Post-exposure prophylaxis for HIV infection

What elements of post-exposure prophylaxis for HIV infection are necessary for infection prevention and control?

Transmission of HIV through occupational exposure in healthcare personnel is rare. Indication for HIV Post-Exposure Prophylaxis (PEP) is driven by:

(1) Is source patient known to be HIV + or if unknown, is the source at high risk for HIV?

  • In occupational settings, the HIV antibody assay can usually resolve this.

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  • Results from rapid HIV antibody (Ab) assays should be considered as valid as standard HIV antibody assay results for making PEP decisions.

  • Occasionally, a source patient may be in the seroconversion “window period” (very recent HIV infection, before antibodies are measureable in serum).In these cases testing the source patient for HIV RNA or HIV p24 antigen (and Hepatitis C RNA) may be indicated.

  • Consider the seroconversion window period if the source patient had a recent (last 1-8 weeks) high risk HIV exposure, or if they have signs suggestive of an acute viral syndrome (e.g., fever, rash, fatigue, lymphadenopathy, myalgias, jaundice, or an aseptic meningitis, acute hepatitis, influenza-like, or mononucleosis-like syndrome).

  • Source patient should also be tested for Hepatitis B surface antigen (sAg), Hepatitis C Ab, and rapid plasma regain (RPR) for syphilis.

  • In non-occupational (sexual) exposure settings, source patient should be tested if available, but often is not, so a risk assessment should be performed.

(2) What is the timing of the exposure?

  • After mucosal exposure to HIV, establishing initial HIV infection may take 36-72 hours as infectious HIV is “shuttled” on the surface of mobile antigen presenting cells to the germinal centers of regional lymph nodes.HIV is then presented to CD4+ T-cells, which become infected and the HIV DNA “provirus” becomes integrated into the host’s DNA.

  • Beyond this 36-72 hour period, it may be more difficult to prevent HIV infection.

  • PEP should be initiated as soon as possible “hours, not days” and ideally within 24-36 hours. There is no evidence of PEP efficacy when initiated past 72 hours.

  • In view of this critical window for intervention, it is often advisable to initiate PEP immediately even if questions remain, re-evaluating over the next few days and discontinuing PEP if indicated.

  • PEP should be discontinued if a source patient of unknown serostatus is later found not to be HIV infected.

(3) What is the extent of the exposure?

Occupational:

  • Risk of transmission of HIV from percutaneous exposure is estimated to be about 0.3% (3 per 1000 exposures)].

  • Factors that increase risk of transmission include exposure through a visibly bloody device (odds ratio [OR], 6.2), through a device used to cannulate a blood vessel (OR, 4.3), via a deep injury (including intramuscular and subcutaneous exposure) (OR, 15.0), and from a source individual with more advanced HIV disease (and plasma HIV RNA level > 1500 copies/mL) (OR, 5.6).

  • Risk of transmission from splashing-type mucous membrane (e.g. conjunctiva, oral or nasal mucosa) or broken skin exposure is estimated as 0.09%.

  • For HIV transmission, substances or fluids that are considered infectious include blood, plasma, tissue, semen, vaginal secretions, and pus, as well as cerebrospinal, amniotic, pericardial, peritoneal, pleural, and synovial fluids.

  • Unless visibly bloody, substances generally considered non infectious include urine, feces, nasal secretions, gastric fluid, sputum, tears, sweat, and vomitus.

  • Non bloody saliva from bites, while generally felt to be minimally or non infectious can rarely be associated with HIV transmission.

Non-Occupational:

  • Risk of HIV infection from non-occupational exposure varies widely based on the nature of the exposure.

  • The estimated risk of transmission associated with sharing needles for injection-drug use is approximately 0.67% per needle-sharing contact.

  • The per episode risk associated with receptive anal intercourse is estimated to be ~ 1 to 30%, insertive anal or receptive vaginal intercourse, ~ 0.1 to 10.0%, and ~ 0.1 to 1.0% with insertive vaginal intercourse.

