Human immunodeficiency virus infection, Part II

The acceptance of highly active antiretroviral therapy (HAART) among patients and health care providers has had a dramatic impact on the epidemiology and clinical characteristics of many opportunistic infections associated with human immunodeficiency virus (HIV). Previously intractable opportunistic infections and syndromes are now far less common. In addition, effective antibiotic prophylactic therapies have had a profound impact on the risk of patients developing particular infections and on the incidence of these infections overall. Most notable among these are Pneumocystis carinii, disseminated Mycobacterium avium complex, tuberculosis, and toxoplasmosis. Nevertheless, infections continue to cause significant morbidity and mortality among patients who are infected with HIV. The role of HAART in many clinical situations is unquestioned. Compelling data from clinical trials support the use of these therapies during pregnancy to prevent perinatal transmission of HIV. HAART is also recommended for health care workers who have had a "significant" exposure to the blood of an HIV-infected patient. Both of these situations are discussed in detail in this article. In addition, although more controversial, increasing evidence supports the use of HAART during the acute HIV seroconversion syndrome. An "immune reconstitution syndrome" has been newly described for patients in the early phases of treatment with HAART who develop tuberculosis, M avium complex, and cytomegalovirus disease. Accumulating data support the use of hydroxyurea, an agent with a long history in the field of myeloproliferative disorders, for the treatment of HIV. Newer agents, particularly abacavir and adefovir dipivoxil, are available through expanded access protocols, and their roles are being defined and clarified.     

Lung diseases in HIV-infected children

Pulmonary diseases, including opportunistic and bacterial infections, lymphoproliferative disorders, and neoplasia, substantially contribute to morbidity and mortality in HIV-infected children. Current treatment modalities are largely successful and thus justify invasive aetiological diagnostic procedures.     

A changed pattern of opportunistic infections and malignancies in HIV-seropositive patients after the introduction of intensive anti-HIV-combination therapy

The application of potent combinations of antiretroviral drugs ('highly active antiretroviral therapy' (HAART)) makes effective therapy of HIV infection feasible. Consequently, the pattern of opportunistic infections and other secondary complications has changed. The incidence of infections and mortality due to aids has declined significantly. Further, the occurrence of other infections and syndromes, till now unknown in patients with aids, has been observed. It is thought that these are caused by HAART-induced inflammation, a phenomenon due to immune enhancement following HAART. An important issue is whether primary and secondary prophylaxis against opportunistic infections can be discontinued after improvement of the immune system: indeed, there are reports that discontinuation is safe in patients with persistent CD4+ cell counts above the critical level for that particular infection while CD4+ cell counts are monitored carefully.     

St Jude Children's Research Hospital's International Outreach Program

Over 80% of children with cancer live in developing countries, where access to medical services is limited to varying degrees. In many of these countries, economic conditions and general health care have improved sufficiently to permit the development of more sophisticated medical services. The introduction of pediatric oncology programs becomes appropriate as deaths from malnutrition and infections decrease and cancer emerges as an important cause of childhood mortality. In the absence of such services, the worldwide war against pediatric cancer will ultimately be lost because of the rapidly growing pediatric populations in developing countries that now lack the facilities and expertise to treat childhood malignancies. We believe that the development of pediatric cancer centers in many of these countries is both appropriate and feasible. Partnerships in which established pediatric oncology centers work with the governments and private sectors of developing nations to implement key facilities are an efficient and cost-effective way to introduce such services. The challenges of these outreach efforts are significant -- as are the expected benefits.     

Cytokine messenger RNA expression by donor-specific cytotoxic T-cell clones after allogeneic heart transplantation

