More than 90% of new infections with the human immunodeficiency virus (HIV) occur in the developing world, where the global pandemic is still expanding in traditionally underserved populations and has an overwhelming impact on community-wide patterns of morbidity and mortality. Under such circumstances, the most important areas of HIV management concern the strategies for prevention of mother-to-child transmission and models to improve access to resources and care. The issue of research as direct development aid for many countries is contrasted with ethical questions concerning therapeutic research on populations who are unlikely to benefit from such research.
The situation concerning HIV in industrialized countries is sharply different. In these countries, the research emphasis has shifted toward lessening the number of missed opportunities for prevention and to optimizing the outcome of a chronic condition in a reducing number of new patients.
Similar epidemiologic differences to those listed between the developed and the developing world also exist within societies of all countries. The research issue of improving access to and compliance with care and management advice applies equally to socially disadvantaged children in the developed world.
The gut is the most common portal of entry for vertically acquired postnatal HIV infection. Physiologic alterations affect gut mucosal function and the nutritional state even before the onset of frequent opportunistic infections. In the developing world, this evolving condition may be aggravated by gut damage from both undernutrition and from repeated infections due to environmental contamination, insufficient safe water and inadequate hygiene.
Because gut epithelial cells do not express the CD4 receptor, HIV gains entry to the lamina propria by means of additional receptors and coreceptors. Coreceptor expression may be inducible and appears to affect susceptibility to infection. The mechanisms of mucosal infection and susceptibility remain areas of intense research.
The pathogenesis of HIV enteropathy involves mucosal immune factors, lamina propria infection and inflammatory mediators. Immunomediated gut disease is associated with indicators of mucosal inflammation and damage.
Malnutrition, wasting and poor growth are considered to be of multifactorial origin in HIV-infected children. Contributors include anorexia secondary to physical, pharmacological and psychosocial factors, emesis, diarrhea and alterations in metabolic rate and energy use, predominantly via increased proinflammatory cytokines.
The introduction and widespread use of highly active antiretroviral therapy (HAART) has raised new concerns regarding its long-term use and side effects, as well as the differences in its availability, affordability and access. In many centers, the management of HIV/AIDS has now changed from that of treating opportunistic infections to that of managing a chronic condition. Long-term metabolic toxicities include lipodystrophy and mitochondrial damage in many different organ systems. The presence of these complications requires that interruption of antiretroviral therapy be weighed against virologic progression and the risk of development of drug resistance. Adherence to treatment schedules and compliance with medications has a number of determinants but is considered to be critical to long-term virologic success. Immune system reconstitution with a successful response to HAART is paradoxically accompanied by heightened inflammatory reactions in some instances.
The scale and extent of the HIV pandemic are nothing short of overwhelming. The most effective response will require the development of new paradigms in global health care that are built on unprecedented international communication and cooperation.
The unprecedented magnitude of the HIV/AIDS epidemic has resulted in huge research efforts and large funding opportunities at international, national, and local levels. International alliances include the United Nations Programme on AIDS (UNAIDS) as well as governmental and nongovernmental organizations and charitable foundations. Cooperative research opportunities are available on many different levels between universities, research organizations and institutes and sites in the developing world.
The ethical controversies sparked by the maternal-fetal transmission trials in developing countries during the 1990s provided an impetus for revision of the Helsinki Declaration. However, it remains unresolved how to deal with absolutist ethical guidelines, which are applicable to donor countries but which may potentially prevent appropriate research into essential drugs and vaccines from taking place in developing countries, where such research might actually be welcomed as a form of direct development aid.
Health Ministries should support local independent, authoritative and credible ethics committees in their own countries in their ability to decide what research is appropriate.
Improved Understanding of the Determinants of Mother-to-Child Transmission of HIV Infection
A huge gap has developed between the epidemiologic patterns of childhood HIV disease applicable to the developed and the developing world. In many countries without access to the means and infrastructure to mount effective preventive and management strategies, the epidemic persists at an escalating level, and the majority of pediatric hospital admissions and deaths are now due to HIV-related complications (1). The economic and social impact of this epidemic has national and international consequences. Family and community systems are breaking down around children infected or affected by HIV through loss of caretakers and through physical, social and economic deprivation.
Epidemiologic differences also apply within the societies of all countries. Social, economic and educational stratification influences the risk of infection, access to, and compliance with therapy. Even in the developed world, socially disadvantaged children have a higher risk of infection and show lesser rates of compliance with care and management advice.
