Pharmacokinetic interactions between HIV antiretroviral therapy and drugs used to treat opioid dependence

Injection drug use is a common risk factor for HIV infection, and opioid use and dependence is the underlying condition that often fuels HIV risk behaviour and subsequent HIV seroconversion among injection drug users (IDUs). Treatment of opioid dependence often requires continued opioid administration in the form of substitution therapy, which means that opioid-using IDUs often continue receiving opioids even after cessation of illicit drug use. The concurrent use of both antiretrovirals and opioids in HIV-positive individuals is thus common. This review was undertaken to summarise current knowledge on the interactions between the opioids and antiretrovirals and to make recommendations on the treatment of HIV-positive opioid-dependent patients.     

Dual antiretroviral therapy for HIV infection

Introduction: For two decades, triple combinations of antiretrovirals have been the standard treatment for HIV infection. The challenges of such lifelong therapy include long-term side effects, high costs and reduced drug adherence. The recent advent of more potent and safer antiretrovirals has renewed the interest for simpler HIV regimens.

Areas covered: We discuss the pros and cons of dual antiretroviral therapies in both drug-naïve and in treatment-experienced patients with viral suppression (switch strategy).

Expert opinion: Some dual antiretroviral regimens are safe and efficacious, particularly as maintenance therapy. At this time, combinations of dolutegravir plus rilpivirine represent the best dual regimen. Longer follow-up and larger study populations are needed before supporting dolutegravir plus lamivudine. In contrast, dual therapy based on maraviroc is less effective. Although dual regimens with boosted protease inhibitors plus either lamivudine or raltegravir may be effective, they are penalized by metabolic side effects and risk for drug interactions.

The newest dual regimens could save money, reduce toxicity and spare drug options for the future. For the first time in HIV therapeutics, less can be more. Dual therapy switching has set up a new paradigm in HIV treatment that uses induction-maintenance.     

Salvage antiretroviral therapy in HIV infection

Highly-active antiretroviral (ARV) therapy (HAART) has lead to a sharp decline in AIDS-related morbidity and mortality. Treatment failure is a common, significant problem and as many as 50% of patients have detectable plasma HIV RNA despite being on combination ARV therapy. Clinicians must be knowledgeable about the reasons for treatment failure and the best options available for management. Treatment failure can occur because of non-compliance, drug discontinuation, lack of drug potency, inadequate drug plasma concentration and drug resistance. Strategies used when selecting salvage therapy include the use of resistance testing to choose a regimen, the exploitation of pharmacokinetic interactions by boosting protease inhibitor (PI) trough levels and counselling the patient on compliance. When selecting the agents to use in salvage therapy, the new regimen should ideally include as many new agents to which no or minimal resistance is anticipated and at least one new class of drugs if possible. Data on salvage therapy mostly comes from anecdotal reports and retrospective cohort studies. With a paucity of clinical trial data, clinicians are often forced to prescribe unproven regimens based on what is anticipated about cross-resistance and drug interactions. It is important that new agents and new targets continue to be developed as an increasing number of patients in practice have exhausted all treatment options.     

Salvage antiretroviral therapy in HIV infection

Highly-active antiretroviral (ARV) therapy (HAART) has lead to a sharp decline in AIDS-related morbidity and mortality. Treatment failure is a common, significant problem and as many as 50% of patients have detectable plasma HIV RNA despite being on combination ARV therapy. Clinicians must be knowledgeable about the reasons for treatment failure and the best options available for management. Treatment failure can occur because of non-compliance, drug discontinuation, lack of drug potency, inadequate drug plasma concentration and drug resistance. Strategies used when selecting salvage therapy include the use of resistance testing to choose a regimen, the exploitation of pharmacokinetic interactions by boosting protease inhibitor (PI) trough levels and counselling the patient on compliance. When selecting the agents to use in salvage therapy, the new regimen should ideally include as many new agents to which no or minimal resistance is anticipated and at least one new class of drugs if possible. Data on salvage therapy mostly comes from anecdotal reports and retrospective cohort studies. With a paucity of clinical trial data, clinicians are often forced to prescribe unproven regimens based on what is anticipated about cross-resistance and drug interactions. It is important that new agents and new targets continue to be developed as an increasing number of patients in practice have exhausted all treatment options.     

