HIV-Related Lipodystrophy in Africa and Asia

Key words: HIV/AIDS, Lipodystrophy, Africa, Asia, Literature review

In 2005, members of the Group of Eight (G8)-an international forum for the governments of Canada, France, Germany, Italy, Japan, Russia, the United Kingdom, the United States, and the European Union-along with the African Union and the heads of state attending the 2005 United Nations World Summit, joined with the UNAIDS Secretariat in committing themselves to providing universal access to HIV care, prevention, and treatment for all those in need by 2010. Two years after the declaration, the percentage of those receiving antiretroviral treatment had increased from 20% to 31% in the developing world, and the decreases in HIV-related mortality and morbidity were comparable to those seen in high-income countries.^1,2 In parallel with these positive outcomes, persons receiving antiretroviral therapy in low- and middle-income countries also experience many of the same medication-related adverse effects and toxicities as do persons in high-income countries.

Of these complications, lipodystrophy is one of the most significant, persistent, and difficult to treat. The morphological changes associated with lipodystrophy can be stigmatizing, potentially leading to decreased adherence to or the discontinuation of antiretroviral therapy. Lipodystrophy has been associated with a decreased quality of life^3,4; alterations in lipid, glucose, and insulin metabolism^5-8; and an increased risk of diabetes mellitus and cardiovascular disease.^9,10

In the West, there are now more than 20 approved antiretroviral drugs spanning 6 different mechanistic classes that can be used to design effective antiretroviral regimens. This abundance of therapeutic alternatives allows providers to select medications-especially for antiretroviral-naive persons-that have significantly fewer associations with lipodystrophy than either stavudine or zidovudine.^11-13

Unfortunately, in the developing world, either stavudine or zidovudine plus lamivudine, administered as a generic fixed-dose combination with nevirapine or efavirenz, constitutes the NRTI backbone for first-line antiretroviral therapy. Because generic fixed-dose combinations are far less expensive than newer, brand-name alternatives, persons who have HIV/AIDS must choose between dying of AIDS and living with lipodystrophy.

This article reviews the medical literature for information about lipodystrophy in Africa and Asia. These 2 regions were selected because both are of particular interest to the declaration for universal access. Africa represents the epidemic’s epicenter. Asia, especially India and China, will soon have HIV/AIDS prevalence rates that will outstrip those seen in the rest of the world combined.¹⁴ The methodology is summarized first: how articles were selected, the inclusion and exclusion criteria used, and how information was synthesized. The results and discussion focus on 3 specific areas: how lipodystrophy is defined and measured, the study populations, and the persons excluded from these studies. A summary of what is and what is not yet known about lipodystrophy in Africa and Asia is also included.

METHODS
The focus of the literature search was on articles and abstracts from the scientific literature that dealt with HIV-related lipodystrophy, lipoatrophy, and/or lipohypertrophy among adults living in resource-limited areas of Africa and Asia. Ovid, Medline, PubMed, Web of Science, and the public domain were searched for pertinent scientific articles and abstracts using combinations of the following key words: Africa (as well as individual country names), Asia (as well as individual country names), lipodystrophy, lipoatrophy, lipohypertrophy, lipoaccumulation, human immunodeficiency virus, HIV, acquired immune deficiency syndrome, AIDS, lipid, toxicity, antiretroviral therapy, highly active antiretroviral therapy, and HAART.

The searches were not limited by year of publication. The references from the articles identified were also reviewed to find sources not included in the initial search. In addition, abstracts presented at the 2008 International AIDS Conference held in Mexico City were reviewed by hand to identify other studies of interest.

No parameters limiting the type of article that could be included were established. Journal articles, letters to the editor, and scientific abstracts all provided information for the review. Articles and abstracts from studies that included children were excluded, as was one article from Singapore, which, although part of Asia, is not resource-limited. Articles from Hong Kong were included if they were published after 1997, when Hong Kong’s governance returned to the People’s Republic of China. If an abstract presented information that was more fully developed in a subsequent article, only the later article was reviewed. Because there were few articles that addressed this topic, the decision was made to include all identified studies and to focus the discussion not just on the outcomes but also on the quality of the data presented.

