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Because HIV medications are used in combination, it is important to develop multiplex assays to streamline the therapeutic drug monitoring process and provide rapid turnaround. This article reports full validation of an analytical method that combines atazanavir with 6 HIV-protease inhibitors (indinavir, amprenavir, saquinavir, nelfinavir, ritonavir, and lopinavir) and 2 nonnucleoside reverse transcriptase inhibitors (nevirapine and efavirenz). Using 200 microL of plasma and a simple liquid-liquid extraction method, this analytical method achieved a clean baseline and high extraction efficiencies (90.0% to 99.5%). A Zorbax C-18 (150 x 4.6 mm, 3.5 microm) analytical column was used along with a 27-minute linear gradient elution of the mobile phase to provide sharp peaks at 210 nm. This method was validated over a range of 25 to 10,000 ng/mL and is accurate (90.4% to 110.5%) and precise (precision within a day and between days ranged from 2.3% to 8.3%). Because this method is simple and inexpensive, it may have applicability in countries with low resources.

IntroductionDiarrhea poses a substantial burden for patients with human immunodeficiency virus (HIV), negatively impacting quality-of-life (QoL) and adherence to antiretroviral therapy. During the combination antiretroviral therapy (cART) era, as incidence of opportunistic infection as a cause of diarrhea decreased, incidence of noninfectious diarrhea (including diarrhea as an adverse event [AE] of cART and HIV enteropathy) increased proportionately. A literature search was conducted for information on prevalence, etiology, and treatment options for noninfectious diarrhea in patients with HIV.ResultsFor marketed antiretroviral therapies, up to 28% of patients live with >4 loose or watery stools per day. The US Food and Drug Administration (FDA) does not require pharmaceutical manufacturers to include, within approved prescribing information, prevalence rates for all grades of diarrhea. Traditionally, noninfectious diarrhea management focused on avoiding use of diarrhea-associated cART; symptom management (nonpharmacologic and/or pharmacologic); and, as a last resort, changing cART. Examining the evidence upon which this approach is based reveals that most strategies rely upon anecdotal information and case reports. This review summarizes the literature and updates clinicians on the most recent options for management of noninfectious diarrhea in patients with HIV.ConclusionDiarrhea in patients with HIV is a significant unmet clinical need that contributes to worsening QoL and complicates medical management. Approaching management using a stepwise method of nonpharmacologic (diet), nonprescription (over-the-counter) and, finally, prescription agent changes (modification of cART or addition of an evidence-based antidiarrheal) appears reasonable, despite a lack of clear scientific evidence to support the initial two steps of this approach. If diet modifications, including psyllium and fiber introduction, fail to resolve noninfectious diarrhea in patients with HIV, loperamide followed by crofelemer should be considered. Clinicians are encouraged to review the most recent literature, not rely upon prescribing information. Continued vigilance by HIV providers to the presence of gastrointestinal AEs, even in patients taking the most recently approved antiretroviral agents, is warranted. Additional research is justified in identifying the etiology and management of HIV-associated diarrhea in patients on successful cART regimens.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-014-0047-5) contains supplementary material, which is available to authorized users.

Secretory diarrhea is a leading cause of morbidity and mortality worldwide. Crofelemer is a first-in-class antidiarrheal agent that simultaneously targets two distinct channels, the cystic fibrosis conductance regulator and calcium-activated chloride channel, responsible for chloride and fluid secretion in the GI tract. Crofelemer is a novel compound extracted from the stem bark latex of the Croton lechleri tree found in the western Amazonian region of South America. There is little to no systemic absorption of crofelemer when given orally and studies have shown minimal toxicity beyond mild gastrointestinal effects. In studies in diarrheal illness associated with primarily a secretory component, such as cholera, travelers' diarrhea and acute infectious diarrhea, crofelemer has shown improvements in stool consistency and duration of symptoms. Less clear, but interesting, results have been observed in other diarrheal diseases associated with a mixed pathology, including diarrhea in patients with HIV and diarrhea-predominant irritable bowel syndrome.

We investigated the impact of germline CYP2D6 genotyping done using the non-tumor specimen on endoxifen concentrations and/or clinical outcomes in breast cancer (BC) patients treated with tamoxifen in published studies. We evaluated published data from 13 001 patients in 29 studies. Mean±s.d. endoxifen concentrations were significantly lower in poor metabolizers (PM) versus extensive metabolizers (EM) (8.8±7.2 versus 22.3±11.8 ng ml; P<0.05). The PM status did not influence clinical outcomes in majority of the studies. However, only one study followed the Gaedigk activity scoring for phenotypic assignments, which predicted recurrence-free survival in CYP2D6 poor metabolizers. In two independent studies with 1676 patients, low endoxifen concentrations predicted poor BC-free survival. From our review of published data we found that standardization of CYP2D6 genotype-phenotype classification is needed in order to ensure effective evaluation of associations between CYP2D6 polymorphisms and endoxifen concentrations and BC outcomes. Universal implementation of this standardization classification system should be a priority among researchers and laboratories. Furthermore, additional clinical research is warranted to determine whether patients with CYP2D6 PM phenotypes or low endoxifen levels will have better clinical outcomes with increased tamoxifen dosing compared to standard dosing.

We evaluated the prevalence of serum 25-hydroxyvitamin D [25(OH)D] deficiency and the risk factors for vitamin D deficiency in HIV-infected patients in the South-Central United States. The study consisted of a cross-sectional assessment of vitamin D levels in HIV-infected patients receiving routine clinical care from a private practice in Houston, Texas (latitude 29°N). Vitamin D deficiency was defined as 25(OH)D less than 20 ng/ml (<50 nmol/liter). Two-hundred enrolled patients were surveyed with a vitamin D questionnaire to determine daily supplemental vitamin D intake, dietary vitamin D intake, and average sunlight exposure (minutes/day). Multivariate logistic regression analysis was used to determine significant risk factors for vitamin D deficiency. Median 25(OH)D was 15.5 ng/ml (interquartile range 10.9-24.6) for the total population (n=200). Approximately, two-thirds (64%) of patients had vitamin D deficiency and 20.5% had severe vitamin D deficiency [25(OH)D <10 ng/ml or <25 nmol/liter]. In univariate analysis, African-American race, current tobacco use, increased body mass index (BMI), lower serum calcium level, no supplemental vitamin D use, and low daily supplemental and total daily vitamin D intake were significantly associated with vitamin D deficiency. In multivariate analysis, African-American race [adjusted odds ratio (AOR) 3.53 (95% confidence interval (CI) 1.83-6.82)], higher BMI [AOR 1.07 (95% CI 1.002-1.139)], and low daily vitamin D supplemental intake [AOR 0.997 (95% CI 0.996-0.999)] were significantly associated with vitamin D deficiency. No HIV factors including antiretroviral class use were significantly associated with either vitamin D deficiency or severe vitamin D deficiency. Vitamin D deficiency and severe vitamin D deficiency were highly prevalent in this HIV population. In the HIV population, African-Americans or patients with a high BMI may benefit from vitamin D supplementation.

Crofelemer possesses a novel mechanism of action that shows promise in treating secretory diarrhea of several etiologies. However, results from further Phase 3 clinical trials are still needed in order to fully evaluate the efficacy and safety of this agent.

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