  • Oral sexual activity seems to be associated with a small but real risk based on case reports of HIV infection in persons in whom the only reported risk factor was oral intercourse.

  • In addition to type of exposure, risk of sexual HIV transmission is modified by numerous factors, among them presence or absence of active genital ulcers, cervical or anal dysplasia, male circumcision, and quantity of genital secretion HIV RNA.

  • Following initiation of ART, decline in the HIV RNA in genital tract secretions parallels that seen in the plasma.

  • Most but not all individuals with an undetectable plasma viral load also have an undetectable genital tract viral load.

  • Although suppressive antiretroviral therapy (ART) reduces the likelihood of HIV transmission, an undetectable plasma viral load does not mean an individual is noninfectious.

  • If an individual has unprotected vaginal or anal intercourse with someone known to be HIV positive on ART, it is currently accepted that PEP is still recommended even if the source is known to have a recent undetectable HIV RNA. This recommendation may be re-evaluated since the results of HPTN 052 were published showing that ART treatment was associated with a 96% risk reduction in sero-discordant couples [13]. It is important to note that HPTN 052 subjects in both the ART and no ART arms o this randomized trial were instructed in condom use.

  • The use of PEP in cases of non-occupational exposure (nPEP) is controversial (see discussion in “Controversies”).Risk assessments are used to help guide decisions on a case by case basis (see Figure 1).

After exposure, patients deemed at risk for HIV infection (with or without use of PEP) should have:

(1) Baseline and follow up laboratory testing:

  • Baseline: HIV Ab, Hepatitis B sAb, sAg, Hepatitis C Ab, RPR, serum creatinine, liver function tests, and complete blood count (CBC) with differential.

  • Follow up (typically at 4, 12, and 24 weeks): HIV Ab, and if initially negative (and source patient positive or unknown serology), Hepatitis B sAb, sAg, Hepatitis C Ab, and RPR.

  • Patients on zidovudine containing PEP should have liver function tests and CBC done at 2 weeks.

  • Patients should have symptom directed testing as needed for possible toxic side effects, typically including creatinine, electrolytes, liver function tests, and CBC with differential.

(2) Evaluation for Hepatitis B, Hepatitis C, and other sexually transmitted diseases:

  • Hepatitis B vaccination is recommended if the patient is Hepatitis B sAb and sAg negative.

  • Patients who have been exposed recently (within 1 week) to an HBsAg-positive source patient and who are negative for Hepatitis B sAb should considered for treatment with Hepatitis B immune globulin. Note: this will give the patient a positive Hepatitis B Ab test but does not imply they are infected. Hepatitis B sAg or DNA testing and hepatologist consultation may be useful in these cases.

  • Certain HIV drugs used for PEP are active against Hepatitis B (tenofovir, lamivudine, and emtricitabine) and require special consideration in exposed persons with pre-existing, active Hepatitis B (as evidenced by circulating Hepatitis B sAg and/or Hepatitis B DNA). These drugs suppress Hepatitis B replication and acute hepatitis flares may result when PEP is withdrawn. Extended transaminase monitoring, alternative PEP, and hepatologist consultation may be indicated.

  • Like Hepatitis B, Hepatitis C can be transmitted both percutaneously and sexually (especially among men who have sex with men).

  • If patient is Hepatitis C seronegative at baseline and at risk for Hepatitis C (source is Hepatitis C seropositive or in the seroconversion “window period”) consider baseline and 4, 12, and 28 week Hepatitis C RNA evaluations. Early Hepatitis C treatment may reduce possibility of chronic disease.

  • Screening and treatment (as needed) for syphilis, gonorrhea, and chlamydial infections should also be performed in patients who seek care after sexual exposure.

(3) Toxicity monitoring, as adverse event rates may reach 76% with gastrointestinal, headache, and fatigue complaints predominating:

  • Hepatitis, lactic acidosis, and toxic skin rashes are rare but potentially life threatening and typically require drug cessation.

