Barriers to early diagnosis and management of oral cancer in Latin America and the Caribbean.

OBJECTIVE: This study aimed to explore perceived barriers to early diagnosis and management of oral cancer, as well as potential pathways for improvement in Latin America and the Caribbean (LAC). METHODS: This cross-sectional study used a self-administered online questionnaire created via the Research Electronic Data Capture platform. The survey was distributed to health professionals trained in Oral Medicine, Oral Pathology, Oral and Maxillofacial Surgery, and Dentists with clinical and academic expertise in oral potentially malignant disorder (OPMD) and oral cancer. Data obtained were systematically organized and analyzed descriptively using Microsoft Excel. RESULTS: Twenty-three professionals from 21 LAC countries participated. Major barriers included the limited implementation of OPMD and oral cancer control plans (17.4%), low compulsory reporting for OPMD (8.7%) and oral cancer (34.8%), unclear referral pathways for OPMD (34.8%) and oral cancer (43.5%), and a shortage of trained professionals (8.7%). Participants endorsed the utility of online education (100%) and telemedicine (91.3%). CONCLUSION: The survey highlights major perceived barriers to early diagnosis and management of OPMD and oral cancer in LAC, as well as potential avenues for improvement.

Rhabdomyosarcoma with TFCP2 Rearrangement or Typical Co-expression of AE1/AE3 and ALK: Report of Three New Cases in the Head and Neck Region and Literature Review.

BACKGROUND: Rhabdomyosarcoma (RMS) harboring EWSR1/FUS-TFCP2 fusions has been recently described as a distinct form of RMS with an aggressive course and predilection for the craniofacial bones, especially the jaws. METHODS: We report three new cases of this rare entity, two from Brazil and one from Guatemala, with detailed clinicopathologic, immunohistochemical, and molecular descriptions. Additionally, we explored the English-language literature searching RMS with TFCP2 rearrangement or typical immunophenotype with co-expression of AE1/AE3 and ALK in the head and neck region. RESULTS: Case 1 is a 58-year-old male with a 3-month history of painful swelling in the anterior maxilla. Case 2 is a 22-year-old male presenting with right facial swelling and proptosis. Case 3 is a 43-year-old female with a rapidly growing tumor located in the zygomatic region. Imaging examinations revealed highly destructive intraosseous masses in the first two cases, and a soft tissue tumor with bone invasion in case 3. Microscopically, all cases showed a hybrid spindle and epithelioid phenotype of tumor cells which expressed desmin, myogenin and/or Myo-D1, AE1/AE3, and ALK. FISH confirmed molecular alterations related to TFCP2 rearrangement in Cases 1-2. In case 3, there was no available material for molecular analysis. The patients were subsequently referred to oncologic treatment. Additionally, we summarized the clinicopathologic, immunohistochemical, and molecular features of 27 cases of this rare RMS variant in the head and neck region reported in the English-language literature. CONCLUSION: RMS with TFCP2 rearrangement is a rare and aggressive tumor with a particular predilection for craniofacial bones, especially the jaws. Knowing its clinicopathologic and immunohistochemical profile can avoid misdiagnosis.

Molecular profile of head and neck rhabdomyosarcomas: A systematic review and meta-analysis.

OBJECTIVE: This systematic review aimed to identify the molecular alterations of head and neck rhabdomyosarcomas (HNRMS) and their prognostic values. STUDY DESIGN: An electronic search was performed using PubMed, Embase, Scopus, and Web of Science with a designed search strategy. Inclusion criteria comprised cases of primary HNRMS with an established histopathological diagnosis and molecular analysis. Forty-nine studies were included and were appraised for methodological quality using the Joanna Briggs Institute Critical Appraisal tools. Five studies were selected for meta-analysis. RESULTS: HNRMS predominantly affects pediatric patients (44.4%), and the parameningeal region (57.7%) is the most common location. The alveolar variant (43.2%) predominates over the embryonal and spindle cell/sclerosing types, followed by the epithelioid and pleomorphic variants. PAX-FOXO1 fusion was observed in 103 cases of alveolar RMS (79.8%). MYOD1 mutation was found in 39 cases of sclerosing/spindle cell RMS (53.4%). FUS/EWSR1-TFCP2 gene fusions were identified in 21 cases of RMS with epithelioid and spindle cell morphologies (95.5%). The 5-year overall survival rate of patients was 61.3%, and MYOD1 mutation correlated with significantly higher mortality. CONCLUSION: The genotypic profile of histologic variants of HNRMS is widely variable, and MYOD1 mutation could be a potential prognostic factor, but more studies are required to establish this.

