5. NRTI-induced mitochondrial toxicity Proposed Pathogenesis CELL glucose pyruvate lactate Acetyl CoA Krebs cycle NADH FADH 2 Oxidative phosphorylation ATP MITOCHONDRION mtDNA DNA pol γ Fatty Acids 0
6. CELL glucose pyruvate lactate Acetyl CoA Krebs cycle NADH FADH 2 Oxidative phosphorylation ATP MITOCHONDRION mtDNA DNA pol γ Fatty Acids NRTIs NRTI-induced mitochondrial toxicity Proposed Pathogenesis 0
7. NRTI-induced mitochondrial toxicity Proposed Pathogenesis CELL glucose pyruvate lactate Acetyl CoA Krebs cycle NADH FADH 2 Oxidative phosphorylation ATP MITOCHONDRION mtDNA DNA pol γ Fatty Acids NRTIs 0
8. NRTI-induced mitochondrial toxicity Proposed Pathogenesis CELL glucose pyruvate lactate Acetyl CoA Krebs cycle NADH FADH 2 Oxidative phosphorylation ATP MITOCHONDRION mtDNA DNA pol γ Fatty Acids NRTIs 0
9. NRTI-induced mitochondrial toxicity Proposed Pathogenesis CELL glucose pyruvate lactate Acetyl CoA Krebs cycle NADH FADH 2 Oxidative phosphorylation ATP MITOCHONDRION mtDNA DNA pol γ Fatty Acids NRTIs 0
10. NRTI-induced mitochondrial toxicity Proposed Pathogenesis CELL glucose pyruvate lactate Acetyl CoA Krebs cycle NADH FADH 2 Oxidative phosphorylation ATP MITOCHONDRION mtDNA DNA pol γ Fatty Acids NRTIs 0
11. NRTI-induced mitochondrial toxicity Proposed Pathogenesis CELL glucose pyruvate lactate Acetyl CoA Krebs cycle NADH FADH 2 Oxidative phosphorylation ATP MITOCHONDRION mtDNA DNA pol γ Fatty Acids NRTIs 0
12. Classification of Lactic Acidemia *Symptoms and signs that suggest lactic acidemia consist of nausea, vomiting, abdominal pain, weight loss, fatigue, myalgias, abdominal distention, abdominal pain, dyspnea, and cardiac dysrhythmias. Source: HIV Web Study (www.hivwebstudy.org); Schambelan M et al. JAIDS 2002;31:257-75 0
13.
14. Risk Factors for the Development of Lactic Acidemia in Persons Taking NRTIs *Most cases have involved stavudine **Especially with the use of stavudine plus didanosine Source: HIV Web Study (www.hivwebstudy.org) 0
15.
16. Recommendations for the Management of Lactic Acidemia Source: HIV Web Study (www.hivwebstudy.org); Carr A. Clin Infect Dis 2003;36 (Suppl 2):S96-100. 0
31. Risk Factors for Lipoatrophy and Lipohypertrophy Lichtenstein KA. JAIDS 2005;39:395-400. Percentage of studies showing statistically significant associations between risk factors and either lipoatrophy (LA) (9 studies) or lipohypertrophy (LH) (8 studies) using multivariate analysis.
48. J Acquir Immune Defic Syndr 2002 February 1;29(2):117-121 ? Etiology of Lipoatrophy: Evidence of Mitochondrial Toxicity in Adipocytes
49. HIV infection may independently contribute to mitochondrial toxicity Non-HIV Infected (n = 24) HIV Infected, naïve to antiretrovirals (n = 47) HIV Infected, with mitochondrial toxicity, before stopping ARVs (n = 8) HIV Infected, with mitochondrial toxicity, after stopping ARVs (n = 7) N Engl J Med 2002; 346:811-820, Mar 14, 2002. mtDNA:nDNA ratio
63. The DAD Study Group, N Engl J Med 2003;349:1993-2003 Incidence of Myocardial Infarction According to the Duration of Exposure to Combination Antiretroviral Therapy
64. The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group, N Engl J Med 2003;349:1993-2003 0
65.
66. Switch HAART regimen or initiate lipid-lowering pharmacotherapy? Trend of mean plasma triglyceride levels of 130 evaluable patients switched from protease inhibitor to nevirapine (arm A) or efavirenz (B), or treated with pravastatin (C) or bezafibrate (D), at baseline and after 3, 6, 9 and 12 months of follow-up. Calza L et al. AIDS 2005: 19(10), 1051-8.
