The researchers who originally linked HIV-associated body fat abnormalities to protease inhibitors now believe that nucleoside analogues or NRTIs (AZT, d4T, 3TC, ddI, ddC, abacavir) play an important role in the lipodystrophy syndrome.
Speaking at the Annual Conference of the Australasian Society for HIV Medicine (ASHM), researchers from the National Centre for HIV Epidemiology and Clinical Research in Sydney reported that fat wasting and abdominal fat accumulation are associated with NRTIs.
Earlier this year, Dr Kees Brinkman proposed that NRTIs may damage the DNA contained within cell structures known as mitochondria, producing elevations in lactate and a range of side-effects including wasting and peripheral neuropathy. Mitochondria exist within cells and play a crucial role in the body’s energy production and metabolism.
Recent findings by the Australian team support Brinkman’s theory. Researcher John Miller presented a study of 14 patients who had never taken protease inhibitors (PIs). These individuals reported wasting with or without a swollen belly, plus the recent onset of fatigue and nausea after an average of 61 months on treatment with NRTIs. The group was compared with treatment-naive, HIV-infected individuals and others on protease inhibitor therapy with or without wasting.
The Australian team suggested that the physical signs of the NRTI-associated syndrome are indistinguishable from PI-related lipodystrophy. However, when NRTIs are the culprit, laboratory markers such as lactate, C-peptide and ALTs are elevated while cholesterol, triglycerides, glucose and insulin levels are lower.
Ten of the 14 men ceased all treatment having lost an average of six kilograms. Symptoms such as nausea and fatigue resolved, and after four months follow-up the average weight gain was 2.5 kg.
The National Centre team have concluded that an NRTI-associated syndrome of wasting, lactic acidemia and liver dysfunction may occur among HIV-infected individuals on treatment. However, Dr Fraser Drummond from the Albion Street Centre in Sydney reported that elevated lactate levels were not associated with lipodystrophy although only a handful of individuals in this study had experienced body fat changes.
No-one knows why some people develop NRTI-related side-effects while others remain unaffected. The study presented by John Miller found that older age, increased CD4 count, current treatment with d4T, and duration of treatment were associated with a greater risk of these side-effects.
Switching study disaster
Further disappointing results were presented to the ASHM meeting by Dr Andrew Carr. Preliminary data from the PILR study suggests that switching from a PI regimen may not improve lipodystrophy. In fact, fat loss was greater among men who switched from a PI-based regimen to abacavir/adefovir/nevirapine/hydroxyurea, compared with those who continued their PI-regimen.
The PILR study enrolled 80 men taking a PI regimen who had developed lipodystrophy. All had viral loads below 400 copies for at least six months and over five years experience of anti-HIV treatment. Average baseline CD4 count was approximately 450. 60% were randomised to switch to the non-PI regimen.
At six months, the men who switched had an average CD4 decline of 70, possibly associated with the use of hydroxyurea. The switch group also lost more fat and lean mass than the control group. On a more positive note, central fat accumulation, lipids and glucose intolerance did decline in the switch group.
It is not understood why fat and muscle loss was greater in the switch group. Clearly the study points to NRTI-associated wasting, and the possibility that the experimental drugs adefovir and/or hydroxyurea may have exacerbated mitochondrial toxicity in these individuals.
Prevalence
The sobering news continued with a report that 40% of 1,337 HIV-infected Australians have moderate to severe peripheral fat loss and wasting. Furthermore, 21 of 41 individuals treated during primary HIV infection reported signs of body fat changes after 12 months of therapy. While these studies may not give an accurate picture of prevalence, due to the possibility that people with body fat changes may be more likely to participate in such studies, they do indicate that significant numbers of HIV-infected people are affected by body fat abnormalities.
References
For more details, see Body fat and metabolic changes whilst on treatment and Lactic acidosis.
Eleventh Annual Conference of the Australasian Society for HIV Medicine, Perth, 9-11th December, 1999. Abstracts IN52, OR104, PR105, OR119, OR120, OR121, OR122, OR123.
Brinkman K et al. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 354(9184):1112-1115, 1999b