[Rhabdomyolysis and severe hepatotoxicity due to a drug-drug interaction between ritonavir and simvastatin. Could we use the most cost-effective statin in all human immunodeficiency virus-infected patients?]. / Rabdomiólisis y hepatotoxicidad grave por interacción entre ritonavir y simvastatina. ¿Puede emplearse la estatina más coste-efectiva en todos los pacientes infectados por el virus de la inmunodeficiencia humana?

INTRODUCTION: Drugs like statins may induce rhabdomyolysis. Simvastatin and lovastatin have a high hepatic metabolism and their potential toxicity could be increased by interactions with other drugs that reduce their metabolism. PATIENTS AND METHODS: A case-report is presented of an HIV-infected patient treated with antiretroviral drugs who developed a rhabdomyolysis-induced renal failure and liver toxicity when simvastatin was substituted for atorvastatin. A literature review is also presented. RESULTS: The patient required hospital admission and showed a favorable response after hydration and urine alkalinization. There were 4 additional cases published of which there was one death. CONCLUSIONS: Drug-drug interactions can increase the risk of statin induced rhabdomyolysis. In order to evaluate them properly, physicians at all levels of clinical care should be aware of all drugs prescribed to their patients and the contraindicated combinations.

Co-administration of rimonabant prevents glucose intolerance in Sprague-Dawley rats treated chronically with lopinavir/ritonavir and zidovudine: an experimental study design.

Introduction: treatment of HIV infection with Protease Inhibitors (PIs) and Nucleoside Reverse Transcriptase Inhibitors (NRTIs) can lead to insulin resistance and changes in body fat distribution. Overactivity of the endogenous cannabinoid system produces similar disturbances in metabolic syndrome within the general population. However, Cannabinoid receptor type 1 antagonism, in both human and animal studies, reverses many of these biochemical and physical derangements observed in the metabolic syndrome. Methods: using an experimental study design, fifteen adult male Sprague-Dawley rats housed under standard conditions were randomized into three groups; Control, combined Anti-Retroviral Therapy (cART) only and cART + rimonabant. Drugs were administered daily by oral gavage for four weeks. After four weeks, insulin tolerance tests were conducted, the rats were euthanised and fat depots were excised and weighed. Experimental data were analysed using STATA 16.0 with the significance level set at p<0.05. The Shapiro-Wilk test determined normalcy. In cases of significance, post hoc analysis was performed by either the Dunn test or the Tukey HSD test. Results: Sprague Dawley rats treated with cART + rimonabant demonstrated better insulin sensitivity (p = 0.0239) and lower body weight (p = 0.044) than rats treated with cART alone. They had leaner body composition with 58% less adiposity than cART-only rats. Conclusion: the study results suggest a role for the endogenous cannabinoid system in cART induced metabolic derangements and physical changes. Future studies can directly assay ECS activity in cART associated metabolic syndrome.

Evidence and speculations: vaccines and therapeutic options for COVID-19 pandemic.

A novel coronavirus (2019-nCov) emerged in China, at the end of December 2019 which posed an International Public Health Emergency, and later declared as a global pandemic by the World Health Organization (WHO). The International Committee on Taxonomy of Viruses (ICTV) named it SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2), while the disease was named COVID-19 (Coronavirus Disease- 2019). Many questions related to the exact mode of transmission, animal origins, and antiviral therapeutics are not clear yet. Nevertheless, it is required to urgently launch a new protocol to evaluate the side effects of unapproved vaccines and antiviral therapeutics to accelerate the clinical application of new drugs. In this review, we highlight the most salient characteristics and recent findings of COVID-19 disease, molecular virology, interspecies mechanisms, and health consequences related to this disease.

Guidance on Minimizing Risk of Drug-Induced Ventricular Arrhythmia During Treatment of COVID-19: A Statement from the Canadian Heart Rhythm Society.