The most serious impediment to the introduction of cost-effective strategies for the prevention of mother-to-child transmission is a lack of the capacity and infrastructure required to provide counseling, testing, and management follow-up of all eligible women in many countries of the developing world. Prerequisites to the prevention of mother-to-child transmission are an efficient system of identification of infected women during the antenatal period by informed counseling and voluntary testing, resolution of all the issues of access, availability of therapy options and compliance and support at both the community and the healthcare system levels.
In all environments, locally operative epidemiologic factors that may confer additional risk of, or indeed protection against, transmission or disease progression need to be researched in greater detail and must be documented to develop rational community-specific strategies for management and prevention.
Plans to Achieve Research Goal
In the developed world, the concern must be to improve identification, access and compliance in reducing numbers of patients. Multicenter studies help to maximize information gained from the study of individual patients. Research networking through scientific meetings and electronic communication must be strengthened to enable sharing of experiences, information, and even biologic materials. An instrument to follow infected children should be developed in an open, Internet-based forum and made widely available. Caregivers involved with HIV-infected children worldwide should be encouraged to enter their patients' data into the instrument every 3 to 4 months. A paid consultant should review and present the findings at 2 years and at the next international conference.
In the developing world, much research effort must be trained on reducing the transmission rates to young women and their babies. Environmental factors such as intestinal parasites may influence the risk of vertical transmission by their effects on the nutritional state, gut mucosal integrity or coreceptor expression (2). Such studies should be initiated. Multicenter and multicountry cooperation supports service delivery in developing countries and maximizes research opportunities.
Research is still needed to fully elucidate the role of breast milk in mother-to-child transmission in the context of societal traditions and norms, so that the impact of feeding advice and policy on community-wide patterns of infant feeding can be appreciated. In resource-limited countries with high infant mortality rates, excess deaths are usually due to gastrointestinal and respiratory infections and malnutrition. If the availability, safety and nutritional adequacy of replacement feeding cannot be guaranteed, a lowered HIV transmission rate could be cancelled out by increased morbidity and mortality from enteral infection and malnutrition in non-breast-fed infants.
Improved Understanding and Management of Intestinal and Hepatic Side-Effects of Highly Active Antiretroviral Therapy
The introduction of HAART has improved the outlook for children infected by HIV. Pediatric patients potentially face many decades of living with HIV/AIDS and its therapies. In view of the special requirements for childhood growth and maturation, the long-term effects and side effects of drug treatment pose particular challenges related to growth itself, metabolic toxicities, hypersensitivity reactions, compliance and virologic outcome.
Poor growth is found in about 50% of HIV-infected children and is associated with the HIV RNA load, insufficient nutrient intake, and inconsistent relationships with gut abnormalities, malabsorption or neuroendocrine abnormalities. Suppression of HIV replication with HAART has a favourable effect on growth (3).
Hyperlipidemia and body fat redistribution occur in 22% to 75% of adult patients exposed to HAART. This appears to be related to mitochondrial dysfunction, a direct drug effect and altered cytokine profiles. Nucleoside reverse transcriptase inhibitors cause mitochondrial dysfunction, and proteinase inhibitor drugs additionally inhibit specific enzymes in the metabolism of fat. Lipodystrophy is common and increases with duration of proteinase inhibitor use (4). At present, the long-term risks of lipodystrophy and hypercholesterolemia are unknown, as is optimal management of these conditions.
Metabolic toxicities due to HAART are common and principally mediated via damage to mitochondria (5). These include presentations with anemia, myopathy, pancreatitis, neuropathy, hepatic steatosis and lactic acidosis. In addition, altered glucose metabolism and insulin resistance are seen, as are osteoporosis and osteonecrosis. The long-term effects of life-long therapy with HAART are not fully known at this stage.
Apart from coping with numerous side effects, a critical element of therapy is adherence to complicated treatment schedules. Frequent regimen changes are related to virologic failure or toxicity (6). Adherence with HAART is associated with lower viral loads, and virologic failure may be related to issues of compliance.
Viral suppression with HAART is followed by reconstitution of CD4 counts due to a falling viral load. Paradoxically, this may be associated with heightened inflammatory responses due to persistent immune system dysregulation, leading to atypical presentations of several coinfections (7). Research efforts are directed at possibilities of stimulating immune reconstitution in patients on HAART and counteracting injurious cytokine effects (8).
