In this study, EFV-based ARV therapy in previously untreated HIV-infected individuals was associated with an increase in CRP levels over a 96-week period that was significant only in women and not in men. The inclusion of ABC in a base regimen of 3TC/ZDV/EFV did not result in an increase in hsCRP levels. Changes in CRP did not correlate with changes in any fasting metabolic blood parameter over 96 weeks.
The CRP in the systemic circulation is believed to act as the final end product of various converging inflammatory pathways that may reflect the cumulative effect of local vascular inflammation in predicting atherosclerosis risk.15
The level of CRP predicts cardiovascular risk in the general population even among apparently healthy adults followed long-term over 8–10 years.16–18
Its predictive value is independent of classic risk factors for coronary artery disease including the presence of diabetes, triglycerides, and BMI across all levels of the Framingham Risk Score.16,18,19
High rates of CRP have been reported in HIV-infected subjects3,20
and recently the association between elevated CRP levels and increased myocardial infarction risk was shown specifically in HIV-infected subjects.21
In that study, CRP and HIV independently increased the risk and the presence of both elevated CRP and HIV increased the odds of acute myocardial infarction to more than 4-fold compared with patients with neither elevated CRP nor HIV infection. High CRP levels of HIV-infected men in the Multicenter AIDS Cohort Study (MACS) were associated with HIV disease progression independent of CD4 lymphocyte counts and HIV RNA levels.2
Regardless of progression to AIDS, this study found that HIV-infected individuals had a significant increase in CRP over time. CRP levels have been linked to a greater than 3-fold increased risk of death in HIV-infected women independent of age, BMI, CD4 count, and HIV RNA.3
Similarly, in a resource-poor setting, high maternal CRP levels independently predicted HIV disease progression as well as maternal and child mortality.22
Considering these associations, the impact of ARV therapy on CRP levels is of significant interest. Changes in CRP levels following PI therapy were studied in ACTG 5056s. This study assessed changes in CRP levels following indinavir-based HAART and noted that CRP levels remained stable or decreased slightly over an average of 42 months.4
A similar slight decline overall was seen in the HEAT study over 96 weeks following initiation of lopinavir/ritonavir given with either ABC/3TC or tenofovir/emtricitabine.23
The overall trend of decreasing CRP levels over time in both studies was observed only in men. Our study utilizing NNRTI-based HAART over 96 weeks found a slight nonstatistically significant increase in CRP in men. Whether this indicates that NNRTI-based regimens differ from PI-based therapy in altering CRP levels is unclear. CRP is mainly produced by hepatocytes in response to interleukin-6 (IL-6). As HAART can be expected to result in a substantial decrease in proinflammatory cytokines including IL-6, the failure of CRP to decrease following NNRTI-based HAART in our study is puzzling. However, other types of cells including adipocytes24
and coronary artery smooth muscle cells25
also produce CRP and production from these cells may account for the failure of CRP to decrease in our study. As CRP is also impacted by various other states and conditions such as genetic polymorphisms, dietary patterns, and many medical conditions that may not be inflammatory in nature, it is theoretically possible that the discrepancies between these studies were also due to such confounding conditions.26
A significant increase in hsCRP was seen only in women. This marked increase in hsCRP in women at week 96 resulted in 31% of women falling into the “outlier” category that the AHA recommends be discarded in the context of assessing cardiovascular disease risk in the general population. However, a later study assessing CRP across a full range of values found that levels >10
mg/liter may still be clinically useful for cardiovascular risk prediction.18
Gender differences in hsCRP have been reported in the general population. Women with National Cholesterol Education Program (NCEP)-defined metabolic syndrome have higher hsCRP levels compared to men with the metabolic syndrome.27
The use of oral contraceptives, particularly in overweight women, has been associated with significant rise in CRP.28,29
Data on oral contraceptives were unfortunately not collected in A5095. At least two studies have cross-sectionally examined the differences in CRP levels specifically in HIV-infected women compared to HIV-seronegative controls. One study reported that CRP levels in HIV-infected women were comparable to that of HIV-seronegative controls.20
Another study reported that CRP levels were higher in HIV-infected women and that the levels correlated with alterations in body composition, but not with HIV status.30
The increase in CRP levels in women in our study is not likely to be due to changes in body composition as our study found no correlation between change in CRP levels and change in BMI or in WHR in women. Coinfection with hepatitis C has been reported to lower hsCRP levels,20
but in our study the percent of subjects infected with hepatitis C was not markedly different.
CRP levels in the HIV population have been reported to correlate with traditional cardiovascular risk factors including LDL-cholesterol, HDL-cholesterol, cigarette smoking, increased BMI, and WHR.30–32
Our study found no correlation between changes in hsCRP and changes in any metabolic parameters.
Some studies have suggested that ABC as part of ARV regimens is associated with an increased cardiovascular risk, with a risk that is particularly high with the recent initiation of ABC therapy.5–8
Other studies have shown no increased risk.9–11
We found that randomization to ABC in subjects previously naive to all ARV medications had no significant effect on changes in hsCRP levels over a 96-week period. This study presented the ideal situation to isolate the effect of ABC during first-time ARV therapy as the two treatment groups contained the same backbone of 3TC/ZDV/EFV and differed only in the random addition of ABC in one of the two groups. Early time points were not assessed in this study and it is possible that an early increase with subsequent decrease in hsCRP on ABC-containing therapy may have been missed.
The strengths of this study include the use of sera collected, processed, and banked under rigorous standardized criteria utilized by the ACTG, the availability of carefully obtained fasting metabolic parameters, and the ability to isolate the effect of ABC given in a randomized fashion within two treatment groups that otherwise utilized the same identical ARV medications. The limitations of this study include the lack of hsCRP data at very early time points or beyond 96 weeks following initiation of ART, the smaller percentage of women that comprised the cohort, and the lack of availability of certain data, such as hormonal contraceptive status, that may have helped to explain the higher CRP levels in women.
In summary, durably suppressive therapy with EFV-based regimens did not improve hsCRP levels over a 96-week period. Levels of hsCRP increased significantly in women. Randomization to ABC had no significant effect on changes in hsCRP levels. Changes in hsCRP levels did not correlate with change in insulin resistance or with changes in fasting lipids over the same time interval. In view of the significant increases in hsCRP seen in women in our study, further investigations to elucidate the causes and the implications of such an increase are warranted.