This clinical review is kindly supported by the Diana, Princess of Wales Memorial Fund.

• Studies support the direct link between stavudine (d4T) and to a lesser extent zidovudine and lipoatrophy.
• While lipoatrophy in itself is not life-threatening the physical changes in appearance are psychologically damaging and stigmatising, leading to fear of disclosure, social isolation, poor adherence, stopping of treatment as well as suicide.
• Most first-line regimens in resource-poor settings include either stavudine or zidovudine. In spite of extensive advocacy efforts as well as a recommendation from WHO for the phasing out of stavudine, its use and repercussions continue and are expected to persist for a number of years.
• Where phasing out stavudine is not possible WHO recommends a reduced dose of stavudine from 40 mg to 30 mg in adults weighing more than 60 kg. Preliminary findings show that this helps prevent early neuropathy and lipoatrophy.
• Lipoatrophy is essentially a clinical diagnosis formed once all other explanations for (under the skin) fat loss have been ruled out making early diagnosis very difficult. Once established, changes in body shape are difficult to reverse.  Preventive strategies that include earlier detection need to be explored.
• Provider understanding and acknowledgement of the psychological effects are essential to effective treatment and improved quality of life.
• Substitution of stavudine with either tenofovir or abacavir has shown improvements in the form of weight gain and lipoatrophy scores.  These findings support the urgent need for increased availability as well as early substitution of tenofovir or abacavir as part of antiretroviral therapy in resource-poor settings.

Antiretroviral treatment has a number of well-established side-effects, most of which are associated with specific drugs.

Lipoatrophy (a distinct component of lipodystrophy syndrome) is one of particular significance and is extremely difficult to treat. The resulting physical changes in appearance because of subcutaneous fat loss from the face, legs, arms and buttocks  (lipoatrophy) and lipohypertrophy, (accumulation of fat in the stomach, neck or breasts) can be psychologically damaging and stigmatising leading to fear of disclosure, social isolation, poor adherence, stopping of treatment as well as suicide. 

Lipoatrophy is linked to antiretroviral treatment and in particular stavudine (d4T) and to a lesser degree zidovudine (AZT) and didanosine (ddI).¹

Stavudine, didanosine (ddI) as well as zidovudine (AZT) are also linked to other metabolic disorders that include hyperlactatemia and lactic acidosis as well as peripheral neuropathy but are beyond the scope of this article.   See HATIP April 2006 for lactic acidosis and HATIP 133, March 2009 for peripheral neuropathy.

Since 2004, because of the frequency and seriousness of the side-effects, use of stavudine has been phased out in first-line regimens in high-income countries. World Health Organization (WHO) revised guidelines published this month now recommend for the same reasons that stavudine be phased out in first-line regimens in resource-poor settings too.²   

WHO 2006 guidelines based on studies in high-income countries recommend replacing stavudine (d4T) with tenofovir (TDF) or abacavir (ABV) when lipoatrophy occurs.³  Better still, lipoatrophy can be almost entirely avoided if tenofovir is used from the outset.

However, the reality is that in most resource-poor settings choice is severely limited. Most first-line regimens include either stavudine or zidovudine plus lamivudine with nevirapine or efavirenz.   Choice of antiretroviral regimen is determined by cost and availability in spite of known toxicities. Cost considerations often mean quality of life issues are not a priority in policy decision-making.

In South Africa, for example, despite longstanding and extensive demands for the phasing out of stavudine, its use continues in public health settings and is expected to continue for a number of years.⁴  So in spite of recent recommendations the practicalities of an immediate change of regimen mean that d4T and, importantly, its side effects will persist for some time in resource-poor settings.

Where replacement of, or the phasing out of d4T is not feasible WHO has recommended a reduced dose of stavudine (from 40 mg to 30 mg for adults weighing 60 kg or more) with the expectation of countering  long term side effects while not compromising treatment efficacy. Preliminary findings support this,⁵ notably in the prevention of early neuropathy and lipoatrophy,⁶ but there is still a need for the further evaluation of long-term side effects.

