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.

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.

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.

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.

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/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.

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.

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.

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.

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.

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.

Sofosbuvir for the treatment of chronic hepatitis C virus infection.

Sofosbuvir is a nucleotide analogue selective inhibitor of the RNA-directed RNA polymerase (NS5B) enzyme of the hepatitis C virus (HCV) genome. It has shown potent antiviral activity across all HCV genotypes and in a variety of patient populations, including treatment-naive patients; treatment-experienced patients who had failed previous standard therapy; patients with decompensated liver disease, including cirrhosis; and HIV co-infected patients. It is administered as a single, once-daily 400-mg tablet, has no food restrictions, has low potential for drug interactions, and requires no dose adjustment in mild to moderate kidney or liver impairment. When sofosbuvir is combined with pegylated interferon and/or ribavirin, its clinical and laboratory safety profile is similar to that which is expected from pegylated interferon or ribavirin alone. Rates of treatment discontinuation and dose reduction with sofosbuvir-containing regimens were lower than those commonly observed with pegylated interferon and ribavirin.

Dolutegravir, an HIV integrase inhibitor for the treatment of HIV infection.

Dolutegravir, a next-generation integrase strand transfer inhibitor, was recently approved by the United States Food and Drug Administration to treat antiretroviral therapy-naive as well as treatment-experienced HIV-infected individuals, including those who have been treated with other integrase strand transfer inhibitors. Dolutegravir is the first stand-alone agent in its class, with a pharmacokinetic profile that allows once-daily administration without the requirement for pharmacologic boosting. It is metabolized primarily by UDP-glucuronosyltransferase 1-1 (UGT1A1) and is expected to have a limited propensity for drug-drug interactions. Furthermore, dolutegravir retains significant virologic activity against raltegravir- or elvitegravir-associated HIV-1 resistance mutations.

Cobicistat, a pharmacoenhancer for HIV treatments.

Cobicistat is a novel cytochrome P450 3A4 (CYP3A4) inhibitor in advanced clinical evaluation for use as a pharmacoenhancer of antiretroviral drugs. It lacks significant anti-HIV activity and is more selective than ritonavir in its enzyme inhibition. In addition, its water solubility may lend itself to coformulation with other drugs. Renal adverse effects and a considerable drug interaction potential limit its clinical utility and caution is required when using it. A fixed-dose combination product containing cobicistat in addition to elvitegravir, tenofovir and emtricitabine, and providing a one-pill, once-a-day, antiretroviral regimen was recently approved.

Simeprevir: a macrocyclic HCV protease inhibitor.

Simeprevir is a macrocyclic NS3/4A HCV protease inhibitor with potent activity against genotypes 1, 2, 4, 5 and 6 of the hepatitis C virus (HCV). Phase II and III studies of simeprevir combined with pegylated interferon (peg-IFN) and ribavirin (RBV) demonstrated that the combination was safe and effective in HCV genotype 1 patients, with more than 75% of treatment-naive patients attaining a sustained virological response (SVR). Simeprevir is administered once daily as a single 150-mg capsule. It has a moderate drug interaction potential, but less than that of the first-generation HCV protease inhibitors. Based on positive results from the product's phase III clinical program, simeprevir was approved and launched in Japan, the U.S. and Canada in late 2013 for use in combination with peg-IFN/RBV in HCV genotype 1 infections. Phase II interferon-free studies of simeprevir are ongoing.

Cobicistat-boosted elvitegravir-based fixed-dose combination antiretroviral therapy for HIV infection.

A fixed-dose co-formulated antiretroviral drug containing elvitegravir, a new integrase strand transfer inhibitor, boosted by a novel pharmacokinetic enhancer cobicistat, and further containing the nucleoside pair of tenofovir and emtricitabine was recently approved by the U.S. Food and Drug Administration as a single-tablet, once-a-day treatment of HIV-1 infection in antiretroviral therapy-naive adults. This drug was found to be noninferior to two currently preferred antiretroviral regimens in clinical practice in two large, 48-week, phase III studies. Renal adverse effects limit its use to those with creatinine clearance > 70 mL/min; its considerable drug interaction potential requires care and attention when used. Nevertheless, the availability of this fixed-dose combination product is an important progress in the management of HIV infection for a number of reasons: It provides a third option for a one-pill, once-a-day antiretroviral regimen; it is the first such regimen that is not based on a non-nucleoside reverse transcriptase inhibitor; and it provides an alternative to ritonavir for the pharmaco-enhancement of other antiretroviral drugs.

Current status of treatment for chronic hepatitis C virus infection.

Chronic hepatitis C virus (HCV) infection is responsible for substantial mortality and morbidity worldwide. Until recently, the standard of care for the treatment of chronic HCV infection had been a combination of pegylated interferon (peg-IFN) and ribavirin (RBV). The recent availability of two directly acting agents, telaprevir and boceprevir, has led to significantly improved outcomes for those patients with HCV genotype 1. Unfortunately, each of these agents must be combined with peg-IFN and RBV for optimal efficacy, and substantial treatment-related toxicity continues to challenge clinicians. However, the drug development pipeline for chronic HCV infection is very robust and the emergence of new therapies and therapeutic strategies in the near future for managing chronic HCV infection is eagerly anticipated.

Telaprevir: looking for a sustained virologic response in hepatitis C virus infection.

Telaprevir, a hepatitis C virus (HCV) NS3/NS4A protease inhibitor, was recently approved by the U.S. Food and Drug Administration for the treatment of chronic HCV genotype 1 infection. When given in combination with pegylated interferon and ribavirin, it demonstrated improved efficacy over conventional pegylated interferon and ribavirin therapy. Improvement in efficacy was also noted in African American patients who traditionally respond less well to conventional anti-HCV treatment. While the role of telaprevir in the management of chronic HCV infection remains to be fully defined, its development and licensure represents an important milestone in anti-HCV therapeutics.