Pharmacokinetics and Safety of the Integrase Inhibitors Elvitegravir and Dolutegravir in Pregnant Women With HIV.

Objective: To synthesize data on the pharmacokinetics and safety of dolutegravir and elvitegravir in pregnant women living with HIV. Data Sources: A PubMed, EMBASE, Web of Science, and Google Scholar literature search (January 2010 to December 2018) was performed using the search terms dolutegravir, elvitegravir, women, pregnant*, and HIV. Additional reports were identified from conference abstracts and review of reference lists. Study Selection and Data Extraction: English-language studies reporting pharmacokinetic and/or safety data in pregnant women receiving dolutegravir or elvitegravir/cobicistat were included. Data Synthesis: A total of 17 studies were selected. Studies demonstrated a modest decrease in dolutegravir concentrations in pregnancy. Preliminary data suggest an increased risk of neural tube defects when dolutegravir is used at the time of conception. Available pharmacokinetic data in pregnant women showed significantly reduced plasma concentrations of elvitegravir/cobicistat which may increase the risk of virological failure. Current guidelines recommend that dolutegravir should not be initiated in women who have the potential to become pregnant or women in their first trimester of pregnancy and elvitegravir/cobicistat should be avoided during pregnancy. Relevance to Patient Care and Clinical Practice: This review highlights pharmacokinetic and safety data for dolutegravir and elvitegravir/cobicistat in pregnant women. Clinicians need to be aware of these data to convey the risks and benefits of using these agents in women of child-bearing potential. Conclusions: Changes in guideline recommendations reflect emerging data regarding the use of dolutegravir and elvitegravir/cobicistat in pregnancy. Until further information is available, raltegravir or other first-line agents are recommended for women with HIV planning to become pregnant.

Dolutegravir Dual Therapy as Maintenance Treatment in HIV-Infected Patients: A Review.

OBJECTIVE: To review available evidence for dolutegravir-based dual therapy as maintenance treatment in HIV-1 infected patients. DATA SOURCES: A literature search was conducted using PubMed, MEDLINE, and Google Scholar to the end of January 2018. Conference abstracts and article bibliographies were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All English-language, randomized, and observational studies were included. DATA SYNTHESIS: In all, 12 studies were identified: 10 were observational, and 2 were randomized trials. Rilpivirine or lamivudine were the most common second agent used in combination with dolutegravir. Virological suppression seen in observational studies appear promising; however, the most compelling evidence to date is the 48-week results from 2 large open-label randomized trials (SWORD 1 and 2). These studies found that dual therapy with rilpivirine and dolutegravir was noninferior to 3- or 4-drug combination antiretroviral therapy (cART). The long-term efficacy, safety, and tolerability of dual therapy, as compared with usual cART, are less clear and require further data. CONCLUSIONS: Regimen switching in virally suppressed HIV-1-infected patients may be considered to reduce pill burden or dosing frequency, decrease short- or long-term toxicity, prevent or manage drug-drug interactions, and/or decrease cost. Based on available evidence, a switch to dual therapy with dolutegravir and rilpivirine appears viable for virologically suppressed patients without prior resistance mutations to these agents. Randomized studies of other dual-therapy regimens that include dolutegravir and longer-term follow-up as well as cost-effectiveness analyses are needed to provide confirmation that this strategy offers advantages to traditional cART regimens.

Probable interaction between levothyroxine and ritonavir: Case report and literature review.

PURPOSE: A case of probable interaction of levothyroxine and ritonavir is presented along with a review of the relevant literature and recommendations on clinical management. SUMMARY: A 37-year-old woman with human immunodeficiency virus infection who had recently undergone thyroidectomy for a benign multinodular goiter presented to a clinic with hypothyroidism (she was also found to be pregnant), and treatment with levothyroxine 75 µg daily was initiated. While receiving antiretroviral therapy (abacavir-lamivudine and lopinavir-ritonavir) during pregnancy, the patient had persistently elevated serum thyroid-stimulating hormone (TSH) concentrations (up to 125.89 µIU/mL) despite gradual escalation of the levothyroxine dosage to 175 µg daily. An interaction between ritonavir and levothyroxine was suspected, and dolutegravir was substituted for lopinavir-ritonavir. Within 4 months, the TSH concentration had normalized. The daily levothyroxine dose was tapered over a 5-month period and stabilized at 125 µg, and TSH concentrations remained within the normal range over an 18-month follow-up period. Scoring of the case using the Drug Interaction Probability Scale yielded a score of 6 out of 11, indicating a probable interaction between levothyroxine and ritonavir. A literature search identified 4 reported cases of interactions involving levothyroxine and ritonavir. CONCLUSION: A potentially serious and underrecognized drug interaction between ritonavir and levothyroxine was observed in a pregnant woman with postthyroidectomy-related hypothyroidism. This case and a review of other cases reported in the literature indicate that higher-than-usual doses of levothyroxine may be required in patients who are taking ritonavir concurrently.

