(This is a preliminary report on Lipodystrophy. A more detailed report will follow)
     Written for NATAP by Dr. Gilbert Kaufmann, Med. Poliklinik, University Hospital Basel, Petersgraben Switzerland

Lipodystrophy Syndrome
The lipodystrophy syndrome is one of the major adverse events of potent antiretroviral therapy, affecting a large proportion of 20-80% of treated HIV-1 infected individuals. The exact pathogenesis however is still unclear, but alterations in adipogenesis (formation of fat tissue) and adipolysis (breakdown of adipose tissue) have been reported. There is much controversy about the diagnostic criteria and the true incidence (rate) of this syndrome as well as whether it is only one syndrome or several syndromes. Initially associated with the use of protease inhibitors (PIs), subsequent studies provided evidence that the use of nucleoside (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) may similarly be associated with this syndrome.

Incidence of Body Changes & Lipodystrophy
Goujard and colleagues presented a study that evaluated the incidence of the lipodystrophy syndrome in 121 patients with acute HIV-I infection who have been treated with HAART (highly active antiretroviral therapy) for more than 6 months. Twenty-two patients (18.2%) presented with at least one clinical sign of lipodystrophy after a mean follow-up of 24 months. The proportion of patients with lipodystrophy syndrome increased to 30% at 36 months. This study confirms previous reports that lipodystrophy can already occur in very early stages of treated HIV-1 infection and that duration of HIV infection might not be a major cause.

Kingsley and colleagues studied the prevalence of the lipodystrophy syndrome and metabolic abnormalities in the Multicenter AIDS Cohort Study (MACS), consisting entirely of men. 868 participants underwent a physical examination and laboratory assessment. Changes of body shape were detected in 33% of HIV negative and in 63% of HIV-1 positive men. Due to the high prevalence (rate) of body changes in HIV-uninfected subjects, the investigators tried to find a better case definition for the lipodystrophy syndrome that would allow a better discrimination between the actual lipodystrophy syndrome and other, unspecific body changes. A symptom combination of moderate or severe peripheral wasting (thinning of arms or legs) and central adiposity (increase in abdomen or breasts, or loss in buttocks) was the best working definition which resulted in a relatively low prevalence of 20% of patients with signs of lipodystrophy in the HAART group. The low prevalence is in contrast with previously reported higher rates of up to 80%, indicating that a case definition for the lipodystrophy syndrome is crucial to estimate the true prevalence of this syndrome. A further interesting finding of this study was that the prevalence of lipodystrophy reached a plateau after 2 years, suggesting that the syndrome usually occurs in the first 2 years of HAART.

D4T & Lipoatrophy
Joly and colleagues presented the NOVAVIR study. 96 Patients were randomized to receive either AZT (Retrovir, zidovudine, NRTI drug) or d4T (Zerit, stavudine, NRTI drug), in combination with 3TC (Epivir, lamivudine, NRTI drug) and indinavir (Crixivan, PI drug). At 30 months, the proportion of patients with signs of lipoatrophy (fat loss under the skin) was significantly larger and the number of clinical signs of lipoatrophy was significantly higher in the d4T arm. There were no significant differences between the two arms in the rates of central fat accumulation. The study suggests that d4T increases the incidence of lipoatrophy compared to AZT.

Lipodystrophy & Abnormal Lipids/glucose in Children
Two small studies (Amaya et al.; Meneilly et al.) showed that the lipodystrophy syndrome including abdominal fat accumulation and peripheral fat loss could affect children in a similar way as adults. Moreover, a large proportion of individuals with hypercholesterolemia (increased blood cholesterol), hypertriglyceridemia (increased blood fats) and insulin resistance (pre-diabetic state or diabetes) have been observed in these two cohorts.

Insulin Resistance & Lipodystrophy in HCV/HIV Coinfected
Duong and colleagues found in a cross-sectional study that HIV/HCV- (hepatitis C virus) and HCV-infected patients had a significant increase in insulin resistance when compared with HIV-infected patients without HCV. HIV- and HIV/HCV patients were taking HAART. Moreover, lipoatrophy was observed significantly more frequently in HIV/HCV co-infected patients than in HIV-infected patients (48% vs 19.5%). The mechanisms for the enhanced metabolic alterations in HIV/HCV co-infection is unclear and needs further investigation.