67. Switch HAART regimen or initiate lipid-lowering pharmacotherapy? Trend of mean plasma total cholesterol levels of 130 evaluable patients switched from protease inhibitor to nevirapine (arm A) or efavirenz (B), or treated with pravastatin (C) or bezafibrate (D), at baseline and after 3, 6, 9, and 12 months of follow-up. Calza L et al. AIDS 2005: 19(10), 1051-8.
75. Studies on Osteopenia in HIV Adapted from Arnsten JH et al, 10 th CROI, Boston 2003, Abstract 103 * combined prevalence of osteopenia and osteoporosis Study Sample Prevalence* Risk Factors Carr, 2001 Australia 221 HIV+ men, Wt. 70-75 kg 25% Lactate level low weight Huang, 2001 Boston, MA 41 HIV+ men, BMI 25 18 HIV- men, BMI 25 BMD reduced in HIV+ men w/ high visceral fat Historical low weight; high visceral fat McDermott, 2001 New England 203 HIV+ men, BMI 24 62 HIV+ women, BMI 25 BMC reduced in men on HAART HAART use and duration Knobel 2001 Spain 58 HIV+ men, 22 HIV+ women, BMI 23 overall 100 HIV- controls, BMI 23 89% in HIV+ 30% in HIV- Weight, BMI Nolan, 2001 Australia 183 HIV+ men BMI 23-24 56% in PI-treated; 49% in PI-naïve Low pre-HAART BMI; Indinavir protective Gold, 2002 Australia 110 HIV+ men lean mass 57 kg 55% Age, lean body mass, duration of NRTI use Mondy, 2003 St. Louis, MO 108 HIV+ men, 17 HIV+ women; BMI 25 46% BMI, smoking, wt loss, steroids Arnsten, 2003 New York, NY 200 HIV+ women: BMI 28 205 HIV- women: BMI 32 30% in HIV+ 24% in HIV- Age, race, BMI; PI use > 1 year protective
Carr A, Miller J, Law M, Cooper DA. A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome. AIDS. 2000;14:F25-32. Boubaker K, Flepp M, Sudre P, et al A. Hyperlactatemia and antiretroviral therapy: the Swiss HIV Cohort Study. Clin Infect Dis. 2001;33:1931-7. Moyle GJ, Datta D, Mandalia S, Morlese J, Asboe D, Gazzard BG. Hyperlactataemia and lactic acidosis during antiretroviral therapy: relevance, reproducibility and possible risk factors. AIDS. 2002;16:1341-9. Lafeuillade A, Hittinger G, Chadapaud S. Increased mitochondrial toxicity with ribavirin in HIV/HCV coinfection. Lancet. 2001;357:280-1. Bonnet F, Bonarek M, Morlat P, et al. Risk factors for lactic acidosis in HIV-infected patients treated with nucleoside reverse-transcriptase inhibitors: a case-control study. Clin Infect Dis. 2003;36:1324-8. Arenas-Pinto A, Grant AD, Edwards S, Weller IV. Lactic acidosis in HIV infected patients: a systematic review of published cases. Sex Transm Infect. 2003;79:340-4.
