Drug failure during HIV-1 treatment. New perspectives in monitoring drug resistance.

Since the discovery of 3'-azido-3'deoxthymidine (zidovudine) as an effective antiretroviral agent against human immunodeficiency virus type 1 (HIV-1), drug therapy has been widely used in the treatment of AIDS. To date, new combination therapies have significantly altered the longterm prognosis for HIV-infected patients showing a reduction of plasma viral load, associated with clinical and immunological recovery. Nevertheless, in various circumstances treatment can fail for several reasons, such as patient noncompliance with the therapeutic regimen, suboptimal antiviral drug concentrations, drug pharmacokinetics, and virus resistance to one or more drugs. Virus drug resistance is the most important factor contributing to the failure of antiretroviral therapy. Since some evidence indicates that viral resistance and treatment failure are closely linked, this brief review explores the routine determination of drug resistance and its importance to shed more light on the meaning of mutations correlated to drug resistance.

Prevalence of multiple dideoxynucleoside analogue resistance (MddNR) in a cohort of Italian HIV-1 seropositive patients extensively treated with antiretroviral drugs.

As the emergence of highly resistant virus might compromise antiretroviral regimens in HIV-1 infected patients, a constant analysis of genotypic mutations should be performed to establish the magnitude of mutation prevalence and gauge their impact in patients treated extensively with combination therapy. The frequency of multiple dideoxynucleoside analogue resistance (MddNR) was evaluated in a group of Italian HIV-1 seropositive patients who failed to respond to therapy despite a long-lasting drug treatment. Results showed the presence of one or more mutations (A62V, V75I, F77L, F116Y and Q151M) able to confer resistance to all NRTIs in a relatively high percentage (7.9%) of patients enrolled in the study. Moreover, a significantly lower HIV-1 viral replication in patients with MddNR, suggested the importance of monitoring HIV-1 subjects not only by viral load, but also by drug resistance testing, so that a correct drug regimen may be chosen.

In vivo effects of recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF), alone and associated with zidovudine, on HIV-1 replication.

The effects of the administration of recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) on HIV-1 replication were evaluated in 15 patients with advanced HIV-1 disease and severe leukopenia, by monitoring immunocomplex dissociated p24 antigenemia, during 21 overall courses of therapy with rHuGM-CSF (lasting 2 to 27 weeks), alone or associated with zidovudine. During most treatment courses with rHuGM-CSF (17 out of 21), no significant modifications of HIV-1 antigenemia were recognized. A remarkable increase in viral replication occurred in only two courses out of 13 performed with rHuGM-CSF alone, while a significant reduction of antigenemia was observed in two courses of rHuGM-CSF out of 8 administered with zidovudine, after 10 weeks of combined treatment. Our experience is discussed on the grounds of both experimental and clinical investigations dealing with interactions between rHuGM-CSF and zidovudine during HIV-1 disease, focusing on risks of increased viral burden during treatment with rHuGM-CSF alone, and the synergistic activity of the combination with zidovudine against HIV-1 replication.