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Past Issues
Volume 21, numbers 3 & 4
July – December 2007
Human Rights and HIV/AIDS in Brazil
A rights-based approach to the epidemic
AIDS Vaccine Update
Merck's candidate fails efficacy trials. What happened and what's next?
HIV Lipodystrophy
Options and updates from a community activist
Migration and HIV
Rights, risks, and justice for African workers
Human Rights and HIV/AIDS in Brazil
Kelly Safreed-Harmon
Specific legal obligations and general human rights principles have helped shape AIDS policies in many countries, and have influenced the way HIV-infected and -affected people are treated This article examines how human rights principles and laws have informed the national response to HIV/AIDS in Brazil, where effective public health strategies are credited with reducing the overall impact of HIV/AIDS. One central element of Brazil's national AIDS plan is an ongoing government-led campaign against HIV-related stigma and discrimination; another is free universal distribution of antiretroviral drugs to everyone who needs them. The following analysis of these issues is prefaced with an overview of the human rights models that are central to a discussion of the Brazilian experience.
Health and Human Rights
A wide array of players has been calling attention to human rights dimensions of the global AIDS epidemic since its early years. Activists, community leaders, physicians, academics, public officials, and others have found many different ways to relate HIV/AIDS to human rights.
The conceptual and legal framework for considering HIV/AIDS and other health problems as human rights issues has evolved largely through the work of the United Nations (UN). The Universal Declaration of Human Rights (UDHR), adopted by the UN General Assembly in 1948, became the foundation for the subsequent body of international human rights treaties, and stands today as the touchstone of the modern human rights movement. UDHR was intended to define the full body of fundamental human rights principles, among them "the right to a standard of living adequate for the health and well-being of himself and his family, including food, clothing, housing and medical care and necessary social services."
In 1966, the UN General Assembly adopted two treaties that elaborate on many aspects of UDHR: the International Covenant on Civil and Political Rights (ICCPR) and the International Covenant on Economic, Social and Cultural Rights (ICESCR). These treaties bestow specific responsibilities upon ratifying parties under international law. That is, countries are legally obligated to ensure that their citizens enjoy the rights named in the treaties. To date, 160 countries have ratified ICCPR, and 157 ICESCR. Brazil is a party to both.
It is commonly understood that some rights cannot be implemented in absolute terms. A government's commitment to the right of its people to medical care, for example, does not translate into an economically untenable obligation to immediately build and staff health clinics in all under-resourced communities. States are, however, obligated to make measurable ongoing progress on those issues, a concept known as the progressive realization of rights.
The body of human rights described in the international treaties is intended to function as a set of fully interrelated principles, with no rights superseding any of the others. Rights are also understood to inform each other. For example, two rights that have great significance in the field of health are the right to participate in decision-making processes that affect one's well-being and the right to be free from discrimination. Thus, a state's efforts to realize its citizens' right to health should be characterized by the participation of community representatives at national and local planning levels, and by the enactment of interventions that serve all groups of citizens equally.
Background: HIV/AIDS in Brazil
Brazil, the world's fifth most populous country, has an estimated adult HIV prevalence rate of 0.5 percent, with approximately 610,000 adults thought to be living with HIV.1 Brazil's AIDS epidemic first manifested itself in the early 1980s in the urban gay community, particularly in Sao Paolo, the nation's largest city. The epidemic gradually made inroads into heterosexual populations, and since the mid-1990s, heterosexual sex has been by far the most common mode of transmission.2 This trend has been accompanied by a shift in the gender ratio, with women now accounting for more than one-third of reported AIDS cases.3 At the same time, HIV/AIDS is increasingly burdening poorer populations.4
In 1994, the World Bank estimated that Brazil would have almost 1.2 million cases of HIV infection by 2002. The caseload even now is little more than half that number. This can be attributed to two major factors: the strong commitment of the Brazilian government to implementing a comprehensive multifaceted national AIDS plan, and the deep involvement of civil society in many aspects of HIV/AIDS prevention, care and treatment.
Treatment is one of the most widely discussed components of Brazil's national AIDS plan. Since 1996, the government has distributed combination antiretroviral therapy for free through the national health system (Sistema Único de Saóde, or SUS). Brazil's position as one of the few developing countries with a domestic pharmaceutical industry has contributed to the economic feasibility of this policy, with Brazilian companies manufacturing generic versions of earlier antiretrovirals. The government has negotiated with the pharmaceutical industry for discounts on more recent antiretrovirals that cannot be copied because of patent laws. However, as demand grows for second- and third-line antiretroviral regimens that include imported drugs, the cost of sustaining the treatment program looms as one of Brazil's biggest AIDS-related challenges.
Conditions Supporting a Rights-Based Response in Brazil
AIDS emerged as a public health threat just as the nation of Brazil was beginning to undergo an immense transformation. Beginning in 1964, a series of military dictatorships ruled Brazil. Widespread opposition to this system of governance led to a gradual "redemocratization" process throughout much of the 1980s, driven by a broad-based political and social movement with a strong human rights element. The diverse elements of Brazilian society that banded together to bring about this transition included the sanitary reform movement — an informal coalition of health professionals, academics, and others "who demanded a public health system responsive to and controlled by the public and who defended the right to health as a fundamental human right to be guaranteed by the constitution."5
Brazil became a party to ICESCR in 1992. When its new constitution was enacted in 1998, it included significant human rights protections for Brazilian citizens, including the right to health. Enshrining the right to health in its constitution could thus be viewed as a significant step in the progressive realization of the right to health as called for in the treaty because this established an important point of reference for all of the country's future health-related legislation.
