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

Mandala et al. BMC Pharmacology and Toxicology 2014, 15:77 Liver and renal safety of tenofovir disoproxilfumarate in combination with emtricitabineamong African women in a pre-exposureprophylaxis trial Justin Mandala1*, Kavita Nanda2, Meng Wang2, Irith De Baetselier3, Jennifer Deese2, Johan Lombaard4,Fredrick Owino5, Mookho Malahleha6, Rachel Manongi7, Douglas Taylor2 and Lut Van Damme1,8 Background: Safety of tenofovir disoproxil fumarate/emtricitabine (TDF-FTC) has been studied more extensivelyamong 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 levelscontrolling for TDF-FTC adherence.
Methods and findings: FEM-PrEP was a randomized, blinded, placebo-controlled trial of daily TDF-FTC among womenin Africa. Enrolled women were in general good health, HIV antibody negative, 18 to 35 years old, hepatitis B surfaceantigen negative, and had normal hepatic and renal function at baseline. AST, ALT, phosphorus and serum creatininewere 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 statisticallydifferent between TDF-FTC and placebo arms. The cumulative probabilities of grade 1+ ALT and AST toxicities werehigher among participants in the TDF-FTC arm than in the placebo arm (p = 0.03 for both). The proportions ofgrade 1+ and grade 2+ ALT or AST toxicities were significantly higher in participants who were hepatitis B virus surfaceantibody (HBsAb) positive than in those who were HBsAb-negative. Women with good adherence had highermean change from baseline to week 4 in their AST levels (2.90 (0.37, 5.42); p = 0.025) than women with less thangood adherence.
Conclusions: We did not observe a significant relationship between randomization to TDF-FTC and creatinine orphosphorus 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 toweek 4 among women who had higher adherence to TDF-FTC during that interval.
Trial register: , February 19, 2008.
Keywords: Pre-exposure prophylaxis, HIV, Safety, Women, Africa, Tenofovir disoproxil fumarate, Emtricitabine * Correspondence: 1FHI 360, 1825 Connecticut Ave, Suite 800, NW, Washington, DC 20009, USAFull list of author information is available at the end of the article 2014 Mandala et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver applies to the data made available in this article,unless otherwise stated.
Mandala et al. BMC Pharmacology and Toxicology 2014, 15:77 Context: FEM-PrEP study Decades into HIV prevention research, there is strong The details of the FEM-PrEP study have been described evidence that the use of antiretrovirals (ARV) as pre- elsewhere The trial was approved by all applicable exposure prophylaxis (PrEP) significantly reduces the ethical and regulatory committees and participants pro- risk of acquiring HIV infection in men and women vided written informed consent before any procedures While the safety of tenofovir disoproxil fumarate were performed. Women were recruited from Pretoria and (300 mg)/emtricitabine (200 mg) (TDF-FTC) has been Bloemfontein, South Africa; Bondo, Kenya; and Arusha, extensively studied among HIV-infected patients, limited Tanzania. Eligibility criteria required that women be HIV data are available among HIV-uninfected people antibody negative, 18 to 35 years old, in general good Here we report on the hepatic and renal safety of TDF- health, hepatitis B virus surface antigen (HBsAg) ne- FTC in a pre-exposure prophylaxis clinical trial – FEM- gative and have no evidence of abnormal hepatic or renal PrEP – among HIV negative women in Africa function at baseline (i.e., serum creatinine < 1.5 mg/dl, cre- FEM-PrEP was a randomized, double-blind, placebo- atinine clearance ≥ 60 ml/min estimated by the Cockcroft- controlled trial of once-daily oral TDF-FTC in Africa Gault method, ALT and AST <2× local upper limit of among women at high risk of acquiring HIV via sexual normal [ULN] and serum phosphorus levels above intercourse. The study was stopped early due to futility, the lower limit of the normal range and below DAIDS likely due to low adherence to the daily oral regimen by grade 3). Participants attended study visits at screening, study participants ].