Discontinuing Pneumocystis jirovecii Pneumonia Prophylaxis in HIV-Infected Patients With a CD4 Cell Count <200 cells/mm3.

OBJECTIVE: To review the evidence for discontinuing primary and secondary Pneumocystis jirovecii pneumonia (PJP) prophylaxis in HIV-infected patients with a CD4 count <200 cells/mm(3). DATA SOURCES: We conducted a literature search in MEDLINE, EMBASE, Cochrane Library, Google Scholar, and the International Aids Society Library (up to August 2015) using the following key search terms: Pneumocystis jirovecii, pneumonia, human immunodeficiency virus, primary prophylaxis, secondary prophylaxis, and discontinuation. STUDY SELECTION AND DATA EXTRACTION: All English-language studies that evaluated discontinuation of primary and/or secondary PJP prophylaxis in HIV-infected patients with CD4 count <200 cells/mm(3) were included. DATA SYNTHESIS: Five studies were identified, which varied in design, sample size, outcomes, and duration of follow-up. Three studies examined discontinuation of primary and secondary PJP prophylaxis; 1 study evaluated discontinuing primary PJP prophylaxis; and 1 study evaluated stopping secondary PJP prophylaxis. Two out of the 5 studies pooled data for all opportunistic infections. Overall, there was a low incidence of PJP among HIV-infected patients who discontinued primary PJP prophylaxis and were well controlled on antiretroviral therapy (ART). CONCLUSIONS: Discontinuation of primary PJP prophylaxis appears to be safe in patients on combination ART with a suppressed HIV viral load and a CD4 count >100 cells/mm(3). Additional data are needed to support the safety of discontinuing secondary PJP prophylaxis. Decisions to discontinue PJP prophylaxis in patients with a CD4 count <200 cells/mm(3) should be done on an individual patient basis, taking into consideration clinical factors, including ongoing adherence to ART.

The Use of Therapeutic Drug Monitoring in Complex Antituberculous and Antiretroviral Drug Dosing in HIV/Tuberculosis-Coinfected Patients.

UNLABELLED: We report 2 cases coinfected with HIV and tuberculosis (HIV/TB), requiring drug dose adjustments guided by therapeutic drug monitoring (TDM) and/or serum drug concentrations. CASE 1: Over the course of the 9-months of TB treatment, drugs that required increased doses due to low concentrations included efavirenz (800 mg), rifampin (900 mg), and isoniazid (450 mg). Higher drug doses were well tolerated until the end of treatment. CASE 2: Over the 12-month course of TB therapy, drugs that required increased doses due to incomplete and/or delayed absorption were rifampin (1500 mg), moxifloxacin (800 mg), and ethambutol (1600 mg). Higher drug doses were well tolerated until the end of treatment. Due to delayed/incomplete drug absorption and weight gain during therapy, higher antituberculous doses may be required in patients coinfected with HIV/TB. A daily dose of efavirenz 800 mg was well tolerated in both patients (weight over 70 kg). Managing patients coinfected with HIV/TB is complex, and, therefore, TDM of drug concentrations can help guide clinical decision making.

Antiretroviral-Related Alopecia in HIV-Infected Patients.

