Double "d" Drug Danger
Double "d" Drug Danger
Beyond adherence, the greatest obstacle to long-term therapy for HIV infection remains drug toxicity. Broadly, adverse effects of antiretroviral agents may be considered "early," those occurring within the first 6 months of therapy, and "late," those occurring in persons who are well established on a medication and have been tolerating the medication for some time. The majority of early toxicities, such as nausea and other GI side effects, rash, and CNS side effects, are generally manageable with advice and palliative medications and only occasionally require treatment modification. Late side effects, such as anemia, peripheral neuropathy (PN), pancreatitis, lipoatrophy, and lactic acidosis, whilst occurring only in a minority of persons, are less amenable to management with palliative medications and generally lead to therapeutic modification or treatment interruption. In addition, some of these late side effects may lead to permanent disability or stigmatizing morphologic changes and are potentially life-threatening. Avoiding or limiting the use of drug combinations that are associated with an increased risk of late side effects is therefore prudent.
There is now conclusive evidence that a relative contraindication to the combination of 2 dideoxynucleoside analogues should be included in treatment guidelines. The most well-studied combination of 2 dideoxynucleoside analogues is that of stavudine (d4T) and didanosine (ddI), although a study illustrating the risk of combining d4T and zalcitabine (ddC) has also reported data. The combination of d4T and ddI appears to be associated with an increased risk of PN, hyperlactatemia, and possibly lactic acidosis and a more rapid loss of subcutaneous fat during therapy relative to regimens that contain 1 of these agents combined with lamivudine (3TC) (or emtricitabine [FTC]) and/or to regimens that do not include dideoxynucleoside analogues. The inclusion of hydroxyurea with d4T-ddI, an approach now rarely used, further increases the risk of toxicity. In addition, both the AIDS Clinical Trials Group (ACTG) 384 study and the more recent FTC-301 study indicate that initial regimens using the d4T-ddI backbone have inferior efficacy relative to other nucleoside analogue backbones when used with efavirenz (EFV).
Beyond adherence, the greatest obstacle to long-term therapy for HIV infection remains drug toxicity. Broadly, adverse effects of antiretroviral agents may be considered "early," those occurring within the first 6 months of therapy, and "late," those occurring in persons who are well established on a medication and have been tolerating the medication for some time. The majority of early toxicities, such as nausea and other GI side effects, rash, and CNS side effects, are generally manageable with advice and palliative medications and only occasionally require treatment modification. Late side effects, such as anemia, peripheral neuropathy (PN), pancreatitis, lipoatrophy, and lactic acidosis, whilst occurring only in a minority of persons, are less amenable to management with palliative medications and generally lead to therapeutic modification or treatment interruption. In addition, some of these late side effects may lead to permanent disability or stigmatizing morphologic changes and are potentially life-threatening. Avoiding or limiting the use of drug combinations that are associated with an increased risk of late side effects is therefore prudent.
There is now conclusive evidence that a relative contraindication to the combination of 2 dideoxynucleoside analogues should be included in treatment guidelines. The most well-studied combination of 2 dideoxynucleoside analogues is that of stavudine (d4T) and didanosine (ddI), although a study illustrating the risk of combining d4T and zalcitabine (ddC) has also reported data. The combination of d4T and ddI appears to be associated with an increased risk of PN, hyperlactatemia, and possibly lactic acidosis and a more rapid loss of subcutaneous fat during therapy relative to regimens that contain 1 of these agents combined with lamivudine (3TC) (or emtricitabine [FTC]) and/or to regimens that do not include dideoxynucleoside analogues. The inclusion of hydroxyurea with d4T-ddI, an approach now rarely used, further increases the risk of toxicity. In addition, both the AIDS Clinical Trials Group (ACTG) 384 study and the more recent FTC-301 study indicate that initial regimens using the d4T-ddI backbone have inferior efficacy relative to other nucleoside analogue backbones when used with efavirenz (EFV).
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