Use of combination antiretroviral therapy in pregnant women with HIV disease

Important advances in human immunodeficiency virus (HIV) medicine have brought about numerous changes in the clinical care of HIV-infected individuals. The availability of protease inhibitors to treat HIV infection, the introduction of HIV-RNA polymerase chain reaction viral load tests to monitor responses to therapy, and the greater clinical benefit offered by combination highly active antiretroviral therapy (HAART) over monotherapy have dramatically decreased morbidity and mortality rates. The safety and efficacy of HAART has not been proved in pregnant women with HIV, although withholding HAART in HIV-infected women because of pregnancy is not recommended. This article presents an overview of important clinical issues relevant to the use of combination antiretroviral therapy in pregnancy.     

Lack of reactivation of cytomegalovirus (CMV) retinitis after stopping CMV maintenance therapy in AIDS patients with sustained elevations in CD4 T cells in response to highly active antiretroviral therapy

The suppression of human immunodeficiency virus (HIV) replication and elevation in CD4 cells observed with protease inhibitor combination regimens known as HAART (highly active antiretroviral therapy) may allow AIDS patients to undergo an immune recovery that allows them to suppress the progression of cytomegalovirus (CMV) retinitis. Eleven AIDS patients receiving HAART with healed CMV retinitis in whom CMV-specific maintenance therapy was discontinued were studied. Median CD4 cell counts were 42 before the initiation of HAART and 183 at discontinuation of anti-CMV therapy. While a median 1.1 log10 drop in plasma HIV-1 RNA was obtained between starting HAART and withdrawal of maintenance therapy for CMV, only 3 of 11 patients maintained plasma HIV RNA below the limits of detection. Reactivation of CMV retinitis after withdrawal of anti-CMV therapy did not occur in any of the patients observed for a median of 156 days (range, 92-558).     

Diagnosis and management of esophageal disease in the acquired immunodeficiency syndrome

BACKGROUND: Esophageal disorders are common complications of human immunodeficiency virus (HIV)-infected patients. In a significant number of patients, the esophagus may be the site of the first acquired immunodeficiency syndrome (AIDS)-defining opportunistic illness. METHODS: We reviewed pertinent articles, obtained from a MEDLINE search, on the diagnosis and treatment of esophageal diseases in HIV disease. RESULTS: Infections are the most common cause of esophageal disease, and opportunistic disorders such as cytomegalovirus and idiopathic esophageal ulceration rarely present until the CD4 lymphocyte count falls below 100/mm3. Endoscopy is the most valuable tool for evaluating esophageal complaints in AIDS. CONCLUSIONS: Almost all esophageal infections in patients with AIDS are treatable; therefore, a thorough work-up is indicated. With the widespread use of more effective antiretroviral therapy including the protease inhibitors, there is a general consensus that the incidence of many opportunistic diseases appears to be decreasing.     

AIDS-related malignancies

In the US over one million persons are currently infected with the HIV, over half a million have had AIDS, and over 300,000 have died from AIDS. Worldwide, it is estimated that more than 17 million people are currently infected with HIV, and over 1,200,000 cases of AIDS have been reported to the World Health Organization. By some estimates, up to 40% of patients with AIDS will ultimately develop some form of cancer. Non-Hodgkin's lymphoma, Kaposi's sarcoma and invasive cervical cancer have a higher incidence in persons with HIV infection and all three are AIDS-defining illnesses. In addition, several reports suggest that a number of other malignancies may occur at an increased incidence in persons with HIV infection, including squamous-cell carcinoma of the head, neck and anus, plasmacytoma, melanoma, small-cell lung cancer, basal-cell cancer, and germ-cell tumours. Clinicians should become familiar with HIV-related malignancies as their incidence is expected to further increase as more effective therapies for HIV and associated opportunistic infections allow patients to live longer in an advanced state of immunodeficiency. In the current article, we will review the clinical and therapeutic aspects of the most common AIDS-related malignancies including non-Hodgkin's and Hodgkin's lymphomas, Kaposi's sarcoma and anogenital epithelial neoplasias.     

