Resistencia genotípica del HIV a los antirretrovirales en niños de Argentina entre 2006 y 2021 / HIV genotypic drug resistance to antiretrovirals in children in Argentina between 2006 and 2021

Introducción: La resistencia del HIV a los antirretrovirales (ARVs) es una de las principales causas de fallo terapéutico en niños, niñas y adolescentes que conviven con el virus. Desde el año 2006, el Laboratorio de Biología Celular y Retrovirus del Hospital Garrahan realiza el estudio genotípico de resistencia (ER) del HIV-1 a los ARVs a fin de identificar mutaciones que disminuyen la susceptibilidad del virus a los fármacos que componen el tratamiento ARV. Objetivos: El objetivo del trabajo fue estudiar el tipo y frecuencia de resistencia del HIV a los ARVs, a través de un análisis de 371 ER realizados entre los años 2006 y 2021 en niños, niñas y adolescentes con HIV-1 adquirido por transmisión vertical y con solicitud médica de ER por presentar fallo terapéutico. Resultados: Entre los años 2006 y 2013 la proporción de casos con resistencia a al menos una clase de fármaco ARV fue mayor al 90%, sugiriendo una asociación directa entre el fallo virológico y la disminución en la susceptibilidad del HIV-1 a uno o más componentes del TARV. A partir del año 2012, se observa una disminución progresiva del nivel de resistencia de HIV-1, llegando al 50% en 2021 (p<0.0001). La frecuencia de mutaciones de resistencia fue diferente para cada una de las clases de ARVs. Mientras que la resistencia a INNTR no sufrió cambios significativos a lo largo del período de estudio, oscilando entre 27% y 75%. La proporción de mutaciones a IPs en pacientes con fallo virológico disminuyó de 87% en 2006 a 17% en 2021 y para los INTR, disminuyó de 79% en 2006 a 45% en 2021. Conclusión: El nivel de resistencia a los ARVs ha disminuido de manera sustancial a lo largo de los últimos 16 años, probablemente por el uso de nuevos fármacos ARV con alta potencia que posibilitaron la intensificación de los tratamientos ARV y la implementación de criterios de fallo terapéutico más estrictos tanto a nivel clínico como virológico (AU)

Introduction: HIV resistance to antiretroviral (ARV) drugs is one of the main causes of therapeutic failure in children and adolescents living with the virus. Since 2006, the Cell Biology and Retrovirus Laboratory of the Garrahan Hospital has been performing the genotypic study of HIV-1 resistance to ARV drugs in order to identify mutations that reduce the susceptibility of the virus to the drugs that constitute ARV treatment. Objectives: The aim of this study was to assess the type and frequency of HIV resistance to ARV drugs through an analysis of 371 genotype studies performed between 2006 and 2021 in children and adolescents with HIV-1 acquired through motherto-child transmission and with medical request for genotype study due to therapeutic failure. Results: Between 2006 and 2013, the proportion of cases with resistance to at least one ARV drug class was greater than 90%, suggesting a direct association between virologic failure and decreased susceptibility of HIV-1 to one or more components of ART. From 2012 onwards, a progressive decrease in the level of HIV-1 resistance was observed, reaching 50% in 2021 (p<0.0001). The frequency of resistant mutations was different for each of the ARV classes, while resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) did not change significantly over the study period, ranging from 27% to 75%. The proportion of drug-resistant mutations to protease inhibitors (PI) in patients with virologic failure decreased from 87% in 2006 to 17% in 2021 and for NNRTIs from 79% in 2006 to 45% in 2021. Conclusion: The level of resistance to ARV drugs has decreased substantially over the last 16 years, probably due to the use of new ARV drugs with high potency that allowed the intensification of ARV treatments and the implementation of stricter criteria for therapeutic failure both clinically and virologically (AU)

