新指南建议HIV暴露后预防至少用3种药物

《感染控制与医院流行病学》杂志日前刊登了经过修订的HIV暴露后医务人员处理指南，该指南建议暴露后预防(PEP)应一律使用至少3种药物，而不宜按照之前更新版本建议的那样，评估风险后再决定该使用多少种药物(2013 Aug. 7 [doi: 10.1086/672271])。这是自2005年发布更新版以来首次对该指南进行修订。

指南主要作者、美国疾病预防控制中心(CDC)的David T. Kuhar博士指出，关于暴露后预防的优选方案，修订版指南推荐的药物比既往推荐药物的耐受性更好，从而有望使更大比例的医务人员得以完成28天的预防性治疗。


Ronald Goldschmidt博士

修订版指南的另一个重要改变是，如果采用新的第四代联合HIV p24抗原/HIV抗体检测，则对医务人员进行暴露后预防性随访HIV检测的推荐时间从6个月缩短至4个月。

暴露后预防的原则仍然不变：医务人员一旦发生HIV职业暴露，应视为紧急医疗问题，应立即报告并根据所在机构的规程迅速加以处理。在有条件的情况下，应确定可能导致医务人员暴露于HIV的患者血液或其他体液中的HIV状态，以便更好地判断是否需要进行暴露后预防。在符合暴露后预防指征的情况下，应尽快(在数小时内)启动暴露后预防。建议进行专家会诊，但不得因等待会诊而延误暴露后预防的启动。应在HIV暴露后72 h内开始严密随访，包括咨询、基线和随访HIV检测，以及药物毒性监测。

据加州大学旧金山分校家庭与社区医学系的Ronald Goldschmidt博士介绍，美国临床医生暴露后预防热线(PEPline，888-448-4911)2012年接到的求助电话中，约有1万次来自可能发生了HIV暴露的临床医生。Goldschmidt博士是全国HIV/AIDS临床医生咨询中心的主任，PEPline便是该中心建立的。他也参与了指南的更新。自2005年指南更新以来，已有数种新型抗逆转录病毒药物获准上市，我们也获得了更多有关暴露后预防药物使用与副作用的数据。

在优选的暴露后预防用药方案方面，本次修订的指南推荐口服raltegravir(Isentress)400 mg、2次/d和truvada(含有替诺福韦300 mg和恩曲他滨200 mg的复方片剂)1次/d。“可能发生HIV职业暴露的科室应当事先将这两种药物配成单剂小药包，以便在需要时立即启动暴露后预防。”

Goldschmidt博士同时提醒道，只有在确认没有肾脏问题的情况下才能使用truvada。如果有肾脏病史，应咨询HIV专家或考虑改用其他药物。修订版指南的附表中列出了推荐和禁用的替代药物。

2001年更新版指南建议，如果可能发生了HIV职业暴露，应首先评估医务人员的风险水平。2005年更新版指南就暴露后预防用药提出了新的建议，但并未简化HIV风险评估，仍建议在确定风险后再决定暴露后预防究竟该使用多少种药物。临床医生对此有颇多怨言。本次修订的指南建议，所有的职业暴露后预防均应使用至少3种药物并且应选择耐受性较好的药物，从而减少了决策制定过程的不确定性，有利于临床医生及时采取充分的暴露后预防措施。

尽管尚无新的决定性数据显示三联暴露后预防方案对HIV职业暴露的效果优于双联方案，但鉴于有研究显示联用3种而非2种抗逆转录病毒药物可进一步降低HIV感染患者的病毒负荷，加上考虑到耐药问题以及一些新药的安全性和耐受性更佳，修订版指南推荐使用至少3种药物。该指南还增加了一条说明：假如难以获得抗逆转录病毒药物或者存在依从性/毒性问题，在咨询相关专家后，也可考虑采用双联暴露后预防方案。

