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The Journal of Antimicrobial... Jul 2017HIV-1 subtype C might have a greater propensity to develop K65R mutations in patients with virological failure compared with other subtypes. However, the strong...
OBJECTIVES
HIV-1 subtype C might have a greater propensity to develop K65R mutations in patients with virological failure compared with other subtypes. However, the strong association between viral subtype and confounding factors such as exposure groups and ethnicity affects the calculation of this propensity. We exploited the diversity of viral subtypes within the UK to undertake a direct comparative analysis.
PATIENTS AND METHODS
We analysed only sequences with major IAS-defined mutations from patients with virological failure. Prevalence of K65R was related to subtype and exposure to the NRTIs that primarily select for this mutation (tenofovir, abacavir, didanosine and stavudine). A multivariate logistic regression model quantified the effect of subtype on the prevalence of K65R, adjusting for previous and current exposure to all four specified drugs.
RESULTS
Subtype B patients ( n = 3410) were mostly MSM (78%) and those with subtype C ( n = 810) were mostly heterosexual (82%). K65R was detected in 7.8% of subtype B patients compared with 14.2% of subtype C patients. The subtype difference in K65R prevalence was observed irrespective of NRTI exposure and K65R was frequently selected by abacavir, didanosine and stavudine in patients with no previous exposure to tenofovir. Multivariate logistic regression confirmed that K65R was significantly more common in subtype C viruses (adjusted OR = 2.02, 95% CI = 1.55-2.62, P < 0.001).
CONCLUSIONS
Patients with subtype C HIV-1 have approximately double the frequency of K65R in our database compared with other subtypes. The exact clinical implications of this finding need to be further elucidated.
Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Female; Genetic Association Studies; Genotype; HIV Infections; HIV-1; Humans; Male; Multivariate Analysis; Mutation; Reverse Transcriptase Inhibitors; Sequence Analysis, DNA; Stavudine; Tenofovir
PubMed: 28379449
DOI: 10.1093/jac/dkx091 -
PloS One 2017Understanding the mechanisms of drug resistance can facilitate better management of antiretroviral therapy, helping to prevent transmission and decrease the morbidity...
BACKGROUND
Understanding the mechanisms of drug resistance can facilitate better management of antiretroviral therapy, helping to prevent transmission and decrease the morbidity and mortality of people living with HIV/AIDS. However, there is little data about transmitted drug resistance and acquired drug resistance for HIV/AIDS patients in Shanghai.
METHODS
A retrospective cohort study of HIV-infected patients who visited the Department of Infectious Disease from June 2008 to June 2015 was conducted in Shanghai, China. Logistic regression analysis was performed to analyze risk factors for drug resistance among HIV-infected people with virological failure. The related collected factors included patient age, gender, marital status, infection route, baseline CD4 count, antiretroviral therapy regimens, time between HIV diagnosis and initiating antiretroviral therapy. Factors with p<0.1 in the univariate logistic regression test were analyzed by multivariate logistic regression test.
RESULTS
There were 575 subjects selected for this study and 369 participated in this research. For the antiretroviral therapy drugs, the rates of transmitted drug resistance and acquired drug resistance were significantly different. The non-nucleoside reverse transcriptase inhibitor (NNRTI) had the highest drug resistance rate (transmitted drug resistance, 10.9%; acquired drug resistance, 53.3%) and protease inhibitors (PIs) had the lowest drug resistance rate (transmitted drug resistance, 1.7%; acquired drug resistance, 2.7%). Logistic regression analysis found no factors that were related to drug resistance except marital status (married status for tenofovir: odds ratio = 6.345, 95% confidence interval = 1.553-25.921, P = 0.010) and the time span between HIV diagnosis and initiating antiretroviral therapy (≤6M for stavudine: odds ratio = 0.271, 95% confidence interval = 0.086-0.850, P = 0.025; ≤6M for didanosine: odds ratio = 0.284, 95% confidence interval = 0.096-0.842, P = 0.023; ≤6M for tenofovir: odds ratio = 0.079, 95% confidence interval = 0.018-0.350,P<0.001).