1
The HOPS is a well-established cohort of patients from a number of US treatment centers, and is coordinated by the Centers for Disease Control and Prevention. A prospective analysis was presented on 337 patients who had no sign of lipoatrophy in an initial assessment, and who were evaluated again 21 months later to identify factors associated with the development of lipoatrophy. [5] Standardized interviews and physician assessments of clinical signs were performed on each occasion. The incidence of moderate or severe fat loss of the extremities, hips, or buttocks and sunken cheeks (without total body weight loss, to differentiate such cases from HIV wasting) was analyzed, and multivariate analyses were performed to assess their relationship to immunologic, virologic, clinical, and drug treatment variables. The proportion of patients who developed moderate or severe lipoatrophy between the 2 surveys was 13.1% (44 of 337 patients). This is broadly in accordance with the 2-year rates of new onset reported in other studies. [6] Multivariate analyses indicated that disease and host factors were more critical to the development of new lipodystrophy than were drug factors. Specifically, white race was associated with a 5-fold increase in the relative odds of developing lipodystrophy. This racial association has been reported previously and may be linked to the relative prevalence of specific TNF-a promoter genes in the white population. The CD4+ cell count nadir and the magnitude of change in the CD4+ cell count were also associated with increased risk: Individuals with a history of a CD4+ cell count < 100 cells/mm 3 and those whose CD4+ cell count had risen by < 100 cells/mm 3 were more likely to develop lipodystrophy. Individuals with body mass index < 24 had a 2.4-fold greater odds of developing lipodystrophy. There was no association between the onset of lipoatrophy and duration, initiation, continuation, or discontinuation of any antiretroviral medication. Where does this study point us in the investigation and management of lipoatrophy? Certainly away from drugs and more towards the way in which the immune system recovers in an individual. Avoidance of a low CD4+ cell count may be a critical issue in reducing the risk of lipoatrophy, which may have implications for the debate regarding when to start antiretroviral therapy. Equally important may be dietary interventions to aggressively manage weight loss before it becomes substantial. The use of immune modulators may also have a role, because achieving a rapid increase in CD4+ cell count may reduce the risk of lipoatrophy. This question is being examined in substudies of the SILCAAT and ESPRIT studies of interleukin-2. Finally, if white race is a specific risk factor for lipoatrophy, we need to identify the genetic differences between whites and other ethnicities that might reveal potentially modifiable genetic markers of risk of lipodystrophy; eventually, treatment guidelines may need to consider different approaches for patients of different ethnic backgrounds. Lichtenstein K, Delaney K, Ward D, Moorman A, Wood K, Holmberg S. Incidence and risk factors for lipoatrophy (abnormal fat loss) in ambulatory HIV-1-infected patients. Program and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections; February 24-28, 2002; Seattle, Washington. Abstract 684a.
So the initial perception that lipoatrophy and lipohypertrophy stem from a single central mechanism is probably not true, but the two disorders do share a number of risk factors.
A further study in 2258 HIV-positive patients assessed adipose tissue alterations by gender.16 Logistic regression analysis demonstrated that men had a significantly lower adjusted risk of presenting with any alteration than women (OR: 0.47; 95% CI: 0.38–0.58; P , 0.0001) and a significantly lower risk of lipohypertrophy (P = 0.0022) and mixed fat redistribution (P , 0.0001), whereas risk of lipoatrophy was similar between genders.
The enzyme 11-b-HSD1 has also been implicated as potentially playing a role in fat redistribution syndromes. This enzyme helps catalyze the conversion of the hormonally inactive cortisone to cortisol, which is required for adipocyte differentiation. It is expressed to a higher degree in visceral fat than in subcutaneous fat and is elevated in the presence of cortisol. The differential expression of 11-b-HSD1 in visceral fat, its association with cortisol, and the well-established prevalence of elevated cortisol levels in HIV suggest that this enzyme may play a role in the pathogenesis of central fat accumulation in HIV.26
Rosiglitazone increases subcutaneous fat in type 2 diabetic patients and reverses the block of adipocyte differentiation induced by HAART in vitro
Rosiglitazone increases subcutaneous fat in type 2 diabetic patients and reverses the block of adipocyte differentiation induced by HAART in vitro
Rosiglitazone increases subcutaneous fat in type 2 diabetic patients and reverses the block of adipocyte differentiation induced by HAART in vitro
To investigate if possible mitochondrial injury can be found in adipose tissue of nucleoside analogue reverse transcriptase inhibitor (NRTI)–treated patients, subcutaneous fat was taken from the buttocks of 24 HIV-positive patients and 8 HIV-negative controls. The content of mitochondrial DNA (mtDNA) was quantified using a Southern blot technique. Fat biopsies were examined by electron microscopy and screened by restriction fragment length polymorphism analysis for the presence of the nt 8344 and 3243 mtDNA point mutations. Age, sex, and body mass index did not differ between the HIV-negative controls, the HIV-positive patients currently treated with NRTIs (NRTI group, n = 19), and the HIV-positive patients without NRTIs (no-NRTI group, n = 5). The mean mtDNA content was 44% lower in the NRTI group compared with the no-NRTI group ( p = .01) but did not differ between the control group and the no-NRTI group. When the HIV-infected patients were stratified to a group with clinical signs of lipoatrophy at the biopsy site (LA group, n = 11) and a group without lipoatrophy (no-LA group, n = 13), the mean mtDNA content in the LA group was 39% lower than that in the no-LA group ( p = .02). No point mutations or deletions were observed. The adipocytes of patients with lipoatrophy contained multiple small lipid vacuoles, and the mitochondria harbored inclusions reminiscent of mtDNA cytopathies. mtDNA depletion and ultrastructural abnormalities of adipocytes suggest a link between mitochondrial damage, the use of NRTIs, and lipoatrophy in HIV-infected patients.