BACKGROUND: Aspergillosis is an uncommon yet serious opportunistic infection in patients with AIDS. It has been extensively reported in HIV-infected adult patients. To our knowledge there are no studies that describe the epidemiology, clinical manifestations and outcome of aspergillosis in a large HIV-infected pediatric population. METHODS: We reviewed the records of all 473 HIV-infected children followed in the Pediatric Branch of the National Cancer Institute for 9 years from 1987 through 1995 for the presence of Aspergillus infection. RESULTS: Seven (1.5%) patients developed invasive aspergillosis during the study period. All patients had low CD4 counts reflecting severe immunosuppression. Sustained neutropenia (> 7 days) or corticosteroid therapy as a predisposing factor for invasive aspergillosis was encountered in only two patients (28%). Invasive pulmonary aspergillosis developed in five patients and cutaneous aspergillosis in two. The most common presenting features in patients with pulmonary aspergillosis were fever, cough and dyspnea. Patients with cutaneous aspergillosis were diagnosed during life and successfully treated with amphotericin B and surgery, whereas diagnosis of pulmonary aspergillosis was made clinically in only one patient. CONCLUSIONS: Aspergillosis is an uncommon but highly lethal opportunistic infection in HIV-infected children. Invasive pulmonary aspergillosis should be considered in the differential diagnosis in febrile, HIV-infected children with persistent pulmonary infiltrates.     

Bacterial diarrhoea

Diarrhoeal disease caused by enteric bacterial pathogens has become less prevalent in industrialized countries, but remains an important cause of morbidity and mortality in developing countries. Although better management of acute diarrhoeal episodes has led to more favourable outcomes, persistent diarrhoea remains a problem for which risk factors are being recognized and associated bacterial pathogens identified. Unusual or intractable diarrhoea should alert health workers to the possibility of impaired immune function, which is associated with a range of enteric pathogens and opportunistic infections. Improved microbiological methods have resulted in more frequent detection of pathogens in association with diarrhoea, as well as greater understanding of pathogenesis. Clinical features of diarrhoeal disease and mechanisms involved in pathogenesis are discussed in relation to specific bacterial enteric pathogens.     

Correlation of intestinal structure and function in HIV infection

The gastrointestinal tract has great importance in HIV infection because of its role as a primary barrier to the external environment and consequent need for effective immune function. Many factors promote the development of diarrhea in HIV-infected individuals. Understanding the genesis of the symptom is key to formulating effective therapy. Ultimate control of the problem depends on preventing HIV replication and immune depletion, as well as avoiding the development of opportunistic enteric infections in patients with severe immune deficiency.     

Rapid shift in peak melatonin secretion associated with improved performance in short shift work schedule

OBJECTIVE: To describe the changes in the characteristics of human immunodeficiency virus (HIV)-related deaths in children with perinatally acquired infection. METHODS: A retrospective review of all deaths that occurred in HIV-infected children managed at The New York Hospital-Program for Children with AIDS during a 7-year period from January, 1990, to December, 1996. Differences in the characteristics at death between 15 children who died in 1990 and 10 children who died in 1996 were analyzed. RESULTS: Fifty-eight deaths in our cohort of HIV-infected children were identified during the 7-year period. The mean age at death was 4.43 years. Sixty-nine percent of children were black, 55% were male and 94% were receiving Medicaid. The mean weight/age Z score was -3.9 and the mean CD4 index was 0.067 with 65% having <50 CD4 cells/microl at the time of death (TOD). The most common organ/organ systems to be involved at the TOD were lung (78%) and central nervous system (61%). Mycobacterium avium complex (MAC) was the most common isolate at the TOD (26%) followed by Pneumocystis carinii (20%) and Pseudomonas aeruginosa (17%). The leading non-infectious cause of death was cardiac failure (9%). Comparison of the characteristics at the TOD between 1990 and 1996 revealed significant differences in mean age (2.1 vs. 9.2 years, P < 0.0001), mean CD4 count index (0.18 vs. 0.02, P < 0.03), mean number of organ/organ system involvement (3.9 vs. 5.9, P < 0.05), percent receiving antiretroviral therapy (33% vs. 70%, P < 0.02), mean number of years receiving antiretroviral therapy (0.88 vs. 3.86 years, P < 0.01), percent receiving P. carinii pneumonia prophylaxis (27% vs. 100%, P < 0.001), percent receiving MAC prophylaxis/therapy (0% vs. 100%, P < 0.0001), and cause of death from P. carinii pneumonia (53% vs. 0%, P < 0.01). CONCLUSIONS: Compared with children who died in 1990, HIV-infected children who died in 1996 were significantly older, more lymphopenic and more likely to have a greater number of organ system involvements and to have received antiviral therapy and antimicrobial prophylaxis. In 1996 no child died of P. carinii pneumonia. In 1996 MAC and P. aeruginosa were the two most important opportunistic infections causing death. These changes in the characteristics at death will warrant review of resources used in treating these children and may be critical in advising parents and care givers about the prognosis of this chronic infection.     

