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Thore Lorenzen and Katrin Graefe

The risk of HIV transmission is present if an HIV-negative person comes into contact with the blood, semen or vaginal fluids of an HIV-positive source person. But exposure of intact skin to HIV-contaminated body fluids (e.g. blood) is not sufficient to transfer the virus. Transmission is possible if HIV-containing material enters the body by:

• accidental needlestick injury or incision by surgical instruments
• exposure of damaged skin or mucosal membranes
• unprotected sexual intercourse with an infected person
• IDU sharing needle or equipment
• transfusion of HIV-contaminated blood or blood products

HIV is not a very contagious pathogen. The transmission rate after contact is about 1:1000 to 1:100. Compared with HIV, the transmission rate for hepatitis C is 10 times higher, and 100 times higher for hepatitis B. Factors for the probability of transmission are the amount of incorporated virus and the exposure time. Contact with body fluids of a patient with a high viral load supposably holds a higher risk of contagion than a similar contact with body fluids of a patient under HAART with a suppressed viral load. Additionally, quick removal of infectious material e.g. from damaged skin or mucosal membrane by washing or disinfection presumably decreases the risk of an HIV infection. For percutaneous contact with HIV-containing blood, an infectiousness of 0.3 % in total is assumed. According to retrospective data, calculations have been established to assess the transmission risks of accidental exposure more precisely (see Table 1).

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Table 1: Calculations to assess estimated individual transmission risk after HIV exposure * Type of Exposure Relative Risk Deep needlestick injury or cut 16 : 1 Fresh blood on the penetrating instrument 5 : 1 Penetrating needle previously placed in blood vessel 5 : 1 Source person with high viral load 6 : 1 Exposition of mucosal membrane 1 : 10 Exposition of inflammatory damaged skin 1 : 10 * Source: German-Austrian recommendations for Post-Exposure Prophylaxis against HIV infection 2004 Table 2 provides information about the assumed transmission risk of other types of exposure to HIV, for example unsafe sexual contact. Since only few data exist, these risk estimates vary enormously and should be judged with caution. Table 2: HIV transmission risk for unprotected sexual contacts * Type of unprotected contact Transmission risk per contact Receptive anal sex with HIV- infected person 0.82 % (0.24 - 2.76) Receptive anal sex with person of unknown HIV status 0.27 % (0.06 - 0.49) Insertive anal sex with person of unknown HIV status 0.06 % (0.02 - 0.19) Receptive vaginal sex 0.05 - 0.15 % Insertive vaginal sex 0.03 - 5.6 % Oral sex Probability unknown, single cases have been reported, particularly with incorporation of semen in the mouth. * Source: German-Austrian PEP recommendations 2004 In primary HIV infection the establishment of the virus in various tissue reservoirs does not occur immediately after incorporation of the virus. Within a small time frame the establishment of the virus might be prevented by post-expositional intervention. Simian models show that in mucosal membranes HIV primarily infects the local immunocompetent cells such as Langhans' cells. These cells or their siblings migrate to regional lymph nodes: detection of HIV in the blood occurs days later. The process of local infection and migration of the cells to the lymph nodes takes approximately 24 to 48 hours (Spira 1996, Otten 2000). Theoretically, treatment with appropriate substances may avert a systemic infection. Effectiveness and limitations of PEP Early reports on the use of AZT after occupational needlestick injuries date from 1989. An analysis of retrospective case-control studies shows that even prophylaxis with a single substance after exposure reduces the probability of an infection by approximately 80 % (Tokars 1993). The combination of multiple drugs is supposedly even more potent. Unfortunately there have been transmissions despite the use of PEP. Transmission of HIV infection cannot always be prevented. Many of the described cases of PEP failure were treated with AZT mono-prophylaxis. But there are also reports about failures of antiretroviral combination therapies. With increasing prevalence of resistance under antiretroviral therapy future problems might arise with transmission of resistant virus strains. International surveillance studies report increasing transmissions rates of mutant viruses. But, what to do is still unclear: resistance testing takes days or more. So results would be too late to avoid spread of resistant viruses using appropriate antiretrovirals. When is PEP indicated? The indication to provide a PEP should be considered by a physician experienced in HIV treatment. It is important to ascertain whether the source person has a supposed or confirmed HIV infection. Unclear HIV status should be clarified: the source person should be asked for consent to perform HIV testing. But denial of consent has to be respected. If the source person agrees to be tested, it should be performed immediately. For source persons with confirmed HIV infection, the actual HIV viral load, stage of disease, former and current HAART have to be taken into