Pros and cons of artificial intelligence implementation in diagnostic pathology.

The rapid introduction of digital pathology has greatly facilitated development of artificial intelligence (AI) models in pathology that have shown great promise in assisting morphological diagnostics and quantitation of therapeutic targets. We are now at a tipping point where companies have started to bring algorithms to the market, and questions arise whether the pathology community is ready to implement AI in routine workflow. However, concerns also arise about the use of AI in pathology. This article reviews the pros and cons of introducing AI in diagnostic pathology.

Navigating Human Immunodeficiency Virus and Primary Care Concerns Specific to the Transgender and Gender-Nonbinary Population.

Human immunodeficiency virus (HIV) prevention and treatment remain critically important to outpatient care among transgender and gender-nonbinary individuals. Epidemiologically, trans men and trans women are significantly more likely to have HIV compared with all adults of reproductive age. Here, we provide an overview of unique primary care considerations affecting transgender and gender-nonbinary individuals, including screening and treatment of HIV and other sexually transmitted infections as well as cancer screening and fertility preservation options. We also seek to review current literature and clinical practice guidelines related to drug-drug interactions between antiretroviral therapy (ART) and gender-affirming hormonal therapy (GAHT). In short, integrase strand transfer inhibitor-based therapy is not expected to have significant drug interactions with most GAHT and is preferred in most transgender individuals, including those on GAHT. Clinicians should also remain aware of current GAHT regimens and consider tailoring ART and GAHT to reduce cardiovascular and other risk factors.

Association of deranged cerebrovascular reactivity with brain injury following cardiac arrest: a post-hoc analysis of the COMACARE trial.

BACKGROUND: Impaired cerebrovascular reactivity (CVR) is one feature of post cardiac arrest encephalopathy. We studied the incidence and features of CVR by near infrared spectroscopy (NIRS) and associations with outcome and biomarkers of brain injury. METHODS: A post-hoc analysis of 120 comatose OHCA patients continuously monitored with NIRS and randomised to low- or high-normal oxygen, carbon dioxide and mean arterial blood pressure (MAP) targets for 48 h. The tissue oximetry index (TOx) generated by the moving correlation coefficient between cerebral tissue oxygenation measured by NIRS and MAP was used as a dynamic index of CVR with TOx > 0 indicating impaired reactivity and TOx > 0.3 used to delineate the lower and upper MAP bounds for disrupted CVR. TOx was analysed in the 0-12, 12-24, 24-48 h time-periods and integrated over 0-48 h. The primary outcome was the association between TOx and six-month functional outcome dichotomised by the cerebral performance category (CPC1-2 good vs. 3-5 poor). Secondary outcomes included associations with MAP bounds for CVR and biomarkers of brain injury. RESULTS: In 108 patients with sufficient data to calculate TOx, 76 patients (70%) had impaired CVR and among these, chronic hypertension was more common (58% vs. 31%, p = 0.002). Integrated TOx for 0-48 h was higher in patients with poor outcome than in patients with good outcome (0.89 95% CI [- 1.17 to 2.94] vs. - 2.71 95% CI [- 4.16 to - 1.26], p = 0.05). Patients with poor outcomes had a decreased upper MAP bound of CVR over time (p = 0.001), including the high-normal oxygen (p = 0.002), carbon dioxide (p = 0.012) and MAP (p = 0.001) groups. The MAP range of maintained CVR was narrower in all time intervals and intervention groups (p < 0.05). NfL concentrations were higher in patients with impaired CVR compared to those with intact CVR (43 IQR [15-650] vs 20 IQR [13-199] pg/ml, p = 0.042). CONCLUSION: Impaired CVR over 48 h was more common in patients with chronic hypertension and associated with poor outcome. Decreased upper MAP bound and a narrower MAP range for maintained CVR were associated with poor outcome and more severe brain injury assessed with NfL. Trial registration ClinicalTrials.gov, NCT02698917 .

Infectious Diseases Learning Unit: Understanding Advances in the Treatment of Latent Tuberculosis Infection Among People With Human Immunodeficiency Virus.