CONCLUSION
NNRTI had a higher DR rate compared with nucleoside reverse transcriptase inhibitor (NRTI) and PIs, consequently, LPV/r was a reasonable choice for patients with NNRTI drugs resistance in China. Only married status and a time span≤6 month between the HIV confirmed date and the time initiating antiretroviral therapy were risk factors for TDF drug resistance. Both baseline HIV-RNA load and resistance test is crucial for TDR diagnosis, and frequent monitoring of HIV-RNA load is crucial for ADR identification and intervention. Treatment adherence still plays a positive role on the outcome of ART.
Topics: Adult; Antiviral Agents; China; Drug Resistance, Viral; Female; HIV Infections; Humans; Male; Middle Aged
PubMed: 28187212
DOI: 10.1371/journal.pone.0165110 -
HIV Medicine Sep 2017Single nucleotide polymorphisms in the cytochrome P450 (CYP) 2B6 gene have been associated with high interindividual variation in efavirenz pharmacokinetics. However,... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Single nucleotide polymorphisms in the cytochrome P450 (CYP) 2B6 gene have been associated with high interindividual variation in efavirenz pharmacokinetics. However, clinical data on the relationship of CYP2B6 polymorphisms with the occurrence of efavirenz-induced central nervous system (CNS) symptoms are limited.
METHODS
We analysed four polymorphisms in the CYP2B6 (516 G>T), CYP3A5 (6986 A>G) and ATP-binding cassette, sub-family B, member 1 (ABCB1) (2677 G>T/A and 3435 C>T) genes in HIV-infected adults virologically suppressed on a protease inhibitor-based regimen who switched to a regimen containing emtricitabine, didanosine and efavirenz in the setting of the ANRS ALIZE trial. Kaplan-Meier methods and Cox regression analysis were used to investigate their association with efavirenz plasma levels and CNS events up to 48 months after switching.
RESULTS
In total, 191 patients with a median age of 41 years, who were 87% male and 85% Caucasian, were enrolled in the study. Variant allelic frequencies were 0.49, 0.93, 0.59 and 0.63 for CYP2B6 516, CYP3A5 392, ABCB1 2677 and ABCB1 3435, respectively. The median efavirenz plasma concentration (MEPC) was 2.2 mg/L [interquartile range (IQR) 1.7-2.8 mg/L] and was significantly higher in patients with the deficient CYP2B6 516T. Overall, 242 CNS events were reported in 104 individuals (54%). No correlation was found between MEPC and CNS events. The occurrence of a first CNS event was lower in patients with the CYP2B6 516 G/G genotype vs. CYP2B6 516 T genotypes [50% (IQR: 40-60%) vs. 66% (IQR: 56-75%), respectively; P = 0.02]. In an adjusted Cox regression model, there was a tendency towards a higher risk of a first CNS event among carriers of the variant CYP2B6 516 T allele (relative risk 1.4 [95% CI, 0.99-2.1]; P?=?.06), compared with noncarriers.
CONCLUSIONS
The deficient CYP2B6 516 T allele is associated with higher efavirenz plasma drug levels and more frequent CNS-related symptoms.
Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Central Nervous System Diseases; Cyclopropanes; Cytochrome P-450 CYP2B6; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Genetic Predisposition to Disease; HIV Infections; Humans; Male; Middle Aged; Plasma; Polymorphism, Single Nucleotide
PubMed: 28145050
DOI: 10.1111/hiv.12488 -
The Journal of Infection May 2017Tenofovir disoproxil fumarate (TDF) is widely used in the treatment or prevention of HIV and hepatitis B infection. TDF may cause renal tubulopathy in a small proportion... (Observational Study)
Observational Study
OBJECTIVES
Tenofovir disoproxil fumarate (TDF) is widely used in the treatment or prevention of HIV and hepatitis B infection. TDF may cause renal tubulopathy in a small proportion of recipients. We aimed to study the risk factors for developing severe renal tubulopathy.
METHODS
We conducted an observational cohort study with retrospective identification of cases of treatment-limiting tubulopathy during TDF exposure. We used multivariate Poisson regression analysis to identify risk factors for tubulopathy, and mixed effects models to analyse adjusted estimated glomerular filtration rate (eGFR) slopes.
