EDITORIAL
Dideoxynucleoside therapy for HIV infection D.M. Burger and J.H. Beijnen
In 1987, zidovudine (AZT, Retrovir | became available as the first drug for the t r e a t m e n t of infection with the h u m a n immunodeficiency virus (HIV), the causative agent of the acquired immunodeficiency syndrome (AIDS). Since t h a t t i m e several investigations h a v e confirmed zidovudine's efficacy in delaying progression to AIDS in a s y m p t o m a t i c HIV-seropositive individuals and patients with AIDS-related complex (ARC), and in increasing survival in patients with AIDS. Despite its proven efficacy an alternative for zidovudine is urgently needed for several reasons. Firstly, zidovudine's toxicity (predominantly a n a e m i a and neutropenia) often leads to dose reductions or even cessation of zidovudine therapy. Secondly, resistance of HIV strains to zidovudine m a y be induced after prolonged treatment, as established in vitro. Now we are on the eve of the introduction of didanosine, the second antiretroviral drug, in a n u m b e r of E u r o p e a n countries. On page 297, F r a n s s e n et al. review current knowledge of this novel purine dideoxynucleoside drug. Didanosine (2',3'-dideoxyinosine, ddI, Videx | h a s already been approved by the United States Food and Drug A d m i n i s t r a t i o n (FDA) in N o v e m b e r 1991 for the t r e a t m e n t of HIV-infected individuals who no longer tolerate zidovudine or who deteriorate despite zidovudine administration. The extremely rapid approval in the US, for FDA standards, has been based m a i n l y upon results from phase-I trials, as described by F r a n s s e n et al. But additional information is now available. I m p o r t a n t developments were divulged in a recent issue of the New England J o u r n a l of Medicine [1] and at the E i g h t h I n t e r n a t i o n a l Conference on AIDS, held in A m s t e r d a m in July 1992 [21. K a h n et al. compared continued zidovudine t h e r a p y (600 m g daily) with switching from zidovudine to didanosine (500 or 750 mg daily) in 913 p a t i e n t s who had tolerated zidovudine for at least 16 weeks [1]. Although there was no benefit from didanosine in patients who had already developed AIDS, a significant benificial effect of the drug over zidovudine was established in delaying progression to AIDS in a s y m p t o m a t i c s and patients with ARC. These results are the first proof of didanosine's clinical efficacy and justify rapid legislation in other countries. Several trials with didanosine are now going on in order to further establish the clinical potential of the drug [2]. More insight has also been gained about toxicity of didanosine therapy. Pancreatitis and sensory peripheral n e u r o p a t h y were the most serious ad-
verse effects in the phase-I trials. The comparative trial of K a h n et al. [1] showed t h a t pancreatitis was more common in the high-dose group of didanosine (and was fatal in 2 persons), whereas peripheral n e u r o p a t h y developed at the same r a t e in both didanosine groups and in the zidovudine group. Investigations into resistance to antiretroviral drug t h e r a p y are u n d e r w a y all around the world [2]. In vitro resistant isolates of H I V have been found after prolonged t r e a t m e n t with zidovudine, didanosine or any other antiretroviral drug. Differences in resistance r a t e s between the several drugs have not yet been established. The laboratory observations that zidovudineresistant strains are, in general, sensitive to didanosine (and vice versa), and the findings t h a t zidovudine-resistant strains m a y again become zidovudine-sensitive once zidovudine administration has been stopped, rationalize f u r t h e r investigations of the clinical efficacy of combination and a l t e r n a t i n g therapy. F r o m the p h a r m a c e u t i c a l point of view, special attention m u s t be adressed to didanosine's formulation characteristics. The compound is extremely acid-labile, and its absorption is greatly reduced by simultaneous food ingestion [3]. In most clinical trials sachets with didanosine and an antacid were used. Doubts about the variable bioavai]ablity associated with these sachets prompted research for other formulations, leading to a new formulation of didanosine, a chewable tablet. However, its hardness h a m p e r s effective chewing, and its taste often causes n a u s e a and vomiting. More research is, therefore, urgently needed in the field of formulation and bioavailability. It is r e m a r k a b l e , but also undesirable, t h a t so m a n y patients h a v e been t a k i n g didanosine while its formulation is still subject of research and debate. It reflects perfectly the current state of antiretroviral drug research: some answers, m a n y questions [4], also on the p h a r m a c e u t i c a l level. References 1 Kahn JO, Lagakos SW, Richman DD, Cross A, Pettinelli C, Lion S-H, et al. A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. N Engl J Med 1992; 327(9):581-7. 2 Book of Abstracts of the Eighth International Conference on AIDS; 1992 July 19-24; Amsterdam. Amsterdam: Congrex Holland BV, 1992. 3 Shyu WC, Knupp CA, Pittman, Dunkle L, Barbhaiya RH. Food- induced reduction in bioavailability of didanosine. Clin Pharmacol Ther 1991;50(5):503-7. 4 Groopman JE, Molina J-M. Nucleoside therapy for HIV infection - some answers, many questions. N Engl J Med 1992;327(9):639-41.
D.M. Burger and J.H. Beijnen: Department of Pharmacy, Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, the Netherlands.
