Eduardo Shahar

Genotypic variation of HIV-1 reverse transcriptase and protease: comparative analysis of clade C and clade B.

Objective To compare drug-resistant variants from untreated (naive) and treated patients infected with clade B or C virus. Methods Consecutive samples (165) from patients throughout Israel were analyzed. All those in the treated group were failing highly active antiretroviral therapy. Results There were 78 clade C (20 naive) and 87 clade B (14 naive) with significant differences in the prevalence of known drug-resistance mutations between the clades: in naive patients in the protease region M36I 7% and 95% (P < 0.0001), K20R 0% and 27% (P = 0.063), A71V 18% and 0% (P = 0.063), M46I 0% and 13%, and V77I 18% and 0% (P = 0.063), respectively, and in the reverse transcriptase region A98G/S 0% and 20% (P = 0.12), respectively. Most clade C viruses also showed significant differences from clade B consensus sequence at additional protease sites: R41K 100%, H69K/Q 85%, L89M 95% and I93L 80% (P < 0.0001). There were also significant differences (P < 0.03 to < 0.0001) in treated patients in clades B and C: in the protease region L10I 40% and 12%, M36I 26% and 95%, L63P 67% and 40%, A71I 38% and 7%, G73I and V77I 18% and 0%, I84V 16% and 3%, and L90M 40% and 12%, respectively; in the reverse transcriptase M41L 41% and 17%, D67N 41% and12%, K70R 30% and 7%, T215Y 48% and 29%, K219Q 21% and 7%, and A98G/S 3% and 24%, respectively. Conclusion Significantly differences between clade B and C viruses may be associated with development of differing resistance patterns during therapy and may affect drug utility in patients infected with clade C.

Treatment of severe chronic idiopathic urticaria with oral mycophenolate mofetil in patients not responding to antihistamines and/or corticosteroids.

Background  Urticarial patients are usually treated with oral antihistamines and 50% respond well to this treatment; however, the other 50% do not respond to antihistamines and need a more aggressive approach, such as short or prolonged courses of oral corticosteroids or cyclosporine. Potential adverse effects, however, limit this regimen.

The autologous serum skin test in a cohort of chronic idiopathic urticaria patients compared to respiratory allergy patients and healthy individuals.

Background  A positive autologous serum skin test (ASST) is considered to reflect the presence of anti‐FceRI and/or anti‐IgE autoantibodies that are capable of activating mast and basophil cell degranulation. The ASST is regarded as a reliable in vivo test in chronic idiopathic urticaria (CIU) patients, with diagnostic, therapeutic and prognostic implications. However, positive ASST results have also occasionally been demonstrated in patients with other diseases and in healthy subjects.

Absence of APOL1 Risk Variants Protects against HIV-Associated Nephropathy in the Ethiopian Population

Background: Susceptibility to end-stage kidney disease (ESKD) among HIV-infected Americans of African ancestral heritage has been attributed to APOL1 genetic variation. We determined the frequency of the APOL1 G1 and G2 risk variants together with the prevalence of HIV-associated nephropathy (HIVAN) among individuals of Ethiopian ancestry to determine whether the kidney disease genetic risk is PanAfrican or restricted to West Africa, and can explain the previously reported low risk of HIVAN among Ethiopians. Methods: We studied a cohort of 338 HIV-infected individuals of Ethiopian ancestry treated in one Israeli and one Ethiopian center. We sought clinical evidence for HIVAN (serum creatinine >1.4 mg/dl or proteinuria >30 mg/dl in a spot urine sample). Genetic analyses included the genotyping of the APOL1 G1 and G2 variants, and a panel of 33 genomic ancestry-informative markers. Statistical analysis compared clinical and genetic indices for HIV-infected individuals of Ethiopian ancestry and overall Ethiopians to those reported for HIV-infected African-Americans, overall African-Americans, West Africans and non-Africans. Findings: Three (0.8%) of 338 HIV-infected patients of Ethiopian ancestry showed clinical criteria compatible with renal impairment. Two of these 3 patients also have severe poorly controlled diabetes mellitus. The third nondiabetic patient underwent renal biopsy which ruled out HIVAN. This absence of clinically apparent HIVAN was significantly different from that reported for African-Americans. The APOL1 G1 and G2 risk variants were found, respectively, in 0 and 2 (heterozygote state) of the 338 HIV-infected individuals. Global ancestry and the frequencies of the APOL1 G1 and G2 variants are not statistically different from their frequencies in the general Ethiopian population, but are significantly and dramatically lower than those observed among HIV-infected African-Americans, African-Americans and West Africans. Interpretation: The coinciding absence of HIVAN and the APOL1 risk variants among HIV-infected individuals of Ethiopian ancestry support a Western rather than Pan-African ancestry risk for ESKD, and can readily explain the lack of HIVAN among individuals of Ethiopian ancestry.

