Drug interactions in patients infected with human immunodeficiency virus

Patients with AIDS who are receiving optimal medical care, including combination therapy with antiretroviral agents and more effective prophylaxis and therapy for opportunistic infections and neoplasms, are surviving longer. However, the potential for drug interactions in these patients is increased because many of the currently used antibiotics and antiviral agents have profound effects on the hepatic cytochrome P-450 enzyme system, on renal tubular function, and on bone marrow function. In this AIDS Commentary, Dr. Piscitelli and colleagues have succinctly reviewed the current state of our knowledge regarding the potential for additive or synergistic drug interactions that can result in enhanced toxicity or, alternatively, augmented therapeutic benefit. Information on these interactions will become more important as more intensive and effective therapy becomes available for persons with far-advanced infection due to human immunodeficiency virus type 1.     

Randomized study of two doses of didanosine in children infected with human immunodeficiency virus

2'3'-Dideoxyinosine (didanosine) is a nucleoside analog active in vitro against human immunodeficiency virus. Few data are available regarding its use for the treatment of children. In a single-center, randomized, open-label trial, we compared two dosages of didanosine (120 vs 270 mg/m2 per day) for at least 6 months in 34 children infected with human immunodeficiency virus who had become resistant to or were intolerant of zidovudine. Serum levels of didanosine 1 hour after administration were significantly different in the two groups and remained stable with time. There was a significant reduction in human immunodeficiency virus-p24 antigenemia and quantitative cellular viremia with time but no difference between the two groups. The intensity of the biologic response, however, was significantly higher in the patients who had more than 50 CD4+ cells 10(6)/L at inclusion. No pancreatic or neurologic toxic effects were observed. In five children, liver function abnormalities developed that are unusual in this setting, and the death of one child from unexplained hepatocellular failure suggests that didanosine may be hepatotoxic. Three of these five children had preexisting liver disease. Although no definite conclusion can be made as to the optimal dose, there were no major differences between the two administration schedules in terms of biologic effects and tolerability.     

Cavitary pulmonary lesions in patients infected with human immunodeficiency virus

The differential diagnosis of cavitary pulmonary lesions in individuals infected with human immunodeficiency virus (HIV) is broad, especially in patients with advanced disease. In patients with Pneumocystis carinii pneumonia, cavitation is an uncommon manifestation of a common disease. It is unusual in patients with pulmonary cryptococcosis, coccidioidomycosis, and histoplasmosis but occurs frequently in patients with invasive pulmonary aspergillosis. In patients with pulmonary tuberculosis, cavities are more common during earlier stages of HIV disease, when cellular immunity is relatively preserved. Mycobacterium avium complex is an uncommon cause of lung disease and infrequently produces cavities. However, Mycobacterium kansasii, is often associated with cavitation. Cavities can complicate any bacterial pneumonia and are especially common with pneumonia due to Pseudomonas aeruginosa, Nocardia asteroides, and Rhodococcus equi. Noninfectious causes of cavitary lesions are rare, but cavitary lesions caused by pulmonary Kaposi's sarcoma and non-Hodgkin's lymphoma have been reported. Because of the broad differential diagnosis and because most cavities are caused by treatable opportunistic infections, a definitive diagnosis is essential.     

Serum and plasma markers of nutritional status in children infected with the human immunodeficiency virus

OBJECTIVE: To determine whether reduced serum or plasma protein and micronutrient levels are common in children infected with the human immunodeficiency virus (HIV) and whether these levels are different in children with growth retardation compared to those with normal growth. SUBJECTS: Children were separated into three groups: (a) HIV-infected with growth retardation (HIV + Gr); (b) HIV-infected with normal growth (HIV+); (c) HIV-uninfected with normal growth (HIV-). All children were afebrile and free of acute infection at the time of study. During a 24-hour stay in the Pediatric Clinical Research Unit, blood was drawn for analysis of total protein, albumin, zinc, selenium, and vitamin A levels; growth measurements were obtained; and dietary intake was assessed by 24-hour weighed food intake and 24-hour dietary recall. STATISTICAL ANALYSIS: Mean differences between groups were assessed by analysis of variance, and differences in the frequency of nutrient deficiency were determined by chi 2 analysis. RESULTS: Thirty-eight children between 2 and 11 years of age were studied: 10 HIV + Gr, 18 HIV+, and 10 HIV-. No statistically significantly differences were noted in mean levels of albumin, prealbumin, zinc, and selenium. Mean serum level of vitamin A was significantly higher in the HIV + Gr group than in the other two groups. There were no significant differences between groups in the frequency of deficiency for any nutrient studied. Mean energy and nutrient intake was similar among groups. APPLICATIONS/CONCLUSIONS: Abnormal serum or plasma protein or micronutrient levels were uncommon in this cohort of HIV-infected children, even in children with growth retardation. Routine monitoring of the level of proteins and micronutrients studied is unnecessary in the absence of specific clinical indicators of deficiency.     