Once the articles were identified and reviewed, data collection sheets were developed so that outcomes, methodology, and research design could be gathered, described, and compared consistently.

RESULTS
Study Summary
Twenty-one articles and abstracts were identified: 9 from Africa (6 from Rwanda, 3 from South Africa) and 12 from Asia (1 from Korea, 4 from Thailand, 3 from China, 2 from India, 2 from Cambodia) (Table 1. To view this table, please see the printed article in the April issue). Nine of the studies were cross-sectional; 7 were longitudinal; 1 study combined cross-sectional and longitudinal designs; and 1 study used a retrospective design. There were 2 randomized clinical trials and 1 review article (not included in Table 1). Six of the sources were abstracts, 1 was a letter to the editor, and 14 were journal articles.

The longitudinal, cross-sectional, combined, and retrospective studies fell into 1 of 2 general categories: those that focused specifically on lipodystrophy and those that reviewed antiretroviral efficacy and toxicity in general, with lipodystrophy as 1 of other potential adverse effects. Studies from the first group provided specific information regarding lipodystrophy; those from the second provided a better picture of the importance of lipodystrophy in the context of other toxicities and in terms of immunological and virological responses to antiretroviral therapy.

The 2 articles describing the outcomes of a single randomized clinical trial focused on an exercise intervention, conducted by one research group, in a Rwandan population. The first article reported on the effect of an exercise program on quality of life,¹⁵ and the second addressed the metabolic and anthropometric outcomes of this program.¹⁶

The review article¹⁷ focused on the relationship between HIV infection and the cardiometabolic syndrome in the developing world, although the focus was primarily to review the articles written by the same research group from research conducted in Rwanda.^15,18

Definitions of Lipodystrophy
Recurring limitations of the studies reviewed included the lack of a consistent definition for lipodystrophy, a wide variety of assessment methods, and a unidirectional approach to site-specific measurements of fat loss or gain.¹⁹ The various definitions of lipodystrophy in these studies included the following: (a) lipoatrophy alone, lipohypertrophy alone, and a combination of both; (b) both lipoatrophy and lipohypertrophy; (c) lipoatrophy; and (d) lipohypertrophy (Table 2. To view this table, please see the printed article in the April issue). Some studies included gynecomastia and the presence of lipomas.^20,21 Others limited the definition to facial lipoatrophy,²² and still others simply referred to “body shape change”²³ or to the amount of peripheral and central fat at each body part.²¹

The methods used to assess whether or not a person had lipodystrophy were as varied as its definition (Table 2. To view this table, please see the printed article in the April issue). The self-report method was most frequently used, especially in conjunction with a clinical examination by a health care provider. This often was a 2-step process: a standardized form was used to determine whether the participant had lipodystrophy, and then an additional questionnaire was used to determine the relative severity of the lipodystrophy (on the basis of a 0 to 3^24-26 or 1 to 4¹⁸ scale, with the lower number representing no lipodystrophy and the higher the number, the more severe the lipodystrophy). Some authors reported that lipodystrophy was diagnosed either by patient self-report or by physician examination²⁵; others reported using physician examination only²⁷; and still others reported using patient self-report only.^{23,28, 29} Many studies, particularly those that addressed lipodystrophy as 1 of many adverse effects or toxicities of antiretroviral therapy, did not describe how lipodystrophy was assessed.^30-33

