[Intravitreal injections: AFSSAPS guide to good practice]. / Injections intravitréennes: mise au point de l'AFSSAPS.

Intravitreal injections are very commonly performed in the daily practice of Ophthalmology and become a leading procedure in the management of age-related macular degeneration, diabetic retinopathy, infectious endophthalmitis or retinitis, uveitis and retinal vein occlusions. Based on the comments of a group of experts, including ophthalmologists, pharmacists and hygienists, the French Agency for the Safety of Health Products (AFSSAPS) edited a guide to good practice of intravitreal injections, revisiting those previously published in 2006. The overall experience accumulated during time is a valuable source of information to determine the most appropriate protocol. Therefore, the simplification of the procedure is reasonably proposed even though safety remains a major issue, in order to avoid complications, especially infections.

MVA-nef induces HIV-1-specific polyfunctional and proliferative T-cell responses revealed by the combination of short- and long-term immune assays.

Several vaccination trials are evaluating the modified vaccinia virus Ankara (MVA) as a delivery vector in various clinical settings. In this paper, we present the reevaluation of a therapeutic vaccination trial in human immunodeficiency virus (HIV)-1-infected individuals treated with highly active antiretroviral therapy using MVA-expressing HIV-1 nef. Immunogenicity of MVA-nef was assessed using multicolor flow cytometry. Vaccine-induced polyfunctionality and proliferative capacity, which are associated with nonprogressive HIV-1 infection, were detectable by combining two immune assays. By means of short-term polychromatic intracellular cytokine staining, we observed a significant increase in polyfunctional Nef-specific CD4 T cells expressing interferon-γ, interleukin (IL)-2 and CD154 after vaccination, whereas changes in the quality of CD8 T-cell response could not be observed. Only the additional use of a long-term polychromatic Carboxyfluorescein succinimidyl ester (CFSE)-based proliferation assay revealed vaccine-induced Nef-specific CD8, as well as CD4 T cells with proliferative capacity. The correlation between vaccine-induced IL-2 production by CD4 T cells and the increase in proliferating Nef-specific CD8 T cells suggests a causal link between these two functions. These results highlight the importance of combining sophisticated immunomonitoring tools to unravel concealed effects of immunological interventions and support the use of the poxvirus-derived MVA vector to stimulate highly functional HIV-1-specific T-cell responses. However, the clinical benefit of these functional T cells remains to be determined.

Efficacy of FOLFIRI-3 (irinotecan D1,D3 combined with LV5-FU) or other irinotecan-based regimens in oxaliplatin-pretreated metastatic colorectal cancer in the GERCOR OPTIMOX1 study.

BACKGROUND: Second-line irinotecan-based chemotherapy is commonly used in metastatic colorectal cancers after first-line oxaliplatin-based chemotherapy. No standard schedule of irinotecan has been established in this situation. PATIENTS AND METHODS: Metastatic colorectal cancer patients included in the OPTIMOX1 phase III study received first-line oxaliplatin-based chemotherapy (FOLFOX). No second line was defined in the protocol, but data concerning second line were prospectively registered. Inclusion criterion was patients receiving an irinotecan-based second-line chemotherapy. Second-line progression-free survival (PFS) and tumor response were evaluated according to type of irinotecan-based regimen administered. RESULTS: A total of 342 patients received irinotecan-based chemotherapy as second-line chemotherapy: FOLFIRI-3 [n = 109, irinotecan 100 mg/m(2) days 1 and 3 combined with leucovorin (LV) 400 mg/m(2) day 1 and 46-h continuous 5-fluorouracil (5-FU) 2000 mg/m(2)], FOLFIRI-1 (n = 112, irinotecan 180 mg/m(2) day 1 combined with LV 400 mg/m(2) day 1, 5-FU bolus 400 mg/m(2) and 46-h continuous 5-FU 2400 mg/m(2)) and other various irinotecan-based regimens (n = 121). Median second-line PFS was 3.0 months (FOLFIRI-3: 3.7 months; FOLFIRI-1: 3.0 months; other regimens: 2.3 months). In multivariate analysis, FOLFIRI-3 regimen (relative risk 0.43, 95% confidence interval 0.28-0.68, P = 0.0003) and lactate deshydrogenase level at inclusion (P = 0.0006) in OPTIMOX1 were associated with a longer second-line PFS. CONCLUSION: In unselected patients pretreated with oxaliplatin, PFS in second line appeared to be improved by FOLFIRI-3 regimen.

