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Tenofovir

Klassificering: A

Preparat: Atripla, Descovy, Efavirenz/Emtricitabine/Tenofovir disoproxil Krka, Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan, Efavirenz/Emtricitabine/Tenofovir disoproxil Teva, Emtenef, Emtricitabin/Tenofovirdisoproxil Ebb, Emtricitabine/Tenofovir disoproxil Accord, Emtricitabine/tenofovir disoproxil Krka, Emtricitabine/Tenofovir disoproxil Mylan, Emtricitabine/Tenofovir disoproxil Sandoz, Emtricitabine/Tenofovir disoproxil STADA, Emtricitabine/Tenofovir disoproxil Teva, Eviplera, Genvoya, Ictady, Odefsey, Padviram, Stribild, Symtuza, Tenofovir disoproxil Accord, Tenofovir disoproxil Glenmark, Tenofovir disoproxil Mylan, Tenofovir disoproxil Sandoz, Tenofovir disoproxil STADA, Tenofovir disoproxil Teva, Truvada, Vemlidy, Viread, Viread®

ATC kod: J05AF07, J05AF13, J05AR03, J05AR06, J05AR08, J05AR09, J05AR17, J05AR18, J05AR19, J05AR22

Substanser: tenofoviralafenamid, tenofoviralafenamidfumarat, tenofovirdisoproxil, tenofovirdisoproxilfosfat, tenofovirdisoproxilfumarat, tenofovirdisoproxilmaleat, tenofovirdisoproxilsuccinat

Sammanfattning

Påtagligt färre kvinnor än män var inkluderade i de pivotala studierna. En studie som analyserade könsskillnader visade likartad effekt hos båda könen. Vad gäller biverkningar har illamående och lipodystrofi visats vara vanligare hos kvinnor. Försämrad njurfunktion har beskrivits hos patienter behandlade med tenofovir men könsanalyser saknas.

Additional information

Antiretrovirals for treatment of HIV are always given as a combination of at least three medicines. Cobicistat is used to boost the effect of other antiretroviral drugs. As studies on HIV patients always include patients receiving combination therapy it is difficult to know which of the studied medicines that cause changes in effect and/or adverse events.

Pharmacokinetics and dosing

In patients on triple highly active antiretroviral therapy regimen including 300 mg of tenofovir disoproxil (20 men, 7 women), women were found to have higher tenofovir triphosphate concentrations compared to men [1]. The manufacturer reports that there are no major differences in pharmacokinetics between men and women with the caveat that this is based on limited data [2, 3]. The manufacturer does not recommend different dosing in men and women [2, 3].

Effects

Both men and women have been included in most of the randomized studies of the effect and safety of tenofovir, but the number of women was low, overall (around 20%) [4].

In a randomized study on HIV-1-infected adults (1040 men, 328 women) treated with rilpivirine or efavirenz plus tenofovir/emtricitabine or tenofovir/emtricitabine, zidovudine/lamivudine or abacavir/lamivudine no difference between men and women was found in response rate [5]. In contrast, a cross-sectional observational study from Zimbabwe in non-pregnant or breast-feeding HIV patients (32 men, 86 women) on stavudine, tenofovir or zidovudine combined with lamivudine and nevirapine or efavirenz women had a lower odds ratio of treatment failure [6].

In an Ethiopian analysis of a treatment program with tenofovir disoproxil fumarate in patients with chronic Hepatitis B (162 men, 138 women), men had higher risk of fibrosis [7]. Similar findings were made in a Zambian cohort of HIV-positive patients with and without HBV infection treated with tenofovir disoproxil fumarate-containing antiretroviral treatment (214 men, 249 women) [8].  Significant fibrosis/cirrhosis was found to decreased in frequency from 14.0% to 6.7%. Higher age, male sex, and HBV coinfection predicted significant fibrosis/cirrhosis at 1 year [8]. Also a registry based cohort study in patients with chronic Hepatitis B treated with entecavir or tenofovir  (923 men, 402 women) found the risk of hepatocellular carcinoma to be higher in men [9]. Other associated risk factors were lower platelet, higher age and presence of cirrhosis [9].

