Perspectives on hormonal, mitochondrial and metabolic changes

1 December 2002. Related: Side effects, Lipodystrophy and metabolic complications.

Mike Youle MD, for NATAP

The great white charger against lipid and metabolic abnormalities has to be atazanavir since all the studies to date have suggested this agent to have little of the negative profile that other protease inhibitors have.

It remains to be seen how the lipodystrophy story pans out since no controlled data on this agent compared to others has yet been presented. At lot of the data that came out of the 42nd ICAAC Meeting in San Diego in September has had previous airings notably at the Lipodystrophy Workshop held during the previous week. However some new information made its way into the Monday poster session.

Work by a Spanish group built on earlier data that suggested that around 13% of HIV patients have some thyroid dysfunction. [1] In 202 subjects prospective assessments of thyroxine (FreeT4) the hormone that controls energy levels were performed as well as the hormone TSH that stimulates production [2].

There was tight correlation of T4 with CD4 count with abnormally low levels in 1.3% of subjects. Higher levels were associated with a lack of an AIDS diagnosis and in subjects without concurrent hepatitis with the TSH level also being predictive of the Free T4 levels. In addition further data supported the higher rate of dysfunction when Calza and co-workers assessed 84 subjects (49 on HAART) [3]. In the HAART treated individuals 12.2% had low FreeT4 whilst none of the treatment naïve subjects did (p27 months), although reports have previously been made of hypothyroidism with efavirenz.

Another hormone that is poorly monitored in patients with HIV by many units and irregularly replaced is testosterone. Cohan and his group at Pacific Oaks in Los Angeles looked at the efficacy and utility of Androgel, a topical testosterone product in 30 hypogonadal subjects who were stable on intra-muscular injections of testosterone cypionate [4].

After eight weeks of topical therapy quality of life assessments showed a 10% improvement in physical and emotional well being as well as more stable serum levels of testosterone as well as greater patient acceptability.

Continuing on the hormonal trail, two abstracts further evaluated the aspects of human growth hormone (HGH) in childhood development and HIV related lipodystrophy. Ezeanolue and colleagues described three African-American children in whom growth failure was identified, two HIV+ and one HIV- [5]. They also had HGH deficiency and ILGF-1 levels below normal, an uncommon condition.

On MRI their pituitary glands were small but with exogenous HGH they have regained their growth curves. The authors mused on the link between this phenomenon and the exposure to nucleoside analogues since their mothers had all been exposed to AZT during pregnancy. Moyle reported the effect of maintenance low-dose alternate day therapy with HGH used to treat lipodystrophy in 12 subjects who were given 4mg/kg daily for 12 weeks followed by a blinded phase of placebo, alternate day or twice weekly 1mg/kg doses [6].

The sustained responses over 12 weeks of higher dose were lost on placebo and both fat free mass and visceral adipose tissue gains were maintained on the alternate day dosing.

NewFill is a physical intervention involving injections of polylactic acid into the face to correct areas of subcutaneous fat loss [7]. Developed in France it has gained popularity in Europe but has been effectively banned in the USA, a source of some consternation. In a small study of this approach 30 patients were randomised to immediate injections or delayed treatment. Self-perception, visual analogue scores of self assessed appearance and standard depression tools all showed a benefit for the immediate treatment group, which was sustained through 24 weeks. This further confirmed previous work from France on the acceptability of this intervention for facial wasting.

Thromboembolic complications are one of the least understood adverse events in HIV. It has become increasingly obvious that clotting disorders, such as protein S deficiency and embolic events, especially deep-vein thromboses are common in HIV disease, and not all attributable to long flights across the Atlantic. In one study presented, 25 subjects without haemophilia and on PI based regimens were assessed for a wide range of markers of coagulation [8]. Contrary to published reports these subjects showed increases in circulating anticoagulants although the thrombin time was significantly reduced after one month (p<0.05). Many of those with reported episodes have been on nucleoside analogues for a long period so further studies where the classes are distinguished may add to the knowledge base concerning these problems.

Conflicts in findings in mitochondrial studies

There were a few further titbits of data on mitochondrial changes occurring under different treatment regimens. McComsy and her co-workers presented a Phase IV open-label switch study from stavudine (d4T, Zerit) to zidovudine (ZDV, AZT, Retrovir) or abacavir (ABC, Ziagen) (if zidovudine experienced), the TARHEEL trial [9]. One hundred and eighteen subjects were enrolled of whom 86 switched to abacavir. Using DEXA whole body scans and single slice CT scans both increased limb fat (35% in the arms and 12% in the legs) as well as a slight reduction in visceral fat (2%) with an improvement in truncal subcutaneous fat of 4% (p<0.001).