There was inconsistency even within the self-report category. Some authors used the self-report questionnaire from Carr and colleagues³⁴ (the Lipodystrophy Case Definition Study [LCDS]-based questionnaire) to determine the presence or absence of lipodystrophy. Some used the HIV Outpatient Study (HOPS) questionnaire, either by itself or in addition to the LCDS-based questionnaire, to evaluate severity.^18,24,26 Unfortunately, no description of how these instruments were culturally adapted was offered. Finally, some authors failed to specify a method beyond simply stating that they used “patient self-report.”^{20,23,28,29,35}

Methods that approximate the measurement of body fat distribution, such as anthropometry and bioimpedance analysis,³⁶ were also used, as were technologies that assessed body composition, including dual-energy x-ray absorptiometry.^20,21 Even though a quantitative assessment of fat distribution changes with antiretroviral therapy is useful, these methods do not provide a categorical diagnosis of the presence or absence of lipodystrophy. Diagnostic cut-points based on quantitative data that correlate with patient perception or with long-term complications do not yet exist.

The early assumption that HIV-related lipodystrophy included fat loss in the periphery and fat gain in central areas of the body¹⁹ has led to a large number of studies that only evaluated alterations in body fat distribution according to this predefined pattern.^{20, 24,25,35} Studies that used bidirectional measurements (measuring fat loss as well as fat gain) at both central and peripheral sites¹² have demonstrated that this characterization is inaccurate; that is, HIV-related lipodystrophy is most consistently associated with central as well as peripheral fat loss. Measurements on HIV-negative persons have demonstrated that central fat gain is related to the normal aging process and to the return to health and not to HIV disease or its treatment.¹²

One of the studies reviewed used a bidirectional approach to the measurement of body fat²¹ and found no difference in central fat mass among patients in the different antiretroviral groups. This study, however, did not evaluate anthropometrics over time in HIV-negative participants, and thus it is impossible to determine whether any of the alterations noted were unique to HIV.

Study Populations
Recruitment strategies play a role in determining many of the characteristics of study populations. For example, if participants are recruited as they present to a clinic for care, the study population will be characterized by those qualities or attributes found in the type of person who presents for care. Those who do not present to a clinic or who present less consistently will not be included, and they are likely to differ from the study population on a variety of characteristics, some of which could influence study outcomes. It is therefore important for studies to describe their recruitment strategies.

However, in the literature reviewed, recruitment strategies were inconsistently described. Some studies used information from routine clinic visits and were thus able to include all patients who had ever presented for care and who met the inclusion criteria for the study.^23,26,28 Other studies recruited persons as they presented to local HIV clinics or programs,^18,33,35,37 and 1 study selected persons from a local clinic by using a random number generator.²¹ In some of the studies, however, the recruitment process was not clearly described.^{20, 25, 29}

Sample sizes ranged from 8 to 2694 participants (Table 1. To view this table, please see the printed article in the April issue). Most participants were HIV-positive and were receiving antiretroviral therapy. Some studies included comparison groups, for example, HIV-positive patients who were receiving antiretroviral therapy but who did not have lipodystrophy,^16,18 HIV-positive persons who were not receiving treatment,^20,21 and HIV-negative persons.^16,20

In the longitudinal studies (Table 1. To view this table, please see the printed article in the April issue), participants were largely antiretroviral-naive at baseline and as such were generally quite ill before the onset of therapy. Some studies excluded those with opportunistic infections, but others reported that 72% of participants were at World Health Organization (WHO) stage III (which includes unexplained chronic diarrhea for longer than a month, severe bacterial infections, and pulmonary tuberculosis),²⁴ 56% at WHO stage IV (which includes AIDS-defining illnesses, such as toxoplasmosis of the brain; candidiasis of the esophagus, trachea, bronchi, or lungs; and Kaposi sarcoma),²³ and 95% at WHO stage III or IV.³³ Across all studies, the CD4⁺ cell counts at baseline ranged from 5/µL to 300/µL.

