Doravirine: a new non-nucleoside reverse transcriptase inhibitor for the treatment of HIV infection.

Doravirine is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) that was approved by the United States Food and Drug Administration (FDA) on August 30, 2018, for the treatment of HIV infection in adult patients. The product was also approved in the E.U. and Japan in November 2018 and January 2020, respectively. It is currently available as a single stand-alone tablet as well as part of a single-tablet regimen in a fixed-dose combination with tenofovir disoproxil and lamivudine. Similarly to other NNRTIs, doravirine exerts its antiviral effect through a noncompetitive inhibition of HIV-1 reverse transcriptase. It has a novel resistance pathway so that it retains in vitro activity against clinically relevant NNRTI viral mutations K103N, Y181C and G190A. In randomized clinical trials, doravirine was noninferior to efavirenz- and darunavir-based regimens, with fewer adverse events. Doravirine has a more favorable drug interaction profile compared with earlier NNRTIs as it neither inhibits nor induces the cytochrome P450 3A4 (CYP3A4) enzyme. Doravirine has been added to the category of Recommended Initial Regimens in Certain Clinical Situations in the United States Department of Health and Human Services Antiretroviral Guidelines for Adults and Adolescents.

Emergence of dual antiretroviral therapy as a viable regimen option for the treatment of patients with HIV infection.

Current antiretroviral therapy is not curative. The need for life-long therapy brings with it concerns regarding long-term toxicity and cost. Thus, investigations into simpler regimens with comparable efficacy and improved safety have been undertaken and continue to be conducted. Various 2-drug combinations have been evaluated with variable results. The combinations of dolutegravir plus lamivudine and dolutegravir plus rilpivirine were found to be comparable in efficacy to conventional 3-drug regimens and have now been approved by the United States Food and Drug Administration (FDA) and have entered into clinical practice. Dolutegravir/rilpivirine was approved for the treatment of adults with HIV-1 infection whose virus has been suppressed on a stable regimen for at least 6 months, with no history of treatment failure and no known substitutions associated with resistance to the individual components of the combination. Dolutegravir/lamivudine was approved for the treatment of HIV infection in adults with no antiretroviral treatment history and with no known or suspected resistance to the individual components of the combination.

Dolutegravir plus lamivudine dual therapy - a new option for initial antiretroviral therapy.

The current standard of care for treating HIV infection is the use of three antiretroviral drugs: a combination of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and a third agent from either the integrase strand transfer inhibitor (INSTI), boosted protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) classes. In an effort to minimize the long-term adverse effects and cost of antiretroviral therapy, the use of regimens with fewer drugs in the combination has been under active investigation. To this end, the combination of dolutegravir (DTG) plus lamivudine (3TC), two antiretroviral drugs with a long track record of efficacy and safety in the treatment of HIV infection, is undergoing clinical evaluation in treatment-naive HIV-infected participants. The promising results of the PADDLE study, with 90% of study participants achieving the primary endpoint of HIV-1 RNA lower than 50 copies/mL, were confirmed by the results of ACTG A5353, a phase II, single-arm, open-label study. Subsequently, GEMINI-1 and -2, two phase III, double-blind, noninferiority studies, compared DTG + 3TC to a three-drug regimen of DTG, tenofovir disoproxil fumarate and emtricitabine in 1,433 antiretroviral treatment-naive adults, and demonstrated noninferior efficacy at 48 weeks with no emergence of NRTI or INSTI mutations and a more favorable safety profile. This dual regimen should be avoided in those patients with existing mutations and chronic hepatitis B virus infection. In addition, data in patients with CD4 counts less than 200/mm3 is limited.

Bictegravir, a novel integrase inhibitor for the treatment of HIV infection.

Bictegravir (BIC), a second-generation integrase strand transfer inhibitor (INSTI) approved for HIV treatment in fixed-dose combination with emtricitabine and tenofovir alafenamide, has potent antiviral activity in vitro to wild-type virus and strains with resistance to first-generation INSTIs. As part of combination therapy, BIC's virologic suppression rates in clinical trials are comparable to those of first-line combination antiretroviral drug regimens. BIC has demonstrated a high genetic barrier to resistance development in vitro, can be administered with or without food, and has a bioavailability of > 70%. A median plasma half-life of 18 hours allows once-daily dosing. Clearance is primarily hepatic through cytochrome P450 3A4 (CYP3A4) oxidation and UDP-glucuronosyltransferase 1A1 (UGT1A1) glucuronidation. Thus, potent inducers of UGT1A1 and CYP3A4 (e.g., rifamycins/anticonvulsants) should be avoided due to significantly decreased BIC serum exposure. Chelation with polyvalent cations can decrease absorption; otherwise, drug-drug interactions are few. BIC is well tolerated; diarrhea, nausea and headache are the main adverse effects associated with its use.