The COVID-19 pandemic has led to efforts at rapid investigation and application of drugs which may improve prognosis but for which safety and efficacy are not yet established. This document attempts to provide reasonable guidance for the use of antimicrobials which have uncertain benefit but may increase risk of QT interval prolongation and ventricular proarrhythmia, notably, chloroquine, hydroxychloroquine, azithromycin, and lopinavir/ritonavir. During the pandemic, efforts to reduce spread and minimize effects on health care resources mandate minimization of unnecessary medical procedures and testing. We recommend that the risk of drug proarrhythmia be minimized by 1) discontinuing unnecessary medications that may also increase the QT interval, 2) identifying outpatients who are likely to be at low risk and do not need further testing (no history of prolonged QT interval, unexplained syncope, or family history of premature sudden cardiac death, no medications that may prolong the QT interval, and/or a previous known normal corrected QT interval [QTc]), and 3) performing baseline testing in hospitalized patients or those who may be at higher risk. If baseline electrocardiographic testing reveals a moderately prolonged QTc, optimization of medications and electrolytes may permit therapy. If the QTc is markedly prolonged, drugs that further prolong it should be avoided, or expert consultation may permit administration with mitigating precautions. These recommendations are made while there are no known effective treatments for COVID-19 and should be revisited when further data on efficacy and safety become available.

Protecting the fetus against HIV infection: a systematic review of placental transfer of antiretrovirals.

BACKGROUND: Maternal-to-fetal transfer of antiretroviral drugs contributes to prevention of vertical transmission of HIV. OBJECTIVE: This systematic review discusses published studies containing data pertaining to the pharmacokinetics of placental transfer of antiretrovirals in humans, including paired cord and maternal plasma samples collected at the time of delivery as well as ex vivo placental perfusion models. METHODS: Articles pertaining to placental transfer of antiretrovirals were identified from PubMed, from references of included articles, and from US Department of Health and Human Services Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission guidelines. Articles from non-human animal models or that had no original maternal-to-fetal transfer data were excluded. PRISMA guidelines were followed. RESULTS: A total of 103 published studies were identified. Data across studies appeared relatively consistent for the nucleoside reverse transcriptase inhibitors (NRTIs) and the non-nucleotide reverse transcriptase inhibitors (NNRTIs), with cord to maternal ratios approaching 1 for many of these agents. The protease inhibitors atazanavir and lopinavir exhibited consistent maternal-to-fetal transfer across studies, although the transfer may be influenced by variations in drug-binding proteins. The protease inhibitors indinavir, nelfinavir, and saquinavir exhibited unreliable placental transport, with cord blood concentrations that were frequently undetectable. Limited data, primarily from case reports, indicate that darunavir and raltegravir provide detectable placental transfer. CONCLUSION: These findings appear consistent with current guidelines of using two NRTIs plus an NNRTI, atazanavir/ritonavir, or lopinavir/ritonavir to maximize placental transfer as well as to optimally suppress maternal viral load. Darunavir/ritonavir and raltegravir may reasonably serve as second-line agents.

Inhaled corticosteroids in persons with HIV infection: not that harmless.

There is a growing group of HIV-seropositive patients at risk for chronic lung disease due to their life style and age. The interaction between certain antiretroviral drugs and corticosteroid inhalation therapy is potentially dangerous but often unrecognised. We present three cases from our HIV-clinic of whom two developed full blown Cushing's syndrome over a short period of time and one presented with asymptomatic hypocortisolaemia due to serious drug interactions between HIV-drugs and inhaled corticosteroids. General practitioners, HIV and chest physicians should all be aware of this potentially life-threatening interaction and the combination of those products should be avoided where possible.

High-sensitivity C-reactive protein levels fall during statin therapy in HIV-infected patients receiving ritonavir-boosted protease inhibitors.

HIV-infected patients are at an increased risk of developing cardiovascular disease. Elevated levels of C-reactive protein (CRP) are associated with an increased risk of cardiovascular disease in the general population and are reduced by statin therapy. We examined the effect of pravastatin and rosuvastatin on CRP levels in 58 dyslipidemic HIV-infected patients. A 45-day course of either statin reduced the median CRP level from 3.0 to 2.4 mg/l (P < 0.001) with no correlation with changes in lipid parameters.