Are elevated lipid levels associated with an increased risk for coronary heart disease (CHD)?
Based on other patient populations, it has to be assumed that patients treated with potent antiretroviral therapy (HAART) and elevated cholesterol and triglyceride levels are similarly at risk for CHD like other patient groups. Klein and colleagues reported an update about the rate of coronary heart disease (CHD) events in 4,541 HIV-infected men receiving protease inhibitors in the Kaiser Permanente HMO (health maintenance organization) in Northern California. The cases were compared to 43,118 randomly selected, age- and sex-matched control members not known to be HIV-infected. The incidence was 5.2 events per 1,000 patients per year for individuals taking anti-HIV therapy without a protease inhibitor and 5.8 for patients taking a protease inhibitor. The rate in HIV-uninfected men was 3.4. Regarding other CHD risk factors, HIV positive patients had a significantly lower rate of hypertension (high blood pressure, 13% vs 21%), a non-significantly higher rate of increased cholesterol levels (21% vs 15%) and similar rates of diabetes (6%) and smoking (29%) as control members. The study suggests that protease inhibitor use does not increase the short-term risk for CHD, when compared to anti-HIV therapy without a PI drug. However, the higher rate of CHD events among HIV-infected persons remained unexplained. Whether other possible co-factors for CHD, including cytomegalovirus (CMV) and chlamydiae, or HIV itself might explain the difference, is unknown.

Mary-Krause and colleagues studied the course of CHD in the French Hospital HIV Database. Myocardial infarction ("heart attack") was diagnosed in 84 of 42,787 men exposed to protease inhibitor therapy. The incidence rate of myocardial infarction increased in parallel with the time of exposure to protease inhibitors (after 18 months of therapy, up to 30 months) and was three times higher among those with at least 30 months of PI drug exposure than the expected incidence in the general population of HIV-negative men. However, the statistical analysis was not adjusted for CHD co-factors. Although this study provides some preliminary evidence that the risk for CHD is increased in patients with long-term exposure to protease inhibitors, a longer follow-up period is required to estimate the full impact of long-term elevations of lipid levels on the development of CHD in this cohort of patients.

"Mitochrondrial Toxicity" and "Lactic Acidemia:" New Classification Proposed
Andrew Carr gave a state-of-the-art lecture on mitochondrial (energy producer of cell) toxicity. Different nucleoside analogue reverse transcriptase inhibitors (NRTIs) are thought to inhibit the mitochondrial "polymerase gamma" enzyme to varying degrees, resulting in toxicity. Elevated lactate levels (lactic academia, increased blood acid level) may be one of the consequences of mitochondrial toxicity. He proposed the following classification of lactic acidemia: normal less than 2 millimoles per liter (mmol/L), mild increase: 2-5, moderate increase: 5-10 and severe: greater than 10 mmol/L. Subjects with mild lactic acidemia may be asymptomatic (no symptoms), whereas patients with moderate lactic acidemia may show symptoms such as fatigue, malaise, gastrointestinal (stomach-colon) symptoms including nausea. The severe form of lactic acidemia is often acidotic (lactic acidosis syndrome, grouping of abnormalities), which is associated with a high mortality (death rate), particularly in women who are overweight. With regard to these serious consequences, Carr recommended that NRTI therapy should be discontinued when lactate levels increase above 5-10 mmol/L. However, he did not recommend routine testing of lactate levels, but clinicians and patients should be alerted by symptoms associated with this syndrome.

Lonergan and colleagues found that the incidence of lactic acidemia was more than ten times higher for any d4T (Zerit, stavudine)-containing regimen compared with a regimen without d4T. The greatest risk occurred when ddI (Videx, didanosine) or ddI/3TC (Epivir, lamivudine) was combined with d4T. However, patients with lactic acidemia could be safely rechallenged with other NRTIs such as abacavir (Ziagen) or ZDV (Retrovir, zidovudine) or both.