  • Regular follow up, even weekly, in person, by email, or by telephone has been recommended to monitor toxicity and adherence.

(4) Adherence reinforcement, as the degree of adherence required for maximal benefit is not known (rates of 70-80% are typical).

(5) Counseling may be required to deal with the effects of this stressor on mental health.

Post Exposure Prophylaxis (PEP)

The goals for post-exposure management are to prevent HIV transmission while avoiding unnecessary PEP and PEP toxicity, and provide counseling and follow-up for exposed individuals. Guidelines for managing exposures and prescribing PEP for occupational and non occupational exposure to HIV have been published by the US Public Health Service (USPHS).

Guidance on risk assessment, PEP, and testing after exposure is available through PEPline, the National Clinicians’ Post-Exposure Prophylaxis Hotline. The PEPline service is staffed by trained HIV PEP experts and is available 24 hours a day, 7 days a week, free of charge at 888-448-4911. Generally, it may be preferable to start a basic 2 drug regimen awaiting consultation, rather than delay PEP.

When an HIV-positive source is already on ART, the PEP regimen should be adapted to the history of treatment, the degree of the source’s virologic suppression, and available drug resistance mutation analysis. Expert consultation may be advisable in these cases.

Empiric decisions regarding initial PEP selection are difficult when a source patient’s HIV is known or suspected (as suggested by a detectable HIV RNA or clinical progression of disease) to contain antiviral resistance mutations. Resistance testing of the source virus at the time of an exposure is impractical because the results will not be available in time to influence the choice of the initial PEP regimen. A small number of healthcare worker transmissions have be documented to occur when the source HIV strain was resistant to the agents used in PEP. Expert consultation is advised in this instance to help select drugs the virus is likely to be sensitive to. Note that no data suggest that modification of a PEP regimen after resistance testing results become available (usually 1–2 weeks) improves efficacy of PEP.

HIV PEP typically consists of a 28-day course of a basic (2 drug) or an expanded (3+ drug) regimen, depending on the severity or volume of exposure and HIV infection characteristics of the source person. USPHS PEP treatment algorithms were shown in Figure 1..

USPHS PEP recommendations for occupational HIV exposures are listed in Table I (percutaneous exposure) and Table II (mucous membrane and non intact skin exposure).

  • HIV-seropositive class 1 refers to a source individual with an asymptomatic infection or a plasma HIV RNA level less than 1500 copies/mL.

  • HIV-seropositive class 2 refers to a source individual who is symptomatic, has AIDS, has a plasma HIV RNA greater than 1500 copies/mL, or has known or suspected acute seroconversion illness as these individuals are typically highly infectious.

Where the HIV serostatus of the source individual is unknown, PEP should be considered based on exposure risk (as defined in Table I and Table II) in selected high-risk source populations among whom the seroprevalence of HIV infection is considered to be sufficient to justify the potential toxicity and cost of treatment. These high risk populations include: men who have sex with men, men who have sex with both men and women, commercial sex workers, injection-drug users, persons who are perpetrators of sexual assault, persons with a history of incarceration, persons from a country where the seroprevalence of HIV is 1% or greater, and persons who have a sexual partner belonging to one of these groups.

See Table III and Table IV for more information.

Diverging somewhat from the USPHS recommendations, New York State’s guidelines recommend one specific first-line regimen (zidovudine, lamivudine, and tenofovir). In addition, while included in the 2005 USPHS recommended PEP options, some experts have expressed concern over the use of efavirenz in PEP as resistance to this drug is common in some areas and have suggested that the protease inhibitors darunavir 800mg or atazanavir 300mg (each given with ritonavir 100mg once a day) may be substituted for lopinavir/ritonavir as part of a 3 drug PEP regimen. These once a day protease inhibitor options are more convenient and possibly better tolerated than lopinavir/ritonavir.

