Neuromuscular complications of human immunodeficiency virus infection and antiretroviral therapy.

At least 4 distinct peripheral neuropathy syndromes occur in patients infected with the human immunodeficiency virus. The most common, painful sensory neuropathy, may be related to the viral infection or may be medication induced and is treated symptomatically. The other 3, chronic inflammatory demyelinating polyradiculoneuropathy, mononeuropathy multiplex (some patients), and the progressive polyradiculopathies related to the acquired immunodeficiency syndrome, may all respond to appropriate therapy. Both inflammatory myopathy and zidovudine myopathy also abate with early diagnosis and treatment.     

Progressive neurological dysfunction during latent HIV infection.

OBJECTIVE--To determine whether the delayed conduction through the spinal cord and peripheral nerves seen in patients with AIDS is related to infection with HIV or to the presence of an immunodeficient state. DESIGN--Two year prospective follow up study of electrophysiological measurements in subjects positive for HIV antibody but without AIDS. SETTING--HIV screening clinic and clinical departments in a university hospital in Copenhagen, Denmark. SUBJECTS--Twelve homosexual men positive for HIV antibody who had not developed AIDS. RESULTS--Eight latencies were measured: from the ankle to T12, the wrist to C7, T12 to the cerebral cortex, C7 to the cerebral cortex, the ankle to the gluteal crease (tibial nerve), the gluteal crease to T12, the wrist to Erb''s point (median nerve), and Erb''s point to C7. Spinal latencies increased in all subjects at C7 by a mean of 4.2% (SE 0.9%) and in all except one at T12 by a mean of 5.5% (1.0%). The conduction time from the gluteal crease to T12 was increased by a mean of 32.0% (5.0%) whereas that in the median and tibial nerves by only 5.6% (1.0%) and 2.2% (2.2%) respectively. CONCLUSIONS--A mild and slowly progressive peripheral neuropathy of the axonal type and a more severe progressive myelopathy or myeloradiculopathy occur concomitantly with early HIV infection, possibly as the result of a direct neurotropic action of HIV.     

Profit-sharing in health care institutions.

Zidovudine (AZT) is the first antiretroviral agent to be licensed for the treatment of human immunodeficiency virus (HIV) infection. Since the initial placebo-controlled trial showing improved survival among patients with acquired immunodeficiency syndrome (AIDS) or symptomatic HIV infection (AIDS-related complex [ARC]) zidovudine has been evaluated in other stages of HIV infection. This review offers physicians who treat patients with HIV infection a comprehensive analysis of the current data on the clinical efficacy of zidovudine in various stages of HIV infection and on zidovudine''s adverse effects. After a search of MEDLINE for pertinent articles published since 1985, controlled studies and studies of long-term zidovudine therapy, of zidovudine therapy for HIV-related conditions and of the incidence and management of adverse reactions were evaluated. In addition, abstracts from international meetings were reviewed. No significant difference in clinical outcome was found between high-dose and low-dose zidovudine therapy, but there were significantly fewer toxic effects in the low-dose group. In two other studies zidovudine was found to delay disease progression in patients with asymptomatic or mildly symptomatic HIV infection who had an absolute CD4 count of less than 0.5 x 10(9)/L; the low incidence of adverse reactions may have been due to either the early stage of the infection or the low dose used. The demonstration of zidovudine-resistant isolates after at least 6 months of therapy has yet to be correlated with clinical deterioration. When to begin zidovudine therapy among asymptomatic patients with a CD4 count of less than 0.5 x 10(9)/L remains unclear. Zidovudine can be used safely to delay progression to AIDS or ARC in certain patients with asymptomatic or mildly symptomatic HIV infection and can prolong survival in those with more severe infection. Further studies are necessary to identify indicators that could better define when to start treatment and how to alleviate toxic effects. Combination therapy with such agents as interferon alpha may become the preferred choice of therapy to prevent toxic effects and zidovudine resistance. Zidovudine prophylaxis has been used after HIV exposure. Although studies with animal models have had encouraging results infection has occurred despite immediate prophylaxis and thus further investigation is required.     

