Managing Pharmacotherapy in People Living With HIV and Concomitant Malignancy.

Objective: To describe data with selected malignancies in people living with HIV (PLWH) and HIV in individuals affected by both conditions and to summarize drug-drug interactions (DDIs) with clinical recommendations for point-of-care review of combination therapies. Data Sources: Literature searches were performed (2005 to December 2018) in MEDLINE and EMBASE to identify studies of malignancies in PLWH in the modern era. Study Selection and Data Extraction: Article bibliographies and drug interaction databases were reviewed. Search terms included HIV, antiretroviral therapy, antineoplastic agents, malignancies, and drug interactions. Data Synthesis: In the pre-antiretroviral therapy (ART) era, malignancies in PLWH were AIDS-defining illnesses, and life expectancy was shorter. Nowadays, PLWH are living longer and developing malignancies, including lung, anal, and prostate cancers. Concurrently, the oncology landscape has evolved, with novel oral targeted agents and immunotherapies becoming routine elements of care. The increased need for and complexity with antineoplastics in PLWH has led to recommendations for multidisciplinary care of this unique population. Evaluation of DDIs requires review of metabolic pathways, absorption mechanisms, and various drug transporters associated with antineoplastics and ART. Relevance to Patient Care and Clinical Practice: This review summarizes available data of non-AIDS-defining malignancies, principles of HIV care in the patient with malignancy, and guidance for assessing DDIs between antineoplastics and ART. Summary DDI tables provide point-of-care recommendations. Conclusions: The availability of ART has transformed AIDS into a chronic medical condition, and PLWH are experiencing age-related malignancies. Pharmacists play an important role in the management of this patient population.

Citius, Altius, Fortius: The New Paradigm in the Treatment of Chronic Hepatitis C Disease.

With the advent of the direct-acting antiviral agents (DAAs) for chronic hepatitis C infection, the treatment paradigm has dramatically changed, especially the duration, tolerability, and response to therapy. The DAAs fall into several classes and are variously indicated in the treatment of one or more genotypes of infection. All these agents are orally administered and, as they are largely renally eliminated (with exceptions), do not require adjustment in mild to moderate renal insufficiency. Most of these agents demonstrate a high barrier to resistance and are extremely well-tolerated by patients. Overall efficacy rates are ≥90%.

A Bitter Pill to Swallow: Why Medication Safety Is Critical in Hepatitis C Treatment.

PURPOSE: To provide medication safety tips to optimize the management of patients receiving treatment for chronic hepatitis C virus (HCV) infection. SUMMARY: Ensuring safe medication use in patients who receive treatment for HCV infection is a crucial component in providing optimal patient care. Because of the complexity of available treatment options, numerous challenges exist in preventing medication errors with HCV therapies. This article will focus on the selection of appropriate treatment options along with proper dosing and duration, awareness of concomitant disease states and drug interactions, identifying adverse drug reactions (ADRs) and patient counseling points, the provision of adherence counseling and prevention of treatment interruptions, improving communication with patients and between pharmacies, and recognizing the importance of a multidisciplinary approach. CONCLUSION: Maintaining awareness of medication safety strategies geared toward HCV pharmacotherapy is critical for providing optimal care for patients while minimizing the opportunity for errors.

Sofosbuvir in the treatment of chronic hepatitis C: new dog, new tricks.

The existing standard of care for chronic hepatitis C virus (HCV) infection includes the use of pegylated interferon and ribavirin as primary components of treatment, with the addition of a direct-acting antiviral for genotype 1 infection. Sofosbuvir, an oral nucleotide inhibitor of the HCV nonstructural protein 5B RNA-dependent RNA polymerase enzyme, was recently approved for use in combination with ribavirin and/or pegylated interferon for chronic HCV infection, depending on the genotype. Sofosbuvir is orally administered, and peak plasma concentrations are not affected by food. The drug is renally eliminated and does not require adjustment in mild to moderate renal insufficiency or in any degree of hepatic impairment. Sofosbuvir is not metabolized by cytochrome P450 isoenzymes, nor does it induce or inhibit the metabolism of agents that are substrates of these enzymes. Sofosbuvir demonstrates a high barrier to resistance and was well tolerated by patients in clinical trials. Overall efficacy rates vary between 70% and 90%.

Use of daptomycin to treat infections with methicillin-resistant Staphylococcus aureus isolates having vancomycin minimum inhibitory concentrations of 1.5 to 2 µg/mL.

