1. XVI International AIDS Conference
Long-Term Changes in Lipids and Glucose/Insulin among HIV-Infected Antiretroviral Naïve Persons Randomized to PI vs. NNRTI vs. PI+NNRTI-based strategies: Results of the CPCRA 061 Metabolic Study
J. Shlay, G. Bartsch, G. Peng, J. Wang, C. Gibert, F. Visnegarwala, S. Raghavan, Y Xiang, M. Farrough, H. Perry, D. Kotler, C. Grunfeld, W. El-Sadr for the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA)
To the organizers of this conference, I want to thank you for giving us the opportunity to present our findings.
All of the authors wish to acknowledge that this study would not have been possible without all of the hard work performed by the CPCRA study nurses. We also would like to thank all of the patients who participated in the study.
XVI International AIDS Conference
Abstract # ThABO101

2. Background
Morphologic changes (lipoatrophy and lipohypertrophy), insulin resistance, and dyslipidemia are important metabolic consequences of antiretroviral therapy in patients with HIV/AIDS
However, long-term comparative data on the metabolic effects of initiating different ART strategies in ART-naïve patients are limited
Morphologic changes which includes both lipoatrophy and lipohypertrophy, insulin resistance, and dyslipidemia are important metabolic consequences of antiretroviral therapy in patients with HIV/AIDS.
While previous studies have implicated protease inhibitors and certain NRTIs, long-term comparative data on the metabolic effects of initiating different ART strategies in ART-naïve patients are limited, with few prospective studies focusing on various ART class strategies.

3. Objectives
To assess long-term changes in metabolic parameters and body composition among antiretroviral-naïve patients randomized to three highly active antiretroviral therapy (ART) strategies
The objectives of our study were to assess long-term changes in metabolic and body composition among antiretroviral-naïve patients randomized to three highly active antiretroviral therapy strategies. Today I will present the metabolic findings. The body composition findings were highlighted in a poster presented yesterday by Cynthia Gibert.

4. Patient meets eligibility requirements
Randomized to 3 strategy arms (1:1:1)
N=1,397
PI + NRTIs
N=470
NNRTI + NRTIs N=463
PI + NNRTI + NRTI(s)
N=464
PI Strategy
N=141
in Metabolic substudy
NNRTI Strategy N=141 in Metabolic substudy
PI + NNRTI Strategy
N=140
in Metabolic substudy
This schematic diagram illustrates the FIRST study which involved randomizing antiretroviral naïve patients to one of three treatment strategies; a PI strategy, an NNRTI strategy; or a PI + NNRTI strategy in the presence of an NRTI backbone.
The treatment groups were defined by classes of drugs, not specific drugs. Any licensed antiretroviral drug within the class assigned was possible for use.
The FIRST study enrolled 1,397 patients, with an equal distribution in each of the 3 treatment strategies. The results of this study have already been presented by Roger MacArthur at this conference.
The metabolic study was a substudy of FIRST and 30% of patients enrolled into the FIRST study were co-enrolled into the metabolic study.
The metabolic study opened in August 1999 and closed in September 2005, with 422 participants enrolling in the three treatment strategies; 141 in the PI strategy, 141 in the NNRTI strategy, and 140 in the PI+NNRTI strategy and this is the group I will describe for you today.
The median follow-up was 62 months.
During follow-up, 87% of required metabolic measurements were obtained. The overall lost-to-follow-up rate, defined as missing the last two required measurements, was 13.8% for the metabolic measurements, with no differences by treatment strategy.
C•P•C•R•A

5. Baseline Characteristics – 1*
PI (N=141)
NNRTI (N=141)
PI + NNRTI (N=140)
Age (years)
Female (%)
Race African American (%)
Prior AIDS (%)
CD4 (cells/mm3)
RNA (log10 copies/mL)
Baseline characteristics for the three treatment strategies are shown on this slide.
There were no significant differences in age, gender, race, prior AIDS defining illness, mean CD4 count or mean viral load between the groups.
As seen in other CPCRA studies, the majority of participants were non-white.
* No significant differences among treatment strategies

6. Baseline Characteristics - 2
PI (N=141)
NNRTI (N=141)
PI + NNRTI (N=140)
P-Value
Triglycerides (mg/dL) NS
Total Cholesterol (mg/dL) * HDL Cholesterol (mg/dL) NS LDL Cholesterol (mg/dL) *
Glucose (mg/dL) NS
Insulin (µ/mL) NS
Baseline characteristics of the various metabolic parameters by the three treatment strategies are shown on this slide.
At baseline, both total cholesterol and LDL cholesterol levels were higher in the PI+NNRTI strategy compared to the other two strategies. However, in the subsequent statistical analyses described, these differences were adjusted for.
* Significant differences among treatment strategies: p < 0.05

7. ART Prescribed after Randomization
PI (N=141)
NNRTI (N=140)
PI + NNRTI (N=140)
PI (%) NFV IDV RTV-boosted Other
NNRTI (%) EFV NVP Other
NRTI (%) ZDV + 3TC d4T + 3TC ABC + 3TC ddI + d4T Single NRTI Other
This slide presents the antiretroviral therapy prescribed after randomization by treatment strategy.
The most commonly used PI was nelfinavir (61%), followed by ritonavir-boosted PIs (24%) and indinavir (12%) for the PI and PI+NNRTI strategies. In terms of boosted-PIs, indinavir and lopinavir were most commonly used. For the NNRTI strategy, the majority of participants used efavirenz (63%) while in the PI+NNRTI strategy, nevirapine or efavirenz use were equivalent. For the PI and NNRTI strategies, similar NRTI combinations were used, with most being ZDV+3TC (53%), followed by d4T+3TC (19%), abacavir+3TC (11%), or ddI+d4T (12%).
For the PI+NNRTI strategy, the NRTI combinations commonly used were ZDV+3TC (37.9%), followed by abacavir+3TC (16%), and ddI+d4T (14.3%). Single NRTIs were used in 19% of the PI+NNRTI strategy, with the majority using d4T. Approximately 35% of patients were on d4T-containing regimens in all three ART strategies.

