Effect of Rifabutin in Dolutegravir Dosing: A Case Series.

Background: Tuberculosis (TB) is the leading cause of death in human immunodeficiency virus (HIV)-infected people worldwide. Currently there are no studies examining the use of Rifabutin (RBN) and Dolutegravir (DTG) in co-infected persons. This is a case series of 4 co-infected patients receiving both agents who underwent Pharmacokinetic (PK) analysis. Methods and Results: This is a retrospective chart review study of four patients diagnosed with both HIV and TB, receiving RBN and DTG and undergoing therapeutic drug monitoring. All 4 cases had lower than expected DTG concentrations at least once, including those on the current recommended dose of DTG with RBN, and even those receiving higher doses. Conclusions: Given the frequency of low DTG and RBN concentrations, therapeutic drug monitoring (TDM) for these drugs is advisable. Prospective clinical studies are needed to further determine the PK interactions between RBN and DTG, and virologic response to treatment.

Cardiovascular disease and prevention among people living with HIV in South Florida.

ABSTRACT: Antiretroviral therapy (ART) has improved survival of patients living with HIV (PLWH); however, this has been accompanied by an increase in cardiovascular disease (CVD). Although preventative measures for CVD among the general population are well described, information is limited about CVD prevention among PLWH. The goal of this study was to characterize the prevalence of CVD in our population and to assess the use of primary and secondary prevention.We performed a retrospective review of PLWH receiving primary care at a large academic center in Miami, Florida. We characterized the prevalence of CVD, CVD risk, and the use of aspirin and statins for primary and secondary CVD prevention.A total of 985 charts were reviewed (45% women, 55% men). Average age was 52.2 years. Average CD4 count was 568 cells/microL. 92.9% were receiving ART, and 71% were virologically suppressed. The median 10-year ASCVD risk was 7.3%. The prevalence of CVD was 10.4% (N = 102). The odds of having CVD was lower in patients on ART (OR 0.47, 95% CI: 0.25-0.90, P = .02). The use of medications for primary and secondary prevention of CVD based on current guidelines was low: 15% and 37% for aspirin respectively, and 25% and 44% for statins.CVD risk and rates of CVD are high among PLWH and receiving ART could protect against CVD. However, the use of medications for primary and secondary prevention is low. Increased awareness of CVD risk-reduction strategies is needed among providers of PLWH to decrease the burden of CVD.

Evaluation of super-boosted lopinavir/ritonavir in combination with rifampicin in HIV-1-infected patients with tuberculosis.

Rifampicin induces the metabolism of many drugs. To overcome the reduction in serum concentrations of lopinavir/ritonavir (LPV/r) when used in combination with rifampicin, 800/200 mg or 400/400 mg doses are used. This study evaluated super-boosted LPV/r (400/400 mg) in HIV/TB co-infected patients for adequate concentrations as well as short-term safety, tolerability and clinical response to therapy. This was an open-label, non-randomised pharmacokinetic (PK) study in HIV/TB patients. The primary objective was to determine the PK profile of super-boosted LPV/r when given with a rifampicin-based TB regimen. Secondary objectives were short-term safety, tolerability and clinical response. Primary endpoints were a lopinavir trough concentration (Cmin) >1.0 µg/mL and a rifampicin maximum concentration (Cmax) of 8-24 µg/mL. Secondary PK endpoints were a rifampicin area under the concentration-time curve from 0-24 h (AUC0-24) of 44-70 µg·h/mL, a lopinavir Cmax of 6-14 µg/mL and a lopinavir AUC0-12 of 56-130 µg·h/mL. Eleven patients (10 male, age 25-43 years) were enrolled. Two patients were discontinued due to non-compliance. A lopinavir Cmin of >1.0 µg/mL was achieved in a least one of the PK samplings in all nine subjects who completed treatment. All patients met lopinavir Cmax and AUC0-12 targets. Five patients achieved the primary endpoint of rifampicin Cmax (≥8 µg/mL) in at least one of the PK samplings, and five achieved the minimum rifampicin AUC0-24 (≥44 µg·h/mL). One grade 3 adverse event was reported. Super-boosted LPV/r was safe and effective in HIV/TB patients. [ClinicalTrials.gov ID NCT01700790.].