Ibalizumab for the treatment of multidrug-resistant HIV-1 infection.

Ibalizumab, a humanized monoclonal antibody to CD4, was recently approved by the United States Food and Drug Administration (FDA) for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen. Ibalizumab is the first in a new class of antiretroviral drugs designated as post-attachment inhibitors. It exerts its antiviral effect by noncompetitive binding of CD4, thereby blocking conformational changes in the CD4-gp120 complex that are essential for viral entry. Clinical studies have demonstrated ibalizumab's significant antiviral activity in patients with advanced HIV disease and extensive treatment experience, who had limited treatment options. Ibalizumab is administered intravenously at a dose of 800 mg every 2 weeks following a single intravenous loading dose of 2000 mg. The most common adverse reactions reported with the use of ibalizumab are diarrhea, dizziness, nausea and rash.

Glecaprevir/pibrentasvir for the treatment of chronic hepatitis C virus infection in adults.

The fixed-dose combination of glecaprevir (GLE), a nonstructural protein 3/4A (NS3/4A) protease inhibitor, and pibrentasvir (PIB), an NS5A inhibitor, was recently approved for the treatment of adult patients with chronic hepatitis C virus (HCV) genotypes 1-6 (GT-1-6) without cirrhosis or with compensated cirrhosis, and for the treatment of HCV GT-1 patients who have failed treatment with either NS5A inhibitors or NS3/4A protease inhibitors, but not both. This combination, administered over 8 or 12 weeks, has resulted in high cure rates in all six HCV genotypes, including patients with HIV coinfection. GLE/PIB was well tolerated, with the most common adverse events being headache and fatigue. GLE/PIB is recommended to be taken as three tablets (total daily dose: GLE 300 mg and PIB 120 mg) orally once daily with food. No dose adjustment is required in patients with any degree of renal impairment or in patients undergoing hemodialysis. Dose adjustment is also not required in patients with Child-Pugh A liver disease. However, the use of GLE/PIB is not recommended in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.

Sofosbuvir/velpatasvir fixed-dose combination for the treatment of chronic hepatitis C virus infection.

The fixed-dose combination of sofosbuvir, a nucleotide analogue NS5B polymerase inhibitor, and velpatasvir, a second-generation NS5A inhibitor, has been approved by the United States Food and Drug Administration and the European Medicines Agency for the treatment of adult patients with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5 or 6 infection. This combination, administered over 12 weeks as a single-tablet regimen, has resulted in high cure rates in all 6 HCV genotypes and in a variety of patient populations, including patients without cirrhosis, patients with compensated cirrhosis and patients with HIV coinfection. In patients with decompensated cirrhosis, high cure rates were also achieved over 12 weeks with sofosbuvir/velpatasvir plus ribavirin. Patients who had failed prior treatment with an NS5A-containing regimen were able to achieve high cure rates following 24 weeks of treatment with sofosbuvir/velpatasvir plus ribavirin. Sofosbuvir/velpatasvir was well tolerated, the most common adverse events being headache, fatigue and nausea.

Sofosbuvir/ledipasvir fixed-dose combination for treatment of chronic hepatitis C virus infection in children.

The United States Food and Drug Administration recently approved sofosbuvir and the fixed-dose combination of ledipasvir/sofosbuvir for the treatment of hepatitis C virus (HCV) infection in children ages 12 to 17. These are the first direct-acting antiviral treatments approved for children and adolescents with HCV. Pharmacokinetic data confirm equivalent drug exposure in this population as that found in adults during clinical trials. The efficacy and safety of these drugs has been shown in clinical trials.

Tenofovir alafenamide fumarate for the treatment of HIV infection.

Tenofovir alafenamide fumarate is a recently developed prodrug of tenofovir, a nucleotide analogue reverse transcriptase inhibitor with potent inhibitory activity against HIV. The utility of a previously developed tenofovir prodrug, tenofovir disoproxil fumarate, had been hampered by renal and bone mineral adverse events. Tenofovir alafenamide fumarate overcomes the shortcomings of tenofovir disoproxil fumarate by delivering high intracellular concentrations of the parent drug, tenofovir, while substantially reducing systemic exposure. Tenofovir alafenamide fumarate is currently available as a component of three fixed-dose products: i) coformulation with emtricitabine; ii) coformulation with elvitegravir, cobicistat and emtricitabine; and iii) coformulation with rilpivirine and emtricitabine.

Isavuconazonium sulfate for the treatment of fungal infection.