Design Randomized, open-label 24-week study. Setting Seventeen hospital HIV outpatient clinics and primary care centers in Australia and England, with randomization from June 2000 through January 2001. Participants A total of 111 adults (109 men) with moderate or severe lipoatrophy who were receiving stavudine (n = 85) or zidovudine (n = 26) and had stable plasma HIV RNA levels below 400 copies/mL and no prior abacavir therapy. Intervention Patients were randomly assigned to switch from stavudine or zidovudine to abacavir, 300 mg twice per day, while continuing all other antiretroviral therapy (n = 54) or to continue all antiretroviral therapy (n = 57). Main Outcome Measures The primary end point was limb fat mass, measured by dual-energy x-ray absorptiometry; key secondary end points were plasma HIV RNA levels, adverse events, physician-assessed (via subjective measures) lipodystrophy severity, total and central fat mass, and fasting metabolic (lipid, glycemic, and lactate) levels. Results There was a significant increase in limb fat in the abacavir group relative to the stavudine/zidovudine group (0.39 vs 0.08 kg; mean difference, 0.31; 95% confidence interval [CI], 0.06-0.57 kg), as well as significant relative increases in subcutaneous thigh ( P = .01), arm ( P <.001), and abdominal ( P = .001) fat areas on computed tomography. Switching had no significant effect on secondary end points, including plasma HIV RNA (for unadjusted comparison between groups at week 24, odds ratio, 1.38; 95% CI, 0.48-3.96). Change in limb fat mass at week 24 did not correlate with change in subjectively determined perceived lipoatrophy severity ( r = -0.06; P = .53 by Spearman correlation). Hypersensitivity to abacavir was seen in 5 patients (10%). Conclusions In this sample of lipoatrophic HIV-infected adults, switching from stavudine or zidovudine to abacavir for 24 weeks led to significant, albeit modest, objectively measured increases in limb fat. Clinical lipoatrophy, as assessed subjectively, did not resolve, however, and at the rate of increase observed may take years to resolve with use of this strategy. Longer-term follow-up is needed.
Rosiglitazone increases subcutaneous fat in type 2 diabetic patients and reverses the block of adipocyte differentiation induced by HAART in vitro
Background Lipodystrophy commonly complicates antiretroviral therapy of HIV-1 infection. Thiazolidinediones such as rosiglitazone promote subcutaneous fat growth in type 2 diabetics and adults with congenital lipodystrophy, and can prevent HIV-1 protease inhibitor toxicity to adipocytes in vitro. We postulated that rosiglitazone would improve HIV lipoatrophy. Methods 108 HIV-1-infected lipoatrophic adults on antiretroviral therapy were randomised to rosiglitazone 4 mg twice daily (n=53) or matching placebo (n=55) for 48 weeks. The study had 80% power to detect a 0·5 kg difference in changes in limb fat (using dual-energy X-ray absorptiometry) between groups at week 48 by intention-to-treat analysis, and a 0·7 kg difference within each protease inhibitor stratum. Findings Limb fat increased by 0·14 kg in the rosiglitazone group and 0·18 kg in the placebo group (mean difference –0·04 kg [95%CI –0·29 to 0·21]; p=0·74 by t test), with three participants (one on rosiglitazone and two controls), lost to follow-up. Rosiglitazone had no significant benefit on any other measure of lipodystrophy, despite large relative increases in plasma adiponectin (4·2 mmol/L [102%]; p<0·0001) and in three markers of insulin sensitivity (p=0·01 to 0·02). Six participants ceased study drug in each group, four participants (three on rosiglitazone and one control) for related adverse events. The main adverse effects, which seem to be almost unique to this population, were asymptomatic hypertriglyceridaemia (mean relative increase 0·9 mmol/L at week 48; p=0·04) and hyper-cholesterolaemia (1·5 mmol/L; p=0·001). Interpretation Rosiglitazone for 48 weeks did not improve lipoatrophy in HIV-1-infected adults receiving antiretroviral therapy. Use of less toxic antiretroviral treatment is necessary to prevent lipoatrophy.