Objective: To review the literature evaluating antiretroviral-related alopecia and to provide guidance on the differential diagnosis and management of this condition. DATA SOURCES: A literature search was performed using PubMed, MEDLINE, Embase, International Pharmaceutical Abstracts (IPA), Cumulative Index to Nursing and Allied Health (CINAHL), and the Cochrane database (through May 2014). Relevant conference abstracts and product monographs were reviewed. Search terms included antiretroviral, individual antiretroviral classes and names, highly active antiretroviral therapy, HIV, AIDS, alopecia, hair, hair loss and drug. STUDY SELECTION AND DATA EXTRACTION: English-language studies and case reports were included. A total of 16 articles and 1 conference abstract were retrieved, with a total of 46 patients with hair loss. DATA SYNTHESIS: The protease inhibitor class, in particular indinavir, was most commonly reported to cause hair loss, followed by the NRTI, lamivudine. The majority of cases presented with alopecia of the scalp alone, with a median time of onset of 2.5 months. Management involved discontinuing the drug in most cases, with at least partial reversal in half the cases. CONCLUSIONS: In antiretroviral-induced alopecia, discontinuation of the suspected agent is the optimal management, and hair regrowth should occur within 1 to 3 months. Management may also include replacing the offending medication with an antiretroviral less likely to cause hair loss. It is essential to rule out other causes of alopecia with a complete patient history, including characterization of the hair loss and assessment of the patient's medical history, medication use, and family history of alopecia.

Antiretroviral and Medication Errors in Hospitalized HIV-Positive Patients.

OBJECTIVE: To summarize the literature regarding antiretroviral and other medication errors in hospitalized HIV-positive patients and to discuss potential interventions and solutions that have been studied to minimize drug error. DATA SOURCES: A systematic search of MEDLINE, PubMed, and EMBASE (2000-April 2014) was conducted. Search terms included HIV/AIDS, HAART, hospitalization, patient admission, inpatient, patient transfer, medication error, inappropriate prescribing, drug interaction, drug omission, drug toxicity, and contraindication. STUDY SELECTION AND DATA EXTRACTION: English-language research articles, case reports, conference abstracts, and letters to the editor were reviewed. DATA SYNTHESIS: A high overall medication error rate was reported in HIV-positive inpatients. Errors occurred mainly at the time of prescribing on admission but were also detected throughout hospitalization and at discharge. Errors in the antiretroviral regimen, dosing, scheduling, and drug-drug and drug-food interactions were the most common. The most successful interventions involved a clinical pharmacist, who specializes in infectious diseases and/or HIV, completing medication reconciliation on admission, reviewing orders daily, and screening for errors at discharge. CONCLUSIONS: Although studies varied greatly in methodology, overall, a large number of medication errors occurred in this patient population. This underscores the important role the pharmacist has in optimizing care to hospitalized HIV-positive patients and provides further insights into the types of medication errors that occur and proposed solutions to reduce these errors. Because medication errors are multifactorial, ongoing initiatives to improve the quality of medication reconciliation processes, educate the health care team on antiretroviral medications, and improve the drug distribution system are required.

Iatrogenic Cushing syndrome after intra-articular triamcinolone in a patient receiving ritonavir-boosted darunavir.

Drug interactions involving human immunodeficiency virus protease inhibitors are common due to their inhibition of the cytochrome P450 3A4 isoenzyme. We describe the case of an HIV-infected patient treated with ritonavir-boosted darunavir who developed cushingoid features following an intra-articular injection of triamcinolone acetate. We review the probable mechanism for this interaction and describe similar cases of Cushing syndrome in patients receiving concomitant ritonavir and triamcinolone.

Adverse effects of antiretrovirals in HIV-infected pregnant women.

BACKGROUND: Current guidelines for the use of antiretroviral (ARV) therapy during pregnancy recommend that women be offered treatment with combination ARV therapy used in nonpregnant HIV-infected individuals. It is unclear whether the risk of ARV-related adverse drug reactions (ADRs) is increased during pregnancy. OBJECTIVE: To evaluate the frequency and severity of ADRs likely caused by ARV therapy in pregnant women who are HIV-positive. METHODS: A retrospective analysis of HIV-infected women who received ARV therapy during pregnancy and delivered between January 1997 and February 2006 was conducted. Incidence of maternal ADRs was determined through evaluation of laboratory findings, documented physical examinations, and patient self-reports. An AIDS Clinical Trials Group severity grading scale was applied to the ADRs. Cause-effect relationship was adjudicated based on the Naranjo probability scale and, if causality was found, that information was included. RESULTS: There were 103 women who accounted for 133 pregnancies that resulted in deliveries. Of the 111 pregnancies in which treatment was received, regimens included 26 nucleoside reverse transcriptase inhibitor monotherapy, 40 nonnucleoside reverse transcriptase inhibitor (NNRTI)-based, 44 protease inhibitor (PI)-based, and 1 PI/NNRTI combination therapy. Ninety-eight ADRs were documented in 49 pregnancies. The most common ADRs were gastrointestinal (n = 48), followed by central nervous system symptoms (n = 15), anemia (n = 15), elevated liver/pancreatic enzyme levels (n = 11), and cutaneous reactions (n = 8). Severe ADRs included elevations in liver/pancreatic enzymes (n = 3), nausea and vomiting (n = 3), and anemia (n = 2). Seven women required a change in therapy due to an ADR. CONCLUSIONS: Approximately 7 ADRs were reported for every 10 pregnancies in this cohort. Most ADRs were mild to moderate. Short exposure times in most women (second and third trimester) may have accounted for the lack of long-term toxicities. Although ADRs did not pose a major barrier to use of ARVs in pregnancy, close monitoring of pregnant women receiving ARV therapy continues to be warranted.