Plans to Achieve Research Goal
Large multicenter trials are needed to track HAART-treated children and to document the evolution of metabolic and other consequences. An Internet-based HAART utilization instrument should be established in which investigators prescribing these medications would track their efficacy and side effects. Supplemental funding should be provided so that investigators conducting therapeutic trials on HAART side effects would be encouraged to share results with other investigators, adding data to this website. Cooperative trials will be needed to delineate the best management for the complications and side effects of HAART.
Improved Understanding of the Epidemiology, Pathogenesis, Pathophysiology and Management of HIV Enteropathy
The gut is a common portal of entry for vertically acquired HIV infection. After crossing the gastrointestinal epithelium, HIV infects macrophages and lymphocytes in the lamina propria. Viral replication occurs in the mucosa throughout the natural history of HIV infection.
In HIV infection, there is dysregulation of gut immunity (9). The immune disorder leads to both humoral and cell-mediated immune defects. Mucosal inflammation occurs with increased lamina propria mononuclear cells and increased numbers of intraepithelial lymphocytes in areas of enterocyte damage. A decrease in the CD4 cells of the lamina propria appears to be an early event. As this decline in CD4 cells continues, the histologic examination shows villous atrophy and crypt hyperplasia. This is more common in cases in which the lamina propria cells express p24 antigen.
The disordered immune system itself contributes to mucosal injury, termed “HIV enteropathy” (10). Activation of T cells results in the release of various cytokines, particularly tumor necrosis factor α (TNF-α) and interferon-γ. These cytokines affect enterocyte differentiation and function. Ultrastructural studies reveal irregular, joined bases, shortened and broadened microvilli, mitochondrial swelling, formation of lysosomal and vesicular bodies and dilated endoplasmic reticulum, as well as tubuloreticular inclusions in the endothelial cells (11). Further studies are needed to elucidate the precise pathogenesis of intestinal injury and possible methods of management.
Initially, the ongoing immune response to HIV infection results in disease; later, this is due to opportunistic infection. Adult studies suggest that the earliest stage is characterized by delayed hypersensitivity phenomena. In the intermediate stage, there is generalized activation of all classes of cytokines. In the late stage of HIV infection, there is predominant activation of the proinflammatory cytokines TNF-α and interleukin-1β. These immune reactions are likely directed at HIV, but some features are similar to graft-versus-host disease and may include autoimmune processes.
Some studies did not support the role of inflammatory mediators and CD4 T-cell activation in the pathogenesis of HIV enteropathy (12). Thus, the relative role and importance of direct HIV-mediated effects or cytokine-mediated mucosal changes has yet to be clearly elucidated.
The mucosal inflammation is accompanied by disproportionately severe functional disturbance. As a result, the patients develop diarrhea, malnutrition, growth retardation and immune dysfunction. The pathogenesis of the wasting syndrome in patients with HIV infection is most likely to be multifactorial. Possible contributing factors are insufficient intake due to anorexia, vomiting, psychosocial factors, malabsorption, increased energy requirements and increased circulating cytokines such as TNF-α, interleukin-1 or interleukin-6. Derangements in lipid cycling and metabolism compromise the growth of HIV-infected children in between opportunistic infections. Because depression of immune function secondary to malnutrition is potentially reversible, nutritional rehabilitation in HIV-infected children may have a positive effect on immune function, lower serum cytokine levels, decrease opportunistic infection and diminish HIV replication (13). The role of proactive nutritional management, including gastrostomy feeding, needs to be defined in relation to its potential beneficial effect on immune status and outcome.
Altered gut motility can be caused by several mechanisms, including potassium and magnesium depletion, as well as by altered release of gastrointestinal hormones and autonomic dysfunction. In adult patients, jejunal autonomic nerve degeneration has been shown to occur quite early in the disease.
In the late stage of HIV infection, gastrointestinal disease is most commonly due to opportunistic and nosocomial infection. The same spectrum of enteric pathogens is seen as in HIV-uninfected children, but certain pathogens are more often associated with chronic diarrhea.
Continued exclusive breast-feeding of infected infants supplies protective factors and avoids exposure to potentially contaminated food and water, but at the same time permits continued exposure to infectious virus. The role of breast-feeding in nutritional management of HIV-infected children still needs to be defined.
Plans to Achieve Research Goal
Prior to assigning a diagnosis of HIV enteropathy, standardized investigations should be used and specific infections ruled out. The results of these investigations as well as other serial data should be entered into an Internet database, developed and supported with appropriate funding. A salaried consultant should be responsible for reviewing these data and preparing reports to define the natural course of HIV enteropathy in 2 years and again at the next international meeting.