Clinical Manifestations and the Natural History of HIV Infection in Adults

The clinical expression of infection with the human immunodeficiency virus (HIV) appears increasingly complex. It includes manifestations due to opportunistic diseases, as well as illness directly caused by HIV itself. Neurologic disease may include involvement of the brain, spinal cord and peripheral nerves and is probably directly caused by HIV, as is lymphocytic interstitial pneumonia. The etiology of the chronic diarrhea and a papular pruritic skin eruption associated with HIV infection is unclear. Between 2% and 8% of HIV-infected persons progress to the acquired immunodeficiency syndrome (AIDS) per year, with no apparent decrease in the rate of disease progression over time. A chronically activated state secondary to chronic microbial antigenic exposure may increase both the susceptibility to HIV infection and development of disease. Increased HIV gene expression, followed by persistent antigenemia, appear to be triggering factors in clinical deterioration. The role, if any, of environmental and/or genetic cofactors remains unclear.     

The neurobiology of human immunodeficiency virus infections

A variety of diseases of the central and peripheral nervous systems evolves during the course of human immunodeficiency virus (HIV) infections. Most are not related to documented opportunistic infections and may be the direct result of HIV infections, as large proportions of healthy and ill HIV-infected persons show evidence of nervous system infection. These diseases occur at different times during the infection and have diverse inflammatory, demyelinating, or degenerative pathological features that suggest different pathogenetic mechanisms. The route and determinants of HIV invasion of the nervous system are unknown. Within the brain, viral antigen and RNA are found predominantly in macrophages, but the reason why profound dementia and cortical atrophy result from this infection remains a mystery. By analogy to other lentivirus infections, particularly visna virus in sheep, neuropathological changes may be mediated by cytokines. Other possible pathogenetic mechanisms include toxicity of viral polypeptides, transactivation of viral or cellular genes, autoimmunity, or other opportunistic infections. Clarification of the pathogenesis of HIV-related diseases is critical to the design of rational therapies.     

Evidence for recent changes in sexual behaviour in homosexual men in England and Wales

Over 80% of cases of Acquired Immune Deficiency Syndrome (AIDS) in England and Wales have occurred in homosexual men. Changes in sexual behaviour in this group may have a substantial influence on the incidence of Human Immunodeficiency Virus (HIV) infection and will therefore be crucial in determining future cases of AIDS. This paper critically weighs the indirect and direct evidence for changes in behaviour in homosexual men since the advent of the AIDS epidemic. The paper reports on falling incidence of gonorrhoea, hepatitis B and syphilis in homosexual men, the changes being most marked from 1985 onwards. Data on temporal trends in HIV prevalence and incidence in homosexual men are reviewed. These suggest that the maximum incidence of HIV infection occurred in 1982-84 and may have fallen since then. Evidence for a concomitant change in sexual behaviour is reported from several sources. This points towards a recent change in sexual behaviour characterized by reduction in the numbers of partners and adoption of safer sexual practices. In some places change may have occurred as early as 1983. A change became apparent generally in 1985 and this appears to have been sustained in 1986-87. Nevertheless, a substantial proportion of homosexual men studied continue to practice high risk sexual practices, such as anal intercourse, including relationships with casual partners.     

Human retroviral infections in The Gambia: prevalence and clinical features

The prevalence of infection with human immunodeficiency virus type 1 (HIV 1) is lower in west Africa than in other parts of Africa. Human immunodeficiency virus type 2 (HIV 2) has been isolated from west African patients and may be transmitted by heterosexual contact. The prevalence of antibodies to HIV 1 and HIV 2 was studied by enzyme linked immunosorbent assay (ELISA) among various groups of subjects in The Gambia, west Africa—namely, prostitutes, blood donors, patients with suspected infection with HIV, patients attending clinics for sexually transmitted diseases, and patients with tuberculosis. Four cases of the acquired immune deficiency syndrome (AIDS) due to infection with HIV 1 were detected, of which three had been acquired abroad. No other subject was found to be positive for antibodies to HIV 1. The prevalence of antibodies to HIV 2 among the patients attending clinics for sexually transmitted diseases was found to have increased from 0/117 in 1984 to 10/185 (5%) in the last six months of 1986. One out of 278 blood donors was positive for antibodies to HIV 2 as were 10 out of 80 patients with suspected AIDS.HIV 2 seems to be transmitted sexually, and, although it has been present for only a short time, it seems to be endemic in The Gambia and is pathogenic.     

Targeted therapy of human immunodeficiency virus-related disease.