Working with these restrictions makes long-term adherence difficult for patients and is especially challenging for providers.⁷  

A recent literature review of HIV-related lipodystrophy in Africa and Asia revealed a total of 21 abstracts and articles on the subject (excluding those related to children).⁸ The paucity of research underscores the difficulties and dilemmas both patient and provider face and include:   

• Absence of a uniform definition. Studies included the following variations:  lipoatrophy alone, lipohypertrophy alone, and a combination of both; both lipoatrophy and lipohypertrophy; liopatrophy; and lipohypertrophy; gynaecomastia as well as the presence of lipomas have been included. Other studies have limited the definition to facial lipoatrophy and others simply referred to “body shape change” or the amount of peripheral and central fat at each body part.⁹
• Lack of commonly agreed standards of measurement; wide variety of assessment methods
• Difficulties of (early) diagnosis
• Lack or absence of treatment
• Change of antiretroviral regimen is not an option

While continuing advocacy efforts to ensure that stavudine is phased out are crucial, appropriate management of its damaging and disfiguring side effects is urgently needed.

Providers need to be very familiar with the evolution of these side effects and know how to manage them with what is available in their settings.¹⁰  

Up to now very little guidance has been provided for clinicians for diagnosis and management of lipoatrophy in WHO and national guidelines, in contrast with most other side-effects where clear management guidelines exist, based on the grading/severity of the toxicity.¹¹

Although these changes in body fat distribution are not life-threatening, they are a major cause of suffering for people living with HIV because they can have a hugely stigmatising effect, and may increase a person’s sense of discomfort in their own body to such an extent that they become suicidal. A survey among HIV-positive patients in the United States found that “HIV patients with body fat redistribution would trade off length of life or accepted greater risks of mortality in order to maintain a life free of body fat alterations.”¹²

Although less is known about the psychological experience of living with lipoatrophy or lipodystrophy in resource-limited settings, there is little reason to believe that these body fat changes will be any less difficult to live with among people in less wealthy regions of the world. Indeed, given the intense stigma that surrounds HIV infection, and the association between stigma and loss to follow-up, there is every reason to believe that lipoatrophy will have a profound effect on the quality of life and the long-term health of any individual who develops it while receiving antiretroviral treatment in low and middle-income countries.

This clinical review looks at what is known about the incidence and presentation of body fat redistribution in resource-limited settings, how it is diagnosed, and what can be done to prevent or alleviate the problems, in particular lipoatrophy, the most frequent and stigmatising problem.

Lipodystrophy is a syndrome characterised by abnormal fat distribution and metabolic disturbances in the way the body processes fats (lipids) and sugar (glucose). Depending on its severity lipodystrophy can increase someone’s risk of diabetes and heart disease.

HIV-related lipodystrophy includes two distinct phenomena: lipoatrophy (subcutaneous fat loss) and lipohypertrophy (fat accumulation). They may be present in a patient at the same time but the two conditions are not part of a single syndrome (in other words, fat from the periphery is not moving to the central fat stores). Although central fat accumulation is not specific to HIV disease, and was not found to be more common among HIV-positive than HIV-negative men in the FRAM case-control study of lipodystrophy,^{13, 14}   its rapid emergence in a sizeable minority of patients soon after starting antiretroviral therapy has led many experts in the field to maintain the view that fat accumulation in people on ART is an adverse effect of treatment, not lifestyle.

Lipoatrophy involves loss of fat in the face, extremities (especially the legs, with leg veins becoming more prominent), buttocks, and subcutaneous tissue of the abdominal area. It can lead to a wasted appearance and must be differentiated from wasting resulting from HIV disease progression and/or opportunistic infections that involve loss of muscle mass as well as fat.

Fat accumulation, lipohypertrophy, can present in the neck and back area, abdomen and breasts as well as other areas.^{15, 16}  The fat which accumulates is not subcutaneous fat, but visceral, or central fat, which accumulates around the organs in HIV-negative people with metabolic syndrome. Fat accumulation must be differentiated from obesity, which can occur when patients with HIV infection are started on antiretroviral therapy and become healthier or regain appetite. 