Multicenter cooperative studies should be done to further define the evolution and management of enteropathy separate from infectious gut disease. Studies are needed in the developing world to identify the relative importance of the continuing exposure to HIV in breast milk in the rate of progression of disease and nutritional deterioration. Agreements to exchange biologic materials and research expertise, such as with specific cytokines or receptor studies, or molecular hybridization studies, will enable greater scientific advances to be made. Photomicrographs of autopsy and biopsy materials should also be transmitted via the Internet to create a morphologic evolution of HIV enteropathy.
The interventions with the largest impact include those that concern policies on prevention and care and engender public involvement.
Improved Access to Care and Implementation of Strategies to Prevent Infections
Because antiretroviral drugs are not a cure, access to HIV care needs to be intimately linked to prevention efforts. Treatment will in fact provide new opportunities for prevention, because it will create a larger demand and infrastructure for HIV testing, providing new entry points to the healthcare system for those who are infected, including critical opportunities to support them, their sexual partners and families to prevent ongoing transmission. Children and families with diverse clinical and social needs should be able to access care in an integrated fashion for voluntary counseling and testing, for health and social services, and for community-based support and home care (14,15). Major challenges for healthcare systems include building and sustaining human resources, ensuring quality and consistency of services and making better use of existing infrastructure.
Plans to Achieve Intervention Goal
There must be structured linkages of primary, secondary and tertiary care in different disciplines and at different facilities. Regional subspecialty programs with special expertise in treating and monitoring children with HIV infection can be linked to primary care and community service programs. The regional subspecialty program should have multidisciplinary expertise and a strong knowledge of and commitment to community linkages.
In addition to public education campaigns, free, voluntary, confidential counselling and testing services must be made available in public health facilities and antenatal services to pregnant women and their partners. HIV-positive women should then be offered counselling, management and follow-up support in line with the best available package applicable to that particular country or community. Mothers who have taken prophylaxis and delivered uninfected infants in areas with high prevalence should be recruited to encourage pregnant women from their area to participate in the programs.
Where women can be given the choice of replacement feeding in developing countries, a supply of either free or subsidized formula must be guaranteed. However, the question of infant feeding advice to HIV-infected mothers must be particularly sensitive to each individual woman's context and needs, acknowledging the multi-factorial nature of the breast-feeding decision. Where breast-feeding is chosen, this should be fully supported and exclusive.
Improved Availability and Accessibility of Drugs
Problems related to costs, affordability, distribution, dispensing and monitoring of antiretroviral drugs keep them out of reach of most children in developing countries. Even in the context of universal healthcare systems in the developed world, there are substantial challenges in improving access to antiretroviral drugs among marginalized groups. The healthcare sector plays a central role in providing treatment and care, promoting and delivering other effective interventions, mobilizing resources and providing leadership.
Plans to Achieve Intervention Goal
Countries should be encouraged to adopt a public health approach to facilitate the scale-up of antiretroviral drug use in resource-limited settings. Widespread access to antiretrovirals for people living with HIV/AIDS must be an established goal of all initiatives. Drug access can be improved not only by guidance on the rational selection and use of antiretroviral drugs but also by improved affordability and sustainability of drug financing and by accessible, appropriate and competent healthcare services. The least expensive, generic medications must be made available. The choice of medicine regarding efficacy, side effects and cost should be reviewed by an independent pharmacologist on an annual basis.
The following aspects should be considered: further reductions in drug prices including negotiated waivers of patent rights, increased competition from generic manufacturers, an increased role for international agencies regarding distribution, and the establishment of charitable agencies to provide additional funding. Strategies should be developed to distribute and monitor antiretrovirals through the public-health system. Key aspects of these strategies include definition of locations at which people could receive drugs, creation of a system to track the distribution of drugs, and establishment of a network of laboratories for clinical examinations. Distribution should be tracked by Internet-based pharmaceutical registries so that progress in this area, as well as adverse effects of medications, can be closely monitored. The World Health Organization (WHO) should be involved, together with UNAIDS, in public monitoring of the intervention results.
Establishment of Practical Guidelines on Investigation and Management of HIV Enteropathy
In the developing world, the progressively evolving gut condition of HIV enteropathy is superimposed on and aggravated by a high prevalence of infective and nutritional gut disorders. Under such circumstances, a cost-effective guideline is needed for the evaluation and management of HIV-infected children presenting with chronic or persistent diarrhea or nutritional deterioration.