Since the discovery of human immunodeficiency virus (HIV) as a pathogenic retrovirus linked to acquired immunodeficiency syndrome (AIDS), a number of potentially useful strategies for antiretroviral therapy of AIDS and its related diseases have emerged. One such strategy involves use of the broad family of 2',3'-dideoxynucleosides, to which 3'-azido-2',3'-dideoxythymidine (AZT) belongs. AZT has been shown to reduce the replication of HIV in vivo and to confer significant clinical benefits in patients in both early and advanced stages of infection. Other members of the family, 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddI), and 2',3'-didehydro-2',3'-dideoxythymidine (d4T), have also been reported to be active against HIV in short-term clinical trials. The armamentarium of antiretroviral agents is rapidly growing. Various nonnucleoside agents have recently been identified to be active against HIV in vitro. HIV-1 protease inhibitors are notable as possible new therapies for HIV-1-related diseases. However, we have faced several new challenges in the antiretroviral therapy in AIDS. These include long-term drug-related toxicities; emergence of drug-resistant HIV variants; and development of various cancers, particularly as effective therapies prolong survival. Progress in understanding structure-activity relations and clinical effectiveness will continue with dideoxynucleoside analogs. However, it seems certain that a variety of nonnucleoside analogs affecting multiple steps in viral replication will become available before long, and combination therapies using multiple antiretroviral drugs will be available. Such therapies will exert major effects against the moribidity and mortality caused by HIV.     

Immunopathogenesis of Pneumocystis carinii pneumonia

Pneumocystis carinii pneumonia (PCP) is a life-threatening infection that occurs in immunocompromised individuals, particularly those with advanced human immunodeficiency virus (HIV) infection. Interestingly, morbidity and mortality is related to the underlying cause of immunosuppression, with AIDS patients faring better than oncology patients for example. In addition, the prognosis of PCP has been correlated with markers of inflammation rather than with organism numbers. There is now increasing evidence that lung damage occurring during PCP is a result of the type and extent of the host inflammatory response to P. carinii rather than a result of direct damage by the organism. This review will discuss the experimental and clinical data demonstrating how the host-mediated inflammatory response to infection with P. carinii determines the ultimate outcome of PCP. A better understanding of the pathophysiology of PCP should lead to the development of improved therapies for the treatment of PCP.     

Could adrenal insufficiency serve as a predictor of immune reconstitution inflammatory syndrome (IRIS) in HIV disease?

Immune reconstitution inflammatory syndrome (IRIS) is an inflammatory manifestation that occurs subsequent to initiation of highly active antiretroviral therapy in terminal (HAART) HIV infection, mainly due to the restoration of robust immune responses directed against latent microbial antigens. IRIS is believed to be multifactorial and less studied. Herein, we postulate that hypothalamo-pituitary-adrenal (HPA) dysregulation, a well-documented manifestation in HIV/AIDS, could possibly disturb the balance between pro-inflammatory and anti-inflammatory cytokines leading to clinical IRIS. Drugs, opportunistic infections, stress and numerous intrinsic and extrinsic factors have been described to be the possible causes of IRIS in HIV illness.     

Incidence of AIDS and excess of mortality associated with HIV in haemophiliacs in the United Kingdom: report on behalf of the directors of haemophilia centres in the United Kingdom.

OBJECTIVE--To estimate the cumulative incidence of AIDS by time since seroconversion in haemophiliacs positive for HIV and to examine the evidence for excess mortality associated with HIV in those who had not yet been diagnosed as having AIDS. DESIGN--Analysis of data from ongoing national surveys. SETTING--Haemophilia centres in the United Kingdom. PATIENTS--A total of 1201 men with haemophilia who had lived in the United Kingdom during 1980-7 and were positive for HIV. INTERVENTION--None. END POINTS--Diagnosis of AIDS; death in those not diagnosed as having AIDS. MEASUREMENTS AND MAIN RESULTS--Estimation of cumulative incidence of AIDS and number of excess deaths in seropositive patients not diagnosed with AIDS. Median follow up after seroconversion was 5 years 2 months. Eight five patients developed AIDS. Cumulative incidence of AIDS five years after seroconversion was 4% among patients aged less than 25 at first test positive for HIV, 6% among those aged 25-44, and 19% among those aged greater than or equal to 45. There was little evidence that type or severity of haemophilia or type of factor VIII or IX that had caused HIV infection affected the rate of progression to AIDS. Mortality was increased among those who had not been diagnosed as having AIDS, especially among those with "AIDS related complex." Thirteen deaths were observed among 36 patients diagnosed as having AIDS related complex against 0.65 expected, and 34 deaths in 1080 other patients against 22.77 expected; both calculations were based on mortality rates observed in haemophiliacs in the United Kingdom in the late 1970s. CONCLUSIONS--Rate of progression to AIDS depended strongly on age. There is a substantial burden of fatal disease among patients positive for HIV who have not been formally diagnosed as having AIDS.     

