Animal Studies

The applicability of findings from studies of PEP in animals to human exposures to HIV is limited by differences in controlled variables (e.g., choice of viral strain (based on the animal model used), inoculum size, route of inoculation, time of prophylaxis initiation, and drug regimen).¹⁴ Most animal studies have used SIV or other nonhuman retroviruses that have different pathogenetic mechanisms from HIV-1 in humans. Furthermore, studies done to date have used higher viral inocula than are likely to be encountered in human exposures, as well as routes of exposure that may not be comparable to needlestick injuries or nonoccupational exposures. In studies of PEP in nonhuman primates, efficacy was greatest when prophylaxis was begun before or within a few hours after exposure; there was less apparent effect when drugs were begun later than 24–36 h postexposure, and when PEP was taken for shorter lengths of time. In one study performed in macaques, intravenously administered tenofovir (TDF) blocked SIV infection if administered within 24 h of intravenous viral inoculation and continued for 28 days. In comparison, only half of macaques treated for 10 days and none treated for 3 days were protected. Delaying initiation of treatment to 48 or 72 h postexposure also was less effective.¹⁵ Another study of macaques used a combination antiretroviral regimen of zidovudine (ZDV), lamivudine (3TC), and indinavir (IDV) initiated 4 h after intravenous simian/human immunodeficiency virus (SHIV) challenge and continued for 28 days. All animals became infected but had reduced viral loads.¹⁶

More recently, refinements in methodology have resulted in studies that are more relevant; in particular, the mucosal exposure routes have been used and viral inocula have been reduced to levels more analogous to human exposures but sufficient to cause infection in untreated animals.^17,18 These studies provide encouraging evidence of postexposure chemoprophylactic efficacy in the experimental setting. In a study of PEP following vaginal HIV-2 exposure, all macaques administered (R)-9-(2-phosphonylmethoxypropyl) adenine (now known as TDF) for 28 days, beginning 12 h (four animals) or 36 h (four animals) after exposure were protected. Breakthrough infection was observed in one of four animals treated 72 h after exposure, providing additional support for earlier administration of PEP.¹⁷

Human Studies

The data used to assess the efficacy of PEP after occupational exposures in humans are largely indirect. Because seroconversion after occupational HIV exposure is uncommon, a prospective trial would have to enroll thousands of exposed HCP to achieve the statistical power necessary to demonstrate PEP efficacy. During 1987–1989, the Burroughs-Wellcome Company sponsored a prospective placebo-controlled clinical trial among HCP to evaluate PEP with 6 weeks of ZDV.¹⁹ This trial was terminated prematurely because of low enrollment.²⁰ In view of current indirect evidence of PEP efficacy, it is unlikely that a placebo-controlled trial in HCP would ever be considered ethical.

The previously mentioned retrospective case-control study of HCP that assessed potential risk factors for HIV transmission after percutaneous exposure also found that use of ZDV as PEP was associated with a reduction in the risk of HIV infection by ∼81% (95% CI = 43–94%).⁴ ZDV was the only antiretroviral drug available for use as PEP during the period of this study.⁴ Additional supportive data on the efficacy of PEP come from studies of perinatal HIV transmission. In a randomized, controlled, prospective trial (AIDS Clinical Trial Group protocol (ACTG) 076), ZDV was administered to HIV-infected pregnant women and their infants. Administration of ZDV to the mother during pregnancy, labor, and delivery and to the newborn reduced transmission by 67%.²¹ This study showed that only 9–17% (depending on the assay used) of the protective effect of ZDV was explained by reduction of the HIV viral load in the maternal blood. This suggested that ZDV prophylaxis in part involves a mechanism other than the reduction of maternal viral burden.²² Subsequent studies of various PEP regimens to prevent perinatal transmission lend further support to the role of antiretroviral agents as prophylaxis against HIV infection transmission.^23,24 The chapter on management of the pregnant patient (Chapter 35) gives additional information about prevention of perinatal transmission of HIV.

The limitations of all of these studies in animals and humans must be considered when reviewing evidence of PEP efficacy. The extent to which data from animal studies can be extrapolated to humans is largely unknown, and the exposure route for mother-to-infant HIV transmission is not similar to occupational exposures; therefore, these findings may not be directly applicable to PEP in HCP.

Human data relevant to the potential efficacy of PEP for nonoccupational exposures are limited to observational studies and registries. There is no study analogous to the case-control study in HCP cited above.⁴ In general, the conclusions drawn from observational and registry data on nonoccupational exposures are limited by relatively small sample sizes and a relatively low number of seroconversions. Moreover, given the repetitive nature of the behaviors with which nonoccupational exposures are often associated, it can be difficult to determine with certainty whether a given infection resulted from the exposure for which PEP was taken. In the CDC registry of nonoccupational PEP (nPEP) use, among 785 reported exposures only one seroconversion was noted, which occurred in a person who took PEP following an insertive anal exposure. Because exposures occurred before and after the period in which nPEP was taken, it was difficult to determine whether the infection represented a true nPEP failure (CDC, unpublished data). Among 702 patients who received nPEP in a large feasibility study in San Francisco, seven seroconversions occurred. Three individuals reported no additional exposures after nPEP initiation which could have been the source of infection, though all reported other potential exposures in the 6 months prior to nPEP initiation.²⁵ In Australia, among 869 persons who returned 4 or more weeks postexposure for repeat HIV testing, no HIV seroconversions definitely related to treatment failure were observed.²⁶

Selection of HIV PEP Regimens

Determining which agents and how many to use as well as when to alter a PEP regimen is largely empiric.⁴⁷ In HIV-infected patients, combination regimens with three or more antiretroviral agents have proved superior to monotherapy and dual therapy regimens in reducing HIV viral load, reducing the incidence of opportunistic infections and death, and delaying onset of drug resistance in patients with established HIV infection.²⁷ Guidelines for the treatment of HIV infection, a condition usually involving a high total body burden of HIV, recommend the use of three or more drugs²⁷; however, the applicability of these recommendations to prevention of HIV transmission using antiretroviral PEP remains unknown.

Other guidelines (e.g., New York State, European Union) recommend different HIV PEP regimens for managing occupational exposures^48,49 as do guidelines for managing nonoccupational HIV exposure.^{2,38,50–54a,55,55a} The primary difference between the United States Public Health Service (USPHS) PEP recommendations for occupational HIV exposures and other PEP recommendations is the routine use of three or more drugs in PEP regimens. There are no definitive data that support the superiority of one HIV PEP regimen over another in preventing HIV transmission.