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.     

Advances in brain targeting and drug delivery of anti-HIV therapeutic agents

Introduction: Human immunodeficiency virus (HIV) is a neurotropic virus that enters the central nervous system (CNS) early in the course of infection. Although antiretroviral drugs are able to eliminate the majority of the HIV virus in the bloodstream, however, no specific treatment currently exist for CNS infections related to HIV. This is mainly attributed to the poor penetrability of antiretroviral therapy across the blood–brain barrier (BBB), and the protective nature of the BBB. Therefore, in order to increase the efficacy of anti-HIV drugs, novel drug delivery methodologies that can exhibit activity in the CNS are most needed and warranted.

Areas covered: In this review article, the authors discussed the challenges with delivering drugs to the brain especially under HIV infection pathophysiology status. Also, they discussed the approaches currently being investigated to enhance brain targeting of anti-HIV drugs. A literature search was performed to cover advances in major approaches used to enhance drug delivery to the brain.

Expert opinion: If drugs could reach the CNS in sufficient quantity by the methodologies discussed, mainly through intranasal administration and the utilization of nanotechnology, this could generate interest in previously abandoned therapeutic agents and enable an entirely novel approach to CNS drug delivery.     

Switching antiretroviral regimes for the treatment of HIV: safety implications

ABSTRACT

Introduction: There are multiple reasons to switch from a virologically successful antiretroviral regimen. Some of them are related to toxicity. Lately, combination antiretroviral treatment (cART) switches have often been related to drug-drug interactions which may also eventually entail safety issues as well.

Areas covered: The purpose of this review is to analyze causes of switching between virologically successful cART regimes related to safety issues. The most relevant papers were selected and summarized.

Expert opinion: Switching cART has been a popular strategy to address safety issues throughout the antiretroviral era. The myriad of switching studies have paralleled the study and release into clinical practice of new antiretroviral drugs with different and often improved safety profiles. Most of them have been successful in improving antiretroviral toxicity while keeping HIV replication under control. However, it should be taken into account that, whenever a new drug is given, there is a possibility of new drug-related toxicity. Notwithstanding that, an increase in cART switching is foreseen, given the fact that we have a wide antiretroviral drug armamentarium and that people living with HIV are ageing and thus more prone to developing age-related co-morbidities whose therapies may entail new interactions and eventually new toxicities.     

Screening and selecting for optimized antiretroviral drugs: rising to the challenge of drug resistance

ABSTRACT

Background: Resistance to antiretroviral (ARV) drugs constitutes one of the greatest limitations to effective long-term therapy for human immunodeficiency virus (HIV) infection – a problem alleviated, but by no means overcome, by the application of carefully selected, sequential combination regimens. The rational development of novel therapeutics with the ability to suppress viraemia effectively and also address the complex problems of resistance offers a useful way forward for HIV therapy. The investigational drug TMC114 (darunavir) was designed to be active against both wild-type HIV and strains that are resistant to currently available protease inhibitors.

Scope: This review describes the challenges posed by HIV drug resistance and the novel approach taken in the design and selection of TMC114. Articles were identified by searching MEDLINE in September 2005 (search limits: 1995–2006) using the terms: TMC114, darunavir, resistance, screening, selection, ARV therapy, HIV and HAART. Additional data included bibliographies from identified articles.

Findings: With the continuing problem of resistance, ARV drugs must be designed with broadspectrum activity forming a central part of their development and screening. Drugs must not only be able to treat existing resistant strains, but must also possess more intrinsic resilience to the development of resistance. TMC114 was designed and selected with strong emphasis on potent activity across a range of both wild-type and resistant HIV strains and high binding affinity to HIV protease.

Conclusion: This review illustrates that future treatment strategies should include screening against multiple-resistant strains to optimize the identification of novel therapeutic agents for the treatment of HIV.     