Internal Medicine Residents' Knowledge and Practice of Pulmonary Tuberculosis Diagnosis.

BACKGROUND: Internal medicine physicians are often the first providers to encounter patients with a new diagnosis of tuberculosis. Given the public health risks of missed tuberculosis cases, assessing internal medicine residents' ability to diagnose tuberculosis is important. METHODS: Internal medicine resident knowledge and practice patterns in pulmonary tuberculosis diagnosis at 7 academic hospitals were assessed utilizing (a) a 10-item validated pulmonary tuberculosis diagnosis assessment tool and (b) a retrospective chart review of 343 patients who underwent a pulmonary tuberculosis evaluation while admitted to a resident-staffed internal medicine or infectious disease service. Our primary outcomes were the mean score and percentage of correct responses per assessment tool question, and the percentage of patients who had Centers for Disease Control and Prevention-recommended tuberculosis diagnostic tests obtained. RESULTS: Of the 886 residents who received the assessment, 541 responded, yielding a response rate of 61%. The mean score on the assessment tool (SD) was 4.4 (1.6), and the correct response rate was 57% (311/541) or less on 9 of 10 questions. On chart review, each recommended test was obtained for ≤43% (148/343) of patients, other than chest x-ray (328/343; 96%). A nucleic acid amplification test was obtained for 18% (62/343) of patients, whereas 24% (83/343) had only 1 respiratory sample obtained. Twenty patients were diagnosed with tuberculosis. CONCLUSIONS: Significant knowledge and practice gaps exist in internal medicine residents' abilities to diagnose tuberculosis. As residents represent the future providers who will be evaluating patients with possible tuberculosis, such deficiencies must be addressed.

Developing an Assessment Framework for Essential Internal Medicine Subspecialty Topics.

BACKGROUND: Assessing residents by direct observation is the preferred assessment method for infrequently encountered subspecialty topics, but this is logistically challenging. OBJECTIVE: We developed an assessment framework for internal medicine (IM) residents in subspecialty topics, using tuberculosis diagnosis for proof of concept. METHODS: We used a 4-step process at 8 academic medical centers that entailed (1) creating a 10-item knowledge assessment tool; (2) pilot testing on a sample of 129 IM residents and infectious disease fellow volunteers to evaluate validity evidence; (3) implementing the final tool among 886 resident volunteers; and (4) assessing outcomes via retrospective chart review. Outcomes included tool score, item performance, and rates of obtaining recommended diagnostics. RESULTS: Following tool development, 10 infectious disease experts provided content validity. Pilot testing showed higher mean scores for fellows compared with residents (7 [SD = 1.8] versus 3.8 [SD = 1.7], respectively, P < .001) and a satisfactory Kuder-Richardson Formula 20 (0.72). Implementation of the tool revealed a 14-minute (SD = 2.0) mean completion time, 61% (541 of 886) response rate, 4.4 (SD = 1.6) mean score, and ≤ 57% correct response rate for 9 of 10 items. On chart review (n = 343), the rate of obtaining each recommended test was ≤ 43% (113 of 261), except for chest x-rays (96%, 328 of 343). CONCLUSIONS: Our assessment framework revealed knowledge and practice gaps in tuberculosis diagnosis in IM residents. Adopting this approach may help ensure assessment is not limited to frequently encountered topics.

Abuse and mental health concerns among HIV-infected Haitian women living in the United States.

This study describes the prevalence of abuse and mental health issues among a cohort of HIV-infected Haitian women living in the United States. We present data on 96 women, ages 19-73 years (M = 47.6, SD = 11.1), who were screened for mental health concerns between 2009 and 2012. Results demonstrated that 12.5% of the women reported a history of abuse. However, posttraumatic stress disorder (PTSD) secondary to HIV was reported by approximately 34% of women. Depression and anxiety were also highly reported, with rates of 49% and 43%, respectively. Women who reported a history of abuse were more likely to report anxiety, PTSD, and PTSD related to HIV symptoms than those without. Our findings suggest that Haitian HIV-infected women may underreport abuse and experience significant depression and anxiety. These preliminary results could be used to develop future studies and to design and implement culturally sensitive interventions for this underserved population.