enrollment (2–4 weeks later), and at 4-week intervals The primary safety endpoints included grade 2+ cre- thereafter for up to 60 weeks (52 weeks on product atinine toxicities and grade 3+ alanine aminotransferase followed by eight weeks off product). Plasma and upper (ALT), aspartate aminotransferase (AST), and phos- layer packed cell (ULPC) aliquots were stored for TDF- phorus based on the U.S. NIH, NIAID Division of AIDS FTC concentration testing at monthly visits; hepatic and (DAIDS) grading table and on local normal ranges renal (AST, ALT, creatinine and phosphorus) parameters Secondary safety outcomes included grade 1+ ALT, AST were evaluated at weeks 4, 12, 24, 36, 52, 56 and when and creatinine toxicities and grade 2+ phosphorus. Due clinically indicated ].
to overall low TDF-FTC exposure in the study popula-tion, we also conducted exploratory analyses controlling Laboratory analysis for actual TDF drug levels AST, ALT, phosphorus and serum creatinine assays were We report on the cumulative probabilities of grade 1+ performed according to manufacturer procedures. Sam- ALT, AST and creatinine toxicities and grade 2+ phos- ples were processed within two hours after collection. The phorus; ALT/AST toxicities by baseline hepatitis B status; VITROS DT II instrument (Ortho-Clinical Diagnostics, and change in means of creatinine, phosphorus, ALT and Inc., Johnson & Johnson, Buckinghamshire, UK) was used AST levels controlling for TDF-FTC adherence.
in Kenya until May 2010, thereafter the VITROS 250(Ortho-Clinical Diagnostics, Inc., Johnson & Johnson,Buckinghamshire, UK), the CX5 Beckman Chemistry Analyzer (Beckman Coulter, Inc, Fullerton, CA, USA) was used at both South African sites and the Cobas Integra 400 The trial and informed consent forms were approved by Plus (Roche Diagnostics GmbH, Mannheim, Germany) all applicable ethics and regulatory committees: The Pro- was used at the Tanzanian site.
tection of Human Subjects Committee of FHI360, the US Site-specific laboratory normal ranges (LNR) were Food and Drug Administration, the ethics committee (EC) used due to unknown population similarities/differences of the University Hospital of Antwerp, the Institutional and different instrumentation used across sites. Manu- Review Board of ITM, the Kenyatta National Hospital/ facturer recommended, or nationally/regionally estab- University of Nairobi Ethics and Research Committee, the lished LNRs were used during the first two to three Republic of Kenya Ministry of Health (MoH- Pharmacy & months of the trial while site-specific LNRs were deve- Poisons Board), Kilimanjaro Christian Medical Center loped. The local LNR was identified and verified, using Research EC of Tanzania, National Institute for Medical Sigma Diagnostic guidelines, by the central laboratory Research of Tanzania, London School of Hygiene and (Institute of Tropical Medicine, Antwerp, Belgium) Tropical Medicine EC, Tanzania Food and Drugs Authority, Details of the verification process will be described in a Medunsa Campus Research and EC of South Africa, separate manuscript. Locally verified ranges were used University of the Free State EC and Medicines Control for final grading of all biochemistry toxicities in Kenya Council of South Africa. Written informed consent was and South Africa. In Tanzania, due to the delay in study obtained from all participants prior to conducting any initiation and early closure of the trial, local LNR were study procedures.
not verified; manufacturer LNRs were used instead.
Mandala et al. BMC Pharmacology and Toxicology 2014, 15:77 The central laboratory provided on-site training in Study product was immediately discontinued in partici- good clinical laboratory practice and technical training pants who HIV seroconverted.
for all protocol-required laboratory tests, and conductedquality assurance activities including co-development of site standard operating procedures (SOPs) and analytical The analysis population consisted of all women rando- plans, assay and equipment validation, external quality mized into the trial, excluding participants who never re- assessment (EQA) schemes, and equipment calibration ceived study product, returned all product unused, or and maintenance. In addition, central lab staff conducted, never returned for a follow-up visit. TDF-FTC concen- at a minimum, annual site visits to verify proper conduct tration data were available for a random sub-cohort of of laboratory procedures and review source data.
