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Joseph Cofrancesco, Jr., M.D., M.P.H.
01-11-2010
- No specific data from Zambia, but with extensive past use of d4T and AZT, expected pattern of lipoatrophy > fat accumulation.
- Study 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.
- Lipodystrophy is one of most common reasons for switching from a d4T-based regimen.
- 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. Switching to AZT leads to continued fat loss and progressive lipoatrophy.
Zambia Information Author: David Riedel, M.D.
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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
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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." Increasing data suggest that FA may not be as prevalent, with some changes due to normal aging and obesity.
- Both LA and FA can be associated with hyperlipidemia and/or insulin resistance.
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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.
- FA 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.
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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.
- ACTG 5142 found that in subjects using either AZT or d4T, LA more common with EFV than LPV/r.
- In clinical practice, pt history and PE most commonly used.
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LA: Close examination of extremities, buttock and subcutaneous tissue of abdomen. Old photographs may be helpful. DEXA scans used for research purposes.
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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 affect a number of metabolic parameters and lead to higher TG, worsening lipids and insulin resistance
- Prevention and early detection are key
- Medical treatment is controversial. Studies focus on pts with established and often severe changes; prevention or intervention at earlier stages may yield better results.
- Address insulin resistance if present: consider metformin (500 mg once-daily -1000 mg twice-daily); magnitude of effect on FA variable. Studies inconclusive and may lead to worsening of LA. Metformin not approved for HIV-associated FA .
- Exercise: min. 1 hr resistance training and aerobic exercise TIW, general weight reduction can sometimes help, but watch for further LA.
- Studies changing ART, including eliminating PIs,have failed to demonstrate significant impact on FA. There may be less FA with ATV especially if insulin resistant, although data not conclusive.
- Recombinant human growth hormone (rhGH): (optimal dose/dosing schedule unclear, max: 0.1 mg/kg/d or 6 mg/d; range 3-6 mg once-daily or every other day) if no insulin resistance and no lipoatrophy. Multiple side effects including insulin resistance & fluid retention, and very costly. Not approved for use in HIV-associated FA . Changes reverse after cessation of rhGH.
- Growth hormone releasing hormone (investigational). Restores normal GH levels. Studies show promising results, somewhat less than rhGH, but without worsening LA or glucose parameters.; 1- 2 mg subcutaneously, daily. Changes likely to reverse after cessation.
- 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.
- Prevention is critical. For LA, avoid thymidine analogs and possibly ddI, with preferential use of TDF or ABC.
- 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 for LA. See Toxicity & side effects: switching therapy.
- Some studies suggest that switching from thymide analogs (esp. AZT) less effective if done after 3 years of exposure.
- Thiazoledinediones: mixed results with rosiglitazone. Some promise with pioglitazone based on small studies. Rosiglitazone may raise TG. This class not approved for HIV-associated LA in the US.
- Uridine: preliminary results promising for those remaining on thymidine analog
- Dermatologic/plastic surgery: "face fillers" classified as temporary or permanent. Many are used "off label." Undesirable side effects, including granulomas, migration, and lumpiness, can depend on purity of compound and skill of provider. Require multiple visits with high cost, generally not covered by insurance. Best results often seen with combination of techniques. Better results with milder LA. Polylactic acid (Sculptra) al and calcium hydroxylapatite (Radiesse) approved in US for HIV-associated facial LA. Permanent fillers can sag if LA progresses.
| Drug | Recommendations/Comments |
| Thymidine Analogs | LA most strongly associated with use of d4T, and to a somewhat lesser degree AZT (possibly ddI). Avoiding these drugs or switch to ABC or TDF in pts with LA. Act early when LA is mild, before it progresses. Consider restorative dermatologic or surgical procedures if affordable. |
| rosiglitazone/pioglitazone | May be useful for pts with LA who also have insulin resistance, though data disappointing. |
| metformin | May be be useful for pts with FA who also have insulin resistance but watch for worsening LA. |
| 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. |
| Growth hormone releasing hormone | May be useful for FA , appears not to worsen LA but results less dramatic than with GH. |
| Uridine | Early results promising, but only for those still on thymidine analogs |
- 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 supplements unproven.
- Given decreased use of thymidine analogs, LA becoming less common.
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