consideration. Optimally, a resistance analysis would also be available (Puro 2003). The affected person should be asked about the first aid procedures that have already been performed. After clarification of these queries, the exposed person has to be informed about possible risks of pharmaceutical PEP. It should be emphasized that none of the administered substances is approved for use in this special setting. This is also important with regard to the coverage of cost, especially for sexual exposure. The medication cannot be prescribed at the expense of the health insurance. PEP for occupational exposure is usually covered by statutory accident insurance (in Germany). Table 3 gives an overview of situations in which PEP is recommended according to current guidelines. This serves as an orientation, although deviations may be necessary in individual cases. Potential risks of PEP The risks of PEP mainly concern the adverse effects of the antiretroviral substances, most frequently gastrointestinal symptoms such as nausea, vomiting or diarrhea. Changes of hematology, transaminases or creatinine are also possible. Additionally, there have been reports of elevated triglycerides and cholesterol levels, and insulin resistance even in short term use of protease inhibitors (Parkin 2000). It is unknown whether the temporary use of antiretroviral substances may lead to long term side effects, but this seems to be secondary since the main emphasis is to prevent a chronic and potentially life-threatening disease. For pregnant women particular caution is required since data concerning teratogenicity are lacking. Table 3: Overview of recommendations for usage of PEP Occupational Exposure · Percutaneous needlestick injury with hollow needle (body fluids with high viral load: blood, liquor, material from biopsies, cultured virus) Deep injury (e.g. cuts), apparently blood stained Needle used before for intravenous injection Recommended Recommended Recommended · Superficial injury (e.g. with surgical needle) Where required, exemption, if source person has AIDS or high viral load Considered Recommended · Contact of mucosal membrane or damaged skin with fluids with high viral load Considered · Percutaneous contact with body fluids other than blood (e.g. urine, saliva) Not Recommended · Contact of intact skin with blood (including high viral load) Not Recommended · Contact of skin or mucosal membranes with body fluids such as urine or saliva Not Recommended Non-occupational Exposure · Transfusion of HIV containing blood products (or if HIV contamination is highly probable) Recommended · Unprotected receptive sex with an HIV-infected person Recommended · IDU sharing contaminated needle or equipment Recommended · Unprotected receptive oral sex with ejaculation with an HIV-infected person Considered · Kissing and other sexual contacts without semen-/blood-mucosal membrane contact Not Recommended · Accidental needlestick injury Not Recommended Sources: CDC Guidelines for the management of occupational exposure to HIV 2005; UK guidelines for the use of posr-exposure prophylaxis for HIV following sexual exposure 2006 Initial interventions According to actual guidelines, depending on the type of exposure, different procedures are recommended following HIV-exposure. Following needlestick or cut injuries with HIV-contaminated instruments, fluid should be expressed by squeezing the tissue surrounding the wound and striking out proximal blood vessels towards the wound. Too intense massage or contusions have to be avoided. The wound should be flushed with an alcoholic, virucidal antiseptic for a minimum of 10 minutes. For skin that has been in contact with blood or body fluids removal of the infectious material and subsequent extensive disinfection with a skin antiseptic appears sufficient. After contamination of an eye, immediate flush with PVP iodine solution 2.5 % is recommended. If such a solution is not available the eye should be washed with water. The oral cavity should be washed several times (about 10-15 seconds each) with an aqueous solution or preferably 80 % alcohol after contact with potentially infectious material. Needlestick or cut injury Contamination of damaged skin, eye or oral cavity Expressing fluid by squeezing the tissue surrounding the wound (³ 1 minute) Intensive washing with easily accessible liquid: high proof alcohol (undenaturated for the oral cavity), water or isotonic saline solution, possibly PVP iodine solution Intensive antiseptic washing or application of an antiseptic depot of antiviral agent Figure 1: Recommended initial interventions after HIV exposure (Source: German-Austrian recommendations for Post-Exposure Prophylaxis against HIV infection 2004) Persons, who, through sexual exposure, have contact of anal or genital mucosae to infectious material, should wash the penis with soap and water; genital mucosae should be flushed with water after urination, which might wash contaminated material from the urethra. Intense washing of the vagina or intestines is not recommended due to an elevated risk of injuries. After these initial interventions, an expert in HIV treatment and antiretroviral therapy should be consulted for the decision whether pharmaceutical PEP needs to be started. Accurate evaluation and documentation of the course of the accident is very important, especially for occupational