Introduction

Although the introduction of highly active antiretroviral therapy (HAART) in the mid-1990s has resulted in a decrease of the morbidity and mortality in the HIV-1 patient population that has access to treatment, therapy failure still occurs. The surrogate markers for therapy failure, which ultimately results into clinical progression, are CD4 cell count and viral load. As changes in viral load mostly precedes changes in CD4 count, the determination of the viral load is the most relevant laboratory procedure to monitor the short-term in vivo activity of a therapy given to an individual patient. Lack of adherence, lack of therapy potency, pharmacological reasons, drug-drug interactions, and preexisting drug resistance can be factors resulting into therapy failure and rising viral loads.

The evolution of resistance against HIV-1 inhibitors within a patient depends on the generation of genetic variation, reflected by substitutions, insertions, deletions, and recombination events, and on the selection of drug-resistant variants during antiretroviral therapy. The high HIV-1 genetic variability is caused by the error-prone nature of HIV-1 reverse transcriptase, by the absence of any enzymatic proofreading activity, and by the huge rate of HIV-1 replication in vivo. Some of the created genetic variants will result in alterations to the structure and function of the molecules targeted by the antiviral drugs (currently reverse transcriptase, protease, and glycoprotein gp41). These alterations could confer changes in susceptibility to one or more of these drugs. In the presence of therapy, the variants with some level of resistance will gradually overgrow the wild-type variants. Under the continuous selective pressure of inhibitors and with the presence of residual replication as a result of insufficient potency of the treatment, additional mutations will accumulate.

Thus, the main goal of HAART is to reduce the viral load as much as possible to prevent further clinical progression. However, its immediate goal is to reduce the viral load to prevent the formation of variants that result in antiviral resistance to the current therapy and that, because of the phenomenon of cross-resistance within drug classes, ultimately might lead to a limitation or even lack of future treatment options.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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