Trends in mortality statistics in England and Wales with particular reference to AIDS from 1984 to April 1987

Death certification should be able to provide accurate data on the number of deaths due to AIDS as a basis for predicting future deaths from the syndrome. Trends in deaths from other causes may identify conditions that have not been recognised to be associated with HIV infection. Mortality statistics with reference to AIDS in England and Wales were completed from death certificates. Increases in deaths from selected causes likely to be associated with AIDS or HIV infection suggested that in some patients with HIV infection, AIDS was not stated on the death certificate or subsequently notified by the doctor who signed the certificate. From calculations of excess deaths between the beginning of 1985 and the end of April 1987, compared with 1984 at least 495 deaths possibly associated with HIV infection were estimated to have occurred among men aged 15-54 during that period. In 261 AIDS or HIV infection was stated on the original or amended death entry as the cause of death, and of these 198 were included in the estimated number of excess deaths.Accurate notification of the underlying cause of death and associated diseases is required for the precise monitoring of trends in mortality from AIDS and possible identification of unrecognised conditions associated with HIV infection.     

Impact of HIV on tuberculosis in Zambia: a cross sectional study.

OBJECTIVE--To examine the contribution of HIV infection to the apparently increasing incidence of tuberculosis in central Africa. DESIGN--Cross sectional study. SETTING--Outpatient clinic in teaching hospital, Lusaka, Zambia. PATIENTS--346 Adult patients with tuberculosis. RESULTS--Overall, 206 patients (60%; 95% confidence interval 54% to 65%) were positive for HIV--in one or both assays used. The peaks for both tuberculosis and HIV infection were among men aged 25-34 years and women aged 14-24 years. Of patients with confirmed pulmonary tuberculosis, 73/149 (49%; 41% to 57%) were positive for HIV; 67/83 (81%; 70% to 89%) patients with pleural disease and 16/19 (84%; 60% to 97%) patients with pericardial disease were positive. HIV positive patients with positive sputum culture were less likely to have had a positive sputum smear, and their chest x ray films less often showed classic upper zone disease or cavitation. Of 72 patients who fulfilled clinical criteria for AIDS, 17 were negative for HIV. CONCLUSIONS--The high prevalence of HIV in patients with tuberculosis suggests that an epidemic of reactivating tuberculosis is arising in those who are infected with HIV. The redirection of public health priorities towards tuberculosis would focus on a major treatable and preventable complication of the AIDS epidemic.     

Epidemiology of Invasive Fungal Infections in Patients with Acquired Immunodeficiency Syndrome at a Reference Hospital for Infectious Diseases in Brazil

Invasive fungal infections (IFIs) represent one of the main causes of morbimortality in immunocompromised patients. Pneumocystosis, cryptococcosis and histoplasmosis are the most frequently occurring IFIs in patients with acquired immunodeficiency syndrome (AIDS). Fungi, such as Candida spp. and Aspergillus spp., may cause severe diseases during the course of an HIV infection. Following the introduction of highly active anti-retroviral therapy, there has been a marked reduction of opportunistic fungal infections, which today is 20–25 % of the number of infections observed in the mid-1990s. This study is an observational and retrospective study aimed at the characterising IFI incidence and describing the epidemiology, clinical diagnostic and therapeutic features and denouement in HIV/AIDS patients. In HIV/AIDS patients, the IFI incidence is 54.3/1,000 hospitalisation/year, with a lethality of 37.7 %. Cryptococcosis represents the main opportunistic IFI in the population, followed by histoplasmosis. Nosocomial pathogenic yeast infections are caused principally by Candida spp., with a higher candidemia incidence at our institution compared to other Brazilian centres.     