Discovery of Novel Pyrazolopyrimidines as Potent, Selective, and Orally Bioavailable Inhibitors of ALK2.

Activin receptor-like kinase 2 (ALK2) is a transmembrane kinase receptor that mediates the signaling of the members of the TGF-ß superfamily. The aberrant activation of ALK2 has been linked to the rare genetic disorder fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) that are associated with severely reduced life expectancy in pediatric patients. ALK2 has also been shown to play an essential role in iron metabolism by regulating hepcidin levels and affecting anemia of chronic disease. Thus, selective inhibition of ALK2 has emerged as a promising strategy for the treatment of multiple disorders. Herein, we report the discovery of a novel pyrazolopyrimidines series as highly potent, selective, and orally bioavailable inhibitors of ALK2. Structure-based drug design and systematic structure-activity relationship studies were employed to identify potent inhibitors displaying high selectivity against other ALK subtypes with good pharmacokinetic profiles.

Inhibition of ALK2 with bicyclic pyridyllactams.

Activin receptor-like kinase 2 (ALK2) has been implicated as a key target in multiple rare diseases. Herein, we describe the design of a novel bicyclic lactam series of potent and selective ALK2 inhibitors. This manuscript details an improvement in potency of two orders of magnitude from the initial bicyclic structure as well as a two-fold improvement in cellular potency from the original monocyclic inhibitor. Furthermore, we provide a detailed strategy for progressing this project in the future.

Discovery of Pemigatinib: A Potent and Selective Fibroblast Growth Factor Receptor (FGFR) Inhibitor.

Aberrant activation of FGFR has been linked to the pathogenesis of many tumor types. Selective inhibition of FGFR has emerged as a promising approach for cancer treatment. Herein, we describe the discovery of compound 38 (INCB054828, pemigatinib), a highly potent and selective inhibitor of FGFR1, FGFR2, and FGFR3 with excellent physiochemical properties and pharmacokinetic profiles. Pemigatinib has received accelerated approval from the U.S. Food and Drug Administration for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or other rearrangement. Additional clinical trials are ongoing to evaluate pemigatinib in patients with FGFR alterations.

Fully digital pathology laboratory routine and remote reporting of oral and maxillofacial diagnosis during the COVID-19 pandemic: a validation study.

The role of digital pathology in remote reporting has seen an increase during the COVID-19 pandemic. Recently, recommendations had been made regarding the urgent need of reorganizing head and neck cancer diagnostic services to provide a safe work environment for the staff. A total of 162 glass slides from 109 patients over a period of 5 weeks were included in this validation and were assessed by all pathologists in both analyses (digital and conventional) to allow intraobserver comparison. The intraobserver agreement between the digital method (DM) and conventional method (CM) was considered almost perfect (κ ranged from 0.85 to 0.98, with 95% CI, ranging from 0.81 to 1). The most significant and frequent disagreements within trainees encompassed epithelial dysplasia grading and differentiation among severe dysplasia (carcinoma in situ) and oral squamous cell carcinoma. The most frequent pitfall from DM was lag in screen mirroring. The lack of details of inflammatory cells and the need for a higher magnification to assess dysplasia were pointed in one case each. The COVID-19 crisis has accelerated and consolidated the use of online meeting tools, which would be a valuable resource even in the post-pandemic scenario. Adaptation in laboratory workflow, the advent of digital pathology and remote reporting can mitigate the impact of similar future disruptions to the oral and maxillofacial pathology laboratory workflow avoiding delays in diagnosis and report, to facilitate timely management of head and neck cancer patients. Graphical abstract.

Preclinical characterization of itacitinib (INCB039110), a novel selective inhibitor of JAK1, for the treatment of inflammatory diseases.