Evolving trends revealed by autopsies of patients with the acquired immunodeficiency syndrome. 565 autopsies in adults with the acquired immunodeficiency syndrome, Los Angeles, Calif, 1982-1993 [corrected

OBJECTIVE: To determine changes in causes of death, survival, and organ system distribution of major opportunistic infections and neoplasms in adults dying with the acquired immunodeficiency syndrome (AIDS) following the widespread use of antiretroviral therapy and prophylaxis for opportunistic infections since 1988. DESIGN: A retrospective review of autopsy records with gross and microscopic pathologic findings, laboratory data, and clinical histories in cases of AIDS, comparing findings from 1982 through 1988 with those from 1989 through May 1993. SETTING: All autopsies were performed on persons dying in the metropolitan Los Angeles, Calif, area from January 1982 through May 1993. RESULTS: In 565 adult cases of AIDS at autopsy, Pneumocystis carinii pneumonia (PCP) remained the most common cause of death, but both the frequency of and number of deaths of PCP declined over time. Deaths from bacterial sepsis, cytomegalovirus infection, Mycobacterium avium complex infection, and toxoplasmosis also declined during this period, but mortality from fungal infections, tuberculosis, encephalopathy, and causes unrelated to AIDS increased. The death rate from malignant lymphoma remained high. Kaposi's sarcoma (KS) continued to occur more frequently in patients whose risk factor for human immunodeficiency virus infection (HIV) was homosexuality or bisexuality, but the death rate from KS was greatest for patients with a risk factor of blood exposure to HIV. Survival was shorter and deaths from tuberculosis more common in patients with a history of intravenous drug use. Overall survival of patients in other AIDS risk groups increased over time, particularly in those treated with antiretroviral therapy. The organ system distribution of major opportunistic infections and neoplasms was similar throughout the years of the study. The lung was the most frequent organ involved by AIDS-associated diseases leading to death, followed by the gastrointestinal tract and the central nervous system. CONCLUSIONS: The causes of death in AIDS have evolved since 1988 following the widespread use of prophylactic and antiretroviral therapies in patients with HIV infection. This has occurred primarily from changes in overall frequency and death rates from infections. Organ system involvement by AIDS-associated diseases has not changed significantly over time.     

Safety of GM-CSF in patients with AIDS: a review of the literature

We performed a literature search for all clinical studies reporting outcomes in patients with the acquired immunodeficiency syndrome (AIDS) receiving granulocyte-macrophage colony-stimulating factor (GM-CSF) for any indication. Safety outcomes included human immunodeficiency virus replication, immune status, and frequency of opportunistic infections and neoplasms. Data were synthesized qualitatively. We identified 22 studies (274 patients): 12 addressed AIDS neutropenia, 8 AIDS cancer therapy, and 2 opportunistic infections. Viral burden was assessed by serum p24Ag in 15 studies. Nine reported no change in levels, three net decreases, and three net increases. All studies showing net increases involved patients receiving GM-CSF without a concurrent antiretroviral. The CD4 counts were unchanged in 5 studies, increased in 3, and not reported in 14. The incidence of neoplasms or new opportunistic infections was low. The literature suggests no increased risk of viral replication or clinical deterioration in patients with AIDS who take GM-CSF concurrently with zidovudine.     

Preventing and treating major opportunistic infections in AIDS. What's new and what's still true

New highly active antiretroviral therapies are boosting the blood absolute CD4+ counts of many patients with AIDS and are decreasing the prevalence of AIDS-related opportunistic infections. Nevertheless, the prevention, diagnosis, and treatment of opportunistic infections remain important features of management of HIV infection. In recent years, significant advances have been made in the prevention and treatment of opportunistic diseases such as Pneumocystis carinii pneumonia, Cytomegalovirus retinitis, disseminated Mycobacterium avium-intracellulare infection, and mucosal candidiasis. Tuberculosis, cryptococcal meningitis, herpes simplex virus infection, shingles, and infectious enteritis also continue to be troublesome. Kaposi's sarcoma may be the newest AIDS-related opportunistic infection to be identified. The immune system effects of highly active antiretroviral therapy are as yet poorly understood. Therefore, an aggressive approach to diagnosis and treatment of opportunistic infections remains mandatory, and patients receiving antiretroviral therapy should continue to adhere to recommendations for prophylaxis against such infections.     

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.     