Pleural effusion in patients infected with the human immunodeficiency virus

In order to analyze the etiology, cytological and biochemical characteristics, and outcome of pleural disease in patients infected with HIV, the medical records of 86 HIV-positive patients with pleural effusion were reviewed. Controls were 106 HIV-negative patients with parapneumonic or tuberculous effusion. Most HIV-positive patients were intravenous drug abusers (95.3%). Pleural effusions in HIV-positive patients were caused by infections in 76 (89.4%) cases. Parapneumonic effusion was diagnosed in 59 patients and tuberculous pleuritis in 15 patients. Staphylococcus aureus was the most frequently isolated bacteria. Parameters for differentiating complicated cases of parapneumonic exudate from uncomplicated cases, such as pleural fluid pH < 7.20 (sensitivity 80% vs. 84.3%), pleural fluid glucose < 35 mg/dl (sensitivity 45% vs. 56.25%) pleural fluid LDH > 1600 UI/l (sensitivity 85% vs. 62.50%), showed similar sensitivity in HIV-positive and HIV-negative patients. Monocytes in pleural fluid were significantly decreased in tuberculous pleuritis in HIV-positive patients (506 +/- 425 vs. 1014 +/- 1196 monocytes/ml, p < 0.05). No significant differences were detected in the outcome of HIV-positive and HIV-negative patients with pleural disease. It can be concluded that the pleural effusion was of predominantly infectious etiology in HIV-positive patients from populations with a high prevalence of intravenous drug abuse. Neither the biochemical parameters in pleural fluid nor the outcome differed significantly between HIV-positive and HIV-negative patients.     

Timing of lymphocyte activation in neonates infected with human immunodeficiency virus

PURPOSE: To report the results of vitreoretinal surgery for the management of complications associated with congenital retinoschisis in children. METHODS: We conducted a review of consecutive children with complications of congenital retinoschisis treated with advanced vitreoretinal techniques. Nine eyes of seven patients with congenital retinoschisis had vitreoretinal surgery for one of the following complications of congenital retinoschisis: hemorrhage within a large schisis cavity with a dense vitreous hemorrhage; rapid progression of schisis threatening the macula; obscuration of the macula by the overhanging inner wall of a schisis cavity; a combined schisistraction retinal detachment; or a combined schisis-rhegmatogenous retinal detachment. Vitreoretinal surgery consisted of vitrectomy, inner schisis wall retinectomy, fluid-gas exchange, endolaser treatment, and perfluoropropane gas injection. After vitreoretinal surgery, patients were followed up for a mean of 26 months (range, 9 to 67 months). Retinal reattachment, visual acuity, and visual fields were used as outcome measures. RESULTS: Eight of nine eyes had successful retinal reattachment. Six eyes postoperatively had improved visual acuity or visual field, or both. One eye had stabilization of visual acuity, and two eyes had a decrease in visual acuity. CONCLUSION: In children with complications of congenital retinoschisis, vitreoretinal surgery with excision of the inner wall of the peripheral schisis cavity may be effective in achieving retinal reattachment, thereby improving visual acuity or visual field size.     

Cervical cytology findings in women infected with the human immunodeficiency virus

It has been suggested that immunocompromised, HIV-infected patients are at risk of developing HPV infection and SIL. The well documented role of HPV and SIL in cervical carcinogenesis should lead to frequent, careful evaluation of HIV infected women. Forty-four cervical smears from 23 patients (20 HIV and 3 AIDS) were reviewed. While 11 of the 23 patients produced negative smears, 11 had abnormal cytological findings on at least one occasion. Sixteen smears (36 percent) from 10 patients (43%) showed evidence of HPV and/or SIL. Two smears (two patients) were assigned to the benign epithelial atypia category. (One of these showed keratosis which may indicate HPV infection.) Six smears (three patients) represented either a severe Trichomonas, fungal (Candida sp.), or Herpes infection. Three smears were deemed unsatisfactory for diagnosis due to severe acute inflammation or obscuring blood. Five biopsies were available. In four, histologic findings supported the original cytologic diagnosis. One patient with a negative smear had a biopsy showing condyloma. This study further supports an association of HPV and/or cervical dysplasia with HIV. Careful evaluation and follow-up of HIV-infected women is essential.     