Before & after Examples from VEGA Clinical change after PLA injections between baseline and week 96, after five and four sessions of injections, for patient 1 and patient 2 respectively. (a-d) Patient 1, at day 0 (a, c) and week 96 (b, d)
Methods: The goal of this open-label, single-arm, pilot study was to evaluate the efficacy and safety of facial injections of poly-L-lactic acid (PLA) (New-Fill)® in HIV-infected patients with severe facial lipoatrophy. Patients received four sets of injection at day 0 and then every 2 weeks for 6 weeks. Patients were evaluated by clinical examination, facial ultrasonography, and photography at screening and at weeks 6, 24, 48, 72, and 96. Results: Fifty patients were enrolled. At entry, the median facial fat thickness was equal to zero (range, 0.0-2.1 mm). The median total cutaneous thickness (TCT) increased significantly from baseline : +5.1 mm (range, 2.2-8.6 mm) at week 6, +6.4 mm (range, 3.1-9.1 mm) at week 24, +7.2 mm (range, 4.2-9.6 mm) at week 48, +7.2 mm (range, 3.5-9.6 mm) at week 72 and +6.8 mm (range, 3.9-10.1 mm) at week 96 ( P < 0.001). The proportion of patients with TCT > 10 mm was observed in 19% at week 6, 41% at week 24, 61% at week 48, 52% at week 72 and 43% at week 96. In 22 (44%) patients, palpable but non-visible subcutaneous micronodules were observed with a spontaneous resolution in six patients at week 96. Conclusion: The benefit of PLA for the correction of the facial lipoatrophy in HIV-infected patients was clearly demonstrated, with an evident aesthetic and quality of life improvement. The efficacy, safety profile, and the simplicity of the injection schedule of PLA make this filling material a potentially attractive treatment. The first European data was submitted by Amard and Saint Marc in September of 2000. Twenty-six lipoatrophy patients were treated with New Fill. Ultrasound measurement was used to measure dermal thickness. A 151% increase in dermal thickness was found at 3 months, 196% at 6 months, and 131% at 54 weeks.[ 4 ] A 96-week study was presented at the 10th Conference for Retroviral and Opportunistic Infection in Boston in February of 2003. Researchers from this VEGA study presented the results of 50 HIV-positive patients after receiving Sculptra for correction of facial lipodystrophy. Change in dermal thickness was evaluated using ultrasound and color Doppler preformed by the same trained radiologists. They found a threefold increase in dermal thickness, which was sustained at 72 and 96 weeks.[ 5 ] Another study presented by Lafaurie from St Louis Hospital in Paris, France involved treating 40 patients with lipodystrophy. In this study, the product was diluted with 3 mL of sterile water and the patients were treated with 150 mg per cheek every 15 days. Efficacy was evaluated at 2 months and after 6 months utilizing photos analyzed by digital surface photogrammetry software. Results showed a mean increase of dermal thickness of 2.4 mm after two injections. Results were maintained at 2 and 6 months.[ 6 ] The Chelsea Westminster study was done in London. A total of 30 patients with lipoatrophy were treated with Sculptra. These patients were randomized into two groups. The first group was treated every 2 weeks for a total of three treatments. The second group had no treatment for the first 12 weeks and then received three treatments as well at weeks 12, 14, and 16, thus acting as a negative control. Both groups were evaluated at weeks 0, 12, and 24, utilizing ultrasound and serial photographs. Statistically significant increases in dermal thickness were noted in all patients with maintenance of clinically significant results to 2 years.[ 7 ] In July 2002 an investigational device exemption (IDE) was submitted and accepted from Blue Pacific Aesthetic Medical Group in Hermosa Beach, California.[ 7 ] We enrolled 100 patients who received one to six treatments spaced 3 weeks apart. Caliper skin thickness was used to measure changes in transcutaneous thickness. Baseline laboratory values were taken and repeated every 3, 6, and 12 months to verify no change in lactic acid level. A well-being questionnaire was filled out prior to treatment, at the end of treatment, and at 6 and 12 months.