Water stress augments silicon-mediated resistance of susceptible sugarcane cultivars to the stalk borer Eldana saccharina (Lepidoptera: Pyralidae).

Silicon (Si) can improve resistance of plants to insect attack and may also enhance tolerance of water stress. This study tested if Si-mediated host plant resistance to insect attack was augmented by water stress. Four sugarcane cultivars, two resistant (N21, N33) and two susceptible (N26, N11) to Eldana saccharina Walker were grown in a pot trial in Si-deficient river sand, with (Si+) and without (Si-) calcium silicate. To induce water stress, irrigation to half the trial was reduced after 8.5 months. The trial was artificially infested with E. saccharina eggs after water reduction and harvested 66 days later. Silicon treated, stressed and non-stressed plants of the same cultivar did not differ appreciably in Si content. Decreases in numbers of borers recovered and stalk damage were not associated with comparable increases in rind hardness in Si+ cane, particularly in water-stressed susceptible cultivars. Overall, Si+ plants displayed increased resistance to E. saccharina attack compared with Si- plants. Borer recoveries were significantly lower in stressed Si+ cane compared with either stressed Si- or non-stressed Si- and Si+ cane. Generally, fewer borers were recovered from resistant cultivars than susceptible cultivars. Stalk damage was significantly lower in Si+ cane than in Si- cane, for N21, N11 and N26. Stalk damage was significantly less in Si+ combined susceptible cultivars than in Si- combined susceptible cultivars under non-stressed and especially stressed conditions. In general, the reduction in borer numbers and stalk damage in Si+ plants was greater for water-stressed cane than non-stressed cane, particularly for susceptible sugarcane cultivars. The hypothesis that Si affords greater protection against E. saccharina borer attack in water-stressed sugarcane than in non-stressed cane and that this benefit is greatly enhanced in susceptible cultivars is supported. A possible active role for soluble Si in defence against E. saccharina is proposed.

Metabolic and anthropometric changes one year after switching from didanosine/stavudine to tenofovir in HIV-infected patients.

BACKGROUND: Nucleoside analogues such as Didanosine and Stavudine are known to cause metabolic and body habitus changes during antiretroviral therapy. The most frequently observed are lactic acidosis, hypercholesterinaemia, hypertriglyceridaemia and lipodystrophy. METHODS: Over one year we monitored a cohort of 43 patients who switched from either Stavudine, Didanosine or the combination of both to Tenofovir. A group of 11 patients was kept on their original regimen and acted as control group. Blood samples were taken every 3 months from baseline, anthropometric measurements were performed at baseline, after 6 and 12 months. RESULTS: During observation the levels of lactic acid and cholesterol decreased significantly in the switch group while virologic and immunologic efficacy remained stable. Serum creatinine levels rose significantly in patients switched to Tenofovir, but remained within physiological limits. The mean skin fold thickness increased significantly by 1.8 mm in the switch group after 6 months (p < or =0.001 - p = 0.032). CONCLUSION: These results implicate an improvement of lipid profiles, serum lactate and lipodystrophy in HIV-positive patients after switch to Tenofovir. As a moderate increase in serum creatinine levels was observed, the renal function of patients on a Tenofovir-based regimen should be monitored closely.

Clinical news from the XVI International AIDS Conference: The attempt of a summing up.

