AIDS 2006; Toronto, Canada; August 13-18, 2006

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The Body PRO Covers: The XVI International AIDS Conference

Five-Year Study Demonstrates Similar Outcomes for NNRTI-Based and PI-Based Regimens

August 15, 2006

The FIRST (Flexible Initial Retrovirus Suppressive Therapies) study,1 which was carried out by Community Programs for Clinical Research on AIDS (CPCRA), a federally funded national network of community-based research groups, was a rather large study with two objectives.2 The first objective was to compare a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based strategy to a protease inhibitor (PI)-based strategy. The second objective was to determine whether the use of a triple-class regimen confers any advantages over a two-class regimen.

The study, which began recruiting in February 1999, enrolled 1,397 individuals over three years. Participants were randomly assigned to one of three possible treatment arms:

  1. NNRTI + NRTI (nucleoside/nucleotide reverse transcriptase inhibitor) backbone

  2. PI + NRTI backbone

  3. NNRTI + PI + NRTI backbone

The study population consisted of antiretroviral-naive individuals age 13 or older (median age of 38) and was predominantly male (79%), with a median CD4+ cell count of 163 cells/mm3. Over 70% of the participants were of either African-American (54%) or Hispanic (17%) origin. Interestingly, although the minimum age for enrollment was 13, it is not clear what proportion of study participants were pediatric.

The trial participants have been followed for a median of 60 months. The main endpoint for the NNRTI versus PI comparison was progression to AIDS or death or a CD4+ cell count below 200 cells/mm3. Secondary endpoints were virologic suppression or discontinuation of therapy due to intolerance and toxicity. The primary endpoint for the triple-class versus two-class comparison was difference in CD4+ cell count after 32 months of follow-up.

The results showed no significant differences in the composite endpoint of disease progression (AIDS or death) or a CD4+ cell count of less than 200 cells/mm3 between the NNRTI arm and the PI arm, an endpoint that was reached by 388 individuals overall.

It is important to note that few recent studies have been designed with clinical endpoints as a primary outcome measure as is the case with the FIRST study. Studies on starting strategies generally will have relatively few participants and it would be likely that the occurrence of clinical events, such as progression to AIDS or death, would be so low that the result would not be interpretable.

Importantly, the PIs chosen in this study were permitted to be either unboosted or boosted. Sixty-one percent of those on the PI arm were treated with nelfinavir (NFV, Viracept), a drug that is no longer generally recommended in any contemporary treatment guidelines. Twenty-six percent of the patients in the PI arm were given a ritonavir (RTV, Norvir)-boosted PI. It is unclear what PI was used in the remaining percentage of patients in the PI arm of the study.

In the NNRTI arm, the majority (63%) of participants used efavirenz (EFV, Sustiva, Stocrin). In all three treatment arms, the most common NRTI backbones chosen were zidovudine (AZT, Retrovir) + lamivudine (3TC, Epivir) and stavudine (d4T, Zerit) + lamivudine, again in contrast to current clinical practice and guidelines.

The results of the study, which were presented by Rodger D. MacArthur, demonstrate no significant difference in the clinical endpoints between the NNRTI and PI arms of the study. The NNRTI versus PI hazard ratios for the composite endpoint, AIDS or death, and virologic failure respectively were 1.02, 1.07 and 0.66. Perhaps this is not surprising given our knowledge of the success of antiretroviral therapy at maintaining health in the majority of recipients and the availability of second- and third-line options when virologic failure is experienced.

The regimen containing both an NNRTI and a PI was the least well tolerated, with twice as many participants needing to switch from this regimen -- 80% of individuals on this combination had to perform at least one switch. This was almost double the rate seen with the other two arms (hazard ratio 1.58). There were no differences between groups in mean change in CD4+ cell outcomes.

One outcome of interest was that, out of the three regimens, NNRTI-based regimens were more likely to have superior virologic outcomes. This supports previous studies -- especially when unboosted PIs have been used. Both PI-containing arms had a more rapid time to loss of virologic response.

Some resistance data was also presented from individuals who were experiencing treatment failure. Fifty percent had no demonstrable resistance on genotype testing, 13.8% had PI resistance (either the 30N or 90M, as would be expected on nelfinavir failure), and 22% had NNRTI resistance, with mostly the 103N. Triple-class resistance was experienced by 14.2% of participants.

The study adds to the accumulating data supporting NNRTI-based first-line regimens as being the current standard. It also supports other studies that have shown triple-class regimens to be intolerable and inferior.

What is really needed now is a study comparing different contemporary starting strategies -- such as regimens using ritonavir-boosted PIs versus regimens using NNRTIs or using thymidine analog sparing nucleoside/nucleotide backbones. Unfortunately, as with this study, any study that is begun today will leave unanswered questions as new classes of drugs are integrated into our starting regimens and older drugs fall by the wayside.


  1. MacArthur RD, Novak RM, Peng G, et al, for the CPCRA 058 Study Team and the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). Long-term clinical and immunologic outcomes are similar in HIV-infected persons randomized to NNRTI vs PI vs NNRTI+PI-based antiretroviral regimens as initial therapy: results of the CPCRA 058 first study. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUAB0102.
    View slides: Download PowerPoint

  2. CPCRA 058 (FIRST) Executive Summary. February 3, 2006.

It is a part of the publication The XVI International AIDS Conference.

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