[ 8 ] As of October 2004, 100 patients were enrolled in the study, 99 completed treatment, 76 had completed the 6-month follow-up, and 54 completed the 12-month follow-up. A mean average of 57.8% increase in transcutaneous thickness was noted at the end of the study. At 6 months the increase in total cutaneous thickness (TCT) was 53.5% and this was shown to be maintained at 1 year with a 54.9% increase in thickness. Actual measurements were: initially (prior to treatment), 7.1 mm; end of treatment, 11.2 mm; 6-month follow-up, 10.9 mm; and 1 year, 11.0 mm. These results showed the augmentation not only held at 1 year but actually increased. Our study was used to establish clinical safety with Sculptra in submission to the FDA. There was one additional U.S. study done by Peter Engelhart and colleagues in Florida. This was APEX 002, which was an investigator-initiated study. His results on efficacy and safety were similar to ours.[ 9 ] In all studies, there were no serious adverse results. Although bruising and other injection related complications are always a possibility, the only device-related complication was that of subcutaneous nodules. These nodules are defined as being less than 5 mm, not visible but palpable. In our study nodule formation occurred with an incident of 9.2%. The average onset was 6 months and 46% spontaneously resolved (Tables [ 1 ] and [ 2 ]). If spontaneous resolution does not occur, a subcision with a 25-gauge needle, followed by localized steroid or saline injection, may improve resolution. This may be repeated weekly and used in conjunction with massage. As a final treatment to any resilient nodules, a 5FU and steroid combination in very small quantities may be injected locally into the nodule. This may be repeated monthly as needed. Complete resolution may take 5 to 8 months. REFERENCES 1 Brady JM, Cutright DE, Miller RA, Barristone GC. Resorption rate, route, route of elimination, and ultrastructure of the implant site of polylactic acid in the abdominal wall of the rat. J Biomed Mater Res 1973; 7: 155-166 2 Cutright DE, Perez B, Beasley JD, Larson WJ, Posey WR. Degradation rates of polymers and copolymers of polylactic and polyglycolic acids. Oral Surg Oral Med Oral Pathol 1974; 37: 142-152 3 Sattler G. Long-lasting results with polylactic acid. Derm 2003; 9: 422-423 4 Amard & Saint Marc. Polylactic acid in the treatment of HIV-associated lipoatrophy. Second Lipodystrophy Workshop, Toronto, Canada: September 2000 5 Mest DM, Humble G. Hermosa Beach, California, Current IDE#G020113. 6 Lafaurie M. Dolivio, St. Louis Hospital, Paris, FranceTreatment of lipoatrophy with injections of polylactic acid. Tenth Conference for Retrovirus and Opportunistic Infection. February 2003 7 Moyle GJ, Lysakova L, Brown S. A randomized open-label study of immediate versus delayed polylactic acid injections for the cosmetic management of facial lipoatrophy in persons with HIV infection. HIV Med 2004; 5: 82-87 8 Mest D, Humble G. Safety and efficiency of intradermal poly-L-lactic acid (Sculptura) injections for patients with HIV associated facial lipoatrophy. Antivir Ther 2004; 9: L36 9 Engelhard P, Knies M. Safety and efficacy of New-Fill® (polylactic acid) in the treatment of HIV-associated lipoatrophy of the face (HALF). XIV International AIDS Conference Barcelona, Spain: July 7-12, 2002
Studies cited in Schambelan et al: 1. Grunfeld C et al. J Clin Endocr Metab 1992;74:1045-52. 2. Zangerle R et al. JAIDS 1994;7:1149-56. 3. Feingold KR et al. J Clin Endocr Metab 1993;76:1423-7. 4. Grunfeld C et al. Am J Med 1989;86:27-31. 5. Noor MA et al. AIDS 2001;15:F11-F18. 6. 9th CROI, February 2001. 7. Echevarria KL et al. Ann Pharmacother 1999;33:859-63. 8. Periard D et al. Circulation 1999;100:700-5. 9. Carr A et al. Lancet 1999;353:2093-9. 10. Mulligan K et al. JAIDS 2000;23:35-43.