150 participants assigned TDF-FTC, (50 from each of TDF-FTC concentration analysis on stored samples was the three sites where HIV infections took place, i.e., conducted at the University of North Carolina at Chapel Bloemfontein, Pretoria and Bondo).
Hill. Tenofovir (TFV) was measured in plasma and teno-fovir diphosphate (TFV-DP) in ULPC. Laboratory proce- Statistical analyses dures for TDF-FTC concentration analysis were published Cumulative probabilities of grade 1+ creatinine, ALT and previously ]. Adherence was qualitatively classified AST and grade 2+ phosphorus were plotted with data on a 6-point scale based on drug concentration data, with pooled across sites by treatment group over time using the top two adherence scores being "good" and "excellent" Kaplan-Meier methods. In addition, the number and of (good = plasma TFV levels >10 ng/ml and ULPC intracel- percentage of women experiencing toxicities by grade lular TFV-DP between 100,000-1,000,000 femtomoles/ were summarized by baseline HBsAg status and treat- million cells, excellent = plasma TFV levels >10 ng/ml and ment group; fisher exact tests were used to compare dif- ULPC intracellular TFV-DP between >1,000,000 femto- ferences between groups.
moles/million cells) For the random sub-cohort of 150 women in the TDF- FTC arm, we further assessed the association between ad- Management of toxicity and study product interruptions herence to TDF-FTC and change from baseline to week 4 Protocol-defined toxicities were defined and managed in creatinine, phosphorus, ALT, and AST levels using according to clinical assessment, grade and relatedness generalized linear models, with adjustment for baseline to the study product as assessed by study clinicians level, age, body mass index, oral contraceptive (OC) use at Study product was temporarily or permanently with- enrollment and study site. A similar analysis was done for drawn as per protocol-described criteria.
change from last visit on-product and first visit after pro- Hepatotoxicity grade 2 was defined as 2.6 -5.0 × upper duct use ceased (at study exit or earlier product with- limit of normal (ULN), if determined to be related to the drawal). SAS 9.3 (SAS Institute, Cary, NC) was used for study product, the study product was interrupted and all analyses; statistical significance was defined as p ≤ 0.05.
was restarted only if AST/ALT decreased to ≤ grade 1.
Hepatotoxicity grade 3 was defined as 5.1 - 10.0 × ULN and study product was interrupted independent of re- Characteristics of enrolled population latedness assessment. Study product was restarted if AST/ The analysis included a total of 2,058 women who were ALT decreased to ≤ grade 1. Hepatotoxicity grade 4 was enrolled during June 2009 to April 2011. There were 701 defined as > 10.0 × ULN and study product was perma- and 707 person-years of follow up in the TDF-FTC and nently withdrawn independent of relatedness.
placebo arms respectively. Demographic characteristics, Creatininemia grade 1 was defined as 1.1 -1.3 × ULN medical history and self-reported sexual behavior at and grade 2 as 1.4 -1.8 × ULN; study product was inter- baseline have been reported elsewhere and were ge- rupted for both grades regardless of the relatedness to nerally similar between both groups At enrolment study product use and was restarted if creatininemia de- 20.8% and 21.4% of participants were hepatitis B surface creased to < grade 1 or < 1.3× baseline. Study product antibody (HBsAb) positive in the TDF-FTC and placebo was permanently withdrawn for creatininemia grade 2 arms respectively.
determined to be related to the study product, and forany creatininemia grade 3 (>1.8 × ULN) Study product was also permanently withdrawn when The cumulative probabilities of grade 1+ creatinine or there was hypophosphatemia associated with elevated grade 2+ phosphatemia toxicities were higher in the creatininemia, low creatinine clearance or proteinuria. In TDF-FTC arm, although neither of these differences case of pregnancy, study product was interrupted and re- were statistically significant (Figures and sumption allowed after delivery and completion of breast- Six participants developed grade 2+ creatininemia: feeding or with evidence of pregnancy loss/termination).