Pharmacological modulation of the Janus kinase (JAK) family has achieved clinically meaningful therapeutic outcomes for the treatment of inflammatory and hematopoietic diseases. Several JAK1 selective compounds are being investigated clinically to determine their anti-inflammatory potential. We used recombinant enzymes and primary human lymphocytes to assess the JAK1 specificity of itacitinib (INCB039110) and study inhibition of signal transducers and activators of transcription (STAT) signaling. Rodent models of arthritis and inflammatory bowel disease were subsequently explored to elucidate the efficacy of orally administered itacitinib on inflammatory pathogenesis. Itacitinib is a potent and selective JAK1 inhibitor when profiled against the other JAK family members. Upon oral administration in rodents, itacitinib achieved dose-dependent pharmacokinetic exposures that highly correlated with STAT3 pharmacodynamic pathway inhibition. Itacitinib ameliorated symptoms and pathology of established experimentally-induced arthritis in a dose-dependent manner. Furthermore, itacitinib effectively delayed disease onset, reduced symptom severity, and accelerated recovery in three distinct mouse models of inflammatory bowel disease. Low dose itacitinib administered via cannula directly into the colon was highly efficacious in TNBS-induced colitis but with minimal systemic drug exposure, suggesting localized JAK1 inhibition is sufficient for disease amelioration. Itacitinib treatment in an acute graft-versus-host disease (GvHD) model rapidly reduced inflammatory markers within lymphocytes and target tissue, resulting in a marked improvement in disease symptoms. This is the first manuscript describing itacitinib as a potent and selective JAK1 inhibitor with anti-inflammatory activity across multiple preclinical disease models. These data support the scientific rationale for ongoing clinical trials studying itacitinib in select GvHD patient populations.

Oral and maxillofacial cancer in pediatric patients: 30 years experience from a Brazilian reference center.

OBJECTIVE: The aim of this study is to determine the relative frequency, demographic distribution and clinicopathological features of pediatric oral and maxillofacial cancer (POMC). METHODS: Medical records were retrospectively reviewed for all cancer cases diagnosed from 1986 to 2016 affecting patients aged 19 years and younger. Demographic variables, anatomical site, and histopathological diagnoses were collected and analyzed by descriptive statistics. RESULTS: Fifty-five (0.77%) POMCs were found among 7181 pediatric malignancies. Mean age at diagnosis was 8 years and patients aged 5-9 years presented the higher prevalence of malignant tumors (40%). White male patients were more frequently affected (78.18% and 65.45%, respectively). The most common cancer type was lymphomas (52.73%) followed by sarcomas (27.27%) and carcinomas (20%). Burkitt lymphoma (32.73%), rhabdomyosarcoma (14.55%), diffuse large B-cell lymphoma (9.09%), and mucoepidermoid carcinoma (9.09%) were the most common histopathological diagnoses. The main affected anatomical site was the oropharynx (38.18%), followed by salivary glands (30.91%), maxillofacial bone (20%), and oral cavity (10.91%). CONCLUSION: POMC has a low incidence; however, highly aggressive tumors, such as lymphomas and sarcomas, are common in this scenario. A better knowledge about the clinicopathological distribution of POMC may contribute to early diagnosis and improve survival rates.

Analysis of Story Recall in Military Veterans With and Without Mild Traumatic Brain Injury: Preliminary Results.

Purpose: The purpose of this study was to determine whether detailed analysis of story recall performance reveals significant differences between veterans with and without history of mild traumatic brain injury (mTBI). Method: Twenty-one military veterans participated, with 7 reporting history of mTBI. All participants were administered the Logical Memory I and II subtests from the Wechsler Memory Scale-Fourth Edition (Wechsler, 2009). Responses were scored for total correct ideas (TCI) and total words produced (TWP). Results: Although the groups did not differ in scaled scores, other measures did reveal significant differences. After a delay, the mTBI group showed a greater drop in TCI relative to the control group. Additionally, the control group showed an increase in TWP when the recall was delayed versus immediate; a pattern not observed for the mTBI group. Conclusions: The mTBI and control groups did not significantly differ in scaled scores. However, group differences were observed in TCI and TWP. The findings suggest that, relative to the control group, the mTBI group were less successful in retrieving episodic information and eliciting self-cueing. Small sample size limited data interpretation, and larger sample sizes are needed to confirm the findings. The results indicate that veterans with mTBI may present with symptoms persisting beyond the acute state of the injury.

Pharmacological characterization of INCB3344, a small molecule antagonist of human CCR2.