The PEP regimen should take into account potential drug interactions with concomitant medications. Protease Inhibitors including lopinavir/ritonavir are metabolized in part by the liver cytochrome p450 enzyme system and therefore may either reduce the efficacy (e.g., anti-epileptics, oral contraceptives, rifampin, and certain herbal medicine like Saint John’s wort) or increase the risk of toxicity (e.g., certain anti-arrhythmics, anti-cancer agents, anti-depressants, anti-fungal agents, macrolide antibiotics, calcium channel blockers, narcotics, sildenafil, statin drugs, ergot derivatives, some sedative/hypnotics, some recreational drugs such as ecstasy, and even some inhaled corticosteroids such as fluticasone). Non-nucleoside Reverse Transcriptase Inhibitors also have numerous drug-drug interactions. It is essential to review the patients other medications and updated PEP agent package inserts for drug-drug interactions. Expert consultation with an HIV specialist or pharmacist is recommended when potential for such interactions are suspected.

Individuals working abroad, particularly in developing countries and/or areas with high HIV seroprevalence, may want to consider taking a per­sonal supply of PEP if they are likely to be at risk from occupational HIV exposure (e.g., medical volunteers). Local antiretroviral options for PEP may be limited or of questionable authenticity.

Expert Consultation by local expert or by contacting the National Clinicians’ Post-Exposure Prophylaxis Hotline (telephone 888-448-4911) is advised by the USPHS for:

  • Known or suspected HIV source patient ART resistance.

  • Delayed (e.g., later than 48-72 hours – the interval after which benefit from PEP is undefined) exposure presentations.

  • Unknown source (e.g., needle in sharps disposal container or street) as PEP use is decided on a case-by-case basis.

  • Known or suspected pregnancy in the exposed person (use of optimal PEP regimens is not precluded).

  • Breastfeeding by the exposed person (use of optimal PEP regimens is not precluded).

  • Potential drug-drug interactions.

  • Toxicity of the initial PEP regimen. Adverse symptoms (e.g., nausea and diarrhea) are common with PEP and may be manageable without changing PEP regimen by prescribing antimotility or antiemetic agents, taking with meals, etc.

Summary of important clinical trials, meta-analyses, case control studies, case series, and individual case reports related to infection control and post-exposure prophylaxis for HIV infection.

A Cochrane review and current PubMED reviews identify no randomized clinical trials evaluating PEP efficacy at preventing occupationally acquired HIV infection. A single case-control study found that HIV transmission was significantly associated with deep injury (OR 15, 95% CI 6.0 – 41), visible blood on the device (OR 6.2, 95% CI 2.2 – 21), procedures involving a needle placed in the source patient’s blood vessel (OR 4.3, 95% CI 1.7 – 12), and advanced illness in the source patient (OR 5.6, 95% CI 2.0 – 16). Cases had significantly lower odds of having taken zidovudine after exposure compared to controls (OR 0.19, 95% CI 0.06 – 0.52). Another study suggested PEP was approximately 65% efficacious in preventing transmission to infants born to untreated HIV infected women when initiated within 48 hours of peripartum exposure.

A retrospective analysis of administration of non-occupational HIV PEP in a single Swiss center where tracing and testing of source patients was carried out systematically between 1998 and 2007 [23]. PEP requests increased by 850% over the 10 years. Among 910 events, 58% were heterosexual exposures, 15% homosexual exposures, 6% sexual assaults and 20% nonsexual exposures. In 208 events (23%), the source was reported to be HIV positive. In the remaining cases, active source tracing enabled 298 HIV tests to be performed (42%) and identified 11 HIV infections (3.7%). PEP was able to be avoided or interrupted in 31% of 910 events when the source tested negative. Of 710 patients who started PEP, 396 (56%) reported side effects, among whom 39 (5%) had to interrupt. There were two HIV seroconversions; neither was attributed to PEP failure.

Additional indirect evidence of PEP efficacy include macaque studies that show superior efficacy when PEP is given with 36 hours as compared to 72 hours post simian immunodeficiency virus (SIV) exposure. Tenofovir-Emtricitabine has been shown to be effective as pre-exposure prophylaxis in men who have sex with men.