RESULTS
Between October 2002 and June 2013, 60 (0.4%) of 15,983 patients who had received TDF developed tubulopathy after a median exposure of 44.1 (IQR 20.4, 64.4) months. Tubulopathy cases were predominantly male (92%), of white ethnicity (93%), and exposed to antiretroviral regimens that contained boosted protease inhibitors (PI, 90%). In multivariate analysis, age, ethnicity, CD4 cell count and use of didanosine or PI were significantly associated with tubulopathy. Tubulopathy cases experienced significantly greater eGFR decline while receiving TDF than the comparator group (-6.60 [-7.70, -5.50] vs. -0.34 [-0.43, -0.26] mL/min/1.73 m/year, p < 0.0001).
CONCLUSIONS
Older age, white ethnicity, immunodeficiency and co-administration of ddI and PI were risk factors for tubulopathy in patients who received TDF-containing antiretroviral therapy. The presence of rapid eGFR decline identified TDF recipients at increased risk of tubulopathy.
Topics: Adult; Anti-HIV Agents; Female; Glomerular Filtration Rate; HIV Infections; Humans; Kidney Diseases; Male; Middle Aged; Tenofovir
PubMed: 28130143
DOI: 10.1016/j.jinf.2017.01.010 -
World Journal of Hepatology Dec 2016To identify significant liver disease [including nodular regenerative hyperplasia (NRH)] in asymptomatic Didanosine (DDI) exposed human immunodeficiency virus (HIV)...
AIM
To identify significant liver disease [including nodular regenerative hyperplasia (NRH)] in asymptomatic Didanosine (DDI) exposed human immunodeficiency virus (HIV) positive patients.
METHODS
Patients without known liver disease and with > 6 mo previous DDI use had liver stiffness assessed by transient elastography (TE). Those with alanine transaminase (ALT) above upper limit normal and/or TE > 7.65 kPa underwent ultrasound scan (U/S). Patients with: (1) abnormal U/S; or (2) elevated ALT plus TE > 7.65 kPa; or (3) TE > 9.4 kPa were offered trans-jugular liver biopsy (TJLB) with hepatic venous pressure gradient (HVPG) assessment.
RESULTS
Ninety-nine patients were recruited, median age 50 years (range 31-70), 81% male and 70% men who have sex with men. Ninety-five percent with VL < 50 copies on antiretroviral therapy with median CD4 count 639 IU/L. Median DDI exposure was 3.4 years (range 0.5-14.6). Eighty-one had a valid TE readings (interquartile range/score ratio < 0.3): 71 (88%) < 7.65 kPa, 6 (7%) 7.65-9.4 kPa and 4 (6%) > 9.4 kPa. Seventeen (17%) met criteria for TJLB, of whom 12 accepted. All had HVPG < 6 mmHg. Commonest histological findings were steatosis ( = 6), normal architecture ( = 4) and NRH ( = 2), giving a prevalence of previously undiagnosed NRH of 2% (95%CI: 0.55%, 7.0%).
CONCLUSION
A screening strategy based on TE, liver enzymes and U/S scan found a low prevalence of previously undiagnosed NRH in DDI exposed, asymptomatic HIV positive patients. Patients were more likely to have steatosis highlighting the increased risk of multifactorial liver disease in this population.
PubMed: 28083085
DOI: 10.4254/wjh.v8.i36.1623 -
Medical Mycology Journal 2016The risk of invasive fungal infections (IFIs) is extremely high in patients with hematological malignancies due to the prolonged and profound neutropenia and... (Review)
Review
The risk of invasive fungal infections (IFIs) is extremely high in patients with hematological malignancies due to the prolonged and profound neutropenia and immunosuppression after chemotherapy and hematopoietic stem cell transplantation. There has been increasing interest in mucormycosis despite its relatively uncommon occurrence, because occasional breakthrough infections have been observed under anti-aspergillus prophylaxis. The aggressive nature of mucormycosis easily leads to high mortality because of delays in diagnosis and incorrect treatment decisions, which are due in part to lack of adjunctive diagnostic tools and having similar clinical and radiological features with aspergillosis. The only currently available antifungals against Mucorales in Japan are amphotericin B formulations. Thus, comprehensive therapeutic strategies, including surgery, should be considered in order to achieve a successful outcome.