OBJECTIVE: To evaluate daptomycin use for the treatment of infections with methicillin-resistant Staphylococcus aureus (MRSA) isolates having vancomycin minimum inhibitory concentrations (MICs) of 1.5 to 2 µg/mL. DATA SOURCES: The literature was retrieved through PubMed and EMBASE (January 2006 to August 2013). STUDY SELECTION AND DATA EXTRACTION: English articles were reviewed. Studies that included separate daptomycin data (clinical outcome or in vitro surveillance) for MRSA isolates with vancomycin MICs of 1.5 to 2 µg/mL by any testing methodology were included. DATA SYNTHESIS: Clinical and microbiological outcomes associated with daptomycin used as first-line or subsequent therapy for MRSA infections with vancomycin MICs of 1.5 to 2 µg/mL were reported in 7 retrospective clinical studies; susceptibility information involving such isolates was reported from 12 surveillancestudies. Although not all studies demonstrated outcome differences between daptomycin and comparator treatments (usually vancomycin), when differences were reported, they were in favor of daptomycin. Individual studies found lower 60-day (8% vs 20%, P = .046) and 30-day mortality (3.5% vs 12.9%, P = .047) and increased treatment success with daptomycin (68.6% vs 43.1%, P = .008; 76.9% vs 53.8%, P = .048) in bacteremic patients. The median doses used for treatment of bacteremia were greater than that approved by the FDA for this indication (6 mg/kg/d). CONCLUSIONS: Current published evidence indicates daptomycin may be an acceptable alternative to vancomycin for MRSA infections, especially bacteremia, involving isolates with vancomycin MIC values of 1.5 to 2 µg/mL. Additional evidence is needed to fully elucidate daptomycin utility in this area.

Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate single tablet for HIV-1 infection treatment.

OBJECTIVE: To review the clinical trials, pharmacologic characteristics, safety, and efficacy of the elvitegravir/cobicistat/emtricitabine/tenofovir single tablet formulation (Stribild). DATA SOURCES: Literature searches were performed in MEDLINE (1948-September 2012) and PubMed (1966-September 2012) using the search terms GS-9137, elvitegravir, GS 9350, cobicistat, quad pill, Stribild, and integrase inhibitors. Abstracts from HIV/AIDS conferences were reviewed. STUDY SELECTION AND DATA EXTRACTION: Phase 3 studies evaluating the safety and efficacy of Stribild were preferentially evaluated, as well as relevant references from the published studies. DATA SYNTHESIS: Stribild contains complete antiretroviral therapy for HIV-1 infection in a single tablet. It is the first once-daily therapy option available with an integrase inhibitor and a novel pharmacokinetic boosting agent. Stribild has shown noninferiority in viral load suppression at 48 weeks when compared with dual nucleoside/nucleotide reverse transcriptase inhibitor and either a ritonavir-boosted protease inhibitor or nonnucleoside reverse transcriptase inhibitor regimen. Stribild was well tolerated, but some patients experienced increases in serum creatinine early in treatment that stabilized over time. CONCLUSIONS: Stribild is the first single-tablet regimen for HIV-1 infection treatment containing an integrase inhibitor. It is expected to have a prominent place in the formularies of health plans providing care for individuals with HIV-1 infection.

Tesamorelin: a growth hormone-releasing factor analogue for HIV-associated lipodystrophy.

OBJECTIVE: To evaluate the efficacy and safety of tesamorelin, a growth hormone releasing factor analogue approved by the Food and Drug Administration in November 2010 for the treatment of lipodystrophy associated with HIV infection. DATA SOURCES: Literature was obtained through MEDLINE (1948-November 2011) and International Pharmaceutical Abstracts (1970-October 2011) using the search terms tesamorelin, TH9507, growth hormone releasing factor, and HIV-associated lipodystrophy syndrome. Additional publications were obtained through review of references within primary literature publications as well as pertinent Web sites. STUDY SELECTION AND DATA EXTRACTION: All articles published in English identified from the data sources were evaluated and all pertinent information was included. All studies relevant to the evaluation of efficacy and safety of tesamorelin in the management of HIV-associated lipodystrophy were included, with a focus on trials completed in humans. DATA SYNTHESIS: In 2 Phase 3 clinical trials and their pooled analyses, tesamorelin was proven to significantly decrease waist circumference and visceral adipose tissue (VAT) following 26 weeks of treatment. Both trials also demonstrated significant improvements in some subjective body image parameters. Both studies had 26-week extension phases that confirmed maintenance of VAT improvements on treatment without adverse impact on blood glucose and lipid parameters. Limited data support off-label uses of tesamorelin at this time. CONCLUSIONS: Tesamorelin is effective in improving visceral adiposity and body image in patients with HIV-associated lipodystrophy over 26-52 weeks of treatment. Potential limitations for its use include high cost and lack of long-term safety and adherence data. Tesamorelin provides a useful treatment option for management of patients with significant lipodystrophy related to HIV infection.