Human immunodeficiency virus replication in AIDS patients with Mycobacterium avium complex bacteremia: a case control study. California Collaborative Treatment Group

The development of opportunistic infections and the administration of vaccines have been associated with transient increases of human immunodeficiency virus (HIV) RNA plasma levels in HIV-infected patients. To determine the relationship between Mycobacterium avium complex (MAC) bacteremia and HIV RNA levels, HIV RNA levels in patients who developed MAC bacteremia (cases) were compared with levels in patients who remained free of MAC disease (controls). Cases and controls were matched for CD4 cell count, prophylaxis against MAC disease, antiretroviral therapy, and duration of follow-up. Mean baseline HIV RNA levels were 4.8 log10 copies/mL in cases and 4.6 log10 copies/mL in controls (P = 0.22). HIV RNA levels increased by a median of 0.4 log in cases but not controls at the time of MAC bacteremia (P = 0.01). In AIDS patients, the onset of MAC bacteremia is associated with a modest but significant increase in serum HIV RNA levels. Increased HIV replication may contribute to the higher mortality associated with MAC bacteremia.     

Efficacy of antitat gene therapy in the presence of high multiplicity infection and inflammatory cytokines

Because human immunodeficiency virus type 1 (HIV-1) infection is characterized by a large number of viral replication cycles and rapid cell turnover in vivo, successful gene therapy requires an approach effective under these conditions. The antitat gene has been proposed for gene therapy because it effectively blocks Tat function and the replication of HIV-1. However, neither antitat nor any other antiviral gene has been shown to inhibit HIV in the presence of high viral load and inflammatory cytokines, a condition closer to the in vivo situation. We show that cells transduced with antitat retrovirus vector are resistant to high multiplicity of HIV infection. In the presence of inflammatory cytokines, including interleukin-1 and tumor necrosis factor, both known to activate viral gene expression independently of Tat, antitat suppressed virus replication. HIV-1 inhibition was observed when cell were treated with a mixture of inflammatory cytokines able to induce acquired immunodeficiency syndrome (AIDS) Kaposi's sarcoma cell growth. These molecules have been shown to be increased in HIV-1-infected individuals, and it is suggested they play a role in the pathogenesis of AIDS. Our results suggest that antitat is effective under conditions present in vivo and therefore a primary candidate for HIV-1 gene therapy.     

Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. AIDS Clinical Trials Group 243 Team

BACKGROUND: Progressive multifocal leukoencephalopathy affects about 4 percent of patients with the acquired immunodeficiency syndrome (AIDS), and survival after the diagnosis of leukoencephalopathy averages only about three months. There have been anecdotal reports of improvement but no controlled trials of therapy with antiretroviral treatment plus intravenous or intrathecal cytarabine. METHODS: In this multicenter trial, 57 patients with human immunodeficiency virus (HIV) infection and biopsy-confirmed progressive multifocal leukoencephalopathy were randomly assigned to receive one of three treatments: antiretroviral therapy alone, antiretroviral therapy plus intravenous cytarabine, or antiretroviral therapy plus intrathecal cytarabine. After a lead-in period of 1 to 2 weeks, active treatment was given for 24 weeks. For most patients, antiretroviral therapy consisted of zidovudine plus either didanosine or stavudine. RESULTS: At the time of the last analysis, 14 patients in each treatment group had died, and there were no significant differences in survival among the three groups (P=0.85 by the log-rank test). The median survival times (11, 8, and 15 weeks, respectively) were similar to those in previous studies. Only seven patients completed the 24 weeks of treatment. Anemia and thrombocytopenia were more frequent in patients who received antiretroviral therapy in combination with intravenous cytarabine than in the other groups. CONCLUSIONS: Cytarabine administered either intravenously or intrathecally does not improve the prognosis of HIV-infected patients with progressive multifocal leukoencephalopathy who are treated with the antiretroviral agents we used, nor does high-dose antiretroviral therapy alone appear to improve survival over that reported in untreated patients.     

Hormone replacement therapy: why are general practitioners not prescribing more?

The recent progress of our understanding of the pathophysiology of human immunodeficiency virus (HIV) infection and the availability of new antiretroviral compounds has markedly improved the prognosis of patients infected with HIV. It has been postulated as early as 1991 that potent community-wide treatment of HIV infection could paradoxically lead to an increased spread of the HIV epidemic if treatment is not associated with a reduced infectivity of HIV. In the past few years, several groups have demonstrated a good correlation of the quantity of HIV present in semen with factors that are known to increase the likelihood of sexual transmission of HIV. A similar correlation has recently been demonstrated for the presence of HIV in female genital secretions. During the past year, a number of studies have demonstrated a marked effect of antiretroviral treatment on the shedding of HIV in the male and female genital tract, indicating a potential role of antiretroviral treatment for the prevention of HIV infection. Although potent antiretroviral therapy is beneficial on a public health basis, patients with no detectable virus in their blood or semen under treatment should not be considered non-infectious and patients should keep up with safer sex practices.     