Well before the new constitution was in place, the human rights dimension of the democracy movement had already greatly informed early efforts to address HIV/AIDS. In the early 1980s, human rights activists and gay rights activists joined forces to quickly mobilize an organized response to the epidemic taking hold in the state of Sao Paolo. This community-based coalition found allies in the municipal and state public health agencies. It was here that the sanitary reform movement had helped instill a strong human rights-oriented perspective in the government's conception of its health-related responsibilities.6,7,8 Thus, the HIV/AIDS policies and programs that emerged in Sao Paolo State — which became a model for other states and later for the national AIDS program — embodied a sophisticated understanding of the relationship between health and human rights. This relationship had significant bearing on stigma and discrimination, and on access to medicines.
Stigma and discrimination
The prominence of human rights perspectives has contributed to widespread opposition to HIV-related stigma and discrimination since very early in the Brazilian AIDS epidemic. According to Dr. Alan Berkman and his coauthors, "A critical number of gay men and human rights activists, as well as men and women infected or affected by HIV, openly confronted the stigma, demanding that the rights of people living with AIDS be respected by the government and by their fellow citizens."9
In the state of Sao Paolo, community leaders found that this stance resonated with the State Department of Health, which recognized that countering stigma and discrimination would be an important part of the fight against AIDS. Health officials, in fact, drew parallels between the social responses to HIV and Hansen's disease (leprosy). The first person to head the state AIDS program, in 1983, later wrote:
From the beginning, the Sao Paulo AIDS Program was organized with all the components still existent today, including prevention, epidemiological surveillance, treatment and human rights, in addition to a strong component of linkage with [community organizations].... It was significant that the State Dermatology Division already had a multidisciplinary [Hansen's disease] team emphasizing community involvement and the struggle for the rights of affected individuals. The longstanding experience with Hansen's disease both supported and provided the initial structure needed to set up the AIDS Program. At the time, there was a strong link between AIDS and homosexuality, which also proved problematic. If there had not been a team in place to deal with the issues pertaining to rights, stigma and minorities as a government commitment and responsibility, it might have been much more difficult to create an AIDS Program with the above-mentioned characteristics.10
The Sao Paolo effort to counter stigma and discrimination was recognized by other states and later by the national program as an essential component of an effective HIV/AIDS plan. Meanwhile, by the late 1980s, community-based NGOs were taking their human rights-based campaign into the legal realm. NGOs filed lawsuits seeking to defend HIV-positive people from discrimination in housing, education, the workplace, and elsewhere. They also used lawsuits to challenge policies that required people to undergo HIV tests in order to qualify for jobs and be admitted to public exams.11
Legislative initiatives emerged to reinforce the courts' often favorable rulings. A 1988 law requires employers to extend workplace disability protection to HIV-positive employees. Laws also prohibit HIV-related discrimination in the workplace, in health care and in access to public facilities, and forbid medical personnel from revealing confidential medical information about HIV-positive people.12 With government encouragement, NGOs provide legal aid to HIV-positive people as part of their ongoing efforts to have the anti-discrimination laws upheld. A 2003 article reported that an estimated 36 NGO legal projects, located throughout the country, were then receiving funds from the Ministry of Health.13
Access to medicines
The Brazilian movement to provide access to AIDS medicines has also been driven in part by human rights-based arguments put forth by community members and health officials. A landmark 1996 law requiring free distribution of antiretroviral drugs through the public health system had its roots in actions that both of those groups had taken in the 1980s.
As one source explains, "The passing of this law reflected in part the efforts of community groups which had filed lawsuits, beginning in 1988, against state and local governments to guarantee assistance to people with AIDS and treatment with medication for AIDS-related opportunistic infections."14 Although the government was the target of the lawsuits, this did not mean government entities necessarily opposed the campaign for universal treatment. Some public health officials considered such a goal to be very much in line with the principles of the sanitary reform movement, which continued to influence the SUS. Berkman and his colleagues state:
Integral care was a core concept of the sanitary reform movement in Brazil before the debate about the need for linking treatment and prevention emerged within the international AIDS movement. Integrality…asserts that prevention must be integrated with care and treatment. The right to health extends to those already ill and in need of treatment, and there is recognition that having people access the health system will improve the whole range of public health initiatives. Integrality also is based on a commitment to the human rights of those afflicted: a prevention-only approach to health violates those rights and the dignity of those in need of care, devalues their lives and adds to the stigma that may accompany illness.15
The director of Sao Paolo State's first AIDS program suggests that his agency even deliberately helped spur the universal access campaign by purchasing the small amount of AZT that it did in 1989, initially only enough to treat seven percent of people in need of treatment.
It was a deliberate initiative as part of a strategy to create need, to generate demands and to spark involvement by society on the issue of antiretroviral treatment in Brazil.…These initiatives helped mobilize public opinion and the community, and in 1990 the Ministry of Health decided to begin purchasing all the AIDS drugs available on the market, including…medicines for opportunistic infections.16
The Sao Paolo State Department of Health set a similar precedent by beginning to distribute protease inhibitors as part of triple combination antiretroviral therapy in 1995, in response to preliminary reports of the efficacy of the new treatment strategy. The national AIDS program followed suit in 1996. At first, in the absence of legislation, the distribution of combination therapy reflected merely a policy rather than a clear-cut legal obligation on the part of Brazil's Ministry of Health. The legal obligation was imposed in November 1996, when Brazil's president signed Law 9313, which required the federal government to provide free AIDS medicines through the public health system to all people who needed them. Human rights arguments provided an important rationale for the enactment of the legislation.
The human rights frame has continued to shape the judiciary's interpretation of the government's treatment-related obligations in significant ways. For example, community advocates sued the federal government in 2000 to challenge the public health system's policy of providing genotyping tests only to patients who were taking protease inhibitors. The judge who heard the case ultimately agreed with the advocates' argument that access to genotyping tests should not depend on the use of protease inhibitors, and should be extended to people taking all forms of antiretroviral regimens. The judge's explanation for his ruling made reference to "all principles that guide the health program, in particular the right to life, as established in the preamble to Article 5 of the Federal Constitution."17
Conclusion
The international community has expressed strong interest in the accomplishments of government and civil society in regard to HIV/AIDS in Brazil, and there has been much discussion about how "the Brazilian model" might provide guidance for other developing countries where AIDS is a major health crisis. Of course the extent to which that model is taken up elsewhere depends in part on factors beyond the control of any single individual or group. As Berkman and his associates observed, "The political crisis of military rule that precipitated the social mobilization of large numbers of Brazilians cannot be artificially recreated in other countries." Likewise, the centrality of human rights principles in the government and civil society response to HIV/AIDS in Brazil reflects a unique convergence of circumstances.