At first people with HIV and their health care providers thought changes in body shape were caused by protease inhibitors. Since most patients take a regimen of combined antiretroviral medications it was difficult to identify a specific class of antiretrovirals associated with lipodystrophy. Many different patterns of body fat changes are seen so it is possible that different combinations of drugs cause different patterns of changes. Generally the protease inhibitors have been linked to fat accumulation while the thymidine analogue nucleoside reverse transcriptase inhibitors (NRTIs) stavudine (d4T), and to a lesser extent zidovudine (AZT), have been linked to fat loss.

Most studies agree that d4T (stavudine) is a major cause of lipoatrophy. At least three major studies, ACTG 384, Gilead 903 and ACTG 5142 – have indicated that d4T is more strongly associated with body fat changes, specifically fat loss (lipoatrophy) than other NRTIs.^{17, 18}

The precise mechanism by which nucleoside analogues might cause fat loss is unclear. One suggestion is that nucleoside analogues may damage the DNA of mitochondria in fat cells (adipocytes) that store fat in the limbs. NRTI-related fat loss has been linked to alterations in mitochondrial DNA, high levels of lactate in the blood and liver dysfunction.^{19, 20, 21}

There is also evidence from retrospective analyses of clinical cohorts that a low nadir CD4 count, body composition prior to treatment, gender, age and ethnicity all affect the risk of developing lipoatrophy. This evidence is discussed in more detail in Risk factors for fat changes in the aidsmap.com guide to lipodystrophy.

Estimates of the incidence and prevalence of lipodystrophy in people on antiretroviral therapy in resource-poor settings in Africa and Asia vary considerably due to the lack of a standard definition, difficulties in measurement and wide variations in assessment and the paucity of published studies. Definitions have been investigator-driven and vary widely as noted above. Incidence and prevalence is thought to be comparable to resource-rich settings, and notably the United States, with an estimated prevalence rate of 28-38%.²²

Dr. Johan van Grienvsen of the Institute of Tropical Medicine, Antwerp, who has been involved in the development of HIV treatment services in Rwanda,  told HATIP that there could be a number of explanations for the different prevalences observed in different settings and programmes. Besides true differences, and differences in diagnostic method, the following  factors could contribute:

• ‘Age’ of the ART programme: percentage of patients on ART for more than 1-2 years.
• Clinical focus of the clinicians: in a program with diagnostic tools and a high index of suspicion for lactic acidosis, some cases of lipoatrophy might be labelled as symptomatic hyperlactatemia since lipoatrophy can be associated with nausea; on the other hand, some cases might be labelled as neuropathy, since some patients present with neuropathy and lipoatrophy at the same time. Consequently, the same patient might receive two different diagnoses depending on the attending physician.
• In settings where there is no routine screening for lipoatrophy, especially no clinical assessment, cases might be missed easily, since in Dr van Griensven’s experience patients tend not to report body fat changes spontaneously.
• On the other hand, in programmes with routine screening, a high prevalence might be found, but mostly consisting of mild cases.

Some examples of studies which have reported prevalence, in ascending order of prevalence are:

