Non-nucleoside reverse transcriptase inhibitors

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Discovery and development of non-nucleoside reverse -transcriptase inhibitors (engl. N on N ucleoside R everse T ranscriptase I nhibitor , NNRTI) are drugs from the group of antiviral agents . The first active ingredient was developed in 1990. These are active substances that inhibit the viral enzyme reverse transcriptase and thus inhibit the reproduction of retroviruses .

effect

In contrast to the nucleosidic reverse transcriptase inhibitors , the NNRTIs bind non-competitively to the reverse transcriptase of HIV-I , near the substrate binding site for nucleosides . This blocks the catalytically active binding site. Fewer nucleosides can now bind and the polymerization is slowed down significantly.

Side effects

The side effects of NNRTIs vary greatly depending on the active ingredient. Please note the corresponding information in the articles on the different substances.

application areas

They are used to inhibit reverse transcription in retroviruses . So far, active substances against HIV exist .

HIV therapy

The three currently available substances nevirapine , efavirenz and delavirdine were developed to market readiness between 1996 and 1998 . Although studies showed early on that NNRTIs could be an important building block in an effective combination therapy , the public reaction was significantly less than when the HIV protease inhibitors were introduced .

One reason for this was that it quickly became clear that monotherapy with NNRTIs was ineffective. Another crucial weak point is the rapid and frequent development of resistance in insufficiently controlled therapy regimens. A mutation at position 103 (K103N) of the hydrophobic binding site of reverse transcriptase is sufficient to produce resistance to all NNRTIs. The resistance rate after a single perinatal nevirapine mono- prophylaxis was between 14 and 65%. Breaks in therapy pose a particular challenge and must be precisely planned and weighed up under NNRTI combination therapy. Often, NNRTI resistance is also transmitted. This class of substances is not an effective treatment option for the majority of those infected.

Despite enormous resistance problems, many studies show that NNRTIs are very effective in combination with nucleoside analogues. In their effect, NNRTIs even seem to be superior to protease inhibitors under certain conditions.

The manageable number of doses and the overall good tolerability have contributed to the fact that NNRTIs have become an important part of HAART .

Nevirapine and efavirenz are metabolized by the cytochrome P450 system. Nevirapine acts as an inducer, efavirenz also as an inhibitor of the cytochrome P450 isoenzymes. Interactions with saquinavir or lopinavir often make dose adjustments necessary. To date, no significant divergences in effectiveness have been demonstrated between nevirapine and efavirenz. Studies that certify an advantage for efavirenz are hardly meaningful because of the poor homogeneity of the patients. The only significant difference is an advantage of the efavirenz arm over the dual NNRTI arm. The main reason for this is the increased toxicity in the latter. Hepatic side effects are more common with nevirapine. Lipid disorders were more common with efavirenz. Delavirdine is rarely used today for various reasons (side effects, toxicity, ...).

Switch studies such as NEFA show that the NNRTI choice should be based primarily on the side effect profile and patient-specific factors. Etravirine and delavirdine are second generation NNRTIs. They have been available for the first time since 2007. Both are also effective against NNRTI-resistant strains.

Active ingredients

Approved drugs

Active ingredients not further developed

  • Atevirdine, Upjohn focused on Delavirdine
  • DPC 083 (BMS-561390), May 2003, bad PK / security data
  • DPC 961, suicidal thoughts of the subjects, DPC 963
  • Emivirin (MKC-442, Coactinon) - quite well developed from Triangle to 2002, but then too weak
  • GW420867X, GSK, classic analog preparation
  • GW8248, GSK, too poor bioavailability
  • HBY-097, Hoechst-Bayer, unfavorable side effects
  • Loviride, Janssen Pharmaceuticals, too weak in the (at that time relatively advanced) clinical studies (CAESAR study)
  • MIV-150, Medivir / Chiron, bioavailability too poor, is still being developed as a microbicide
  • PNU 142721, Pharmacia & Upjohn, Efavirenz too similar
  • TMC 120 (dapivirin), Tibotec, poorly available orally
  • Capravirine (AG1549) too weak. Pfizer returned the rights to Shionogi in July 2005 , the future uncertain