尚无抗逆转录病毒药物被美国食品药品管理局(FDA)批准用于暴露后预防。

Kuhar博士报告称无相关利益冲突。他的一些合著者报告称与百时美施贵宝、杨森等公司有利益关系。Goldschmidt博士无利益冲突披露。

专家点评：仔细监测副作用

如今，发生暴露的医务人员和处置这类暴露的人员有了更多的药物可供选择。这确实有利于采取个体化的暴露后预防，但另一方面，缺乏HIV暴露处置经验的人可能会因选项的增多而更加迷茫或紧张。因此，诸如HIV PEPline之类的专家资源就愈发显得重要了。

联用3种或更多药物的方案费用更高。目前没有任何数据提示三联方案在暴露后预防中有更好的效果。指南作者表示，提出三联方案的建议主要出于以下考虑：(1)有研究显示三联方案在减少HIV感染患者的病毒负荷方面优于双联方案；(2)担心引起职业暴露的患者本身对常用于暴露后预防的药物存在耐药；(3)新型抗HIV药物的安全性和耐受性可能更好；(4)由于副作用较少，加用新药有可能改善暴露后预防的依从性。并且修订版指南同意在特定情况下仍使用双联方案。

然而，不管怎么说，使用的药物种类越多，副作用的风险必然越高。尽管获得推荐的药物一般都具有较好的安全性和耐受性，但仔细监测副作用仍然非常重要。


C. Bradley Hare医生

点评专家C. Bradley Hare医生是旧金山总医院HIV/AIDS门诊部主任。他担任了吉利德、百时美施贵宝、杨森、默克和AbbVie等抗HIV药物生产商的顾问或讲者。

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By: SHERRY BOSCHERT, Ob.Gyn. News Digital Network

Revised federal guidelines for managing health care workers who are exposed to HIV recommend using at least three drugs for prophylaxis in all cases instead of assessing a person’s risk to decide on the number of drugs, among other updates to the guidelines.

Changes in the recommended drugs in preferred postexposure prophylaxis (PEP) regimens should make them easier to tolerate than earlier regimens and may increase the proportion of health care workers who are able to complete the 28-day treatment, Dr. David T. Kuhar and his associates said in the new document from the U.S. Public Health Service.
 
Another change is that follow-up HIV testing in health care workers on PEP can be shortened to 4 months instead of 6 months if a newer fourth-generation combination HIV p24 antigen/HIV antibody test is used, the guidelines state. The document, which updates 2005 guidelines, was published online in the journal Infection Control and Hospital Epidemiology (2013 Aug. 7 [doi: 10.1086/672271]).

The updates are based on expert opinion in a working group comprised of representatives from the Centers for Disease Control and Prevention (CDC), the National Institutes of Health, the Food and Drug Administration, and the Health Resources and Services Administration, in consultation with a panel of experts, wrote Dr. Kuhar of the CDC and his associates.

The principles of PEP remain the same: Occupational exposures to HIV in health care workers should be considered urgent medical concerns, and should be reported and managed promptly under your institution’s procedures. Determine the HIV status of the patient whose blood or other bodily fluids potentially exposed the health care worker to HIV, if possible, to guide the need for PEP. Start PEP as soon as possible (within hours) after the exposure if PEP is indicated. Expert consultation is recommended, but PEP initiation should not be delayed while waiting for a consult. Close follow-up should start within 72 hours of HIV exposure and include counseling, baseline and follow-up HIV testing, and monitoring for drug toxicity, according to the guidelines.

Clinicians can consult experts locally or can call the National Clinicians’ Post-Exposure Prophylaxis Hotline (PEPline) at 888-448-4911.

The PEPline received approximately 10,000 calls in 2012 from clinicians about potential occupational exposures to HIV, said Dr. Ronald Goldschmidt of the department of family and community medicine at the University of California, San Francisco. He is director of the university’s National HIV/AIDS Clinicians’ Consultation Center, which includes the PEPline. Dr. Goldschmidt was a member of the panel of experts that consulted on the guidelines update.