Vrouenraets and colleagues found a 22% prevalence of elevated lactate levels among 223 patients taking NRTI therapy and 8% among untreated patients. Consistent with the previous study, they found an increased risk for d4T-containing regimens, but also for AZT and abacavir. DdI- and 3TC-containing regimens were not statistically associated with elevated lactate. Neither hepatitis virus co-infection (hepatitis C or B) nor increased liver enzyme (ALT) was statistically associated with increased lactate levels.

Treatment for Metabolic Complications and Lipodystrophy
Miller and colleagues evaluated the safety and efficacy of gemfibrozil (Lopid) for elevated triglyceride (blood fats) levels. Gemfibrozil was well tolerated and did not appear to be associated with additional protease inhibitor toxicity, but had only a modest effect on hypertriglyceridemia. Gemfibrozil is FDA-approved to treat high blood triglyceride levels in HIV negative persons.

Martinez and colleagues studied the impact of substituting efavirenz (Sustiva, NNRTI drug) for a protease inhibitor in combination therapy. The randomized study among 93 HIV-infected adults with lipodystrophy syndrome. At 12 months after switching, patients on efavirenz had significant decreases in measured severity scores of several types of lipodystrophy, as well as improvements of insulin sensitivity and HDL (high density lipoprotein or "good")-cholesterol. However, the efavirenz arm did still have a further decrease in fat under the skin (worsened lipoatrophy), but less of a decrease than the PI arm. The substitution of efavirenz (after 12 months) for a protease inhibitor appears therefore to slow the evolution of body fat changes, although it does not prevent them. Both arms maintained undetectable HIV viral loads.

In contrast, Estrada and colleagues found somewhat different results in a non-randomized study of 41 patients with lipodystrophy syndrome. One year after switching to an efavirenz-based from a PI-based regimen, there were no significant changes in insulin sensitivity. Also, waist-to-hip ratio (one measurement of abdominal obesity) did not change significantly. HIV viral load remained undetectable in all but one patient.

Yet, Walli and colleagues showed that switching from a protease inhibitor to an abacavir (Ziagen, NRTI)-based regimen results in an improvement of insulin sensitivity and a decrease in both total cholesterol and triglycerides in the majority of patients up to 12 months.

Although these reports might appear somewhat promising, it appears that some body shape changes cannot be easily reversed. Conflicting study results occurs sometimes & that is confusing. One of the problems with lipodystrophy research is that the studies are not adequately designed to answer the questions with certainty. Part of the reason for this difficulty is that it's difficult to design such studies.

"Osteopenia" and "Osteoporosis" (Loss of bone mineral density) in Adults & Children
Several cross-sectional studies evaluated the incidence of osteopenia (mild loss of bone mineral density) and osteoporosis (severe loss). Osteoporosis is common in elderly, HIV-negative women and some elderly, HIV-negative men and increases the risk of bone fractures. McGowan and colleagues found a 24% osteopenic rate and a 2% osteoporotic rate among 151 HIV positive patients who were antiretroviral-naïve (never took any treatment).

Similarly, Knobel and colleagues found osteopenia in 25% of therapy-naïves, in 40% of protease inhibitor treated, in 33% of non-protease inhibitor treated and in 16% of healthy adults. In this study of 80 patients, the association between the use of HAART and reduced bone mineral density was not statistically significant.

Similarly, Chang and colleagues reported that osteoporosis and osteopenia were not more prevalent in a HAART-experienced group than in a HAART-naïve group. Yet in this study of 109 Asians (Korean), rates of decreased bone mineral density in the lumbar spine (low back) were quite similar when comparing HIV negative controls, HIV-positive, HAART-naïve and HAART-experienced patients. Interestingly, in a separate report, Chang also reported that lipodystrophy was not detected in a study of 122 Koreans, including 45 HIV patients taking HAART, 32 treatment-naïve patients and 45 healthy controls. Lipodystrophy was measured using DEXA (dual energy x-ray absorptiometry). The length of HAART treatment was not stated in the abstract. Metabolic changes were observed in the HAART patients, including significantly increased triglycerides, decreased HDL (high density lipoprotein or "good") cholesterol and insulin resistance. The findings suggest that manifestations of HIV and/or adverse events of anti-HIV drugs are not always identical when comparing race-ethnic groups. A lower rate of lipodystrophy has been reported previously among HIV positive African-Americans taking HAART.