Tuberculosis (TB) remains the leading cause of death among people with human immunodeficiency virus (PWH). The diagnosis of latent TB infection (LTBI) and treatment with TB preventative therapy (TPT) can reduce morbidity and mortality in this population. Historically, isoniazid has been recommended for TPT in PWH due to the absence of drug-drug interactions with most antiretroviral therapy (ART). However, newer rifamycin-based regimens are safer, shorter in duration, associated with improved adherence, and may be as or more effective than isoniazid TPT. Current guidelines have significant heterogeneity in their recommendations for TPT regimens and acceptability of drug interactions with modern ART. In this Infectious Diseases learning unit, we review common questions on diagnosis, treatment, and drug interactions related to the management of LTBI among PWH.

Facteurs de risque d'éclosion de SRAS-CoV-2 dans les résidences pour aînés en Ontario, au Canada: étude de cohorte à l'échelle de la population.

CONTEXTE: L'épidémiologie de l'infection au SRAS-CoV-2 dans les résidences pour aînés (offrant une aide à la vie autonome), est pour une bonne part inconnue. Nous avons étudié le lien entre les caractéristiques des résidences et des communautés avoisinantes et le risque d'éclosion de SRAS-CoV-2 dans les résidences pour aînés depuis le début de la première vague de la pandémie de COVID-19. MÉTHODES: Nous avons procédé à une étude de cohorte rétrospective dans la population des résidences pour aînés certifiées en Ontario, au Canada, entre le 1er mars et le 18 décembre 2020. Notre paramètre principal était toute éclosion de SRAS-CoV-2 (≥ 1 cas confirmé parmi les résidents ou le personnel au moyen d'un test d'amplification des acides nucléiques). Nous avons utilisé la méthode des risques proportionnels avec prédicteurs chronologiques pour modéliser les liens entre les caractéristiques des résidences et des communautés avoisinantes et les éclosions de SRAS-CoV-2. RÉSULTATS: Notre cohorte a inclus l'ensemble des 770 résidences privées pour aînés (RPA) certifiées en Ontario qui hébergeaient 56 491 résidents. On a dénombré 273 (35,5 %) résidences pour aînés qui ont connu 1 éclosion de SRAS-CoV-2 ou plus; 1944 résidents (3,5 %) et 1101 employés (3,0 %) ont contracté l'infection. Ces cas étaient inégalement distribués entre les résidences. En effet, 2487 cas parmi les résidents et le personnel (81,7 %) sont survenus dans 77 résidences (10 %). Le rapport de risque ajusté d'une éclosion de SRAS-CoV-2 dans une résidence a été clairement associé aux établissements qui avaient une grande capacité d'accueil, qui comportaient des unités de soins de longue durée, qui appartenaient à de plus grandes bannières et offraient plusieurs services sur place, qui se trouvaient dans des régions marquées par une hausse de l'incidence régionale de SRAS-CoV-2 et où la concentration ethnique à l'échelle de la communauté était supérieure. INTERPRÉTATION: Certaines caractéristiques facilement identifiables des résidences pour aînés sont associées de manière indépendante aux éclosions de SRAS-CoV-2 et peuvent faciliter l'évaluation des risques et orienter la priorisation de la vaccination.

Risk factors for outbreaks of SARS-CoV-2 infection at retirement homes in Ontario, Canada: a population-level cohort study.

BACKGROUND: The epidemiology of SARS-CoV-2 infection in retirement homes (also known as assisted living facilities) is largely unknown. We examined the association between home-and community-level characteristics and the risk of outbreaks of SARS-CoV-2 infection in retirement homes since the beginning of the first wave of the COVID-19 pandemic. METHODS: We conducted a population-based, retrospective cohort study of licensed retirement homes in Ontario, Canada, from Mar. 1 to Dec. 18, 2020. Our primary outcome was an outbreak of SARS-CoV-2 infection (≥ 1 resident or staff case confirmed by validated nucleic acid amplification assay). We used time-dependent proportional hazards methods to model the associations between retirement home- and community-level characteristics and outbreaks of SARS-CoV-2 infection. RESULTS: Our cohort included all 770 licensed retirement homes in Ontario, which housed 56 491 residents. There were 273 (35.5%) retirement homes with 1 or more outbreaks of SARS-CoV-2 infection, involving 1944 (3.5%) residents and 1101 staff (3.0%). Cases of SARS-CoV-2 infection were distributed unevenly across retirement homes, with 2487 (81.7%) resident and staff cases occurring in 77 (10%) homes. The adjusted hazard of an outbreak of SARS-CoV-2 infection in a retirement home was positively associated with homes that had a large resident capacity, were co-located with a long-term care facility, were part of larger chains, offered many services onsite, saw increases in regional incidence of SARS-CoV-2 infection, and were located in a region with a higher community-level ethnic concentration. INTERPRETATION: Readily identifiable characteristics of retirement homes are independently associated with outbreaks of SARS-CoV-2 infection and can support risk identification and priority for vaccination.

