Page 1 of 2HAART (Highly Active Anti–Retroviral Therapy)
An antiretroviral regimen that can reasonably be expected to reduce the viral load to < 50 c/mL in treatment–naive patients.
Treatment regimens used in patients who have failed at least two antiretroviral regimens and have had extensive exposure to antiretroviral agents. Some prefer the term “Rescue therapy”, and some use these terms for any patient who has failed HAART.
The addition of antiretroviral agents to an existing regimen, usually due to failure to achieve a desired virologic response despite evidence of antiviral activity. This may be done in early treatment (VL >500 c/mL at 12–16 weeks) or at the time of viral rebound.
Genetic Barrier to Resistance
The mutations required by antiretroviral agents for evolution of phenotypic or clinically significant resistance. Examples of drugs with large genetic barriers include all protease inhibitors and all NRTIs except 3TC.
Pharmacologic Barrier to Resistance
The achievement of tissue levels of pharmacologically active drugs substantially above the IC50 or IC90 for prolonged periods. Examples of drugs with large pharmacologic barriers include efavirenz, nevirapine and ABT–378/r.
Second Generation PIs and NNRTIs
Drugs currently in development that are active against HIV strains resistant to current members of that class.
Regimens that avoid exposure to drug classes, allowing the preservation of these agents for subsequent therapy. NNRTI/NRTI combinations are often referred to as “PI–sparing”. NRTI based regimens, such as AZT/3TC/ABC or ddI/d4T/HU, spare both PIs and NNRTIs.
No Detectable Virus or Undetectable Virus
This is the virologic goal of therapy, but the definition depends on the threshold of the assay used to determine plasma HIV RNA levels. Common thresholds are 400–500 c/mL or 20–50 c/mL.
The predominant virus in a region or population. At present, the majority of strains are pan–sensitive, but this could change with time.
Genotypic resistance testing measures mutations on the reverse transcriptase and/or protease gene that impart partial or complete resistance to HIV. Results are interpreted on the basis of established patterns of mutations associated with phenotypic resistance, but assesses only the predominant strain(s), requires expertise for interpretation and usually does not detect resistance to discontinued agents due to substitution by wild–type strains. Phenotypic resistance provides IC50, IC90, or IC95 data (concentration necessary to inhibit 50%, 90% or 95% of strains), and is most easily interpreted by care providers, but the test is expensive (~$900/test), results are not available for three weeks, and only the dominant strains are tested.
Genotypic antiretroviral resistance testing.
Generally defined as detectable HIV RNA with an assay that has a threshold of detection of 20–50 c/mL after 20–24 weeks on initiating therapy or implementing a new regimen. HIV RNA levels >500 c/mL at >16–20 weeks also indicates virologic failure and levels >500 c/mL at 12–16 weeks generally predicts virologic failure.
Viral Load–CD4 Count Disconnect
This term generally refers to the observation that many patients fail to achieve adequate viral suppression, but nevertheless have a robust CD4 cell response or sustained CD4 counts at high levels.
For example, analysis of the Swiss Cohort showed that patients with persistent viral suppression had an average CD4 count increase of 138/mm3 compared to an increase of 130/mm3 in those with only a transient virologic response (Lancet 1998, 351:723). By contrast, other studies have shown that discontinuation of antiretrovirals is associated with a precipitous fall in CD4 count. Similar conclusions result from analyses of opportunistic infections. A 30 month follow–up of 2674 patients treated with protease inhibitor combination regimens showed the frequency of opportunistic infections was 6.6% for those with viral rebound, 20.1% for non–responders and about 55% for historic controls (Lancet 1999, 353:863). These studies show that virologic failure with “Triple therapy” often results in CD4 responses that translate to reduced disease progression. In most cases there is partial viral suppression so that the “Disconnect” component of the term may be inappropriate. Benefit may be observed even when viral load returns to baseline, possibly due to reduced “Fitness” of HIV. Two important unknowns are the durability of this benefit beyond the 1–2 years observed in the studies summarised above and the applicability of these observations to antiretroviral regimens that do not contain protease inhibitors.
The implication is that certain mutations including mutations that confer resistance may decrease the replicative capacity of HIV. This can be measured by comparative growth kinetics of strains with and without selected mutations or with a competitive assay (J Virol 1999, 73:3744). An example is the RT 215 mutation that confers AZT resistance also reduces HIV fitness for replication. In vitro studies of this phenomenon are inconsistent: protease mutations at codon 30 and 90 reduce in vitro replicative capacity, multiply mutated strains resistant to indinavir showed no difference compared to wild–type virus (J Virol 1999, 73:3744).