Nonetheless, those seeking to influence how government and civil society address AIDS in other hard-hit countries might still draw powerful lessons from what has happened in Brazil. A striking feature of the Brazilian experience is that human rights principles have been integrated very concretely into multiple facets of the national response to HIV/AIDS. That is, when various players invoke human rights, they are bringing more than philosophical arguments to bear on the challenges they are facing. The Brazilian government has a legal mandate to honor the right to health and other human rights, and this mandate has particularly influenced responses to HIV-related stigma and discrimination and to the treatment needs of HIV-positive people.
Many countries have the same health-related treaty obligations as Brazil, yet have failed to operationalize the right to health to the same extent as Brazil. What sets Brazil apart? Affirming the right to health in the national constitution is an important factor, but again, Brazil is hardly alone in that regard. The concept of the human right to health has influenced Brazil's fight against AIDS in such significant ways because government and civil society took the crucial next steps. Brazil's executive and legislative branches have developed a body of law that provides clear direction on how the right to health is to be actualized The judiciary has provided critical guidance on implementation through rulings that address many different HIV-related issues from a human rights perspective. Finally, the role of civil society cannot be overstated. Since its earliest days, a strong community-based movement has conceptualized its objectives in terms of human rights principles.
Community advocates recognized that opposing HIV-related stigma and discrimination on human rights grounds was imperative. They also asserted that the right to health implies the right to treatment with the best available drugs. While civil society representatives engaged in dialogue with government agencies, they also pursued their rights-based goals through the legal system. Ultimately, the forces of government and civil society working together have shaped a strategy that demonstrates, through its success, both the moral and practical relevance of human rights in the global fight against AIDS.
1 Brazil [UNAIDS country profile]. Accessed 12/31/07 at www.unaids.org/en/CountryResponses/Countries/brazil.asp.
2 Berkman A, Garcia J, Muñoz-Laboy M, Paiva V, Parker R. A critical analysis of the Brazilian response to HIV/AIDS: lessons learned for controlling and mitigating the epidemic in developing countries. Am J Public Health. 2005 Jul;95(7):1162–72.
3 Greco DB, Simão M. Brazilian policy of universal access to AIDS treatment: sustainability challenges and perspectives. AIDS. 2007 Jul;21 Suppl 4:S37–45.
4 Berkman, ibid.
5 Berkman, ibid.
6 Galvão J. Brazil and access to HIV/AIDS drugs: a question of human rights and public health. Am J Public Health. 2005 Jul;95(7):1110–6.
7 Berkman, ibid.
8 Parker R. Building the foundations for the response to HIV/AIDS in Brazil: the development of HIV/AIDS policy, 1982-1996. Divulgação em Saóde para Debate. 2003 Aug;27:143–83.
9 Berkman, ibid.
10 Teixeira P. Universal access to AIDS medicines: the Brazilian experience. Divulgação em Saóde para Debate. 2003 Aug;27:184–91.
11 Passarelli A, Terto V. Nongovernmental organizations and access to antiretroviral treatments in Brazil. Divulgação em Saóde para Debate. 2003 Aug;27:252–64.
12 Bacon O, Pecoraro M, Galvão J, Page-Shafer K. HIV/AIDS in Brazil. AIDS Policy Research Center, University of California San Francisco. 2004.
13 Ventura M. Strategies to promote and guarantee the rights of people living with HIV/AIDS. Divulgação em Saóde para Debate. 2003 Aug;27:239–46.
14 Bacon, ibid.
15 Berkman, ibid.
16 Teixeira, ibid.
17 Passarelli, ibid.
AIDS Vaccine Update: Disappointment and questions after candidate fails in the STEP study
Cindra Feuer and Emily Bass, AIDS Vaccine Advocacy Coalition (AVAC)
The HIV vaccine research field suffered a blow in Fall 2007 with the announcement that Merck's promising HIV vaccine candidate was not effective and may have even increased susceptibility to acquiring HIV. The candidate, known as MRK-Ad5, used a disabled version of a common cold virus, known as adenovirus-5, to carry synthetic fragments of HIV genetic material. The vaccine was designed to induce immune responses that developers hoped would either prevent infection and/or reduce viral load in HIV negative people who received the vaccine and went on to become infected with HIV through high risk exposure.
The vaccine failed to show efficacy in two large trials, known as STEP and Phambili. In the STEP study, volunteers who received the vaccine were more likely to acquire HIV as compared to volunteers who received the placebo. This effect was strongest in volunteers who had been exposed to cold-causing adenovirus prior to receiving the vaccine.
The lack of efficacy and the possibility of vaccine-related enhancement of susceptibility to HIV infection have raised serious questions for AIDS vaccine researchers and prevention advocates: Why did the vaccine fail to reduce viral load setpoint or the risk of infection? What is the explanation for the apparent increase in susceptibility to HIV infection? Were the unexpected results a fatal knockout to all Ad5-vector vaccines, or a knockdown punch to a single candidate? And finally, how do prevention advocates respond to the crisis?
What happened
After extensive preclinical testing and several prior studies in humans, MRK-Ad5 was being tested in STEP (which enrolled MSM and heterosexual women in the US, Latin America and the Caribbean and Australia) and Phambili (which enrolled heterosexual men and women in South Africa). Both studies were jointly conducted by Merck & Co., and the HIV Vaccine Trials Network (HVTN) which is funded by the National Institutes of Health (NIH).
The vaccine candidate was designed to elicit T-cell based immunity. There is strong evidence that this type of "cell-mediated" immunity can play a role in control of HIV.
