Incidence of neuropathy in HIV-infected patients on monotherapy versus those on combination therapy with didanosine, stavudine and hydroxyurea

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Abstract
Sensory neuropathy is a common adverse effect of the nucleoside analogue anti-retroviral drugs didanosine (ddI) and stauvudine (d4T). These drugs are increasingly being used in combination, and it is not currently known whether the incidence of neuropathy is higher with combination compared to individual drug use. It is also not known if hydroxyurea, used to potentiate the antiviral efficacy of these drugs, may also increase the risk of neuropathy. The purpose of this analysis is to investigate if the combination of ddI and d4T, with or without hydroxyurea, has a higher incidence of neuropathy than a single drug regimen. Data were obtained from patients followed longitudinally by the Johns Hopkins AIDS Services. Incidence rates of development of neuropathy were calculated for each of five regimens: ddI (± hydroxyurea), ddI + d4T (± hydroxyurea), and d4T. Cox proportional hazard regression was used to compare the relative risk of neuropathy for each regimen adjusting for CD4 cell count, other drugs received, and time on therapy. A total of 1116 patients received at least one of the five regimens. There were 117 cases of neuropathy. The crude incidence rate of neuropathy ranged from 6.8 cases per 100 person-years for ddI to 28.6 cases per 100 person-years for ddI + d4T + hydroxyurea. Compared with ddI alone, and adjusting for CD4 cell counts and other variables, the relative risk of neuropathy was 1.39 [95% confidence interval (CI): 0.84–2.32] for d4T alone, 2.35 (95% CI: 0.69–8.07) for ddI + hydroxurea, 3.50 (95% CI: 1.81–6.77) for ddI + d4T, and 7.80 (95% CI: 3.92–15.5) for ddI + d4T + hydroxyurea. Based on the data, the risk of neuropathy is additive or even synergistic for ddI + d4T + hydroxyurea compared with ddI or d4T alone. The combination of ddI + d4T also increases the risk of neuropathy but less than when hydroxyurea is included.