Too many patients are diagnosed with HIV infection late in the course of their disease when not only is their CD4+ cell count below 100 cells/mm³, but they have evidence of opportunistic complications.

What is the most powerful first-line treatment for these individuals? Should they be treated with a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen as initial therapy? The answer is still being debated.

One previous cohort study suggested that for these patients, efavirenz (EFV, Sustiva, Stocrin) may be more effective than an unboosted PI.¹ But the trend in PI therapy has been towards greater use of boosting with ritonavir (RTV, Norvir), and many clinicians consider boosted PI-based therapy to represent the gold standard, at least with regard to potency.

As a result, many clinicians treat naive patients who have advanced disease with a boosted PI-anchored cocktail instead of an NNRTI-based combination in the belief that the high potency of the boosted PI may lead to better results.

Unfortunately, there are scant data supporting this notion. This current study was undertaken in order to directly compare these different approaches and determine their respective impact on immune restoration in patients entering treatment for the first time with advanced HIV infection.

Study

This was a prospective trial that randomized 66 treatment-naive subjects to 2 nucleosides: zidovudine/lamivudine (AZT/3TC, Combivir) plus either efavirenz or indinavir (IDV, Crixivan) 800 mg boosted by ritonavir 200 mg twice a day. In order to qualify for enrollment, subjects had to have a CD4+ cell count under 100 cells/mm³.

Over the course of this 48-week study, there was frequent, ongoing measurement of markers of viral and immunologic activation. This included CD28+, activation marker CD38+, and measures of proliferative responses to mitogens. Standard measurements of HIV RNA and CD4+ lymphocyte changes were also performed.

There was a trend favoring better virologic response in the efavirenz-treated subjects, which was driven by fewer adverse effects compared to the indinavir plus ritonavir-treated subjects. The intention to treat (ITT) analysis showed that, at 48-week follow-up, the efavirenz group had a 79% response rate for viral load under 200 copies/mL (P = .17) versus 61% in the indinavir plus ritonavir group.

The degree of immune reconstitution, as determined by CD4+ lymphocyte changes, numerically favored the efavirenz group. There was a median 214 CD4+ cell increase in the efavirenz group versus 117 cells in the indinavir plus ritonavir group, although these differences did not reach statistical significance (P = .12).

Patients in the efavirenz arm had fewer CD8 CD38+ cells than the indinavir plus ritonavir group at week 48, suggesting less overall immune activation. There was also a trend for higher levels of CD8+ memory cells in those who had been randomized to efavirenz. However, these immunologic changes may have been influenced by the greater percentage of patients with undetectable viral load as well as the more pronounced increase in CD4+ cells in the efavirenz-treated patients.

Comment

The primary endpoint of the study was the proportion of patients with a viral load under 200 and CD4+ cell count above 200. However, it was not optimally powered in this regard and although differences were seen, they did not reach statistical significance.

In addition, the most commonly used boosted PI today is lopinavir/ritonavir (LPV/r, Kaletra) which previous studies have suggested is superior to boosted indinavir. This lessens the relevance of this data to contemporary therapy.

There is a large AIDS clinical trial group (ACTG) study underway for treatment-naive patients that compares boosted PI versus NNRTI-anchored therapy. The outcome of this trial is eagerly anticipated and should help clinicians better determine optimal initial therapy.

This study does add some significant and interesting information regarding immune restoration in patients with advanced disease. Although there was a trend favoring NNRTI-based therapy, major differences were not seen between the groups, and despite the advanced status of the patients in this study, patients in both arms experienced significant immune restoration.

Of note, this well-executed study did not support the commonly held belief that boosted-PI therapy is superior to NNRTI-based treatment for patients who enter treatment with advanced disease. Hence, both approaches are acceptable in advanced patients and we must wait for larger trials to tell if smaller advantages exist for one approach over the other.

Footnote

1. Pulido F, Arribas JR, Miro JM, et al, and the EfaVIP Cohort Study Group. Clinical, virologic, and immunologic response to efavirenz- or protease inhibitor-based highly active antiretroviral therapy in a cohort of antiretroviral-naive patients with advanced HIV infection (EfaVIP 2 Study). JAIDS. April 1, 2004;35(4):343-350.