Nucleosidic Reverse Transcriptase Inhibitors

from Wikipedia, the free encyclopedia

Nucleoside reverse transcriptase inhibitors (English. Nucleoside Reverse Transcriptase Inhibitors , NRTIs ) are drugs from the group of antivirals . They are nucleoside analogs that are similar to natural nucleosides . Your starting point is the enzyme reverse transcriptase of retroviruses that the viral RNA genome into DNA rewrites . They compete with natural nucleosides, but differ in their slight modifications to the ribose (sugar molecule), i. that is, they do not have a 3'-hydroxy group at which the chain extension takes place.

effect

Nucleoside analogs are taken up by the cell and are only effective through intracellular phosphorylation. Three phosphate residues are gradually transferred. The incorporation of the nucleoside analogs as the wrong DNA building block during the reverse transcription causes a break in the newly formed DNA chain and leads to the termination of the polymerization and thus the reverse transcription.

Side effects

Long-term side effects are often myelotoxicity , lactic acidosis , polyneuropathy , lipoatrophy or pancreatitis . You are probably due to a toxicity of the mitochondria, which are important for cell metabolism . Since mitochondria are also dependent on nucleosides, the incorporation of the wrong building blocks leads to metabolic disorders and ultimately to degeneration. There are major differences between the substances in terms of mitochondrial toxicity.

Nucleoside analogs are mainly eliminated renally. They do not interact with substances that are metabolized by enzyme systems in the liver. There is therefore no significant potential for interaction. A dose adjustment may be required if ribavirin is co-administered or in patients with renal impairment .

application areas

They are used to combat the replication of viruses. So far, there are active substances against HIV and HBV .

HIV therapy

Nucleoside analogs were the first drugs used in HIV therapy in 1987. It is easy to use and a simple daily dose is usually sufficient. Frequent complaints in the first few weeks are - despite relatively good tolerability - tiredness, headaches and gastrointestinal problems such as B. bloating, nausea, vomiting or diarrhea .

In HIV therapy, the active ingredients zidovudine (azidothymidine, AZT) and stavudine (d4T) correspond to the DNA building block thymidine , lamivudine (3TC) correspond to cytidine , while didanosine (ddl) is a guanosine analogue, analogous to inosine and abacavir (ABC) .

In highly active antiretroviral therapy (HAART), two NRTIs are often combined with a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (+ ritonavir for boosting). Often there is cross resistance between different nucleoside analogues.

HBV therapy

For a long time, interferon-α was the only drug approved in Germany that has been shown to have a positive effect on the course of hepatitis B. With long-term therapy, good results have already been achieved in many patients. Treatment with interferon is often associated with severe side effects of various kinds.

The introduction of the nucleoside analogues lamivudine and adefovir represents a major step forward in the treatment of hepatitis B. Both substances are administered orally and usually have few side effects. Recently, nucleotide analogues (such as tenofovir and entecavir ) have become preferred. These lead to resistance less often and thus appear more suitable for long-term therapy.

Usually, NRTIs are combined with interferon to increase their effectiveness.

As a prophylactic measure, NRTIs in combination with hepatitis B immunoglobulin are administered to HBV carriers with a transplant to prevent reinfection.

Active ingredients

HIV

In use / clinical studies

Active ingredients not further developed

  • SPD-756
  • SPD-761
  • Adefovir dipivoxil from Gilead, hardly any activity against HIV, nephrotoxicity
  • FddA (Lodenosin ® ) from Bioscience, 1999, liver / kidney damage
  • dOTC Biochem Pharma, toxicity in monkeys
  • Lobucavir BMS, carcinogenicity
  • GS 7340 Gilead, unsatisfactory clinical data
  • MIV-310 (Alovudin, FLT) Boehringer, March 2005, disappointing phase II study
  • Dexelvucitabine (Reverset) Incyte, 2006, pancreatitis

HBV

Individual evidence

  1. ^ M. Galli, AL Ridolfo, F. Adorni et al.: Body habitus changes and metabolic alterations in protease inhibitor-naive HIV-1-infected patients treated with two nucleoside reverse transcriptase inhibitors. In: JAIDS. 29, 2002, pp. 21-31. PMID 11782586 .
  2. ↑ K. Brinkman, JA Smeitink, JA Romijn, P. Reiss: Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of ART-related lipodystrophy. In: The Lancet . 354, 1999, pp. 1112-1115. PMID 10509516 .
  3. ↑ SC Piscitelli, KD Gallicano: Interactions among drugs for HIV and opportunistic infections. In: N Engl J Med . 344, 2001, pp. 984-996.
  4. ↑ RKI guide for doctors: Hepatitis B
  5. ↑ Chronic Hepatitis B - Where Are We Today? In: German Liver Aid Signs of Life. Issue 2/2011, p. 15.

