Pharmacological Characterization of a Novel Beta 3 Adrenergic Agonist, Vibegron: Evaluation of Antimuscarinic Receptor Selectivity for Combination Therapy for Overactive Bladder.

Although the physiologic role of muscarinic receptors in bladder function and the therapeutic efficacy of muscarinic antagonists for the treatment of overactive bladder are well established, the role of ß3-adrenergic receptors (ß3ARs) and their potential as therapeutics is just emerging. In this manuscript, we characterized the pharmacology of a novel ß3AR agonist vibegron (MK-4618, KRP-114V) and explored mechanistic interactions of ß3AR agonism and muscarinic antagonism in urinary bladder function. Vibegron is a potent, selective full ß3AR agonist across species, and it dose dependently increased bladder capacity, decreased micturition pressure, and increased bladder compliance in rhesus monkeys. The relaxation effect of vibegron was enhanced when combined with muscarinic antagonists, but differentially influenced by muscarinic receptor subtype selectivity. The effect was greater when vibegron was co-administered with tolterodine, a nonselective antagonist, compared with coadministration with darifenacin, a selective M3 antagonist. Furthermore, a synergistic effect for bladder strip relaxation was observed with the combination of a ß3AR agonist and tolterodine in contrast to simple additivity with darifenacin. To determine expression in rhesus bladder, we employed a novel ß3AR agonist probe, [3H]MRL-037, that selectively labels ß3 receptors in both urothelium and detrusor smooth muscle. Vibegron administration caused a dose-dependent increase in circulating glycerol and fatty acid levels in rhesus and rat in vivo, suggesting these circulating lipids can be surrogate biomarkers. The translation of our observation to the clinic has yet to be determined, but the combination of ß3AR agonists with M2/M3 antimuscarinics has the potential to redefine the standard of care for the pharmacological treatment of overactive bladder.

One world, one hope: the cost of providing antiretroviral therapy to all nations.

OBJECTIVE: To estimate the potential direct cost of making triple combination antiretroviral therapy widely available to HIV-positive adults and children living in countries throughout the world. METHODS: For each country, antiretroviral costs were obtained by multiplying the annual cost of triple antiretroviral therapy by the estimated number of HIV-positive persons accessing therapy. Per capita antiretroviral costs were computed by dividing the antiretroviral costs by the country's total population. The potential economic burden was calculated by dividing per capita antiretroviral costs by the gross national product (GNP) per capita. All values are expressed in 1997 US dollars. RESULTS: The potential cost of making triple combination antiretroviral therapy available to HIV-positive individuals throughout the world was estimated to be over US$ 65.8 billion. By far the greatest financial burden was on sub-Saharan Africa. The highest per capita drug cost in this region would be incurred in the subregions of Southern Africa (US$ 149) followed by East Africa (US$ 116), Middle Africa (US$ 44), and West Africa (US$ 42). In the Americas, subregional data indicated the highest per capita drug cost would be in the Latin Caribbean (US$ 22), followed by the Caribbean (US$ 17), Andean Area (US$ 7), the Southern Cone (US$ 6), North America (US$ 6), and Central American Isthmus (US$ 5). In Asia and Europe the percentage of the GNP necessary to finance drug therapy was less than 1% in most countries examined. CONCLUSION: Our results demonstrate that the cost of making combination antiretroviral therapy available worldwide would be exceedingly high, especially in countries with limited financial resources.

PIP: In 1997, an estimated 5.8 million people worldwide were infected with HIV, of whom 90% lived in developing countries, especially in sub-Saharan Africa. While antiretroviral therapy has been shown to prolong survival in people with HIV/AIDS, many of the countries with the highest rates of HIV infection have little or no access to antiretroviral therapy, for a number of reasons, including cost. Findings are presented from a study conducted to estimate the potential direct cost of making triple combination antiretroviral therapy widely available to all of the world's HIV-infected population. The potential cost of making such therapy available to HIV-positive people worldwide was estimated to be over US$65.8 billion, in 1997 US dollars, with the greatest expenditures needed in sub-Saharan Africa. The highest per capita drug cost in sub-Saharan Africa would be incurred in Southern Africa (US$149), followed by East Africa (US$116), Middle Africa (US$44), and West Africa (US$42). In the Americas, per capita drug costs would be US$22 in the Latin Caribbean, US$17 in the Caribbean, US$7 in the Andean Area, US$6 in the Southern Cone and North America, and US$5 in the Central American Isthmus. In Europe and Asia, the percentage of GNP needed to finance drug therapy was less than 1% in most countries examined. For each country, antiviral costs were determined by multiplying the annual cost of triple antiretroviral therapy by the estimated number of HIV-positive people accessing therapy. Per capita therapy costs were calculated by dividing the antiretroviral costs by the country's total population. The potential economic burden was calculated by dividing per capita antiretroviral costs by the gross national product (GNP) per capita.