Allogeneic bone marrow transplantation with post-transplant cyclophosphamide for patients with HIV and haematological malignancies: a feasibility study.

BACKGROUND: Allogeneic blood or marrow transplantation (alloBMT) is a potentially life-saving treatment for individuals with HIV and haematological malignancies; challenges include identifying donors and maintaining antiretroviral therapy (ART). The objectives of our study were to investigate interventions to expand donor options and to prevent ART interruptions for patients with HIV in need of alloBMT. METHODS: This single-arm, interventional trial took place at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center (Baltimore, MD, USA). Individuals with HIV who were at least 18 years of age and referred for alloBMT for a standard clinical indication were eligible. The only exclusion criterion was a history of documented resistance to enfuvirtide. We used post-transplant cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis to expand donor options and an optimised ART strategy of avoiding pharmacoenhancers and adding subcutaneous enfuvirtide during post-transplant cyclophosphamide and during oral medication intolerance. Our primary outcome was the proportion of participants who maintained ART through day 60 after alloBMT. We measured the HIV latent reservoir using a quantitative viral outgrowth assay. This study is registered on ClinicalTrials.gov, NCT01836068. FINDINGS: Between June 1, 2013, and August 27, 2015, nine patients who were referred for transplant provided consent. Two patients had relapsed malignancy before donor searches were initiated. Seven patients had suitable donors identified (two matched sibling, two matched unrelated, two haploidentical, and one single-antigen mismatched unrelated) and proceeded to alloBMT. All patients maintained ART through day 60 and required ART changes (median 1, range 1-3) in the first 90 days. One patient stopped ART and developed HIV rebound with grade 4 meningoencephalitis at day 146. Among six patients who underwent alloBMT and had longitudinal measurements available, the HIV latent reservoir was not detected post-alloBMT in four patients with more than 95% donor chimerism, consistent with a 2·06-2·54 log10 reduction in the HIV latent reservoir. In the two patients with less than 95% donor chimerism, the HIV latent reservoir remained stable. INTERPRETATION: By using post-transplant cyclophosphamide as GVHD prophylaxis, we successfully expanded alloBMT donor options for patients with HIV. Continuing ART with a regimen that includes enfuvirtide post-alloBMT was safe, but life-threatening viral rebound can occur with ART interruption. FUNDING: amfAR (the Foundation for AIDS Research), Johns Hopkins University Center for AIDS Research, and National Cancer Institute.

Development and Validation of HIV-ASSIST, an Online, Educational, Clinical Decision Support Tool to Guide Patient-Centered ARV Regimen Selection.

BACKGROUND: Multiple antiretroviral (ARV) regimens are effective at achieving HIV viral suppression, but differ in pill burden, side effects, barriers to resistance, and impact on comorbidities. Current guidelines advocate for an individualized approach to ARV regimen selection, but synthesizing these modifying factors is complex and time-consuming. METHODS: We describe the development of HIV-ASSIST (https://www.hivassist.com), a free, online decision support tool for ARV selection and HIV education. HIV-ASSIST ranks potential ARV options for any given patient scenario using a composite objective of achieving viral suppression while maximizing tolerability and adherence. We used a multiple-criteria decision analysis framework to construct mathematical algorithms and synthesize various patient-specific (eg, comorbidities and treatment history) and virus-specific (eg, HIV mutations) attributes. We then conducted a validation study to evaluate HIV-ASSIST with prescribing practices of experienced HIV providers at 4 large academic centers. We report on concordance of provider ARV selections with the 5 top-ranked HIV-ASSIST regimens for 10 diverse hypothetical patient-case scenarios. RESULTS: In the validation cohort of 17 experienced HIV providers, we found 99% concordance between HIV-ASSIST recommendations and provider ARV selections for 4 case-scenarios of ARV-naive patients. Among 6 cases of ARV-experienced patients (3 with and 3 without viremia), there was 84% and 88% concordance, respectively. Among 3 cases of ARV-experienced patients with viremia, providers reported 20 different ARV selections, suggesting substantial heterogeneity in ARV preferences in clinical practice. CONCLUSIONS: HIV-ASSIST is a novel patient-centric educational decision support tool that provides ARV recommendations concordant with experienced HIV providers for a diverse set of patient scenarios.

