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British Medical Bulletin 2005 73-74(1):93-105; doi:10.1093/bmb/ldh053
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Published online 5 October 2005

© The Author 2005. Published by Oxford University Press on behalf of The British Council. All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org

Prophylaxis of HIV infection

Ali S. Omrani* and Andrew Freedman

Infectious Diseases Unit, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK

* Correspondence to: Dr Ali S. Omrani, Infectious Diseases Unit, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK. E-mail: ali.omrani{at}doctors.org.uk


   Abstract
Top
 Abstract
Introduction
 Rationale for post-exposure...
 The risk of transmission...
 Management of exposure incidents
 Drug regimens
 Pre-exposure prophylaxis
 Conclusion
 References
 
The number of people infected with HIV continues to increase relentlessly. Post-exposure prophylaxis (PEP) following exposure to HIV infection may prevent established HIV infection. Such intervention is supported by biological plausibility and limited data from animal and human studies. Antiretroviral prophylaxis is associated with significant side effects and the risk should be weighed against the potential benefits. PEP should be considered after significant occupational and non-occupational exposures. However, PEP is not suitable for individuals with repeated high-risk behaviour who are not willing to adhere to risk reduction practices. Primary prevention strategies remain the mainstay for control of the HIV epidemic and cannot be replaced by PEP. Guidance for PEP following exposure to HIV infection is available in many countries worldwide.


   Introduction
Top
 Abstract
 Introduction
Rationale for post-exposure...
 The risk of transmission...
 Management of exposure incidents
 Drug regimens
 Pre-exposure prophylaxis
 Conclusion
 References
 
It has been over 20 years since the first description of the acquired immune deficiency syndrome (AIDS) and the subsequent isolation of the causative agent, the human immunodeficiency virus (HIV).1 Today, an estimated 40 million people live with the virus, including nearly 5 million infected in the year 2004.2 Although sub-Saharan Africa remains by far the worst affected region, the epidemic is rapidly growing in other parts of the world including East Asia, Eastern Europe and the Caribbean.2,3 Even in Western Europe and North America, where the wide availability of antiretroviral therapy has resulted in marked reduction in HIV-associated morbidity and mortality,4 the number of new cases diagnosed with HIV continues to rise year on year.2

Prevention of exposure is probably the only truly effective measure to control the HIV epidemic. However, despite global and local efforts to promote sexual abstinence and safer sex practices, over 90% of all new HIV infections are acquired sexually.2 Strategies such as counselling to reduce sexual risk behaviour,5 screening and treatment of sexually acquired infections,6 wider use of condoms,7 the use of vaginal microbicides,8 prevention of percutaneous sharps injuries among health care workers,9 needle-exchange programmes for intravenous drug users,10 and male circumcision11 may all be helpful, but have proved very difficult to implement and have disappointing success rates.2 Furthermore, although significant progress has been made, a safe and effective HIV vaccine is not likely to become available in the near future.12

With exposure proving impossible to eliminate, prophylaxis has emerged as a strategy to reduce the risk of transmission of HIV infection.


   Rationale for post-exposure prophylaxis
Top
 Abstract
 Introduction
 Rationale for post-exposure...
The risk of transmission...
 Management of exposure incidents
 Drug regimens
 Pre-exposure prophylaxis
 Conclusion
 References
 
The scientific rationale for post-exposure prophylaxis (PEP) using antiretroviral agents is supported by the finding that the virus is detectable in regional lymph nodes within 2 days of mucosal HIV infection and that systemic dissemination occurs after 4–11 days,13 allowing a window of opportunity for suppression of viral replication and possibly prevention of established infection. Support is also available from some animal studies. Macaques were protected against infection with simian immunodeficiency virus (SIV) when tenofovir was administered within 24 h of intravenous challenge and continued for 28 days, but not when it was commenced after 48 or 72 h, or when discontinued after 3 or 10 days.14,15 Tenofovir PEP was also successful in a HIV-2 pig-tailed macaque model when initiated up to 36 h after vaginal exposure.16 However, administration of antiretroviral PEP with zidovudine, lamivudine and indinavir within 4 or 72 h of exposure failed to protect macaques against infection with an SIV–HIV chimera.17 The results of such studies are influenced by the variation of the susceptibility of individual animals to infection and the pathogenicity of the virus strain used and cannot be directly extrapolated to humans. However, they do provide proof-of-concept that prompt PEP can protect against establishment of infection under defined experimental conditions.18

The efficacy of PEP in humans has not been examined in a large randomized controlled trial. A retrospective case–control study of HIV seroconversion in health care workers after percutaneous exposure showed that a 4-week course of zidovudine reduced the risk of HIV infection by 81% (95% confidence interval (CI), 48–94%).19 The study included 33 health care workers with occupationally acquired HIV infection from France, Italy, the UK and the USA. The cases and controls were identified using different data sources, and the authors conceded that, because of the study design, reporting and ascertainment bias could not be fully excluded.