Adverse effects

If the risk of tenofovir associated nephrotoxicity differs in men and women is unclear as different studies have shown conflicting results. An Italian cohort study in HIV patients on antiretroviral treatment (1082 men, 423 women) a higher risk of renal impairment was seen in women, older patients, those who had diabetes and/or hypertension, and in patients with higher baseline CD4. Current exposure to didanosine, tenofovir or protease inhibitors was the major determinants [10]. Similarly, a retrospective data base study in tenofovir disoproxil fumarate treated HIV patients (114 men, 49 women) found a negative impact of high through concentrations of tenofovir on renal filtration in both men and women. In women but not in men, a tenofovir disoproxil fumarate concentration >90 ng/mL was predictive of renal impairment which suggests an earlier or greater susceptibility of renal toxicity in women [11]. In contrast to this in a study where patients with HIV and a few co-infected with HBV or HCV (in all, 171 men, 104 women) were retrospectively followed-up for three years to evaluate risk factors involved in impaired renal function men were found to have a higher risk. Of these, 97% were on tenofovir/lamivudine based treatment. After 36 months of tenofovir use, patients showed impairment of renal function that worsened over time, men more than women [12]. Yet another retrospective case-note audit from the UK of children (31 boys, 39 girls) with perinatally-acquired HIV treated with tenofovir disoproxil fumarate found no association between children’s sex and nephrotoxicity [13].

Nausea and lipodystrophy have been found to be more common in women treated with antiretroviral treatments containing tenofovir [5, 14-16]. In a randomized study on HIV-1-infected adults (1040 men, 328 women) treated with rilpivirine or efavirenz plus tenofovir/emtricitabine or tenofovir/emtricitabine, zidovudine/lamivudine or abacavir/lamivudine nausea was more common in women than in men in both treatment groups while abnormal dreams/nightmares were more frequent in men. Diarrhoea was more frequent in men in the efavirenz group [5]. Similarly, a study of side effects in persons receiving post-exposure treatment with zidovudine, lamivudine, and tenofovir found women at higher risk for nausea [14].

A retrospective analysis of the presence of lipodystrophy in a randomized, placebo-controlled study of tenofovir disoproxil fumarate or stavudine (d4T) in antiretroviral-naive adults (444 men, 156 women) increasing age, female sex and higher baseline triglycerides were found to be independent risk factors [15]. A similar finding was made in a large European cohort study of safety and tolerability in HIV patients on antiretroviral treatment (958 men, 336 women). Women had a higher risk of treatment discontinuation than men (hazard ratio [HR], 1.54; 95%CI: 1.28, 1.85) but no increased risk of viral failure (HR, 1.06; 95%CI: 0.85, 1.33). Compared to men, women had less diarrhea and severe lipid disturbances but more lipodystrophy [16] .

In a small cohort study in HIV-1 infected adults on stable antiretroviral regimes comparing biochemical and bone mineral density parameters between patients receiving either tenofovir or another nucleoside reverse transcriptase inhibitor (43 men, 13 women) non-white men but not women, on tenofovir had higher PTH levels than non-white men not on tenofovir (mean difference 3.1 pmol/L, 95% CI 5.3 to 0.9; p = 0.007) [17].

In a study on glucose tolerance in HIV-infected adults on efavirenz, tenofovir, and emtricitabine (40 men, 30 women) half of the subjects were obese and these were matched with 30 obese HIV-negative controls. HIV-infected women on non-nucleoside reverse transcriptase inhibitor-based antiretroviral treatment had superior glucose tolerance and lower plasma metabolites associated with the development of diabetes compared with men with similar metabolic disease risk profiles. The relationship between patients’ sex and plasma metabolite levels did not significantly differ according to HIV-status among obese subjects, suggesting the observed sex-differences may not be specific to HIV infection [18].

In a prospective study of patients with chronic Hepatitis B (69 men, 38 women) treated with lamivudine (7,5%), tenofovir (35.5%), entecavir (31.8%) or combined treatment (25.2%) found a significant time trend for developing lactic acidosis over time in women with cirrhosis [19].

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).

Other information

A descriptive retrospective Brazilian study on HIV patients on highly active antiretroviral therapy those who modified their treatment within the first year of treatment (52 men, 35 women) were mostly men. Efavirenz was the most often changed drug, followed by tenofovir, zidovudine and lopinavir/ritonavir [20].

