Important note: Information in this article was accurate in March 2004. The state of the art may have changed since the publication date. 
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A number of abstracts at the 11th CROI meeting focused on long-term complications of HIV treatment. Although there were excellent basic science reports, I will focus here on the clinical studies.
In a randomized study of 237 participants receiving stavudine (d4T) or ABC combined with lamivudine (3TC) and efavirenz (EFV), patients in the d4T arm had significantly more moderate-to-severe lipoatrophy (20% vs 3%, P =0.001), with more loss of fat in the face, upper extremities and buttocks after 48 weeks [Podzamczer D, et al. Abstract 716]. DEXA scans performed at baseline and 48 weeks in 78 patients confirmed these results. Fasting cholesterol and triglyceride levels increased in both arms of the study, while lactate levels increased only in the d4T arm (P<0.001 compared to baseline). Baseline characteristics were similar between arms. Drug discontinuation rates were similar in both arms (14% vs 15%), and there were no differences in virologic response (VL <50 c/mL by intent-to-treat analysis). These results are quite consistent with those of the GS 903 trial, which compared tenofovir DF (TDF) with d4T, both in combination with 3TC and EFV.
Another prospective, double blind randomized trial of 751 ART naïve subjects compared emtricitabine (FTC) with d4T, both combined with enteric coated didanosine (ddI) and EFV [Powderly W, et al. Abstract 717]. Patients in the FTC arm had more favorable lipid profiles and body habitus over 72 weeks of follow-up. Finally, Murphy reported on a sub-study of 82 patients from the large Atlantic study, which compared indinavir (IDV), nevirapine (NVP) and 3TC with a nucleoside backbone of d4T/ddI in naïve subjects [Abstract 718]. Based on questionnaires, DEXA scans and abdominal CT scans, peripheral lipoatrophy was common (25% at baseline) and progressed over 4 years in all arms. IDV use was associated with significantly higher visceral adipose tissue by abdominal CT scan after a median of 144 weeks (N=53). NVP was associated with significant increases in HDL cholesterol compared to the other arms.
Taken together these studies continue to confirm that the choice of the NRTI backbone has an important impact on the likelihood of developing metabolic and morphologic changes. These data from large blinded trials in naïve patients offer strong support to prior cross-sectional studies that implicated d4T as the NRTI most likely to cause lipoatrophy, and also as a contributor to drug-related hyperlipidemia.
In an attempt to evaluate the safety of extended-release formulation of d4T, investigators at Bristol-Myers Squibb performed a post-hoc analysis from two different randomized, multinational, double-blind, placebo-controlled studies of comparing immediate versus extended release d4T used in combination with 3TC and EFV in antiretroviral naïve patients [Noor M, et al. Abstract 722]. A subgroup of 877 (94%) had available fasting triglyceride levels. Baseline characteristics were similar between groups. Lipoatrophy was noted in both arms, although less overall lipoatrophy was seen in the extended release group (8% vs 14%). Multivariate logistic regression found that triglyceride levels <200 mg/dL at baseline, age <40 years, and use of the extended release formulation predicted a lower risk of lipoatrophy, while gender, race, baseline BMI, fasting glucose, waist circumference, baseline CD4, and viral load did not. These data are encouraging, as they suggest that the extended release formulation of d4T, which is not yet commercially available, may be less toxic than standard d4T. However, the data are limited by the fact that this study did not compare d4T to other NRTIs, and by the fact that this was a post-hoc analysis of data from two different studies.
Whole body DEXA and single slice CT scans at the L4 level were performed at baseline, week 24, and week 48, along with multiple fasting chemistry measurements, in a subset of TORO 1 and 2 patients [Cooper DA, et al. Abstract 715]. Only a small number of patients had DEXA or CT evaluable at week 48 (N=12), so caution is needed in evaluating results. Nonetheless, glucose levels, lipid profiles and C peptide levels were similar in the ENF-containing regimens compared to those on optimized background therapy without ENF, and there was no appreciable impact of ENF on body composition.