The chemokine receptor 2 (CCR2) directs migration of monocytes and has been proposed to be a drug target for chronic inflammatory diseases. INCB3344 was first published as a small molecule nanomolar inhibitor of rodent CCR2. Here, we show that INCB3344 can also bind human CCR2 (hCCR2) with high affinity, having a dissociation constant (K(d)) of approximately 5nM. The binding of the compound to the receptor is rapid and reversible. INCB3344 potently inhibits hCCR2 binding of monocyte chemoattractant protein-1 (MCP-1) and MCP-1-induced signaling and function in hCCR2-expressing cells, including ERK phosphorylation and chemotaxis, and is competitive against MCP-1 in vitro. INCB3344 also blocks MCP-1 binding to monocytes in human whole blood, with potency consistent with in vitro studies. The whole blood binding assay described here can be used for monitoring pharmacodynamic activity of CCR2 antagonists in both preclinical models and in the clinic.

Risk factors for chronic ulceration in patients with varicose veins: a case control study.

BACKGROUND/OBJECTIVE: Identifying which patients with varicose veins are at risk of progressing to more severe forms of chronic venous disease could help in assigning clinical priorities and targeting appropriate treatments. The aim of this study was to determine, in subjects with varicose veins, the characteristics of venous disease and other factors associated with an increased risk of ulceration. METHODS: One hundred twenty subjects with varicose veins and an open or healed venous leg ulcer were compared with 120 controls with varicose veins and no history of venous ulcer on this case control study. Subjects were recruited from hospital settings and primary care. Each subject completed a questionnaire on lifestyle and medical history and underwent an examination comprising of clinical classification of venous disease (CEAP), duplex scanning, quantitative digital photoplethysmography, and measurement of dorsiflexion. Multiple logistic regression analyses and calculation of receiver operating characteristic (ROC) curves were performed to identify the combination of factors which most accurately predicted which patients with varicose veins will develop leg ulcers. RESULTS: An increased risk of ulceration was associated with the severity of clinical venous disease, especially with the presence of skin changes (P < .0001). Other significant risk factors included history of deep vein thrombosis (DVT) (P = .001), higher body mass index (BMI) (P = .006), smoking (P = .009), and reflux in the deep veins (P = .0001). Ulceration was associated with reduced volume of blood displaced as reflected by photoplethysmography and a limited range of ankle movement (not wholly due to the effects of an active ulcer) (both P < .05). Multivariate analyses showed that skin changes including lipodermatosclerosis (odds ratio [OR] 8.90, 95% confidence interval [CI] 1.44-54.8), corona phlebectatica (OR 4.52, 95% CI 1.81-11.3) and eczema (OR 2.87, 95% CI 1.12-7.07), higher BMI (OR 1.08, 95% CI 1.01-1.15), and popliteal vein reflux (OR 2.82, 95% CI 1.03-7.75) remained independently associated with increased risk of ulceration while good dorsiflexion of the ankle (OR 0.88, 95% CI 0.81-0.97) and an effective calf muscle pump (OR 0.96, 95% CI 0.92-0.99) remained protective factors. ROC curve analyses indicated that a model based on clinical observation of skin changes, duplex scanning for popliteal reflux, and calf muscle pump tests would be the most accurate in determining which patients with varicose veins develop leg ulcers. CONCLUSIONS: The results of this study confirm that, in patients with varicose veins, those with skin changes of chronic venous insufficiency and deep vein incompetence are at greatly increased risk of ulceration. However, the risks may also be increased in those who smoke, are obese, and have restricted ankle movement and reduced calf muscle pump power.

Advantages of laparoscopic transabdominal preperitoneal herniorrhaphy in the evaluation and management of inguinal hernias.