Nephrotoxicity associated with antiretroviral therapy in HIV-infected patients

Background: With the success of modern antiretroviral therapies in increasing longevity of patients with HIV infection, chronic conditions including renal disease have assumed a greater importance in patient management. Some antiretroviral therapies have themselves been identified to have clinically significant nephrotoxicity. Objective: To review the risk factors and mechanisms for renal toxicity of antiretroviral drugs, and their impact on the clinical management of patients with HIV. Methods: Current literature and HIV treatment guidelines are reviewed. Results/conclusions: Background rates of renal disease and associated risk factors are significant in the HIV clinic population, and renal function should be assessed in all HIV-infected patients. Modern HIV treatment regimens have a relatively low but clinically significant nephrotoxic potential; therefore, renal function should be evaluated on an ongoing basis in patients receiving antiretroviral therapy.     

Small molecule HIV entry inhibitors: Part II. Attachment and fusion inhibitors: 2004 – 2010

Introduction: The first US FDA approved HIV entry inhibitor drug Enfuvirdine belongs to the fusion inhibitor category. Earlier efforts in this area were focused on peptides and monoclonal antibodies; recently, the focus has shifted towards the development of small molecule HIV attachment and fusion inhibitors. They can be used for prophylactic purposes and also hold potential for the development of HIV microbicides.

Areas covered: In a previous paper (‘Small molecule HIV entry inhibitors: Part I’), we reviewed patents and patent applications for small molecule chemokine receptor antagonists from major pharmaceutical companies. In this paper, the development of small molecule HIV attachment and fusion inhibitors is discussed in detail. It covers patents and patent applications for small molecule HIV attachment and fusion inhibitors published between 2004 and 2010 and related literature with a focus on recent developments based on lead generation and lead modification.

Expert opinion: To augment the potency of currently available antiretroviral drug combinations and to fight drug-resistant virus variants, more effective drugs which target additional steps in the viral replication cycle are urgently needed. HIV attachment and fusion processes are such targets. Inhibitors of these targets will provide additional options for the treatment of HIV drug-resistant strains. Small molecule HIV attachment inhibitors such as BMS-378806 and analogs from Bristol Myers Squibb, N-aryl piperidine derivatives from Propharmacon, and NBD-556 and NBD-557 from New York Blood Center may have potential as vaginal microbicidal agents and can be an economical alternative to monoclonal antibodies.     

Potential of polymeric nanoparticles in AIDS treatment and prevention

Importance of the field: Acquired immunodeficiency syndrome (AIDS) remains one of the greatest challenges in public health. The AIDS virus is now responsible for > 2.5 million new infections worldwide each year. Despite significant advances in understanding the mechanism of viral infection and identifying effective treatment approaches, the search for optimum treatment strategies for AIDS remains a major challenge. Recent advances in the field of drug delivery have provided evidence that engineered nanosystems may contribute to the enhancement of current antiretroviral therapy.

Areas covered in this review: This review describes the potential of polymeric nanoparticle-based drug delivery systems in the future treatment of AIDS. Polymeric nanoparticles have been developed to improve physicochemical drug characteristics (by increasing drug solubility and stability), to achieve sustained drug release profile, to provide targeting to the cellular and anatomic human immunodeficiency virus (HIV) latent reservoirs and to be applied as an adjuvant in anti-HIV vaccine formulations.

What the reader will gain: The insight that will be gained is knowledge about the progress in the development of polymeric nanoparticle-based drug delivery systems for antiretroviral drugs as alternative for AIDS treatment and prevention.

Take home message: The advances in the field of targeted drug delivery can result in more efficient strategies for AIDS treatment and prevention.     

HIV integrase inhibitors: a new era in the treatment of HIV

Introduction: Integrase inhibitors (INIs) are the latest class of antiretroviral drugs approved for the treatment of HIV infection and are becoming ‘standard’ drugs in the treatment of both naïve as well as heavily pretreated individuals with HIV.

Areas covered: Data on efficacy, safety, tolerability, pharmacokinetics, drug-drug interactions and resistance are reviewed from the pivotal Phase III clinical trials published in PubMed high-impact medical journals or presented at international meetings.

