Liver and renal safety of tenofovir disoproxil fumarate in combination with emtricitabine among African women in a pre-exposure prophylaxis trial

Justin Mandala, Kavita Nanda, Meng Wang, Irith De Baetselier, Jennifer Deese, Johan Lombaard, Fredrick Owino, Mookho Malahleha, Rachel Manongi, Douglas Taylor, Lut Van Damme, Justin Mandala, Kavita Nanda, Meng Wang, Irith De Baetselier, Jennifer Deese, Johan Lombaard, Fredrick Owino, Mookho Malahleha, Rachel Manongi, Douglas Taylor, Lut Van Damme

Abstract

Background: Safety of tenofovir disoproxil fumarate/emtricitabine (TDF-FTC) has been studied more extensively among HIV-infected patients than among HIV-uninfected people. Using data from a pre-exposure trial - FEM-PrEP -, we determined the cumulative probabilities of grade 1+ ALT, AST and creatinine and grade 2+ phosphorus toxicities; ALT/AST toxicities by baseline hepatitis B status; and change in mean creatinine, phosphorus, ALT and AST levels controlling for TDF-FTC adherence.

Methods and findings: FEM-PrEP was a randomized, blinded, placebo-controlled trial of daily TDF-FTC among women in Africa. Enrolled women were in general good health, HIV antibody negative, 18 to 35 years old, hepatitis B surface antigen negative, and had normal hepatic and renal function at baseline. AST, ALT, phosphorus and serum creatinine were measured regularly throughout the trial. TDF-FTC concentrations were measured to assess adherence to TDF-FTC. The cumulative probabilities of grade 1+ creatininemia and grade 2+ phosphatemia toxicities were not statistically different between TDF-FTC and placebo arms. The cumulative probabilities of grade 1+ ALT and AST toxicities were higher among participants in the TDF-FTC arm than in the placebo arm (p = 0.03 for both). The proportions of grade 1+ and grade 2+ ALT or AST toxicities were significantly higher in participants who were hepatitis B virus surface antibody (HBsAb) positive than in those who were HBsAb-negative. Women with good adherence had higher mean change from baseline to week 4 in their AST levels (2.90 (0.37, 5.42); p = 0.025) than women with less than good adherence.

Conclusions: We did not observe a significant relationship between randomization to TDF-FTC and creatinine or phosphorus toxicities. Women randomized to TDF-FTC had higher rates of mild to moderate ALT/AST toxicities, especially women with prior hepatitis B virus exposure. We also observed a significant increase in AST from baseline to week 4 among women who had higher adherence to TDF-FTC during that interval.

Trial register: #NCT00625404, February 19, 2008.

Figures

Figure 1
Figure 1
Cumulative probability of grade 1+ creatinine toxicity, with number of participants at risk at the start of 4-week intervals (log-rank test, stratified on site, p = 0.128).
Figure 2
Figure 2
Cumulative probability of grade 2+ phosphorus toxicity, with number of participants at risk at the start of 4-week intervals (log-rank test, stratified on site, p = 0.621).
Figure 3
Figure 3
Cumulative probability of grade 1+ AST toxicity, with number of participants at risk at the start of 4-week intervals (log-rank test, stratified on site, p = 0.025).
Figure 4
Figure 4
Cumulative probability of grade 1+ AST toxicity, with number of participants at risk at the start of 4-week intervals (log-rank test, stratified on site, p = 0.025).

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Pre-publication history
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