New Resistance "Cut-Offs" May Be Needed: Baseline Genotype and Phenotype Do Not Predict Response to ABT-378/Ritonavir in PI-Experienced Patients at 24 and 48 Weeks

More on Fat Redistribution and Lipodystrophy: African-Americans, when treated during acute infection, osteopenia, amprenavir

Two abstracts suggested that African-American patients may have a lower incidence of lipodystrophy than do Caucasians. Wanke and colleages (abstract 24) reported African-American men and women were less likley to develop fat deposition (p<0.002 for men and 0.06 for women) than others. They defined fat deposition as BM1 <27, waist:hip ratio >0.90 for women and >0.95 for men). The problem as I see it, and others see it as well, is that the various studies presented at Retrovirus and other conferences define fat redistrubtion and deposition or accumulation differently. This makes it difficult to compare studies and to draw conclusions. As well, most studies are unable to sort out and identify the causes or strong associations that may lead to fat redistribution. But several researchers have anecdotally reported that their observations are that fat redistribution is seen less in African-Americans. Although there is an international study about to start led by David Cooper and Andrew Carr of Australia attempting to craft a case definition of lipodystrophy for studies to use uniformly, I have doubts that it is possible to define this syndrome based on what we know or will find out. Fortuneatly, Carr and Cooper think they will have study data to show within 1 year. I think the best way to understand this syndrome and possibly develop interventions is to conduct basic science research. For example, studies of the type as fat cell and liver biopsies may uncover what is really going on. Then we can craft clinical studies to explore the hypothesis' found in the basic science studies. Some studies are ongoing but its difficult to track all the studies.

Dr Graeme Moyle authored an overview of fat redistribution and metabolic complications from this conference and its available on the NATAP web site along with numerous other reports. I'm writing this additional report to highlight and detail presentations from Retrovirus that may be of particular interest.

Prior to the Retrovirus Conference Bristol Myers Squibb held a meeting of international researchers and thought leaders with experience researching lipodystrophy. At that meeting several researchers said they feel the liver may play a key role in this syndrome rather than fat cells. One investigator said that in 60 people with lipodystrophy they found no lactate in 56 of them. However, the methodology commonly used to study lactate has been questioned including saying that the way samples are collected and stored may not be appropriate. As you may know its been suggested that mitochondrial toxicity which can be related to NRTI therapy may play in causative role in fat redistribution. In a study reported by Ruiz and colleagues at Retrovirus, serum lactate, lactate/piruvate ratio and free and total L-carnitine were performed in a subgroup of 35 patients with lipodystrophy and long-lasting plasma HIV supression to investigate mitochondrial toxicity. It was an open-label randomized study. However, its been suggested that measuring lactate by current methods may be difficult. Lactic acidemia was detected in only 1 of 35 (2.7 mmol/I).

Another thought provoking study was reported by Miro and colleagues exploring lipodystrophy in 17 individuals treated with HAART during primary HIV-infection. Below is the full abstract but in brief--after median of 18 months (6-24), HIV-RNA was <200 copies/ml and <20 copies/ml in 100% and 75%, respectively. Thus, this group was well suppressed. Six patients (35%) developed "lipodystrophy" (4 men ans 2 women). By 24 months 57% (n=7) had developed "lipodystrophy". The authors suggested these findings should be taken into account when considering initiating therapy during acute infection.

One study conducted by Glaxo Wellcome compared APV+NRTIs (n=245) to IDV+NRTIs (n=241) from study PROAB3006. Subjects were treated for median of 56 weeks (max. 76 weeks) They searched the database for symptoms of fat redistribution and retinoid like symptoms (dry skin, xerostomia,, taste disorders, hair or nail problems). They found 3% incidence of fat distribution in APV regimen and 11% in the IDV arm. Retinoid-like symptoms in APV arm: Dry Skin 7(3%), Xerostomia 3(1%), Taste Disorders 4(2%), Hair loss/alopecia 1(<1%); in the IDV arm: Dry Skin 34(14%)Xerostomia 22(9%), Taste Disorders 20(8%), Hair loss/alopecia 16(7%).

Several researchers have said that they feel this syndrome may be divided into distinct entities. For example, fat depletion in the periphery may result from different causation than fat accumulation. Possibly fat redistribution is more related to NRTIs and elevated lipids more related to PIs. Nonetheless, it appears to me that these suggestions are merely that--suggestions. Again, I think clinical research will lead us to these confusing and discrepant results. There are too many confounding factors in these studies, which prevents drawing conclusions.

There were two reports about the development of osteopenia. One study found 21% of those taking a protease inhibitor regimen had severe osteoporosis compared with 6% among controls. The authors concluded that their study suggests that body fat redistribution does not lead to osteporosis but that HAART does. In the second study 80 patients with lipodystrophy (defined by total body fat <20% on DEXA scanning) and suppressed viremia (viral load <400 copies/ml) enrolled in the PIILR study. Patients were randomized to switch to evidence of osteopenia at baseline, and a further 7 (9.5%) had osteoporosis. There was no change in the proportion of individuals with osteopenia, over 24 weeks. But its possible 24 weeks may be too soon to see changes.
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Incidence of Lipodystrophy in Patients with Primary HIV-1 Infection (PHI) Treated with HAART (6 of 14 patients had lipodystrophy by 18 months)

J Miro and others from Barcelona reported on the development of lipoodystrophy following treatment during acute infection with HAART. There is little information on the incidence of lipodystrophy in patients with PHI treated with triple therapy regimen including a protease inhibitor (HAART).