Virologic markers of human immunodeficiency virus type 1 in cerebrospinal fluid of infected children

Heme oxygenase (HO) is the rate-limiting enzyme in the catabolism of heme to bilirubin. Cobalt chloride (CoCl2) and many other agents that generate oxidant stresses induce the HO-1 isoform. Furthermore, HO-1 has been shown to protect against oxidant stress in vitro and in vivo by mechanisms involving increased ferritin synthesis. However, little is known about the inducibility of hepatic HO-1 during the very early postnatal period, and whether HO-1 induction is associated with increased ferritin synthesis in neonates. Therefore, we studied hepatic HO-1 mRNA, HO-1 protein concentration, total HO activity, and ferritin protein levels in neonatal rats. Neonatal rats 0-5 d of age were injected with 250 mumol/kg body weight of CoCl2. 6H2O in saline or with an equal volume of saline in age-matched controls. Liver samples were collected 4 h after injection for HO-1 mRNA analysis and 20 h after injection for analysis of HO-1 protein concentration, total HO activity, and ferritin protein levels. In CoCl2-treated rats, hepatic HO-1 mRNA was 3-10 times the levels in control rats (p < 0.05), HO-1 protein concentration was 2-5 times the levels in control rats (p < 0.05), and total HO activity was higher by 20-80% than in control rats (p < 0.05). There were no differences in hepatic ferritin protein levels between CoCl2-treated neonatal rats and controls; however, in CoCl2-treated adult rats, hepatic ferritin protein levels were 1.6 times the levels in controls (p < 0.05). Thus, neonatal rats can up-regulate hepatic HO-1 mRNA, HO-1 protein concentration, and total HO activity in response to CoCl2; however, no upregulation of hepatic ferritin protein levels was observed in neonatal rats after CoCl2 administration or subsequent HO-1 induction. We speculate that neonatal rats induce hepatic HO-1 and up-regulate ferritin by different mechanisms than do adult rats.     

Adverse reactions to thalidomide in patients infected with human immunodeficiency virus

Thalidomide is emerging as a useful agent in the management of several complications of disease due to human immunodeficiency virus (HIV). We conducted three prospective studies of 56 HIV-infected patients who were treated with thalidomide for 14-21 days; 24 (43%) of these patients discontinued therapy owing to adverse reactions. Cutaneous and/or febrile reactions were the most frequent toxicities, arising in 20 (36%) of the patients. These reactions occurred after a mean interval (+/-SD) of 10 +/- 3 days and were associated with significantly lower CD4 T lymphocyte counts in reactors than in nonreactors (median count, 52.5/mm3 vs. 242 cells/mm3, respectively; P = .009). Four of four rechallenged patients experienced accelerated hypersensitivity; hypotension occurred in one case. Although sedation was an almost universal side effect among the patients, it was moderate or severe in only seven (13%); constipation was moderate or severe in five (9%) of the patients. Severe neuropathic symptoms and mood changes were each noted in two (4%) of the 56 patients. We conclude that the increasing use of thalidomide to treat HIV-infected patients must be accompanied by recognition of the drug's increased potential for toxicity in this population.     

Drug-induced pulmonary edema in a patient infected with human immunodeficiency virus

Adverse reactions to drugs are common in patients infected with the human immunodeficiency virus (HIV). In these patients pulmonary reactions to drugs may be difficult to differentiate from opportunistic pulmonary infections. We report a HIV-infected patient who on two occasions developed acute pulmonary edema related to the administration of ibuprofen.     