Topics highlighted at the XVI International AIDS Conference in Toronto included HIV/AIDS vaccine research, entry inhibitors, integrase inhibitors, new NNRTIs and PIs, single-agent therapies, pre-exposure prophylaxis and microbicides. Beside the large scientific part, policy and funding were of great concern. Within this article we are trying to focus on topics with direct clinical relevance. This includes new epidemiological and resistance data, results from current studies investigating established and novel antiretroviral drugs and drug classes as well as new findings in therapy management and strategies.

A randomized, open-label study to compare the effects of two different doses of recombinant human growth hormone on fat reduction and fasting metabolic parameters in HIV-1-infected patients with lipodystrophy.

BACKGROUND: Several studies have shown beneficial effects of recombinant human growth hormone (r-hGH) in reducing visceral adipose tissue (VAT) in HIV-1-infected patients with lipodystrophy. METHODS: Patients were randomized to r-hGH 4 mg daily (group A) or three times per week (group B) over 12 weeks, followed by a 2 mg daily maintenance dose for 12 weeks. Magnetic resonance imaging (MRI) scans were performed to assess body composition. RESULTS: A total of 26 subjects were included in the study. VAT was reduced overall by 35.1 cm(2) (29.5%) at week 12 and by 49 cm(2) (39.9%) at week 24, respectively, compared with baseline (P<0.001 for both comparisons). By week 12, VAT was reduced by 27 and 29% (A vs B; P=0.47) while facial fat was reduced by 3.3 and 2.6 cm(2) in groups A and B, respectively (P=0.96). Over 24 weeks, VAT was reduced by 42 and 38% (P=0.35) and facial fat by 3.2 and 2.4 cm(2) in groups A and B, respectively (P=0.91), compared with baseline. There was a greater increase in high-density lipoprotein (HDL) in group A than in group B (4.9 vs 2.4 mg/dL in week 12 and 7.1 vs -0.4 mg/dL in week 24; P=0.03). Fasting insulin levels increased, whereas glucose and insulin measured in oral glucose tolerance tests remained unchanged. Drug-related side effects were transient and reversible, but more common in group A (67%) than in group B (29%). CONCLUSIONS: This study confirms reports that r-hGH effectively reduces VAT, with a relatively small reduction of facial and limb fat.

Treatment interruption in HIV therapy: a SMART strategy?

Continuous HAART is standard of care for HIV-infected patients but lifelong adherence and tolerance are important concerns. Use of ART is associated with potential risks, e. g., adverse events, metabolic and cardiovascular complications, and HIV resistance. Stopping HIV therapy may reduce costs and side effects, but carries the risk of increased immune suppression and of emergence of resistance. Treatment interruption is a strategy of much interest, but its safety and efficacy have not been established. The clinical and biological characteristics that influence the outcome of structured treatment interruptions have not been fully clarified. In the following we will present the results of recent studies aimed to compare the long-term consequences of two antiretroviral-management strategies: continuous therapy versus scheduled treatment interruption.

A phase II study of FOLFIRI-3 (double infusion of irinotecan combined with LV5FU) after FOLFOX in advanced colorectal cancer patients.

In advanced colorectal cancer previously treated with oxaliplatin, efficacy of irinotecan-based chemotherapy is poor and the best regimen is not defined. We designed FOLFIRI-3 and conducted a phase II study to establish its efficacy and safety in advanced colorectal cancer patients previously treated with FOLFOX. FOLFIRI-3 consisted of irinotecan 100 mg m-2 as a 60-min infusion on day 1, running concurrently with leucovorin 200 mg m-2 as a 2-h infusion on day 1, followed by 46-h continuous infusion of 5-fluorouracil (5FU) 2000 mg m-2, and irinotecan 100 mg m-2 repeated on day 3, at the end of the 5FU infusion, every 2 weeks. Sixty-five patients entered the study. The intent-to-treat objective response rate was 23% (95% CI 13-33%). Disease was stable in 37% of patients, progressed in 26% and was not assessable in 14%. From the start of FOLFIRI-3, median progression-free survival was 4.7 months and median survival 10.5 months. Main toxicities (% of patients) were grade 3-4 diarrhoea 23% and grade 4 neutropenia 11%. FOLFIRI-3 is a promising regimen achieving high response rate and progression-free survival in patients previously treated with FOLFOX with a moderate toxicity.