Iatrogenic Cushing's Syndrome due to Coadministration of Ritonavir and Inhaled Budesonide in an Asthmatic Human Immunodeficiency Virus Infected Patient

Introduction. Iatrogenic Cushings syndrome (CS) is caused by exposure to glucocorticoids and may be promoted by interaction with additional drugs. It is well known in asthmatic human immunodeficiency virus (HIV)-infected patients treated with inhaled fluticasone with ritonavir-containing antiretroviral regimen (cART). Case Report. The authors present an asthmatic HIV-infected Ethiopian woman, treated with fluticasone/salmeterol, commencing cART with tenofovir, emtricitabine, and lopinavir/ritonavir. During 7 months she gained 9 kg and hyperpigmentation, mild edema, marked abdominal striae, and increase in blood pressure were noted. Plasma am and urine free cortisol levels confirmed CS diagnosis and fluticasone was discontinued. Complete resolution of CS occurred within 2 months. However, frequent asthma symptoms required resumption of inhaled corticosteroid (ICS) treatment, and budesonide/formeterol was prescribed. Soon reemergence of symptomatic CS was noted. Ritonavir dose was halved, but CS symptoms continued to develop. Budesonide was stopped and montelukast initiated. Resolution of cushingoid symptoms was observed within weeks. Discussion. Corticosteroids are metabolized by cytochrome P450 3A4 (CYP3A4). Fluticasone has the longest glucocorticoid receptor–binding half-life and is 300 times more lipophilic than budesonide. Inhaled fluticasone possesses a high suppression rate of hypothalamic-pituitary-adrenal axis. Ritonavir, a potent CYP3A4 inhibitor, may inhibit corticosteroid degradation and increase its accumulation. Inhaled budesonide is less likely to cause adrenal suppression. Diagnosing Cushings syndrome presents a clinical challenge due to similarities with clinical manifestations and side effects related to cART. In patients treated with inhaled or intranasal corticosteroids together with cART there may be a higher incidence of iatrogenic CS. CS should be looked for, and management considered carefully.

Continuous G-CSF therapy for isolated chronic mucocutaneous candidiasis: complete clinical remission with restoration of IL-17 secretion.

know whether the colocalization we observed represents replicative infection of airway macrophages, or simple endocytosis of the virus. Finally, under specific conditions, airway epithelial cells may take on features of phagocytic cells, including CD68 expression. Nevertheless, based on costaining with CD11b and morphologic differences, RV-, CD68-double positive cells in the airway epithelium are likely to be monocytes. We conclude that RV is ingested by recruited CD68-positive and CD11b-positive macrophages in asthmatic humans, providing direct evidence that tissue macrophages in the lower airways contribute to anti-RV responses in vivo. A prospective study is needed to definitively characterize the role of monocytic infection in RV-induced asthma exacerbations. J. Kelley Bentley, PhD Uma S. Sajjan, PhD Marta B. Dzaman, MD Nizar N. Jarjour, MD Wai-Ming Lee, PhD James E. Gern, MD Marc B. Hershenson, MD

Autoimmune progesterone dermatitis: effective prophylactic treatment with danazol

Background Autoimmune progesterone dermatitis is a rare condition appearing during the perimenstrual period or following progesterone treatment. Various treatment modalities have been suggested, but most have proved to be ineffective.

Transmission patterns of HIV-subtypes A/AE versus B: inferring risk-behavior trends and treatment-efficacy limitations from viral genotypic data obtained prior to and during antiretroviral therapy.