In another study, Arpadi and colleagues measured the total body bone mineral content in 51 HIV-infected children and 282 healthy controls. Significant reductions in bone mineral density were observed among the HIV positive children, which progressively increased with age, but were independent of protease inhibitor treatment. Only 6% of the HIV-positive children were treatment-naïve.

These studies suggest that there is no clear relationship between HAART and reduced bone mineral density. There appears to be increasing information that HIV by itself might increase the risk for loss of bone mineral density. Graeme Moyle reported at the Resistance Workshop this past Fall that osteopenia may be related to immune dysfunction from HIV & not HIV therapies. Bone disorders have been seen in HCV and are more common in chronic viral diseases. However, the cross-sectional design of these studies represents a major limitation. The preliminary results require therefore confirmation in longitudinal well-controlled trials.

Hepatotoxicity (Liver toxicity)
Boxwell and Toerner from the US FDA (Food and Drug Administration) reported that the combination of hydroxyurea (HU, Hydrea, Droxia) and NRTI drug(s) increases the risk for serious hepatotoxicity. Hydroxyurea is an FDA-approved drug to help treat certain cancers and sickle cell anemia. Among 34 reported cases of hepatotoxicity associated with NRTI and HU usage, 25% were fatal. Among all of the cases, ddI was reported in 91%. The combination of ddI/ d4T/HU combination may further increase the risk of fatal outcome (61% rate). The authors concluded, "Patients taking HU and NRTIs, in particular ddI and d4T, should therefore be aggressively monitored for hepatotoxicity." Regular testing of liver enzymes (ALT, AST), in addition to pancreas gland enzyme (amylase, see "pancreatitis" below) would be reasonable for patients taking NRTI drugs, and particularly when combined with hydroxyurea. Liver and/or pancreas toxicity associated with NRTI drug usage also is associated with increased blood lactate levels and life-threatening lactic acidosis (see above). One limitation of the study is the voluntary nature of the reporting system.

Sulkowski and colleagues studied the incidence of severe hepatotoxicity (grade 3 [severe] or 4 [life-threatening] changes for AST/ALT, liver enzymes) associated with efavirenz (EFV, Sustiva) and nevirapine (NVP, Viramune, both NNRTI drugs). Severe hepatotoxicity was observed in 13.8%, including 16.7% of NVP and 8.3% of EFV users. However, they reported that the incident rate for severe hepatotoxicity as measured by cases per 100 person-months was similar (1.3 vs 1.2).
(Comments from Jules Levin: this study was not randomized, and previous studies show that the first 12 weeks of NVP use represent the period when ALT elevations and hepatotoxicity are most likely to present problems. So, I think that using "cases per 100-person-months" masks what occurs in first 12 weeks.) Interestingly, the researchers found no significant association between chronic HCV or HBV infection and the risk for severe liver toxicity for either NNRTI drug.

Similarly, Bartlett and colleagues reported on hepatotoxicity in Study FTC-302, which took place in South Africa. Among the 468 treatment-naïve patients, 87% were Black. He reported that 17% of the 385 patients taking NVP combination therapy showed severe hepatotoxicity, defined by greater than a 5-fold increase of liver enzymes. None taking efavirenz developed hepatotoxicity. Interestingly, hepatotoxicity was significantly associated with female gender. In a previous study in the US from Judith Aberg increased incidence rash occurred in women but not increased hepstotoxicity. Patients also were taking d4T plus either 3TC or FTC (Coviracil, emtricitabine, experimental NRTI drug). Those with a baseline viral load less than 100,000 copies per milliliter were randomized to NVP, while those with a level greater than that were randomized to efavirenz (Sustiva, NNRTI drug). Two patients with severe hepatotoxicity progressed to liver failure and died. One had hepatitis B co-infection at baseline.

Therefore, as a result of these studies and others, liver enzymes should be closely monitored in patients receiving nevirapine.

Pancreatitis (inflammation of the pancreas gland)
Moore and colleagues reported that the risk for pancreatitis (inflammation of the pancreas digestive gland) increased 4-fold in patients treated with hydroxyurea (HU, Hydrea, Droxia). HU is an FDA-approved drug to treat certain cancers and sickle cell anemia. The combination of hydroxyurea with other agents such as ddI and d4T has been associated with pancreatitis in the current and previous studies. The authors concluded, "Use of [hydroxyurea] and ddI should probably be discouraged."