An east African registry based studied lipid profiles in patients with HIV (55 men, 176 women) treated with zidovudine (76%), efavirenz (66%), zidovudine and efavirenz in combination with lamivudine (42%), zidovudine and lamivudine in nevirapine (34%), and the remaining tenofovir-based treatments (24%). They found increased LDL in 60% of the patients, no difference between men and women. However, men were twice as likely to have decreased HDL-C [21]

A review has described drug exposure in the genital tract of men and women which is of interest in viral transferal and in effect of pre-exposure prophylactic treatment. In men, concentrations in seminal fluid were described to be highest for nucleoside analogues and lowest for protease inhibitors and efavirenz. Seminal accumulation of raltegravir and maraviroc was defined as moderate. The rank order of accumulation presented in the review is nucleoside/nucleotide reverse transcriptase inhibitors [lamivudine/zidovudine/tenofovir/didanosine > stavudine/abacavir] > raltegravir > indinavir/maraviroc/nevirapine >> efavirenz/protease inhibitors [amprenavir/atazanavir/darunavir > lopinavir/ritonavir > saquinavir] > enfuvirtide. In the female genital tract, the nucleoside analogues also were described as having high accumulation ratios, whereas protease inhibitors have limited penetration; however, substantial variability exists. Second generation non-nucleoside reverse transcriptase inhibitor etravirine, and maraviroc and raltegravir, have been found to demonstrate effective accumulation in cervicovaginal secretions. The rank of accumulation presented in the review is nucleoside/nucleotide reverse transcriptase inhibitor [zidovudine/lamivudine/didanosine > emtricitabine/tenofovir] > indinavir > maraviroc/raltegravir/darunavir/etravirine > nevirapine/abacavir > protease inhibitors [amprenavir/atazanavir/ritonavir] > lopinavir/stavudine/efavirenz > saquinavir [22].

Försäljning på recept

Fler män än kvinnor hämtade ut läkemedel innehållande tenofovirdisoproxil (ATC-kod J05AF07) på recept i Sverige år 2017, totalt 696 män och 453 kvinnor [23].

Fler män än kvinnor hämtade ut läkemedel innehållande tenofoviralafenamid (ATC-kod J05AF13) på recept i Sverige år 2017, totalt 44 män och 20 kvinnor [23].