Background HIV subtypes A and CRF01_AE (A/AE) became prevalent in Israel, first through immigration of infected people, mostly intravenous-drug users (IVDU), from Former Soviet-Union (FSU) countries and then also by local spreading. We retrospectively studied virus-transmission patterns of these subtypes in comparison to the longer-established subtype B, evaluating in particular risk-group related differences. We also examined to what extent distinct drug-resistance patterns in subtypes A/AE versus B reflected differences in patient behavior and drug-treatment history. Methods Reverse-transcriptase (RT) and protease sequences were retrospectively analyzed along with clinical and epidemiological data. MEGA, ClusalX, and Beast programs were used in a phylogenetic analysis to identify transmission networks. Results 318 drug-naive individuals with A/AE or patients failing combination antiretroviral therapy (cART) were identified. 61% were IVDU. Compared to infected homosexuals, IVDU transmitted HIV infrequently and, typically, only to a single partner. 6.8% of drug-naive patients had drug resistance. Treatment-failing, regimen-stratified subtype-A/AE- and B-patients differed from each other significantly in the frequencies of the major resistance-conferring mutations T215FY, K219QE and several secondary mutations. Notably, failing boosted protease-inhibitors (PI) treatment was not significantly associated with protease or RT mutations in either subtype. Conclusions While sizable transmission networks occur in infected homosexuals, continued HIV transmission among IVDU in Israel is largely sporadic and the rate is relatively modest, as is that of drug-resistance transmission. Deviation of drug-naive A/AE sequences from subtype-B consensus sequence, documented here, may subtly affect drug-resistance pathways. Conspicuous differences in overall drug-resistance that are manifest before regimen stratification can be largely explained in terms of treatment history, by the different efficacy/adherence limitations of older versus newer regimens. The phenomenon of treatment failure in boosted-PI-including regimens in the apparent absence of drug-resistance to any of the drugs, and its relation to adherence, require further investigation.

Effective acute desensitization for immediate- type hypersensitivity to human granulocyte- monocyte colony stimulating factor

BACKGROUND Granulocyte-monocyte colony stimulating factor (GM-CSF) is the treatment of choice for patients with life threatening neutropenias. Hypersensitivity to GM-CSF may lead to cessation of treatment. Acute desensitization is an alternative mode of managing drug hypersensitivity, especially when other common modes like substitution of offending drug or premedication with antihistamines and/or corticosteroids are not available or fail. CASE REPORT A 42-year-old woman with a 17-year history of severe chronic mucocutaneous candidal infections became resistant to all common antifungal drugs. As her disorder was associated with defective functions of monocytes and granulocytes, GM-CSF treatment was started yielding a very good clinical effect. After a short period of treatment, however, the patient developed anaphylactic reactions which could not be abolished by preadministration of antihistamines and/or corticosteroids. Replacement of therapy by G-CSF caused identical hypersensitivity phenomena. METHODS Prick skin tests with 100, 200, or 400 microg/mL of GM-CSF or G-CSF, using also negative and positive controls, were performed on the patient and three healthy control subjects. A positive local reaction was observed only in patient at the prick point of 200 microg/mL GM-CSF or 400 microg/mL G-CSF. Acute desensitization to GM-CSF was initiated adopting a protocol used for parenteral desensitization to penicillin. RESULTS The patient tolerated the desensitization procedure very well and we could resume the administration of GM-CSF. For the past 30 months the patient has been treated uneventfully by subcutaneous administration of GM-CSF, 500 microg twice weekly, and is free of candidal infections. Skin prick tests were repeated 1 month postdesensitization and resulted in a very weak response to GM-CSF compared with the predesensitization response. CONCLUSIONS Acute desensitization can be utilized in patients who develop drug hypersensitivity reactions to GM-CSF. As GM-CSF is a very unique agent and in most cases cannot be replaced by another one, acute desensitization may play a very important role in managing failure of GM-CSF treatment due to hypersensitivity reactions.

Successful desensitization protocol for hypersensitivity reaction caused by sunitinib in a patient with a gastrointestinal stromal tumor.

Sunitinib is an orally bioavailable small molecule that inhibits multiple receptor tyrosine kinases. Generalized hypersensitivity reactions (HSR) to sunitinib have not been described. A patient with a gastrointestinal stromal tumor (GIST) who developed a type I HSR to sunitinib and who was successfully treated by drug desensitization is reported. A 51-year-old man with metastatic GIST developed a type I HSR during sunitinib treatment. Four days after treatment initiation, the patient presented to the Emergency Department with acute generalized urticaria and facial and throat swelling. Sunitinib was restarted 1 week later, using a desensitization protocol in which 10 escalating reduced doses, beginning with 0.05 mg, were given following pre-medication with prednisone and promethazine. This protocol was well tolerated and allowed us to continue the treatment, obtaining partial remission of the liver metastasis that was followed by complete resection. Sunitinib was temporarily discontinued before the operation and renewed after surgery by repeating the same desensitization procedure. At the time of this report, sunitinib has been continued for 1 year without evidence of recurrent disease. Oral desensitization appears to be an option for patients with hypersensitivity type I to sunitinib and may permit its safe administration to patients who experience HSR to this life-prolonging medication.