four (0.4%) in the TDF-FTC arm and two (0.2%) in the Mandala et al. BMC Pharmacology and Toxicology 2014, 15:77 Hepatic toxicityThe cumulative probabilities of grade 1+ ALT and ASTtoxicities were higher among participants in the TDF-FTC arm than in the placebo arm (p = 0.03 for both)(see Figures and Sixteen participants developed grade 3+ ALT and/or AST toxicities: eight in the TDF-FTC arm and eight inthe placebo arm. Baseline AST/ALT levels among theseparticipants were comparable to the average ALT/ASTin their respective sites. In three of these 16 participants,the grade 3+ ALT/AST occurred at the time of HIVseroconversion (one in the TDF-FTC arm and two inthe placebo arm), and 11 of the 16 (six in the TDF-FTCarm and five in the placebo arm) events occurred in par- Figure 1 Cumulative probability of grade 1+ creatinine toxicity, ticipants who had received the hepatitis B vaccine. Six with number of participants at risk at the start of 4-week participants (two in the TDF-FTC arm and four in the intervals (log-rank test, stratified on site, p = 0.128).
placebo arm) with grade 3+ ALT/AST toxicities reportedtaking a concomitant medication at the time of the placebo arm. Their baseline creatininemia levels were event; medications included acetaminophen, ibuprofen, comparable to the average baseline creatininemia at diclofenac and metronidazole. All grade 3+ ALT/AST their respective sites. Among the four participants in the toxicities were resolved between two and eight weeks TDF-FTC arm, the grade 2+ creatininemia resolved after without any difference in time to resolution between 1, 2, 16 and 28 weeks respectively; among the two in the TDF-FTC and placebo arms. One participant (in the pla- placebo arm, one resolved after 6 weeks and decreased cebo arm) with grade 3+ ALT at week 12 never returned to a grade 1 for 10 weeks in the second participant. The to the study clinic despite intense tracing efforts. Drug latter participant was referred to a nephrologist at the level data were available for seven participants in the closing of the trial; she later self-reported that her cre- TDF-FTC arm with grade 3+ ALT/AST: two were clas- atinine returned to normal, though results could not be sified as having excellent adherence, one as having good validated by the study team.
adherence and four as non-adherent in the interval be- None of the six participants with grade 2+ creatininemia fore the event.
reported taking concomitant medication at the time of the At one site – Bondo – the proportion of grade 2+ AST event. TDF-FTC drug concentration data were available toxicities was significantly higher in the TDF-FTC arm for the four participants in the TDF-FTC arm: one was (5.0%) than in the placebo arm (1.9%) (p = 0.02). Also, classified as having excellent adherence, two as having overall, Bondo observed higher proportions of grade 1+ good adherence, and one as not adherent in the interval AST toxicities (43.1% in TDF-FTC arm vs. 36.4% in prior to the event.
placebo arm) compared to Bloemfontein (5.7% vs. 3.7% Figure 2 Cumulative probability of grade 2+ phosphorus Figure 3 Cumulative probability of grade 1+ AST toxicity, with toxicity, with number of participants at risk at the start of number of participants at risk at the start of 4-week intervals 4-week intervals (log-rank test, stratified on site, p = 0.621).
(log-rank test, stratified on site, p = 0.025).
Mandala et al. BMC Pharmacology and Toxicology 2014, 15:77 study drug, making it impossible to assess the impact ofcontinuous exposure over longer periods and liver/kidney function. However, the percentage of womenwith evidence of good adherence in their first four weeksof participation ( 40%) was sufficient to assess the im-pact of short-term drug use. We observed that womenwith evidence of good adherence had higher meanchange from baseline to week 4 in their AST levels (2.90(0.37, 5.42); p = 0.025) as compared to women with lessthan good adherence. However, corresponding changesin ALT (1.54 (−1.44, 4.52); p = 0.31), creatinine (0.19(−2.60, 2.98); p = 0.89) and phosphorus (0.02 (−0.04,0.08); p = 0.53) were not statistically significant. We didnot observe an association between adherence to TDF- Figure 4 Cumulative probability of grade 1+ AST toxicity, with FTC and change in ALT, AST, creatinine or phosphorus number of participants at risk at the start of 4-week intervals levels between the final drug-use interval and four weeks (log-rank test, stratified on site, p = 0.025).