Expert opinion: Due to their outstanding data of efficacy, tolerability, safety – shared by all three drugs (raltegravir, elvitegravir, dolutegravir) currently belonging to this new family of antiretrovirals – INIs have become part of the recommended initial antiretroviral therapy options. Some differences in dosing, drug-drug interactions and robustness/genetic barrier among the three drugs will provide the physician the characteristics to make the best choice.     

Approaches for CNS delivery of drugs – nose to brain targeting of antiretroviral agents as a potential attempt for complete elimination of major reservoir site of HIV to aid AIDS treatment

Introduction: Human immune-deficiency virus (HIV) infection causing acquired immune-deficiency syndrome (AIDS) is one of the most life-threatening infections. The central nervous system (CNS) is reported to be the most important HIV reservoir site where the antiretroviral drugs are unable to reach.

Areas covered: This article includes the review about HIV infections, its pathogenesis, HIV infections in CNS, its consequences, current therapies, challenges associated with the existing therapies, approaches to overcome them, CNS delivery of drugs – barriers, transport routes, approaches for transporting drugs across the blood–brain barrier, nasal route of drug delivery, and nose to brain targeting of antiretroviral agents as a potential approach for complete cure of AIDS.

Expert opinion: Various approaches are exploited to enhance the drug delivery to the brain for various categories of drugs. However, very few have investigated on the delivery of antiretrovirals to the brain. Targeting antiretrovirals to CNS through oral/nasal routes along with oral/parenteral delivery of drug to the plasma can be a promising approach for an attempt to completely eradicate HIV reservoir and cure AIDS, after clinical trials. Further research is required to identify the exact location of the HIV reservoir in CNS and developing good animal models for evaluation of different newly developed formulations.     

Therapeutic drug monitoring in highly active antiretroviral therapy

Importance of the field: Despite the efficacy of combination antiretroviral therapy (ART), a large proportion of patients living with HIV/AIDS on ART does not achieve or maintain adequate virological suppression. Therapeutic drug monitoring (TDM) has been utilised to improve treatment outcomes of ART.

Areas covered in the review: The potential incorporation of TDM into the clinical HIV management is supported by the existing relationship between drug exposure and efficacy/toxicity, the high inter-patient variability pharmacokinetics, and the accurate, specific and rapid method for drug level determination. The current status of TDM in ART is reviewed in this article with discussions on its feasibility, potential use and limitations.

What the reader will gain: Mounting evidence from clinical trials has indicated the potential use of TDM in reducing the rates of treatment failure and adverse effect, avoiding the drug interactions, and special populations, such as children, pregnant women and patients with co-infections. TDM may play an important role even in resource-limited settings, to safeguard expanded use of bioequivalent generic antiretroviral drugs and avoid drug interactions with traditional Chinese medicines.

Take home message: TDM is still in the centre of controversy in that several critical issues need to be addressed, such as limited adherence assessment, inappropriate response predictors, insufficient validation of target concentration windows and lack of the quality control of assay. The utility of TDM will remain experimental until more data are obtained from large clinical trials showing the benefit of TDM.     

A prospective, observational cohort study to elicit adverse effects of antiretroviral agents in a remote resource-restricted tribal population of Chhattisgarh

Objective:

To assess the adverse effects of antiretroviral therapy (HAART) and its adherence in HIV-infected patients, in remote and tribal area with restricted resources.

Materials and Methods:

This was a prospective, observational study carried out at Department of Medicine, Government Medical College, Jagdalpur. A set of questions were asked and adverse drug reactions (ADRs) were recorded for every patient.

Results:

79 HIV positive patients were analyzed. Among them, 68 (86%) had at least one ADR. The mean ADR per patient was 1.64 (±1.09). The most common ADR in our study was peripheral neuropathy (20.83%), followed by skin rashes (15.83%). Twenty-one patients (26.58%) had severe (grade-3 and grade-4) ADRs. Female patients had more ADRs (45.71%) than males (11.36%); severe ADRs had a statistically significant positive correlation with sex and CD4 cell count of the patients.

Conclusion:

In spite of high ADRs, HAART is the only answer to HIV/AIDS; thus, management requires a highly precise balance between benefits of durable HIV suppression and the risks of drug toxicity to achieve the therapeutic goals, with conventional drugs or with newer less toxic agents.     