Treatment of infections in the patient with acquired immunodeficiency syndrome

Modern technology has led to a contemporary medical practice that must be able to manage a variety of opportunistic infections in the immunocompromised host. The most common causes of immune suppression are immunosuppressive therapy after organ transplantation, granulocytopenia secondary to cancer chemotherapy, and the human immunodeficiency virus (HIV). All of these forms of immunosuppression predispose patients to a wide variety of opportunistic infections caused by reduction in T- and B-cell lymphocyte function as well as depression of neutrophils. However, the acquired immunodeficiency syndrome (AIDS) has presented the clinician with the greatest challenge in this area. Therefore, it is imperative that physicians and other health care professionals have a comprehensive understanding of the recommended therapy as well as the epidemiology, pathogenesis, and diagnosis of the various infections in these patients.     

Critical role for CD4(+) T cells in controlling retrovirus replication and spread in persistently infected mice

Reactivations of persistent viral infections pose a significant medical problem in immunocompromised cancer, transplant, and AIDS patients, yet little is known about how persistent viral infections are immunologically controlled. Here we describe a mouse model for investigating the role of the immune response in controlling a persistent retroviral infection. We demonstrate that, following recovery from acute Friend virus infection, a small number of B cells evade immunological destruction and harbor persistent virus. In vivo depletions of T-cell subsets in persistently infected mice revealed a critical role for CD4(+) T cells in controlling virus replication, spread to the erythroid lineage, and induction of erythroleukemia. The CD4(+) T-cell effect was independent of CD8(+) T cells and in some cases was also independent of virus-neutralizing antibody responses. Thus, the CD4(+) T cells may have had a direct antiviral effect. These results may have relevance for human immunodeficiency virus (HIV) infections where loss of CD4(+) T cells is associated with an increase in HIV replication, reactivation of persistent viruses, and a high incidence of virus-associated cancers.     

Respiratory infections in patients with HIV

Pneumocystis carinii pneumonia has long been considered the predominant pulmonary disease in patients with HIV, but several factors are changing this perception. The population infected with HIV is increasingly composed of injection drug users, and racial and ethnic minorities, which represent groups that have a high incidence of bacterial pneumonia and tuberculosis. The increased longevity attributed to antiretroviral therapy and P. carinii pneumonia prophylaxis is accompanied by more profound immunosuppression, rendering patients susceptible to Pseudomonas, Aspergillus, and other opportunistic pneumonias. Trimetrexate and atovaquone are now available for the treatment of P. carinii pneumonia. Both are less effective than standard regimens of trimethoprim-sulfamethoxazole, but have fewer adverse effects. The diagnosis of respiratory infections complicating HIV usually depends on isolation of the pathogen. The routine use of transbronchial biopsy during bronchoscopy is controversial because the prevalence of P. carinii pneumonia is high in most centers caring for patients with AIDS, and bronchoalveolar lavage is usually diagnostic in this disease. However, biopsy enhances the yield of bronchoscopy, especially in the diagnosis of noninfectious pulmonary disorders and infections other than P. carinii pneumonia.     

Human immunodeficiency virus-associated neoplasms: epidemiology, pathogenesis, and review of current therapy

The development of cancer in the setting of human immunodeficiency virus (HIV) infection is a devastating event and highlights the role of impaired immunity in the generation of various neoplasms. Improved strategies to suppress viral replication and prevent opportunistic infections generally have enabled patients with HIV to live longer and more productively. Unfortunately, acquired immune deficiency syndrome (AIDS)-associated neoplasia is increasing. Kaposi's sarcoma (KS), primary central nervous system lymphoma, intermediate- and high-grade B-cell lymphoma, and invasive cervical carcinoma are AIDS-defining conditions and the most commonly encountered malignancies. Recent information suggests an indirect role for HIV in the pathogenesis of these tumors. Effective treatment involves addressing complex variables encountered specifically in patients with AIDS. This review focuses on the epidemiology, pathogenesis, and treatment of KS and non-Hodgkin's lymphoma.