Non-occupational postexposure prophylaxis for HIV: a systematic review.

OBJECTIVES: To review the evidence on the clinical effectiveness and cost-effectiveness of non-occupational postexposure prophylaxis (PEP) for HIV. DATA SOURCES: Eleven electronic databases were searched from inception to December 2007. REVIEW METHODS: Selected studies were assessed, subjected to data extraction using a standard template and quality assessment using published criteria. Studies were synthesised using a narrative approach with full tabulation of results from all included studies. RESULTS: One clinical effectiveness study meeting the inclusion criteria was identified, a cohort study of PEP in a high-risk HIV-negative homosexual male cohort in Brazil. The quality of the study was generally weak. Seroincidence in the cohort as a whole (2.9 per 100 person-years) was very similar to that expected in this population (3.1 per 100 person-years, p > 0.97), despite the seroconversion to HIV being 1/68 in the PEP group and 10/132 in the group not receiving PEP. High-risk sexual activities declined over time for both PEP and non-PEP users. Four economic evaluations met the inclusion criteria of the review. The methodological quality of the studies was mixed. The studies are constrained by a lack of published data on the clinical effectiveness of PEP after non-occupational exposure, with effectiveness data derived from one study of occupational PEP. Their generalisability to the UK is not clear. Results suggest that PEP following non-occupational exposure to HIV was cost saving for men who have unprotected receptive anal intercourse with men, whether the source partner is known to be HIV positive or not; heterosexuals after unprotected receptive anal intercourse; and intravenous drug users sharing needles with a known HIV-positive person. PEP following non-occupational exposure to HIV was cost-effective for all male-male intercourse (unprotected receptive and insertive anal intercourse, unprotected receptive oral sex, and 'other') and was possibly cost-effective for intravenous drug users and high-risk women. Four additional studies were identified giving further information about adverse events associated with PEP after non-occupational exposure to HIV. The majority of participants experienced adverse events with the most common being nausea and fatigue. Rates were generally higher in participants receiving triple therapy than in participants receiving dual therapy. Completion of PEP therapy was variable, ranging from 24% to 78% of participants depending on type of therapy. Toxicity was the main reason for discontinuation of treatment. CONCLUSIONS: It is not possible to draw conclusions on the clinical effectiveness of non-occupational PEP for HIV because of the limited evidence available. The review of cost-effectiveness suggests that non-occupational PEP may be cost-effective, especially in certain population subgroups; however, the assumptions made and data sources used in the cost-effectiveness studies mean that their results should be used with caution.

Patient preferences among third agent HIV medications: a US and German perspective.

The objective is to assess patient preferences for attributes associated with third agent HIV medications, including fosamprenavir/ritonavir (FPVr), fosamprenavir (FPV), lopinavir/ritonavir (LPVr), atazanavir (ATZ), and efavirenz (EFV). Subjects with HIV were recruited in the US and Germany to complete a computerized adaptive conjoint survey that assessed 13 attributes, including moderate to severe side effects, regimen convenience, drug resistance and efficacy. Literature on the target third-agent HIV drugs was used to identify percentage risk and severity level descriptions for each attribute. The derived preference (utility) weights for each attribute level informed the calculation of relative importance estimates for each attribute and the desirability of combinations of attributes matching the respective target third agents. The analysis included 288 HIV-positive participants (US: 132; Germany: 156), 205 of whom were treatment-experienced and 83 of whom were treatment-naïve. Of the 13 medication attributes evaluated, developing drug resistance, the risk of lipodystrophy, the risk of gastronitestinal side effects (diarrhoea, nausea and vomiting) and regimen convenience had the greatest impact on preferences. The profile based on FPVr was most preferred. Differences in the risk of developing drug resistance, risk of lipodystrophy, risk of gastrointestinal side effects and regimen convenience would likely be most influential in the perceived relative value of a third-agent medication. Physicians may wish to consider these features, especially when discussing HIV treatment options with their patients.