Pre-exposure prophylaxis for HIV infection: how antiretroviral pharmacology helps to monitor and improve adherence

Introduction: Pre-exposure prophylaxis (PrEP) with antiretroviral drugs is a novel biomedical intervention that can prevent HIV transmission among high-risk populations. As findings from multiple PrEP studies have suggested that adherence is vital to achieve the full prevention benefits of PrEP, it is important to understand the clinical pharmacology and pharmacokinetic (PK) properties of PrEP antiretrovirals, the association of PK and PrEP efficacy, and the potential for drug concentration measurement to be used as a tool to monitor PrEP adherence.

Areas covered: This review examines studies related to PrEP adherence with attention to the clinical pharmacology and PK of current and novel PrEP agents. Studies of animal models, PK, and clinical trials related to PrEP and adherence were reviewed.

Expert opinion: In summary, when combined as part of a comprehensive prevention strategy that includes use of condoms and risk-reduction counseling, PrEP has tremendous promise as an adjunctive biomedical HIV prevention intervention, providing that adherence is maintained.     

Enfuvirtide: from basic investigations to current clinical use

Importance of the field: Drug resistance is a major challenge in the treatment of HIV infection. Enfuvirtide is the first entry inhibitor to have been approved for clinical use.

Areas covered in this review: Relevant information through searches of MEDLINE (1998 to June 2010) and meeting abstracts of major HIV/AIDS conferences (2003 – June 2010) using the search terms ‘enfuvirtide’, ‘T-20’ and ‘fusion inhibitor’.

What the reader will gain: Enfuvirtide blocks HIV fusion to host cells. It works against the different HIV-1 variants but is not active against HIV-2. The recommended dosage of enfuvirtide is 90 mg b.i.d. subcutaneously. The two large Phase III pivotal clinical trials TORO 1 and 2 showed that enfuvirtide is an effective therapeutic option as rescue therapy in combination with other active antiretroviral drugs. Resistance to enfuvirtide is conferred by mutations in the HR1 region of gp41. Single and double mutations have been shown to result in high-level resistance to enfuvirtide. Postmarketing studies have been helpful to define more precisely the place of enfuvirtide in the sequence of antiretroviral therapy.

Take home message: The emergence of new compounds and new classes of drugs, highly active against multiresistant virus but more convenient to administer than enfuvirtide, will probably prevent the extensive use of enfuvirtide. This drug remains attractive in some subgroups of patients because of its excellent systemic tolerance and the lack of interactions with the major cytochrome P450 isoenzymes.     

Clinical pharmacology of HIV protease inhibitors: focus on saquinavir, indinavir, and ritonavir

In this review the clinical pharmacology of HIV protease inhibitors, a new class of antiretroviral drugs, is discussed. After considering HIV protease function and structure, the development of inhibitors of HIV protease is presented. Three protease inhibitors are reviewed in more detail: saquinavir, indinavir, and ritonavir. Clinical trial results with these agents are evaluated. Furthermore, adverse effects, resistance, dosage and administration, clinical pharmacokinetics, pharmacokinetic-pharmacodynamic relationships, and drug interactions are discussed.     

HIV drug interactions: the good, the bad, and the other.

Highly active antiretroviral therapy, involving treatment with three or four antiretroviral agents, has greatly improved the effectiveness of therapy for human immunodeficiency virus (HIV) infection. It has also extended the number of possible drug interactions that may occur in treated patients. There are 105 possible two-drug interactions among the 15 currently approved antiretroviral agents. Well-characterized interactions involving inhibition of drug metabolism have been exploited to reduce dose size or frequency and to simplify treatment regimens. Many additional interactions are possible with other drugs used to treat or prevent complications of HIV infection. Interactions with methadone and other opiate abuse therapies are also of concern. The usefulness of therapeutic drug monitoring for antiretroviral drugs remains controversial. However, drug measurements before introduction of an interacting drug can establish patient-specific targets that can guide subsequent dosing adjustment.