Figure 1. Incidence of Myocardial Infarction According to the Duration of Exposure to Combination Antiretroviral Therapy. The incidence of primary events was assessed beginning at base line according to the cumulative duration of combination antiretroviral therapy since the initiation of therapy, stratified in one-year intervals from the initiation of therapy to four years, more than four years of exposure, and no exposure. The rate of myocardial infarction was generally lower among the patients not exposed to combination antiretroviral therapy than in any of the treated groups. The untreated patients had, a priori, a lower risk of myocardial infarction than the treated patients.26 As compared with the rate of myocardial infarction among the patients treated for less than one year, the univariable relative rate among the patients with no exposure to therapy was 0.24 (95 percent confidence interval, 0.07 to 0.89); among those with one to less than two years of exposure, 1.34 (95 percent confidence interval, 0.58 to 3.10); among those with two to less than three years of exposure, 1.73 (95 percent confidence interval, 0.80 to 3.76); among those with three to four years of exposure, 1.98 (95 percent confidence interval, 0.94 to 4.15); and among those with more than four years of exposure, 2.55 (95 percent confidence interval, 1.25 to 5.20) (P for trend <0.001). The vertical bars represent the 95 percent confidence intervals.
1 Investigators from the HIV Outpatient Study (HOPS) group, an ongoing CDC-supported study at 10 sites around the United States, examined the incidence of and risk factors for myocardial infarction in their cohort since 1993. [1] They compared data from patients taking protease inhibitors (PIs) and those not taking PIs. A total of 13 of the 3013 persons taking PIs developed a myocardial infarction, angina, or cerebrovascular accident, for an incidence of 1.2 per 1000 person-years, compared with 2 of 2665 patients not taking PIs (0.5/1000 person-years). The association with PIs remained even when other cardiovascular risk factors were taken into account. However, most incidents of cardiovascular disease occurred in persons with known risk factors. Holmberg S, Moorman AC, Tong T, et al. Protease inhibitor drug use and myocardial infarction in ambulatory HIV-infected patients. Program and abstracts of the 39th Annual Meeting of the Infectious Diseases Society of America; October 25-28, 2001; San Francisco, California. Abstract 941.
Nonetheless, we should not ignore the hyperlipidemia associated with HIV. Treatment may be difficult, however, as noted by Dr. Judith Aberg,[3] who presented updated information from ACTG 5087, a randomized trial of pravastatin vs fenofibrate. This study was halted by its data and safety monitoring board because fewer than 5% of patients responded to either drug alone, when response was defined as a composite end point of reductions in low-density lipoprotein (LDL) cholesterol and triglycerides levels. At this meeting, Dr. Aberg reported the initial results on 136 patients who, having failed either pravastatin or fenofibrate as monotherapy, then received 12 weeks of combination therapy. Overall, only 10% of patients responded. Of interest, better responses were seen among patients who had received prior fenofibrate monotherapy before starting both drugs, compared with those who started with pravastatin monotherapy. Only 3 subjects (5%) on dual therapy who initially started on pravastatin achieved the composite goal, compared with 10 subjects (16%) on dual therapy who initially started on fenofibrate. Overall, there were some differences between the drugs. Pravastatin appeared to be the more effective at lowering LDL cholesterol, while patients who received fenofibrate had larger increases in high-density lipoprotein (HDL) cholesterol and decreases in triglycerides. Combination therapy was well tolerated through 12 weeks of treatment: only 4 patients discontinued treatment and there were no cases of hepatitis or rhabdomyolysis. However, as Dr. Aberg pointed out, the overall results in terms of correction of hyperlipidemia were poor, suggesting that alternative strategies will be needed.