Cerebrovascular autoregulation following cardiac arrest: Protocol for a post hoc analysis of the randomised COMACARE pilot trial.

BACKGROUND: Approximately two-thirds of the mortality following out of hospital cardiac arrest is related to devastating neurological injury. Previous small cohort studies have reported an impaired cerebrovascular autoregulation following cardiac arrest, but no studies have assessed the impact of differences in oxygen and carbon dioxide tensions in addition to mean arterial pressure management. METHODS: This is a protocol and statistical analysis plan to assess the correlation between changes in cerebral tissue oxygenation and arterial pressure as measure of cerebrovascular autoregulation, the tissue oxygenation index, in patients following out of hospital cardiac arrest and in healthy volunteers. The COMACARE study included 120 comatose survivors of out of hospital cardiac arrest admitted to ICU and managed with low-normal or high-normal targets for mean arterial pressure, arterial oxygen and carbon dioxide partial pressures. In addition, 102 healthy volunteers have been investigated as a reference group for the tissue oxygenation index. In both cohorts, the cerebral tissue oxygenation was measured by near infrared spectroscopy. CONCLUSIONS: Cerebrovascular autoregulation is critical to maintain homoeostatic brain perfusion. This study of changes in autoregulation following out of hospital cardiac arrest over the first 48 hours, as compared to data from healthy volunteers, will generate important physiological information that may guide the rationale and design of interventional studies.

Noninvasive Monitoring of Dynamic Cerebrovascular Autoregulation and 'Optimal Blood Pressure' in Normal Adult Subjects.

BACKGROUND: Cerebrovascular autoregulation can be continuously monitored from slow fluctuations of arterial blood pressure (ABP) and regional cerebral oxygen saturation (rSO2). The purpose of this study was to evaluate the index of dynamic cerebrovascular autoregulation (TOx) and the associated 'optimal' ABP in normal adult healthy subjects. METHODS: Twenty-eight healthy volunteers were studied. TOx was calculated as the moving correlation coefficient between spontaneous fluctuations of ABP and rSO2. ABP was measured with the Finometer photoplethysmograph. The ABP with optimal autoregulation (ABPOPT) was also determined as the ABP level with the lowest associated TOx (opt-TOx). RESULTS: Average rSO2 and TOx was 72.3 ± 2.9% and 0.05 ± 0.18, respectively. Two subjects had impaired autoregulation with a TOx > 0.3. The opt-TOx was - 0.1 ± 0.26. ABPOPT was 87.0 ± 16.7 mmHg. The difference between ABP and ABPOPT was - 0.3 ± 7.5 mmHg. In total, 44% of subjects had a deviation of ABP from ABPOPT exceeding 5 mmHg. ABPOPT ranged from 57 to 117 mmHg. CONCLUSIONS: TOx in healthy volunteers on average displays intact autoregulation and ABP close to ABPOPT. However, some subjects have possible autoregulatory dysfunction or a significant deviation of ABP from ABPOPT, which may confer a susceptibility to neurological injury.

Effectiveness of the McKenzie Method of Mechanical Diagnosis and Therapy for Treating Low Back Pain: Literature Review With Meta-analysis.

Study Design Literature review with meta-analysis. Background The McKenzie Method of Mechanical Diagnosis and Therapy (MDT), a classification-based system, was designed to classify patients into homogeneous subgroups to direct treatment. Objectives To examine the effectiveness of MDT for improving pain and disability in patients with either acute (less than 12 weeks in duration) or chronic (greater than 12 weeks in duration) low back pain (LBP). Methods Randomized controlled trials examining MDT in patients with LBP were identified from 6 databases. Independent investigators assessed the studies for exclusion, extracted data, and assessed risk of bias. The standardized mean difference (SMD) and 95% confidence interval were calculated to compare the effects of MDT to those of other interventions in patients with acute or chronic LBP. Results Of the 17 studies that met the inclusion criteria, 11 yielded valid data for analysis. In patients with acute LBP, there was no significant difference in pain resolution (P = .11) and disability (P = .61) between MDT and other interventions. In patients with chronic LBP, there was a significant difference in disability (SMD, -0.45), with results favoring MDT compared to exercise alone. There were no significant differences between MDT and manual therapy plus exercise (P>.05) for pain and disability outcomes. Conclusion There is moderate- to high-quality evidence that MDT is not superior to other rehabilitation interventions for reducing pain and disability in patients with acute LBP. In patients with chronic LBP, there is moderate- to high-quality evidence that MDT is superior to other rehabilitation interventions for reducing pain and disability; however, this depends on the type of intervention being compared to MDT. Level of Evidence Therapy, level 1a. J Orthop Sports Phys Ther 2018;48(6):476-490. Epub 30 Mar 2018. doi:10.2519/jospt.2018.7562.