Reviewing the cardiovascular complications of HIV infection after the introduction of highly active antiretroviral therapy

Studies published before the introduction of highly active antiretroviral therapy (HAART) have tracked the incidence and course of human immunodeficiency virus (HIV) infection in relation to cardiac disease.The introduction of HAART regimens, by preventing opportunistic infections and reducing the incidence of myocarditis, has reduced the prevalence of HIV-associated cardiomyopathy of about 30% and the prevalence of cardiac involvement of AIDS-associated malignancies of about 50%. However, HAART regimens, especially those including protease inhibitors have been shown to cause, in a high proportion of HIV-infected patients, a metabolic syndrome (lipodystrophy/lipoatrophy, dyslipidemia, type 2 diabetes mellitus, insulin resistance) that may be associated with an increased risk of cardiovascular disease (approximately 1.4 cardiac events per 1000 years of therapy according to the Framingham score). A careful stratification of the cardiovascular risk and cardiovascular monitoring of patients under HAART according to the most recent clinical guidelines is needed.     

Metabolic disorders and cardiovascular consequences of HIV infection and antiretroviral therapy

Metabolic disturbances associated with HIV disease have become an important factor in patient management and have important implications for long-term outcomes, both in regards to mortality and healthcare burden. Recent research has implicated both HIV infection itself and specific antiretroviral therapies in the development of these disorders. This review examines recent findings from research into insulin and glucose dysregulation, serum lipid abnormalities, adipose tissue and derangements in bone metabolism. This review then describes the cardiovascular consequences and management of these metabolic disorders, and summarizes current thinking on the pathogenesis and effects of antiretroviral therapy. Finally, the review raises some questions regarding ongoing challenges and unmet needs in this field of research.     

Pharmacogenetics of the lipodystrophy syndrome associated with HIV infection and combination antiretroviral therapy

INTRODUCTION: Antiretroviral drugs have been associated with several toxicities that limit their success. Of the chronic toxicities, the lipodystrophy syndrome is of special concern due to the metabolic alterations that can accompany it. Why some patients treated with a particular antiretroviral regimen develop lipodystrophy, while others do not, is a medical mystery, but it has been suggested that individuals may (or may not) have a genetically conditioned predisposition. Pharmacogenetics is the science that studies how the genetic composition of individuals can give rise to interindividual variations in response to drugs and drug toxicity. AREAS COVERED: This article reviews the published investigations on the association between host genetic determinants in treated HIV-infected patients and the presence of lipodystrophy. Studies were identified through a PubMed database search. Case-control and longitudinal studies into pharmacogenetic association were selected. Areas covered include the data on the genetic variants of mitochondrial parameters, cytokines, adipokines, proteins involved in adipocyte biology and proteins involved in stavudine metabolism. EXPERT OPINION: Most studies provide inconsistent data due to partial genetic evaluation, different assessment of lipodystrophy and low number of patients evaluated. The pharmacogenetics of lipodystrophy in HIV-infected patients treated with antiretroviral drugs still belongs in the research laboratory.     

Interactions between antifungal and antiretroviral agents

Importance of the field: Since the advent of combination antiretroviral therapy, the incidence of opportunistic infections has declined and the life expectancy of HIV-infected people has significantly increased. However, opportunistic infections, including fungal diseases, remain a leading cause of hospitalizations and mortality in HIV-infected people. With the availability of several new antiretroviral and antifungal agents, drug–drug interactions emerge as a potential safety concern.

Areas covered in this review: Relevant literature was identified using a Medline search of articles published up to March 2010 and a review of conference abstracts. Search terms included HIV, antifungal agents and drug interactions. Original papers and relevant citations were considered for this review.

What the reader will gain: Readers will gain an understanding of the pharmacokinetic properties of antiretroviral and antifungal agents, and insight into significant drug–drug interactions which may require dosage adjustments or a change in therapy.

Take home message: Azole antifungal drugs, with the exception of fluconazole, pose the greatest risk of two-way interactions with antiretroviral drugs through CYP450 enzymes effects. Limited studies suggest the risk of interactions between antiretroviral drugs and echinocandins is much lower. The combination of tenofovir and amphotericin B should be used with caution and close monitoring of renal function is required.     

Neuropsychiatric complications of antiretroviral therapy.

