Betty J. Dong

Center for the Advancement of Pharmacy Education 2013 Educational Outcomes

An initiative of the Center for the Advancement of Pharmacy Education (formerly the Center for the Advancement of Pharmaceutical Education) (CAPE), the CAPE Educational Outcomes are intended to be the target toward which the evolving pharmacy curriculum should be aimed. Their development was guided by an advisory panel composed of educators and practitioners nominated for participation by practitioner organizations. CAPE 2013 represents the fourth iteration of the Educational Outcomes, preceded by CAPE 1992, CAPE 1998 and CAPE 2004 respectively. The CAPE 2013 Educational Outcomes were released at the AACP July 2013 Annual meeting and have been revised to include 4 broad domains, 15 subdomains, and example learning objectives.

Raltegravir: The first HIV integrase inhibitor

BACKGROUND The availability of new classes of antiretroviral drugs has made it possible for HIV-infected individuals who are highly treatment experienced to achieve the goals of immunologic recovery and virologic suppression. Raltegravir is the first integrase inhibitor to be approved by the US Food and Drug Administration for use in antiretroviral treatment- experienced adult patients with viral resistance. OBJECTIVE This article reviews the pharmacology, pharmacokinetics, pharmacodynamics, efficacy, tolerability, resistance profile, drug interactions, and dosing and administration of raltegravir. METHODS Searches of MEDLINE and International Pharmaceutical Abstracts from 1964 to July 2008 were conducted using the terms integrase, raltegravir, and MK-0518. Relevant information was extracted from the identified clinical trials and review articles. Abstracts from the Conference on Retroviruses and Opportunistic Infections (1998-2008); Interscience Conference on Antimicrobial Agents and Chemotherapy (1999-2007); International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (2001-2007); and European AIDS Conference (2001-2007) were also searched. RESULTS Raltegravir blocks HIV replication by inhibiting essential strand-transfer activities of integrase. Raltegravir is rapidly absorbed, with a median T(max) of approximately 4 hours in the fasting state. No dose adjustment is recommended in patients with moderate renal or hepatic insufficiency, and raltegravir may be taken without regard to meals. In Phase II studies in treatment-naive patients, raltegravir had efficacy similar to that of standard initial therapies. In 2 interrelated Phase III clinical studies in treatment-experienced patients with drug-resistant disease, the addition of raltegravir to an optimized background regimen significantly lowered HIV RNA compared with optimized background treatment alone (62.1% vs 32.9%, respectively; P < 0.001). Raltegravir was generally well tolerated. The most common adverse effects reported in Phase II/III trials in treatment-experienced patients were diarrhea (16.6%), nausea (9.9%), and headache (9.7%). Cytochrome P450-related drug interactions are not expected, as raltegravir is not a CYP substrate, inducer, or inhibitor. However, to prevent failure of raltegravir, the drug should not be coadministered with rifampin. CONCLUSION Raltegravir is a potent and generally well tolerated antiretroviral agent that may play an important role in the treatment of patients harboring resistance to other antiretrovirals.

The impact of HIV clinical pharmacists on HIV treatment outcomes: a systematic review

Objective Due to the rapid proliferation of human immunodeficiency virus (HIV) treatment options, there is a need for health care providers with knowledge of antiretroviral therapy intricacies. In a HIV multidisciplinary care team, the HIV pharmacist is well-equipped to provide this expertise. We conducted a systematic review to assess the impact of HIV pharmacists on HIV clinical outcomes. Methods We searched six electronic databases from January 1, 1980 to June 1, 2011 and included all quantitative studies that examined pharmacist’s roles in the clinical care of HIV-positive adults. Primary outcomes were antiretroviral adherence, viral load, and CD4+ cell count and secondary outcomes included health care utilization parameters, antiretroviral modifications, and other descriptive variables. Results Thirty-two publications were included. Despite methodological limitation, the involvement of HIV pharmacists was associated with statistically significant adherence improvements and positive impact on viral suppression in the majority of studies. Conclusion This systematic review provides evidence of the beneficial impact of HIV pharmacists on HIV treatment outcomes and offers suggestions for future research.

Nevirapine pharmacokinetics and risk of rash and hepatitis among HIV-infected sub-Saharan African women.