Is impaired cerebrovascular autoregulation associated with outcome in patients admitted to the ICU with early septic shock?

OBJECTIVE: To investigate the correlation between early changes in cerebrovascular autoregulation (CVAR) and neurological outcome and mortality in patients admitted to the intensive care unit with septic shock. DESIGN, SETTING AND PARTICIPANTS: A prospective observational study in a tertiary, university-affiliated ICU, of 28 patients with septic shock (median age, 66 years; interquartile range [IQR], 56-74 years), with a median APACHE III score of 86 (IQR, 55-119). MAIN OUTCOME MEASURES: We used the correlation in time between cerebral tissue oxygenation (measured with near infrared spectroscopy) and mean arterial pressure to determine the tissue oxygenation reactivity index (TOx) as a measure of CVAR. Low TOx represents intact CVAR and high TOx represents impaired CVAR. We performed the measurements in the first 3 days after admission to the ICU. Survival and neurological outcomes, measured using the modified Rankin Scale and the Cerebral Performance Category scale, were censored 3 months later. RESULTS: All survivors of septic shock had a good neurological outcome. The TOx for Days 1-3 was higher (P < 0.001) in non-survivors (median, 0.04 [IQR, 0.12- 0.24]) compared with survivors (median, -0.02 [IQR, -0.13 to 0.05]). The TOx was independently associated with survival at 3 months (odds ratio, 0.13 [95% CI, 0.01-0.69]; P < 0.05) using logistic regression analysis. CONCLUSIONS: CVAR is impaired early in septic shock and is independently associated with mortality at 3-month follow-up. Information based on bedside monitoring of CVAR in the ICU could form a valuable adjunct to guide haemodynamic optimisation in patients with septic shock.

Non-invasive Monitoring of Dynamic Cerebrovascular Autoregulation Using Near Infrared Spectroscopy and the Finometer Photoplethysmograph.

BACKGROUND: Near infrared spectroscopy (NIRS) enables continuous monitoring of dynamic cerebrovascular autoregulation, but this methodology relies on invasive blood pressure monitoring (iABP). We evaluated the agreement between a NIRS based autoregulation index calculated from invasive blood pressure monitoring, and an entirely non-invasively derived autoregulation index from continuous non-invasive blood pressure monitoring (nABP) using the Finometer photoplethysmograph. METHODS: Autoregulation was calculated as the moving correlation coefficient between iABP and rSO2 (iTOx) or nABP and rSO2 (nTOx). The blood pressure range where autoregulation is optimal was also determined for invasive (iABPOPT) and non-invasive blood pressure measurements (nABPOPT). RESULTS: 102 simultaneous bilateral measurements of iTOx and nTOx were performed in 19 patients (median 2 per patient, range 1-9) with different acute pathologies (sepsis, cardiac arrest, head injury, stroke). Average iTOx was 0.01 ± 0.13 and nTOx was 0.01 ± 0.11. The correlation between iTOx and nTOx was r = 0.87, p < 0.001, 95 % agreement ± 0.12, bias = 0.005. The interhemispheric asymmetry of autoregulation was similarly assessed with iTOx and nTOx (r = 0.81, p < 0.001). Correlation between iABPOPT and nABPOPT was r = 0.47, p = 0.003, 95 % agreement ± 32.1 mmHg, bias = 5.8 mmHg. Coherence in the low frequency spectrum between iABP and nABP was 0.86 ± 0.08 and gain was 1.32 ± 0.77. CONCLUSIONS: The results suggest that dynamic cerebrovascular autoregulation can be continuously assessed entirely non-invasively using nTOx. This allows for autoregulation assessment using spontaneous blood pressure fluctuations in conditions where iABP is not routinely monitored. The nABPOPT might deviate from iABPOPT, likely because of discordance between absolute nABP and iABP readings.