The STEP and Phambili trials involved participants who were HIV negative but at high risk for infection. All of the volunteers received ongoing risk reduction counseling, condoms, and STD treatment. During the informed consent process and the follow-up study visits, volunteers were counseled not to assume that they had received the vaccine, and not to assume that the vaccine provided any protection. All volunteers were urged to practice safe sex and other risk reduction strategies.
In September 2007, the Data and Safety Monitoring Board (DSMB) for the STEP study recommended that the trial halt immunizations after a scheduled data analysis showed "futility," meaning that there was no possibility that the vaccine would prove efficacious for either preventing infection or reducing viral load. Out of 1,850 men in the trial, there were 49 seroconversions in those who received the vaccine, compared with 33 in those who received the placebo. There was only one HIV infection in STEP's cohort of 1,150 women. This was not evidence that the vaccine worked better in women, since there were almost no infections among women in either the vaccine or the placebo arm. All subsequent analysis of STEP data related to vaccine effects focused on the male volunteers.
Immediately after the STEP DSMB recommendation that immunizations be halted, the Phambili trial also halted immunizations. Within three weeks, the DSMB for that study recommended that volunteers be unblinded, meaning that they were informed about whether they had received the vaccine or the placebo. The DSMB also recommended that they be counseled that receiving the vaccine might have increased their risk of HIV infection.
Understanding the data
The primary finding from the STEP study is of great concern; it is also quite confusing. While there were more infections among male volunteers who received the vaccine, as compared to male volunteers who received the placebo, scientists have yet to come up with an explanation for this apparent effect, which was most pronounced in volunteers who had levels of pre-existing immunity to adenovirus.
As part of ongoing research to try to understand the mechanism which might explain the finding, researchers are looking at samples stored from STEP participants. They are asking all volunteers from both STEP and Phambili to continue coming for study visits, where additional, intensified risk-reduction counseling is being made available.
An expanded research agenda for understanding the STEP data was discussed at the February 2008 Conference on Retroviruses and Opportunistic Infections (CROI) in Boston. Among other things, scientists are trying to understand whether and how pre-existing immunity to adenovirus might have affected vaccine-induced immune responses and subsequent susceptibility to HIV infection. They are also looking at other variables like circumcision status, HSV-2 status (whether or not volunteers had herpes simplex virus type 2) and other issues, which might explain the difference.
One reason for this is that there were noteworthy differences in some of the demographic characteristics of men in the high and low Ad5 titer groups. For example, there were considerably more non-white, non-US men in the high Ad5 titer group. This group also had significantly more uncircumcised men and more men under the age of 30. However, in the analyses that have been conducted to date, none of these demographic differences explain the observed trend towards increased rates of infection in vaccine recipients.
In discussions of this data analysis, scientists have emphasized repeatedly that it is quite possible that there may never be a clear answer about what happened in the STEP study.
Where to from here?
What is the best way to move forward in the context of such great disappointment and uncertainty?
This is one of the primary questions facing the prevention research world today. The reality is that for any drug or vaccine which reaches the market, there are many, many candidates which fail. The fact that MRK-Ad5 failed to provide any protection is hugely disappointing, but its failure is part of the product development pathway. The search for an AIDS vaccine, an effective microbicide and other new biomedical prevention strategies to use alongside existing methodologies must not be abandoned.
While there are many questions, there are also some clear lessons from the STEP data, particularly about the animal models that are used to evaluate future candidates. MRK-Ad5, like all candidate vaccines, was advanced into human trials after extensive pre-clinical testing and studies in non-human primates. In the primary non-human primate study that showed vaccine-related benefit, monkeys were given a candidate vaccine closely resembling MRK-Ad5 and challenged with a viral strain called SHIV 89.6p. Monkeys that received the vaccine had lower viral loads than those that did not get the vaccine. Based on the subsequent failure of the candidate in human clinical trials, there is a strong sense that animal model challenge experiments using SHIV 89.6p should not be used as the basis for advancing candidates.
The extremely low rate of HIV infections in women enrolled in the STEP study is also prompting some hard thinking, particularly on the part of US-based researchers and advocates. The fact that women in the STEP study got infected at much lower rates than men could have something to do with the prevention package provided at the trial sites; it could be that the criteria used to classify women as "high risk" for HIV infection did not identify women who fit into this category. It could be a combination of these and other factors. Going forward, it is critical to understand how to reach and engage with high risk women, both for prevention research and for prevention services in general, and there are emerging efforts at both the HVTN and the HIV Prevention Trials Network to develop studies which could get at these questions.
In terms of next steps for HIV vaccine development, one of the major questions facing the field is whether or not to proceed with an efficacy trial of a vaccine strategy developed by the US NIH's Vaccine Research Center. This strategy combines two types of vaccines in a prime-boost strategy — the priming vaccine is a DNA-based vaccine candidate and the boosting vaccine uses an adenovirus-5 vector which is similar, though not identical, to the MRK-Ad5 candidate.
An efficacy trial known as PAVE 100 of this vaccine combination strategy was scheduled to start in late 2007, and was put on hold after the STEP results were announced. Subsequent discussion has led to consensus in the scientific community that this strategy could only be tested in people who have no pre-existing immunity to adenovirus. This is a critical safety precaution, given the apparent trend towards increased susceptibility in people with pre-existing Ad5 immunity in the STEP trial.
Conducting a trial of the VRC strategy in "Ad5 seronegatives" could provide an answer about whether a different strategy (combining two vaccines, aiming at different qualities of immune responses) could have better results that the MRK-Ad5 product. However, at this time, it is difficult to imagine that an Ad5-vectored candidate could be taken through the full series of efficacy evaluations and licensed for use, given the safety concerns raised by the STEP data.
