Tolerability of Two Different Combinations of Antiretroviral Drugs Including Tenofovir Used in Occupational and Nonoccupational Postexposure Prophylaxis for HIV

Dear Editor:

Before 1996, one study concerning occupational exposure in nurses have suggested that treatment with zidovudine soon after exposure to HIV decreases the risk of infection. ¹ Now, based on the assumption that the maximal suppression of viral replication afforded by highly active antiretroviral therapy (two nucleosidic analogue plus one protease inhibitor) will provide the best chances of preventing infection, postexporsure prophylaxis (PEP) French guidelines recommended the use of a three-drug combination in cases of both occupational and nonoccupational exposures. ²

However, during full 4-week PEP regimen, side effects have been very frequently reported. Antiretroviral agents appeared more poorly tolerated among persons taking HIV PEP than among HIV-infected patients on antiretroviral medications; adverse events occur in more than two thirds of otherwise healthy persons receiving multidrug PEP regimen ³ and one author has suggested that the frequency of adverse events was approximately 8 times higher during PEP than during treatment of documented HIV infection. ⁴ Then, as a result of toxicity and side effects, a substantial proportion of the persons receiving PEP are unable to complete a full 4-week course of HIV PEP (range, 17%–47%). ⁵ Thus, to improve the efficacy of PEP, the choice of regimens must be considered in order to increase the adherence rate and to decrease the treatment interruption rate.

We have previously successively tested two antiretroviral combinations. Using zidovudine/lamivudine plus nelfinavir association (AZT/3TC/NFV), 85% of subjects experienced adverse effects, resulting in nelfinavir discontinuation in 35% of cases. ⁶ Then, we have recommended that nelfinavir be avoided in PEP. Afterwards, we have evaluated in similar conditions the tolerability of the zidovudine/lamivudine plus lopinavir/ritonavir soft-gel capsules combination (AZT/3TC/LPVsg): 59% of subjects experienced adverse effects, resulting in PEP discontinuation in 20% of cases. ⁷ Although AZT/3TC/LPVsg PEP combination appeared significantly better tolerated than the AZT/3TC/NFV combination (adverse events 59% versus 85%, p = 0.0002; PEP discontinuation for adverse events 20% versus 35%, p = 0.025), tolerability was not reasonably good. We thought that better-tolerated PEP combinations must therefore be sought and compared to AZT/3TC/LPVsg PEP.

Considering other available antiretroviral agents, several are recommended to be avoided because of possible toxicity: abacavir because rechallenge has been associated with life-threatening hypersensitivity reactions; nevirapine because fulminant liver failure has been reported when used as PEP medication ⁸ ; efavirenz because serious central nervous adverse effects may be occurred specially in emotionally unstable victims of HIV exposure; indinavir because its use is frequently associated with nephrolithiasis; stavudine plus didanosine combination due to the risk of lactic acidosis and lipoatrophy occurrence.

Multiple primate model studies have established the efficacy of (R)-9-(2-phosphomethoxypropyl) adenine (PMPA) or its derivative, tenofovir DF, in preventing simian immunodeficiency virust (SIV) and SHIV transmission after significant exposures. ^9,10 Administering tenofovir 24 hours after virus inoculation for 4 weeks prevented SIV infection in all of the macaques. So we first decided to evaluate the association of tenofovir with zidovudine/lamivudine (AZT/3TC/TDF).

In order to improve the adherence, we have decided to test another PEP regimen with a reduced pill burden (reduced number of pills and reduced number of daily intake): tenofovir and lamivudine again, associated with atazanavir, the first protease inhibitor that could be used once a day in France, when boosted by ritonavir (TDF/3TC/ATZ/r).

This letter reports results regarding tolerability concerning these two PEP regimens. Two single-arm, multicenter, prospective studies were successively conducted between 2004 and 2007, under the same conditions and with the same methodology used during our previously published studies. ^6,7 Adult subjects (18 or more years of age) who were attending the hospitals' emergency departments within the first 48 hours of an exposure associated with risk of HIV transmission and who were able to give informed consent were included. The study treatment was selected for first-line PEP when resistance to these drugs was neither suspected nor proven in the source patient. Subsequently, at week 2 and at week 4, biologic and clinical evaluation was performed, and adherence and toxicity were recorded using a standardized form; 171 subjects were included in the AZT/3TC/TDF and 152 in the TDF/3TC/ATZ/r study; subjects were male in 58.5% and 57.5% of the cases, respectively; inclusion occurred after sexual exposure in 58.5% and 72% of the cases, respectively; 13.5% and 17% of subjects were lost to follow-up, respectively. PEP was discontinued before day 28 because the source patient was tested negative for HIV or because the injury was reassessed as “low risk” in 17% and 14% of the cases, respectively; 2% and 3% of these subjects, respectively, experienced at least one adverse event before PEP discontinuation.

PEP was discontinued before day 28 for adverse effects in 18% and 21%, respectively; the median duration of treatment before discontinuation was 7 and 7.5 days, respectively. PEP was continued for 28 days, as scheduled, in 57% and 55%, respectively, but these subjects experienced at least one adverse effect (which did not lead to stop PEP) in 45.5% and 43.5%, respectively.

The most frequent adverse events reported were, respectively, in AZT/3TC/TDF and TDF/3TC/ATZ/r study: nausea-vomiting, 89% and 64%; diarrhea, 40% and 38%; asthenia, 78% and 77%. No clinical grade 3 or 4 adverse event was observed. Concerning biologic data, no grade 4 abnormalities were observed; liver toxicity of grade 3 occurred rarely: 0.8% and 0.9%, respectively. Concerning TDF/3TC/ATZ/r PEP, hyperbilirubinemia (≥grade 1) was observed in 87% of the cases: grade 3, 8%; grade 4, 1%; ocular icterus and/or jaundice was observed in 66% of the cases but only two persons stopped PEP because jaundice occurred. At the end of the study, serologic data were available for the majority of subjects and no HIV infection has been documented.

Tolerability data recorded during these two successive studies were compared with those collected during previous studies (Table 1). We did not find significant difference in term of tolerability when comparing the two-drug combinations, AZT/3TC/TDF and TDF/3TC/ATZ/r. Also, we did not find differences between either of the two-drug regimens and AZT/3TC/LPV used as PEP and previously evaluated in similar conditions. However, these three-drug combinations appeared significantly better tolerated than AZT/3TC/NFV PEP.

Considering the similar rate of discontinuation due to adverse events, the many cases of jaundice that appeared during TDF/3TC/ATZ/r PEP even though patients did not complain about this, and that PEP appeared more expensive than AZT/3TC/LPV we finally did not recommend TDF/3TC/ATZ/r as PEP.

Tolerability appeared similar between AZT/3TC/LPV and AZT/3TC/TDF. And the latest combination appeared less expensive than AZT/3TC/LPV. So, even if latest French guidelines ¹¹ recommended the use of protease inhibitors because, in theory, a combination of drugs with activity at different stages in the viral replication cycle might offer an additive preventive effect in PEP, we think that AZT/3TC/TDF must be considered as an alternative to the use of AZT/3TC/LPV as PEP.