Are changes in cerebrovascular autoregulation following cardiac arrest associated with neurological outcome? Results of a pilot study.

PURPOSE: To investigate the association between impaired cerebrovascular autoregulation (CVAR) and outcome in comatose survivors of cardiac arrest. METHODS: The correlation in the time domain between cerebral tissue oxygenation (cStO2) using near infrared spectroscopy (NIRS) and mean arterial pressure was used to determine the tissue oxygenation index (TOx) as a reflection of normal (TOx<0) or impaired (TOx>0) CVAR. Daily measurements (>1h recording time) were performed in the first three days post cardiac arrest. Survival and neurological outcome was assessed at three months following cardiac arrest. A control group of healthy volunteers was also investigated. RESULTS: 23 patients and 28 volunteers were studied. All survivors (n=8) of cardiac arrest had a good neurological outcome. The TOx (median [interquartile range] for days 1-3) was higher (Mann Whitney test, p<0.001) in non-survivors (0.04 [-0.02 to -0.16]) compared to survivors (-0.11 [-0.19 to -0.02]) and healthy volunteers (-0.15 [-0.27 to -0.04]) on every day and for days 1-3 following cardiac arrest. The TOx was not significantly different between survivors and healthy volunteers. The cStO2 did not discriminate survivors (67 [62-72]%) from non-survivors (71 [65-75]%). Logistic regression analysis demonstrated TOx to be independently associated with survival at three months post cardiac arrest (odds ratio [95% confidence interval] 0.01 [0.01-0.50], p=0.04). CONCLUSIONS: Early impairment of CVAR following cardiac arrest is independently associated with mortality at three months follow-up. Assessments of CVAR could add to the management and prognostication during post-resuscitation care and should be further investigated as a guide to optimise cerebral perfusion pressure.

A Review of the Toxicity of HIV Medications II: Interactions with Drugs and Complementary and Alternative Medicine Products.

For many patients today, HIV has become a chronic disease. For those patients who have access to and adhere to lifelong antiretroviral (ARV) therapy, the potential for drug-drug interactions has become a real and life-threatening concern. It is known that most ARV drug interactions occur through the cytochrome P450 (CYP) pathway. Medications for comorbid medical conditions, holistic supplements, and illicit drugs can be affected by CYP inhibitors and inducers and have the potential to cause harm and toxicity. Protease inhibitors (PIs) tend to inhibit CYP3A4, while most non-nucleoside reverse transcriptase inhibitors (NNRTIs) tend to induce the enzyme. As such, failure to adjust the dose of co-administered medications, such as statins and steroids, may lead to serious complications including rhabdomyolysis and hypercortisolism, respectively. Similarly, gastric acid blockers can decrease several ARV absorption, and warfarin doses may need to be adjusted to maintain therapeutic concentrations. Illicit drugs such as methylenedioxymethamphetamine (MDMA, "ecstasy") in combination with PIs lead to increased toxicity, while the concomitant administration of sedative drugs such as midazolam and alprazolam in patients taking PIs can result in prolonged sedation, delayed recovery, and increased length of stay. Even supplements like St. John's Wort can alter PI concentrations. In theory, any drug that is metabolized by CYP has potential for a pharmacokinetic drug-drug interaction with all PIs, cobicistat, and most NNRTIs. When adding a new medication to an ARV regimen, use of a drug-drug interaction software and/or consultation with a clinical pharmacist/pharmacologist or HIV specialist is recommended.

Clinical practice guideline for the management of chronic kidney disease in patients infected with HIV: 2014 update by the HIV Medicine Association of the Infectious Diseases Society of America.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

A review of the toxicity of HIV medications.