exposure. The process of informing the patient about the risks of PEP needs to be documented carefully and the patient should sign an informed consent. Initiation of PEP Time is the most important factor for initiation of PEP. The best chance to prevent transmission is within the first 24 hours of exposure. After that time period, the risk of systemic spread of the virus increases. Initiating PEP after more than 72 hours following exposure does not seem reasonable. PEP should be initiated as soon as possible, preferably within 2 hours of exposure. If, in this short time frame, consultation with a physician experienced in HIV treatment is not possible, it might be advantageous to just initiate PEP. Interrupting a regimen that isn't indicated is always an option. Actual recommendations prefer a regimen with a combination of antiretroviral substances given over 4 weeks, preferably consisting of two NRTIs and one PI (see Table 5). NNRTIs, especially nevirapine, should not be used for PEP because of the risk of severe adverse effects (hepatotoxicity) (CDC 2001). For efavirenz such severe adverse effects have not been reported but the impact on the CNS, particularly in the first weeks of intake, limits its use for PEP. As far as possible, known resistance against antiretroviral substances of the source person should be taken into account; in many cases, this information will not be available. Therefore use of standard regimens for PEP has proven practical. Recommended combinations are shown in Table 5. To remark: Except Nelfinavir all protease inhibitors are recommended to be used boosted with Ritonavir. In addition, since 2003, the fusion inhibitor T-20 (Fuzeon™) has been approved for HIV therapy. Other substances, such as attachment inhibitors or coreceptor antagonists are under investigation. These new substances with their mechanism to inhibit viral cell entry might also be interesting with regard to increasing efficiency of PEP. Focusing on enfuvirtide, the subcutaneous route of application and high costs currently prevent its routine use. Furthermore, difficulties in monitoring a possible seroconversion might occur as development of antibodies against enfuvirtide may lead to cross reaction with gp41 and a positive result in the HIV-ELISA test. During pregnancy, PEP should only be used after careful consideration of the benefits since there are only limited data on teratogenic effects. In any case, advice of a physician experienced in HIV treatment and pregnancies should be obtained. After contact with potentially infectious material, not only HIV, but also other diseases might be transmitted. Apart from HIV, testing should be performed for hepatitis B and C. Persons exposed to HBV should receive hepatitis B immunoglobulin and a vaccine series simultaneously if they have no sufficient vaccination status. Table 4: Recommended antiretroviral combinations for HIV Post-exposure Prophylaxis * NRTI PI 1. AZT + 3TC (Combivir™) or 2. TDF + FTC (Truvada™) or 3. TDF + 3TC (Viread™+Epivir™) or 4. d4t + 3TC (Zerit™+ Epivir™) plus Lopinavir/r (Kaletra™) or Saquinavir (Invirase™) or Fosamprenavir (Lexiva™ or Telzir™) or Nefinavir (Viracept™) * Sources: CDC Guidelines for the management of occupational exposure to HIV 2005; UK guidelines for the use of posr-exposure prophylaxis for HIV following sexual exposure 2006 After unprotected sexual contacts, transmissions of other STDs such as syphilis or gonorrhea should be taken into consideration. Testing is recommended at 2 and 4 weeks after exposure. Management of PEP After initiation of PEP, the patient should not be discharged without a follow-up consultation. Persons exposed to HIV are under high psychological pressure. It is important to accompany the patiens and to emphasize the generally low risk of transmission but not to dramatize the situation. Adverse effects generally include gastrointestinal symptoms. Less frequent are changes in hematology, liver enzymes or creatinine. These should be tested after 14 days and at the end of the PEP. Despite close monitoring, different studies report discontinuation rates of 40-50 %. At the end of a completed course or discontinued PEP, HIV testing should be performed after 6 weeks, 3 and 6 months. An HIV PCR only needs to be performed if there is reasonable suspicion of a primary HIV infection. In any case, the patient has to be advised to practice safer sex until a reliable negative test result is achieved. References 1. 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Parkin JM, Murphy M, Anderson J, El-Gadi S, Forster G, Pinching AJ. Tolerability and side-effects of post-exposure prophylaxis for HIV infection. Lancet 2000 ; 355: 722-3. http://amedeo.com/lit.php?id=10703807 16. Puro V. Genotypic resistance tests for the management of postexposure prophylaxis. Scand J Infect Dis Suppl. 2003 ; 35 Suppl 106: 93-8. http://amedeo.com/lit.php?id=15000596 17. Puro V, Cicalini S, De Carli G et al. Towards a standard HIV post exposure prophylaxis for healthcare workers in Europe. Euro Surveill. 2004 ; 9. http://www.eurosurveillance.org/em/v09n06/0906-222.asp 18. Spira AI, Marx PA, Patterson BK, et al. Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques. J Exp Med 1996 ; 183: 215-25. http://amedeo.com/lit.php?id=8551225 19. Tokars JI, Marcus R, Culver DH, et al. 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