However, even though it is not life-threatening, the side effect that, in seems to generate the most scare-mongering is lipoatrophy, the loss of fat on the arms, legs, buttocks and face (facial wasting).
“I have had women who have stopped their treatment because of it,” said Dr Francesca Conradie of Helen Joseph Hospital in Johannesburg South Africa. “We have 4000 patients our programme and are enrolling two women for each one man. d4T is in our first line. With the program being 20 months old, we are seeing more and more lipoatrophy. It is disfiguring.”
The causes of fat loss during antiretroviral treatment are still not fully understood, but analysis of clinical trials shows that two drugs, d4T (stavudine) and AZT (zidovudine) are strongly associated with the syndrome. These two drugs damage fat cells by inhibiting a component of the DNA of mitochondria, small bodies within human cells that generate energy for the cell’s everyday processes. Other toxicities of the two drugs, such as peripheral neuropathy, are also due to mitochondrial damage.
However, not everyone who is treated with these drugs will experience fat loss or other mitochondrial toxicities. Other factors seem to increase the risk of fat loss when treated with AZT or d4T:
- High triglyceride or cholesterol levels before starting treatment
- Large increase in triglycerides within the first two months of treatment
- Older age (above 40)
- Hepatitis C coinfection
- AIDS diagnosis
- Use of AZT or d4T in combination with a protease inhibitor
However an analysis of one study, ACTG 384, presented last November at an international workshop on lipodystrophy (see http://www.aidsmap.com/en/news/3B58DF3A-E1A1-447D-A18F-6ADFD17C2B6A.asp), found that drug effects were more important than any other previously identified risk factors, and that a low CD4 cell count before starting treatment did not increase the risk of fat loss.
How frequently does it occur?
Surprisingly few prospective studies have been able to come up with reliable observations on the proportion of people who develop lipodystrophy after exposure to specific drugs. Cross-sectional studies (studies which take a snapshot of people at one specific point in time) have come up with estimates as high as 30-40%, but the more reliable prospective studies, which follow people over a number of years show a lower prevalence.
A cross-sectional study in India, for example, showed that 26% of d4T-treated patients and 10% of AZT-treated patients had developed lipodystrophy after median of 18 months of treatment with triple therapy that also included nevirapine and 3TC (Pujari 2005) (see http://www.aidsmap.com/en/news/B15C0D05-95D8-42BF-ABEF-E51EF79E10BE.asp)
In the Gilead 903 study, which compared two backbones (d4T/3TC vs tenofovir/3TC) in combination with efavirenz, 12% of the d4T-treated group had developed some degree of fat loss after two years of treatment in the opinion of their doctor, compared with less than 1% of the tenofovir group.
In the ACTG 384 study which compared backbones of AZT/3TC or d4T/ddI combined with either nelfinavir or efavirenz, a 102 person substudy of patients evenly distributed between the two nucleoside backbones found that aftyer 64 weeks on treatment, 44 of the d4T group had developed lipoatrophy, compared with 17 in the AZT group, a highly significant difference (P=0.006)
Subsequent studies have tended to observe the development of lipodystrophy by measuring limb fat levels with a test called a DEXA scan, because this is a more objective measure, and plot the degree of fat loss in each treatment group rather than the proportion of patients who experience fat loss. This method is able to pick up more subtle differences and removes observer bias.
In the Gilead 934 study, which compared AZT/3TC with tenofovir/FTC, limb fat levels remained stable over 96 weeks of follow-up in those who received tenofovir, but fell significantly in those who received AZT (see http://www.aidsmap.com/en/news/CC754D1C-9F1C-4A59-B32C-8D6D450B7EAA.asp ).
Several members of HATIP advisory panel reported lipoatrophy in their patients, but it is difficult to say whether there are differences by region or ethnicity. According to Dr Gerald van Osch, who practices on the Caribbean island of St. Maarten, which has a mixed, multi-ethnic population, “Yes I’m seeing lipoatrophy rather frequently in a mix of black and white patients. I have no percentages available, but roughly 5 – 10 % seems a reasonable guess.”
How quickly does it occur?
Some treatment programmes tell us that they are seeing very little lipoatrophy in patients yet. At present it’s not clear whether there may a be a genetic differences between Africans, Asians and Europeans, or even between one ethnic group and another within the same country, that means lipodystrophy will occur at different rates, or whether it’s too early to tell. [Given that we don’t know what genetic difference we are looking for, it seems rather premature to think in terms of races... however those are defined].
Several well-designed studies have found that people will typically gain body fat during the first six months of treatment, and thereafter lose fat from the limbs at a rate of around 13% of total limb fat per year (Mallon 2003; Lichtenstein 2002). However total body weight may remain relatively stable, because limb fat makes up a small proportion of the total body mass. Unfortunately the loss of limb fat and facial fat is highly noticeable, and creates an appearance that most people would identify as sick.
Fat can also accumulate in the abdomen, around the organs, leading to the appearance of a swollen belly. The accumulation of fat in the organs is not a redistribution of fat from the limbs; the processes of fat loss and fat gain in HIV lipodystrophy seem to occur by separate mechanisms (http://www.medscape.com/viewarticle/443352).
How do the patients react?