Isavuconazole is a new azole antifungal drug with a broad antifungal spectrum that includes yeasts, molds and dimorphic fungi. Its prodrug, isavuconazonium sulfate, is currently approved in the United States and Europe for the treatment of the two of the most common and most challenging invasive fungal infections in clinical practice, invasive aspergillosis and invasive mucormycosis. It is available in both oral and intravenous formulations for once-a-day dosing and has favorable safety profile and drug interaction potential in comparison to voriconazole. Its role in the treatment of other fungal infections, besides aspergillosis and mucormycosis, remains to be determined. Similarly, its efficacy in prophylaxis against invasive fungal infections or its utility in patients with prior azole exposure is yet to be elucidated in clinical studies.

Ledipasvir/sofosbuvir fixed-dose combination for treatment of hepatitis C virus genotype 4 infection.

Hepatitis C virus (HCV) genotype 4 accounts for 8-13% of all chronic HCV infections worldwide. Patients with HCV genotype 4 have been reported to have poor treatment responses to PEGylated interferon and ribavirin regimens. Recently a single tablet, fixed-dose combination of sofosbuvir, an RNA-directed RNA polymerase (NS5B) inhibitor, and ledipasvir, a nonstructural protein 5A (NS5A) inhibitor, has been approved for treatment of chronic HCV infection. Two studies using the fixed-dose combination in chronic HCV genotype 4 for 12 weeks reported sustained virologic response rates at 12 weeks (SVR12) of 93-95%. Data also support the use of ledipasvir/sofosbuvir in chronic HCV genotype 4 and HIV co-infection. Administered as a single once-daily oral regimen, this ribavirin- and interferon-free regimen is well tolerated, with low potential for adverse effects and represents a significant advancement in the treatment of chronic HCV genotype 4 infection.

[Bone and joint involvement in human immunodeficiency virus infection].

The bone and joint complications of HIV infection continue to be reported. Some, in particular the metabolic bone disorders have become more prominent in the era of potent antiretroviral therapy. However, the epidemiology and the pathophysiology of these disorders as well as their relationship to the HIV infection itself, to the duration of illness, or to antiretroviral therapy remain largely undefined. This article attempts to provide a broad overview of the complications of HIV and its treatment involving the bone and joints.

Daclatasvir for the treatment of chronic hepatitis C virus infection.

Daclatasvir is a nonstructural protein 5A (NS5A) replication complex inhibitor that has shown potent in vitro activity against multiple hepatitis C virus (HCV) genotypes (GT). It is currently in advanced clinical development as a component of combination treatment regimens in a variety of HCV-infected patient populations. In studies conducted thus far, it has been generally well tolerated. It has been approved for the treatment of HCV GTs 1-4 in the European Union. The combination of daclatasvir and asunaprevir (an HCV NS3/4A protease inhibitor) has been approved in Japan for the treatment of patients with GT1 HCV infection. Here we review the available literature on daclatasvir, including its information on its discovery, mechanism of action, pharmacology, preclinical and clinical activity, resistance and safety.

Asunaprevir plus daclatasvir for the treatment of chronic hepatitis C virus infection.

Daclatasvir is a nonstructural protein 5A inhibitor of hepatitis C virus (HCV) replication. Asunaprevir is an NS3/4A complex inhibitor of HCV replication. The combination of daclatasvir and asunaprevir has been approved in Japan for the treatment of genotype 1 chronic HCV infection. In vitro studies have documented potent activity of these drugs, individually and in combination, against genotype 1 HCV. Results from completed and ongoing clinical studies have confirmed this potent activity in patients, with better responses noted in genotype 1b patients compared to patients with genotype 1a HCV. Response rates are also better in treatment-naive patients compared to those who are treatment-experienced; in these cases, the addition of interferon and ribavirin appears to enhance the treatment response. The combination of daclatasvir and asunaprevir is, in general, well tolerated. Daclatasvir and asunaprevir are substrates for cytochrome P450 3A4 enzymatic pathway; thus, there is a substantial potential for drug interactions.

Recent advances in the management of human immunodeficiency virus infection.

Major advances during the past 2 years have resulted in an unprecedented optimism regarding the perception of human immunodeficiency virus (HIV) infection. An improved understanding of the pathogenesis of HIV infection coupled with the availability of assays to measure HIV-1 RNA and the approval of new antiretroviral drugs has led to the development of new approaches to the management of HIV infection. In this article, we discuss these advances and their implications in the care of HIV-infected patients. In addition, we present the guidelines for the use of antiretroviral therapy for HIV infection.

Antiretrovirals.