Induction effects of ritonavir: implications for drug interactions.

OBJECTIVE: To review the literature on the induction effects of ritonavir on the cytochrome P450 enzyme system and glucuronyl transferase and identify resultant established and potential drug interactions. DATA SOURCES: Primary literature was identified from MEDLINE (1950-April 2008), EMBASE (1988-April 2008) and International Pharmaceutical Abstracts (1970-April 2008) using the search terms ritonavir, cytochrome P450 enzyme system, enzyme induction, glucuronyl transferase, and drug interactions. Additionally, relevant conference abstracts and references of relevant articles were reviewed. STUDY SELECTION AND DATA ABSTRACTION: All English-language articles and abstracts identified were reviewed. DATA SYNTHESIS: Ritonavir is a well-known inhibitor of the metabolism of numerous medications that are substrates of the CYP3A and CYP2D6 pathways. It also exhibits a biphasic, time-dependent effect on P-glycoprotein of inhibition followed by induction. Numerous pharmacokinetic studies suggested that ritonavir induces cytochrome P450 enzymes 3A, 1A2, 2B6, 2C9, and 2C19, as well as glucuronyl transferase. Additionally, several case reports described clinically significant subtherapeutic effects of drugs metabolized by these isoenzymes when coadministered with ritonavir. Both therapeutic and boosting doses of ritonavir appear to induce these enzymes; however, most of the studies of low-dose ritonavir involved a second protease inhibitor such as lopinavir, darunavir, or tipranavir. It is, therefore, difficult to distinguish the relative effects of additional medications unless well-designed, 3-way studies are conducted. CONCLUSIONS: At both therapeutic and boosting doses, ritonavir exhibits a clinically relevant induction effect on numerous drug-metabolizing enzymes. A decrease or loss of therapeutic effect may be observed when ritonavir is coadministered with medications that are substrates for these enzymes. It is important for clinicians to be aware of drugs potentially impacted by ritonavir therapy to identify and manage these interactions.

Complexity of interactions between voriconazole and antiretroviral agents.

OBJECTIVE: To evaluate and summarize pertinent aspects of the literature on interactions between voriconazole and antiretroviral agents. DATA SOURCES: Primary literature was identified through MEDLINE (1950-February 2008), EMBASE (1988-February 2008), and International Pharmaceutical Abstracts (1970-February 2008) using the search terms voriconazole, ritonavir, protease inhibitors, nonnucleoside reverse transcriptase inhibitors, raltegravir, maraviroc, and drug interactions. Additionally, relevant abstracts from infectious diseases and HIV conferences (2004-February 2008), reference citations from relevant publications, and product information monographs were reviewed. STUDY SELECTION AND DATA ABSTRACTION: All articles identified from the data sources and published in English were reviewed. Of these, studies and reports addressing voriconazole pharmacokinetics or interactions with antiretroviral agents were evaluated. DATA SYNTHESIS: The interactions between voriconazole and antiretroviral drugs are complex. Voriconazole and ritonavir exhibit a time- and dose-dependent interaction. Ritonavir initially inhibits voriconazole metabolism, but, with chronic administration, subsequently induces voriconazole metabolism. This interaction is more pronounced with high doses of ritonavir. Coadministration of voriconazole and efavirenz at usual doses is contraindicated because of a 2-way interaction resulting in efavirenz toxicity and decreased therapeutic effect of voriconazole. Dosage adjustments of both drugs are required. Based on pharmacokinetic characteristics, interactions between voriconazole and other protease inhibitors, nonnucleoside reverse transcriptase inhibitors (including etravirine), and maraviroc are likely but have not been well characterized in the literature. Interactions between voriconazole and nucleoside reverse transcriptase inhibitors or raltegravir are not anticipated. CONCLUSIONS: Interactions between voriconazole and antiretrovirals have the potential for serious consequences. However, because there is limited information available, further studies are warranted to establish these interactions and clarify their appropriate management. Until then, clinicians should be aware of the potential for interactions between voriconazole and antiretroviral agents and how to monitor for these interactions in clinical practice.