Pathology of AIDS in children

AIDS in children is a multisystem disease. The various infections, degenerative, proliferative and vascular lesions can be classified into three categories based on the known, presumed or undetermined pathogenesis. The primary lesions are due to HIV infection. The associated lesions are related to direct or indirect sequelae of HIV infection or its treatment. The third category is of lesions of undetermined pathogenesis. The pediatric pathologist plays an important role in the study and management of AIDS by demonstrating new pathologic lesions, by making the etiologic diagnosis of infection in children with AIDS, and by providing clinicopathologic correlation which leads to better understanding of the disease process and its natural history. Diagnosis of neoplastic disorders is also made by the pathologist. There is a dearth of systematic pathologic study of AIDS in children in developing countries. Although no basic differences between pathologic lesions in pediatric AIDS in Western countries, and in developing countries is expected, such a study would lead to better understanding and better management of the disorder as it affects children from the developing countries.     

Audit in the management of T3 fixed-cord laryngeal cancer

EPIDEMIOLOGY: Disseminated MAC-infection is one of the most frequent opportunistic infections occurring in HIV-infected patients. Severely immunocompromised patients with CD4-counts < 50/microliter are at greatest risk for the disease. Survival of untreated infection is very poor (5 to 6 months). With therapy survival is prolonged by about 4 months. CLINICAL PRESENTATION AND DIAGNOSTIC PROCEDURES: The leading symptom of MAC-infection is fever eventually accompanied by weight lost, night sweats, enlarged lymph nodes, hepatosplenomegaly, abdominal pain and anemia. Blood cultures are very sensitive and the most appropriate examination. Other diagnostic procedures include bone marrow cultures, biopsies of the gastrointestinal tract, lymph nodes and the liver. Detection of MAC in sputum and stool samples only proves colonisation but not dissemination. However, colonisation of the gastrointestinal tract frequently precedes disseminated disease. THERAPY: Combination of clarithromycin, rifabutin and ethambutol has proven to be the most efficacious therapy and therefore has to be considered as standard therapy for disseminted MAC-infection. Problems most frequently encountered with this medication include uveitis (rifabutin) gastrointestinal disturbances (clarithromycin) and leucopenia (rifabutin) as well as drug interactions with protease-inhibitors (rifabutin). PROPHYLAXIS: Clarithromycin, rifabutin and azithromycin given as primary prophylaxis can diminish the risk of disseminated MAC-infection. Although a survival benefit has been seen with clarithromycin, primary prophylaxis of MAC-infection is not standard care in many centers. Reasons to withhold MAC-prophylaxis include lower incidence rates in some countries as well as possible side effects and drug interactions. CONCLUSION: Disseminated MAC-infection is a frequent opportunistic disease in HIV-infected persons who are severely immunocompromised. Antibiotic combination therapy with clarithromycin, rifabutin and ethambutol improves clinical symptoms and survival. Primary prophylaxis with different regimens is efficacious but the specific epidemiologic situation in each country has to be considered.     

Pneumocystis carinii meningoradiculitis in a patient with AIDS

Pneumocystis carinii is a common opportunistic pathogen in patients infected with the human immunodeficiency virus (HIV). Pneumocystis carinii pneumonia is common, while extrapulmonary infections with Pneumocystis carinii have been reported sparingly. The clinical features are frequently nonspecific. The detection of Pneumocystis carinii in cerebrospinal fluid (CSF) has not been reported thus far. In this report, an unusual case of Pneumocystis carinii meningoradiculitis in an HIV-infected patient who had previously received primary prophylaxis with trimethoprim-sulfamethoxazole is presented.     