Plans to Achieve Intervention Goal
A guideline must serve to ensure cost-effective treatment of children with HIV-associated gut disease and to prevent nutritional deterioration as far as possible. The nutritional management of patients with enteropathy includes food substitution and modification to exclude malabsorbed components and to maximize digestion and absorption. The targeted energy supply is increased to 150% of recommended daily intake. Locally available staples and traditional methods of refeeding should be used where possible to reduce costs and increase acceptability.
Improved Healthcare Professional Knowledge and Skills to Advise on Prevention of Mother-to-Child Transmission
Because prevention of infection in the HIV-exposed baby is the only realistic curative option, it is incumbent on all healthcare professionals involved in the counselling of HIV-infected women at antenatal clinics to be completely informed about all aspects of mother-to-child transmission during pregnancy, the intrapartum period and through breast-feeding. The aim is to reduce the mother's blood viral load during the latter part of pregnancy and during delivery, to reduce fetal exposure to a virus-contaminated environment during labor and delivery, and to provide short-term therapy as postexposure prophylaxis for the baby who might have been infected during birth.
Plans to Achieve Education Goal
In high-prevalence countries, the leaders of all sectors in society, including politics, religion, culture, the media, business, education and healthcare must be mobilized in public awareness campaigns. This should be complemented by a nonstigmatizing public commitment to optimum affordable management and support. Novel schemes must be sought to educate and recruit affected patients that will increase the community-wide penetration and acceptance of validated principles.
Improved Healthcare Worker Training on Integrated Management Options
Current challenges will require the healthcare sector to strengthen its traditional partnerships and to build new ones with the public-at-large, with communities and individuals infected and affected with HIV, and with the private sector. New models of interaction with the community sector are particularly important to advance advocacy with Ministries of Health and to improve the suitability, quality and uptake of health services.
Plans to Achieve Education Goal
An international network of institutions should be established to support the development and implementation of training programs that provide practical medical information and education for healthcare providers. Training programs offered to institutions in developing countries should be coordinated with national initiatives to minimize overlapping competition.
Efforts to improve treatment for children living with HIV include training of health workers and other caretakers. Research on improved treatment modalities needs to include Internet-based sharing of information about pilot initiatives, so that lessons learned can be applied to scale-up programs. In this way, standards for home care, guidelines and training manuals will be made available for healthcare staff in resource-poor settings.
Caregiver attitudes, perceptions and trust are important components of success and require the addition of behavioral and motivational components to traditional educational approaches. The recruitment of patients who have responded to and adapted favorably to therapy may have a real impact on community perceptions by public role modeling, but must be done with tactful understanding of individual and societal pressures and sensitivities.
Antiretroviral treatment programs should be developed and standardized. Countries should select a single first-line and a limited number of second-line regimens for large-scale use, while recognizing that persons who cannot tolerate or who fail the first-line and second-line regimens would be referred for individualized care by specialist physicians. Treatment programs should be based on the best scientific evidence to avoid the use of substandard treatment protocols that compromise the outcome of treatment in individual clients and create the potential for the emergence of drug-resistant virus.
Improved Knowledge and Skill in Nutritional Care of HIV-Infected Children
Malnutrition and wasting are among the most serious, chronic and difficult to treat problems confronting HIV-infected children. A poor nutritional state and progressive wasting are associated with a poorer outcome, and an improved nutritional state and growth may result from effective viral suppression with HAART. Additionally, successful nutritional rehabilitation may significantly improve immunologic function. Micronutrients, including vitamins, antioxidants and trace elements, have an important role in immunomodulation and therefore in the outcome of HIV-infected children. Deficiencies are common, but excessive supplementation may have unwanted effects.
Plans to Achieve Education Goal
Healthcare professional training should include a greater emphasis on nutritional care. This should be disseminated at conferences, training programs and service sites. Committees should be created to provide specific recommendations and these recommendations should be posted on the Internet. Proactive nutritional guidance is most effective in the early stages of disease and should be provided in parallel with management of other associated conditions, but nutritional interventions should be instituted when the child fails to meet growth standards. The first approach is to increase the feed volume and frequency, then to maximize energy value by the addition of fat or carbohydrate. Where breast-feeding is the only option, this should be offered as the exclusive feed as often as possible and the mother's own nutrition and state of health maintained as optimally as possible. HIV-infected children with diarrhea require close attention in regard to nutritional aspects of maldigestion and malabsorption.
There are many opportunities for fundamental and applied research, practical intervention and education in childhood HIV disease. The commitment of funding for this problem from governments, charities and industrial sources is unprecedented. The challenge that now faces the healthcare sector is to play a significant role in guiding the available resources to have a maximal impact on the largest number of infected individuals.