BACKGROUND: Laparoscopic transabdominal preperitoneal (TAPP) herniorrhaphy provides an opportunity to definitively evaluate both inguinal areas without the need for additional dissection. We aimed to establish the rates and contributing patient factors to errors in the preoperative assessment. METHODS: A retrospective review of consecutive patients undergoing laparoscopic TAPP herniorrhaphy at 2 tertiary-care centers. Preoperative history and physical examination were used to classify the presence of hernia as "definite," "questionable," or "negative." Any discrepancies between preoperative and intraoperative findings were viewed as errors in preoperative assessment. RESULTS: Two hundred sixty-two patients underwent 328 laparoscopic TAPP hernia repairs. Of the 283 hernias diagnosed as "definite" preoperatively, 276 were confirmed at operation (97.8%). An additional 19 of 173 (11.0%) clinically unrecognized hernias were repaired at the time of surgery. Overall, our approach avoided unnecessary groin explorations and/or repairs in up to 16.4% patients and may have prevented inappropriate delays of herniorrhaphy in up to 19.8% of patients. The sensitivity, specificity, and positive predictive value of the clinical assessment of inguinal hernia were 94.5%, 80%, and 88.9%, respectively. Symptom and/or examination findings of inguinal mass were the only significant independent predictor of accuracy (P < .001). CONCLUSION: A high rate of discordance exists between the preoperative clinical assessment and true presence of inguinal hernias. Given the unique ability of laparoscopy to accurately evaluate the contralateral side and the limited added morbidity of bilateral repair, TAPP herniorrhaphy is beneficial in avoiding unnecessary explorations and allowing timely repairs in patients with occult inguinal hernias.

Immunologic effects of hand-assisted surgery on peritoneal macrophages: comparison to open and standard laparoscopic approaches.

BACKGROUND: Exaggerated activation of peritoneal immunity after major abdominal surgery activates peritoneal macrophages (PMs), which may lead to a relative local immunosuppression. Although laparoscopy (L) is known to elicit a smaller attenuation of peritoneal host defenses, compared with open (O) surgery, effects of the hand-assisted (HA) approach have not been investigated to date. METHODS: Eighteen pigs underwent a transabdominal nephrectomy via O, HA, or L approach. PMs were harvested at 4, 12, and 24 hours through an intraperitoneal drain and stimulated in vitro with lipopolysaccharide. The production of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) by the purified macrophage cultures was measured with the use of a standard enzyme-linked immunosorbent assay technique. Statistical comparison was performed by using analysis of variance and Student t test. RESULTS: In vitro lipopolysaccharide-induced IL-6 and TNF-alpha production by PMs increased over the 24-hour period in all 3 groups. Stimulated PMs harvested at 12 and 24 hours postoperatively secreted higher levels of IL-6 in the O group, compared with both the HA group (P = .02, P = .01) and L group (P = .04, P = .001). PMs harvested at 4, 12 and 24 hours postoperatively also produced more TNF-alpha in O group, compared with both the HA group (P = .03, P = .03, and P = .01) and L group (P = .01, P = .05 and P = .03). There was no significant difference between H and L groups in production of either cytokine. CONCLUSIONS: Abdominal surgery attenuates peritoneal host defenses regardless of the surgical approach employed. However, for the first time, we demonstrated that the HA approach, similar to laparoscopy, is superior to open surgery in the degree of PM activation. Overall, in addition to clinical benefits of minimal access, HA surgery may confer an immunologic advantage over laparotomy.

Discovery and pharmacological characterization of a novel rodent-active CCR2 antagonist, INCB3344.

This report describes the characterization of INCB3344, a novel, potent and selective small molecule antagonist of the mouse CCR2 receptor. The lack of rodent cross-reactivity inherent in the small molecule CCR2 antagonists discovered to date has precluded pharmacological studies of antagonists of this receptor and its therapeutic relevance. In vitro, INCB3344 inhibits the binding of CCL2 to mouse monocytes with nanomolar potency (IC(50) = 10 nM) and displays dose-dependent inhibition of CCL2-mediated functional responses such as ERK phosphorylation and chemotaxis with similar potency. Against a panel of G protein-coupled receptors that includes other CC chemokine receptors, INCB3344 is at least 100-fold selective for CCR2. INCB3344 possesses good oral bioavailability and systemic exposure in rodents that allows in vivo pharmacological studies. INCB3344 treatment results in a dose-dependent inhibition of macrophage influx in a mouse model of delayed-type hypersensitivity. The histopathological analysis of tissues from the delayed-type hypersensitivity model demonstrates that inhibition of CCR2 leads to a substantial reduction in tissue inflammation, suggesting that macrophages play an orchestrating role in immune-based inflammatory reactions. These results led to the investigation of INCB3344 in inflammatory disease models. We demonstrate that therapeutic dosing of INCB3344 significantly reduces disease in mice subjected to experimental autoimmune encephalomyelitis, a model of multiple sclerosis, as well as a rat model of inflammatory arthritis. In summary, we present the first report on the pharmacological characterization of a selective, potent and rodent-active small molecule CCR2 antagonist. These data support targeting this receptor for the treatment of chronic inflammatory diseases.