Uppdaterat: 2019-04-08

Litteratursökningsdatum: 2018-07-18

Referenser

  1. Pruvost A, Negredo E, Théodoro F, Puig J, Levi M, Ayen R et al. Pilot pharmacokinetic study of human immunodeficiency virus-infected patients receiving tenofovir disoproxil fumarate (TDF): investigation of systemic and intracellular interactions between TDF and abacavir, lamivudine, or lopinavir-ritonavir. Antimicrob Agents Chemother. 2009;53(5):1937-43. PubMed
  2. Viread (tenofovir disoproxil). Summary of Product Characteristics. European Medicines Agency (EMA); 2018.
  3. Vemlidy (tenofovir alafenamide). Summary of Product Characteristics. European Medicines Agency (EMA); 2018.
  4. Cooper RD, Wiebe N, Smith N, Keiser P, Naicker S, Tonelli M. Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients. Clin Infect Dis. 2010;51(5):496-505. PubMed
  5. Hodder S, Arasteh K, De Wet J, Gathe J, Gold J, Kumar P et al. Effect of gender and race on the week 48 findings in treatment-naïve, HIV-1-infected patients enrolled in the randomized, phase III trials ECHO and THRIVE. HIV Med. 2012;13(7):406-15. PubMed
  6. Chawana TD, Reid A, Bwakura T, Gavi S, Nhachi CF. Factors influencing treatment failure in HIV positive adult patients on first line antiretroviral therapy. Cent Afr J Med. 2014;60(5):29-36. PubMed
  7. Aberra H, Desalegn H, Berhe N, Medhin G, Stene-Johansen K, Gundersen SG et al. Early experiences from one of the first treatment programs for chronic hepatitis B in sub-Saharan Africa. BMC Infect Dis. 2017;17(1):438. PubMed
  8. Vinikoor MJ, Sinkala E, Chilengi R, Mulenga LB, Chi BH, Zyambo Z et al. Impact of Antiretroviral Therapy on Liver Fibrosis Among Human Immunodeficiency Virus-Infected Adults With and Without HBV Coinfection in Zambia. Clin Infect Dis. 2017;64(10):1343-1349. PubMed
  9. Papatheodoridis G, Dalekos G, Sypsa V, Yurdaydin C, Buti M, Goulis J et al. PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy. J Hepatol. 2016;64(4):800-6. PubMed
  10. Tordato F, Cozzi Lepri A, Cicconi P, De Luca A, Antinori A, Colangeli V et al. Evaluation of glomerular filtration rate in HIV-1-infected patients before and after combined antiretroviral therapy exposure. HIV Med. 2011;12(1):4-13. PubMed
  11. Poizot-Martin I, Solas C, Allemand J, Obry-Roguet V, Pradel V, Bregigeon S, Faucher O, Lacarelle B. Renal impairment in patients receiving a tenofovir-cART regimen: Impact of tenofovir trough concentration. J Acquir Immune Defic Syndr 2012 Nov 28; PubMed
  12. Pinto Neto LF, Bassetti BR, Fraga IH, Oliveira Santos CR, Ximenes PD, Miranda AE. Nephrotoxicity during tenofovir treatment: a three-year follow-up study in a Brazilian reference clinic. Braz J Infect Dis. 2016;20(1):14-8. PubMed
  13. Lim Y, Lyall H, Foster C. Tenofovir-Associated Nephrotoxicity in Children with Perinatally-Acquired HIV Infection: A Single-Centre Cohort Study. Clin Drug Investig. 2015;35(5):327-33. PubMed
  14. Luque A, Hulse S, Wang D, Shahzad U, Tanzman E, Antenozzi S et al. Assessment of adverse events associated with antiretroviral regimens for postexposure prophylaxis for occupational and nonoccupational exposures to prevent transmission of human immunodeficiency virus. Infect Control Hosp Epidemiol. 2007;28(6):695-701. PubMed
  15. Law M, Puls R, Cheng AK, Cooper DA, Carr A. Evaluation of the HIV lipodystrophy case definition in a placebo-controlled, 144-week study in antiretroviral-naive adults. Antivir Ther. 2006;11(2):179-86. PubMed
  16. Svedhem-Johansson V, Pugliese P, Brockmeyer NH, Thalme A, Michalik C, Esser S et al. Long-term gender-based outcomes for atazanavir/ritonavir (ATV/r)- containing regimens in treatment-experienced patients with HIV. Curr HIV Res. 2013;11(4):333-41. PubMed
  17. Klassen K, Martineau AR, Wilkinson RJ, Cooke G, Courtney AP, Hickson M. The effect of tenofovir on vitamin D metabolism in HIV-infected adults is dependent on sex and ethnicity. PLoS One. 2012;7(9):e44845. PubMed
  18. Koethe JR, Jenkins CA, Petucci C, Culver J, Shepherd BE, Sterling TR. Superior Glucose Tolerance and Metabolomic Profiles, Independent of Adiposity, in HIV-Infected Women Compared With Men on Antiretroviral Therapy. Medicine (Baltimore). 2016;95(19):e3634. PubMed
  19. Triantos C, Kalafateli M, Aggeletopoulou I, Mandellou M, Assimakopoulos S, Tselekouni P et al. Lactate serum concentrations during treatment with nucleos(t)ide analogues in hepatitis B with or without cirrhosis. Eur J Gastroenterol Hepatol. 2017;29(9):998-1003. PubMed
  20. Bandeira ACPCS, Elias DBD, Cavalcante MG, Lima DGL, Távora LGF. Antiretroviral changes during the first year of therapy. Rev Assoc Med Bras (1992). 2017;63(7):606-612. PubMed
  21. Ombeni W, Kamuhabwa AR. Lipid Profile in HIV-Infected Patients Using First-Line Antiretroviral Drugs. J Int Assoc Provid AIDS Care. 2015;15(2):164-71. PubMed
  22. Else LJ, Taylor S, Back DJ, Khoo SH. Pharmacokinetics of antiretroviral drugs in anatomical sanctuary sites: the male and female genital tract. Antivir Ther. 2011;16(8):1149-67. PubMed
  23. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2017 [cited 2018-07-24.] länk

Författare: Mia von Euler, Linnéa Karlsson Lind

Faktagranskat av: Karin Schenck-Gustafsson

Godkänt av: Karin Schenck-Gustafsson