Objectives:To estimate nevirapine (NVP) pharmacokinetics and examine its association with rash and/or hepatotoxicity in women starting antiretroviral treatment in the AIDS Clinical Trials Group A5208/OCTANE study in Africa. Design:In HIV-infected, nonpregnant women with screening CD4 cell count less than 200 cells/&mgr;l randomized to NVP (twice daily, after 14-day once-daily lead-in period) and tenofovir/emtricitabine, single NVP blood samples were collected 14 and 28 days following randomization. Rash and hepatotoxicity that occurred during therapy, or within 7 days after the last dose of NVP, were defined as toxicity. Methods:NVP pharmacokinetics were modeled by population pharmacokinetic analysis. Individual Bayesian pharmacokinetic estimates were used to calculate clearance, 24-h area under the curve, and predicted plasma concentrations. Results:Median week 4 NVP clearance was 2 l/h. Among the 359 women, 194 (54%) developed a rash of any grade; 82 (23%) had grade 2+ and nine (3%) had grade 3+ rash. Median clearance was 1.7 l/h for participants exhibiting 3+ rash versus 2 l/h in women without 3+ rash (P = 0.046). The odds of developing 3+ rash was 50% higher for every 20% decrease in clearance (P = 0.046). NVP discontinuation due to rash/liver toxicity was significantly more common among women with pretreatment CD4 cell count more than 250 cells/&mgr;l (P = 0.003). Conclusion:In this study, HIV-infected African women starting a NVP-based antiretroviral regimen had a lower NVP clearance compared to previous reports. Severe rash, but not hepatotoxicity, was associated with higher NVP exposure. Albeit observed in a small number of women, baseline CD4 cell count at least 250 cells/&mgr;l was significantly associated with NVP toxicity.

Low-Frequency Nevirapine (NVP)–Resistant HIV-1 Variants Are Not Associated With Failure of Antiretroviral Therapy in Women Without Prior Exposure to Single-Dose NVP

BACKGROUND Low-frequency nevirapine (NVP)-resistant variants have been associated with virologic failure (VF) of initial NVP-based combination antiretroviral therapy (cART) in women with prior exposure to single-dose NVP (sdNVP). We investigated whether a similar association exists in women without prior sdNVP exposure. METHODS Pre-cART plasma was analyzed by allele-specific polymerase chain reaction to quantify NVP-resistant mutants in human immunodeficiency virus-infected African women without prior sdNVP who were starting first-line NVP-based cART in the OCTANE/A5208 trial 2. Associations between NVP-resistant mutants and VF or death were determined and compared with published results from women participating in the OCTANE/A5208 trial 1 who had taken sdNVP and initiated NVP-based cART. RESULTS Pre-cART NVP-resistant variants were detected in 18% (39/219) of women without prior sdNVP exposure, compared to 45% (51/114) with prior sdNVP exposure (P < .001). Among women without prior sdNVP exposure, 8 of 39 (21%) with NVP-resistant variants experienced VF or death vs 31 of 180 (17%) without such variants (P = .65); this compares with 21 of 51 (41%) vs 9 of 63 (14%) among women with prior exposure (P = .001). CONCLUSIONS The risk of VF on NVP-based cART from NVP-resistant variants differs between sdNVP-exposed and -unexposed women. This difference may be driven by drug-resistance mutations emerging after sdNVP exposure that are linked on the same viral genome. CLINICAL TRIALS REGISTRATION NCT00089505.

Provision of clinical pharmacist services for individuals with chronic hepatitis C viral infection: Joint opinion of the GI/liver/nutrition and infectious diseases practice and research networks of the American College of Clinical Pharmacy

The objective of this opinion paper was to identify and describe potential clinical pharmacists’ services for the prevention and management of patients infected with the hepatitis C virus (HCV). The goals of this paper are to guide the establishment and development of pharmacy services for patients infected with HCV and to highlight HCV research and educational opportunities. Recommendations were based on the following: a review of published data on clinical pharmacist involvement in the treatment and management of HCV‐infected patients; a consensus of clinical pharmacists who provide direct patient care to HCV‐infected patients and practice in different pharmacy models, including community‐based and academic settings; and a review of published guidelines and literature focusing on the treatment and management of HCV infections. The recommendations provided in this opinion paper define the areas of clinical pharmacist involvement and clinical pharmacy practice in the treatment and management of patients with HCV. Clinical pharmacists can promote preventive measures and education about reducing HCV transmission, improve medication adherence, assist in monitoring clinical and adverse effects, recommend treatment strategies to minimize adverse effects and drug interactions, and facilitate medication acquisition and logistics that positively improve patient outcomes and reduce the health care system costs.

