CIPLADOC - SCIENTIFIC DOSSIER Duovir-N

SCIENTIFIC DOSSIER

Duovir-N
Combining Potency with Simplicity


ZIDOVUDINE + LAMIVUDINE: A SYNERGISTIC 2-NRTI BACKBONE
It is advantageous to use the zidovudine + lamivudine combination as the 2-NRTI backbone of antiretroviral therapy for the following reasons: 1. All NRTIs require intracellular metabolism to their active triphosphate forms in order to inhibit viral replication. Both zidovudine and lamivudine have different intracellular phosphorylation pathways, and hence do not compete with each other for enzymes essential for their activation (Ref: AIDS 1996;10(5):46-8). 2. The pharmacokinetic profile of either drug is unaffected by co-administration to patients (Ref: JAMA 1996;276(2):111-7). 3. Zidovudine is active in replicating cells, whereas lamivudine is active in resting cells (Ref: Drugs 1997;53(4):657-80). 4. Lamivudine acts synergistically with zidovudine and inhibits zidovudine-resistant virus (Ref: JAMA 1996;276(2):111-7). 5. Resistance mutations to lamivudine usually develop rapidly. In vitro studies suggest that the lamivudine mutation, in the presence of the zidovudine resistance mutation, reverses resistance to zidovudine. Also, data suggest that the lamivudine resistance mutation confers a selective growth disadvantage (Ref: JAMA 1996:276(2):111-7). 6. Data suggest that mutations selected by zidovudine develop more slowly in patients receiving the combination of lamivudine and zidovudine. This unique observation may partly explain the sustained effects of lamivudine-zidovudine combination therapy (Ref: JAMA 1996;276(2):118-25). 7. Moreover, both drugs have non-overlapping toxicities. Zidovudine commonly causes anaemia and myopathy, whereas lamivudine commonly causes gastrointestinal side effects. Thus, the combination of zidovudine + lamivudine offers substantial benefits and has proven synergy.
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THE IMPORTANCE OF ADHERENCE
Adherence i.e. taking medicines as prescribed, has become an important consideration in HIV therapy. This is because although potent antiretroviral therapy has been shown to improve survival as well as quality of life, these benefits do not accrue unless the patient fully adheres to his treatment regimen. For antiretrovirals to be effective, it is essential that they reach and are maintained at concentrations higher than those required to inhibit HIV replication in infected cells. A drop in the concentration of the drug below a critical level allows the virus to continue replicating and provides ideal conditions for the development of drug resistance. Thus, adherence is essential for maintaining consistently inhibitory concentrations of the drugs. Data indicates that near-perfect adherence is required for a maximal response to HIV therapy. In order to achieve rates of HIV viral suppression in patients in clinical practice which are comparable to those observed in clinical trials, patients need to maintain greater than 95% adherence (See figure; Paterson, ICAAC 1998; Abstract I-172) Experience with chronic diseases such as diabetes, renal failure, tuberculosis and hypertension also indicate that a person's adherence has a direct effect on clinical outcome. Non-adherence is more common in chronic illness and when the individual has no symptoms but is being given the treatment to prevent or delay the onset of symptoms or progression of the disease. Some of the most important factors influencing adherence in HIV therapy are: 1. Thrice-daily regimens, especially the afternoon dose which may need to be taken in a relatively public environment. In contrast, both twice- and once-daily regimens are associated with good adherence. 2. Difficulty scheduling around food 3. Adverse effects 4. Size and number of medications 5. Storage specifications Non-adherence is more common among patients with psychological stress, depression and poor adaptive and coping mechanisms. People living with HIV/AIDS may also experiment with doses and timing. Timing of doses may be particularly important for patients receiving protease inhibitors, given their relatively shorter half-lives. As poor adherence generally has no immediate or overtly negative consequences for an individual, and in some cases may result in a lessening of drug-related side effects, they may feel reassured that missing doses is relatively harmless. Thus, optimizing adherence is clearly critical to therapeutic success. The simplification of antiretroviral regimens, with once- or twice-daily dosing without food or other restrictions would greatly enhance patient compliance, and hence therapeutic outcome.

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