Publications

BACKGROUND

Populations such as healthcare workers (HCWs), injection drug users (IDUs), and people engaging in unprotected sex are all at risk of being infected with the human immunodeficiency virus (HIV). Animal models show that after initial exposure, HIV replicates within dendritic cells of the skin and mucosa before spreading through lymphatic vessels and developing into a systemic infection (CDC 2001). This delay in systemic spread leaves a "window of opportunity" for post-exposure prophylaxis (PEP) using antiretroviral drugs designed to block replication of HIV (CDC 2001). PEP aims to inhibit the replication of the initial inoculum of virus and thereby prevent establishment of chronic HIV infection.

OBJECTIVES

To evaluate the effects of antiretroviral PEP post-occupational exposure to HIV.

SEARCH STRATEGY

The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, AIDSearch, and the Database of Abstracts of Reviews of Effectiveness were searched from 1985 to January 2005 to identify controlled trials. There were no language restrictions. Because no controlled clinical trials were retrieved, the search was repeated on 31 May 2005 in MEDLINE, AIDSearch and EMBASE using a search strategy to identify analytic observational studies. Handsearches of the reference lists of all pertinent reviews and studies found were also undertaken. Experts in the field of HIV prevention were contacted.

SELECTION CRITERIA

Types of studies: All controlled trials (including randomized clinical trials and controlled clinical trials). If no controlled trials were found, analytic studies (e.g. cohort and case-control studies) were considered. Descriptive studies (i.e. studies with no comparison groups) were excluded. Types of participants included:HCWs exposed to any known or potentially HIV contaminated product;anyone exposed to a needlestick contaminated by known or potentially HIV-infected blood or other bodily fluid in an occupational setting; andanyone exposed through the mucous membranes to an HIV-infected or potentially infected substance in occupational setting.Excluded: Sex workers (PEP post-sexual exposure is addressed in another Cochrane review (Martín 2005)). Types of interventions: Any intervention that administered single or combinations of antiretrovirals as PEP to people exposed to HIV through percutaneous injuries and/or occupational mucous membrane exposures when the HIV status of the source patient was positive or unknown. Studies comparing two types of PEP regimens were considered, as were studies comparing PEP with no intervention. Types of outcome measures:Incidence of HIV infection in those given PEP versus those given placebo or a different PEP regimen; Adherence to PEP; Complications of PEPTypes of outcome measures: Incidence of HIV infection in those given PEP versus those given placebo or a different PEP regimen; Adherence to PEP; Complications of PEP DATA COLLECTION AND ANALYSIS: Data concerning outcomes, details of the interventions, and other study characteristics were extracted by two independent authors (TY and JA) using a standardized data extraction form (Table 04). A third author (GK) resolved disagreements. The following information was gathered from each included study: location of study, date, publication status, demographics (e.g. age, gender, occupation, risk behavior, etc.) of participants/exposure modality, form of PEP used, duration of use, and outcomes. Odds ratios with a 95% confidence interval (CI) were used as the measure of effect. A meta-analysis was performed for adverse events where two-drug regimens were compared with three-drug regimens. Due to overlap between Puro 2000 and Puro 2005, the former was not included in the combined analysis.

MAIN RESULTS

Effect of PEP on HIV seroconversionNo randomized controlled trials were identified. Only one case-control study was included. HIV transmission was significantly associated with deep injury (OR 15, 95% CI 6.0 to 41), visible blood on the device (OR 6.2, 95% CI 2.2 to 21), procedures involving a needle placed in the source patient's blood vessel (OR 4.3, 95% CI 1.7 to 12), and terminal illness in the source patient (OR 5.6, 95% CI 2.0 to 16). After controlling for these risk factors, no differences were detected in the rates at which cases and controls were offered post-exposure prophylaxis with zidovudine. However, cases had significantly lower odds of having taken zidovudine after exposure compared to controls (OR 0.19, 95%CI 0.06 to 0.52). No studies were found that evaluated the effect of two or more antiretroviral drugs for occupational PEP. Adherence to and complications with PEPEight reports from observational comparative studies confirmed findings that adverse events were higher with a three-drug regimen, especially one containing indinavir. However, discontinuation rates were not significantly different.