Tipranavir: A Protease Inhibitor for HIV Salvage Therapy

Objective: TO review the efficacy, safety, pharmacology, virology, pharmacokinetics, and resistance of the nonpeptidic protease inhibitor (PI) tipranavir. Data Sources and Study Selection: A PubMed search (1966–February 2006) was conducted using the key words tipranavir or PNU-140690, with the limitation of English-language reports. Pharmacokinetic and randomized clinical trials originating from major HIV conferences, such as the Conference on Retroviruses and Opportunistic Infections, International AIDS Society, European AIDS Conference, and Interscience Conference on Antimicrobial Agents and Chemotherapy, published only in abstract form, from 2000 to February 2006, were reviewed for relevance and included in this review. Data Synthesis: Phase III studies have shown that tipranavir is effective in the treatment of PI-resistant HIV compared with other PI-containing regimens. Adverse effects associated with tipranavir/ritonavir therapy include gastrointestinal reactions, hepatotoxicity, and elevations in cholesterol and triglyceride levels. Resistance data suggest that tipranavir/ritonavir should be reserved for salvage therapy in antiretroviral-experienced patients who have previously failed standard PI therapies. The potential for hepatotoxicity and drug interactions and the expense of tipranavir due to required ritonavir boosting may limit its widespread use. Conclusions: Tipranavir/ritonavir is an essential addition to the antiretroviral armamentarium for HIV-infected patients with limited treatment options.

Treatment of AIDS and HIV-related conditions--1997.

Extraordinary developments in antiretroviral therapy against the human immunodeficiency virus (HIV) have profoundly changed the way patients, their families, their physicians, and society now view HIV disease. Only one decade after discovery of the virus, new medications and pharmacologic strategies appear to be able to retard the proliferation of the virus and slow the progression of disease. Although long-term studies of the clinical impact of antiretroviral therapy are not yet available, all indications are that treatment of this chronic disease will be dramatically more promising during the next decade. The prospect of markedly slowing the progression of HIV disease and the acquired immunodeficiency syndrome (AIDS) challenges all clinicians to provide their patients with the most helpful guidance and the most effective therapies. These challenges include selecting antiretroviral strategies, offering prophylaxis against opportunistic infections, treating the major complications of AIDS, and providing comprehensive primary care. This Current Report-HIV is an update of our annual treatment guidelines. 1 It is based on our clinical experience at San Francisco General Hospital, a review of the medical literature, and experience gained from answering calls to our National HIV Telephone Consultation Service. Its purpose is to provide treatment recommendations for most of the medical problems of adults and adolescents with HIV disease and AIDS.

Hypothyroidism Resulting From Generic Levothyroxine Failure

In todays cost-conscious health care system, generic preparations should be prescribed whenever possible provided that safety and efficacy are not compromised. Several reports, however, suggest that generic levothyroxine may not always be interchangeable with the proprietary preparations. Such interchangeability is critical because patients are likely to receive different brands of levothyroxine during the life of their treatment. We report a case of severe hypothyroidism that developed in a patient who had been well controlled before receiving a generic levothyroxine preparation. Analysis of the patients tablet by high-pressure liquid chromatography showed that the levothyroxine content was approximately 30 percent less than its labeled content and outside current Food and Drug Administration (FDA) requirements. It is likely that poor tablet bioavailability was a contributory factor. Euthyroidism was achieved with the same dose of a more potent and possibly more bioavailable brand-name product. Until levothyroxine products become more uniform and the FDA confers therapeutic equivalence, product substitution with expense as the principal consideration should be avoided.

The Nonequivalence of Levothyroxine Products

I. STOFFER SS. Substitution of levothyroxine products (letter). JAMA 1979;241:1229. 2. STOFFER SS,SZPUNAR WE. Potency of brand name and generic levothyroxine products. JAMA 1980;244:1704-5. 3. REES-JONES RW. ROLLA AR. LARSEN PRo Hormonal content of thyroid replacement preparations. JAMA 1980;243:549-50. BETTY 1. DONG, Pharm.D. Associate Clinical Professor of Pharmacy School of Pharmacy and Clinical Pharmacist Thyroid Clinic University of California San Francisco, California 94143