The introduction of potent combinations of antiviral drugs is a major breakthrough in the treatment of HIV. We investigated the long-term virologic outcome and the development of resistance after initiating highly active antiretroviral therapy (HAART) in drug-naive patients in daily clinical practice. Twenty-five treatment-naive HIV-1 patients were started on HAART. Fifteen patients responded with a drop in viral load below the limit of detection during 35.5 (interquartile range: 7) months of therapy. In 6 of 10 patients with virologic failure, virus with resistance-related mutations against the received drugs emerged. Compared with responders (R), nonresponding (NR) patients were in a later disease stage at therapy start (p = 0.0089) with lower CD4 cell counts at baseline (p = 0.040), and a lower proportion of nonresponders showed protease inhibitor (PI) levels above C(min) (p = 0.049). More NR patients showed secondary PI mutations at baseline (p = 0.079), and the CCR2-64I coreceptor polymorphism was absent among NR patients, compared with 38.5% of R patients displaying CCR2-64I (p = 0.053), although the differences were not significant. In conclusion, starting HAART in antiretroviral drug-naive HIV-infected patients followed in daily clinical practice prevented viral breakthrough for up to 44 months in 60% of the patients. Virologic failure was associated with the development of resistance-related mutations, a later stage of disease at start of therapy and lower PI drug levels.

The number of HIV-1-infected patients harboring multidrug-resistant viruses is increasing. Since new antiretroviral drugs with favorable resistance profiles are limited, innovative strategies are urgently needed. Treatment interruptions can lead to a loss in HIV resistance followed by improved response to reinitiated therapy. The authors report the case of a patient with sustained antiretroviral response for 3.5 years after a 7-month treatment interruption. Concomitant with an increase in replication capacity, multidrug-resistant viruses gradually disappeared during treatment interruption. Resistance to protease inhibitors (PI) was completely lost, and resistance to reverse transcriptase inhibitors was still present when therapy was reinitiated. PI-resistant variants were not detected at four time points after treatment reinitiation. The alignment of the nucleic acid sequences from all different time points suggested that the viruses obtained after treatment reinitiation evolved from less-resistant variants prior to treatment interruption. This was supported by in vitro propagation of the viral plasma population and an individual clone derived from the time point of treatment interruption. This is consistent with a model favoring reversible binding of HIV-1 to reservoirs, as has recently been proposed for follicular dendritic cells. Understanding of this process could help to exploit the reduced fitness of drug-resistant viruses for treatment interruptions.

A prominent feature of HIV infection is a progressive anergy of T cells and an increase of activation-dependent T-cell death. CD80 (B7.1), the ligand of CD28, is an important co-stimulatory molecule on antigen-presenting cells that delivers an essential second signal for T-cell activation. To test whether immunologic dysfunction in HIV disease involves CD80, we studied CD80 expression on circulating monocytes in heparinized whole blood of 33 HIV-infected patients and 13 controls. Most monocytes in patients and controls expressed significant amounts of CD80. There was no statistical difference of mean fluorescence intensity (MFI) of CD80 expression when all HIV-infected patients were compared with healthy controls. However, asymptomatic patients in clinical Centers for Disease Control and Prevention (CDC) stage A showed a significantly stronger CD80 expression than did healthy controls. Additionally, patients receiving antiretroviral therapy exhibited significantly higher CD80 expression than did patients not receiving therapy and healthy controls. We did not find a correlation with the presence of HIV p24 antigenemia and counts of CD4+ and CD8+ T cells. Although we studied CD80 expression only on circulating monocytes and not in HIV-infected monocytes or in activated macrophages, our data do not support a role for a general impairment of CD80 expression in induction of anergy in HIV disease.

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