Atevirdine is a non-nucleoside reverse transcriptase inhibitor the family of anti-HIV drugs to which L-697,661 and nevirapine 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.

Atevirdine (sometimes abbreviated to ATV) belongs to the BHAP class of compounds and is also known as BHAP-E or by the codename U-87201E. It is manufactured by Pharmacia & Upjohn.

Current use

Several studies have investigated atevirdine on its own or in combination with AZT. Ongoing studies will be completed, but the manufacturer has decided not to initiate any new studies, preferring to focus research on the related drug delavirdine.

Side-effects of atevirdine may include fever, rash, hepatitis and malaise. Liver abnormalities were seen among HIV-negative women who took the drug during phase I testing, but not among men.

An Australian pilot study suggested that atevirdine may be an effective treatment for HIV-associated dementia.

The development of HIV strains that are resistant to atevirdine has been reported among people receiving the drug on its own or in combination with AZT.

Key research

In preclinical animal studies administration of atevirdine resulted in higher blood levels and more toxicity at higher doses in female animals than in males. Batts reported that in a study in uninfected adults atevirdine (200mg 4 times daily) produced elevations of hepatic enzymes in 3 women but none of the men, which were reversible after drug was discontinued. Contrary to the animal experience, there was no significant difference in the pharmacokinetics of women versus men.

Been-Tiktak enrolled 30 asymptomatic antiretroviral-naive HIV-positive men with CD4 counts between 200 and 500 in a pilot study comparing atevirdine (600mg three times daily) with placebo for 12 weeks. No significant changes in CD4 count or p24 antigen levels were observed. 3 out of 11 treated people had a reduction in HIV RNA (measured by PCR) of at least 0.4 log, and 2 had a greater than 1 log reduction. Four treated people developed rash and one developed hepatitis.

Brew treated 10 people who had AIDS dementia complex stage 1 or 2, AZT or ddI intolerance or failure, neurological impairment and no confounding illness with atevirdine (600mg every 3 days for 12 weeks). 5/10 completed the protocol; of these 4 responded as measured by a decline in the mean combined impairment score from 19.6 at baseline to 5 at week 12. Improvement in responders was evident at week 4. Two participants improved from AIDS dementia complex stage 2 to stage 0, and two from stage 1 to stage 0.5. CSF beta₂-microglobulin and neopterin levels also improved. Of the 5 non-responders, 4 developed infections that were fatal in 3 cases and 1 discontinued due to a drug-related rash.

Campbell reported that clinical isolates with a wide range of IC₅₀s of AZT and ddI were inhibited by atevirdine. Cross-resistance to atevirdine in AZT- or ddI-resistant isolates was not observed. Combinations of atevirdine and AZT were highly synergistic against AZT-resistant clinical isolates of HIV-1. By contrast, these combinations were mostly additive when tested against AZT-susceptible isolates. Combinations of atevirdine and ddI were additive in their effects against both ddI-susceptible and -resistant isolates.

In a phase I study, 1/3 participants developed resistance to atevirdine after an average of 8 weeks' treatment. Demeter tested obtained clinical isolates from 16 people who had received atevirdine and AZT for 6-28 weeks (median of 16 weeks) in a phase I trial (ACTG 199). 5/9 individuals treated for more than 16 weeks had HIV-1 isolates sensitive to atevirdine. 4/9 developed resistance to atevirdine between weeks 6 and 24 of treatment.

Reichman conducted a phase I study of atevirdine (1800 mg/day) in combination with AZT (600 mg/day) in 12 people with AIDS and 8 with ARC. CD4 counts rose by at least 50 in 8 out of 17 participants over a 4-week period. At 24 weeks HIV isolates from 8 out of 13 remained sensitive to atevirdine. 3 participants withdrew because of rash, fever, malaise or hepatitis.

References

Batts D et al. A phase I comparative study of the safety, tolerance and pharmacokinetics (PK) of 14 1/2 days of oral U-87,201E in men versus women. 8^th Intl Conf AIDS, Amsterdam, abstract PoB 3009, 1992.

Been-Tiktak AMM et al. A pilot study of the safety, tolerance, pharmacokinetics and pharmacodynamics of U-87201E in HIV infected persons. 2^nd Intl Congress on Drug Therapy in HIV Infection, Glasgow, abstract 11.4, 1994.

Brew BJ et al. Pilot study of the efficacy of atevirdine in AIDS dementia complex (ADC). 10th Intl Conf AIDS, Yokohama, abstract 232B, 1994.

Campbell TB et al. Inhibition of human immunodeficiency virus type 1 replication in vitro by the bisheteroarylpiperzine atevirdine (U-87201E) in combination with zidovudine or didanosine. JID 168(8): 318-326, 1993.

Demeter L et al. Sensitivity of HIV-1 isolates to atevirdine (ATV) in a phase I clinical trial of ATV and zidovudine (ZDV). 33^rd ICAAC, New Orleans, abstract 45, 1993.

Reichman RC et al. Phase I study of atevirdine, a non-nucleoside reverse transcriptase inhibitor, given in combination with zidovudine for human immunodeficiency virus type 1 infection. J Inf Dis 171: 297-304, 1995.