• In a regional multicentre observational cohort of patients starting ART in 1996 in the Asia-Pacific region: lipodystrophy was diagnosed in 10% (217) of patients. Median duration on ART was 3.8 years, on stavudine 2 years, on zidovudine 1.8 years and on protease inhibitors (PI) 2.6 years. Lipodystrophy was strongly associated with stavudine but PI use was protective in comparison to NNRTI use.²³
• At an HIV clinic in Pune, India lipoatrophy was seen in 26% out of a total of 150 patients taking d4T, 3TC and nevirapine, and 10% of those taking AZT, 3TC and nevirapine after a median of 18 months . Fat accumulation was found in 10% of the d4T-treated patients and 6% of the AZT-treated patients.²⁴
• In Rwanda among 114 patients, of which 112 were getting stavudine, 3TC and nevirapine 24% were diagnosed with body fat changes (of which those with lipoatrophy 12%, lipohypertrophy 4% and mixed patterns 8%)^25. This is part of the data from a study with over 400 patients.²⁶
• Another study in Rwanda involving 571 patients from the Centre Hospitalier Universitaire de Kigali, Treatment and  Research AIDS Center, Hospitalier Universitaire de Butare and HIV/AIDS clinics of Kimironko, Bilyogo-Nyiaranuma, Kinyinya and Kacyiru on ART of which 82% received stavudine, lamivudine and nevirapine. While lipodystrophy was diagnosed (patient self report + clinician confirmation) in 34%. Prevalence reached 70% after 72 weeks on antriretroviral therapy of which 72% had peripheral lipoatrophy combined with abdominal lipohypertrophy.²⁷
• An example of how difference in definition and measurement give widely varying results is illustrated within a single case-controlled study in Senegal in which 83 patients were on antiretroviral treatment regimens that included stavudovine and 63 on regimens containing zidovudine. Moderate to severe lipodystrophy was diagnosed in 31% of patients: 13% had fat loss, 15% fat gain and 35 with a combination of both after a mean duration of five and half a years. The use of d4T was the sole risk factor. When the investigators used a broader definition, they found that almost two-thirds of patients (65%) had developed body fat changes to some extent, ranging from mild to severe: 18% with fat loss, 31% with fat gain and 12% with both. When lipodystrophy was assessed using body measurements 50% of patients were found to have developed body fat changes.²⁸

Because of the almost complete lack of published evidence, prevalence of lipodystrophy among children in resource-poor settings is difficult to ascertain. In Thailand a retrospective study of 90 children who started antiretroviral treatment with either nevirapine or efavirenz with stavudine and lamivudine revealed that prevalence was over 50% after 144 weeks on antiretroviral therapy. Outcome was the same for both treatment regimens. Mean age at entry was 7.6 years. Higher prevalence was seen in females and those with more advanced disease.²⁹

In children with HIV one study from Romania showed that both stavudine and protease inhibitors were linked to the development of lipodystrophy in 42% of children aged 3-19 after five years on antiretroviral treatment.³⁰

In multivariate analyses variables associated with lipoatrophy in adults in resource-poor settings include:

• Older age ^{31, 32, 33}
• Being female  ^{34, 35, 36} 
• Length of time on treatment ; lipoatrophy  usually appears within 2-4 years ^{37, 38, 39} 

Another multivariate analysis in Thailand found that co-infection with hepatitis C put patients at increased risk for lipodystrophy.⁴⁰

In addition evidence from resource-rich settings suggests the risk of lipoatrophy is increased in whites (5.4 odds ratio) when compared to blacks.⁴¹ The possibility of ethnic differences in vulnerability to the development of lipoatrophy and lipohypertrophy is not well explored, but given ethnic differences in the tendency to store fat – and variations in the sites of fat deposition between races – it would be very surprising if ethnic differences did not exist.

With no standard case definition nor evidence of the condition within the general population, diagnosis of HIV-related lipoatrophy is difficult. Diagnosis is clinical and is based on a combination of patient (subjective) self-report and provider experience, assessment and measurement of body changes.⁴² Studies in resource-poor settings indicate methods of assessment fall somewhere within these boundaries and are as varied as the definitions.⁴³ 

Lipoatrophy is not considered significant until it is clinically apparent. This complicates a provider’s ability to make a timely (early) diagnosis. Lipoatrophy in particular is progressive, and studies of drug-switching show that any subsequent fat gain is slow. Thus the best hope of effective action is early intervention, making regular monitoring imperative. As noted earlier clear national and WHO guidelines for diagnosis and management of lipoatrophy are urgently needed.

Recent large clinical trials (in resource-rich settings), for example ACTG 5142,⁴⁴ have used a subjective fat loss of 20 percent as the criterion for lipoatrophy. However, subcutaneous fat loss of 20%  is rarely clinically apparent. Other clinical trials indicate that 40-50% fat loss is necessary for lipoatrophy to be clinically apparent.^{45, 46} 

As lipoatrophy is a clinical diagnosis it is important to consider other causes of fat loss from the extremities, buttocks, abdomen and face. These may include HIV-associated wasting, diarrhoea syndromes (including cryptosporidiosis and microsporidiosis), tuberculosis/mycobacterial disease or reduction in calorie intake/malnutrition.⁴⁷  The latter causes will include loss of lean body mass (muscle) as well as fat. Some studies have suggested that lipoatrophy is associated with recent weight loss.⁴⁸  Treatment failure which typically occurs after a long period on ART and could involve weight loss is also a possibility.