Topics: Amphotericin B; Didanosine; Early Diagnosis; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Lung Diseases, Fungal; Mucormycosis; Neutropenia; Risk; Surgical Procedures, Operative
PubMed: 27904061
DOI: 10.3314/mmj.16.006 -
The Pediatric Infectious Disease Journal Mar 2017There are few data on gynecomastia in HIV-infected children. Within the UK/Ireland's national cohort, 56 of 1873 (3%) HIV-infected children had gynecomastia, of which 10...
There are few data on gynecomastia in HIV-infected children. Within the UK/Ireland's national cohort, 56 of 1873 (3%) HIV-infected children had gynecomastia, of which 10 (0.5%) were severe. All 10 had received antiretroviral therapy for a median of 27.5 (21, 42) months; 4 of 10 had received efavirenz, 7 of 10 and 6 of 10 had received stavudine and/or didanosine respectively. Five were nonreversible, despite changing antiretroviral therapy, and required breast reduction surgery.
Topics: Adolescent; Anti-Retroviral Agents; Child; Cohort Studies; Female; Gynecomastia; HIV Infections; Humans; Ireland; Male; Prevalence; United Kingdom
PubMed: 27879556
DOI: 10.1097/INF.0000000000001424 -
Viruses Oct 2016In light of the recent outbreak of Ebola virus (EBOV) disease in West Africa, there have been renewed efforts to search for effective antiviral countermeasures. A range...
In light of the recent outbreak of Ebola virus (EBOV) disease in West Africa, there have been renewed efforts to search for effective antiviral countermeasures. A range of compounds currently available with broad antimicrobial activity have been tested for activity against EBOV. Using live EBOV, eighteen candidate compounds were screened for antiviral activity in vitro. The compounds were selected on a rational basis because their mechanisms of action suggested that they had the potential to disrupt EBOV entry, replication or exit from cells or because they had displayed some antiviral activity against EBOV in previous tests. Nine compounds caused no reduction in viral replication despite cells remaining healthy, so they were excluded from further analysis (zidovudine; didanosine; stavudine; abacavir sulphate; entecavir; JB1a; Aimspro; celgosivir; and castanospermine). A second screen of the remaining compounds and the feasibility of appropriateness for in vivo testing removed six further compounds (ouabain; omeprazole; esomeprazole; Gleevec; D-LANA-14; and Tasigna). The three most promising compounds (17-DMAG; BGB324; and NCK-8) were further screened for in vivo activity in the guinea pig model of EBOV disease. Two of the compounds, BGB324 and NCK-8, showed some effect against lethal infection in vivo at the concentrations tested, which warrants further investigation. Further, these data add to the body of knowledge on the antiviral activities of multiple compounds against EBOV and indicate that the scientific community should invest more effort into the development of novel and specific antiviral compounds to treat Ebola virus disease.