Thrombocytopenia in patients infected with human immunodeficiency virus: treatment update

Thrombocytopenia that is associated with infection due to human immunodeficiency virus (HIV) is an important and common hematologic abnormality. Although this condition is often asymptomatic, it may manifest clinically as a spectrum of bleeding problems including petechiae, ecchymoses, epistaxis, or menorrhagia or as hemorrhage of the gingivae, gastrointestinal tract, or CNS. Thrombocytopenia may be present in patients at any stage of immunodeficiency, and spontaneous remission can occur. We review the natural history of HIV-related thrombocytopenia and discuss treatment options.     

Filgrastim restores interleukin-2 production in blood from patients with advanced human immunodeficiency virus infection

BACKGROUND & AIMS: Malondialdehyde and acetaldehyde react together with proteins and form hybrid protein conjugates designated as MAA adducts, which have been detected in livers of ethanol-fed rats. The aim of this study was to examine the immune response to MAA adducts and other aldehyde adducts during long-term ethanol exposure. METHODS: Rats were pair-fed for 7 months with a liquid diet containing either ethanol or isocaloric carbohydrate. Circulating antibody titers against MAA adducts and acetaldehyde adducts were measured and characterized in these animals. RESULTS: A significant increase in antibody titers against MAA-adducted proteins was observed in the ethanol-fed animals. Competitive inhibitions of antibody binding indicated that the circulating antibodies against MAA-modified proteins in the ethanol-fed rats recognized mainly a specific, chemically defined MAA epitope. Antibody titers to reduced and nonreduced acetaldehyde adducts were very low, and no significant differences were observed between ethanol-fed and control animals. Significant plasma immunoreactivity to not only MAA-adducted but also unmodified rat liver proteins (cytosol, microsomes, and especially plasma membrane) were also observed in the ethanol-fed rats. CONCLUSIONS: Long-term ethanol feeding generates circulating antibodies not only against MAA epitopes but possibly also against unmodified, native (self) protein epitopes, suggesting that MAA adducts could trigger harmful autoimmune responses.     

Varicella-zoster virus infection in children with underlying human immunodeficiency virus infection

This article describes a prospective longitudinal study of varicella-zoster virus (VZV) infections in human immunodeficiency virus (HIV)-infected children, designed to determine their natural history of VZV infection and possible effects of VZV on the progression of HIV infection. Varicella was usually not a serious acute problem, and it did not seem to precede clinical deterioration. The rate of zoster was high: 70% in children with low levels of CD4+ lymphocytes at the time of development of varicella. It is predicted that immunization with live attenuated varicella vaccine is unlikely to be deleterious to HIV-infected children. Moreover, if they are immunized when they still have relatively normal levels of CD4+ lymphocytes, they may have a lower rate of reactivation of VZV than if they were allowed to develop natural varicella when their CD4+ cell counts have fallen to low levels as a result of progressive HIV infection.     

Interferon-gamma and interleukin-4 responses in relation to serum IgE levels in persons infected with human T lymphotropic virus type I and Strongyloides stercoralis

Possible immunologic interaction between infection with human T lymphotropic virus type 1 (HTLV-1), a retrovirus, and the intestinal parasite Strongyloides stercoralis was investigated in persons infected with one or both agents. This was done by examining the cytokine responses of peripheral blood mononuclear cells (PBMC) to mitogens and Strongyloides antigen. PBMC of subjects infected with HTLV-1 spontaneously produced interferon (IFN)-gamma with levels that correlated inversely with serum IgE levels. HTLV-1-infected subjects also had poor interleukin (IL)-4 responses to mitogenic stimulation, unlike persons without HTLV-1 infection. It is postulated that the IFN-gamma produced by activated T cells in some HTLV-1-infected persons acts to down-regulate IL-4 with consequent reduction of serum IgE levels. The impaired IgE responses and other effects of IL-4 down-regulation may be contributing factors to more severe disease and impaired response to treatment of strongyloidiasis in some HTLV-1-infected persons.     

Significance of mild cytologic atypia in women infected with human immunodeficiency virus

This study examined the cross over between alcoholics and habitual gamblers. A group of Alcoholics Anonymous members (n = 30) and a group of pathological gamblers (Gamblers Anonymous members) (n = 23) and self-identified habitual gamblers (n = 21) were asked to respond to two inventories--the South Oaks Gambling Screen (SOGS, Lesieur & Blume, 1987) and the Substance Abuse Subtle Screening Inventory (SASSI-2, Miller, 1994). Results of our analyses suggested there were not significant degrees of cross over.