In another study from Brazil, 200 individuals from a well-characterized cohort of high-risk HIV-seronegative homosexual men were provided with a 4-day course of zidovudine and lamivudine and instructed to commence PEP immediately after any high-risk sexual exposure. A full 28-day course was subsequently prescribed if the exposure was deemed significant. Thirty-four per cent of the participants initiated PEP during the follow-up period, with 10 seroconversions among the non-PEP users and only one PEP failure. However, the overall rate of new HIV infections did not differ significantly from that predicted in the absence of a PEP strategy, and the authors consequently questioned the public health impact of the intervention.20

Antiretroviral therapy has a clear role in the prevention of mother-to-child transmission of HIV infection.21 Antepartum and postpartum administration of zidovudine to mother and newborn, respectively, results in substantial reduction in perinatal transmission of HIV infection. Only a proportion of the protective effect of zidovudine is due to a reduction of the HIV titre in maternal blood, suggesting a direct protective effect for the fetus/infant.22 Rates of mother-to-child transmission of HIV infection were also significantly reduced following postnatal administration of zidovudine23 or zidovudine and nevirapine24 to infants born to HIV-infected mothers who received no antenatal or antepartum prophylaxis.

When considered together, the data support a potential protective role for PEP following exposure to HIV. However, the protective benefit of PEP in occupational and non-occupational settings will only be fully clarified by a prospective randomized controlled trial. Such a trial would be almost impossible to undertake, given the low HIV seroconversion rates following exposure, and the wide incorporation of HIV PEP into standard practice. Guidance on PEP following occupational25–27 and non-occupational28–30 exposure to HIV infection is available in many countries worldwide.


   The risk of transmission of HIV infection
Top
 Abstract
 Introduction
 Rationale for post-exposure...
 The risk of transmission...
Management of exposure incidents
 Drug regimens
 Pre-exposure prophylaxis
 Conclusion
 References
 
The likelihood of an individual acquiring HIV infection following exposure is a function of multiple factors relating to the individual, the source patient and the circumstances of the exposure.

Some individuals are less susceptible to HIV infection, including some high-risk commercial sex workers and homosexual men who remain HIV seronegative despite repeated exposure.31 Such reduced susceptibility may be due to underlying genetic variation. HIV binds to the CD4 molecule on susceptible cells, but cell entry requires the presence of a co-receptor. One example of a genetic variation conferring reduced susceptibility to HIV infection is seen in individuals who are homozygous for a deletion in the CCR5 co-receptor gene, resulting in relative resistance to HIV infection.32

Regardless of the circumstances of the exposure, high plasma HIV viral load is associated with increased infectiousness.19,22,33 Primary HIV infection, advanced HIV disease and failing antiretroviral therapy are all associated with high plasma HIV viral loads and thus increased HIV transmissibility.19,33 Sexual transmission of HIV infection is also increased by the presence of concomitant genital tract infection, menstruation and cervical ectopy.33

The nature and details of the exposure bear considerably on the probability of transmission of HIV infection (Table 1). In health care settings, the estimated risk of transmission of HIV infection is 0.3% (95% CI, 0.18–0.45%) after a documented percutaneous exposure to blood from an HIV-seropositive source and 0.03% (95% CI, 0.006–0.19%) after mucosal exposure to a similar source.34 The risk of transmission is higher after percutaneous exposure to larger volumes of blood as evidenced by deep injury, visible blood on the device causing the injury, or injury involving a device placed in the source patient’s artery or vein.19 Transfusion of HIV-antibody-positive blood is associated with an 89.5% (95% CI, 84.1–94.5%) risk of infection.35


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  		Table 1 Estimated risk of transmission of HIV infection per exposure

 