Neuropsychiatric adverse effects related to potent antiretroviral therapy are among the complications that can lead to poor adherence, treatment interruptions, or change of antiretroviral therapy regimens. For a historical perspective, we review early literature and case reports with CNS adverse effects attributed to antiretrovirals. The variability of the cerebrospinal fluid penetration of individual antiretrovirals may contribute to their potential for behavioural and psychiatric manifestations.The majority of neuropsychiatric complications related to potent antiretroviral therapy have been associated with the use of the efavirenz. Updates on the risk of neuropsychiatric manifestations with efavirenz use in patients with a history of psychiatric disorders or substance abuse are reviewed. We include a critical review of recently published data on the long-term CNS adverse effects with efavirenz. Special attention is given to the results of recent investigations on the relationship between the pharmacogenomics of genes responsible for efavirenz metabolism and the plasma concentration of efavirenz. It is important to note that there is no established direct correlation of efavirenz concentrations and symptoms. It is not recommended for practitioners to adjust efavirenz doses in order to prevent or alleviate CNS adverse effects. Patients may be placed at risk for virological failure and resistance if they receive suboptimal doses of efavirenz. The aim of this article is to give a concise review and an update on recent literature concerning neuropsychiatric effects of antiretroviral use in HIV-infected patients. Our intent is to present practitioners with data that can be used in a practical way to both educate and improve outcomes in the HIV-infected patient population.     

Affective disorders in patients with HIV infection: impact of antiretroviral therapy

At the beginning of the AIDS pandemic, affective disorders (such as depressed mood) were seen in a considerable number of HIV-1-infected individuals. These disorders were a result of the poor physical condition of the patients, brain involvement by the virus (e.g. encephalopathy) or a reaction to disadvantageous living conditions (losing friends, jobs, etc.). In the era of highly active antiretroviral therapy (HAART), mental illness related to physical weakness is declining, as is the incidence of HIV-1-associated encephalopathy. However, depressed mood and fatigue caused by efavirenz (a standard component of HAART) is becoming increasingly important, particularly in individuals who are infected long-term with HIV-1. Whatever the cause of affective disorders, their presence has been shown to negatively influence adherence to HAART and HIV-1 disease progression. Specialist knowledge of HIV-1 infection, and HAART and its psychiatric complications (particularly in subgroups of patients such as drug abusers and older people), is needed to care adequately for patients. Furthermore, prospective studies are needed to more fully differentiate between the various aetiologies of affective disorders seen in individuals living with HIV/AIDS and to determine their incidence and prevalence. Such information is important to ensure that affective disorders are recognised and adequately treated, which will in turn improve the efficacy of HAART.     

Adherence to antiretroviral therapy among HIV positive men who inject drugs in Pakistan

BackgroundPeople who inject drugs (PWID) living with HIV have poorer adherence to HIV antiretroviral therapy (ART) and elevated mortality compared to other populations. Little is known about factors associated with adherence among PWID in low-and middle-income countries, including in countries where opioid agonist therapy (OAT) is unavailable. We aimed to estimate ART adherence among men who inject drugs (MWID) living with HIV in Pakistan and identify factors independently associated with adherence.MethodsNai Zindagi Trust (NZT) provides a range of HIV prevention, testing and treatment services to PWID in Pakistan. This study utilized data from HIV positive MWID who received ART refill/s from public sector ART Centres via NZT's Social Mobilizer Adherence Support Unit between September 2016 and December 2018. Multivariable logistic regression modelled factors independently associated with ART adherence.ResultsAmong 5,482 HIV positive MWID registered with NZT who had attended the AAU and were supplied with ART refills between September 2016 and December 2018., 55% were adherent to ART. Independent predictors of adherence were being married (AOR 1.38, 95% CI:1.23–1.55, p<0.001) and >5 years of education compared to those with no education (AOR 1.19, 95% CI:1.05–1.35, p = 0.005). MWID living on the street at night had lower adjusted odds of ART adherence (AOR 0.75, 95% CI:0.62–0.91, p = 0.003).ConclusionsFindings indicate that MWID living with HIV continue to face barriers to ART adherence in Pakistan. Despite considerable evidence supporting the impact of OAT in increasing ART adherence among PWID, OAT remains illegal and inaccessible in Pakistan. Evidence-based interventions, including OAT, are needed to increase adherence and improve clinical outcomes, health equity and survival among PWID living with HIV in Pakistan.