Virologic and Immunologic Benefits of Initial Combination Therapy with Zidovudine and Zalcitabine or Didanosine Compared with Zidovudine Monotherapy

Abstract

A randomized controlled study was done to determine whether initial combination therapy with zidovudine and zalcitabine or zidovudine and didanosine would delay the emergence of zidovudine-resistant virus. Human immunodeficiency virus (HIV)-1-infected patients with <300 CD4 cells/mm3 and <4 weeks of prior zidovudine therapy were randomized to zidovudine, zidovudine plus zalcitabine, or zidovudine plus didanosine. Combination therapy did not delay the emergence of zidovudine-resistant virus isolates. However, combination therapy resulted in a significant increase in CD4 cells through 72 weeks compared with zidovudine monotherapy and a greater and more sustained decline in serum HIV-1 RNA. Although this trial was not designed as a clinical end-point study, patients assigned to zidovudine plus didanosine combination therapy experienced a significant delay in time to first AIDS-defining event or death compared with those assigned to zidovudine monotherapy.

Selective inhibition of syncytium-inducing and nonsyncytium-inducing HIV-1 variants in individuals receiving didanosine or zidovudine, respectively.

“…However, neither total cellular virus load, CD4 ϩ T cell numbers, nor serum RNA load were much affected, which combines well with the observations on the minor clinical benefit of ddI monotherapy in heavily-pretreated, late stage HIV-1-infected individuals such as the subjects in this and other studies (40,47). Combination therapy of ddI and ZDV resulted in a 1.5-2.5 log decline in both infectious cellular (both in NSI and SI load) and in serum HIV-1 load, again correlating with the in vivo clinical benefit observed in several large clinical trials (35)(36)(37)(38).…”

“…Others have since shown that ddI treatment results in a loss of SI variants in bulk cocultures (30,31). Moreover, results of several large clinical trials have now shown the increased clinical benefit of the combined treatment with ZDV and ddI (35)(36)(37)(38). To further understand and elucidate this phenomenon we studied the clonal composition of HIV-1 populations in several additional subjects treated with either ddI alone or in combination with ZDV.…”

“…Four antiretroviral treatment-naive HIV-1-infected individuals attending the Academic Medical Centre were treated with a combination of ZDV and ddI within two previously described trials (35,36) that started in 1991 and 1993 (dose 600 mg ZDV daily and 200-400 mg ddI daily). One of these four individuals (d271) was diagnosed with AIDS based on Pneumocystis carinii pneumonia and received cotrimoxazol before the start of the study.…”

“…In addition, despite its capacity to pass the blood-brain barrier (32), ddI does not have the pronounced and long lasting effect on reversing AIDS dementia in adults as observed for ZDV (33,34), which suggests different targets for the two drugs. Indeed, in vitro, ZDV and ddI have been shown to work synergistically, and several large clinical trials, together representing HIV-1-infected individuals in different stages of HIV-1 infection with a broad range of CD4 ϩ T cell numbers, have shown the increased clinical benefit of combined ZDV and ddI (35)(36)(37)(38). To further investigate this viral phenotype-dependent response to nucleoside analog treatment, we studied treatment responses in serum and in infectious cellular virus loads during ZDV or ddI monotherapy or ZDV/ddI combination therapy.…”

Randomised trial of addition of lamivudine or lamivudine plus loviride to zidovudine-containing regimens for patients with HIV-1 infection: the CAESAR trial

“…20,21 In contrast, didanosine or zalcitabine do not appear to delay the onset of zidovudine-associated mutations. 22 Other studies have shown that HIV-1 variants that are resistant to zidovudine regain phenotypic sensitivity to zidovudine in the presence of lamivudine. 20 The increase in the number of mutations required to confer phenotypic resistance to zidovudine in the presence of lamivudine has been proposed as a mechanism for this observation.…”