HIV-associated renal diseases and highly active antiretroviral therapy-induced nephropathy.

Renal disease is becoming an increasingly prevalent entity in human immunodeficiency virus (HIV)-infected patients; it occurs in a variety of clinical settings and is associated with histopathological changes. HIV-related renal impairment can present as acute or chronic kidney disease; it can be caused directly or indirectly by HIV and/or by drug-related effects that are directly nephrotoxic or lead to changes in renal function by inducing metabolic vaculopathy and renal damage. Acute renal failure is frequently caused by the toxic effects of antiretroviral therapy or nephrotoxic antimicrobial substances used in the treatment of opportunistic infections. Chronic renal disease can be caused by multiple pathophysiological mechanisms, leading to HIV-associated nephropathy, a form of collapsing focal glomerulosclerosis, thrombotic microangiopathy, and various forms of immune complex glomerulonephritis. The increase in life expectancy and alteration of lipid metabolism due to receipt of highly active antiretroviral therapy are expected to result in an increased prevalence of diabetes and hypertension and, thus, to secondary diabetic and hypertensive renal damage. Antiretroviral agents, such as indinavir and tenofovir, have been associated with nephrotoxic drug effects that have been shown to be reversible in most cases. In this article, we review the current knowledge about acute and chronic HIV-associated renal disease, metabolic alterations and related nephropathies, and toxic drug effects of combination antiretroviral pharmacotherapy.

What's New in HIV/AIDS? Chemokine receptor antagonists: a new era of HIV therapy?

Chemokine receptors are essential for human immunodeficiency virus (HIV) cell entry. CXCR4 and CCR5 are the two most relevant receptors and by inhibition of each of them a delayed onset of disease could be achieved. As both receptors are used at different stages of disease due to the domination of different HIV strains, a dual blockage of CXCR4 and CCR5 could be highly valuable for inhibiting viral transmission and replication.

What's new in HIV/AIDS? Neutralizing HIV antibodies: do they really protect?

Neutralizing antibodies work as a second line of defence. They are detected more or less in nearly every HIV-1-infected individual. 2G12, 2F5 and 4E10 represent antibodies with broadly neutralizing activity made from B cells of HIV- 1-infected humans. Unfortunately these antibodies are extremely rare and all attempts to elicit them via vaccine immunogens have failed. The discovery of autoreactive features of these antibodies could now explain why. Additionally, new results show the delayed viral rebound under antibody treatment in some HIV-1-infected individuals.

HIV genetic diversity: any implications for drug resistance?

At least nine different genetic HIV-1 subtypes and several circulating recombinant forms exist, which in addition to HIV-1 subgroups and HIV-2 account for the global AIDS pandemic. Even though HIV-1 subtype C and A predominate globally, antiretroviral drugs have been designed based on sequences of clade B reverse transcriptase (RT) and protease enzymes due to the domination of HIV-1 subtype B in highly industrialized countries. Since there is no clarity about possible effects of the genetic diversity of HIV-1 on therapy outcome and drug resistance, multiple studies have been performed with divergent results. Up to now this question remains to be answered.

Susceptibility to HIV/AIDS: an individual characteristic we can measure?

