Tolerability of Fosamprenavir/Ritonavir Associated With Zidovudine-Lamivudine Used as Postexposure Prophylaxis for HIV Infection

To the Editor: The French 2003 guidelines for management of postexposure prophylaxis (PEP) for human immunodeficiency virus (HIV) infection1 recommend the use of a 4-week course of triple antiretroviral therapy with 2 nucleoside analogues and 1 protease inhibitor in cases of both occupational and nonoccupational exposures. To our knowledge, the combination of zidovudine-lamivudine (Combivir) and fosamprenavir/ritonavir twice a day has not been tested for this indication. We decided to test this association; this choice was based on multiple arguments: The need to use a protease inhibitor as recommended in France with a limited burden of pills to improve patient adherence and with a not too expensive cost. We prospectively conducted a multicenter, single-arm study. Duration planned for study recruitment was 12 months. Adult subjects (18 years and older) who were attending the hospitals' emergency departments within the first 48 hours of an exposure associated with risk of HIV transmission (eg, occupational, accidental, sexual, needle share among intravenous drug users) and who were able to give informed consent were included. Initially, the clinician prescribed 3 days of medication. Further advice was given on day 2 by a physician specializing in HIV/AIDS, who decided to stop or to complete a 4-week course of treatment. The study treatment was selected for first-line PEP when resistance to these drugs was neither suspected nor proven in the source patient. If source patient was known to be infected by HIV, then an AIDS specialist was immediately consulted and helped to choose a regimen taking into account the source patient's medication history and any drug resistance. Before therapy, baseline sociodemographic characteristics, description of the exposure event, and HIV serostatus of the source patient were collected on a standardized form. First biological assessment was performed before first drug intake at day 0: HIV serology, hepatitis B surface antigen (HBsAg), anti hepatitis B surface antigen antibodies (HBsAc), hepatitis C virus (HCV) serology (except in case of sexual exposure or patient source known as HCV negative), complete blood cell count, aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea, creatinine, phosphatemia, amylase, blood glucose, triglycerides, cholesterol, and pregnancy testing (for women of child-bearing potential). Subsequently, at week 2 and at week 4, biological evaluations included complete blood cell count, AST, ALT, blood urea, creatinine, phosphatemia, amylase, blood glucose, triglycerides, and cholesterol. A clinical evaluation was also performed, and adherence and toxicity were recorded using a standardized form; this monitoring was done by a doctor to collect tolerability data and to call the persons included if they did not come back to the hospital; this method had a favorable impact on the number of lost to follow-up. Four weeks after treatment discontinuation, HIV p24 Ag was assessed. HIV and HCV serologies were assessed 3 months after treatment discontinuation. In case of occupational PEP, these serologies were repeated 6 months after treatment, as recommended in France. Between November 2005 and April 2006, 54 persons were included in the study in 6 French hospitals. Participants were mostly women (n = 31; 57.5%); mean age was 29.8 ± 9 years. Concerning the nature of exposure, the majority was sexual (n = 36; 66.7%) with 53% of men and a mean age of 28.3 years. Among these, 6 were men having sex with men; 30 participants reported heterosexual exposure (13 men and 17 women), of the latter, 3 cases involved rape. Occupational exposures accounted for 29.6% of cases (n = 16), with 75% of women and a mean age of 31.5 years. The remaining 2 cases (3.7%) were from other types of exposure. Both were women with a mean age of 45 years. The source patient was identified for 42 of the 54 cases. HIV serologic status was known for 18 source patients and was positive for 6. After these exposures, 5 study participants received a complete course of treatment and 1 had his treatment stopped at day 7 for intolerance. HIV serostatus remained unknown for 24 source patients. Five subjects were lost to follow-up before day 2 of PEP. Three persons withdrew from the study because of the decision to stop the study prematurely (see below). Safety analyses were based on the remaining 46 subjects (Fig. 1).FIGURE 1: Outcome of the persons included in the study.Twenty-four persons (52.2%) discontinued the treatment prematurely. Six discontinuations were due to adverse events, with a median onset time of 2 days. The median duration of treatment before discontinuation was 7.5 days. For the 18 others, treatment was stopped after the reevaluated HIV transmission risk was low or because the source patient was identified as HIV seronegative; 8 of these 18 subjects experienced at least one adverse event. Of the 22 subjects who completed their 28 days of treatment, 10 subjects reported no side effect and 12 (54.5%) had at least one self-reported significant adverse event. Overall, 26 of 46 subjects (56.5%) reported at least one adverse event. The most frequent adverse events were gastrointestinal: nausea and/or vomiting in 19 subjects (73%) and diarrhea in 15 subjects (57.5%). Sixteen subjects (61.5%) also reported asthenia and/or malaise. Cutaneous rash occurred in 3 subjects (11.5%, grade ≤2) of which 1 represented grade 2 generalized macular-papular rash. There was no significant difference in terms of tolerability according to age, sex, or type of exposure. Considering the 28 subjects who should have taken 28 days of treatment because of the high exposure risk, 18 (64.3%) reported at least one adverse event, which was the cause of treatment discontinuation for 6 of them. No clinical or biological grade 3 or 4 adverse event was observed in this cohort; no HIV, HCV, or hepatitis B virus infection has been documented. However, during the study, we were alerted by one participating center of the occurrence of 2 severe (grade 4) liver toxicities in subjects treated with zidovudine-lamivudine-fosamprenavir/ritonavir PEP outside the study.2 The decision was taken to discontinue the cohort immediately as other treatments were available at that time to prevent HIV infection transmission risk. Although the number of persons treated in our study is limited, we did not find high risk of toxicity when analyzing this combination tolerability in all the centers who participated in this study, specially when compared with other combinations, previously PEP combination tested in the same conditions: zidovudine-lamivudine-nelfinavir,3 zidovudine-lamivudine-lopinavir/ritonavir,4 zidovudine-lamivudine-tenofovir,5 and tenofovir-lamivudine-atazanavir/ritonavir once a day.6,7 However, in the present state of knowledge, we cannot therefore recommend to further prescribe fosamprenavir/ritonavir-zidovudine-lamivudine as a PEP, although this do not affect fosamprenavir use in HIV-infected patients. ACKNOWLEDGMENTS GlaxoSmithKline Laboratories for financial support. Christine Burty, MD* Simona Pavel, MD† Kamel Ghomari, MD† Annie Vermersch, MD† Bernard Christian, MD* Jean Pouaha, MD* Yazdan Yazdanpanah, MD† Thierry May, MD* Christian Rabaud, MD* *CISIH Lorraine Champagne-Ardenne Service de Maladies Infectieuses et Tropicales Centre Hospitalier et Universitaire de Nancy Vandoeuvre les Nancy, France †CISIH Nord, Service de Maladies Infectieuses et du Voyageur Centre Hospitalier de Tourcoing Tourcoing, France