While this could change, we must acknowledge the many unknowns that surround the STEP data and all Ad5-vectored candidates at this time. The AIDS Vaccine Advocacy Coalition (AVAC) has argued that the PAVE collaborators moving ahead with a redesigned PAVE 100 should have a clear agenda for next steps should the study show any benefit. If there were positive results from the study, one possibility would be to try to re-create this success using alternatives to the Ad5 vector as next generation candidates.
Discussions about whether and how to proceed with a redesigned PAVE 100 study are ongoing. AVAC and other advocates have emphasized that input from communities that will be asked to participate in the studies is absolutely essential before any decision to proceed with the study is made, and AVAC is actively working with its partners to gather information on community perspectives. The STEP and Phambili trials have led to a moment of disappointment and confusion in the AIDS vaccine field and in the broader field of prevention research, where trials of candidate microbicides and the diaphragm have also failed to show efficacy in the last 12 months. In this context, it is as important as it has ever been that communities convey clear, accurate messages about what is known and what is not known, both about specific products and about the overall effort to find additional, new interventions to prevent HIV infections.
The toll of new infections is too high to abandon the search for additional strategies. Results from a trial which looks at herpes treatment as a strategy for reducing susceptibility to HIV infection were released at the February 2008 Conference on Retroviruses and Opportunistic Infections. And some data on pre-exposure prophylaxis (PrEP) are expected beginning in the next 12–18 months. These trials could bring positive news, or additional setbacks. Whatever happens, prevention research must continue to be a priority as part of a comprehensive response to the epidemic. This means providing full access to what prevention and treatment options are available today, and continuing to search for additional strategies that can help save lives tomorrow.
For more information visit www.avac.org and www.aidsvaccineclearinghouse.org
HIV Lipodystrophy:
Where are we after ten years?
By Nelson Vergel, Director, Program for Wellness Restoration
Note: The following article expresses the opinions and learned lessons of the writer, not of GMHC, Treatment Issues, or their staff. It is not intended as medical advice and should not be taken as such.
Ten years have passed since the first report of lipodystrophy at an HIV conference. The excitement and hope for a longer life that accompanied the arrival of Highly Active Anti-Retroviral Therapy (HAART) has been tempered by accounts of humps, bellies, and facial wasting. A decade on, many unanswered questions and misconceptions about HIV associated lipodystrophy persist with only a limited number of treatment options available. Frustrated and tired of waiting for answers from the medical community, many people living with lipodystrophy have turned to the internet for advice, treatment and support in hopes of reversing some of the devastating effects of this stigmatizing syndrome.
Lipodystrophy is a condition of abnormal fat redistribution that can lead to either lipohypertrophy (fat accumulation in specific areas of the body such as the neck, belly, upper torso, and breasts) or lipoatrophy (fat loss in the face, buttocks, arms and legs). An online survey of 695 people (predominantly white men, over the age of 40, living with HIV for over 10 years and with exposure to HAART for at least that long) found that 20% had considered suicide because of body shape changes associated with lipodystrophy. Almost 90% of respondents believed that their HIV medications caused lipodystrophy, and 20% had stopped taking their HIV medications altogether due to this concern. Further, over 60% of respondents reported being rejected by potential sexual partners because of the syndrome. A similar number of respondents indicated that they had stopped looking into the mirror because of crippling body dissatisfaction. Nearly all of the respondents attempted to curb the effects of lipodystrophy with diet and exercise or by using costly facial reconstruction procedures, supplements and hormones — treatments not typically covered by insurance companies or drug assistance programs.
Lipoatrophy and HIV Medications
In 1999, the HIV drug Zerit was correlated with the development of lipoatrophy related fat loss under the skin.1 Since then, several studies have concluded that Zerit can affect the way our mitochondria (energy factories in our cells) work and multiply. Later studies also linked lipoatrophy to AZT, although at a lower rate than Zerit. Nucleoside reverse transcriptase inhibitors (NRTIs) like Zerit and AZT, keep HIV from altering the genetic material of healthy T-cells, thereby halting the reproduction of new virus cells. Additionally, NRTIs affect the mitochondria in fat cells under the skin, preventing them from multiplying and causing them to die. Also, those who have taken Zerit and Videx (another NRTI) together report more lipoatrophy than those taking Zerit alone. This combination is not recommended by guideline groups. It appears that Zerit and AZT make fat accumulation worse in the presence of protease inhibitors or non-nucleoside analogs (NNRTIs) like Sustiva, leading researchers to suspect that their negative effect may play a combined role. However, Sustiva taken with Viread (Tenofovir) and Epivir (3TC) seems to cause less lipoatrophy. Due to the high risk of developing lipoatrophy and neuropathy, the US Department of Health and Human Services guidelines committee dropped Zerit from the list of recommended drugs for first line therapy for people new to HAART.
Viread (Tenofovir) and Ziagen (Abacavir), two other NRTIs in the same drug class as Zerit and AZT, do not seem to strongly correlate with the development of lipoatrophy. Some people have even reported a slow reversal of the fat loss after switching from Zerit or AZT to either Ziagen or Viread. However, even after a number of years most patients do not experience re-accumulation of fat in their faces after going off AZT or Zerit. It is also important to note that puzzling new data from a recent study by the AIDS Clinical Trials Group2 showed that 20% of subcutaneous fat loss (loss in body fat closer to the skin's surface) occurred in a small percentage of patients starting HAART for the first time with a combination of Sustiva, Viread and Epivir. More studies are needed to determine why lipoatrophy still occurs in some patients in the absence of Zerit or AZT.
The sales of Zerit and AZT in the industrialized world have dropped considerably in the past years due to their effects on lipoatrophy. Unfortunately, these two drugs are among the primary HIV medications used in the developing world, so millions of people in poorer countries will continue to suffer with body changes.
