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Three Part Question

In [adults who have been sexually exposed to HIV] what is the [optimum timing of initiation and duration of postexposure prophylaxis] to [minimise risk of seroconversion]?

Clinical Scenario

It is 5pm on a Sunday afternoon. Your patient is a gentleman in his mid 20s who tells you that he had unprotected receptive anal sex on Thursday night with a man he now knows to be HIV positive, The patient is aware of PEP through literature he has seen in the GUM clinic, and requests a prescription. You calculate that 69 hours have passed between the exposure and now, and wonder if giving PEP at this time will reduce the risk of seroconversion.
When giving the patient details of the PEP prescription, he is surprised to learn that it is a 28-day course. You wonder if a 28-day course has proven to be more efficacious in reducing the rate of seroconversion compared to a shorter course.

Search Strategy

Medline 06/2006, Embase 1980-06/2006, Cinahl 1982-06/2006 using the OVID interface.
[HIV infection/pc] AND [postexposure prophylaxis.mp. OR PEP.mp.] AND [Anti-HIV agents/ad, tu] AND [NONOPEP.mp. OR NPEP.mp. OR nonoccupational exposure.mp. OR PEPSE.mp.]
exp Adenine AND antiviral agents and Simian Acquired immunodeficiency syndrome/pc
The initial search revealed recent guidelines for the provision of postexposure prophylaxis after sexual exposure to HIV. All cited the same article as evidence re the timing of initiation and the optimum duration of treatment. The keywords of this paper were used to form another search, to identify any other relevant papers.

Search Outcome

Two relevant papers were identified.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Tsai CC Emau P Follis KE Beck TW Benveniste RE Bischofberger N Lifson JD Morton WR 1997 USA	24 cynomologous macaques (12 female, 12 male) 2.5-3.5 years old, all clinically healthy and free of type-D retrovirus and SIV prior to intravenous inoculation with SIV. 5 groups of 4 reeived a PEP regime (administered initially 24 hours post-exposure, continued for 28 days; administered initially 48 hours post-exposure, continued for 28 days; administered initially 72 hours post-exposure, continued for 28 days; administered initially 24 hours post-exposure, continued for 10 days; administered initially 24 hours post-exposure, continued for 3 days) while the sixth group received a placebo.	Animal study.	Systemic infection with SIV (as determined by quantification of SIV RNA in plasma, antibody determination and virus isolation from plasma 46 weeks after exposure.	All four of the placebo group developed systemic infection. Of the group which received PEP initiated 24 hours post-inoculation and continued for 28 days, three out of the four showed no evidence of systemic infection after 46 weeks. Of the group which received PEP initiated 48 hours post-inoculation and continued for 28 days, two out of the four showed no evidence of systemic infection after 46 weeks. Of the group which received PEP initiated 72 hours post-inoculation and continued for 28 days, two out of the four showed no evidence of systemic infection after 46 weeks. Of the group which received PEP initiated 24 hours post-inoculation and continued for 10 days, three out of the four showed no evidence of systemic infection after 46 weeks. Of the group which received PEP initiated 24 hours post-inoculation and continued for 3 days, twoout of the four showed no evidence of systemic infection after 46 weeks.	An animal study, thus results may not be directly applicable to humans. No blinding or randomisation. Small groups; no power calculation reported
Otten RA Smith DK Adams DR Pullium JK Jackson E Kim CN Jaffe H Janssen R Butera S Folks TM 2000 USA	6 naive female pig-tailed macaques aged 3 - 5 years weighing 5.5 - 8.5 kg, inoculated vaginally with at least 100 times the pig-tailed macaque infectious dose of HIV-2 before being commenced (at 12, 36 or 72 hours post-exposure) on a 28-day postexposure prophylaxis regime of tenofovir or a placebo.	Animal study	The presence (or otherwise) of systemic HIV-2 infection (defined as detection of HIV-2 provirus in PMBC or |ILN cells and/or virion-associated HIV-2 RNA 24 weeks post inoculation).	None of the four macaques who received PEP 12 hours after exposure developed systemic infection. None of the four macaques who received PEP 24 hours after exposure developed systemic infection. None of the four macaques who received PEP 36 hours after exposure developed systemic infection. One of the three macaques (initially four, one fatality not due to the treatment) who received PEP at 72 hours developed systemic infection.	Animal study, thus may not be directly applicable to humans

Comment(s)

There exists a window of opportunity between exposure to HIV and development of systemic infection, and PEP exploits that. The median time from sexual exposure to HIV to treatment was shown to be 33 hours in San Francisco, and it is likely to be similar in the UK [[Kahn JO Martin JN Roland ME Bamberger JD Chesney M Chambers D Franses K Coates TJ Katz MH. Feasibility of Postexposure Prophylaxis. Journal of Infectious Diseases 2001;183:707]]. Tsai et al's study administered PEP at 12, 24 and 72 hours, i.e. at timeframes that were within the window of opportunity for the possible prevention of the development of systemic infection, but that were realistic to human behaviour and the ability to access healthcare services.

Clinical Bottom Line

The earlier PEP is initiated, the less likely is seroconversion. PEP should be continued for 28 days to minimise chance of seroconversion.

References

1. Tsai CC Emau P Follis KE Beck TW Benveniste RE Bischofberger N Lifson JD Morton WR Effectiveness of Postinoculation (R)-9-(2-Phosphonylmethoxypropyl) Adenine Treatment for Prevention of Persistent Simian Immunodeficiency Virus Infection Depends Critically on Timing of Initiation and Journal of Virology 1998 4265-4273
2. Otten RA Smith DK Adams DR Pullium JK Jackson E Kim CN Jaffe H Janssen R Butera S Folks TM Efficacy of Postexposure Prophylaxis After Intravaginal Exposure of Pig-tailed Macaques to a Human-derived Retrovirus (Human Immunodeficiency Virus Type 2) Journal of Virology 2000; 9771-9775