Optimal duration of PEP has not been defined by controlled studies, although PEP is generally continued for 28 days, as macaque models have demonstrated incomplete protection when shorter courses PEP courses are employed following intravenous SIV challenge. There are no comparative efficacy studies of the various drugs, or 2 vs. 3 drug combinations used for PEP, so current recommendations are based on presumed efficacy and known tolerability (See Table V).

Overall, 3 drug PEP tends to have a higher (as high as 76%) adverse event rate than 2 drug PEP, with gastrointestinal, headache, and fatigue complaints predominating. Discontinuation rates appear to be similar. Transaminase elevations were seen more commonly in 3-drug PEP but less than 5% required early PEP discontinuation. While the risk benefit ratio of 3 drug may be desirable in higher risk settings or settings where HIV drug resistance is prevalent (>15%), mathematical modeling has suggested 2 drug PEP might be as or more effective due to enhanced tolerability and compliance. Tenofovir-containing regimens are generally better tolerated in PEP but should not be used when renal insufficiency is present.

Summary of current controversies.

1) The decision to initiate PEP is complicated and based on incomplete clinical and biological data. It represents a balance of risk and benefit for each individual patient. At a public health level, the costs of such treatment must be balanced against the risk of transmission associated with a given exposure. The interval after which PEP will have no benefit is not well defined and data are lacking to support a clear benefit when PEP is initiated >48 hours after exposure. Few studies and fewer still randomized trials comparing various regimens for PEP exist. The optimal number of antiretroviral agents to be used in a PEP regimen remains uncertain as the quantity and genetic diversity of infectious HIV typically delivered during all but the worst exposures is several orders of magnitude less that that seen when treating a patient with HIV. Thus, the treatment rules of 3+ drug therapy may not apply.

2) The role of newer antiretroviral agents in PEP needs clarification. Newer ritonavir-boosted protease inhibitors such as darunavir or atazanavir offer once a day dosing and potentially fewer side effects than lopinavir/ritonavir. Indeed, a recent survey showed that PEPline recommendations differed from USPHS guidelines recommendations in 14% of cases. Predictors for recommendations outside of the guidelines included certain source-person characteristics such as current use of specific antiretroviral drugs, prior antiretroviral drug exposure, antiretroviral drug resistance, and clinical status. Alternatives for the expanded regimen recommended by PEPline faculty in this 14% of cases included darunavir/ritonavir in 36% of cases, raltegravir in 31%, atazanavir/ritonavir in 18%, and maraviroc in 6% [33]. Because of their mechanisms of action, raltegravir, the first HIV integrase inhibitor, and maraviroc, the first C-C chemokine receptor 5–receptor antagonist, are both attractive options for prevention. In contrast to protease inhibitors, these drugs work before HIV latency is established, which is theoretically desirable. Experience with these agents for PEP is limited to isolated case reports and small case series in which their use appeared to be safe.

3) The role of mucosal drug concentration for prevention of mucosal /sexual transmission is not fully defined but may be important. Both tenofovir and emtricitabine have been shown to penetrate the genital tract well in animal models, reaching peak levels within 24 h of dosing, characteristics which may be advantageous for PEP in these settings. Both efavirenz and lopinavir had significantly lower concentrations in female genital secretions than tenofovir and lamivudine. Raltegravir and maraviroc have also been shown to achieve high levels in the genital tract.

4) PEP has become the standard of care for occupational exposures, but it remains controversial as a public health intervention for non-occupational exposures. In 2005, the USPHS recommended that “the provision of antiretroviral drugs to pre­vent HIV infection after unanticipated sexual or injection drug-use exposure might be beneficial. For persons seek­ing care <72 hours after (substantial) non-occupa­tional exposure to …a person known to be HIV infected . . . a 28-day course of highly active antiretroviral therapy is recommended”. Substantial was defined as exposure of vagina, rectum, eye, mouth, or other mucous membrane, non-intact skin, or percutaneous contact, WITH blood, semen, vaginal secretions, rectal secretions, breast milk, or any body fluid that is visibly contaminated with blood WHEN the source is known to be HIV-infected. If the source is of unknown HIV serostatus, USPHS recommends handling on a case-by-case basis.