Declining incidence of AIDS dementia complex after introduction of zidovudine treatment.

OBJECTIVE--To assess the incidence of the AIDS dementia complex and the presence of HIV I p24 antigen in cerebrospinal fluid in relation to zidovudine treatment. DESIGN--Retrospective study of a consecutive series of patients with AIDS from 1982 to 1988. SETTING--An academic centre for AIDS. PATIENTS--196 Patients with AIDS and neurological symptoms examined from 1982 to 1988. INTERVENTIONS--Zidovudine treatment, which was introduced to The Netherlands on 1 May 1987 for patients with severe symptoms of HIV infection (Centers for Disease Control groups IVA, B, C, and D). MAIN OUTCOME MEASURES--Diagnosis of AIDS dementia complex and presence of HIV I p24 antigen in cerebrospinal fluid. RESULTS--The AIDS dementia complex was diagnosed in 40 of the 196 (20%) patients with AIDS. Thirty eight of 107 patients with AIDS (36%) not taking zidovudine developed the AIDS dementia complex compared with two of the 89 (2%) taking the drug (p less than 0.00001). The incidence of the AIDS dementia complex increased to 53% in the first half of 1987, after the introduction of zidovudine in May 1987, decreasing to 10% in the second half of 1987 and to 3% in 1988. Dementia was diagnosed before definition of the AIDS dementia complex (1986) according to DSM-III criteria and there was good agreement between diagnosis before and after 1986. Sixteen of 61 samples of cerebrospinal fluid (26%) from patients with AIDS (10 with the AIDS dementia complex) not taking zidovudine were positive for HIV I p24 antigen, whereas none of 37 cerebrospinal fluid samples from patients with AIDS (two with the AIDS dementia complex) taking zidovudine were positive. CONCLUSIONS--The incidence of AIDS dementia complex in patients with AIDS declined after the introduction of systematic treatment with zidovudine; the AIDS dementia complex might be prevented by inhibiting viral replication in the central nervous system.     

The Vancouver Lymphadenopathy-AIDS Study: 5. Antecedent behavioural,clinical and laboratory findings in patients with AIDS and HIV-seropositive controls.

In a group of homosexual men in Vancouver studied prospectively since November 1982, 26 cases of acquired immune deficiency syndrome (AIDS) have arisen. To identify behavioural, clinical and laboratory findings that might predict the development of AIDS in people with antibody to human immunodeficiency virus (HIV), we compared data for 25 patients with AIDS with corresponding data for 80 controls serologically positive for HIV selected from the cohort. The clinical and laboratory data for the patients with AIDS preceded the diagnosis of the syndrome by a mean of 17.5 months. The controls had been both seropositive and AIDS-free for a mean of 16.7 months after acquisition of their data. We detected significant differences between the patients with AIDS and the controls in IgG and IgA levels, absolute number of helper T cells and ratio of helper to suppressor T cells but not in lifetime number of male sexual partners, frequency of receptive anal intercourse or receptive fisting, illicit drug use or history of infectious disease. We also detected an increased risk of AIDS among those who had an elevated number of sexual contacts in AIDS-endemic areas in the 5 years before enrollment. A history of increased early sexual contact in AIDS-endemic areas is likely to be associated with early infection and with an increased risk of AIDS among men with HIV infection of unknown duration. Thus, although our analysis had limited statistical power, we conclude that most lifestyle variables appear to act as exposure factors in HIV infection but not as cofactors in the development of AIDS.     

HIV+/AIDS related bioethical issues in Japan

Annual and cumulative incidences of HIV+ and AIDS in patients reported by the AIDS Surveillance Committee of the Ministry of Health and Welfare are cited to illustrate some characteristics in Japan: nearly 59% of either HIV+ or AIDS patients were infected through injection of blood products or by blood transfusion. A number of plaintiffs have sued the Japanese government and pharmaceutical companies since 1989, but no judicial decisions have yet been made. The incidence of HIV decreases for each of the following routes of infection: the second highest route of transmission being heterosexual, followed by bisexual and unconfirmed or unknown cases, and less frequently homosexual, drug use and lastly via vertical transmission. The most serious bioethical problems with HIV+ and AIDS patients in Japan is the social segregation of these patients. There are many emotional fears among the general public and medical personnel about AIDS because of their inadequate scientific knowledge of this disease. The Japan Hospital Association is doing The Stop AIDS Campaign and made several surveys. Japan has become increasingly aware of the importance of AIDS education and a great deal of effort is being made to enhance bioethical consideration.     