Treatment Options for Lipoatrophy
In recent years many men have relied on an off-label injectable anabolic steroid called nandrolone decanoate (old trade name: Deca Durabolin), to "balance out" their bodies and add muscle to their thin extremities and buttocks affected by lipoatrophy. Even though Watson Laboratories ceased production of nandrolone in March of 2007, it is still available through prescription at compounding pharmacies for a low cost.3
Uridine (Nucleomaxx), a supplement made of sugar cane and available through a German supplier,4 may lessen lipoatrophy in patients taking Zerit, however it may also cause abdominal fat and high triglycerides. These side effects, along with high cost and bad taste, make Uridine an unpopular choice. However, for those who must take Zerit, Uridine may be a viable option to prevent or reverse lipoatrophy. Additionally, for those who are no longer taking Zerit, the diabetes drug Rosiglitazone (Avandia) works well for reversing lipoatrophy. There are side effects however, including weight gain and high triglycerides.
Since 2002 there have been a couple of non-permanent reconstruction procedures available to treat facial lipoatrophy. The face wasting reconstruction option, Sculptra (polylactic acid, old name: NewFill) entails an expensive series of multiple sessions, requiring additional touch ups that can be used to treat those moderately affected by lipoatrophy. Radiesse, another FDA approved option, seems to last a little bit longer but is also costly, requiring 3–5 sessions and yearly touch ups. Some patients treated with face wasting fillers experience side effects such as bruising and treatable granulomas (hardened pimple-like nodules). There are patient assistance programs available for both Sculptra and Radiesse.5
There are no FDA approved permanent solutions for facial lipoatrophy, yet many in the US seek tiny injections of silicone (Silikon 1000) from their doctors. Silikon 1000 can be used legally in an off-label manner for facial lipoatrophy. Silikon 1000 micro-injections can reconstruct patients' faces slowly over five sessions spaced one month apart. There is no patient assistance program for this option and sessions cost anywhere from $600 to $900. Here too, multiple sessions are required. Beware that very few US doctors are well trained in this procedure.
Another permanent product, Polymethylmethacrylate (PMMA), has been used in Brazil for eight years and in Mexico for three with relatively positive results, though more time is needed to determine the long term effects of this procedure. Usually 2–4 sessions are required and no yearly touch ups are needed. Short term, we have seen that PMMA can harden and be lumpy in certain patients, but many people seem pleased with the results. Artefill, a PMMA based product, is FDA approved for cosmetic purposes but not for HIV related lipoatrophy. Artefill is extremely expensive for the amount required to treat lipoatrophy, so some HIV positive people in the US go to Mexico or Brazil for the procedure, where costs can range from $2000 to $6000. PMMA is not removable.
BioAlcamid (poly-alkylamide gel), also permanent, is an injectable filler unavailable in the US (some patients travel to Mexico or Canada for injections). Unfortunately, BioAlcamid forms a "pocket" in the face and buttocks enabling bacteria to penetrate and posing a high risk of infection. As such, extreme caution is warranted before pursuing this option.
It is critical to remember that no long-term data on these experimental facial reconstruction treatments are available, so one must weigh the risks of injecting a foreign substance into one's body. Sadly, many people find that the emotional, psychological and social toll of living with lipoatrophy is so great as to justify these risks.
Understanding Lipohypertrophy
Unlike lipoatrophy, researchers have not been able to attribute lipohypertrophy (fat gain in the belly, back of neck and breasts) to any specific medication or drug class. Protease inhibitors were once thought to be the main culprits. However, researchers have recently discovered that fat gain in the belly may relate to inflammatory responses in the immune system when CD4 cells increase in number. This means that those who start HAART with a lower baseline CD4 count may see greater lipodystrophy. Moreover, recent data shows that patients with a CD4 count of over 250, who start a HAART regime with protease inhibitors boosted with Norvir plus Viread and Epivir, do not experience a gain in visceral fat (fat surrounding the internal organs). It is still too early to tell what happens to those on this particular regimen who start with lower CD4 counts. Some studies have shown that those who begin taking protease inhibitors in combination with Zerit, AZT or Zerit plus Videx seem to have more visceral and hump fat gain than those who start on protease inhibitors with other drugs. It may be that the same drugs that are linked to lipoatrophy may also make fat gain worse, especially in patients who start HAART with fewer CD4 cells.
A common misconception promoted by a few pharmaceutical companies and echoed by some doctors is that HIV medications that do not increase cholesterol, and that triglycerides do not cause fat gain. On the contrary, several studies have shown that people taking lipid friendly drugs like Reyataz with Viread also gain fat in the belly after starting HAART.
Dr. David Nolan, a clinician and researcher at Royal Perth Hospital in Western Australia and an expert on fat metabolism and HIV, was asked about why visceral fat does not get "burned off" by Zerit and AZT like subcutaneous fat does. Dr. Nolan hypothesized that fat cells in the organ cavity may not be as susceptible as subcutaneous fat cells to the mitochondrial toxicity caused by Zerit and AZT.
Fat gain may also be linked to insulin resistance. Insulin resistance can cause glucose intolerance, which has been associated with fat gain, increased triglycerides, and the development of diabetes. Insulin is a hormone produced by the pancreas to control blood sugar-glucose. HIV medications may block or slow down the process by which insulin converts glucose to energy. In laboratory studies, Crixivan and higher doses of Norvir and Zerit have been shown to impair the action of insulin in fat and muscle cells. In this scenario the pancreas will tend to produce more and more insulin to compensate for the decrease in function. High insulin levels may be present for years before type 2 diabetes develops. A glucose tolerance test (GTT) may reveal that problem easily but it is hardly used in clinical practices. Additionally, some people may have a genetic predisposition to insulin resistance. A sedentary lifestyle and a diet rich in sugars and animal fats may also compound this problem. In any case, insulin resistance may just be a part of the mystery of lipohypertrophy. There is no agreement among researchers whether or not monitoring insulin levels in HIV-positive people is justifiable or dependable as a tool to assess insulin resistance and fat gain.