In resource-poor settings lipoatrophy is essentially a diagnosis of exclusion once all other explanations for subcutaneous fat loss have been ruled out. In clinical practice assessment of body changes might include both subjective and objective tools:

• Patient history
• Patient self-report
• Physical examination of extremities, buttocks and subcutaneous tissue of the abdomen, (old photographs may be helpful) and  anthropometric measurements (for example weight, waist to hip ratio)
• Questionnaires
• Classification systems

The availability of baseline measurements will help in making diagnosis easier.  When no alternative to stavudine as part of a first-line regimen is available then routine examination and questioning patients regularly about body changes is important. Change to zidovudine, while somewhat less toxic, is preferable to continuing on stavudine.⁴⁹  

Questionnaires and classification systems, in a two-step process, are used primarily in clinical practice. They are simple and cost-effective but are subject to observer bias.

Lipoatrophy is assessed using the HIV lipodystrophy case definition (LDCD) questionnaire, developed by Carr and colleagues. Fat loss in any of seven body regions (face, neck, arms, breasts, abdomen, buttocks and legs) is systematically assessed.  This is followed by determining the degree of severity of lipoatrophy at each body region using the HIV Outpatient Study (HOPS) scale as follows: absent (score of 0), mild (noticeable on close inspection, score of 1,  moderate (readily noticeable by patient or physician, score of 2, and severe (readily noticeable to a casual observer, score of 3).⁵⁰

Objective assessments used mostly in clinical trials can be costly and are of questionable utility and include:

Anthropometric measurements. These assessments are easy, fast and inexpensive and may compare well with results from expensive imaging techniques and include skin fold and waist measurements as well as waist to hip ratio (WHR). The latter is convenient but of variable accuracy.⁵¹

• Skin fold tests: this test uses calipers to measure the quantity of subcutaneous fat. It needs to be done by a dietician or doctor experienced in use of the test, and can be used to monitor changes in the amount of subcutaneous fat on the arms or legs. However, these changes are not representative of total body fat changes.
• Bioeletrical impedance analysis (BIA): this test passes a small electric current through the body. Since fat is a poor electrical conductor compared to muscle, the body presents an impedance (a more complex measure of electrical resistance) to the current which can be measured and used to determine overall proportions of overall lean body mass, fat, and other body composition compartments. BIA cannot detect regional changes in body fat, only total body fat changes.

Dual-energy X-ray absorptiometry: DEXA scan is a method which can show the distribution of fat, muscle and bone in the body, and can detect changes in different parts of the body. It is likely to produce more accurate measurements of fat loss from the limbs, because it cannot distinguish between subcutaneous (under the skin) and visceral or abdominal (organ) fat. However, this test is expensive, requires elaborate equipment which is largely unavailable in resource-poor settings, and is less accurate in very thin or very fat people.

Self-report combined with clinical examination by a health provider incorporating the LCDS and HOPS questionnaires described above appear to be the most frequent assessment method used in Africa and Asia according to published studies.⁵²

Van Griensven and colleagues assessed weight change using self-reporting, clinical assessment and in particular “weight evolution” to indicate fat recovery after substitution of stavudine with tenofovir or abacavir, although noting that this is a possible limitation of the study. Yet, they argue that in resource-poor settings high numbers of patients, together with staff limitations in both numbers and skills, and a lack of sophisticated technologies, mean that “measurement of body weight is a relevant and easy-to-use parameter for the follow-up of patients on ART, as it can indicate important clinical events such as treatment failure, malnutrition and infections”.⁵³

Lipoatrophy leads to other psychological, social and physical consequences severely impacting quality of life.

The physical changes often cause the most distress.