Active source tracing with rapid HIV tests should be pursued when feasible as this strategy allows nPEP to be avoided or terminated early in many cases. Regardless if nPEP is employed, the healthcare worker should view these encounters as a prevention counseling opportunity.

To date, no pla­cebo-controlled data are available on the efficacy of non-occupational PEP (known as nPEP) and it is unlikely that nPEP clinical trials will be performed. Decisions to use nPEP are often made without knowing the HIV serostatus of the potential source. It may be difficult logistically for emergency departments or urgent care centers to obtain and initiate nPEP, or monitor the course of treatment. Safety and feasibility of nPEP programs have been demonstrated in several U.S and European metropolitan areas. Costs of nPEP may exceed $1000 for a 28-day course of treatment, which may not be a covered expense, effectively eliminating this as an option for some individuals. While nPEP is routinely offered in cases of sexual assault and often offered with isolated high risk exposures, its role with individuals who continue to engage in high risk behavior is particularly hard to define. There are concerns that nPEP could become analogous to a “morning-after pill”, though at least use of nPEP did not lead to an increase in high risk sex behaviors in men who have sex with men participating in the EXPLORE trial. The recent finding that pre-exposure prophylaxis with tenofovir-emtricitabine was shown to be effective in preventing HIV transmission in MSM will certainly become part of this deliberation.

5) Overtreatment in cases of occupational exposure to HIV is common. As long as the patient and healthcare provider are aware of the risks and benefits of PEP, initiating PEP even when there appears to be only minimal risk from the exposure may have the added value in reducing the anxiety typical in these settings. Such overtreatment represents a conservative approach from treating clinician’s perspective who desires to ensure the best chance that no HIV transmission occurs. While costly, few serious toxicities from PEP have been reported. It is worth noting that this approach may be effective, as no new cases of transmission via occupational exposures have been reported in more than 5 years. Certainly, other factors leading to a safer work environment (e.g., improvement in safety devices, personal safety training and practices, and institutional safety procedures) as well as fewer viremic HIV patients hospitalized due to effective treatment have contributed to this encouraging statistic.

What national and international guidelines exist related to post-exposure prophylaxis for HIV infection?

Occupational HIV Postexposure Prophylaxis (PEP) Guidelines

Current international guidelines all recommend the use of PEP for a duration of 28 days following an occupational exposure from with an individual known or likely to be HIV seropositive. Generally, PEP is recommended if it can be given within 72 hours of exposure, however, the European guidelines recommend a limit of 48 hours. All guidelines recommend HIV testing prior to commencing PEP to exclude pre-existing HIV infection. The European guidelines recommend using a three antiretroviral drug combination for PEP in all cases. The US and WHO guidelines recommend using two or three drugs based on risk assessment. See Table VI.

Non-Occupational HIV Postexposure Prophylaxis (nPEP) Guidelines

Current international guidelines recommend the use of nPEP for a duration of 28 days following sexual exposure with an individual known or highly likely to be HIV. Generally, nPEP is recommended if it can be given within 72 hours of exposure, however, the European guidelines recommend a limit of 48 hours. All guidelines recommend HIV testing prior to commencing PEP to exclude pre-existing HIV infection. The US, UK and European guidelines recommend using a three antiretroviral drug combination for PEP in all cases. The Australian and WHO guidelines recommend using two or three drugs based on risk assessment. See Table VII.

Unlike the other guidelines, which recommend a 48-72 hour window for eligibility for postexposure prophylaxis, New York State’s AIDS Institute guidelines recommend a 36-hour window and one specific first-line regimen (zidovudine, lamivudine, and tenofovir). New York ‘s guidelines also emphasize the nature of the exposure and downplay the presumed HIV status of the source. See Table VIII.

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