PDGF stimulates DNA synthesis in human vascular smooth muscle cells via a novel wortmannin-insensitive phosphatidylinositol 3-kinase.

The class 1(A) phosphatidylinositol 3-kinase enzymes consist of a number of heterodimeric complexes of regulatory and catalytic subunits and have been implicated in a number of cellular responses. While platelet-derived growth factor (PDGF)-induced chemotaxis of human vascular smooth muscle cells (HVSMC) is inhibited by both wortmannin and LY294002, DNA synthesis is only inhibited by LY294002. Serum-induced DNA synthesis however is inhibited by LY294002, wortmannin and rapamycin. Similarly PDGF-induced protein kinase B (PKB) activation is inhibited by LY294002 but not by wortmannin or rapamycin. In conclusion PDGF-induced DNA synthesis appears to occur through a phosphatidylinositol 3-kinase (PI3-K)-dependent, but wortmannin-insensitive, PKB/Akt pathway.

N4-acyl-modified D-2',3'-dideoxy-5-fluorocytidine nucleoside analogues with improved antiviral activity.

A series of 2',3'-dideoxy (D2) and 2',3'-didehydro-2',3'-dideoxy (D4) 5-fluorocytosine nucleosides modified with substituted benzoyl, heteroaromatic carbonyl, cycloalkylcarbonyl and alkanoyl at the N4-position were synthesized and evaluated for anti-human immunodeficiency virus type 1 (HIV-1) and anti-hepatitis B virus (HBV) activity in vitro. For most D2-nucleosides, N4-substitutions improved the anti-HIV-1 activity markedly without increasing the cytotoxicity. In the D4-nucleosides series, some of the substituents at the N4-position enhanced the anti-HIV-1 activity with a modest increase in the cytotoxicity. The most potent and selective N4-modified nucleoside for the D2-series was N4-p-iodobenzoyl-D2FC, which had a 46-fold increase in anti-HIV-1 potency in MT-2 cells compared to the parent nucleoside D-D2FC. In the D4-series, N4-p-bromobenzoyl-D4FC was 12-fold more potent in MT-2 cells compared to the parent nucleoside D-D4FC. All eight N4-p-halobenzoyl-substituted D2- and D4-nucleosides evaluated against HBV in HepAD38 cells demonstrated equal or greater potency than the two parental compounds, D-D2FC and D-D4FC. The N4-modification especially in the D2-nucleoside series containing the N4-nicotinoyl, o-nitrobenzoyl and n-butyryl showed a significant reduction in mitochondrial toxicity relative to the parent nucleoside analogue. Although the 5'-triphosphate of the parent compound (D-D4FC-TP) was formed from the N4-acyl-D4FC analogues in different cells, the levels of the 5'-triphosphate nucleotide did not correlate with the cell-derived 90% effective antiviral concentrations (EC90), suggesting that a direct interaction of the triphosphates of these N4-acyl nucleosides was involved in the antiviral activity.

Cellular pharmacology of D-d4FC, a nucleoside analogue active against drug-resistant HIV.

The backbone of effective highly active antiretroviral therapy regimens for the treatment of HIV infections currently contains at least two nucleosides. Among the features that influence the potency of each component of a regimen and the overall efficacy of the combination are the cellular uptake and bioconversion of nucleoside analogues to their active triphosphate form, and the extent of possible interactions in these steps that might occur when more than one nucleoside is used in a regimen. D-d4FC (Reverset), a new cytidine analogue with the ability to inhibit many nucleoside-resistant viral variants, was examined for these parameters. In phytohemaglutinin-stimulated human peripheral blood mononuclear cells, D-d4FC was taken up in a rapid (8 h to 50% maximal value), saturable (plateau above 10 microM parent nucleoside concentration) process, resulting in levels of D-d4FC triphosphate that should provide potent antiviral activity against a variety of virus genotypes. Based on measurement of antiviral effects in cell culture, additive and in some cases, synergistic interactions were observed with protease inhibitors, non-nucleoside reverse transcriptase inhibitors or other nucleosides, including cytidine analogues.