“After surviving many years with HIV a patient of mine began to get lipoatrophy of the face and people began to ask him what was wrong. He thought they knew of his diagnosis. I counselled him and suggested he change his treatment regimen. He could not afford the increased cost. Disgusted and disheartened he stopped treatment and died a few months later. Another patient of mine, a lawyer by profession, could not deal with this side effect and committed suicide”.⁵⁴

Changes in body shape are reported to be associated with negative emotional and social consequences,^{55, 56, 57, 58} and include:

• Lowered self-esteem, poor body image, social withdrawal
• Perceived and experienced stigma and discrimination

The repercussions of which may lead to:

• Fear of or forced HIV disclosure due to facial fat loss
• Poor adherence or stopping of treatment
• Mood disorder including severe depression and suicide

Dr. van Griensven commented: “I think  these body fat changes have a substantial impact on mental health and stigma. Although most quotes and experiences on that are often anecdotal, they speak for themselves.

“For example, we had female patients that were ‘encouraged’ by their husbands to interrupt ART because they did not like the body changes in their wives. Some patients expressed reluctance to start ART in fear of these body changes.”

“Other non-HIV infected patients mentioned that they could locate the ART clinic in any health centre just by looking for the characteristic body habitus changes in this patient population.”

“As such, besides individual suffering, this side-effect could potentially affect the acceptance of ART within a community, and lead to ongoing stigmatisation. Especially now that we aim to test and treat early (ideally starting ART in asymptomatic patients), acceptability and acceptance of ART are key issues.”

We asked Dr van Griensven how he would rate body fat changes as a cause of suffering in his patients in comparison to other drug side-effects seen commonly in ART patients?

Dr. van Griensven replied: “Here there is high individual variability; although the ‘intensity’ of the suffering is not so high, the chronicity and irreversibility could make it an overall important contributor to patient psychological suffering. These issues might become even more important for patients the longer they are on ART.

"In our experience, early detection and drug substitution (after ruling out alternative diagnosis) improves the chances of reversibility.”

Currently there is no treatment available to reverse all body fat changes and people with body fat changes are not in a position to stop taking antiretroviral drugs.

Fat loss from the arms, legs and face may be improved by switching from d4T to abacavir or tenofovir.⁵⁹ However the restoration of fat observed in `switch` studies is very slow, and is often imperceptible to the patient for a long time.

In cases of severe lipoatrophy fat restoration will be particularly difficult because the population of cells that make up the subcutaneous fat layer have been so severely depleted by mitochondrial toxicity.

Waiting until serious fat loss has occurred before switching severely diminishes a patient's chance of experiencing any fat restoration as a result of a therapy switch.

A variety of techniques are being tested to restore the facial appearance of people who have lost fat from the face.  Most of these involve injectable substances such as polylactic acid (New Fill), polyalkylinide gel (Bio-Alcamid) and others. These injectable substances are rarely available in low and middle-income settings, although use has been reported in Latin America, particularly Brazil, where several surgeons have been pioneers in the global field of lipoatrophy repair.

Support and counselling

Given the limited treatment options within resource-poor settings and the limited possibilities for reversing the side effects of lipoatrophy the role of the health provider is especially challenging.  There are no easy solutions. Knowing that no other treatment options exist, the provider may understandably be reluctant to talk of the potential side effects. However if antiretroviral treatment contributes to the patients’ perception of stigma within the context of a highly stigmatised disease then providers need to be concerned about this. To help patients better prepare for and handle the potential side effects doctors and other health care workers need to be more up-front in providing information in advance.⁶⁰ Studies suggest that psychological support and attention to patients’ concerns about the effect of body fat changes may be beneficial.⁶¹

A “patient-centred care approach in which African patients are included in therapeutic decisions and paying attention to patients’ perceptions of the effects of HAART, may contribute towards greater adherence to proposed interventions and develop a more stable quality of life continuum over time," write Mutimura and colleagues. "An assessment of quality of life is integral to efficient treatment outcomes to evaluate long-term strategies that optimize the durability of response to antiretroviral therapy in sub-Saharan Africa”.⁷⁴

Diets and exercise

Mutimura and colleagues have demonstrated that exercise may have a beneficial effect on mood and well-being among people with lipodystrophy in Rwanda,⁶² while research in the developed world has shown that resistance exercise may reduce central fat accumulation. However for others lipoatrophy may actually prevent people from engaging in exercise as they are self conscious of the wasting on their limbs and may fear others’ comments.⁶³

There is no evidence to suggest that change of diet improves the condition.  