8. Change in LDL Cholesterol*
This slide shows changes in LDL cholesterol by the three treatment strategies. At each follow-up visit from months 1 to 64, the mean change from baseline in LDL cholesterol is plotted.
The red line represents the PI treatment strategy, the turquoise line represents the NNRTI treatment strategy, and the yellow line represents the PI+NNRTI strategy. The 95% confidence interval for each mean is plotted and the number of observations at each follow-up visit between 1 and 64 months are listed at the bottom of the graph.
The initial effects of ART which is defined as change from baseline to 1-month, showed increases in mean LDL cholesterol for all three strategies. This is indicated by the three confidence intervals for the mean change at one month not having included zero. Then, comparing these initial 1-month changes among the three strategies, there was a significantly greater increase in LDL cholesterol in the PI+NNRTI strategy compared with the other strategies, with no differences noted between the PI and NNRTI strategies.
For the overall mean change, which is displayed in the upper left-hand side of this graph, there was a significant increase in LDL for all threes strategies compared to zero. Then, comparing these three strategies, a significantly greater increase in mean LDL cholesterol from baseline was seen for the PI+NNRTI strategy compared to either the PI or NNRTI strategies.
The slopes, displayed in the upper right-hand side of the graph, which estimate the rate of change in LDL cholesterol during follow-up, showed a significant decline for all three strategies that did not differ by study assignment.
* If triglycerides ≥ 400, direct LDL, otherwise calculated LDL

9. Change in HDL Cholesterol
This slide presents changes in HDL cholesterol.
For HDL cholesterol, the average change increased significantly during the first month for all three strategies and continued to rise after 1-month follow-up, leveling off between 4 and 8 months with the plateau sustained through the study. The average increase over all follow-up visits was significantly greater in the NNRTI strategy compared with the PI strategy, while the increase in the PI+NNRTI strategy was of borderline significance compared with the increase in the PI strategy.
The three slopes did not differ significantly from zero and were not significantly different from one another.

10. Change in Triglycerides
This slide presents a graph for triglycerides.
Comparing the initial 1-month changes, among the three strategies, there was a significantly greater increase in triglycerides in the PI+NNRTI strategy compared with the other strategies, with no differences noted between the PI and NNRTI strategies.
Overall, there was a significantly greater increase in mean triglycerides from baseline for all three strategies compared to zero. Then, comparing the three strategies, there was a significantly greater increase in mean triglycerides for the PI+NNRTI strategy compared with the PI strategy, but not when compared to the NNRTI strategy
For triglycerides, the rates of change from month 1 to months 64 were significantly different from zero for the PI and NNRTI strategies, with only the NNRTI and PI+NNRTI rates being significantly different from one another.

11. Change in Insulin This slide presents the results for insulin.
Initially after 1-month of follow-up, there was a mean increase in insulin (3.01 /mL) for the PI strategy, with no significant increases noted for the other strategies.
With further follow-up, for all three strategies, there was a significant increase in the overall mean insulin levels for all three strategies.
At 1-month and over the entire follow-up period, mean changes did not differ by strategy.
The rates of change for all three strategies increased significantly during follow-up, with no differences seen by strategy.
Similar findings were seen for both glucose and insulin resistance.

12. Conclusions - I
PI+NNRTI strategy associated with a greater increase in LDL-C and triglycerides compared to the PI or NNRTI strategies; no significant differences noted between PI and NNRTI strategies
LDL-C levels increased primarily within the first few months after initiation of ART, followed by a decline during the remainder of follow-up
This clinical trial assessed the effects of three ART strategies, a PI strategy, an NNRTI strategy, and a PI+NNRTI strategy and found that the PI+NNRTI strategy was associated with a greater increase LDL cholesterol and triglycerides compared to the PI or NNRTI strategies with no significant differences noted between PI and NNRTI strategies.
LDL cholesterol levels increased primarily within the first few months after initiation of ART in all three strategies, followed by a gradual decline during the remainder of follow-up, suggesting that these initial changes were due to a direct effect of the medications.

13. Conclusions - II
Unlike LDL-C, triglyceride levels did not decline with continued therapy
Significantly greater increases in mean HDL-C seen with the NNRTI strategy compared to the PI strategy
PI+NNRTI strategy should be avoided unless no other options are available
Unlike LDL, for triglycerides, there were no significant declines in triglyceride levels with continued treatment, suggesting an ongoing deleterious effect on triglycerides with treatment particularly with the use of the PI+NNRTI strategy.
In our study, significantly greater increases were seen in mean HDL-cholesterol for NNRTI strategy compared to the PI strategy.
Since the PI+NNRTI-based strategy was more deleterious in terms of lipid changes than the other strategies; this type of regimen should be avoided, if other effective ART options are available.

14. Conclusions - III
Increases in insulin and glucose were noted during follow-up, with no differences by ART strategy
Increases in insulin and glucose were gradual and continued throughout follow-up, unlike the pattern of changes noted with the lipids
Findings support the need for ongoing monitoring of glucose levels as well as for the development of diabetes, irrespective of ART regimen used
In our study, increases were noted in insulin and glucose during follow-up, with no differences seen by strategy.
These increases were more gradual and continued throughout follow-up, unlike the pattern of changes noted with the lipid measurements.
Our findings support the need for ongoing monitoring of glucose levels as well as for the development of diabetes, irrespective of ART regimen used.