The durability of the benefits of antiretroviral therapy is a function of a number of patient-, drug- and virus-related factors. With respect to the patient, issues of convenience and tolerability are most important. With respect to the drug, agents for which plasma levels far exceed the drug concentration required to inhibit viral replication could represent a major advance. Finally, with respect to the virus, agents for which there is a higher genetic barrier to resistance could have an advantage in vivo. Some have suggested that Kaletra (a co-formulation of lopinavir 133 mg and ritonavir 33 mg per capsule), the newest entry into the antiretroviral therapy market, addresses all three of these issues effectively. Many abstracts have been presented over the past year to provide us with data to evaluate whether this may be correct.

Therapies that reduce the pill count and frequency of administration address the patient-related issues of convenience and adherence. In the current context, twice-daily administration of the fewest number of pills which can be taken with or without food represents an acceptable standard to meet. As once-daily therapies gain in popularity (and as the data are generated to support their efficacy), a new standard may be established. For the time being, Kaletra meets the fulfills the current criteria of acceptable convenience, requiring a usual dose of three capsules twice daily (not strictly every 12 hours), taken in a non-fasted state (but not requiring a heavy meal, or consumption of any specific type of food).

The inhibitory quotient (IQ) has been defined as the ratio of the trough drug concentration to that required to inhibit replication of 50% of a standard wild-type viral isolate (C_trough/EC₅₀). For Kaletra, at a standard dose of 400/100 mg (3 capsules) bid, the IQ has been determined to be 50 to 100, with levels only mildly attenuated (about 6-fold) by protein binding in human serum [1,2]. This efficacy has been borne out in a number of clinical trials. When used in combination with d4T and 3TC in drug-naive individuals (Study M98-863, n=326), Kaletra produced reductions in plasma viral load to below 50 copies/mL in 67% of individuals (ITT analysis) after 48 weeks of therapy [3]. In a smaller, earlier evaluation (Study 720, n=100), the same regimen was shown to maintain virologic suppression at these levels in 78% study participants (ITT analysis) over 108 weeks [5]. The use of Kaletra within triple class regimens in single-PI (Study 765, n=70) and multiple-PI (Study 957, n=57) experienced adults has produced reductions in plasma viral load below 400 copies/mL in 63-65% subjects over 48-96 weeks (ITT analysis) [6,7]. These results are quite impressive, and better than had been reported with similar regimens in the same patient populations. It could be argued that this is related to the higher IQ achieved by Kaletra in vivo.

The durable efficacy of Kaletra reported to date might also be explained on the basis of virologic principles, including a delay in the emergence of drug resistance. Theoretically, the most advantageous resistance pattern would consist of the following:

• Multiple mutations required to confer high-grade phenotypic resistance
• AND small incremental change in resistance for each mutation that develops
• AND consistently high drug levels, delaying (or preventing) the selection of single mutations in vivo

It is interesting to note that in Study 863 (drug-naïve patients) there was no evidence of genetic changes in the protease genes of HIV isolated from 37 patients receiving Kaletra for whom genotypic data were available following a rebound in plasma viral load [3,4]. In contrast, 15/37 (41%) had evidence of 3TC resistance at 48 weeks. In drug-experienced patients (Studies M97-765 & M98-957), a broader range of resistance to Kaletra was observed in patients following a similar breakthrough [6,7]. This was not associated with a single primary genetic change, but, statistically speaking, with variation at 11 different amino acid positions (10, 20, 24, 46, 53, 54, 63, 71, 82, 84 and 90) in the protease gene [8]. There was an association between the number of mutations, the degree of phenotypic resistance, and the virologic response to therapy, as shown below [9]:

Number of Mutations	Median EC50	% Virologic Response
0-5	0.8-2.7	100
6-7	13.5	70
8-10	44.0	30

In 6 patients with prior exposure to a single PI (and 0-2 baseline mutations in the protease gene), virologic breakthrough was always associated with the development of resistance to the NNRTI in the regimen, nevirapine. In contrast, in 4 patients, with 4-5 baseline mutations in the protease gene, the breakthrough was associated with resistance to both nevirapine and Kaletra. Thus, the barrier to the development of Kaletra resistance appears to be compromised by the prior accumulation of mutations in the protease gene, such as would be selected by prior therapy with another PI. Interestingly, of 4 isolates with high-level Kaletra resistance, 3 remained susceptible to saquinavir, and all 4 remained susceptible to amprenavir [10].

In conclusion, Kaletra represents an important advance in antiretroviral therapy. It is as convenient as other available twice-daily agents and has demonstrated excellent activity in vivo in a wide variety of clinical settings, including 2^nd and 3^rd line therapy. The higher barrier to drug resistance is almost certainly responsible for these observations. It is somewhat surprising that a primary or cardinal mutation associated with resistance has not yet been identified. This may simply have to do with the limited number of highly resistant isolates that have been studied to date, and the need to develop novel methods to generate such isolates in the laboratory. The concept that Kaletra-resistant isolates remain susceptible to amprenavir (and some to saquinavir) is also somewhat surprising. This may simply reflect the absence of the primary mutation for each of these agents, which would emerge quite rapidly if appropriate drug pressure were applied. It remains unclear if we would be able to "salvage" Kaletra-resistant viruses with other PI-based therapies, and this might be as important a reason as any to limit its use in first line therapy until we are clearer on the durability of the benefit of Kaletra-based combinations. Nonetheless, Kaletra represents the first clinically available agent that illustrates the principle of enhanced efficacy linked to a higher barrier to the development of drug resistance.

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