Tigecycline for the treatment of severe Clostridium difficile infection.

OBJECTIVE: To evaluate the evidence for the use of tigecycline in the treatment of Clostridium difficile infection (CDI). DATA SOURCES: Searches were performed (2004 to June 2011), using the EMBASE and MEDLINE databases, with the terms tigecycline, Tygacil, Clostridium difficile, C. difficile, Clostridium difficile infection, and CDI. STUDY SELECTION: Six case reports that described the use of tigecycline for treatment of CDI were included for review. No clinical trials were identified. DATA SYNTHESIS: In all case reports except 1, tigecycline (alone or in combination with other CDI therapies) was used for the treatment of CDI that was refractory to metronidazole and/or vancomycin. In 6 of the cases, treatment success was reported following initiation of tigecycline therapy; 1 patient died following a complicated hospitalization. The treatment duration with tigecycline was 2-4 weeks. In the cases with successful outcomes, symptoms began to improve within 1 week. None of these patients experienced recurrence during follow-up of various lengths. In vitro studies demonstrated a 90% minimum inhibitory concentration range for tigecycline of 0.016-0.25 mg/L for all C. difficile isolates. Tigecycline exhibited good fecal penetration because of primary biliary excretion of unchanged drug. Up to 59% of the dose is recovered in feces following administration over 4 days in healthy volunteers. CONCLUSIONS: Case reports have suggested that tigecycline may be successful for treatment of severe or severe complicated CDI, when prior therapy has failed. Data demonstrating tigecycline use as initial therapy for CDI are limited; therefore, this option should be reserved for patients in whom other therapeutic options, including metronidazole and vancomycin, have failed. A randomized controlled trial is needed to assess the safety and efficacy of tigecycline in this patient population and better define the drug's role in the treatment of CDI.

Boceprevir: a protease inhibitor for the treatment of chronic hepatitis C.

OBJECTIVE: To review the pharmacology, pharmacokinetics, safety, and efficacy of boceprevir, a novel oral hepatitis C virus (HCV) nonstructural 3 (NS3) protease inhibitor for the treatment of chronic HCV infection, specifically, genotype 1. DATA SOURCES: A literature search was conducted through MEDLINE and EMBASE (1966-May 2011) using the terms boceprevir and SCH 503034. Data from the package insert, abstracts obtained from conferences, and unpublished Phase 2-3 clinical trials, obtained through clinicaltrials.gov, were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were evaluated. References from selected articles were used to identify other pertinent citations. Article selection focused on pharmacology, clinical trials, safety analyses, and resistance. Preference was given to human data. DATA SYNTHESIS: Boceprevir is an oral protease inhibitor that binds to the NS3 protein of HCV, ultimately inhibiting viral intracellular replication. Boceprevir displays linear pharmacokinetics and is rapidly absorbed upon oral administration. In clinical studies of treatment-naïve and treatment-experienced patients, boceprevir, in combination with standard of care (pegylated interferon [Peg-IFN]-α-2b with or without ribavirin) achieved greater sustained viral response (SVR) rates compared to standard of care. Safety analyses showed an increased incidence of adverse effects when boceprevir was used with Peg-IFN-α-2b and ribavirin. The most common adverse events reported include fatigue, headache, nausea, dysguesia, and anemia; the incidence of the latter 2 adverse effects may be increased if boceprevir is added to standard therapy. Additional Phase 2 and 3 studies are currently enrolling participants. CONCLUSIONS: Boceprevir should be used in combination with Peg-IFN-α-2b and ribavirin in the treatment of chronic HCV genotype 1 infection. The improved response rates achieved with that combination will make boceprevir a viable option compared with other developing and approved NS3 protease inhibitors for treatment-naïve and treatment-experienced nonresponders/relapsers. Additional data are needed to clarify the potential for resistance and drug interactions.

Fidaxomicin: a macrocyclic antibiotic for the management of Clostridium difficile infection.

