Triple Nucleoside Reverse Transcriptase Inhibitor Therapy in Children

Much of the success attributed to HIV therapy in the last few years has resulted from improved ways of using existing drugs in combination therapy regimens. The availablity of new, more potent drugs such as protease inhibitors and more accurate viral load tests to aid decisions to start or change treatment has also contributed to the success. Published recommendations for pediatric HIV therapy, generated by a panel of experts and specialists, are readily available and regularly updated. Preferred regimens of ‘potent’ therapy (referred to as highly active antiretroviral therapy, or HAART) currently consist of two nucleoside reverse transcriptase inhibitors (NRTIs) combined with either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor. More intense four-drug regimens using an NNRTI or a second protease inhibitor as a fourth drug are being evaluated. Problems with HAART include: unpalatable drug formulations and adverse effects, coupled with lack of data on the pharmacokinetics, efficacy, and safety of various drug combinations.

Adherence is a major factor influencing the efficacy and outcome of antiretroviral therapy. Many children cannot adhere to complex multidrug regimens, which cause virologic failure, despite excellent CD4+ cell count responses. This means a rapid progression through the limited number of treatment regimens available. Simpler regimens such as those containing three NRTIs have been proposed as a method of treatment that will allow suppression of the virus, yet circumvent many of the problems previously mentioned. An additional benefit would be the preservation of antiretroviral drugs from other classes for future treatment options if required.

The major advantages of triple NRTI regimens are the simplicity of the regimen, good tolerability, few drug-drug interactions, and infrequent adverse effects coupled with a low pill burden. However, abacavir hypersensitivity remains a major problem. Up to 3% of patients may develop an early idiosyncratic hypersensitivity reaction — fever, malaise, and mucositis with or without rash, which can progress to more advanced stages of shock and death.

A major concern is the apparently inferior virologic control of triple NRTI therapy as demonstrated in the AIDS Clinical Trials Group A5095 study with zidovudine/lamivudine/abacavir (Trizivir®) combination in adults. Such a combination should only be considered in special situations. Examples cited include informed patient choice based on anticipated poor adherence on other treatment regimens, or if concomitant drugs such as tuberculosis medication are prescribed. The low pill burden of triple NRTI regimens (especially if combined in a single pill such as Trizivir®), offers hope that regimen simplification may still be possible in the future.