31. Post-Exposure Prophylaxis (PEP)

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31. Post-Exposure Prophylaxis (PEP)

Thore Lorenzen and Katrin Graefe

Transmission

According to the current state of knowledge, there is a risk of HIV transmission if an HIV-negative person comes into contact with the blood, semen or vaginal fluids of an HIV-positive source person. In the opinion of leading experts, 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 HIV-infected person – IDU sharing needle or equipment

– transfusion of HIV-contaminated blood or blood products

Transmission risk

HIV is not a very contagious pathogen. The transmission rate after a high-risk con-tact is about 1:1000 to 1:100. Compared with HIV, the transmission rate for hepati-tis C virus is 10 times higher, and 100 times higher for hepatihepati-tis B virus. Factors for the probability of transmission are the amount of incorporated virus and the expo-sure time. Contact with body fluids of a patient with a high viral load probably 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 infec-tious material e.g. from damaged skin or mucosal membrane by washing or disin-fection supposedly decreases the risk of an HIV indisin-fection. For percutaneous contact with HIV-containing blood, experts assume an infectiousness of 0.3 % in total. Ac-cording to retrospective data, calculations have been established to assess the transmission risks of accidental exposure more precisely (see Table 1).

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 (acute HIV infection,

AIDS without ART)

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 in-fection 2004

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698 Post-Exposure Prophylaxis (PEP)

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 contact Transmission risk per contact

Unprotected receptive anal sex with HIV-infected person

0.82 % (0.24 – 2.76)

Unprotected receptive anal sex with person of unknown HIV status

0.27 % (0.06 – 0.49)

Unprotected insertive anal sex with per-son of unknown HIV status

0.06 % (0.02 – 0.19)

Unprotected receptive vaginal sex 0.05 – 0.15 % Unprotected insertive vaginal sex 0.03 – 5.6 %

Oral sex Probability not known, single cases have been reported, particularly with incorporation of se-men in the mouth.

* Source: German-Austrian PEP recommendations 2004

Evaluation of primary HIV infection indicates that the establishment of the virus in various tissue reservoirs does not occur immediately after incorporation of the vi-rus. 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 mi-grate 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 ap-proximately 24 to 48 hours. 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 %. The combination of multiple drugs is supposedly even more potent. Unfortunately there have been transmissions despite the use of PEP. Trans-mission of HIV infection cannot always be prevented. Many of the described cases of PEP failure following accidental exposure 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 prob-lems might arise with transmission of resistant virus strains. International surveil-lance studies report increasing transmissions rates of mutant viruses. But, what to do is still unclear: resistance testing takes days (or perhaps weeks). So results would be too late to avoid spread of resistant viruses using appropriate antiretrovirals.

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When is PEP indicated?

The risk of possible HIV transmission should be considered by a physician experi-enced in HIV treatment. It is important to establish 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. Denial of con-sent has to be respected as per actual jurisdiction. If the source person agrees to be tested, this 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. 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 adverse effects and 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 ex-posure. 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 neces-sary in individual cases.

Potential risks of PEP

The risks of PEP mainly concern the adverse effects of the antiretroviral substances. Most frequently, this refers to 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 lev-els, and insulin resistance even in short term use of protease inhibitors.

It is unknown whether the temporary use of antiretroviral substances may lead to long term side effects, but this seems secondary since the main emphasis is to pre-vent a chronic and potentially life-threatening disease. For pregnant women par-ticular caution is required since data concerning teratogenicity are lacking.

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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 per-son

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 Source: German-Austrian PEP recommendations against HIV infection 2004

Initial interventions

According to actual guidelines, depending on the type of exposure, different proce-dures are recommended following HIV-exposure. Following needlestick or cut inju-ries 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

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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 (≥ 1 minute)

Intensive washing with easily accessi-ble liquid: high proof alcohol (unde-naturated 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 mate-rial from the urethra. Intense washing of the vagina or intestines is not recom-mended due to an elevated risk of injuries.

After implementation of the 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 im-portant, 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 treat-ment 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 sub-stances 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). 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.

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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. Rec-ommended combinations are shown in Table 5.

Tenofovir is not listed in the table of standard prophylaxis. This substance needs one phosphorylization step less for activation compared to the other NRTIs, which might be beneficial concerning time. Until now, no evidence exists confirming this hypothesis, but current trials are ongoing. The new recommendations for nonoccu-pational exposure to HIV in the United States mention tenofovir equally to the other NRTIs.

In addition, since 2003, the fusion inhibitor T-20 (Fuzeon™) has been approved for HIV therapy. Other substances, such as attachment inhibitors or coreceptor antago-nists 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 cur-rently 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 bene-fits 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 dis-eases might be transmitted. Apart from HIV, testing should be performed for hepa-titis B and C. Persons exposed to HBV should receive hepahepa-titis 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 / NNRTI Nelfinavir (Viracept™, 2 x 1,250 mg) or Lopinavir/r (Kaletra™, 2 x 400/100 mg) or Indinavir (Crixivan™, 3 x 800 mg) or AZT + 3TC 1. Combivir™ (2 x 300/150 mg) or 2. Retrovir™ (2 x 250 mg) plus Epivir™(2 x 150 mg or 1 x 300 mg) plus Efavirenz (Sustiva™, 1 x 600 mg)

* Source: German-Austrian PEP recommendations. Comment: routine use of efavirenz is not recommended by the editors of HIV medicine due to high incidence of CNS events.

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.

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Management of PEP

After initiation of PEP, the patient should not be discharged without a follow-up consultation. The consecutive intake of antiretrovirals demands a high amount of discipline and potential adverse effects should be diagnosed early. Persons exposed to HIV are under high psychological pressure. It is important not to dramatize the situation but emphasize the generally low risk of transmission.

Adverse effects generally include gastrointestinal symptoms. Less frequent are changes in hematology, liver enzymes or creatinine. These should be tested after 14 days and again after 4 weeks - 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 nega-tive test result is achieved.

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31. Post-Exposure Prophylaxis (PEP)