The full body dual x-ray absorptiometry (DEXA) scan is the gold standard test in lipodystrophy. It is a highly valuable test that can provide information about body fat, muscle mass and bone density (low bone density has been associated with HIV in several studies.) Both Medicare and private insurance often cover this inexpensive test. While the scan cannot differentiate between fat accumulated in the belly on under the skin in the abdominal area, it can be useful as a baseline to assess body changes and to justify reimbursable therapies for fat, muscle, and bone mass.
Treatment Interventions for Lipohypertrophy
Some people have switched from protease inhibitors to Viramune or Sustiva to combat visceral fat gain, but this has not been shown to make a difference. It is not yet known what happens to belly fat when a patient switches from Zerit or AZT to Viread or Ziagen while taking protease inhibitors or non-nucleoside analogs like Sustiva or Viramune.
The recombinant human growth hormone Serostim is a daily injectable drug approved by the FDA for HIV associated wasting. At approximately $3000 a month, it is an expensive option for treating lipodystrophy. Serostim works well in lowering abdominal fat but has many side effects including joint pain, water retention, carpal tunnel syndrome, and irreversible diabetes. These side effects and the lack of proven longterm health benefits are why the FDA has not approved Serostim for the treatment of HIV related fat accumulation.
Tesamorelin-TH9507, made by Theratecnologies, is a daily injectable growth hormone precursor that is in its last stages of FDA approval. Tesamorelin appears to have fewer side effects than Serostim, but may take a longer time to show benefits in patients. Disappointingly, fat gain returns after discontinuation of both Serostim and Tesamorelin.
Leptin, a hormone that produced by fat cells, is another new contender in the search to decrease visceral fat. Researchers have found that leptin levels in the blood are proportional to an individual's level of body fat. Leptin works in the part of the brain that controls appetite and other basic functions. High levels of leptin generally suppress the appetite and stimulate the burning of fat. Leptin does not appear to have a negative impact on glucose tolerance.
Nowadays, physicians are likely to prescribe testosterone gels, injections, and subcutaneous pellets. A testosterone gel applied to the belly can reduce the waist size in HIV-positive men. This decrease is usually as a result of a reduction in subcutaneous fat, not in visceral fat. In contrast, a small pilot study of Oxandrin (an oral anabolic steroid) has yielded encouraging results in decreasing visceral fat. Increases in the low density lipoprotein (the "bad" cholesterol) and decreases in the high density lipoprotein (the "good" cholesterol) correspond to a small decrease in subcutaneous fat. There are no data yet on a connection with the popular anabolic steroid, nandrolone decanoate, and visceral fat reductions.
Some individuals who have been looking elsewhere for fat burners have fallen prey to advertisements pushing growth hormone supplements or fat burners. These products do little but increase blood pressure and anxiety and are generally considered scams.
Metformin (trade name, Glucophage), is a generic diabetes drug that has been shown to improve glucose tolerance and lower visceral fat. Its effects may be enhanced by exercise. Metformin improves insulin sensitivity, triglycerides and fatty liver but can also cause diarrhea and weight loss. There have also been reports of low blood sugar and dizzy spells associated with this drug.
In addition to the aforementioned treatments many patients explore liposuction. Ultrasound-assisted liposuction can be used to successfully remove fat accumulated in buffalo humps and around the neck.
Some patients complain about the enlargement of salivary glands on each side of the face commonly referred to as the "chipmunk look." While only a few radiologists know how to use it for this purpose, low dose electron radiation has worked very effectively in treating the enlargement of salivary parotid glands. It is unknown whether the "chipmunk look" is related to lipodystrophy or caused by immune reconstitution.
Another under explored intervention is diet and exercise. A study at Tufts University revealed a trend towards less lipodystrophy in those who had higher consumption of soluble fiber (fruits and vegetables) and who exercised. However more research is needed with the use of diets lower in simple carbohydrates. These diets have been shown to improve insulin resistance and visceral fat in non-HIV studies. One observational cohort showed that people with HIV eat more saturated fats. A small pilot on a combination of cardiovascular and resistance exercise showed decreased triglycerides and visceral fat. However, adherence to exercise remains a challenge to many people, and exercise research in HIV generally remains in its infancy.
Increased Lipids: Low density lipoprotein (LDL) and triglycerides)
The most common lipid abnormalities in HIV are high triglycerides and LDL, "bad" cholesterol, and low High Density Lipoprotein (HDL), "good" cholesterol. Before HIV-positive people start HIV medication for the first time, both their high and low density lipoprotein may be lower than normal. However, after HIV drugs are started, low and high density lipoproteins and triglycerides increase in some people. Some studies have shown that LDL increases to "pre-HIV" levels while HDL never returns to normal levels. Increased triglycerides is the most strongly associated lipid change caused by HIV medications such as protease inhibitors, Zerit, AZT, or Sustiva. Among protease inhibitors, Reyataz seems to correlate with the lowest lipid increases.
Many people want to start supplements before they start lipid lowering medications. The only supplements with solid emerging data on lipids are omega-3 fatty acids (fish oils), and niacin (also available as Niaspan). Fish oils can decrease triglycerides but some patients' stomachs cannot tolerate them. Niacin is better than any lipid lowering drug in increasing the "good" cholesterol (HDL). It can cause flushing of the face and a hot sensation for a half an hour at a time, but most people get used to it. Non-flush versions are available but their effectiveness is unknown.
It is not clear if Raltegravir (Isentress, the first integrase inhibitor) or Maraviroc (Celsentry — a CCR5 entry inhibitor) have any effect on body composition. So far, they appear to be lipid friendly when taken with Viread and Epivir. Fuzeon (an injectable entry inhibitor) also seems to be lipid friendly, but it is usually used with boosted protease inhibitors that can cause increases in lipids. It seems that there may be genetic factors that make some patients more prone to increased low density lipoprotein (bad) cholesterol and triglycerides.
Lipid lowering agents like statins (Lipitor, etc) or fibrates (Tricor, etc.) can work wonders in many, but even with their use, some patients never reach "normal" lipid levels. A combination of niacin, lower sugar and animal fat intake, exercise, fish oil supplements or an increase in fatty cold water fish consumption (salmon) and soluble fiber (fruits, vegetables, oats) are sometimes used to treat lipids. Some individuals have tried combining statins and fibrates, but this combo can lead to an increase in muscle related disorders in some patients.