after product withdrawal.
respectively), Pretoria (2.9% vs. 2.4% respectively), and Arusha (0% vs. 3.6% respectively). At baseline, Bondo par- In this article we report on change (grade 1+) in renal ticipants had a higher exposure to hepatitis B.
and hepatic function among African women who were In the TDF-FTC arm, the proportions of grade 1+ and assigned to the active TDF-FTC arm of a randomized, grade 2+ ALT or AST toxicities were significantly higher placebo-controlled clinical trial of HIV pre-exposure in participants who were HBsAb positive than in those prophylaxis. While we did not find significant differences who were HBsAb negative; for grade 1+, 31.6 vs. 22.4% in renal functions, we observed a significant increase in respectively, p < 0.007 and for grade 2+, 5.6 vs. 2.6% re- the cumulative probabilities of grade 1+ hepatotoxicity, spectively, p < 0.047 (Table In the placebo arm, only as measured by ALT and AST, among women assigned the proportion of grade1+ ALT or AST toxicities was significantly more frequent in HBsAb positive parti- Our safety findings are comparable to other PrEP stu- cipants vs. HBsAb negative participants; 29.5 vs. 17.1%, dies which also did not observe more frequent renal p < 0.001 (Table toxicity in the active arm than in the placebo one [ With regard to hepatic toxicity, we observed more fre- TDF-FTC concentrations and observed kidney or hepatic quent elevated ALT or AST in participants with previous exposure to hepatitis B virus; which is consistent with TDF-FTC concentration data from a sub-cohort of 150 the finding in the Bondo site of significantly more grade women indicated that very few consistently took the 2+ AST toxicities and higher population exposure to Table 1 Laboratory toxicities during scheduled follow-up in the TDF-FTC arm by previous exposure to HBV HBsAb negative (N=804) HBsAb positive (N=215) Grade 1 or higher Grade 2 or higher Grade 3 or higher PHO G2+ and creatininemia Grade 1 or higher Grade 2 or higher Grade 3 or higher #Difference in the proportions of participants experiencing toxicities.
Mandala et al. BMC Pharmacology and Toxicology 2014, 15:77 Table 2 Laboratory toxicities during scheduled follow-up in the placebo arm by previous exposure to HBV HBsAb negative (N=808) HBsAb positive (N=224) Grade 1 or higher Grade 2 or higher Grade 3 or higher PHO G2+ and creatininemia Grade 1 or higher Grade 2 or higher Grade 3 or higher #Difference in the proportions of participants experiencing toxicities.
hepatitis B virus (39% in Bondo vs. 13%, 10% and 32%, 2.0 mg/dL . HIV/AIDS patients treated with ARVs can in Bloemfontein, Pretoria, and Arusha, respectively).
develop kidney and/or liver toxicity for many other rea- Additional observations are needed to confirm this pre- sons than the use of TDF-FTC: HIV infection itself, other liminary finding, particularly in settings where hepatitis ARVs or any other medication to manage their HIV/AIDS B virus prevalence is high and TDF-FTC will be con- condition. In our study, participants were HIV uninfected sidered for PrEP. Drug-induced liver injury (DILI) is a and healthy at baseline and took limited concomitant possible explanation of our findings. DILI has been de- medication ].
scribed in patients with pre-existing hepatic illness like Our analysis and conclusions are also limited by non-alcoholic fatty liver disease (NAFLD), hepatitis C short overall TDF-FTC exposure (i.e., follow-up was < = virus related chronic hepatitis Our study was 52 weeks); studies and expert opinions suggest that kid- not designed to verify association between our observa- ney toxicities may increase over time with prolonged ex- tions and any of these specific pre-existing conditions.
posure to TDF-FTC None of the laboratory toxicities observed was accom- The main limitation of our study is the limited adhe- panied by specific renal or hepatic clinical symptoms.
rence of participants to the study drug; only about 40% The lack of clinical symptoms is likely due to the rela- exhibited good adherence during any given test interval, tively moderate level of the toxicities observed, frequent and far fewer exhibited consistently good adherence over testing and subsequent interruption or withdrawal of the the course of their participation Nonetheless, in the study product.