Reducing dosage of stavudine

In 2007 the World Health Organization recommended that resource-poor country treatment programmes use a 30 mg dose of d4T if it was not possible to phase out use of the drug. Their recommendation was based on a number of small studies which showed no negative effect of using a lower dose in adults weighing more than 60 kg. While preliminary findings support this recommendation evaluation of long-term side effects according to dose is recognized as essential.⁶⁴

In a three year retrospective observational study in Rwanda use of 40 mg of d4T was associated with increased risk of lipoatrophy and early (less than six months) neuropathy and is in line with findings from another large three-year cohort study in South Africa.^{65, 66}  

The Rwanda study looked at the independent effect of d4T dosing to assess whether the association of certain side effects with baseline body weight persisted after adjusting for weight-based dosing. Irrespective of the d4T dose (40 mg or 30 mg) higher baseline body weight increased the risk of symptomatic hyperlactatemia/lactic acidosis as well as late neuropathy. Dose reduction (30 mg) resulted primarily in a reduction in early neuropathy as well as lipoatrophy.  The authors noted that one in four patients placed on a d4T-containing fixed dose combination in their programme ended up with significant long-term toxicity. Relevant strategies they feel need to be urgently considered include d4T dose reduction to 30 mg, increased access to safer antiretroviral drugs in low-income countries and close monitoring for those at risk.

Replacing stavudine with abacavir or tenofovir

Evidence from several small studies in resource-rich settings has suggested some benefit from switching from d4T treatment but the numbers treated in these studies are  small, with no matched control groups or randomisation. Current evidence from resource-rich settings suggests that switching from d4T to another nucleoside reverse transcriptase inhibitor seems to produce modest benefits in fat wasting.

Van Griensven and colleagues undertook the first cohort study in Africa to assess weight evolution after substituting stavudine because of lipoatrophy.⁶⁷ Substitution with either tenofovir or abacavir was associated with weight gain, while substitution with zidovudine led to a progressive weight loss over time. Significance in weight change between the two groups developed from six months after stavudine substitution. In addition differences in evolution of lipoatrophy scores were seen between the two groups, adding to the clinical relevance. The authors note that while the two cohorts were not randomly selected those in the tenofovir/abacavir group had more severe lipoatrophy symptoms at baseline making the difference clinically more significant.

The authors note that their findings are consistent with three studies from high-income countries that demonstrate the positive clinical evolution when substituting stavudine with tenofovir or abacavir.^{68, 69, 70} 

These findings add to the evidence that tenofovir or abacavir are better than zidovudine as an alternative to stavudine. The authors stress the need for improved access to tenofovir or abacavir and that earlier substitution with either may well be justified.

When routine replacement of stavudine with tenofovir or abacavir occurs most patients will have been on stavudine for a considerable length of time, also putting them at increased risk for treatment failure. Lipoatrophy typically becomes apparent after 1-2 years of ART, which is the same time that virological failure is increasingly seen. Consequently, there might be a risk that patients change from d4T to tenofovir with a detectable viral load ( a single drug substitution with a ‘failing regimen’). Substituting tenofovir for stavudine in a person on a failing ART regimen will cause resistance to tenofovir. Van Griensven and colleagues suggest that before substitution an assessment of the efficacy of the ART regimen is carried out, preferably with viral load testing. They suggest to consider switching to tenofovir with a protease inhibitor-containing regimen where treatment failure is suspected.⁷¹

Facial fillers

Current estimates suggest that approximately 30 to 40% of people taking antiretroviral therapy will develop some form of facial wasting, and that facial fat loss tends to occur quite rapidly, often within six months. How to prevent or reverse facial wasting remains unknown. Consequently research has focused on reconstructive or surgical procedures to fill out sunken cheeks.

Several approved and experimental procedures are being used in resource-rich settings and include: polylactic acid (New Fill); polymethyl methylcrylate (PMMA); polyvinyl/polyacramide gel (Evolution)/polyalkylimide gel safe (Bio-Alcamid) and fat transfer injections.