Congenital toxoplasmosis and seroconversion at the end of pregnancy: clinical observations

OBJECTIVE: To determine the knowledge of HIV-disease management and the adherence to contemporary guidelines among British Columbia physicians whose practices focused on HIV/AIDS. DESIGN: Self-administered mail survey. PARTICIPANTS: All 659 physicians registered in a province-wide HIV/AIDS drug treatment program. OUTCOME MEASURES: Data on demographic and personal characteristics of respondents, level of HIV-related experience, use of preventive vaccinations and tests, and preferred approaches to the prophylaxis and treatment of common opportunistic infections. Knowledge scores in 4 areas of patient care, as well as an overall score, were computed by comparing respondents' answers with the therapeutic strategies recommended at the time of the survey. Associations between physician characteristics and knowledge scores were identified by linear regression analysis. RESULTS: Of the 659 physicians surveyed, 65% returned responses: only 38% returned completed surveys while a further 27% returned a follow-up survey that asked nonrespondents about their demographic characteristics and HIV-related experience. Scores for specific areas of patient management ranged from 29% for the treatment of opportunistic infections to 62% for preventive measures, with a mean overall score of 47%. Physician knowledge in all areas of patient care was associated with the number of HIV-positive patients in the practice (p = 0.003 to p < 0.001). Physicians who were younger were more knowledgeable regarding preventive measures (p = 0.001); those whose practice location was in Vancouver had a greater knowledge of prophylaxis (p = 0.047); and those who had medical specialty training were more knowledgeable about the treatment of opportunistic infections (p = 0.009). CONCLUSIONS: There is substantial disparity in how physicians approach the management of HIV and related conditions. Deviations from therapeutic guidelines are common and may be associated with physician characteristics, particularly lack of experience in managing HIV.     

Astrovirus infection in association with acute, persistent and nosocomial diarrhea in Bangladesh

BACKGROUND: Diarrhea is an important public health concern in developing countries such as Bangladesh. Diarrhea in children that persists for 14 days or more occurs in 7% of patients in Bangladesh and frequently results in death. Astrovirus has been demonstrated as a cause of acute and nosocomial diarrhea and can be excreted for prolonged periods, yet its importance as a cause of diarrhea among children in a developing country like Bangladesh has not been investigated. METHODS: We tested 629 stool specimens from patients with acute diarrhea, 153 from patients with persistent diarrhea, 175 specimens from 76 patients hospitalized for diarrhea who were sampled repeatedly to detect nosocomial infection and 428 from nonhospitalized healthy children (controls). All children enrolled in the study were <5 years of age. Astrovirus was detected by enzyme immunoassay and other enteropathogens were detected by standard techniques. RESULTS: The detection of astrovirus increased significantly with the duration of diarrhea. Astrovirus was found in 23 (15%) specimens from patients with persistent diarrhea, 26 (4%) patients with acute diarrhea, but only 8 (2%) healthy controls. This trend remained when we limited our analysis to infants <12 months of age and to episodes in which astrovirus was the sole pathogen. Among patients with nosocomial diarrhea, 16% of postadmission specimens were positive for astrovirus when the admission specimen was negative. CONCLUSION: The observation that astrovirus is detected more frequently with diarrhea of increasing duration suggests the need for further studies to determine whether astrovirus plays a causative role in persistent diarrhea or is a secondary agent.     

Management of HIV infection. A 1995-96 overview for the clinician

Although the challenges of HIV/AIDS care may seem overwhelming, we are better able than ever to positively affect the course of HIV for each individual patient. Treatment goals involve three areas: 1) Antiretroviral drugs aimed at retarding the rate of HIV replication, thus reducing the rate of damage to the immune system; 2) drugs used to treat or prevent opportunistic infections seen in the context of HIV-related immune deficiency; and 3) drugs used to treat symptoms or syndromes commonly seen in these patients (including dementia and wasting syndrome). The multitude of clinical problems seen in advanced HIV disease leads to significant polypharmacy and costs resulting in a very complex and confusing situation. I recommend that physicians with little HIV experience link up with an HIV specialist when caring for HIV-infected patients to optimize access to the best therapies or research studies currently available. With no cure in sight, physicians need to focus on educating the public and patients about how to avoid HIV infection and to identify persons who are infected to minimize spread.     