Antiretroviral therapy has changed human immunodeficiency virus (HIV) infection from a near-certainly fatal illness to one that can be managed chronically. More patients are taking antiretroviral drugs (ARVs) for longer periods of time, which naturally results in more observed toxicity. Overdose with ARVs is not commonly reported. The most serious overdose outcomes have been reported in neonates who were inadvertently administered supratherapeutic doses of HIV prophylaxis medications. Typical ARV regimens include a "backbone" of two nucleoside reverse transcriptase inhibitors (NRTI) and a "base" of either a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor. New classes of drugs called entry inhibitors and integrase inhibitors have also emerged. Older NRTIs were associated with mitochondrial toxicity, but this is less common in the newer drugs, emtricitabine, lamivudine, and tenofovir. Mitochondrial toxicity results from NRTI inhibition of a mitochondrial DNA polymerase. Mitochondrial toxicity manifests as myopathy, neuropathy, hepatic failure, and lactic acidosis. Routine lactate assessment in asymptomatic patients is not indicated. Lactate concentration should be obtained in patients taking NRTIs who have fatigue, nausea, vomiting, or vague abdominal pain. Mitochondrial toxicity can be fatal and is treated by supportive care and discontinuing NRTIs. Metabolic cofactors like thiamine, carnitine, and riboflavin may be helpful in managing mitochondrial toxicity. Lipodystrophy describes changes in fat distribution and lipid metabolism that have been attributed to both PIs and NRTIs. Lipodystrophy consists of loss of fat around the face (lipoatrophy), increase in truncal fat, and hypertriglyceridemia. There is no specific treatment of lipodystrophy. Clinicians should be able to recognize effects of chronic toxicity of ARVs, especially mitochondrial toxicity.

Antiretroviral treatment strategies in highly treatment experienced perinatally HIV-infected youth.

BACKGROUND: There is limited information on antiretroviral (ARV) regimens and outcomes in perinatally HIV (PHIV)-infected youth. Substantial drug resistance after long-term ARV use and nonadherence hinder efforts to design suppressive regimens for PHIV-infected youth. This study compares clinical outcomes by expected activity of the prescribed ARV regimens. METHODS: A retrospective cohort study of 13- to 24-year-old PHIV-infected youth on stable ARV regimens for ≥6 months was conducted at a pediatric HIV clinic. ARV regimens were retrospectively categorized as optimal or suboptimal based on accumulated genotypic resistance before study regimen initiation. RESULTS: Fifty-two patients with similar baseline characteristics met inclusion criteria (21 optimal and 31 suboptimal regimens). Patients receiving optimal regimens had significantly higher increases in CD4 than those given suboptimal regimens by week 48 of treatment (+62 versus +8 cells/mm, respectively; P = 0.04) and by the end of study period (+93 versus -1 cells/mm, respectively; P = 0.03). There were no significant differences between the groups in decline of viral load, frequency of opportunistic infections or hospitalizations or accumulation of resistance mutations. Overall, 60% of the optimal and 45% of the suboptimal groups had nonadherence during the study regimen (P = 0.3). CONCLUSIONS: PHIV-infected youth receiving optimal regimens had greater CD4 improvements but no difference in virologic outcomes compared with those receiving suboptimal regimens. In a patient population with significant nonadherence, providers must weigh the immunologic benefits of initiating an optimal regimen versus the potential risks of further resistance accumulation limiting future treatment options.

Antiretroviral therapy adherence and drug-drug interactions in the aging HIV population.

It is estimated that by 2015 more than half of all HIV-infected individuals in the United States will be 50 years of age or older. As this population ages, the frequency of non-AIDS related comorbidities increases, which includes cardiovascular, metabolic, gastrointestinal, genitourinary and psychiatric disorders. As a result, medical management of the aging HIV population can be complicated by polypharmacy and higher pill burden, leading to poorer antiretroviral therapy (ART) adherence. Adherence to ART is generally better in older populations when compared to younger populations; however, cognitive impairment in elderly patients can impair adherence, leading to worse treatment outcomes. Practical monitoring tools can improve adherence and increase rates of viral load suppression. Several antiretroviral drugs exhibit inhibitory and/or inducing effects on cytochrome P450 isoenzymes, which are responsible for the metabolism of many medications used for the treatment of comorbidities in the aging HIV population. The combination of ART with polypharmacy significantly increases the chance of potentially serious drug-drug interactions (DDIs), which can lead to drug toxicity, poorer ART adherence, loss of efficacy of the coadministered medication, or virologic breakthrough. Increasing clinicians awareness of common DDIs and the use of DDI programs can prevent coadministration of potentially harmful combinations in elderly HIV-infected individuals. Well designed ART adherence interventions and DDI studies are needed in the elderly HIV population.