Deaths related to the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome and the incidence of opportunistic infections have been drastically decreased in the industrialized world. These reductions are mainly due to recent advances in the management of HIV infection, including the availability of new therapies. Until November 1995, the antiretroviral drugs available and approved by the Food and Drug Administration for clinical use in the United States consisted of only four nucleoside analogue reverse transcriptase inhibitors: zidovudine, zalcitabine, didanosine, and stavudine. Since then, 2 new classes of agents and 10 new agents have been approved; thus, the number of available antiretroviral drugs has more than tripled. Additional drugs and newer classes of antiretrovirals are in various stages of development. Because of the availability of more drugs, the complexity of HIV treatment has increased. Selecting an appropriate antiretroviral therapeutic regimen involves addressing multiple interdependent issues, including patient adherence, pharmacokinetic properties of the drugs (including food effects and drug-drug interactions), drug resistance, and overlapping adverse effects.

Central nervous system histoplasmosis mimicking a brain tumor: difficulties in diagnosis and treatment.

Neurologic involvement occurs in 10% to 20% of patients with disseminated histoplasmosis. We describe a 20-year-old woman who had headache and diplopia but no evidence of systemic infection. Magnetic resonance imaging showed an enhancing mass in the thalamomesencephalic and third ventricular region. After subtotal resection of what was presumed to be a glioma, the patient had symptoms and signs of meningitis. Subsequent pathological review demonstrated noncaseating granulomas, and serologic tests and cultures confirmed the diagnosis of histoplasmosis. Initiation of antifungal therapy and removal of an infected shunt system resulted in clinical improvement. Clinicians should maintain a high index of suspicion in patients who are from any area endemic for histoplasmosis.

Interleukin-2 liposomes for primary immune deficiency using the aerosol route.

This is the first report of aerosol interleukin 2 (IL-2) liposome administration to individuals with immune deficiency. Parenteral IL-2 therapy has shown beneficial effects in some patients with cancer, common variable immunodeficiency (CVID), and human immunodeficiency virus (HIV) but is problematic because of side effects including fever and malaise as well as local swelling (delayed type hypersensitivity like reaction) after each subcutaneous IL-2 injection. Provision of an IL-2:human albumin liposome formulation via the aerosol route had few side effects in a recent clinical trial in cancer patients. Details of good manufacturing practice (GMP) synthesis and analysis of IL-2 liposomes (N= 6 lots) made without albumin carrier protein and placebo liposomes (three lots) are presented. After centrifugation, IL-2 was closely associated with the liposome pellet (99%). Mean diameter of liposomes was 1.1 microm. Patient acceptance, safety, toxicity, and immune effects of IL-2 liposomes were studied in individuals with primary immune deficiency (N = 15) and subsequently, a larger cohort of patients with hepatitis C. Experience in the immune deficient patients is the subject of this report. Placebo liposomes (12 weeks) and IL-2 liposomes (12 weeks) were provided using a nebulizer. Aerosol placebo liposomes and IL-2 liposomes were well tolerated. No changes in chest X-ray or pulmonary function were seen. Since biologic activity of aerosol IL-2 liposomes has been seen in viral disease (hepatitis C), additional studies of aerosol IL-2 liposomes in individuals with hepatitis C and HIV are planned.

Current status of antiretroviral therapies.

The availability of potent antiretroviral drugs and their use in combination regimens has led to a dramatic decline in the morbidity and mortality associated with HIV infection. Currently, there are 15 FDA-approved antiretrovirals categorised into three classes of drugs. Several others are in various stages of basic and clinical development.

Emerging concepts in disease management: a role for antimicrobial therapy in coronary artery disease.

Coronary artery disease, the leading cause of morbidity and mortality in developed countries, is a chronic inflammatory process that develops in response to a variety of injuries. A number of microbial organisms have been implicated in its pathogenesis. The strongest evidence to date for an association between an infectious agent and coronary heart disease is that for Chlamydia pneumoniae. Evidence implicating other microbial organisms is much less compelling. Sero-epidemiological and pathological data have linked infection with C. pneumoniae to atherosclerotic coronary artery disease. A possible mechanism by which C. pneumoniae may participate in the pathogenesis of atherosclerosis is through immune activation and the initiation of a chronic inflammatory state in the infected arterial wall. Locally secreted inflammatory cytokines trigger a cascade of secondary cellular processes that lead to characteristic structural changes. C. pneumoniae has been detected in atherosclerotic plaques and in the serum of patients with coronary artery disease. It induces foam cells (the hallmark of early atherosclerosis) and it markedly accelerates this disease process in animal models. C. pneumoniae has been associated with elevated levels of inflammatory cytokines and acute phase reactants. Data from three interventional studies in humans have suggested that treatment with antibiotics decreases inflammatory markers and perhaps influences the anti-C. pneumoniae antibody titers; however, adverse clinical events were not uniformly reduced in all trials. Two large prospective clinical trials, the WIZARD trial and ACES, are underway to confirm these preliminary findings and test the hypothesis that antibiotics may be beneficial in preventing or modifying the course of coronary artery disease. At present, antimicrobial therapy for atherosclerosis is not advocated outside of well-controlled research settings.