AUTHORS' CONCLUSIONS

The use of occupational PEP is based on limited direct evidence of effect. However, it is highly unlikely that a definitive placebo-controlled trial will ever be conducted, and, therefore, on the basis of results from a single case-control study, a four-week regimen of PEP should be initiated as soon as possible after exposure, depending on the risk of seroconversion. There is no direct evidence to support the use of multi-drug antiretroviral regimens following occupational exposure to HIV. However, due to the success of combination therapies in treating HIV-infected individuals, a combination of antiretroviral drugs should be used for PEP. Healthcare workers should be counseled about expected adverse events and the strategies for managing these. They should also be advised that PEP is not 100% effective in preventing HIV seroconversion. A randomized controlled clinical trial is neither ethical nor practical. Due to the low risk of HIV seroconversion, a very large sample size would be required to have enough power to show an effect. More rigorous evaluation of adverse events, especially in the developing world, are required. Seeing that current practice is partly based on results from individual primary animal studies, we recommend a formal systematic review of all relevant animal studies.

OBJECTIVES

Activation of sphingosine kinase (SphK), which has two known isoforms, is responsible for the synthesis of sphingosine 1-phosphate (S1P), a cell survival factor. We tested the following hypotheses: 1] cardiac myocytes null for the SphK1 gene are more vulnerable to the stress of hypoxia+glucose deprivation; 2] the monoganglioside GM-1, which activates SphK via protein kinase C epsilon, is ineffective in SphK1-null myocytes; 3] S1P generated by SphK activation requires cellular export to be cardioprotective.

METHODS

We cultured adult mouse cardiac myocytes from wildtype and SphK1-null mice (deletion of exons 3-6) and measured cell viability by trypan blue exclusion.

RESULTS

In wildtype adult mouse cardiomyocytes subjected to 4 h of hypoxic stress+glucose deprivation, cell viability was significantly higher than in SphK1-null cardiomyocytes. SphK1-null cells also displayed more mitochondrial cytochrome C release. Cell death induced by hypoxia+glucose deprivation was substantially prevented by pretreatment with exogenous S1P in both wildtype and SphK1-null myocytes, but S1P was effective at a lower concentration in wildtype cells. Hence, the absence of the Sphk1 gene did not affect receptor coupling or downstream signal transduction. Pretreatment for 1 h with 1 microM of the monoganglioside GM-1 increased survival in wildtype cells, but not in SphK1-null myocytes. Thus, activation of SphK1 by GM-1 leads to cell survival. In wildtype cells, enhanced survival produced by GM-1 was abrogated by pretreatment either with 300 nM of the S1P(1) receptor-selective antagonist VPC23019 or with 100 ng/ml of pertussis toxin for 16 h before exposure to hypoxia+glucose deprivation.

CONCLUSION

As the effect of GM-1 is blocked both at the receptor and the G-protein (Gi) levels, we conclude that S1P generated by GM-1 treatment must be exported from the cell and acts in a paracrine or autocrine manner to couple with its cognate receptor.

Patients with inflammatory or neuropathic pain experience hypersensitivity to mechanical, thermal and/or chemical stimuli. Given the diverse etiologies and molecular mechanisms of these pain syndromes, an approach to developing successful therapies may be to target ion channels that contribute to the detection of thermal, mechanical and chemical stimuli and promote the sensitization and activation of nociceptors. Transient Receptor Potential (TRP) channels have emerged as a family of evolutionarily conserved ligand-gated ion channels that contribute to the detection of physical stimuli. Six TRPs (TRPV1, TRPV2, TRPV3, TRPV4, TRPM8 and TRPA1) have been shown to be expressed in primary afferent nociceptors, pain sensing neurons, where they act as transducers for thermal, chemical and mechanical stimuli. This short review focuses on their contribution to pain hypersensitivity associated with peripheral inflammatory and neuropathic pain states.