Polylactic acid is already used in cosmetic surgery as treatment for fine lines, wrinkles and furrow. It works by stimulating the growth of collagen, a structural component of the skin and other body tissues, and the development of a thicker layer of skin which fills out the wasted regions of the cheeks. Polyactic acid is not immunologically active, and so cannot cause any allergic or inflammatory response. 

Polyalkylimide marketed as Bio-Alcamid is injected into the face and forms a soft gel replacement for lost fat. Studies suggest that both polylactic acid and polyalkylimide can be used safely and effectively reduced the visible symptoms of facial lipoatrophy in HIV-positive patients and improved self-reported anxiety, depression and overall quality of life.⁷²  

Facial fillers are not available in resource-limited settings because they cost anywhere from $1000 - $3000 for a course of treatment. They also require physician or nurse training in how to carry out the injection of the facial filler, and the use of a local anaesthetic. Given these barriers, it is all the more important to look at how lipoatrophy can be avoided in the first place.

Treatment for lipohypertrophy (fat accumulation)

There is very limited evidence concerning the ability of switches in drug treatment to reverse fat accumulation, and the only unequivocal data showing a succesful intervention for treating central fat accumulation concerns the human growth hormone-releasing factor tesamorelin, which reduced belly fat by around 15% over 26 weeks in a randomised study, compared to a 5% reduction in the placebo group.⁷³

Patient demand for treatment

The available evidence suggests that facial fillers are successful. Yet in a study of Africans with lipoatrophy in a London clinic, few of the participants had had New Fill treatment. The findings reveal some interesting insights into patient perceptions of lipoatrophy, and the extent to which patients complain about a stigmatising side-effect, even when corrective treatment is available.

Based on their clinical observations the authors suggested that this may be because:

• Patients are reluctant to speak to their doctor about this and within the context of depression it may be too difficult for them to raise the issue with their doctor
• Depression may make them feel that they are not entitled to it and that nothing will help them so there is no point in mentioning it
• Where many patients have had close family members die of HIV disease, they may feel they have no right to complain about life-saving medication. 

These reasons, the authors stress, place the responsibility on the health provider to raise the issues and be aware of the data which suggest that lipodystrophy syndrome is highly associated with mood disorder, and in the case of this particular study, associated with the perception of HIV stigma.⁷⁴

Pain

In addition to the psychological pain described above pain will be experienced as fat cushioning is lost from bony prominences, for example, from the buttocks, making it difficult for patients to sit even for short periods of time. Measures to relieve pain need to be discussed with patients suffering severe fat loss.

All the available data suggest that patients receiving stavudine-based ART are at high risk of developing lipoatrophy and other body fat changes, and that risk rises as time on treatment lengthens. As yet it is unclear whether there is a subset of patients who are permanently immune to fat loss, or whether some people just take longer than others to manifest the condition, due to genetics or baseline fat levels.

While peripheral neuropathy is difficult to ignore when it is causing crippling pain, many people with HIV do seem to live with lipoatrophy without complaint to their health care providers, accepting it as the price that must be paid for lifegiving treatment.

Yet there is good evidence that eventually the stigmatising effect of lipoatrophy undermines treatment adherence, and has a profound effect on quality of life.

In Europe, Australia and North America people living with HIV had to protest vocally about this side-effect in order for it to be taken seriously, and had it not been for enlightened clinicians who listened to their complaints and undertook extensive research to understand the condition, stavudine-based treatment might still be the norm for first-line treatment on grounds of cost even in the wealthiest countries in the world.

Recent guidance from WHO suggests that countries should begin planning for the phase-out of stavudine as soon as budgets allow. This could be a recipe for inaction. The history of the HIV epidemic shows that strong advocacy by people with HIV, by civil society and by scientists has been necessary for policy change whenever change has come with a price tag.

In the case of first-line treatment, change will not be cheap, but the long-term cost of doing nothing will be to consign a very large number of people to years of treatment with drugs that are not just sub-optimal, but downright harmful.