The increased prevalence of metabolic abnormalities raises concern for cardio-vascular damage. Following up on their recent publication [N Engl J Med. 2003 Nov 20;349(21):1993-2003], the D:A:D study group found that 199 patients experienced at least 1 cardiovascular event (myocardial infarction [MI], cardiovascular death, invasive cardiovascular procedure, or stroke), for an incidence of 5.5/1,000 person-years, which increased with longer exposure to ART [Law MG, et al. Abstract 737]. Rates were comparable and generally higher than predicted using Framingham equations. Similarly, the Kaiser Permanente Northern Californian HMO group presented additional follow-up on HIV-infected patients who were hospitalized for coronary heart disease (CHD) [Klein D, et al. Abstract 739]. During the 7.5-year observation period 4,726 HIV-infected patients experienced 111 CHD events, including 66 MIs. Rates of CHD and MI were significantly higher among HIV-infected participants aged 35-64 compared to HIV negative participants (CHD: 6.6 vs 3.0 events/1000 person-years, P<0.0001; MI: 3.9 vs 2.2, P<0.005). The age-adjusted relative risk for CHD hospitalization per 2 years of PI exposure was 1.17 (P =0.01), but the difference was not statistically significant for MI. Taken together, these studies offer further support that coronary artery disease in HIV-infected individuals will increase over time, and the D:A:D study demon-strated a strong association with duration of ART use. As much of the risk is attributable either to reversible hazards (e.g. smoking, hypertension, hyper-lipidemia, physical inactivity ,and obesity) or to alterations in CAD risks induced by ART (e.g. hyperlipidemia, diabetes), it is important that clinicians attempt to modify those conditions, especially in patients at high risk due to multiple risk factors.
One of the most noteworthy presentations related to complications of HAART was Andrew Carr’s report on the disappointing results of the rosiglitazone study, recently published in Lancet. 2004 Feb 7;363(9407):429-38 [Abstract 79]. A total of 108 patients with lipoatrophy on stable antiretroviral therapy were randomized to receive maximum dose rosiglitazone (4 mg bid) or placebo in a double-blind, 48-week trial. The intention-to-treat analysis demonstrated a modest increase in limb fat in each group (0.14-0.18 kg) with no significant difference between groups. There were no benefits associated with rosiglitazone with respect to subcutaneous thigh fat, subcutaneous abdominal fat, or visceral fat by computed tomography, nor in total fat mass, lean body mass, or objective and subjective severity of lipoatrophy. There were significant increases in plasma adiponectin (101% increase to 4.1 mMol/L) but not leptin (6% increase to 0.2 mMol/L), and significant decreases in 3 markers of insulin resistance in the active arm. No benefits were seen in subgroup analyses, whether by PI use, thymidine analog use, limb fat mass, or insulin resistance at baseline. In each arm, 6 patients discontinued the study drug, 2 in each arm for adverse events attributed to study drug. Key adverse events included asymptomatic hypertriglyceridemia and hypercholesterolemia. In a substudy rosiglitazone did not alter endothelial function at 48 weeks, as measured by brachial artery ultrasound reactivity at rest and after two vasodilatory stimuli [Martin A, et al. Abstract 729].
Prior studies have suggested a possible improvement in lipoatrophy with the use of rosiglitazone, but this carefully conducted trial failed to demonstrate any beneficial effect. Limitations include ART switches: 3 participants in each arm changed from d4T to another NRTI, and 5 and 3 participants in the rosiglitazone and placebo groups changed PIs, potentially affecting the results. However, it is unlikely that these factors would have hidden a true benefit. It is unclear what the effect of this drug will be in HIV infected diabetics as they were excluded from this study. However, given the lack of benefit in glucose intolerant patients, significant benefit in diabetics seems unlikely. Ultimately, it is becoming increasingly clear that clinicians should not count on medications to “reverse” lipoatrophy; prevention is by far the best approach.