The risk of sexual transmission of HIV during unprotected intercourse is increased if it is associated with trauma or ejaculation and in the presence of other genital infections.33,36,37 The risk also varies depending on the type of sexual exposure. Data from epidemiological studies show that receptive anal intercourse between HIV serodiscordant individuals carries the highest risk of sexual transmission of HIV infection at 0.5–3% per contact.36,37 Significant risk is also associated with insertive anal intercourse (0.06%)38 and vaginal intercourse (0.01–0.1%).36,37 Receptive oral intercourse is associated with a relatively small risk of transmission (0–0.04%).38 Sexual transmission is reduced considerably if barrier contraceptives are used during intercourse.33,39 Needle sharing with an HIV-seropositive individual for intravenous drug use is associated with a risk of transmission of HIV infection of approximately 0.67%.40

It must be emphasized that these figures are general estimates and that the final probability of transmission depends on the interplay of the above factors in a particular incident. For example, unprotected intercourse with an individual who has primary HIV infection and an untreated sexually acquired infection would be associated with a much higher probability of infection.36,37 In contrast, the risk of infection is very small with protected vaginal intercourse between long-term serodiscordant partners in whom the HIV infected person is on effective antiretroviral therapy.36,37


   Management of exposure incidents
Top
 Abstract
 Introduction
 Rationale for post-exposure...
 The risk of transmission...
 Management of exposure incidents
Drug regimens
 Pre-exposure prophylaxis
 Conclusion
 References
 
The first stage of management of any exposure incident is a full risk assessment. This requires careful consideration of the individual and the source and circumstances of the exposure.

Occupational exposure

Health care personnel should be made aware of the possible risks from occupational exposure to HIV and other blood-borne viruses and the importance of seeking medical advice following any exposure. All health care employers are expected to have clear and specific local arrangements for the assessment and management of such incidents, including written policies and named departments and personnel responsible for providing such a service.25,26 Education programmes for health care workers should include instructions for immediate treatment of the exposure site. Wounds and skin sites that have been in contact with blood or other body fluids should be washed with soap and water; mucus membranes should be flushed with water. Scrubbing and the use of antiseptic skin washes should be discouraged.25,26

A careful evaluation of the circumstances of the exposure incident should follow. The potential for transmission of HIV infection is assessed based on the type of body fluid or substance involved and the route and severity of the exposure (Fig. 1). A significant exposure is defined as one that involves a body fluid or material and a mode of contact that are capable of transmission of HIV infection. Body fluids and materials which may pose a risk of HIV transmission include blood and any other visibly blood-stained body fluid, semen, vaginal secretions, and amniotic, cerebrospinal, synovial, pleural and pericardial fluids. Other materials, such as urine, vomit, saliva and faeces, are considered low risk unless visibly blood-stained (Table 2).26,41 Percutaneous injury from needles or other sharp objects and exposure through broken skin or mucus membrane are all associated with significant risk of transmission. Other factors associated with increased risk of transmission, such as deep injury or presence of visible blood on the device causing the injury, should also be considered at this stage.


Figure 1
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  		Fig. 1 Summary of the assessment and management of individuals following possible exposure to HIV infection.

 

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  		Table 2 Examples of high- and low-risk body fluids and substances

 

If the initial assessment indicates that an exposure is significant, efforts should be directed to establishing whether the source is infected with HIV. If the exposure is not considered to be significant, the health care worker should be reassured and counselled as appropriate and no further action taken.

The HIV serostatus of the source patient is often already known. If not, HIV testing, after counselling and consent, should be arranged as soon as possible.25–27 If consent for HIV testing is withheld or is not possible to obtain because of the source patient’s clinical status, local rules governing testing patients for serious communicable diseases without consent should be followed. In these circumstances, the importance of input from physicians with expertise in managing HIV-infected patients cannot be overemphasized. When the risk from the exposure is deemed significant, consideration should be given to starting antiretroviral prophylaxis pending the outcome of the HIV testing of the source.25,26

Post-exposure antiretroviral prophylaxis should be recommended to health care workers following a significant occupational exposure to HIV infection25–27 such as percutaneous injury by a sharp object contaminated by blood from a known HIV-infected source. However, antiretroviral therapy is associated with a range of adverse events and the risk of these should be weighed carefully against the potential benefits. PEP should be commenced as soon as possible after the event, ideally within 1 hour, and continued for 28 days. Some experts suggest that where the risk of HIV seroconversion is very high (e.g. following transfusion of HIV-infected blood products), PEP may be considered even if a number of days have elapsed since the exposure.25,26