Objective: To estimate insulin resistance and its relationship to antiretroviral therapy (ART) in a cohort of HIV-infected persons with comparison to HIV-seronegative controls. Design: Prospective cohort of 533 HIV-infected and 755 HIV-seronegative men in the Multicenter AIDS Cohort Study evaluated at 6-month intervals between 1999 and 2003. Methods: Recent ART exposure was assessed by type of treatment in the preceding 6 months [i.e., no ART, monotherapy, combination ART, or highly active antiretroviral therapy (HAART) with and without a protease inhibitor (PI)]. Cumulative exposure was determined for the three major ART classes and for individual medications within each class. Two endpoints, a modified QUICKI index, 100 1/[log10(glucose) þ log10 (insulin)] and fasting hyperinsulinemia (insulin > 15 mU/ml), were assessed. All statistical models were adjusted for age, body mass index, race, nadir CD4 cell count, hepatitis C serostatus and family history of diabetes mellitus. Results: Each of the HIV-infected groups had higher odds of hyperinsulinemia and lower mean QUICKI than the HIV-seronegative men. Each additional year of exposure to nucleoside analogue reverse transcriptase inhibitors (NRTI) was associated with increased odds of hyperinsulinemia [odds ratio (OR), 1.08; 95% confidence interval (CI), 1.02–1.13) and a lower QUICKI (0.04; 95% CI, 0.07 to 0.01). Cumulative exposure to non-nucleoside analogue reverse transcriptase inhibitors or PI drugs was not associated with either insulin resistance marker. Of individual medications examined, stavudine was associated with the highest risk of hyperinsulinemia (OR, 1.2; 95% CI, 1.2–1.3). Conclusions: Fasting surrogate markers suggest increased insulin resistance in HIVinfected men, which is related to cumulative NRTI exposure. 2005 Lippincott Williams & Wilkins AIDS 2005, 19 : 1375–1383
7,219 HIV-infected subjects and 2,792,971 uninfected controls; over 7 million patient-years of followup. Used MediCal claims database. Overall incidence rate of 10.7/100 patient-years for those w/ HIV infxn, compared to 2.9/100 patient-years for those w/o HIV infxn, yielding a RR of 3.32!
Carr A, Miller J, Eisman JA, Cooper DA. Osteopenia in HIV-infected men: association with asymptomatic lactic acidemia and lower weight pre-antiretroviral therapy. AIDS. 2001 Apr 13;15(6):703-9. Huang JS, Rietschel P, Hadigan CM, Rosenthal DI, Grinspoon S. Increased abdominal visceral fat is associated with reduced bone density in HIV-infected men with lipodystrophy. AIDS. 2001 May 25;15(8):975-82. McDermott AY, Shevitz A, Knox T, Roubenoff R, Kehayias J, Gorbach S. Effect of highly active antiretroviral therapy on fat, lean, and bone mass in HIV-seropositive men and women. Am J Clin Nutr 2001 Nov;74(5):679-86 Knobel H, Guelar A, Vallecillo G, Nogues X, Diez A. Osteopenia in HIV-infected patients: is it the disease or is it the treatment? AIDS 2001 Apr 13;15(6):807-8 Nolan D, Upton R, McKinnon E, John M, James I, Adler B, Roff G, Vasikaran S, Mallal S . Stable or increasing bone mineral density in HIV-infected patients treated with nelfinavir or indinavir. AIDS 2001 Jul 6;15(10):1275-80 Gold J, Pocock N, Li Y; Albion St Centre Osteoporosis and HIV Study group. Bone mineral density abnormalities in patients with HIV infection. J Acquir Immune Defic Syndr. 2002 May 1;30(1):131-2. Mondy K et al. CID 2003;36:482-90. Arnsten JH et al, 10th CROI, Boston 2003, Abstract 103
Background: Osteonecrosis has been reported to occur occasionally among HIV-infected patients. The diagnosis of symptomatic osteonecrosis of the hip in two of the authors' patients, together with reports from community physicians, raised a concern that the prevalence of osteonecrosis is increasing. Objective: To determine the prevalence of osteonecrosis of the hip in asymptomatic HIV-infected patients and to identify potential risk factors associated with osteonecrosis. Design: Survey and comparison study. Setting: The Clinical Center of the U.S. National Institutes of Health. Participants: 339 asymptomatic HIV-infected adults (of 364 asked to participate) and 118 age- and sex-matched HIV-negative volunteers enrolled between 1 June and 15 December 1999. Measurements: Osteonecrosis of the hip, as documented by magnetic resonance imaging. Data from clinic records and a patient questionnaire administered before magnetic resonance imaging were used in an analysis of risk factors. A subset of patients was evaluated for hypercoagulable state. Results: Fifteen (4.4% [95% CI, 2.5% to 7.2%]) of 339 HIV-infected participants had osteonecrosis lesions on magnetic resonance imaging, and no HIV-negative participants had similar lesions. Among HIV-infected participants, osteonecrosis occurred more frequently in those who used systemic corticosteroids, lipid-lowering agents, or testosterone; those who exercised routinely by bodybuilding; and those who had detectable levels of anticardiolipin antibodies. Conclusions: Patients infected with HIV have an unexpectedly high occurrence of osteonecrosis of the hip. Although screening asymptomatic patients is not warranted, HIV-infected patients with persistent groin or hip pain should be evaluated for this debilitating complication.
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