Preventing perinatal transmission of HIV--costs and effectiveness of a recommended intervention

OBJECTIVE: To calculate the national costs of reducing perinatal transmission of human immunodeficiency virus through counseling and voluntary testing of pregnant women and zidovudine treatment of infected women and their infants, as recommended by the Public Health Service, and to compare these costs with the savings from reducing the number of pediatric infections. METHOD: The authors analyzed the estimated costs of the intervention and the estimated cost savings from reducing the number of pediatric infections. The outcome measures are the number of infections prevented by the intervention and the net cost (cost of intervention minus the savings from a reduced number of pediatric HIV infections). The base model assumed that intervention participation and outcomes would resemble those found in the AIDS Clinical Trials Group Protocol 076. Assumptions were varied regarding maternal seroprevalence, participation by HIV-infected women, the proportion of infected women who accepted and completed the treatment, and the efficacy of zidovudine to illustrate the effect of these assumptions on infections prevented and net cost. RESULTS: Without the intervention, a perinatal HIV transmission rate of 25% would result in 1750 HIV-infected infants born annually in the United States, with lifetime medical-care costs estimated at $282 million. The cost of the intervention (counseling, testing, and zidovudine treatment) was estimated to be $ 67.6 million. In the base model, the intervention would prevent 656 pediatric HIV infections with a medical care cost saving of $105.6 million. The net cost saving of the intervention was $38.1 million. CONCLUSION: Voluntary HIV screening of pregnant women and ziovudine treatment for infected women and their infants resulted in cost savings under most of the assumptions used in this analysis. These results strongly support implementation of the Public Health Service recommendations for this intervention.     

Reporting maternal behavior during diarrhea in Bedouin children

Diarrhea is still a major cause of morbidity and mortality among children in developing countries. The Bedouin population of southern Israel is in transition from a nomadic to a settled life-style. We examined maternal knowledge and reported behavior when their children had diarrhea. Mothers defined diarrhea as the passing of 4-5 stools per day. The most frequent signs of the illness were an increased number of watery stools with changes in either color or form. The most frequent symptom that prompted mothers to seek medical aid was blood in the stool. All mothers reported increasing fluid intake in their children during diarrhea, and most reported giving herbal tea. About half of the women avoided milk products and used special foods for the treatment of diarrhea. A quarter of the women reported stopping or decreasing the frequency of breast feeding during diarrhea. Reported cessation of breast feeding during diarrhea was associated with changing to special foods, and failure to note the onset of diarrhea or to recognize signs of dehydration. The withdrawal of breast feeding during episodes of illness and diarrhea is related to lack of knowledge regarding diarrhea. These data indicate that even in this population, with free access to preventive and curative medical care, there should be greater efforts to educate mothers to detect diarrheal disease and to maintain breast feeding during the diarrhea.     

Characteristics of acute pneumonia in human immunodeficiency virus-infected children and association with long term mortality risk. National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial Study Group

OBJECTIVE: To describe the epidemiologic, clinical, radiologic, laboratory and treatment characteristics of acute pneumonia and its association with mortality in HIV-infected children. METHODS: Data were collected during a trial of intravenous immunoglobulin (IVIG) for infection prophylaxis (1988 to 1991); CD4+ percentage was measured and HIV RNA was assessed on stored sera collected at baseline and every 3 months. Mortality was recorded during the trial and updated through 1996. All reported physician-diagnosed pneumonia episodes underwent blinded review for trial endpoint classification as acute (new radiologic findings and presence of clinical symptoms) or nonacute. RESULTS: On blinded clinical trial endpoint review of all reported pneumonia episodes (n = 281), only 47% were classified as acute. One hundred thirty-one episodes of acute pneumonia were reported in 93 children (47 in 31 IVIG and 84 in 62 placebo patients, P < 0.01). The incidence of acute pneumonia was 24 episodes per 100 patient years. Findings associated with an acute bacterial process were uncommon (leukocytosis > or =15000/mm3 in 21% and fever > or =103 degrees F in 32% of episodes). Multiple acute episodes occurred in 34% of the children and were associated with increased risk of mortality in a univariate analysis (risk ratio, 2.1; 95% confidence interval, 1.3 to 3.4, P = 0.002), but in a multivariate model only baseline HIV RNA copy number and CD4+ percentage remained independently associated with mortality (relative risk, 2.0 and 1.4, respectively, P < 0.001). CONCLUSION: Acute pneumonia was a common occurrence in HIV-infected children and was associated with long term mortality risk. Multiple episodes of acute pneumonia likely represent a marker of progressive disease and immunologic dysfunction rather than being causally associated with increased long term mortality.     