"Avascular Necrosis" (bone death due to inadequate blood) of the Hip
Keruly and colleagues reported 15 cases of avascular hip necrosis in HIV infected adults. This condition may have no symptoms (diagnosed by x-ray) or may be painful. If required, the treatment is hip bone replacement with a metal prosthesis. The incidence rate in the current study was 47-fold higher than in the general population. There was a significant trend that the annual number of cases increased from 1995 through 2000 at Johns Hopkins University. Risk factors associated with this specific adverse event included steroid drug (prednisone, cortisone, others) use, low CD4 count (less than 200 cells/mm3) and a longer time since HIV diagnosis, but not treatment for HIV. Nearly half of the cases had never taken a PI or NNRTI drug. Similarly, Gaughan and colleagues reported five cases of avascular necrosis in HIV-infected children. The incidence rate was much higher in this cohort than in the general population.

Genetic Risk for Increased Cholesterol Associated with Anti-HIV Drugs
Miseraz and colleagues reported that a genetic variation was significantly associated with an increase in total blood cholesterol after starting a protease inhibitor drug. A naturally occurring "polymorphism" (variation, "genotypes 11/12") of SREBP (sterol-regulatory element binding-protein)-1c was significantly associated with an increase in blood cholesterol after starting PI therapy, when compared to "homozygous" (the same two gene doses) "genotype 22." A total of 67 HIV positive patients were included in the study. While the results would need to be confirmed in larger studies, they suggest that testing for the altered gene one day might help to predict who will develop high cholesterol after starting a PI drug and that that information would be useful when constructing an optimal anti-HIV drug regimen. Additionally, there might be implications for designing new drugs to treat high cholesterol for HIV-positive and HIV-negative populations.

    References:
1. J. Bartlett et al. Severe Liver Toxicity in Patients Receiving Two Nucleoside Analogues and a Non-Nucleoside Reverse Transcriptase Inhibitor. Abstract 19.

2. C. Goujard, F. Boufassa, C. Deveau, D. Laskri, and L. Meyer for the Primo Group. Early Occurrence of Lipodystrophy in HIV-I-Infected Patients Treated during Primary Infection. Abstract 403.

3. S. Arpadi, M. Horlick, J. Thornton, P. Cuff, J. Wang, S. Quezada, and D. Kotler. Decreases in Total Body Bone Mineral Content Progress with Age in HIV-infected Children. Abstract LB9.

4. L. Kingsley, E. Smit, S. Riddler, R. Li, J. Chmiel, F. Palella, B. Visscher, J. Oishi, E. Taylor, A. Dobs, and R. Evans. Prevalence of Lipodystrophy and Metabolic Abnormalities in the Multicenter AIDS Cohort Study (MACS). Abstract 538.

5. V. Joly, P. Flandre, V. Meiffredy, S. Hazebrouck, M. Harel, J. P. Aboulker, and P. Yeni. ANRS, Paris, France. Assessment of Lipodystrophy in Patients Previously Exposed to AZT, ddI or ddC, but Naive for d4T and Protease Inhibitors (PI), and Randomized Between d4T/3TC/ Indinavir and AZT/3TC/Indinavir (NOVAVIR Trial). Abstract 539.

6. J. Miller, A. Carr, D. Brown, and D. A. Cooper. A Randomized, Double-Blind Study of Gemfibrozil (GF) for the Treatment of Protease Inhibitor-Associated Hypertriglyceridemia. Abstract 540.

7. D. Boxwell and J. Toerner. Fatal Hepatotoxicity Associated with Combination Hydroxyurea and Nucleoside Reverse Transcriptase Inhibitors (NRTIs): Cases From the FDA Adverse Event Reporting System (AERS). Abstract 617.

8. M. Sulkowski, S. Mehta, D. Thomas, and R. Moore. Hepatotoxicity Associated with NNRTI Use: Role of Drugs and Chronic Viral Hepatitis. Abstract 618.