Specific antiretroviral drugs were identified in all but 1 of the studies. One of the WHO first-line antiretroviral regimens-stavudine/lamivudine or zidovudine/lamivudine with either nevirapine or efavirenz-had been prescribed for all participants receiving treatment in the African studies. In the Asian cohorts, however, protease inhibitor (PI)-based therapy was used by participants in 7 of the 12 studies.^{20-22,25,32,33,36} Abacavir and didanosine were used infrequently^{16,18,20,21,36} and tenofovir not at all. In keeping with WHO guidelines, most studies included the typical combination of 1 PI or NNRTI and 2 NRTIs. Puttawong and colleagues²⁵ used more unusual drug combinations, including a regimen of 3 NRTIs; 1 NRTI, 1 NNRTI, and 1 PI; and another of 1 NRTI, 1 NNRTI, and 2 PIs. Saghayam and colleagues³⁶ included patients receiving only dual-NRTI therapy.

Sociodemographic information was also inconsistently described. Information regarding the socioeconomic status of the participants was included in only 4 studies.^15,18,21,31 Three of the 20 studies did not provide information on the gender of participants (Table 1. To view this table, please see the printed article in the April issue). Among the studies conducted in Africa, 6 of the 8 provided information on gender. Of these, women represented the majority of the study’s population in 5 of the studies (range, 60% to 78%). Among the 12 Asian studies, 11 provided information on gender. Women also constituted the majority in 3 of the Asian studies (range, 52% to 60%). Participant age was described in all but 2 of the studies. Where reported, the average age of study participants was 33 to 44 years. A measure of weight was reported in more than half of the primary studies (11 out of 20). Where described, the average body mass index (BMI) ranged from 18.6 kg/m² (normal)³³ to 25.0 ± 2.9 kg/m² (overweight),¹⁸ with the majority falling in the normal BMI range (18.5 to 24.9 kg/m²).

Who Was Not Included?
As important as knowing who was included in the study is knowing who was excluded and who failed to complete the study protocol. This information was inconsistently provided in the studies reviewed. Information on those refusing to participate was infrequently included. Attrition was discussed in some articles, but none included demographic or clinical information on those who either died or were lost to follow-up.^{15,16,29,32,33}

Given the Limitations of These Studies, What Do We Know?
Given the limitations of the published lipodystrophy studies, few, if any, definitive conclusions can be drawn regarding this complication in these regions. The range of incidence and prevalence of lipodystrophy in Africa and Asia appears to be similar to that found in the West. In Africa and Asia, the prevalence of lipodystrophy ranged from 0% to 69.6%, and the incidence ranged from 0% to 41.6%. In the West, its prevalence has been cited as ranging from 2% to 84%.³⁸ Given this range, an obvious question is whether lipodystrophy is really a problem, either in the West or in Africa and Asia. If one looks at well-constructed studies (those that at least use bidirectional measurements and that preferably include HIV-negative participants) however, there is evidence that lipoatrophy is prevalent in the United States, ranging from 28%³⁹ to 38%.⁴⁰ In 1 study from Thailand,²¹ lipoatrophy, defined by clinical examination, was found in 40% to 65% of patients treated with PI-based regimens (depending on the site measured), in 5% to 30% of patients treated with PI-sparing regimens, and in 0% to 10% of antiretroviral-naive patients.

Chariyalertsak and colleagues²⁹ reported that in response to a direct question, 14.8% of participants wanted to change their antiretroviral regimen because of lipodystrophy. While this question was not asked in other studies, it suggests an important issue that merits further exploration because it may indicate the potential for long-term adherence issues and for the emergence of highly resistant viruses.

