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 Guide Editors
 Editor In Chief
    Joel E. Gallant, MD, MPH

Pharmacology Editor
    Paul Pham, PharmD, BCPS

Zambia Guideline Team
   Peter Mwaba MMed PhD FRCP
   Alywn Mwinga MMed
   Isaac Zulu MMed MPH
   Velepie Mtonga MMed
   Albert Mwango MBChB
   Jabbin Mulwanda MMed FCS
 

 

 

Diagnosis>Complications of Therapy>
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Lipodystrophy

Joseph Cofrancesco, Jr., M.D., M.P.H.
02-13-2008

Zambia Specific Information

  • No specific data from Zambia, but with extensive past use of d4T , expected pattern of lipoatrophy > fat accumulation.
  • S tudy from Rwanda found lipodystrophy in ~1/3 of pts on ART (90% on d4T-based regimens): ~10% had isolated lipoatrophy, ~5% had isolated lipohypertrophy, ~20% had mixed patterns.
  • Careful assessment needed to distinguish lipoatrophy from general wasting and/or malnutrition to prevent unnecessary modifications of therapy.
  • National guidelines recommend switching patients with signs of toxicity on d4T -based regimen (but not clinical failure) to 1st-line regimen backbone of TDF/FTC.

REFERENCES

Zambia Information Author: David Riedel, M.D.

CLINICAL

  • Lipoatrophy (LA): fat loss in face, proximal extremities (LE>UE), buttocks and subcutaneous tissue throughout body, including subcutaneous abdominal fat. Must be differentiated from wasting, a consequence of HIV disease progression and/or OIs involving loss of muscle and fat. Lipoatrophy associated with use of HAART, especially thymidine analog NRTIs. 
  • Fat accumulation (FA): neck/ dorsocervical fat pad, visceral abdomen, lipomas, breasts. Pts with FA may also have LA, but they are not necessarily part of same "syndrome." 
  • Both LA and FA can be associated with hyperlipidemia and/or insulin resistance.
  • LA : associated with mitochondrial toxicity due to thymidine analog use (d4T>AZT), generally occurring after 2-4 yrs of use. Not associated with use of TDF or ABC. Role of ddI unclear, as most ddI use has been with AZT or d4T, but causes mitochondrial toxicity in vitro.
  • Fat accumulation must be differentiated from normal increase in weight often seen with control of HIV. Before HAART, pts are often underweight, have higher metabolism and need more calories. With VL suppression, these parameters normalize and pt can gain weight without exercise and diet.
  • FA: multifactorial, complex and increasingly controversial. Risk factors may include: (a) Host factors: age >40, gender, baseline body composition, race/ethnicity, and genetics; (b) Disease factors: CD4 nadir, more severe/longer duration of disease, degree of immune reconstitution and (c) Medication factors: duration of ART and more common with PI use, associated with insulin resistance.

DIAGNOSIS

  • In clinical practice, pt history and PE most commonly used.
  • LA: Close examination of extremities, buttock and subcutaneous tissue of abdomen Old photographs may be helpful. DEXA scans used for research purposes.
  • FA: may be difficult to differentiate from "usual" obesity. Waist measurement, or waist/hip ratio may be helpful. Examine dorsocervical area and abdominal area, with close attention to distension/visceral fat accumulation (as opposed to subcutaneous fat accumulation). In some cases, CT or MRI used to detect intra-abdominal fat, but mostly used as research tool. 
  • Change over time important, but allow for normal changes associated with aging
  • Fat changes themselves, either fat loss or fat gain, can impact a number of metabolic parameters and lead to higher TG, worsening lipids and insulin resistance

TREATMENT

General

  • Controversial issue. Studies focus on pts with established and often severe changes; prevention or intervention at earlier stages may yield better results.
Fat accumulation

  • Address insulin resistance if present: consider metformin (500 mg qd -1000 mg bid); magnitude of effect on FA variable. Studies inconclusive and may lead to worsening of LA.
  • Exercise: min. 1 hr resistance training and aerobic exercise TIW, general weight reduction can sometimes help
  • Recombinant human growth hormone (rhGH): (optimal dose/dosing schedule unclear, max: 0.1 mg/kg/d or 6 mg/d; range 3-6 mg qd to qod) if no insulin resistance and no lipoatrophy. Multiple side effects including insulin resistance & fluid retention, and very costly.
  • Consider change in ART: eliminate PIs if safe; if not possible consider change to ATV or possibly FPV, especially if insulin resistant, although data not conclusive.
  • Liposuction (U/S-guided) for dorsocervical fat accumulation. Fat recurs in some studies.
  • For gynecomastia, ensure is breast tissue not tumor, consider workup for hypogonadism.
Lipoatrophy

  • Early detection and change of ARTs (eliminate d4T and  AZT, possibly ddI) to avoid further progression and to allow restoration of subcutaneous fat. TDF, ABC, 3TC, FTC felt to be safe. See Toxicity & side effects: switching therapy.
  • Thiazoledinediones: mixed results with rosiglitazone: mixed results. Some promise with pioglitazone based on preliminary data.
  • Uridine: preliminary results promising.
  •  Dermatologic/plastic surgery: "face fillers" classified as temporary or permanent. Most are used "off label." Undesirable side effects include granulomas, migration, and lumpiness. Purity of compound and skill of provider critical. Require multiple visits with high cost, generally not covered by insurance. Best results often seen with combination of techniques and with earlier LA. Polylactic acid (Sculptra) now approved in U.S. for facial LA; other fillers often used

Drug Comments

DrugRecommendations/Comments
Thymidine Analogs LA most strongly associated with use of d4T, and to a lesser degree AZT (possible ddI). Avoiding these drugs, or substitution with ABC or TDF in pts with LA. Act early when LA is mild, before it progresses
growth Hormone, human May be useful for pts with FA who do not have insulin resistance. May worsen LA. Has multiple side effects and not generally covered by insurance for this indication.
metformin May be be useful for pts with FA who also have insulin resistance but watch for worsening LA.
rosiglitazone/pioglitazoneMay be useful for pts with LA who also have insulin resistance and fat loss, though data disappointing.
Uridine Premature to offer opinion, but early results promising

OTHER INFORMATION

  • Lipodystrophy is major concern for pts. Changes in appearance can negatively affect mood, functional status, self image, and adherence.
  • Suppression of HIV replication is primary objective, but best treatment for LD is prevention, by selecting ARTs carefully, noticing changes early and treating associated metabolic alterations.
  • Use of vitamin and nutrients unproven.

REFERENCES

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