Our advisory panel reported markedly different reactions to lipoatrophy among their patients — but then they serve very different populations. Some, such as the women at Dr Conradie’s hospital in Johannesburg, are so distressed that they discontinue treatment, and this is similar to reports we’ve heard from Khayelitsha in the Western Cape.
Dr Dawood, however, practising in KwaZulu Natal says “it does not appear to worry the patients tremendously, especially after I explain that it is a side effect of the drugs and which drug causes it. I also try and counsel the patients from early on, on what to expect.” But she notes, “the main problem seems to be the comments from friends and people at work.”
According to Dr van Osch, “Only a few in our clinic are actually bringing up the lipoatrophy problem themselves. Most don’t mention it or even when I mention it to the patients they say it’s not that much of a problem. Apparently there is less of a cosmetic pressure in our multi-cultural society (Caribbean, St. Maarten) compared to many Western countries.”
“It is not an issue that prevents people to go on treatment. Patients in general are way too happy to be able to receive treatment. They hardly worry with side-effects. They see it as a task for the doctor to deal with.”
Reactions clearly are different from one culture to another — and much of this may be amplified where there is a fear of Western medicine, or even the medical practice or pharmaceutical products. In Indonesia, Green noted, “Fear of side effects in general, including this, but more specifically Stevens Johnson Syndrome from nevirapine sometimes does impact people’s willingness to go on or continue treatment, particularly (for unclear reasons) in Bali. I suspect lipoatrophy may impact more as the problem becomes more widespread in a year or two.”
He also noted though that Indonesians as well, may not be as worried about physical appearance as some risk groups in Western countries are. “The aging process occurs rapidly in Indonesia,” he said “usually starting around age 30, and maybe lipoatrophy will be seen as just another sign of this?”
How can it be avoided?
Lipoatrophy is best avoided by using tenofovir or abacavir rather than stavudine or zidovudine. British and US treatment guidelines now recommend that stavudine and zidovudine should be avoided.
“I think that putting tenofovir in the first line would solve many of our problems,” said Dr Conradie. Dr Dawood agrees, adding that “tenofovir should also be first line because of lactic acidosis.”
However that’s easier said than done in most resource-limited settings where AZT and d4T form the mainstay of cheap fixed dose combinations. Progress towards cheaper fixed dose combinations that include tenofovir or abacavir is slow.
Indeed tenofovir, manufactured by Gilead, is only registered in six countries, despite the fact that the drug is now being offered at $357 and Truvada at $296 to least-developed countries and most countries in Latin America and the Caribbean. In South Africa both products are licensed by Aspen Pharmacare, but neither product is yet registered in South Africa.
Despite a recent announcement by the Clinton Foundation of a reduced price for generic abacavir, the price ceiling has been set at $440, which suggests that driving that price down will require massive increases in volume and further competition between manufacturers.
So moving towards the use of combinations that do not cause fat loss would more than double the cost of ART.
In the meantime the only treatment proven to reverse fat loss in a small preliminary study, a food supplement called Nucleomaxx, costs around 700 euros a month, considerably more than the cost of triple drug ART. http://www.aidsmap.com/en/news/104869B7-DFA8-4768-ADB5-DD00A4DB77F3.asp
How to manage patients in the meantime
Several of our panel members suggested changing treatments, “ I agree with the dump d4T campaign,” said Dr Conradie. Dr van Osch has the option of switching patients to tenofovir, but in South Africa, the best Dr Conradie can do is “change them to AZT as soon as we see it.”
Everyone agreed on the importance of counselling. Dr Dawood describes the lipoatrophy upfront. “ I tell them that the drugs may cause changes in body shape eg. the veins on the leg may start showing, the cheeks on the face may get thinner and the back of the neck may develop a fat pad.”
Chris Green told us: “We do refer to it in our briefings/trainings to peer educators, but try not to over-emphasise it. We note that while at this time there is no clear treatment for lipoatrophy, there is much research going on to determine the cause as well as identify solutions, which may become available before it becomes a problem for them.”
Meanwhile, Dr van Osch spreads his warnings out over time “Usually I only discuss the short term side-effects with them, depending on the combination prescribed — the side-effects they have to recognise and which we can treat or make more bearable. The long term side-effects I discuss later and bit by bit.”
“I think it’s important for persons to know what the obstacles are, but at the same time I don’t think it makes sense to delve them under a load of all the possible side-effects right at the beginning of the treatment. Patients in our region tend to take life and their disease day by day, and step by step, so I tend to go along with that approach as far as education concerned.”
It also depends on the relationship you have with each patient. The appropriate approach will of course vary by culture and by patient. For Dr van Osch, each patient typically comes from a different culture. “On our island we deal with many different cultures, races, literacy levels and socio-economic levels (last census count 105 different countries represented on our island), which makes it even more interesting but also sometimes challenging to deal with the different ways people deal with their infection/treatment.”
“Some are very interested in all the aspects of treatment and you discuss it broadly with them. Many are still stuck in a very dependent doctor-patient relationship and only slowly can you educate them on their own responsibilities for their health and treatment. Others are really not interested or due to education/literacy challenges just don’t always understand.
In HIV treatment when a person comes in with a CD4 of 3 – 10, an opportunistic infection and a viral load of over 300,000 you sometimes just don’t have the time to sit and discuss all the risks. This doesn’t mean you will never discuss these issues with them, but rather discuss the most important issues first and take the rest as it comes.”