Non-occupational exposure

Exposure to HIV infection may occur outside health care settings in the context of consensual unprotected sexual intercourse, sexual assault, sharing or injury by equipment used by intravenous drug users and accidentally in carers of patients with HIV. Data on the efficacy of PEP outside health care settings are very limited. Nevertheless, a number of PEP advisory groups recommend PEP following significant non-occupational exposure to a known HIV-infected source28–30 or a source of unknown HIV status who belongs to a high-risk group.28,29

The initial evaluation following a non-occupational exposure to HIV infection exposure should follow the pattern described above for the occupational setting. Examples of relatively higher risk exposures include receptive anal and vaginal intercourse and sharing drug-injecting equipment with a known HIV-seropositive individual. If the exposure is considered of significant risk, expert advice should be sought from physicians with experience in management of patient with HIV infection and the issues surrounding HIV PEP.

Whenever possible, the HIV status of the source should be established. In contrast with exposure in occupational settings, this is often not possible, especially in situations of sexual assault, sex with anonymous partners and sharp injuries caused by discarded needles. Knowledge of the background rates of HIV infection in various groups would help to assess the potential risk associated with a particular exposure.

Non-occupational PEP is only appropriate if exposure is not likely to be recurrent. PEP is not a ‘morning-after pill’ and cannot be considered as such. Individuals who undertake repeated high-risk exposures and are not committed to primary prevention and safer sex practices may not be appropriate candidates for PEP. There are concerns that interventions that are perceived to reduce the risk of HIV infection may lead to increased risk-taking behaviour and reduce reliance on established prevention strategies.42 However, the evidence suggests that this is not always the case.20,43

If indicated, PEP should be commenced as soon as possible after the exposure. Many experts do not recommend antiretroviral prophylaxis if >72 hours have elapsed since the non-occupational exposure.28–30 Management of the person considered for post-non-occupational HIV prophyl axis should include testing for HIV infection to confirm that they are not already infected,28–30 together with a detailed discussion of the lack of conclusive evidence of the efficacy of PEP in non-occupational settings, the potential adverse effects of the antiretroviral agents and the importance of adherence to improve efficacy and avoid emergence of resistance. Risk avoidance counselling, screening for sexually acquired infections and referral to drug addiction services should all be considered.


   Drug regimens
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 Abstract
 Introduction
 Rationale for post-exposure...
 The risk of transmission...
 Management of exposure incidents
 Drug regimens
Pre-exposure prophylaxis
 Conclusion
 References
 
Antiretroviral agents in routine use belong to four main classes (Table 3): nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) and entry inhibitors. Regimens for long-term treatment of HIV infection commonly comprise two NRTIs with either an NNRTI or a PI. Less commonly, regimens are made up of three NRTIs or drugs belonging to 3 or more groups. The administration of PIs in combination with a small dose of ritonavir (boosted PI regimen) results in an improved pharmacokinetic profile. Boosted PI regimens have all but replaced single PI therapy in the treatment of established HIV infection.


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  		Table 3 Antiretroviral drugs available for clinical use

 

Zidovudine is the only antiretroviral agent for which there is evidence of a reduction in risk of HIV transmission following occupational exposure.19 Nevertheless, combination antiretroviral therapy is recommended for PEP to achieve better suppression of viral replication.25–30 Furthermore, transmission of drug-resistant HIV is widely reported and has been associated with PEP failure on a number of occasions.34,44 However, post-exposure antiretroviral prophylaxis is poorly tolerated and is prematurely discontinued in 20–43% of cases.45 This has lead some expert groups to recommend regimens consisting of two NRTIs for low-risk exposures, and to reserve regimens incorporating three or more antiretroviral agents to high-risk incidents.25,46 Whenever possible, the specific choice of antiretroviral agents to be included in a PEP regimen should make use of the source’s treatment history and the results of any previous HIV resistance testing. Generic regimens based on the local patterns of HIV resistance may also be suggested.