Medical management of the pregnant woman infected with human immunodeficiency virus type 1 and her child

Heterosexual contact and intravenous drug use continue to result in new cases of human immunodeficiency virus type 1 (HIV-1) infection among adolescents and women of childbearing age. In North American and European surveys, 0.1% to 0.3% of childbearing women are infected with HIV; rates are 10 to 20 times higher in some inner-city areas. Timely, comprehensive, and well-coordinated care of the pregnant HIV-infected mother offers a unique opportunity to significantly influence two lives simultaneously. The mother can be offered therapeutic and prophylactic agents to treat her own infection, including antiretroviral therapy, which has been shown to markedly reduce the risk of vertical HIV-1 transmission. Recent advances in diagnostic virology now make it possible to definitively identify by 3 to 4 months of age those infants who are infected with HIV. Infants infected with HIV can be offered effective prophylaxis against Pneumocystis carinii pneumonia, which has dramatically reduced the incidence of this once common infection. Infected infants also should be monitored closely to institute antiretroviral therapy, and to diagnose and treat opportunistic and intercurrent infections and other acquired immunodeficiency syndrome-defining illnesses in a timely way.     

The effects of phospholipid molecular species on cholesterol crystallization in model biles: the influence of phospholipid head groups

A study of the etiologies of diarrhea in adults in relation to their human immunodeficiency virus (HIV) serostatus and number of CD4+ cells was carried out in the Central African Republic. In cases and controls, multi-parasitism was observed. Salmonella spp. were identified mainly during acute diarrhea, with 50% of the S. enteritidis isolated during the study being responsible for septicemia and/or urinary tract infection in immunodeficient patients. Enteroaggregative Escherichia coli (EAggEC) were the most frequently identified agent in HIV+ patients with persistent diarrhea; 42.8% of the patients with EAggEC as sole pathogens had bloody diarrhea, and these strains were negative for the presence of a virulence plasmid. Coccidia were found in those with acute and persistent diarrhea. Blood was observed in 53.3% of infections involving coccidia as the sole pathogen. Microsporidium spp. and Blastocystis hominis were found only in HIV+ patients with persistent diarrhea. Shigella spp., Campylobacter spp., and Entamoeba histolytica were found in HIV+ and HIV- dysenteric patients; bacteria resembling spirochetes that could not be cultivated were identified only in HIV+ cases with dysentery. Shiga-like toxin-producing E. coli O157:H- was isolated from two cases with hemolytic-uremic syndrome. Fungi were identified as the sole pathogen in 6.4% of the HIV+ patients with persistent diarrhea. Most of enteropathogenic bacteria identified were resistant to ampicillin and trimethoprim-sulfamethoxazole, remained susceptible to ampicillin plus clavulanic acid, and were susceptible to amikacin, gentamicin, and ciprofloxacin.     

Gene therapy strategies for AIDS-related malignancies

AIDS-related malignancies (ARM) include AIDS-defining cancers such as Kaposi's sarcoma, non-Hodgkin's lymphoma and cervical carcinoma. In addition, certain other malignancies are also increased with human immunodeficiency virus (HIV) infection. New antiretroviral agents and better prophylaxis and treatment of HIV-related opportunistic infections are prolonging the lives of HIV-infected individuals. There will thus likely be a continued rise in the incidence and prevalence of ARM in the long term, even if effective antiretroviral and other AIDS-related therapies reduce their appearance in the short term. There are presently no curative regimens for the common ARM, with the possible exception of some lymphomas. Survival is shortened by most, and treatment is often toxic and poorly tolerated. Gene therapies may thus offer a useful adjunct to conventional treatment strategies for selected ARM. Although some gene therapy strategies may work well in the HIV setting, the chronic viral infection, immunodeficient status of the host, the tendency for HIV-infected individuals to have altered drug metabolism and an increased rate of adverse drug reactions will likely present special challenges. This review summarizes the state-of-the-art in the fledgling field of gene therapy for ARM, and explores areas for future research.