Because of the difficulty in defining and measuring lipodystrophy, it is hard to draw any hard and fast conclusions about factors associated with lipodystrophy in Africa and Asia. However, antiretroviral use in general, and stavudine and indinavir use in particular, were consistently associated with lipoatrophy.^21,24,35 Demographic variables associated specifically with lipoatrophy in multivariate analyses included older age^24,26,29 and female gender.^24,29,30

DISCUSSION
Lipodystrophy in resource-limited settings has significant implications for patient health, quality of life, and long-term adherence. It is a central issue when considering the sustainability of antiretroviral therapy in these settings. Unfortunately, until there is a uniform definition for lipodystrophy and a uniform approach to its measurement, conclusive statements about lipodystrophy are not possible. This work is not the sole purview of researchers in resource-limited settings and should provide fruitful grounds for collaboration among groups working in resource-rich and resource-limited settings.

Furthermore, until the sample populations are well defined, including careful descriptions of those who were not able or who refused to participate, extrapolation to clinical populations is impossible. These necessarily detailed descriptions should also include characteristics not typically found in Western populations, such as the distinction between rural and urban groups,¹⁸ and comorbidities not found in Western countries, such as malaria, parasitic diseases, marasmus, and kwashiorkor. Such rich descriptions of a study population will allow clinical researchers to identify factors associated with lipodystrophy and to target interventions that will address issues specific to individual countries and to resource-limited settings more generally.

Lipoatrophy may be an important adverse effect of antiretroviral therapy among the HIV-positive populations studied in Africa and Asia. Causative connections cannot yet be drawn from the literature, but given consistent evidence from the West that stavudine is a key contributor,^41,42 it is reasonable to support the WHO’s effort to remove stavudine from first-line therapy options. Affordability of and access to alternative NRTIs and the newer antiretroviral classes are key issues.

However, the suitability of certain NRTIs, given the lack of access to comprehensive laboratory testing, should also be considered. Abacavir can cause a significant hypersensitivity reaction, and tenofovir can accelerate renal disease in those already at risk. The lack of resources to test for HLA B5701 mutations that predispose a person to the abacavir hypersensitivity reaction or even the lack of resources for routine laboratory tests to measure the serum creatinine level, urinary protein level, and glomerular filtration rate may appear to be stumbling blocks to the use of many antiretrovirals in resource-limited settings.

These limitations provide the basis for future research. Studies that explore population frequencies of HLA B5701 mutations could indicate to providers how concerned they need to be regarding the hypersensitivity reaction. If it is common, then abacavir may not be the drug of choice. If it is infrequent, abacavir would be a powerful addition to the antiretroviral armamentarium, without some of the adverse effects found with other NRTIs. Similar studies could be done to identify the incidence and prevalence of chronic renal insufficiency and risk factors for chronic renal disease that are pertinent to specific settings. In this way, clinical characteristics of patients in need of screening and close follow-up for renal issues could be identified, and the vast majority of patients could be monitored while they derive benefit from the use of tenofovir.

Longitudinal studies exploring the connections between lipoatrophy and cardiovascular disease and diabetes mellitus in these settings are also needed. There is a significant literature warning about the emergence of serious cardiovascular disease and diabetes mellitus epidemics in emerging nations. Whether the treatment of HIV infection will contribute to this epidemic should be of concern.

Fortunately, there is a growing body of literature regarding lipodystrophy in the resource-limited settings of Africa and Asia. Unfortunately, published studies from these regions suffer from many of the same limitations as earlier studies conducted in the West, especially in terms of the lack of a consistent definition for lipodystrophy and the equally inconsistent approaches to its measurement. The previous lack of reporting complete descriptions of recruitment procedures, sample populations and, as far as possible, those who were not included in the study or who withdrew should be comparatively easy to address in future studies.

Researchers in the developing world should not limit themselves to exploring risk factors that have already been associated with lipodystrophy but should expand-as many have done-their search to identify factors characteristic of resource-limited settings. These potential associations will only become evident through careful, detailed population descriptions. Of key importance, however, is that access to less toxic medications would have the most impact on decreasing the incidence of lipodystrophy and its negative sequelae. As providers who are concerned about the health and well-being of HIV-positive patients worldwide, we need to ensure that the improvements in HIV care that are piloted in developed countries are also available to those in other settings.

References:

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