literature

  • H. Crane, R. Harrington, S. Van Rompaey, M. Kitahata: Didanosine and lower baseline body weight are associated with declining renal function among patients receiving tenofovir. Abstract 780, 13th CROI 2006, Denver.
  • R. De la Rosa, M. Harris, L. Uyeda et al .: Life-threatening reaction after first ever dose of abacavir in an HIV-1 infected patient. In: AIDS . 18, 2004, pp. 578-579.
  • HM El-Sahly: Development of abacavir hypersensitivity reaction after rechallenge in a previously asymptomatic patient. In: AIDS. 18, 2004, pp. 359-360.
  • JE Frampton, CM Perry: Emtricitabine: a review of its use in the management of HIV infection. In: Drugs . 65, 2005, pp. 1427-1448.
  • M. Harris, D. Back, S. Kewn et al .: Intracellular carbovir triphosphate levels in patients taking abacavir once a day. In: AIDS. 16, 2002, pp. 1196-1197.
  • J. Heffelfinger, D. Hanson, A. Voetsch et al: Renal impairment associated with the use of tenofovir. Abstract 779, 13th CROI 2006, Denver.
  • G. Moyle, M. Boffito: Unexpected drug interactions and adverse events with antiretroviral drugs. In: Lancet. 364, 2004, pp. 8-10.
  • M. Thompson, R. Haubrich, D. Margolis et al .: Differences in calculated glomerular filtration rate in efavirenz- or tenofovir-treated adults in ESS40006. Abstract 777, 13th CROI 2006, Denver.
  • CA Benson, C. van der Horst, A. Lamarca et al .: A randomized study of emtricitabine and lamivudine in stably suppressed patients with HIV. In: AIDS. 18, 2004, pp. 2269-2276. PMID 15577539 .
  • A. Bonjoch, R. Paredes, J. Galvez et al .: Antiretroviral treatment simplification with 3 NRTIs or 2 NRTIs plus nevirapine in HIV-1 infected patients treated with successful first-line HAART. In: J AIDS. 39, 2005, pp. 313-316. PMID 15980691 .
  • C. Fux, M. Simcock, M. Wolbers et al .: Tenofovir treatment is associated with a decrease in calculated glomerular filtration rates in a large observational cohort. Abstract 834, 14th CROI 2007, Los Angeles. ( Abstract )
  • JE Gallant, E. DeJesus, JR Arribas et al: Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. In: N Engl J Med. 354, 2006, pp. 251-260. PMID 16421366 .
  • JE Gallant, MA Parish, JC Keruly, RD Moore: Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. In: Clin Infect Dis . 40, 2005, pp. 1194-1198. PMID 15791522 .
  • AM Goedken, RA Herman: Once-daily abacavir in place of twice-daily administration. In: Ann Pharmacother . 39, 2005, pp. 1302-1308. PMID 15956231 .
  • JM Llibre, P. Domingo, R. Palacios et al .: Sustained improvement of dyslipidaemia in HAART-treated patients replacing stavudine with tenofovir. In: AIDS. 20, 2006, pp. 1407-1414. PMID 16791015 .
  • S. Mauss, F. Berger, G. Schmutz: Antiretroviral therapy with tenofovir is associated with mild renal dysfunction. In: AIDS. 19, 2005, pp. 93-95. PMID 15627039 .
  • GA McComsey, DM Paulsen, JT Lonergan et al .: Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine. In: AIDS. 19, 2005, pp. 15-23. PMID 15627029 .
  • JM Molina, V. Journot, L. Morand-Joubert et al .: Simplification therapy with once-daily emtricitabine, didanosine, and efavirenz adults in HIV-1-infected with viral suppression receiving a protease inhibitor-based regimen: a randomized trial. In: J Infect Dis . 191, 2005, pp. 830-839. PMID 15717256 .
  • JM Molina, AG Marcelin, J. Pavie et al .: Didanosine in HIV-1 infected patients experiencing failure of antiretroviral therapy: a randomized placebo-controlled trial. In: J Infect Dis. 191, 2005, pp. 840-847. PMID 15717257 .
  • GJ Moyle, CA Sabin, J. Cartledge et al .: A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. In: AIDS. 20, 2006, pp. 2043-2050. PMID 17053350 .
  • D. Podzamczer, E. Ferrer, P. Sanchez et al .: Less lipoatrophy and better lipid profile with abacavir as compared to stavudine: 96-week results of a randomized study. In: J AIDS. 2006 Nov 9. PMID 17106274 .
  • AL Pozniak, JE Gallant, E. DeJesus et al .: Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine / lamivudine and efavirenz in antiretroviral-naive patients: virologic, immunologic, and morphologic changes — a 96-week analysis. In: J AIDS. 43, 2006, pp. 535-540. PMID 17057609 .
  • N. Sosa, C. Hill-Zabala, E. Dejesus et al .: Abacavir and lamivudine fixed-dose combination tablet once daily compared with abacavir and lami-vudine twice daily in HIV-infected patients over 48 weeks (ESS30008, SEAL). In: J AIDS. 40, 2005, pp. 422-427. PMID 16280696 .
  • J. Stekler, J. Maenza, C. Stevens and others: Abacavir hypersensitivity reaction in primary HIV infection. In: AIDS. 20, 2006, pp. 1269-1274. PMID 16816555 .