The objective of this study was to describe the incidence of fat redistribution and metabolic abnormalities in 17 consecutive patients diagnosed with PHI (May 1997-January 1999) who started HAART within 90 days after onset of symptoms (N=14) or seroconversion (N=3) and received more than 6 months of treatment.

Patients with PHI were treated with stavudine (d4T, 30-40 mg bid), lamivudine (3TC, 150 mg bid) and indinavir (IDV, 800 mg tid). Clinical and biological (glucose, cholesterol, triglycerides) follow-up was performed every 3 months including the determination of T-cell subsets and plasma HIV viral load (VL)(Amplicor" Roche). Clinical lipodystrophy was accepted if patients had loss of peripheral fat (limbs, buttocks, face) and/or increase of central fat (abdomen, neck, chest).

14 patients were male and 3 female. Mean age was 36 year (25-50). HIV-1 risk factors were homosexuality in 12 cases, heterosexuality in 4 and i.v. drug abuse in 1. Median follow-up was 20 months (7-28). In two cases (at 6 and 12 months) HAART needed to be changed because of virological failure, being d4T, ddI, nevirapine and nelfinavir the new regimen for both patients. In three patients nelfinavir (2) or nevirapine (1) was substituted for indinavir due to recurrent nephrolithiasis.

After a median of 18 months (6-24), RNA HIV-1 viral load in plasma was <200 copies/mL and <20 copies/mL in 100% and 75% of patients respectively. Six patients (35%) developed lipodystrophy (4 men and 2 women, one with subcutaneous fat nodules). The incidence at 6 (N=17), 12 (N=14), 18 (N=10) and 24 (N=7) months was 6%, 14%, 40% and 57% respectively. No patient had impaired fasting glucose. Cholesterol > 240 mg/dL was detected in 6 cases (33%). Triglyceridemia > 200 mg/dL was seen in 9 cases (53%) being the levels moderate (200-400 mg/dL) and high (>400 mg/dL) in 5 and 4 cases respectively. Nevirapine (3) or efavirenz (1) was substituted for the protease inhibitor in four out of 6 patients with lipodystrophy.

The authors concluded that the incidence of lipodystrophy, hipercholesterolemia and hipertriglyceridemia was high in patients with PHI treated with this antiretroviral regimen. These findings should be taking into account in order to decide whether is necessary to initiate HAART in all patients soon after the PHI.
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A Randomized, Multicenter Study of Protease Inhibitor (PI) Substitution in Aviremic Patients with Antiretroviral (ARV) Lipodystrophy Syndrome.

Carr and Cooper from Australia reported on this study in whivh 80 PI recipients with lipodystrophy syndrome (LDS), no prior abacavir (ABV), NNRTI or adefovir (ADV), and plasma HIV RNA <400 copies/ml for 6 mths were randomized 2:3 to continue current therapy (n=31) or to continue nucleoside analogues and substitute PI(s) with abacavir (ABC), nevirapine (NVP), adefovir and hydroxyurea (HU) for 24 wks (n=49). Primary endpoints were HIV RNA and body composition (questionnaire, physical exam, DEXA, abdo L4 CT). Other assessments were safety, adverse events, biochemical, lipid and glycaemic parameters and CD4 counts.

The mean baseline CD4 count was 450 cells/ml, and all but 2 patients were male. At week 24, 3 (6%) switch pts (vs 6 [19%] PI pts) had HIV RNA >50 copies/ml (p=0.14), despite adverse event-induced cessation of adefovir (ADV) (n=12), HU (n=8), ABV (n=3) and NVP (n=2) for mainly PRTD (ADV, n=8), nausea (HU, n=4) and hypersensitivity (ABV/NVP, n=3). CD4 counts fell a mean 70 cells/ml (p=0.002) in the switch group but there was no new AIDS condition in either group. One PI patient suffered a myocardial infarction. Central fat declined more in the switch group (1.1 vs 0.2 kg; p=0.049) as did total muscle mass. Switch patients, however, rated overall (p=0.008), central (p=0.001) and peripheral LD (p=0.07) as less severe at wk 24 than PI pts. Triglyceride, and total and LDL cholesterol, fell significantly (all p=0.001) in the switch group but C-peptide, insulin, insulin resistance (HOMA) and HDL cholesterol did not change.

The authors concluded PI(s) cessation and substitution with ABV/NVP/ADV/HU in heavily ARV-pretreated LDS patients maintained HIV RNA suppression, despite numerous switch drug adverse event-induced cessations. Switching led to reduced central fat and improvement of some lipid parameters, but decline in peripheral fat and overall muscle mass.