Susceptibility to HIV-1 infections is, beside other factors, determined by individual host genetic variants like HLA class I alleles, CCR5 and CCR2 variants and levels of CCR5 binding chemokines. A new approach to determine the individual risk of acquiring an HIV infection or to estimate the disease progression could now be possible. In a recent study, a significant interindividual and interpopulation difference in the copy number of a segmental duplication encompassing the gene encoding CCL3L1, a potent human immunodeficiency virus-1 (HIV- 1)-suppressive chemokine was found. Possession of a CCL3L1 copy number lower than the population average was associated with markedly enhanced HIV/acquired immunodeficiency syndrome (AIDS) susceptibility. This could lead to a screening test that identifies people who have a higher or lower susceptibility to HIV/ AIDS, potentially enabling clinicians to adapt treatment regimens. Also, this is particularly important for assessment of the efficacy of a protective vaccine.

[Options in HIV therapy: present and future]. / Therapieoptionen bei HIV Realität und Zukunft.

Highly active antiretroviral therapy (HAART) has markedly decreased HIV-associated mortality. It consists of a combination of three antiretroviral drugs from four different classes: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and inhibitors of virus-cell fusion. Increasing resistance against antiretroviral drugs calls for the development of new compounds and drug classes. The growing understanding of molecular mechanisms in HIV-replication led to the identification of further steps which might serve as novel antiretroviral targets. Uninfected cells could be protected from HIV by inhibiting extracellular binding mechanisms. Improvement of existing antiretroviral drugs and further development of novel therapeutic targets will enrich antiretroviral treatment.

Immune reconstitution inflammatory syndrome (IRIS)--another new disease entity following treatment initiation of HIV infection.

After the introduction of highly active antiretroviral therapy (HAART) in 1995 it took 3 years to recognize the new syndrome of lipodystrophy as a long-term complication of HAART [1]. It was found to be a direct toxic consequence of the various drugs used in combination regimens. Another 2 years later, an additional syndrome was described in patients who recently initiated HAART-the immune reconstitution inflammatory syndrome (IRIS) [2-4]. Although already recognized in the pre-HIV era in patients with treatment for tuberculosis [5, 6] and leprosy [7], it became substantially more frequent in HIV-infected patients on HAART. The term IRIS describes a collection of different inflammatory disorders which are associated with paradoxical deterioration of various preexisting infectious processes following commencement of HAART in HIV-infected patients. These preexisting infections in individuals with IRIS may have been previously diagnosed and treated or may have been symptomless and later revealed by the patient's improved capacity to mount an inflammatory response.

Abacavir compared to protease inhibitors as part of HAART regimens for treatment of HIV infection: patient satisfaction and implications for adherence.

The purpose of this study was to compare treatment satisfaction with triple nucleoside reverse transcriptase inhibitor (NRTI) highly active antiretroviral treatment (HAART) regimens including abacavir (ABC) to HAART regimens that include protease inhibitors (PIs) and to estimate the relationship between patient satisfaction and adherence to HAART. Three open-label clinical trials comparing ABC-including HAART regimens with PI-including HAART regimens were completed, two with patients previously untreated with antiretroviral therapy and one with patients successfully treated with PI-including HAART regimens. The HIV Treatment Satisfaction Questionnaire (HIVTSQ) was completed at several time points during each trial. Levels of patient satisfaction with the ABC and PI regimens were compared for all three trials. The correlation between adherence and patient satisfaction scores was measured using data from an adherence questionnaire in one of the studies. In all three clinical trials, patient satisfaction scores were significantly higher with an ABC-including triple NRTI HAART regimen than with a PI-including HAART regimen. The difference was apparent by week 4 of the trial and was maintained throughout the trial time period. Inspection of the item responses in the patient satisfaction questionnaire indicated that treatment convenience, flexibility, impact on lifestyle, and side effects were key factors in the difference in satisfaction between the treatment groups. In addition, patient satisfaction was shown to be significantly correlated with adherence defined as taking 95% or more of prescribed doses. Greater satisfaction was reported by patients given an ABC-including HAART regimen than those given a PI-including HAART regimen. Patient satisfaction may be an indicator for better treatment adherence.