OBJECTIVE: To evaluate the efficacy and safety of fidaxomicin for the treatment of Clostridium difficile infection. DATA SOURCES: Literature retrieval was accessed through MEDLINE (1966-January 2010) and International Pharmaceutical Abstracts (1970-January 2010) using the terms OPT-80, difimicin, PAR-101, fidaxomicin, tiacumicin, lipiarmycin, and Clostridium difficile. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles published in English that were identified from the data sources were evaluated and pertinent information was included. DATA SYNTHESIS: Fidaxomicin is an 18-membered macrocyclic antibiotic with activity against gram-positive aerobes and anaerobes, including C. difficile. Microbiologic studies comparing in vitro activity of fidaxomicin with that of metronidazole and vancomycin have shown good activity against all strains of C. difficile tested; however, minimum inhibitory concentrations were consistently lower for fidaxomicin. Studies showed that fidaxomicin lacks activity against gram-negative pathogens, thereby preserving normal gastrointestinal flora. Small pharmacokinetic trials have shown that fidaxomicin administration leads to low concentrations in plasma, high concentrations in stool, and a postantibiotic effect of greater than 24 hours, all of which are potentially advantageous characteristics for treating C. difficile infection. Data from 2 Phase 2A trials and 1 Phase 3 (multicenter, randomized, double-blind) trial suggest that fidaxomicin is effective for the treatment of mild-to-moderate C. difficile infection at a dose of 200 mg orally every 12 hours. Limited early results from the Phase 3 trial showed favorable outcomes for fidaxomicin when compared to oral vancomycin. Overall, fidaxomicin has been well tolerated to date. CONCLUSIONS: The activity of fidaxomicin and limited clinical data suggest that it may have a future role in the treatment of mild-to-moderate C. difficile infection. The complete pharmacokinetic/pharmacodynamic profile, safety, and place in therapy have yet to be determined as trials comparing this agent to vancomycin are forthcoming.

In the Eye of the Storm: The Role of the Pharmacist in Medication Safety during the COVID-19 Pandemic at an Urban Teaching Hospital.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease (COVID-19) pandemic, has challenged practitioners with complex clinical scenarios as well as conflicting and scarce data to support treatment strategies. The pandemic has also placed strains on institutions due to drug shortages, alterations in medication use processes, economic losses, and staff exposure to the virus. This article provides pharmacist-led suggestions and strategies to various case questions, describing some of the challenges faced by practitioners at an urban teaching hospital during the COVID-19 pandemic. The strategies suggested can be explored at other institutions.

Apricitabine: a nucleoside reverse transcriptase inhibitor for HIV infection.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of apricitabine, a nucleoside reverse transcriptase inhibitor that is currently under investigation and has fast-track approval status with the Food and Drug Administration. DATA SOURCES: A literature search was conducted using PubMed (1966-June 2009) to retrieve relevant material using the search terms apricitabine, SPD754, and AVX754. References from selected articles were evaluated to identify other pertinent trials. Information was also obtained from the manufacturer. STUDY SELECTION AND DATA EXTRACTION: All English-language in vitro and in vivo studies and abstracts evaluating apricitabine were reviewed and considered for inclusion. Preference was given to human data. DATA SYNTHESIS: Apricitabine is a prodrug that is phosphorylated to its active triphosphate form intracellularly, which ultimately results in chain termination and inhibition of reverse transcription. Apricitabine is administered orally, displays linear pharmacokinetics, and is renally excreted with minimal to no hepatic metabolism. It has demonstrated antiretroviral activity against drug-resistant strains both in vitro and in vivo. In clinical studies, in both antiretroviral-naïve and treatment-experienced patients, apricitabine achieved the primary endpoint of significant reductions in plasma viral load versus comparator. Further Phase 2 and 3 studies are currently enrolling. Safety analysis indicates that apricitabine is well tolerated and has a low potential for causing mitochondrial damage. The most common adverse events reported include headache and rhinitis. Development of resistance or further gene mutations has not been shown in clinical studies to date. CONCLUSIONS: Although the role of apricitabine in the treatment of HIV-1 infection has yet to be established, its activity against resistant HIV-1 strains and its tolerability profile will likely make it a viable second-line treatment option in patients who have failed regimens containing lamivudine or emtricitabine.

Daptomycin-induced acute renal and hepatic toxicity without rhabdomyolysis.

