Roy M. Gulick, MD, MPH:
Turning now to the studies of investigational agents in treatment-experienced patients, the MOTIVATE 1 and 2 studies are randomized, double-blind, placebo-controlled, phase IIb/III clinical studies comparing maraviroc once daily, maraviroc twice daily, and placebo, each in combination with an optimized background regimen (OBR) in treatment-experienced patients with CCR5-tropic HIV. The planned interim Week 24 results for 601 patients in MOTIVATE 1 and 475 patients in MOTIVATE 2 were presented 2007 CROI (Capsule Summary).^[15,16]

The other important presentations were interim analyses including Week 24 results from the BENCHMRK-1 and -2 studies (Capsule Summary).^[19,20] BENCHMRK-1 is being conducted in 250 patients in Europe, Asia/Pacific Islands, and Peru, whereas BENCHMRK-2 is being conducted in 349 individuals in North and South America.

Both maraviroc and raltegravir showed substantial potency in treatment-experienced patients, particularly when combined with other active agents. In the MOTIVATE studies, 41% to 49% of maraviroc recipients achieved HIV-1 RNA < 50 copies/mL compared with 21% to 25% of individuals assigned to placebo (P values ≤ .0006). In the BENCHMRK studies, 61% to 62% of patients of raltegravir recipients achieved HIV-1 RNA < 50 copies/mL compared with 33% to 36% of individuals on placebo (P values < .001).

In addition to the high rates of response in the intervention arms, I was surprised by the relatively good rates of suppression achieved by patients in the placebo arms who received an OBR alone. Previously in the TORO studies, only 9% of patients achieved HIV-RNA < 50 at Week 48 on the OBR alone.^[20] However, in the MOTIVATE studies, the response rate (HIV-1 RNA < 400 copies/mL) with just the OBR alone was 23% to 31%, and the response rate with the OBR alone in the raltegravir studies was approximately 42%. In the American raltegravir study, 50% of individuals were taking darunavir for the first time, and 20% were taking enfuvirtide for the first time. These data underscore that use of additional active agents is critical for virologic response and highlight the potency of currently approved antiretrovirals for treatment-experienced patients.

Pedro Cahn, MD, PhD:
The importance of including other active agents in the regimens was also illustrated by the analysis of the baseline genotypic sensitivity scores in the raltegravir studies. Among patients whose genotypic sensitivity score was 0, indicating no genotypic susceptibility to any agents in the OBR, 57% of individuals in the raltegravir arm nevertheless achieved a virologic response (HIV-1 RNA < 400 copies/mL) compared with only 10% of those on an OBR alone. As the genotypic sensitivity scores increased and more active drugs were included in the OBR, the differences between the 2 arms still favored raltegravir but were less pronounced, which is logical: If a patient has 3 or 4 active drugs in their regimen, they have a good chance of virologic response even without using raltegravir.

I found it interesting that the MOTIVATE investigators reported that concomitant use of enfuvirtide was not associated with larger reductions in HIV-1 RNA. However, the proportions of patients who achieved HIV-1 RNA < 400 and 50 copies/mL according to enfuvirtide use were not shown, nor were patients randomized to receive enfuvirtide or no enfuvirtide.

Joep MA Lange, MD, PhD:
To me, it does not make sense that enfuvirtide contributed nothing to virologic response because we know that it is an active drug in enfuvirtide-naive patients. In this analysis, the investigators did not differentiate between enfuvirtide-naive and enfuvirtide-experienced patients. Moreover, the fact that use of enfuvirtide was not randomized means that a selection bias may be present: Patients who did not receive enfuvirtide were probably those who were able to construct an OBR containing at least 2 active drugs without requiring enfuvirtide.

Roy M. Gulick, MD, MPH:
I agree. The patients who used enfuvirtide may have been those with fewer active agents available and therefore less likely to respond well regardless. In my opinion, that is a plausible explanation as to why the investigators did not observe a significant difference with vs without the use of enfuvirtide.

The availability of additional options for treatment-experienced patients will also inevitably affect how existing agents such as enfuvirtide are used. Some patients who have an undetectable HIV-1 RNA on a regimen that includes enfuvirtide may wish to replace enfuvirtide with one of the newer oral agents rather than continue with twice-daily injections. However, clinicians who are considering such a switch need to be cautious about replacing enfuvirtide with maraviroc. They cannot assume that maraviroc will be active because the patient may not currently have CCR5-tropic virus, and in a patient with undetectable HIV-1 RNA, they cannot assay the viral tropism.

Joep MA Lange, MD, PhD:
We may also have more to learn about the impact of existing antiretroviral agents on viral tropism. Some agents may be more active against CCR5-tropic virus and therefore may promote the emergence of CXCR4-tropic virus. Alternatively, the combination of a CCR5 inhibitor with additional agents that are very active against CXCR4-tropic virus may be particularly effective, regardless of the baseline tropism. It may be possible to explore these issues by analyzing whether different OBRs influenced response in the maraviroc studies.

Roy M. Gulick, MD, MPH:
Another observation about tropism, based on MOTIVATE and other studies, is that in approximately 10% of HIV-infected individuals, the detected viral tropism will change between a test performed during the screening visit and a subsequent test performed at study entry, prior to receiving a CCR5 inhibitor. That is, the detected viral tropism may change from CCR5-tropic virus to dual/mixed-tropic virus, or vice versa.

Joep MA Lange, MD, PhD:
In addition, most of the available data come from studies performed in individuals with HIV subtype B. In patients infected with HIV subtypes that are common in sub-Saharan Africa, such as subtypes C and A, CXCR4 tropism is seen less frequently than in patients with subtype B virus. By contrast, patients infected with HIV subtype D quite frequently have CXCR4‑tropic viruses. Clinicians must keep these differences in mind when treating immigrants and other individuals who were infected in different regions.

Roy M. Gulick, MD, MPH:
One of the most interesting questions from the audience after the back-to-back presentations of the MOTIVATE and BENCHMRK studies concerned whether these drugs can be used together. Currently, the expanded access programs for both maraviroc and raltegravir permit the use of the other agent as well. That question reflects current thinking on how to maximize responses in treatment-experienced patients, by using at least 2 active agents with the goal—consistent with the current US Department of Health and Human Services recommendations—of achieving HIV-1 RNA < 50 copies/mL, which is a major change from where the HIV field was only 3 years ago.^[22]