Pharmacokinetic evaluation of rifabutin in combination with lopinavir-ritonavir in patients with HIV infection and active tuberculosis.

BACKGROUND: Human immunodeficiency virus (HIV)-associated tuberculosis is difficult to treat, given the propensity for drug interactions between the rifamycins and the antiretroviral drugs. We examined the pharmacokinetics of rifabutin before and after the addition of lopinavir-ritonavir. METHODS: We analyzed 10 patients with HIV infection and active tuberculosis in a state tuberculosis hospital. Plasma was collected for measurement of rifabutin, the microbiologically active 25-desacetyl-rifabutin, and lopinavir by validated high-performance liquid chromatography assays. Samples were collected 2-4 weeks after starting rifabutin at 300 mg thrice weekly without lopinavir-ritonavir, 2 weeks after the addition of lopinavir-ritonavir at 400 and 100 mg, respectively, twice daily to rifabutin at 150 mg thrice weekly, and (if rifabutin plasma concentrations were below the normal range) 2 weeks after an increase in rifabutin to 300 mg thrice weekly with lopinavir-ritonavir. Noncompartmental and population pharmacokinetic analyses (2-compartment open model) were performed. RESULTS: Rifabutin at 300 mg without lopinavir-ritonavir produced a low maximum plasma concentration (C(max)) in 5 of 10 patients. After the addition of lopinavir-ritonavir to rifabutin at 150 mg, 9 of 10 had low C(max) values. Eight patients had dose increases to 300 mg of rifabutin with lopinavir-ritonavir. Most free rifabutin (unbound to plasma protein) C(max) values were below the tuberculosis minimal inhibitory concentration. For most patients, values for the area under the plasma concentration-time curve were as low or lower than those associated with treatment failure or relapse and with acquired rifamycin resistance in Tuberculosis Trials Consortium/US Public Health Service Study 23. One of the 10 patients experienced relapse with acquired rifamycin resistance. CONCLUSION: The recommended rifabutin doses for use with lopinavir-ritonavir may be inadequate in many patients. Monitoring of plasma concentrations is recommended.

Concurrent PCP and TB pneumonia in HIV infected patients.

We aimed to assess the incidence and clinical characteristics of patients with HIV infection with concurrent Pneumocystis pneumonia (PCP) and tuberculosis (TB). We carried out a retrospective record review of HIV infected patients admitted with pulmonary TB and PCP during the same hospital admission at a large county hospital in Miami, from 1995 to 2004. 2651 patients with HIV infection and possible TB or PCP were identified. There were 99 cases of PCP (81 presumptive and 18 confirmed) and 35 were new cases of TB. There were 17 patients who had a new, concurrent diagnosis of pulmonary TB and PCP. Approximately half of these patients were unaware of their HIV infections and half of them had a negative AFB in sputum. Most were men and had a CD4 count less than 100 cells/mm(3). Chest X-ray disclosed bilateral infiltrates in most of the cases. All but 2 survived the hospital admission. Thus, concurrent TB and PCP in HIV infected patients were not uncommon in this large county hospital in Miami, Florida in the studied period, but its diagnosis was challenging.

Human immunodeficiency virus type 1 pharmacogenomics in clinical practice: relevance of HIV-1 drug resistance testing (Part 2).

Throughout most of the past century, physicians could offer patients no treatments for infections caused by viruses. The experience with treatment of infection by human immunodeficiency virus (HIV) has changed the way healthcare workers deal with viral infections and has triggered a growing rate of discovery and use of antiviral agents, the first fruits of the expanding genomics revolution. HIV treatment also provides an informative paradigm for pharmacogenomics because control of infection and its consequences is limited by the development of viral drug resistance and by host factors. This report summarizes studies published to date on the significance of testing of HIV-1 resistance to antiretroviral drugs. The only Food and Drug Administration-approved kit is commercially available through Visible Genetics, Inc., for HIV drug resistance testing by genotypic sequencing. Genotyping sequencing alone is most likely an adequate test to assist in the therapeutic decision-making process in cases of previous regimen failure, treatment-naïve patients in areas of high prevalence of transmitted resistant virus, and pregnant women. However, in exceptional cases of highly complex mutation patterns and extensive cross-resistance, it may be useful to obtain a phenotype test, because that result may more easily identify drugs to which the virus is least resistant. There are no published clinical trial results on the usefulness of the so-called virtual phenotype over genotypic sequencing alone. The paradigm of viral pharmacogenomics in the form of HIV genotypic sequencing has been not only useful to the treatment of other viral diseases but also important to the real-life implementation of the growing discipline of genomics or molecular medicine. The application of this paradigm to the thousands of potential therapeutic targets that have become available through the various human genome projects will certainly gradually change the landscape of diagnosis and management of many diseases, including cancer.