Polylactic acid (New-Fill) injections, given every 15 days, were evaluated in 94 lipoatrophic subjects (88 male, 6 female) followed for a median of 12 months [Lafaurie M, et al. Abstract 726]. Satisfactory results were reported in 73% on follow-up questionnaire, 59% (at best) by blinded re-ordered digital photos, and 48% by 3D photo (N=50). There was a very low correlation factor between observers (Kappa <0.3), and there were no changes in measured quality of life. The probability of requiring additional injections at 15 months was 45%. Significant side effects included grade 1 or 2 pain in 80%, malaise after the first injection in 7 patients, non-inflammatory small nodules in 12 patients, and minor bleeding in 4 patients. Treatment was stopped in one subject after the first injection because of an anaphylactic reaction. This study, relatively large in comparison with other studies of cosmetic interventions for lipoatrophy, showed a high level of patient satisfaction, which may in part reflect the unblinded nature of the study. Clinicians, however, should be sobered by the <50% success according to 3D photos, the frequent complications, and the need for additional injections within 1-2 years. Also, this was predominantly a study of white males, and it is not clear if results can be extrapolated to other populations. The long term results of New-Fill have yet to be demonstrated.
Don Kottler reported 60-week data for low-dose “maintenance” therapy with recombinant human growth hormone (rhGH) for patients with central fat accumulation [Abstract 80]. A subset (127/142) subjects from an earlier placebo-controlled rhGH study were re-randomized to receive 24 weeks of maintenance therapy at a dose of 1 or 2 mg daily. Subjects with glucose intolerance or diabetes were excluded from the initial study. Significant reductions were found in both the 1 mg and 2 mg maintenance groups at week 60 for trunk fat (-1.1, -1.4 kg), non-HDL cholesterol (-21.2, -23.8 mg/dL), and total cholesterol (-16.9, -18.5 mg/dL). Oral glucose tolerance testing revealed no change from baseline to week 60 in insulin area-under-the-curve, and there were no between-group differences between the 1 and 2 mg doses in any parameters baseline to weeks 36. Arthralgia, however, was more common with the 2 mg dose (12.5% vs 5.7%).
It appears as though low dose main-tenance therapy of 1 mg daily rhGH dosage in patients who initially received high dose therapy may serve some benefit for those with fat accumulation and no insulin resistance. However, rhGH at 1 mg/day is still a supra-physiologic dose, and most clinicians are not yet ready to keep patients on life-long, daily growth hormone. Prior reports suggested that high dose rhGH worsened lipoatrophy, which many patients can’t afford. Finally, glucose intolerant or insulin resistant patients were excluded, and probably should be excluded from use of rhGH, which further limits the number of patients for whom this therapy might be appropriate.
Jim Sosman presented a placebo-controlled, double-blind cross-over study evaluating the impact of 40 mg/day of pravastatin on lipoprotein subfractions and endothelial function, assessed by flow-mediated vasodilatation (FMD) of the brachial artery using high-resolution ultrasound, in 20 patients receiving PIs [Abstract 77]. At entry, many participants had unfavorable lipid parameters. FMD was also impaired, indicating endothelial dysfunction. Pravastatin significantly reduced total cholesterol by 18%, LDL cholesterol by 20%, and non-HDL cholesterol by 22%. Pravastatin therapy was associated with a reduction in LDL by 21% (P =0.03), small LDL by 27% (P =0.1), and small VLDL by 45 % (P =0.023). There was also a trend toward improvement in FMD (P =0.08). This is the first placebo-controlled, blinded study to use sophisticated Nuclear Magnetic Resonance technology to confirm the benefits of statin therapy, which is already being widely used in clinical practice. Pravastatin demon-strated a modest benefit in improving parameters of the lipid profile which would predict a modest decrease in overall cardiovascular risk. Taken with the data on CHD discussed above, it is clear that clinicians can modify a number of important cardiac risk factors, including drug-induced hyperlipidemia.
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