism and transport; and oxidative phosphorylation. We provide evidence for the synergy of HIV and METH dependence on the patterns of DNA methylation on the host brain, which results in a distinctive landscape for the comorbid condition. Importantly, we identified new epigenetic targets that might aid in understanding the aggravated neurodegenerative, cognitive, motor and behavioral symptoms observed in persons living with HIV and addictions.     

Alcohol and Drug Use—Is There a `Safe' Amount?

All human endeavors are associated with quantifiable risks. Knowledge of the risk is essential for personal health maintenance. Nontherapeutic use of psychoactive drugs poses an important danger to individual persons and society. What are the quantitative estimates of these risks? Are they acceptable?Because the basic mechanism of the toxic effect of alcohol or other drugs is unknown, deciding on acceptable risks is difficult. Based on current information, the recreational abuse of inhalants, hallucinogens, stimulants, narcotics and sedative-hypnotic drugs poses unacceptable individual and societal risks. Groups at special risk should not consume alcohol or any drug unless they are under medical supervision. The threshold for increased morbidity from the regular use of alcohol in adults is in the range of three to five drinks per day; this rises sharply after six drinks per day. The apparent “safe” level of alcohol consumption appears to be one to two drinks per day. Further basic studies are required to refine these risk estimates.     

Loss of Control of HIV Viremia With OTC Weight‐Loss Drugs: A Call for Caution?

Improved survival achieved by HIV‐infected patients has complicated their medical care, as increasing numbers of comorbidities have led to polypharmacy and a higher risk of drug–drug interactions. Here, evidence is provided that weight‐loss drugs should be used with caution in HIV‐infected patients treated with lipophilic antiretroviral drugs because of the risk of virologic failure. This is particularly relevant considering that these agents are available on the market as over‐the‐counter medications, thus escaping the control of the physician.     

Study of infection with HIV and related risk factors in young offenders' institution.

OBJECTIVES--To estimate the prevalence of infection with HIV in young offenders in Scotland and to obtain information about related risk factors and previous tests for HIV. DESIGN--Voluntary anonymous study with subjects giving saliva samples for testing for HIV and completing questionnaires about risk factors. SETTING--Polmont Young Offenders'' Institution near Falkirk, Scotland. SUBJECTS--421 of 424 available male prisoners in Polmont. The questionnaires of 17 of the prisoners were excluded because of inaccuracies. MAIN OUTCOME MEASURES--Prevalence of infection with HIV and related risk behaviour. RESULTS--68 (17%) of prisoners admitted misuse of intravenous drugs, of whom 17 (25%) admitted having injected drugs while in prison. Three subjects admitted having anal intercourse while in prison. Prevalence of misuse of intravenous drugs varied geographically: 28% (33/120) of prisoners from Glasgow compared with 9% (7/81) of those from Edinburgh and Fife. A high level of heterosexual activity was reported, with 36% (142/397) of prisoners claiming to have had six or more female sexual partners in the year before they were imprisoned. Altogether 8% (32/389) of prisoners had previously taken a personal test for HIV: 50% (9/18) of those who had started misusing intravenous drugs before 1989, 18% (9/49) of those who started misuse later, and only 4% (14/322) of those who had not misused intravenous drugs. No saliva sample tested positive for antibodies to HIV, but 96 prisoners requested a confidential personal test for HIV as a result of heightened awareness generated by the study. CONCLUSIONS--Voluntary, anonymous HIV surveys can achieve excellent compliance in prisons, and the interest generated by the study suggests that prisons may be suitable sites for providing education and drug rehabilitation for a young male population at high risk of future infection with HIV.     

Drug injection and HIV prevalence in inmates of Glenochil prison.

OBJECTIVE--To determine prevalence of HIV infection and drug injecting behaviour among inmates of Glenochil Prison on a specified date a year after an outbreak of hepatitis B and HIV infection. DESIGN--Cross sectional: voluntary, anonymous HIV salivary antibody surveillance and linked self completion questionnaire on risk factors. SETTING--Glenochil prison, Scotland, a year after an outbreak of hepatitis B and HIV transmission related to drug injection. SUBJECTS--352 prisoners, of whom 295 (84%) took part; 284 questionnaires (96%) passed logical checks. MAIN OUTCOME MEASURES--HIV prevalence; proportion of all inmates who had ever injected drugs, had ever injected inside prison, had started injecting drugs while inside prison. RESULTS--More than half (150/284) the current inmates were also in Glenochil Prison during the critical period of January to June 1993, when hepatitis B and HIV were transmitted. Similar proportions of current inmates and men who were also in Glenochil during the critical period were drug users (27% (75/278) v 30% (44/149)). A quarter of injecting drug users (18/72) had first injected inside prison, irrespective of whether they were in Glenochil in January to June 1993 and regardless of the calendar period when they first injected. Significantly more inmates from Glasgow (41%; 56/138) than from Edinburgh (21%; 7/34) or elsewhere (11%; 12/106) were injecting drug users. On testing for HIV, seven saliva samples out of 293 gave positive results--four were presumed to be from inmates known to be infected with HIV, and the others from injecting drug users from Glasgow, all of whom had been in Glenochil during January to June 1993, when two of the three had injected drugs and had been tested for HIV, with negative results. The ratio of overall (2.4%) to disclosed (1.4%) HIV prevalence was 1.7. For men who had injected drugs in Glenochil during January to June 1993, HIV prevalence was estimated at 29%. CONCLUSION--Between a quarter and a third of prisoners who injected drugs in Glenochil in January to June 1993 were infected with HIV. There is widespread ongoing risk of bloodborne virus infection within prisons, which is probably long standing but demands urgent attention.