swell

  1. ↑ a b Christian Hoffmann: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) ( Memento from February 18, 2006 in the Internet Archive )
  2. ↑ Robbins et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection N Engl J Med . 2003 Dec 11; 349 (24): 2293-303. PMID 14668455
  3. ↑ A novel pattern of lipoaccumulation in HIV-infected men. JAMA . 2006 Aug 16; 296 (7): 766-8. No abstract available, PMID 16905782 .
  4. ↑ 4-benzyl- and 4-benzoyl-3-dimethylaminopyridin-2 (1H) -ones, a new family of potent anti-HIV agents: optimization and in vitro evaluation against clinically important HIV mutant strains. J Med Chem. 2004 Oct 21; 47 (22): 5501-14. PMID 15481987 .
  5. ^ Appropriate use of nevirapine for long-term therapy. J Infect Dis . 2005 Aug 1; 192 (3): 545-6; author reply 546. No abstract available. PMID 15995971 .
  6. ↑ substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with human immunodeficiency virus infection. N Engl J Med. 2003 Sep 11; 349 (11): 1036-46. PMID 12968087 .

literature

  • De Lazzari E, Leon A, Arnaiz J, et al. Risk of hepatotoxicity in virologically suppressed HIV patients switching to nevirapine according to gender and CD4 count. Abstract H1064, 46th ICAAC 2006, San Francisco.
  • Fisac ​​C, Fumero E, Crespo M, et al. Metabolic benefits 24 months after replacing a protease inhibitor with abacavir, efavirenz or nevirapine . In: AIDS , 2005, 19: 917-25. PMID 15905672
  • Haas DW, Bartlett JA, Andersen JW, et al. Pharmacogenetics of nevirapine-associated hepatotoxicity: an Adult AIDS Clinical Trials Group collaboration . In: Clin Infect Dis . 2006, 43: 783-6. PMID 16912957
  • Johnson JA, Li JF, Morris L, et al. Emergence of drug-resistant HIV-1 after intrapartum administration of single-dose nevirapine is substantially underestimated . In: J Infect Dis . 2005, 192: 16-23. PMID 15942889
  • Kappelhoff BS, van Leth F, Robinson PA, et al. Are adverse events of nevirapine and efavirenz related to plasma concentrations ? In: Antivir Ther . 2005, 10: 489-98. PMID 16038474
  • MacArthur RD, Novak RM, Peng G, et al. A comparison of three highly active antiretroviral treatment strategies consisting of non-nucleoside reverse transcriptase inhibitors, protease inhibitors, or both in the presence of nucleoside reverse transcriptase inhibitors as initial therapy (CPCRA 058 FIRST Study): a long-term randomized trial . In: Lancet , 2006, 368: 2125-35. PMID 17174704
  • Martin AM, Nolan D, James I, et al. Predisposition to nevirapine hypersensitivity associated with HLA-DRB1 * 0101 and abrogated by low CD4 T-cell counts . In: AIDS , 2005, 19: 97-9. PMID 15627041
  • Mocroft A, Lacombe K, Rockstroh J, et al. Risk of discontinuation of nevirapine due to toxicities in antiretroviral-naive and experienced patients with high and low CD4 counts. Abstract THAB0104, XVI IAC 2006, Toronto.
  • Muro E, Droste JA, Hofstede HT, et al. Nevirapine plasma concentrations are still detectable after more than 2 weeks in the majority of women receiving single-dose nevirapine: implications for intervention studies . In: J AIDS , 2005; 39: 419-421. PMID 16010163
  • Riddler SA, Haubrich R, DiRienzo G, et al. A prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection: ACTG 5142. Abstract THLB0204, XVI IAC 2006, Toronto.
  • Ritchie MD, Haas DW, Motsinger AA, et al. Drug transporter and metabolizing enzyme gene variants and nonnucleoside reverse-transcriptase inhibitor hepatotoxicity . In: Clin Infect Dis . 2006, 43: 779-82. PMID 16912956
  • Sanne I, Mommeja-Marin H, Hinkle J, et al. Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects . In: J Infect Dis . 2005; 191: 825-9. PMID 15717255
  • Sheran M. The NNRTIs efavirenz and nevirapine in the treatment of HIV . In: HIV Clin Trials , 2005, 6: 158-68. PMID 16192249
  • Storfer S, Leith J, Piliero P, Hall D. Analysis of hepatic events within the 2NN study: controlling for ethnicity and CD4 + count at initiation of nevirapine therapy. Abstract PE9.6 / 2. 10th EACS 2005. Dublin.
  • Wensing AM, van de Vijver DA, Angarano G, et al. Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management . In: J Infect Dis . 2005 192: 958-66. PMID 16107947
  • Wolf E, Koegl C, Theobald T, et al. Nevirapine-associated hepatotoxicity: no increased risk for females or high CD4 count in a single-center HIV cohort. Abstract H1063, 46th ICAAC 2006, San Francisco.

See also