HIV-1 genetic diversity in Argentina and early diagnosis of perinatal infection

HIV-1 diagnosis of perinatally exposed children is usually performed by molecular biology-based methods, allowing the direct detection of the virus. Thus, HIV-1 genomic variability within and across strains plays a major role in relation to the sensitivity of these tests, often leading to misdiagnosis. We describe the performance of an in-house multiplex nested PCR (nPCR) for early detection of HIV-1 infection in perinatally exposed children born in Argentina, where the percentage of diverse BF recombinants is as high as 80%. After evaluation of 1316 HIV-1 perinatally exposed children collected over a 7-year period, the specificity and sensitivity of the diagnostic nPCR was of 100% and 99.2% respectively, with only two false negative cases indicating a good performance of the diagnostic nPCR in the Argentine pediatric cohort. In search of unusual HIV-1 subtypes among 22 HIV-1 infected cases presenting partial or complete HIV-1 gene amplification failure, we performed phylogenetic and recombination analysis of a vpu-env fragment in addition to gag and env Heteroduplex Mobility Assay screening. The most unusual findings included two subtypes A and a novel BC recombinant, while the majority of the strains were a variety of different BF recombinants. These results indicate the presence of novel and heterogeneous genotypes in our country and the need of continuous viral surveillance not only for diagnostic test optimization but also for the eventual implementation of a successful vaccine.

Immunobiological features of the galactoside lectin L-Lc isolated from the Argentine mistletoe Ligaria cuneifolia.

Ligaria cuneifolia has been used in Argentine folk medicine and is currently employed as substitute for the European mistletoe (Viscum album) as hypotensor agent. Extracts from V. album are widely used in cancer therapy and the antineoplasic effect is attributed to their cytostatic/cytotoxic and immunomodulatory actions. When studying immunomodulatory effects of L. cuneifolia extracts (Lc extracts), they inhibited proliferation of murine mitogen-activated lymphocytes, leukaemic lymphocytes (LB) and breast tumour cells (MMT). The aim of this work was to isolate and identify lectins from Lc extracts and investigate their immunobiological actions. A galactoside lectin (L-Lc) of 57 kDa was isolated. A polyclonal antiserum obtained against Lc extract recognised both L-Lc and MLI (V. album lectin), suggesting the possibility of shared epitopes. Treatment of LB tumour cells with L-Lc (0.01 and 0.1 microg/ml) produced up to 40.0+/-6.9% inhibition of cell growth, which seems partly mediated by apoptosis (apoptosis of L-Lc treated cells 58.4+/-10.3% versus non-treated cells 38.1+/-8.8%; P<0.05), analysed by acridine orange and ethidium bromide staining. Inhibitory effect on ConA stimulated splenocyte growth was non-significant, while a mitogenic effect was observed on normal murine splenocytes and MMT cells. L-Lc in non-cytotoxic concentrations (250 ng/ml) modified mRNA expression of IL-10 but neither that of TGF-beta nor of IL-2 produced by LB cells. In addition, 43.9+/-0.5% reduction in NO production by LPS-stimulated murine macrophages was found. Finally, survival rates of LB tumour-bearing mice treated or not with Lc extract or L-Lc failed to show significant differences.

Secondary reconstruction after vascularized fibular transfer.

We evaluated the results of skeletal reconstruction performed through a mature, vascularized fibular graft in five patients. The average time-interval between the original transplant and the secondary reconstruction was sixty-eight months. The indication for the initial graft had been the loss of bone secondary to trauma in one patient, a skeletal defect due to ablation of a tumor in two patients, and osseous loss due to resection of a congenital pseudarthrosis in two patients. The indication for the second reconstruction was non-union of a fracture as a result of a new traumatic injury in two patients and complex angular deformity in three patients; one of the patients in the latter group had an associated leg-length discrepancy. In all five patients, the second reconstruction was successful, and the vascularized fibular graft responded to the procedure in a manner similar to normal cortical bone.

