2007 has the potential to enter history books as the only year in which two new HIV drug classes received U.S. Food and Drug Administration (FDA) approval for the treatment of HIV infection in the HIV treatment-experienced population. This is particularly important and clinically useful since we have learned in the past few years that the use of at least two new potent agents is one of the best predictors for virologic response when building a new antiretroviral regimen for the heavily treatment-experienced patient.

At the 14th Conference on Retroviruses and Opportunistic Infections, in a special late breaker session, new data on the ongoing registrational studies for new compounds were released for the first time to the public. On the program first were the results of the MOTIVATE 1 and 2 studies delivered by Pfizer representatives, which explored the use of maraviroc, a CCR5 entry inhibitor, in experienced HIV-infected patients with CXCR5-tropic virus1,2. In these studies, we observed in general HIV RNA drops of almost 1 log with the addition of maraviroc to an optimized background therapy (OBT).

We were then presented with the data from the BENCHMRK 1 and 2 studies, by David Cooper3 (from the University of South Wales, Sydney) and by Roy Steigbigel4 (from the State University of New York). These studies evaluated the use of MK-0518, whose generic name is to be raltegravir (RTG). This integrase inhibitor was looked at in these studies for the treatment of a heavily experienced HIV-infected population with virologic failure.

MK-0518 is a strand transfer inhibitor of the HIV integrase. It has a potent in vitro antiviral activity with an IC95 = 33nM. It is active against multidrug-resistant HIV-1 and synergistic in vitro with all antiretrovirals tested. Preliminary data on their phase II studies conducted in both the naive and experienced populations have been presented at previous conferences.5-9 In the naive population the proportion of patient with an HIV RNA < 50 copies was ~85 to 95%6 [see "Potent Antiretroviral Effect Seen With the Integrase Inhibitor MK-0518 as Part of Combination ART in Treatment-Naive, HIV-1-Infected Patients"]; and the responses seen in the experienced population were ~57 to 67%.8 [see "MK-0518 Demonstrates Potent Efficacy in Patients With Triple-Class-Resistant Virus: 24-Week Results."]

The BENCHMRK 1 and 2 are two identical, ongoing phase III studies that are being conducted in different countries. They are randomized, double blind, placebo-control trials in which raltegravir 400-mg twice daily is compared to placebo, both in combination with an optimized background therapy selected by the investigator based on baseline resistant tests.

All patients were failing an antiretroviral regimen at the time of enrollment, with documented genotypic or phenotypic resistance to one or more drugs in each of three classes (NRTI, NNRTI and PIs). The results presented at this conference were an interim 24-week analysis, in which all patients completed at least week 16.

Both BENCHMRK studies were equal in design, enrolled similar amount of patients with similar demographics and baseline patient characteristics and yielded similar study results. Among both studies, 699 patients were randomized 2:1 (raltegravirlacebo) with only 22 patients total discontinuing the study at the time of this analysis (15 who were receiving raltegravir and seven on placebo). The median CD4 count at baseline was ~154 cells and approximately a quarter of the patients had a genotypic susceptibility score (GSS) of 0. The use of TMC114 (darunavir, Prezista) or enfuvirtide (T-20, Fuzeon) on the OBT was always counted as an active drug.

The proportion of patients achieving an undetectable viral load of less than 400 copies was highly statistically significant favoring the raltegravir arm over the placebo arm. The mean change in CD4 count from baseline was also highly statistically significant favoring the raltegravir arm, 124 versus 68 cells/mm3. For this analysis all patients had completed at least week 16, and the results for week 24 are for just a fraction of the population that reached week 24 at the time of this analysis.

The use of darunavir and/or enfuvirtide as part of the OBT + raltegravir was associated with a 98% response rate, and the use of at least one of these two drugs added to the raltegravir was associated with 90% response. This again reinforces the importance of selecting two or more active agents when building a new antiretroviral regimen in a heavily treatment-experienced patient.

Virologic failure was observed in 76 (16%) patients who were in the raltegravir arm versus 121 (51%) patients in the placebo arm. A partial analysis based on genotyping 41 samples of raltegravir failures showed 32 patients with changes on the integrase genotypic sequence versus nine patients with no consistent genotypic changes from baseline. In general raltegravir failure was associated with one or two genetic resistant pathways with other associated mutations here shown in parenthesis: N155H (with E92Q, V151I, T97A, G163R and L74M) or Q148K/R/H (with G140S/A, E138K). These mutations were proximal to the catalytic center and they are similar to the ones that have been observed in vitro.

The safety data presented in this study was equally impressive. A similar incidence of clinical adverse events was seen in the raltegravir and placebo arms. The most frequent adverse event was diarrhea, and this was seen with equal frequency among both study arms. Similarly, laboratory abnormalities were also divided equally among both study arms. No significant dyslipidemia, or elevation in creatinine or liver function tests were identified with the use of raltegravir over placebo.

In this interim preliminary data, the use of raltegravir + OBT, in patients with advanced HIV infection who had been failing previous antiretroviral drugs and had evidence of multidrug resistant virus, was not only extremely well tolerated but also potent and certainly superior compared to placebo + OBT. It was quite impressive to see an overall response of more than 90% for patients who were given raltegravir with enfuvirtide and/or darunavir.

The results presented from these four studies (MOTIVATE 1 and 2 and BENCHMRK 1 and 2) at this late breaker session were truly landmarks and have the potential to change treatment paradigms. Although we need to exercise caution given the relative preliminary nature of these data, it is difficult not to get too excited about the future possibilities for our treatment-experienced patients.

Gilead Sciences is also developing an integrase inhibitor with different pharmacokinetic properties for use in experienced patients. The preliminary results of their phase IIb trial is also being presented at this conference. Two other companies, Schering-Plough and Incyte have other CCR5 entry inhibitors that are currently in clinical development.

The availability of one of more of these integrase inhibitors and entry inhibitors, coupled with the recent availability of potent protease inhibitors such as tipranavir (TPV, Aptivus) and darunavir, and the use of enfuvirtide make the treatment armamentarium for the treatment experienced much easier. With all these options the use of a single-active drug, so-called sequential monotherapy, should be avoided since it usually leads to rapid development of resistance to that drug, further limiting future treatment options.

The benefits of plasma HIV-1 RNA suppression to less than 50 copies/mL on durability of response and prevention of emergence of resistance support using persistent elevations above this cutoff as a definition of virologic failure. Previous treatment guidelines9 had recommended establishing a plasma HIV-1 RNA target of at least 0.5 to 1 log10 HIV-1 RNA copies/mL below baseline for patients with more advanced treatment failure and a high level of multidrug resistance. However, with all this data emerging from the evaluation of these new agents that are designed to have activity against multidrug-resistant virus, it is quite possible that a high proportion of our heavily treatment-experienced patients can now achieve HIV-1 RNA levels of less than 50 copies/mL. Thus the goal of therapy should always be the achievement of HIV RNA levels below 50 copies/mL, even for highly treatment-experienced patients.