L-697,661 is a non-nucleoside reverse transcriptase inhibitor the family of anti-HIV drugs to which nevirapine and TIBOL also belong. These drugs act by inhibiting HIV's reverse transcriptase enzyme, but in a different way from the nucleoside analogue drugs like AZT, ddC and ddI.

L-697,661 is also known as pyridinone.

Current use

Early trials showed that, although L-697,661 has anti-HIV activity in the body, HIV rapidly becomes resistant to the drug. Its manufacturer, Merck, stopped trials of L-697,661 on its own and instead concentrated on studying it in combination with AZT, in the hope that resistance would be delayed and effectiveness increased. However, even in combinations resistance developed rapidly and Merck decided to discontinue the development of the drug.

Promising in vitro results were reported with the convergent combination of AZT, ddI and L-697,661. It was thought that this combination of drugs caused mutations in HIV's reverse transcriptase enzyme which totally prevented viral replication or the infection of new cells. However, this research was subsequently shown to be flawed.

Three other related drugs developed by Merck have also been abandoned because of lack of efficacy or resistance.

Key research

Saag reported on 135 participants (68 with CD4 counts between 200-500, 67 with CD4 counts below 200) enrolled in separate 6-week double-blind trials. Participants received either AZT 500 mg/day, placebo or L-697,661 (either 25 mg twice a day, 100 mg three times daily or 500 mg twice a day). 80-85% had over 3 months prior use of AZT. After completing 12 weeks on study, subjects receiving either AZT or placebo were to be re-randomized to one of the three `L-drug' arms. Transient CD4 count increases were observed among participants with CD4 counts below 200 in the two groups receiving higher doses of L-697,661, but not in those receiving the lower dose or AZT. L-697,661 led to rapid, dose-related decreases in plasma p24 antigen levels; however, in some patients this fell below baseline by 6 weeks, coinciding with the emergence of resistant viruses. This change in susceptibility was more frequent among patients receiving the higher doses of L-697,661.

Davey reported that among a subset of participants in this study, mean logarithmic reciprocal titres of plasma virus in patients taking either L-697,661 or AZT decreased by week 4 of therapy; for L-697,661 recipients these changes were dose-dependent and, at the highest dose tested, were comparable in magnitude to those seen with AZT. Viral suppression induced by L-697,661 persisted through 8 weeks of treatment but decreased by week 12. This rebound paralleled emergence of L-697,661-resistant viral isolates.

Sardana reported that resistance to L-697,661 is associated with amino acid substitutions at positions 103, 181 and 108 in the reverse transcriptase enzyme. This mutation results in cross-resistance with most other drugs of the same class (non-nucleoside reverse transcriptase inhibitors) such as nevirapine, BHAP compounds and the TIBO/TIBOL compounds, even though it has never been exposed to them. It is not known if resistant virus will revert to being sensitive after a period of time when the drug is removed.

Staszewski treated 119 people with CD4 counts of 200-500 with either AZT alone, L-697,661 (300 mg/day) plus AZT, L-697,661 (600 mg/day) plus AZT, or L-697,661 (600 mg/day) alone. Therapy was generally well-tolerated. All groups receiving AZT exhibited transient increases in CD4 count, while the L-697,661 monotherapy group exhibited a significant decline and yielded reverse transcriptase 100-fold resistant to L-697,661. The RT from combination recipients was maximally 15-fold less susceptible to L-697,661.

Massari enrolled 93 people with CD4 counts below 250 in a trial comparing L-697,661 (400 mg/day) plus AZT (600 mg/day) with AZT monotherapy. No serious adverse events were attributable to L-697,661. Decreases in p24 antigen and viral RNA were transient and returned to baseline levels or higher by 8-12 weeks. The combination arm did not prevent the emergence of HIV strains resistant to L-697 in all 22 people tested. Consequently Merck decided to abandon development of L-697,661.

Perrin treated four people with primary HIV infection with AZT (250 mg twice daily) plus L-697,661 (500 mg three times daily). Viraemia was reduced to undetectable levels in two after four months of treatment and remained undetectable throughout the six months of treatment. Studies of AZT monotherapy in primary infection have not seen such a marked reduction in viraemia. In the third participant, viraemia decreased sharply during the first 3 months then increased, and in the fourth viraemia remained at its high baseline levels. All responders experienced a rebound once treatment was discontinued.

Chow (1993a) suggested that three-drug combinations including a non-nucleoside reverse-transcriptase inhibitor, AZT, and ddI could completely suppress viral replication in vitro. However, Larder subsequently reported that viable multi-drug resistant HIV-1 is selected in vitro, and Chow (1993b) has reported that the original results were in error.

Harris reported the case of a 52-year-old black man treated for 8 weeks with oral L-697,661 (25 mg twice daily) who developed tinnitus, retinal cotton wool spots, testicular, penile, labial, buccal mucosa, tongue and tonsillar ulcerative lesions; and nodular episcleritis.

References

Chow YK et al. Use of evolutionary limitations of HIV-1 multidrug resistance to optimize therapy. Nature 361(6413):650-653, 1993a.

Chow YK et al. HIV-1 error revealed. Nature 364:679, 1993b.

Davey RT Jr et al. Plasma viremia as a sensitive indicator of the antiretroviral activity of L-697,661. PNAS USA 90(12):5608-5612, 1993.

Goldman ME et al. L-696,229 specifically inhibits human immunodeficiency virus type 1 reverse transcriptase and possesses antiviral activity in vitro. Antimicrobial Agents & Chemotherapy 36(5):1019-1023, 1992.

Harris PJ. Possible toxicity associated with L-697,661 administration in a patient with AIDS (letter). AIDS 6:593-606, 1992.

Larder BA et al. Convergent combination therapy can select viable multidrug-resistant HIV-1 in vitro. Nature 365:451-453, 1993.

Massari F et al. A double-blind, randomized trial of L-697,661 plus zidovudine vs zidovudine alone in advanced HIV infection. 1st Natl Conf on Human Retroviruses, Washington, abstract L9, 1993.

Perrin L et al. AIDS 10:1233-1237, 1996.

Rader R (ed). Trials with non-nucleoside RT inhibitors halted due to resistance. Antiviral Agents Bulletin 4(12):1-3, 1991.

Saag et al. A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. NEJM 329:1065-1072, 1993.

Saari WS et al. HIV-1 specific pyridinone RT inhibitors: II synthesis and structure activity relationships. 7th Intl Conf AIDS, Florence, abstract WA 1061, 1991.

Sardana VV et al. Functional analysis of HIV-1 reverse transcriptase amino acids involved in resistance to multiple nonnucleoside inhibitors. Jrnl Bio Chem 267(25):17526-17530, 1992.

Staszewski S et al. Combination therapy with zidovudine prevents selection of human immunodeficiency virus type 1 variants expressing high-level resistance to L-697,661, a nonnucleoside reverse transcriptase inhibitor. J Inf Dis 171(5):1159-1165, 1995.