C_min is the minimum concentration of a drug measured between one dose and the next, and it's become a focus of maximum competition between the manufacturers of protease inhibitors as they struggle to sell the merits of their products.

Pharmaceutical companies conduct test-tube studies which measure the concentration of a drug needed to inhibit viral replication by 50%, 90% or 95%. These values are known as the IC₅₀, IC₉₀ and IC₉₅. Generally IC values refer to the concentration required to inhibit wild type virus (virus with no resistance mutations). More drug is needed to inhibit resistant virus, so IC values get higher as virus becomes more resistant. Overall, this means that the IC value for one virus may be very different to the IC value for another.

The current controversy

Several studies have found that combinations of particular protease inhibitors (such as ritonavir-boosted indinavir or lopinavir) boost drug levels which in turn produce greater viral suppression. Investigators are particularly interested in whether the C_min is above the IC₅₀ or the IC₉₅ - i.e. whether drug levels fall below the threshold needed to maintain viral suppression.

One of the chief benefits of drug `boosting' is the ability to overcome some loss of sensitivity by swamping the virus with a massive increase in drug concentrations. However, we don't know the real C_min or IC₅₀ for protease inhibitors in drug naﶥ people, let alone in those with some degree of resistance, which can make it hard to interpret resistance tests and the claims of manufacturers regarding the impact of their products on drug-resistant virus.

The inhibitory quotient

The ratio between the C_min and the IC₅₀ gives a value called the inhibitory quotient (IQ). This value is a way of illustrating numerically the comfort zone which exists when a particular drug is used. For example, if the trough level (C_min) of a drug is 50 and the IC₅₀ of a drug is 10, the ratio will be five. In other words, the trough level is five times higher than the minimum concentration needed to inhibit 50% of virus replication.

The C_min/ IC₅₀ or IQ ratio has been proposed as a way of predicting the clinical outcome of treatment but studies are needed to determine the usefulness of the IQ.

Abbott Laboratories investigator Dale Kempf says that lopinavir combined with ritonavir has a C_min/IC₅₀ ratio of 30, compared to ratios in single figures for other PIs when used alone. Similarly, Jon Condra of Merck has calculated that the C_min/IC₉₅ ratio of indinavir and ritonavir varies from 24.2 to 68.5 depending on the dose of ritonavir used. In comparison, the saquinavir/ritonavir combination had a ratio of just 1.7.

Some researchers are sceptical about the validity of such comparisons due to scientific variation and the reliance on statistical averages.

For example, a few people with very high C_min values in a study group will skew the mean, so the median value is a more accurate measure. The C_min is a range of values in different patients so it is necessary to know the variation in a population when looking at data.

HIV-positive individuals have much higher rates of protein binding of drugs than the uninfected medical students who typically volunteer for pharmacokinetic studies. When Dr Andrew Hill and colleagues calculated the IC₅₀ for protease inhibitors using a variety of protein binding estimates, they came up with vast variations, suggesting that companies, clinicians and people with HIV will be unable to compare like with like until researchers standardise the methods they use for measuring drug concentrations.

An analysis of 13 published randomised studies of protease inhibitors failed to show a relationship between inhibitory quotient and virological response at weeks 24 or 48 (Kakuda 2003).

However, Abbott's study is not the only one to show that the IQ is related to the success of new agents in treatment-experienced people. The GART study of switching therapy based on resistance testing and expert advice found a significant relationship between the IQ 12 weeks after switching treatment and viral load reduction at that point. Where the IQ for one drug was greater than the median at week 12, the average viral load reduction was 0.6 log. For 2, 3 and 4 drugs with an IQ greater than the median at week 12, the average reductions were -1.03 log, -0.89 log and -1.39 log respectively. This suggests that measuring the inhibitory quotient is useful, and further supports the case for combining virtual phenotype data with therapeutic drug monitoring in clinical practice.

An IQ (dubbed the 'Virtual IQ') calculated using VIRCO's Virtual Phenotype resistance test has also shown success in predicting response to treatment. A study of 37 people treated for 48 weeks found the Virtual IQ a better predictor of success than either genotypic resistance testing or the Virtual Phenotype (Kempf).

A number of studies have also subjected their results to analysis using a genotypic inhibitory quotient - the ratio of the C_min to the number of primary drug resistance mutations. See Resistance testing to select treatment in Anti-HIV therapy: Resistance for further details.

See Key research on testing for drug levels in Anti-HIV therapy: Testing drug levels for research summaries and references.