An anatomical variation of the palmar cutaneous branch of the median nerve.

A case is presented of an anomalous course of the palmar cutaneous branch of the median nerve. Wide and meticulous exposure is necessary to avoid injury to all variations of this nerve and the use of a "safe" incision will not always avoid risk of injury.

Anatomical variations of the median nerve at the wrist.

A comprehensive review of reported median-nerve variations at the wrist is presented. This includes motor-branch anomalies, multiple divisions of the median nerve, neural loops, and variations in association with aberrant muscles. Inadvertent injury to the median nerve during carpal tunnel surgery can be minimized if the anatomy is understood, variations are recognized, and adequate exposure is achieved.

Intraosseous ganglia of the carpal bones.

Intraosseous ganglia are benign, cystic lesions of bone that are most commonly found in the subchondral region of long bones of the lower extremity. Reports of isolated carpal involvement are rare; however, it has been well documented that these lesions may produce chronic wrist pain. Various theories of pathogenesis have been advanced, including synovial herniation, mucoid degeneration, primary cellular metaplasia, and chronic repetitive trauma. In our study, 11 patients (seven female, four male) with 12 lesions were treated for chronic wrist pain associated with intraosseous carpal ganglia. All patients had similar complaints preoperatively and were unable to obtain relief with rest, immobilization, or nonsteroidal medication. Aside from local tenderness over the involved bone, the physical examination was unremarkable. Acute trauma was not found to be a factor in any of these patients' histories. Eleven lesions in 10 patients were grafted with bone from the distal radius. A complete resolution of symptoms was seen at a 20-month follow-up examination.

Sensory neural loop of the median nerve at the carpal tunnel.

This article discusses a sensory neural loop on the radial aspect of the median nerve in the palm. The surgeon should be aware of this anomaly when the transverse carpal ligament is divided to approach the structures contained in the carpal canal.

The failed ulnar nerve transposition. Etiology and treatment.

Various procedures have been recommended for the treatment of cubital tunnel syndrome. Simple decompression in situ, medial epicondylectomy, subcutaneous transposition, intramuscular transposition, and submuscular transposition all have their advocates. The results of the surgical treatment for cubital tunnel syndrome are related to the severity of the compressive neuropathy at the time of diagnosis and to the adequate decompression of the nerve at all sites of potential compression at the time of surgical treatment. Fourteen patients who had previously undergone surgical treatment for cubital tunnel syndrome were evaluated because of persistent pain, paresthesia, numbness, and motor weakness. All patients had documented persistent compression of the ulnar nerve on clinical and electromyographic evaluation. The indication for repeat surgical exploration in all patients was unremitting pain despite nonoperative treatment. All patients had been treated by neurolysis and submuscular transposition of the ulnar nerve as described by Learmonth. The causes of continued pain after initial surgery included retention of the medial intermuscular septum, dense perineural fibrosis of the nerve after intramuscular and subcutaneous transposition, adhesions of the nerve to the medial epicondylectomy site, and recurrent subluxation of the nerve over the medial epicondyle after subcutaneous transposition. Revision surgery was found to be highly successful for relief of pain and paresthesias; however, the recovery of motor function and return of sensibility were variable and unpredictable.

A neural loop of the deep motor branch of the ulnar nerve: an anatomic study.

A motor neural loop of the deep branch of the ulnar nerve was encountered on three occasions during neurolysis of the ulnar nerve through Guyon's canal. An anatomic study of the course of the deep motor branch of the ulnar nerve at the wrist was done to define the incidence of this neural loop. Seventy-seven cadaveric upper extremities were examined and seven (9%) cases of a neural loop were encountered. One of these cases was bilateral. This variation should be considered when there is an atypical clinical presentation after penetrating injuries or compression neuropathy of the ulnar nerve at the wrist. In addition, care must be taken not to injure this branch during decompression of Guyon's canal or excision of an ununited of the hook of the hamate.