Viral suppression was reasonably well maintained with 87% <50 copies/mL by week 48. Sixteen subjects had elevated lactate at baseline, which normalised (10 subjects had a treatment interruption before achieving this). The study appears to reinforce the advantage of switching away from stavudine for safety reasons. A sub-study assessed mitochondrial DNA (mtDNA) levels in 14 subjects who switched to abacavir and two who changed to zidovudine [10]. Both in muscle and fat, mtDNA content improved toward normal levels over the duration of the study in parallel with fat increases. No genomic deletions or rearrangements were noted in this small study.

Miura for the University of Tokyo in Japan also undertook a study of mtDNA content in 288 samples extracted from PBMCs (blood cells, not fat tissue) taken from 46 HIV positive individuals, 13 of whom were currently not on antiretrovirals and compared them with 11 healthy volunteers. MtDNA content was reduced in untreated HIV positives compared to controls (p=0.0012 and had a positive inverse correlation with T4 count (p=0.028) and a negative one with viral load (p=0.017).

In the subjects who had remained untreated throughout, their mtDNA levels did not change but in those who had commenced therapy with various regimens which contained dual nucleoside analogues (mainly AZT/3TC or d4T/3TC) there was consistent rise in mtDNA levels towards those of the control subjects. The subjects who received AZT/ddC showed a further decline.

This study suggests that there may be conflicting alterations in mitochondrial function under antiretroviral therapy with an improvement mediated by increase in immune function which then is abrogated perhaps by a direct effect of the therapy on mitochondrial enzymes. Clearly much more work needs to be done, both in the laboratory and the clinic and conclusions should not be made in haste.

Source: www.natap.org

References:

1. Grappin M, Piroth L, Verges B et al. Increased prevalence of subclinical hypothyroidism in HIV patients treated with highly active antiretroviral therapy. AIDS 2000 May 26;14(8):1070-2.
   http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd= Retrieve&db=PubMed&list_uids=10853996
2. J. Collazos, S. Ibarra, J. Mayo. Relationship between CD4 Cell Counts and Free Thyroxine (FT4) in Clinically Stable HIV-infected Patients. Abstract H-1910
3. L. Calza, R. Manfredi, F. Chiodo. Subclinical Hypothyroidism Associated with Highly Active Antiretroviral Therapy in HIV-Infected Patients. Abstract H-1911
4. G. R. Cohan, P. R. Wolfe, P. G. Anderson. A Prospective Study of the Safety and Efficacy of a Topical Transdermal Testosterone Gel versus Intramuscular Injections of Testosterone for the Treatment of Testosterone Deficiency in Male HIV-Infected Patients Abstract H-1912
5. E. Ezeanolue, S. L. Hardy, G. Nunlee-Bland et al. Growth Hormone Deficiency in Children with Perinatally Acquired Human Immunodeficiency Virus Infection Abstract H-1913
6. G. Moyle, C. Bldwin, B. Langroudi et al. Growth Hormone Improves Appearance and Lean Mass in Lipoatrophic Patients and These Benefits are Maintained with Alternate Day Dosing Abstract H-1935
7. G. Moyle, L. Lysakova, S. Brown et al. Polylactate (NewFill) Injections Subjectively and Objectively Improve Appearance and Reduce Anxiety and Depression Scores in HIV Positive Persons with Facial Lipoatrophy: A Randomised, Open Label, Immediate vs. Delayed Therapy Study. Abstract H-1934
8. R. Mercier, H. Wright, L. Nadeau et al. Association Between Protease Inhibitors (PIs) and Thromboembolic Complications in HIV-Infected Patients Abstract H-1937
9. G. McComsey, D. Ward, S. Hessenthaler et al. CT Scan Findings at 48-wks Confirm Further Regression of Lipoatrophy (LA) Following the Substitution of Stavudine (d4T) with Either Abacavir (ABC) or Zidovudine (ZDV). Abstract H-1929
10. G. McComsey, D. Paulsen, T. Lonergan et al. Improvements in Mitochondrial (mt) DNA Levels After Substituting ABC or ZDV for d4T in HIV-Infected Patients with Lipoatrophy (LA) Abstract H-1930

All abstracts are from the Poster Session on Metabolic and Other Complications of HIV Disease at the 42nd ICAAC meeting, San Diego, September 2002.