February 25, 2002
Metabolic complications and "lipodystrophy" have been the "price to pay" for the success of highly active antiretroviral therapy (HAART). One of the major metabolic problems our patients frequently encounter is hyperlipidemia. In multiple studies, protease inhibitors have been implicated as the major cause of elevations of cholesterol and triglycerides. (See "Risks for Cardiovascular Disease (CVD) Associated with Antiretroviral Therapy (ART)" ICCAC, 2001).
Over the last few years several studies have also looked into possible ways to improve and possibly correct these lipid abnormalities. One of the most interesting approaches has been changing from a protease-inhibitor-based regimen to a reverse-transcriptase agent (nucleosides or non-nucleosides).
Several studies have addressed the impact of lipid metabolism in patients on first-line therapy, who substitute their protease inhibitor with either abacavir or nevirapine.
The results of these studies have had variable outcomes, but for the most part, they have favored the substitution of a protease inhibitor with a reverse transcriptase agent. (See "Lipid Improvements with Nevirapine" and "Comparison of the Metabolic Disorders and Clinical Lipodystrophy 48 Weeks After Switching from HAART to Trizivir Versus Continued HAART (TRIZAL: AZL30002)" ECCAT 2001 report.)
In this study (ESS40002) presented by Dr. Kumar, investigators compiled even more evidence of the benefits of a protease-inhibitor-sparing regimen. This time, however, they did this on patients who were naïve to antiretroviral therapy.
They evaluated the development of hyperlipidemia as a component of fat redistribution in naïve patients treated with three different regimens: combivir/abacavir vs. combivir/nelfinavir vs. d4T/3TC/nelfinavir.
The demographic characteristics of the population in this study were interesting because they included a high proportion of female patients (50%), intentionally targeted during recruitment. There were also a large number of African-American subjects and Hispanics enrolled from Latin-American study sites. Unfortunately, about one third of the initial 258 patients enrolled in this study were lost during the 48 weeks of follow up, but they were equally divided between the three arms of the study.
The mean LDL, cholesterol, triglycerides and lactate changes from baseline in the ITT analysis at 48 weeks significantly favored the combivir/abacavir arm over the other regimens. In fact, there was no LDL increase from baseline and very minimal and non-significant elevations in cholesterol, triglycerides and lactate in this combivir/abacavir arm. Interestingly, there were fewer lipid abnormalities observed in the combivir/nelfinavir arm when compared to the d4T/3TC/nelfinavir arm. When these results were stratified by gender, the investigators noticed a trend toward more lipid abnormalities in males than in females.
Although this study was not powered to detect differences in efficacy, the proportions of patients with HIV-1 RNA <400 copies/mL, and HIV-1 RNA <50 copies/mL in the three arms were similar.
I couldn't help but notice that only 36% of the patients in the d4T/3TC/nelfinavir arm with a baseline HIV-1 RNA >100,000 and <200,0000 achieved a viral load of <50 copies/mL. This is drastically reduced from all other study results I have seen in the combination of nelfinavir plus two NRTIs regimens in Naïve populations. Rather than being an efficacy problem of this regimen, this low response rate may represent a flaw in the study design, or maybe a problem with the high rate of discontinuations on this study.
The investigators concluded that a regimen with combivir/abacavir was not associated with an increase in LDL cholesterol seen in the protease inhibitor-containing arms. They also observed that the elevation on LDL cholesterol, triglycerides and cholesterol were more pronounced in the protease inhibitor-plus-stavudine arm.
This study is supposed to continue for a total of 96 weeks. So far, there appears to be a significant difference in genders on lipid parameters. These were more pronounced in men than in women. If this gender-related difference continues at the end of the study, it will certainly require more investigation in the future.
The findings in this study are important -- just to further document the effects of protease inhibitor-containing regimens (in this case, nelfinavir) on lipid alterations in naïve patients. It also raises an increasing concern about the potential role of d4T, and probably most thymidine analogues, in the development of these toxicities.
The number of subject discontinuations from this study (97/258) is disturbing and it may have affected the interpretation of some of the data, and possibly the limited efficacy analysis that was performed.
I applaud the investigators for their efforts to include more females in this study (50%), but their effort in recruiting minorities by adding study sites in Latin-America may have introduced other variables that are difficult to control, such as difference in compliance and different dietary habits.
I am personally not a big fan of triple-nucleoside therapy for patients who are naïve to therapy, regardless of their baseline viral load or CD4 count. Nevertheless, it is evident that with the options we have today, patients treated with a triple nucleoside regimen may stand a better chance to avoid alterations in lipid metabolism in the future.
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