The independent long extensor tendon of the fifth toe as a source of tendon grafts for the hand.

The anatomical relationships of the extensor of the fifth toe to the long extensor of the other toes have been studied in 78 cadaver specimens. 50% of the specimens had an independent extensor to the fifth toe without interconnections to the other long toe extensors or the peroneus tertius. The independent fifth toe extensor was consistently of good quality and adequate length for use as a tendon graft, for which purpose it has been successfully used in five patients, with transfer of the adjacent long extensor from the fourth toe to maintain extension of the fifth metatarso-phalangeal joint.

Variation of the deep motor branch of the ulnar nerve at the wrist.

An unusual variation in the course of the deep motor branch of the ulnar nerve is described. This anomaly should be kept in mind during operations for fractures of the hook of the hamate and also in atypical clinical patterns of denervation caused by trauma or compressive neuropathies.

Radiographic evaluation of the hook of the hamate: a new technique.

Radiographic confirmation in cases of suspected hook of hamate fractures can be very difficult. Films, including the carpal tunnel view, may be difficult to interpret. We describe a new semisupine oblique radiographic view of the carpus that permits excellent visualization of the hamate hook, is cost efficient, and allows for patient comfort during the study.

The optimal position for arthrodesis of the metacarpophalangeal joint of the thumb: a clinical study.

Arthrodesis of the metacarpophalangeal joint of the thumb is a well-accepted procedure. Recommendations for position of fusion have varied from 0 to 30 degrees of flexion. Two hundred of these joints in normal subjects were measured in thirteen positions of function for different tasks. The mean of all thirteen measured positions was considered to be the "optimal functional position". Based on this study, we recommend the metacarpophalangeal joint of males be fused in approximately 25 degrees of flexion and females in 20 degrees of flexion.

Hand and wrist joint problems in patients with Ehlers-Danlos syndrome.

Ehlers-Danlos syndrome is a heritable disorder of connective tissue that is clinically characterized by joint hypermobility and skin hyperextensibility and fragility. Four of our patients who fit the criteria for Ehlers-Danlos syndrome are presented. Abnormalities in the hand and wrist joint that are directly related to joint hypermobility are discussed.

Fracture-dislocations of all five carpometacarpal joints: a case report.

Injuries to all five carpometacarpal joints are rare. Only four cases have been reported in the English literature. A case of fracture-dislocations of all five carpometacarpal joints is presented. An excellent result has been obtained 2 years after open reduction and internal fixation. This case is the only one in the English literature so treated and with prolonged follow-up.

Digital ischemia secondary to thrombosis of a persistent median artery.

Digital ischemia secondary to either ulnar arterial or digital arterial thrombosis has been well described. To our knowledge, digital ischemia secondary to thrombosis of a persistent median artery has not been previously reported in the English literature.

Osteochondromas of the hand in hereditary multiple exostosis: report of a case presenting as a blocked proximal interphalangeal joint.

Blocking of motion of an interphalangeal joint in the hand by an osteochondroma has not been reported previously. Osteochondromas, which are uncommon in the hand, are encountered most frequently in patients with hereditary multiple exostosis. They can occur away from the epiphyseal plate region at the distal end of the proximal and middle phalanges. Osteochondromas that occur in these locations characteristically cause angular and rotational deformities. Early recognition and prompt surgical treatment in this child resulted in full motion with minimal angular deformity.

Upper extremity gangrene of the newborn infant.

Ischemia of a limb occurring in the first week of life is uncommon. Gangrene presenting at birth in the upper extremity is fortunately rare. The result in this case and a review of the literature of the last 40 years shows that prompt recognition, early arteriography, and aggressive surgical treatment are necessary.

Bifid median nerve with three thenar branches--case report.

A case of a high division of the median nerve associated with a persistent median artery and three transligamentous thenar motor branches is presented. To our knowledge, three transligamentous motor branches have not been previously reported in the literature.