OBJECTIVE: To report a case of a patient who experienced acute renal and hepatic toxicity following administration of daptomycin and review previously published case reports of renal and hepatic dysfunction with daptomycin. CASE SUMMARY: A 35-year-old man receiving daptomycin 4 mg/kg (275 mg) intravenously once daily (started 5 wk prior to presentation for presumed osteomyelitis) presented to the emergency department with elevations in serum creatinine and hepatic transaminase levels. He did not experience creatine kinase (CK) elevation or rhabdomyolysis. Following discontinuation of daptomycin, his renal and hepatic function improved. DISCUSSION: To our knowledge, this is the first case of daptomycin-induced hepatotoxicity with acute renal failure in the absence of rhabdomyolysis and CK abnormalities. Previously published case reports described patients with a variety of elevations in liver function tests, serum creatinine, and CK with daptomycin. In our patient, the acute renal and hepatic toxicity was probable according to the Naranjo probability scale. CONCLUSIONS: Although daptomycin is a well-tolerated antibacterial agent, clinicians should consider periodic monitoring of liver function and renal function tests to identify potential adverse effects.

Amphotericin B-associated hyperbilirubinemia: case report and review of the literature.

A 53-year-old woman with an intraabdominal infection secondary to Candida albicans experienced hyperbilirubinemia after receiving amphotericin B in two different formulations--amphotericin B deoxycholate and amphotericin B lipid complex. Only a few case reports of amphotericin B-induced hyperbilirubinemia have been documented in the literature, each with different patterns of corresponding abnormalities in liver function tests. The unpredictable nature of this adverse effect warrants monitoring of bilirubin levels and liver function at baseline and potentially during therapy with amphotericin B, regardless of formulation, dosage, or duration of therapy.

Therapeutic Advances in HCV Genotype 1 Infection: Insights from the Society of Infectious Diseases Pharmacists.

Hepatitis C virus (HCV) is the most common blood-borne infection in the United States. The high morbidity and mortality due to untreated infection have prompted updated screening recommendations that now include one-time HCV screening for all patients born between 1945 and 1965, in addition to risk factor-based screening. Current guidelines recommend treatment for all patients with chronic HCV. Treatment for HCV genotype 1 has evolved dramatically since the approval of the direct-acting antivirals. The approval of ledipasvir-sofosbuvir, ombitasvir-paritaprevir-ritonavir and dasabuvir, and simeprevir with sofosbuvir has dramatically altered the treatment landscape. High sustained virologic response (SVR) rates favor treatment, yet access to care poses a challenge for patients and providers. Current and emerging data with new therapies indicate high SVR rates in treatment-naïve and treatment-experienced patients, including patients with cirrhosis and in other special populations. Additional data suggest the addition of ribavirin can decrease treatment duration without compromising SVR rates. Resistance is an increasing area of interest in HCV, with baseline mutations identified and the potential for the development of resistance-associate variants in patients undergoing treatment. Due to the rapid evolution of HCV treatment, pharmacists should address challenges and play an integral role in agent selection, dosing, drug interaction screening, adverse effect monitoring, and the coordination of treatment. Clinical application of the latest information will reduce patient risk and improve outcomes.

Failed triple therapy in a treatment-experienced patient with genotype 6 hepatitis C infection.

PURPOSE: The first published report of the use of triple therapy in a patient with hepatitis C virus (HCV) genotype 6 infection-a treatment that was prescribed due to incorrect HCV genotyping and which ultimately failed-is presented. SUMMARY: A 70-year-old male U.S. resident of Vietnamese descent requested treatment for chronic HCV infection acquired decades earlier. He reported experiencing hepatitis C treatment failures twice before-13 years prior (interferon alfa monotherapy for six months) and 7 years prior (standard dual therapy with pegylated interferon alfa-2b and ribavirin for nine months). Initial viral genotyping indicated infection with HCV genotypes 1a and 6c (a form of mixed HCV disease amenable to triple therapy), and treatment with pegylated interferon alfa-2a, ribavirin, and boceprevir was initiated. By week 8 of triple therapy, the patient's viral load had decreased from 15,700,000 (7.20 log) to 462,882 (5.67 log) IU/mL, but the viral load subsequently rebounded to baseline levels, and treatment was discontinued at week 16. When repeat HCV genotyping was performed, it was discovered that initial genotyping was incorrect and that the man's infection involved not mixed genotypes but only genotype 6; he was not an appropriate candidate for triple therapy. The case emphasizes the need for clinicians to be cognizant of potential HCV genotyping errors, particularly with regard to patients of Southeast Asian descent. CONCLUSION: Three courses of interferon-based treatment, including triple therapy with boceprevir, failed to produce a sustained therapeutic response in a 70-year-old ethnic Vietnamese man with genotype 6 HCV infection.