TDF-FTC arm we observed higher cumulative proba- Although these data indicate that the use of TDF-FTC bilities of grade 1+ of ALT/AST and a higher proportion as PrEP is safe with regard to kidney and hepatic toxicity, of participants with grade 2+ ALT/AST when previously the results must be considered in light of overall low ad- exposed to HBV.
herence to study product. Further, our study used theserum creatinine level and the Cockcroft-Gault formula to assess glomerular filtration and phosphatemia to assess In our study population of healthy young African proximal tubular function. Some studies have suggested women, we did not observe a significant relationship that more sophisticated formulas – e.g. four-variable between randomization to TDF-FTC and creatinine or Modification of Diet in Renal Disease formula (MRDR phosphorus toxicities although we were limited in our equation) ] – and multifactor algorithms are more ability to adequately assess these relationships due to accurate in assessing glomerular filtration and proxi- overall low adherence to the study product. Women ran- mal tubular function. In a study comparing tenofovir- domized to TDF-FTC had higher rates of mild to mo- containing to tenofovir-sparing HAART in patients living derate ALT/AST toxicities, especially women with prior with HIV, Horberg et al., using the MDRD equation, hepatitis B virus exposure. We also observed a signifi- found that the tenofovir-exposed group had a statistically cant increase from baseline to week four in AST values greater percentage of patients with glomerular filtration among women who were highly adherent to TDF-FTC decline but not creatininemia rising to greater than during that interval.
Mandala et al. BMC Pharmacology and Toxicology 2014, 15:77 Competing interests Karras A, Lafaurie M, Furco A, Bourgarit A, Droz D, Sereni D, Legendre C, The authors declare that they have no competing interests.
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to the study staff, to the communities who partnered with us to conduct the Van Damme L, Corneli A, Ahmed K, Agot K, Lombaard J, Kapiga S, trial, and to all of our collaborators in Africa, Belgium, and the United States. The Malahleha M, Owino F, Manongi R, Onyango J, Temu L, Monedi MC, views expressed in this publication do not necessarily reflect those of FHI 360, Mak'Oketch P, Makanda M, Reblin I, Makatu SE, Saylor L, Kiernan H, the funding agencies, or Gilead Sciences, Inc. JM, KN, MW, IDB, JD, JL, FO, MM, Kirkendale S, Wong C, Grant R, Kashuba A, Nanda K, Mandala J, Fransen K, RM, DT and LVD for the FEM-PrEP Study Group.
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Cite this article as: Mandala et al.: Liver and renal safety of tenofovir Thigpen MC, Kebaabetswe PM, Paxton LA, Smith DK, Rose CE, Segolodi TM, disoproxil fumarate in combination with emtricitabine among African Henderson FL, Pathak SR, Soud FA, Chillag KL, Mutanhaurwa R, Chirwa LI, women in a pre-exposure prophylaxis trial. BMC Pharmacology and Kasonde M, Abebe D, Buliva E, Gvetadze RJ, Johnson S, Sukalac T, Thomas Toxicology 2014 15:77.
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Gibt es depressive Tiere? Wird es Fischen nie langweilig? Darf man Menschenaffen einsperren? Interview mit Olivier Pagan, dem Direktor des Basler Zoos «Als Direktor muss man einen Panzer entwickeln»: Olivier Pagan im Basler Zoo etwas engagiert, egal was, gibt es Gegner. Dian Fossey, die sich Dann lassen Sie zu, dass sich Tiere paaren, obwohl Sie wis-

Microsoft word - statewide sexual violence awareness events 2007.doc

Vermont Network Against Domestic and Sexual Violence 802-223-1302 x 23 Vermont Network Against Domestic & Sexual Violence Sexual Violence Awareness Month April is National Sexual Violence Awareness Month. Across Vermont communities will be coming together to raise awareness about the pervasiveness of sexual violence in our state through a variety of events happening in every corner of the state.