Several new antiretroviral agents have been approved since the last update to the guidelines in 2005, and more information has become available about the use and side effects of the PEP medications. Clinicians had struggled with the 2005 version’s recommendations to assess the level of risk of HIV transmission in individual exposure incidents, creating problems in deciding whether to use two or three or more drugs in PEP regiments.

The new guidelines’ preferred HIV PEP regimen is oral raltegravir (Isentress) 400 mg twice daily and once-daily Truvada (a fixed-dose combination tablet containing 300 mg of tenofovir and 200 mg of emtricitabine). "Preparation of this PEP regimen in single-dose ‘starter packets,’ which are kept on hand at sites expected to manage occupational exposures to HIV, may facilitate timely initiation of PEP," the guidelines state.

Dr. Goldschmidt cautioned that Truvada should not be used before checking for preexisting renal problems. If there’s a history of renal problems, consult an HIV expert or consider a different regimen, he said.

An appendix to the document lists recommended and contraindicated alternatives.

Although there are no new definitive data showing greater efficacy with three-drug regimens for PEP compared with two-drug regimens for occupational HIV exposures, the new recommendation to use at least three drugs rests on studies showing greater reduction of viral burden in HIV-infected patients on three antiretroviral drugs instead of two, concerns about drug resistance in source patients of occupational exposures, and better safety and tolerability with some of the newer medications. The guidelines add a caveat that two-drug PEP regimens might be considered in consultation with an expert if antiretrovirals aren’t easily available or because of adherence or toxicity issues.

None of the antiretroviral agents have been approved by the Food and Drug Administration for use as PEP.

The previous complicated recommendations to assess a health care worker’s level of risk after a potential exposure to HIV were enshrined in a 2001 version of the guidelines, Dr. Goldschmidt said. The 2005 revision updated the recommended drugs but didn’t simplify the risk assessment. The current update makes decision-making less confusing by recommending at least a three-drug regimen for all occupational PEP cases and using better-tolerated drugs.

"With the simplification at this point, they’re throwing away those old tables that required clinicians to assess risk" and decreased the likelihood that PEP would be administered appropriately and completed, he said.

Separate guidelines have been published previously for management of nonoccupational HIV exposure (sexual, pediatric, or perinatal exposures).

Dr. Kuhar reported having no financial disclosures. Some of his coauthors reported financial associations with Bristol-Myers Squibb, Janssen, and other companies. Dr. Goldschmidt reported having no financial disclosures.

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Monitor carefully for side effects

Exposed health care workers and those managing their exposures will now have more PEP options to consider. This offers the benefit of being able to individualize therapy to the individual; however, for providers with less experience in managing HIV exposures, having these options may be more confusing or intimidating. For that reason, expert resources like the HIV PEPline (888-448-4911) will be increasingly important.

These regimens will be more expensive. There aren’t any data to suggest that these three-drug regimens will be more effective in PEP. Here’s why the guideline authors said they made the change:

"The recommendation for consistent use of three-drug HIV PEP regimens reflects (1) studies demonstrating superior effectiveness of three drugs in reducing viral burden in HIV-infected persons compared with two agents; (2) concerns about source patient drug resistance to agents commonly used for PEP; (3) the safety and tolerability of new HIV drugs, and (4) the potential for improved PEP regimen adherence due to newer medications that are likely to have fewer side effects. Clinicians facing challenges such as antiretroviral medication availability, potential adherence and toxicity issues, and others associated with a three-drug PEP regimen might still consider a two-drug PEP regimen in consultation with an expert."

Any time you use more drugs, there is an opportunity for side effects. While the medications recommended here are generally safe and well tolerated, careful monitoring for side effects will be important for individuals receiving PEP.

In addition their improved tolerability, I think the other rationale for recommending these exact regimens is based on these regimens being less likely to have resistance.

Dr. C. Bradley Hare is medical director of the HIV/AIDS Clinic at San Francisco General Hospital. He has been a consultant or speaker for the following companies that make HIV medications: Gilead, Bristol-Myers Squibb, Janssen Pharmaceuticals, Merck, and AbbVie Pharmaceuticals.