Incidence of symptoms and AIDS in 146 Swedish haemophiliacs and blood transfusion recipients infected with human immunodeficiency virus.

The times from infection with the human immuno-deficiency virus (HIV) to the onset of the first clinical symptom and the development of AIDS were studied prospectively in 98 haemophiliacs and 48 blood transfusion recipients infected with the virus. Patients were followed up for a median of 61 months after infection, the dates of infection being either known exactly or estimated from the interval between the last negative and first positive HIV antibody test result. The rate of progression to AIDS was significantly higher for the transfusion recipients than for the haemophiliacs. The difference in time to the occurrence of the first clinical symptom was less pronounced between the two groups, though pointing in the same direction. The results suggest that on average roughly half of all patients positive for HIV will develop some clinical sign or symptom within five to six years after infection.     

Epidemiology of HIV infection and AIDS in Croatia--an overview

This article presents an overview of HIV/AIDS epidemiology and surveillance in Croatia 20 years after the first documented case of AIDS in the country. Here we describe strategies employed for HIV/AIDS surveillance in Croatia as well as preliminary results of HIV seroprevalence among most-at-risk populations (MARPs) research conducted by the Infectious Diseases Epidemiology Service at the Croatian National Institute of Public Health (CNIPH). Croatia has a low incidence and prevalence of HIV and AIDS. At the end of 2005, there were 553 documented cases of HIV infection, 239 of which progressed to AIDS. In Croatia, AIDS is being registered within MARPs only and dominantly among men who have sex with men (MSM). AIDS patients and HIV infected persons are found in all parts of the country. Crude prevalence of HIV among MARPs was found to be 0.9%. It is necessary to continue with current prevention and control measures in the country, and to create a culture of awareness and precaution, a strategy that has proven effective in reducing risk of HIV infection.     

The chemical bases of the various AIDS epidemics: Recreational drugs,anti-viral chemotherapy and malnutrition

In 1981 a new epidemic of about two-dozen heterogeneous diseases began to strike non-randomly growing numbers of male homosexuals and mostly male intravenous drug users in the US and Europe. Assuming immunodeficiency as the common denominator the US Centers for Disease Control (CDC) termed the epidemic, AIDS, for acquired immunodeficiency syndrome. From 1981-1984 leading researchers including those from the CDC proposed that recreational drug use was the cause of AIDS, because of exact correlations and of drug-specific diseases. However, in 1984 US government researchers proposed that a virus, now termed human immunodeficiency virus (HIV), is the cause of the non-random epidemics of the US and Europe but also of a new, sexually random epidemic in Africa. The virus-AIDS hypothesis was instantly accepted, but it is burdened with numerous paradoxes, none of which could be resolved by 2003: Why is there no HIV in most AIDS patients, only antibodies against it? Why would HIV take 10 years from infection to AIDS? Why is AIDS not self-limiting via antiviral immunity? Why is there no vaccine against AIDS? Why is AIDS in the US and Europe not random like other viral epidemics? Why did AIDS not rise and then decline exponentially owing to antiviral immunity like all other viral epidemics? Why is AIDS not contagious? Why would only HIV carriers get AIDS who use either recreational or anti-HIV drugs or are subject to malnutrition? Why is the mortality of HIV-antibody-positives treated with anti-HIV drugs 7–9%, but that of all (mostly untreated) HIV-positives globally is only 1–4%? Here we propose that AIDS is a collection of chemical epidemics, caused by recreational drugs, anti-HIV drugs, and malnutrition. According to this hypothesis AIDS is not contagious, not immunogenic, not treatable by vaccines or antiviral drugs, and HIV is just a passenger virus. The hypothesis explains why AIDS epidemics strike non-randomly if caused by drugs and randomly if caused by malnutrition, why they manifest in drug- and malnutrition-specific diseases, and why they are not self-limiting via anti-viral immunity. The hypothesis predicts AIDS prevention by adequate nutrition and abstaining from drugs, and even cures by treating AIDS diseases with proven medications.