9. R. D. Moore, J. C. Keruly, and R. E. Chaisson. Incidence of Pancreatitis in HIV-Infected Patients on Nucleoside RTIs. Abstract 620.

10. J. T. Lonergan, D. Havlir, E. Barber, and W. C. Mathews. Incidence and Outcome of Hyperlactatemia Associated with Clinical Manifestations in HIV-Infected Adults receiving NRTI-Containing Regimens. Abstract 624.

11. S. M. E. Vrouenraets, M. Treskes, R. M. Regez, N. Troost, H. M. Weigel, P. H. J. Frissen, and K. Brinkman. Hyperlactatemia in HIV-Infected Patients: The Role of NRTI Treatment. Abstract 625.

12. McGowan, A. Cheng, S. Coleman, A. Johnson, and H. Genant. Assessment of Bone Mineral Density (BMD) in HIV-Infected Antiretroviral-Therapy-Naive Patients. Abstract 628.

13. H. Knobel, A. Guelar, G. Valdecillo, I. Aymar, A. Díez, and X. Nogués.
Osteopenia in HIV-Infected Patients. Is It the Disease or Is It the Treatment? Abstract 629.

14. K. Chang, J. Kim, S. Hong, Y. Song, H. Lee, and S. Lim. Does Race Influence Bone Mineral Density in HIV-Infected Individuals Receiving HAART? Abstract 630.

15. J. C. Keruly, R. E. Chaisson, and R. D. Moore. Increasing Incidence of Avascular Necrosis of the Hip in HIV-Infected Patients. Abstract 637.

16. D. M. Gaughan, L. M. Mofeson, M. D. Hughes, G. R. Seage, and J. M. Oleske for the PACTG 219 Team. Avascular Necrosis of the Hip (Leggs-Calve-Perthes Disease [LCPD]) in HIV-Infected Children in Long-Term Follow-Up. Abstract 638.

17. R. A. Amaya and M. W. Kline. Antiretroviral-Associated Lipodystrophy Syndrome in HIV- Infected Children. Abstract 649.

18. G. Meneilly, J. Forbes, D. Peabody, V. Remple, and D. Burdge. Metabolic and Body Composition Changes in HIV- Infected Children on Antiretroviral Therapy. Abstract 650.

19. M. Duong, J. M. Petit, L. Piroth, M. Grappin, M. Buisson, P. Chavanet, and H. Portier. Hepatitis C Virus Chronic Infection Constitutes a Risk Factor for Insulin Resistance in HIV/HCV Co-Infected Patients Undergoing Antiretroviral Therapy. Abstract 654.

20. D. Klein, L. Hurley, M. Sorel, and S. Sidney. Do Protease Inhibitors Increase the Risk for Coronary Heart Disease Among HIV Positive Patients-Follow-Up Through June 2000? Abstract 655.

21. M. Mary-Krause, L. Cotte, M. Partisani, A. Simon, and D. Costagliola. Impact of Treatment with Protease Inhibitor (PI) on Myocardial Infarction (MI) Occurrence in HIV-Infected Men. Abstract 657.

22. E. Martinez, J. Romeu, M. A. Garcia-Viejo, L. Cruz, J. L. Blanco, E. Negredo, B. Clotet, and J. M. Gatell. An Open Randomized Study on the Replacement of HIV-1 Protease Inhibitors by Efavirenz in Chronically Suppressed HIV-1-Infected Patients with Lipodystrophy. Abstract 668.

23. R. Walli, K. Huster, J. R. Bogner, and F. D. Goebel. Switching from PI to ABC Improves Insulin Sensitivity and Fasting Lipids-12-Month Follow-Up. Abstract 672.

24. A. Carr A. State-of-the-art summary and discussion: Issues in metabolic complications: controversy or consensus. Session 64.

25. Chang K and others. Does race influence bone mineral density in HIV-infected individuals receiving HAART? Abstract 630.

26. Chang K and others. Does race protect an oriental population from developing lipodystrophy in HIV-infected individuals on HAART? Abstract 648.

27. Miseraz AR and others. Hyperlipoproteinemia in HIV patients is linked to sterol-regulatory element-binding protein (SREBP)-1c. Abstract 500.