Conclusion
We have learned a lot during the past 10 years about body changes associated with HIV, but many more questions remain. It is the hope that those new to HAART therapy will not have to suffer the devastating drug side effects that their predecessors have had to contend with in the past 20 years. As patients, it is our responsibility to stay educated and learn from others about emerging options that may make it possible one day to live fully without HIV related body changes and other side effects.
For more information visit: www.facialwasting.org or to subscribe to the largest internet HIV health discussion group send a blank email to pozhealth-subscribe@yahoogroups.com
1 A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. Saint-Marc T, Partisani M, Poizot-Martin I, Bruno F, Rouviere O, Lang JM, Gastaut JA, Touraine JL. AIDS. 1999 Sep 10;13(13):1659-67.
2 Metabolic Outcomes of ACTG 5142: A Prospective, Randomized, Phase III Trial of NRTI-, PI-, and NNRTI-sparing Regimens for Initial Treatment of HIV-1 Infection. Richard H. Haubrich, S Riddler, G DiRienzo et al.
3 More information is available at www.medibolics.com
4 More information is available at www.nucleomaxx.com
5 More information is available at www.facialwasting.org.
Migration and HIV in Africa: Challenges and Recommendations
Anthony Rutabanzibwa
Increasingly, global responses to migration and to migrants are influencing responses to the HIV/AIDS epidemic itself. African migrants in particular have borne the brunt of xenophobia and discrimination directed toward outsiders. Those who are undocumented have little or no legal protections and limited access to basic health and social services that are fundamental to successful integration into a foreign environment. These barriers, coupled with the complex social, behavior and psychological dynamics of migrancy, form a constellation of risk factors that heightens vulnerability for contracting HIV/AIDS.
The African population has always been extremely mobile. Pre-colonial migratory patterns occurred without barriers or legal restraint, driven by agricultural resources, trade and labor. Similarly, in the post-colonial period migration has become a vehicle for economic betterment as well as an escape valve to overwhelming tensions caused by displacement, conflict, poverty, and resource deprivation. Today, international labor migration is commonplace.
With the increased sophistication of globalization a common pattern of regional and international African migration has emerged. The vast majority of migratory routes now steer northwards towards Europe and westwards towards the Americas. Migratory highways extend from as far as Somalia through Sudan, Libya to Tunisia and across the Mediterranean into Spain and Italy.
According to the International Labor Organization (ILO), over 20 million African men and women are migrant workers. The World Bank reports that remittances by Africans working aboard now account for a substantial portion of the gross domestic product of Lesotho, Senegal, Uganda and Nigeria. In spite of the critical role they play in the economic development of their adoptive countries, these workers are, at best, treated as second class citizens. Recognizing this reality, the international community has sought ways of achieving justice via the creation of specific international migrant worker rights conventions, including the Migration for Employment Convention (Revised) of 1949; the Migrant Workers (Supplementary Provisions) Convention of 1975; and the United Nations Convention on the Protection of the Rights of Migrant workers and their Families, adopted by the United Nations General Assembly in 1990. These legal instruments created principles for the establishment of national laws and judicial and administrative procedures related to the human rights of migrant workers (such as equal treatment in employment, social security, non-discrimination, and anti-trafficking activities). It is important to note that the U.S and most of the western European counties that receive migrant workers have not yet ratified or adopted the recommendations in these aforementioned treaties and therefore are under no legal obligation to extend to migrant workers the kind of protections envisaged in these conventions.
AIDS in Africa is a pandemic — affecting the lives of over 22.5 million people in sub-Sahara Africa alone. In popular lure, migration and HIV/AIDS are often described as associated phenomena, with the migrant commonly considered the host and vector of HIV/AIDS. Despite the prevailing myth that migrants, refugees and other mobile populations spread HIV/AIDS, studies have shown that they have significantly lower prevalence rates than the surrounding communities wherein they reside. In no less than 60 countries, African migrants are forced to undergo mandatory HIV testing as a pre-condition for work permits and immigrant visas. In other countries, mandatory testing is a condition precedent for being granted an extension of work permits. A positive HIV test often leads to repatriation or denial of a visa or work permit for migrants. Mandatory HIV testing for purposes of exclusion must be discouraged; however HIV testing accompanied by assurances of access to appropriate treatment and care following a positive diagnosis should be made available.
In many African countries, regulatory frameworks are being revised with the objective of integrating HIV/AIDS-related human rights principles into a national legal fabric. Some countries are going as far as drafting provisions in the law that clearly stipulate that HIV positive people entering or returning will enjoy the same rights as non-infected persons, reaffirming that one's HIV status will have no bearing on the right of entry, freedom of movement or freedom to work. For example, the economically integrated regional trading blocs in Africa- known as the Regional Economic Communities (RECs) have subscribed to the commitments laid out in the 2001 United Nations General Assembly Special Session on HIV/AIDS Declaration. The declaration stipulates that RECs should develop and implement strategies that incorporate HIV/AIDS awareness, prevention, care and treatment into emergency response and national assistance programs that target refugees, internally displaced persons, and migrants. It is within this context that some African countries, already overburdened with the HIV/AIDS epidemic of their own nationals, have restructured their health systems so as to benefit foreign migrants by providing free HIV/AIDS-related medical services.
Governments have an obligation to safeguard human rights protections for all people, irrespective of HIV status. As such, a strategic conscious-raising and advocacy campaign needs to be undertaken to change worldwide perception on migrant populations. Restrictions imposed on travel, entry and procedures related to immigration and asylum based on one's HIV/AIDS status are a violation of the right to equality of treatment before the law. National governments must ensure that such rights do not disappear once a migrant leaves his or her country of origin.
© 2008 Gay Men's Health Crisis
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