Insulin levels measured with an insulin-specific assay in patients with fasting hypoglycaemia related to endogenous hyperinsulinism.

OBJECTIVE: The finding of insulin levels above a minimum threshold at the time of symptomatic hypoglycaemia is crucial in the diagnosis of endogenous hyperinsulinism. The aim of this study was to evaluate insulin levels at the time of hypoglycaemia with an insulin-specific assay in such patients. DESIGN AND METHODS: We measured insulin levels in 15 patients with fasting hypoglycaemia related to endogenous hyperinsulinism using an insulin-specific immunoradiometric assay (IRMA) without any significant cross-reaction with intact proinsulin. RESULTS: Insulin levels were below 6 mIU/l in all the samples taken at the time of symptomatic hypoglycaemia in 6/15 patients, and in some of the samples in three patients; insulin levels were below 3 mIU/l in samples from 5 patients. C-peptide levels were above 0.6 ng/ml in all these samples. The lowest proinsulin level was 35 pmol/l. Insulin levels were measured with a less specific RIA (40% cross-reaction with proinsulin) in 8/15 patients and were above 6 mIU/l in all samples in seven patients, and all but one sample in the 8th patient. Mean concomitant C-peptide and insulinoma size were lower in those patients with insulin-IRMA levels below 6 mIU/l. CONCLUSION: Symptomatic hypoglycaemia below 0.45 g/l can result from insulin levels below 6 or even 3 mIU/l; lower insulin levels and secretion could be observed preferentially in small insulinomas. If an insulin assay devoid of any significant cross-reaction with intact proinsulin is employed, measuring C-peptide (and/or proinsulin) levels at the time of symptomatic hypoglycaemia is mandatory to make the diagnosis of endogenous hyperinsulinism.

Human immunodeficiency virus type 1 pharmacogenomics in clinical practice: relevance of HIV-1 drug resistance testing (Part 1).

Throughout most of the past century, physicians could offer patients no treatments for infections caused by viruses. The experience with treatment of infection by human immunodeficiency virus (HIV) has changed the way healthcare workers deal with viral infections and has triggered a growing rate of discovery and use of antiviral agents, the first fruits of the expanding genomics revolution. HIV treatment also provides an informative paradigm for pharmacogenomics because control of infection and its consequences is limited by the development of viral drug resistance and by host factors. This report summarizes studies published to date on the significance of testing of HIV-1 resistance to antiretroviral drugs. The only Food and Drug Administration-approved kit for HIV drug resistance testing by genotypic sequencing is commercially available through Visible Genetics, Inc. Genotyping sequencing alone is most likely an adequate test to assist in the therapeutic decision-making process for previous regimen failure, for treatment-naïve patients in areas of high prevalence of transmitted resistant virus, and for pregnant women. However, in exceptional cases of highly complex mutation patterns and extensive cross-resistance, it may be useful to obtain a phenotype test, because that result may more easily identify drugs to which virus is least resistant. There are no published clinical trials results on the usefulness of the so-called virtual phenotype over genotypic sequencing alone. Not only has the paradigm of viral pharmacogenomics in the form of HIV genotypic sequencing been useful in treating other viral diseases, but it is also important to the real-life implementation of the growing discipline ofgenomics or molecular medicine. The application of this paradigm to the thousands of potential therapeutic targets that have become available through the various human genome projects will certainly gradually change the landscape of diagnosis and management of many diseases, including cancer.