14(5) 1992
P h a r m a c e u t i s c h Weekblad Scientific edition
289
Dideoxynucleoside therapy for HIV infection D.M. Burger and J.H. Beijnen
In 1987, zidovudine (AZT, Retrovir | became available as the first drug for the t r e a t m e n t of infection with the h u m a n immunodeficiency virus (HIV), the causative agent of the acquired immunodeficiency syndrome (AIDS). Since t h a t t i m e several investigations h a v e confirmed zidovudine's efficacy in delaying progression to AIDS in a s y m p t o m a t i c HIV-seropositive individuals and patients with AIDS-related complex (ARC), and in increasing survival in patients with AIDS. Despite its proven efficacy an alternative for zidovudine is urgently needed for several reasons. Firstly, zidovudine's toxicity (predominantly a n a e m i a and neutropenia) often leads to dose reductions or even cessation of zidovudine therapy. Secondly, resistance of HIV strains to zidovudine m a y be induced after prolonged treatment, as established in vitro. Now we are on the eve of the introduction of didanosine, the second antiretroviral drug, in a n u m b e r of E u r o p e a n countries. On page 297, F r a n s s e n et al. review current knowledge of this novel purine dideoxynucleoside drug. Didanosine (2',3'-dideoxyinosine, ddI, Videx | h a s already been approved by the United States Food and Drug A d m i n i s t r a t i o n (FDA) in N o v e m b e r 1991 for the t r e a t m e n t of HIV-infected individuals who no longer tolerate zidovudine or who deteriorate despite zidovudine administration. The extremely rapid approval in the US, for FDA standards, has been based m a i n l y upon results from phase-I trials, as described by F r a n s s e n et al. But additional information is now available. I m p o r t a n t developments were divulged in a recent issue of the New England J o u r n a l of Medicine [1] and at the E i g h t h I n t e r n a t i o n a l Conference on AIDS, held in A m s t e r d a m in July 1992 [21. K a h n et al. compared continued zidovudine t h e r a p y (600 m g daily) with switching from zidovudine to didanosine (500 or 750 mg daily) in 913 p a t i e n t s who had tolerated zidovudine for at least 16 weeks [1]. Although there was no benefit from didanosine in patients who had already developed AIDS, a significant benificial effect of the drug over zidovudine was established in delaying progression to AIDS in a s y m p t o m a t i c s and patients with ARC. These results are the first proof of didanosine's clinical efficacy and justify rapid legislation in other countries. Several trials with didanosine are now going on in order to further establish the clinical potential of the drug [2]. More insight has also been gained about toxicity of didanosine therapy. Pancreatitis and sensory peripheral n e u r o p a t h y were the most serious ad-
verse effects in the phase-I trials. The comparative trial of K a h n et al. [1] showed t h a t pancreatitis was more common in the high-dose group of didanosine (and was fatal in 2 persons), whereas peripheral n e u r o p a t h y developed at the same r a t e in both didanosine groups and in the zidovudine group. Investigations into resistance to antiretroviral drug t h e r a p y are u n d e r w a y all around the world [2]. In vitro resistant isolates of H I V have been found after prolonged t r e a t m e n t with zidovudine, didanosine or any other antiretroviral drug. Differences in resistance r a t e s between the several drugs have not yet been established. The laboratory observations that zidovudineresistant strains are, in general, sensitive to didanosine (and vice versa), and the findings t h a t zidovudine-resistant strains m a y again become zidovudine-sensitive once zidovudine administration has been stopped, rationalize f u r t h e r investigations of the clinical efficacy of combination and a l t e r n a t i n g therapy. F r o m the p h a r m a c e u t i c a l point of view, special attention m u s t be adressed to didanosine's formulation characteristics. The compound is extremely acid-labile, and its absorption is greatly reduced by simultaneous food ingestion [3]. In most clinical trials sachets with didanosine and an antacid were used. Doubts about the variable bioavai]ablity associated with these sachets prompted research for other formulations, leading to a new formulation of didanosine, a chewable tablet. However, its hardness h a m p e r s effective chewing, and its taste often causes n a u s e a and vomiting. More research is, therefore, urgently needed in the field of formulation and bioavailability. It is r e m a r k a b l e , but also undesirable, t h a t so m a n y patients h a v e been t a k i n g didanosine while its formulation is still subject of research and debate. It reflects perfectly the current state of antiretroviral drug research: some answers, m a n y questions [4], also on the p h a r m a c e u t i c a l level. References 1 Kahn JO, Lagakos SW, Richman DD, Cross A, Pettinelli C, Lion S-H, et al. A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. N Engl J Med 1992; 327(9):581-7. 2 Book of Abstracts of the Eighth International Conference on AIDS; 1992 July 19-24; Amsterdam. Amsterdam: Congrex Holland BV, 1992. 3 Shyu WC, Knupp CA, Pittman, Dunkle L, Barbhaiya RH. Food- induced reduction in bioavailability of didanosine. Clin Pharmacol Ther 1991;50(5):503-7. 4 Groopman JE, Molina J-M. Nucleoside therapy for HIV infection - some answers, many questions. N Engl J Med 1992;327(9):639-41.
D.M. Burger and J.H. Beijnen: Department of Pharmacy, Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, the Netherlands.
14(5) 1992
P h a r m a c e u t i s c h Weekblad Scientific edition
289