Most experts advise against the routine inclusion of NNRTIs in PEP regimens.25,26,28,30 Nevirapine is associated with hepatotoxicity and skin rashes, and the risk of adverse events appears to be relatively high when it is used in HIV PEP.45,47 The other concern with nevirapine is that its use can result in a single-point mutation in the HIV reverse transcriptase gene, leading to high-level NNRTI resistance. In one study, nevirapine resistance mutations were detected in 19% of women who were tested 6–8 weeks after receiving a single dose of nevirapine to prevent mother-to-child transmission of HIV infection and in 46% of infants who acquired HIV infection despite nevirapine prophylaxis and had samples available for analysis.48 Efavirenz, on the other hand, is associated with considerable central nervous system side effects including sleep disturbances, vivid dreams, impaired concentration, dizziness and headache.49 Efavirenz side effects are particularly common in the first 4 weeks of therapy and may result in poor adherence if it is prescribed for HIV PEP.

A number of novel HIV entry inhibitors are currently at different stages of clinical development. These agents bind to HIV surface proteins or to T-cell co-receptors and inhibit viral attachment and entry to target cells.50 Such mechanisms of action may be attractive in the context of constructing HIV PEP regimens. However, enfuvirtide, which is the only HIV entry inhibitor approved for clinical use at present,51 has to be given by subcutaneous injection, making it unsuitable for routine use in PEP. Oral agents in this group will probably become available in the future,52 and it will be interesting to see their impact in this area.

For maximum efficacy, PEP should be commenced as soon as possible after the exposure. To avoid delays in commencing antiretroviral prophylaxis following significant exposure, starter packs containing a 3-day supply of the recommended medication should be made readily accessible at any time of day or night. Gastrointestinal side effects, such as nausea and diarrhoea, are particularly common with PEP,45 and antiemetics and antidiarrhoeal agents are often prescribed in conjunction with PEP to improve tolerance and adherence.

Follow-up

Regular medical follow-up during the period of PEP is necessary to provide ongoing support, to monitor for possible toxicity and to arrange further HIV testing at 3 and 6 months post-exposure. Failure of post-exposure antiretroviral prophylaxis is well documented,34 and the subject should not be reassured that infection has not taken place unless tests for HIV antibody are negative 6 months after cessation of PEP.26


   Pre-exposure prophylaxis
Top
 Abstract
 Introduction
 Rationale for post-exposure...
 The risk of transmission...
 Management of exposure incidents
 Drug regimens
 Pre-exposure prophylaxis
Conclusion
 References
 
HIV serodiscordant couples, commercial sex workers, individuals unwilling to use condoms and intravenous drug users are groups that are regularly at considerable risk of HIV infection. Pre-exposure antiretroviral prophylaxis has been suggested as a possible strategy for HIV prevention in such circumstances. Placebo-controlled trials are currently under way in Cameroon, Ghana, Malawi, Nigeria, Botswana, Thailand and the USA to assess the safety and efficacy of tenofovir pre-exposure prophylaxis in the prevention of HIV infection in high-risk populations.53,54 Participants in the studies are offered risk reduction counselling, male condoms to use during all sexual contacts and treatment for any symptomatic sexually transmitted infections. If proven, pre-exposure prophylaxis would be of great benefit for those who are less empowered to insist on condom usage, such as African women and commercial sex workers.


   Conclusion
Top
 Abstract
 Introduction
 Rationale for post-exposure...
 The risk of transmission...
 Management of exposure incidents
 Drug regimens
 Pre-exposure prophylaxis
 Conclusion
References
 
The burden of HIV/AIDS is greatest in developing countries, where access to antiretroviral therapy is very limited. Post-exposure antiretroviral therapy may reduce the risk of HIV infection, but cannot replace efforts that help to prevent HIV exposure. Primary prevention strategies continue to be the mainstay for control of the HIV epidemic and should include promotion of safe use and discarding of sharps and appropriate use of personal protective equipment in health care settings, encouraging safer sex practices, such as sexual abstinence, mutual monogamy and consistent use of condoms, provision of drug rehabilitation services and needle-exchange programmes for intravenous drug users, and education on the appropriate sterilization of drug-injecting equipment and the dangers of sharing such equipment.

Accepted for publication September 13, 2005.


   References
Top
 Abstract
 Introduction
 Rationale for post-exposure...
 The risk of transmission...
 Management of exposure incidents
 Drug regimens
 Pre-exposure prophylaxis
 Conclusion
 References
 

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