Abacavir hypersensitivity reaction: an update.

OBJECTIVE: To review the clinical features, risk factors, diagnosis, and management of abacavir hypersensitivity reaction (HSR). DATA SOURCES: A MEDLINE (1950-October 2007) and EMBASE (1980-October 2007) search using key words abacavir, HIV, human immunodeficiency virus, hypersensitivity reaction, HLA-B(*)5701, and patch tests was conducted. Conference abstracts and article bibliographies were reviewed to identify relevant studies. STUDY SELECTION AND DATA EXTRACTION: Studies that investigated the clinical and immunogenetic risk factors for abacavir hypersensitivity and the benefit of genetic screening, as well as articles that focused on the clinical presentation, assessment, and management of abacavir HSR, were considered for this review. DATA SYNTHESIS: Abacavir hypersensitivity is an immune-mediated reaction that typically occurs within the first 6 weeks of therapy. Signs and symptoms of abacavir HSR are nonspecific, which makes the diagnosis challenging, particularly in medically complex patients. Patch testing may improve the diagnosis and confirmation of abacavir HSR, but it remains experimental. Clinical management is aimed at supportive therapy and discontinuation of abacavir. Rechallenge with abacavir is contraindicated due to the risk of precipitating a life-threatening reaction. Appropriate patient education and a clear communication plan are essential for the safe use of this medication. Identification of patients at risk of developing abacavir hypersensitivity through routine genetic screening for human leukocyte antigen (HLA) HLA-B(*)5701 represents a significant advance in the field of pharmacogenomics, with an apparent 100% negative predictive value when used to screen for abacavir HSR. Preliminary data suggest that pharmacogenetic testing for HLA-B(*)5701 is cost effective. However, until routine testing is available, pharmacovigilance is necessary for the safe and effective use of abacavir. CONCLUSIONS: Serious adverse events associated with the use of abacavir can be avoided by appropriate recognition and management of the HSR. Screening patients for HLA-B(*)5701 prior to initiation of abacavir represents a tool to further decrease the risk of HSRs as well as unnecessary discontinuation of this drug.

Pharmaceutical care for HIV patients on directly observed therapy.

BACKGROUND: Inner-city patients infected with HIV can be a challenging group to treat. Homelessness, mental illness, substance abuse, and hepatitis C infection may serve as barriers to effective treatment. A multidisciplinary team including the pharmacist can impact upon the delivery of care to the inner-city HIV patient population. OBJECTIVE: To describe the implementation and provision of pharmaceutical care to inner-city patients taking directly observed therapy (DOT), as well as drug-related problems (DRPs) and their respective outcomes. METHODS: Pharmaceutical care, including the prospective identification and management of DRPs, was provided by a clinical pharmacist. RESULTS: Fifty-seven patients were followed over a 14-month period. Overall, 149 DRPs were identified and >95% were resolved. Those included (1) adverse effects (n = 56; gastrointestinal, central nervous system effects, allergies, laboratory abnormalities), (2) drug interactions (n = 32), (3) drugs indicated for comorbidities (n = 24; safety in pregnancy, tuberculosis, Pneumocystis carinii pneumonia prophylaxis, oral candidiasis, herpes zoster, nutritional supplements), (4) adherence issues (n = 20; altering timing of medication, changing formulation, decreasing pill burden), (5) drugs no longer indicated (n = 10; opportunistic infection prophylaxis, treatment of primary infection), and (6) dosage adjustment (n = 7) for weight and renal insufficiency. CONCLUSIONS: In the provision of pharmaceutical care to HIV-infected patients on DOT, an HIV pharmacist significantly contributed to antiretroviral selection, monitoring of drug therapy, and managing DRPs. An HIV pharmacist can assist in promoting patient adherence and improved outcomes in this setting.