Topics: Animals; Antiviral Agents; Cell Line; Disease Models, Animal; Drug Evaluation, Preclinical; Ebolavirus; Guinea Pigs; Hemorrhagic Fever, Ebola; Humans; Treatment Outcome
PubMed: 27801778
DOI: 10.3390/v8110277 -
Frontiers in Immunology 2016The Surveillance Monitoring for ART Toxicities (SMARTT) cohort of the Pediatric HIV/AIDS Cohort Study includes over 3,500 HIV-exposed but uninfected infants and children... (Review)
Review
The Surveillance Monitoring for ART Toxicities (SMARTT) cohort of the Pediatric HIV/AIDS Cohort Study includes over 3,500 HIV-exposed but uninfected infants and children at 22 sites in the US, including Puerto Rico. The goal of the study is to determine the safety of in utero exposure to antiretrovirals (ARVs) and to estimate the incidence of adverse events. Domains being assessed include metabolic, growth and development, cardiac, neurological, neurodevelopmental (ND), behavior, language, and hearing. SMARTT employs an innovative trigger-based design as an efficient means to identify and evaluate adverse events. Participants who met a predefined clinical or laboratory threshold (trigger) undergo additional evaluations to define their case status. After adjusting for birth cohort and other factors, there was no significant increase in the likelihood of meeting overall case status (case in any domain) with exposure to combination ARVs (cARVs), any ARV class, or any specific ARV. However, several individual ARVs were significantly associated with case status in individual domains, including zidovudine for a metabolic case, first trimester stavudine for a language case, and didanosine plus stavudine for a ND case. We found an increased rate of preterm birth with first trimester exposure to protease inhibitor-based cARV. Although there was no overall increase in congenital anomalies with first trimester cARV, a significant increase was seen with exposure to atazanavir, ritonavir, and didanosine plus stavudine. Tenofovir exposure was associated with significantly lower mean whole-body bone mineral content in the newborn period and a lower length and head circumference at 1 year of age. With ND testing at 1 year of age, specific ARVs (atazanavir, ritonavir-boosted lopinavir, nelfinavir, and tenofovir) were associated with lower performance, although all groups were within the normal range. No ARVs or classes were associated with lower performance between 5 and 13 years of age. Atazanavir and saquinavir exposure were associated with late language emergence at 1 year, but not at 2 years of age. The results of the SMARTT study are generally reassuring, with little evidence for serious adverse events resulting from in utero ARV exposure. However, several findings of concern warrant further evaluation, and new ARVs used in pregnancy need to be evaluated.
PubMed: 27242802
DOI: 10.3389/fimmu.2016.00199 -
Patient Preference and Adherence 2016Weight-based dosing strategy is still challenging due to poor awareness and adherence. It is necessary to let clinicians know of the latest developments in this respect... (Review)
Review
BACKGROUND
Weight-based dosing strategy is still challenging due to poor awareness and adherence. It is necessary to let clinicians know of the latest developments in this respect and the correct circumstances in which weight-based dosing is of clinical relevance.
METHODS
A literature search was conducted using PubMed.
RESULTS
Clinical indications, physiological factors, and types of medication may determine the applicability of weight-based dosing. In some cases, the weight effect may be minimal or the proper dosage can only be determined when weight is combined with other factors. Medications within similar therapeutic or structural class (eg, anticoagulants, antitumor necrosis factor medications, P2Y12-receptor antagonists, and anti-epidermal growth factor receptor antibodies) may exhibit differences in requirements on weight-based dosing. In some cases, weight-based dosing is superior to currently recommended fixed-dose regimen in adult patients (eg, hydrocortisone, vancomycin, linezolid, and aprotinin). On the contrary, fixed dosing is noninferior to or even better than currently recommended weight-based regimen in adult patients in some cases (eg, cyclosporine microemulsion, recombinant activated Factor VII, and epoetin α). Ideal body-weight-based dosing may be superior to the currently recommended total body-weight-based regimen (eg, atracurium and rocuronium). For dosing in pediatrics, whether weight-based dosing is better than body surface-area-based dosing is dependent on the particular medication (eg, methotrexate, prednisone, prednisolone, zidovudine, didanosine, growth hormone, and 13-cis-retinoic acid). Age-based dosing strategy is better than weight-based dosing in some cases (eg, intravenous busulfan and dalteparin). Dosing guided by pharmacogenetic testing did not show pharmacoeconomic advantage over weight-adjusted dosing of 6-mercaptopurine. The common viewpoint (ie, pediatric patients should be dosed on the basis of body weight) is not always correct. Effective weight-based dosing interventions include standardization of weight estimation, documentation and dosing determination, dosing chart, dosing protocol, order set, pharmacist participation, technological information, and educational measures.
CONCLUSION
Although dosing methods are specified in prescribing information for each drug and there are no principal pros and cons to be elaborated, this review of weight-based dosing strategy will enrich the knowledge of medication administration from the perspectives of safety, efficacy, and pharmacoeconomics, and will also provide research opportunities in clinical practice. Clinicians should be familiar with dosage and administration of the medication to be prescribed as well as the latest developments.
PubMed: 27110105
DOI: 10.2147/PPA.S103156