Increasing incidence of HIV infections among young gay and bisexual men in Vancouver.

Since the beginning of the HIV epidemic in north America, the majority of HIV infections have occurred among men who engage in sexual relations with other men. As the HIV epidemic enters its third decade, gay and bisexual men continue to have among the highest rates of HIV infection. Previous studies have highlighted the decline in the incidence of HIV and risk behaviour among gay and bisexual men. However, several studies have suggested that young gay and bisexual men continue to engage in unprotected sexual behaviours and are at continued risk of HIV infection. Recent reports in the media and research literature have indicated an increase in the incidence of HIV among gay and bisexual individuals in many of the world's major cities. The purpose of this study was to determine trends in HIV incidence using data from a prospective cohort of young gay and bisexual men.

Synthesis, biological activity, and conformational analysis of (2S,3R,4S)-MeBmt1-cyclosporin, a novel 1-position epimer of cyclosporin A.

Cyclosporin A (CsA, 1), an immunosuppressive cyclic undecapeptide, contains a unique amino acid, (4R)-4-[(E)-butenyl]-4,N-dimethyl-L-threonine (MeBmt), that appears to be critically involved in the biological activity of CsA. In order to further explore the effect that structural elements in MeBmt have on the conformation and biological activity of CsA, the 4-epimer of MeBmt [(4S)-MeBmt, 2] and the corresponding CsA analogue [(4S)-MeBmt1-CsA, 3] have been synthesized. Biological assay using concanavalin A stimulated thymocytes indicated that (4S)-MeBmt1-CsA (3) has only 2-4% immunosuppressive activity relative to CsA. The NMR analysis by 1D and 2D NMR methods establishes the conformation of 3, of which the 33-membered cyclic peptide ring system in chloroform is very similar to that of CsA. However, the NMR analysis also reveals that the 1-position side chain orientation in (4S)-MeBmt1-CsA (3) is very different from that of CsA. Specifically, the (4S)-MeBmt alpha,beta-torsion angle (chi 1) has been rotated approximately 120 degrees relative to that of CsA, and the orientation of the butenyl side chain relative to the 33-membered peptide backbond is different. The orientation of the (4S)-MeBmt side chain is consistent with the possible conformations calculated for (4S)-MeBmt1-CsA (3) by using molecular mechanics (in vacuo) calculations. The conformational analysis suggests that the loss of biological activity for 3 results from an altered conformation of the 1-position side chain relative to the peptide backbond due to the changed chirality at C4 of MeBmt.

Design and synthesis of P2-P1'-linked macrocyclic human renin inhibitors.

Using a computer model of the active site of human renin developed at Merck, we designed a series of novel P2-P1'-linked, macrocyclic renin inhibitors 3-10. These unique inhibitors incorporate a transition-state isostere within a 13- or 14-membered ring. The three most active compounds in this family were 13-membered-ring glutamine-derived inhibitor 3, 14-membered-ring diaminopropionic acid derived inhibitor 6, and 13-membered-ring diol 9 (IC50 0.61, 0.59, 0.65 microM, respectively). Modification of inhibitor 3 at P4 led to 56 nM macrocyclic renin inhibitor 39. This study shows the viability of renin inhibitor designs which incorporate a scissile-bond replacement within a macrocycle.

Highly potent, orally active diester macrocyclic human renin inhibitors.

Replacing one amide bond in macrocyclic renin inhibitors of the general structure 1 and 2 with an ester linkage gave glutamate-derived inhibitors 3 and serine-derived inhibitors 4. While this oxygen-for-nitrogen exchange had little effect on potency in the glutamate series, potency was dramatically increased in the serine series. In this series, the 14-membered ring compounds proved to be more potent than the corresponding 13-membered ring derivatives. Substitution of the ring at the position corresponding to P2' generally increased potency. The absolute configuration at this center was shown to be R for the 4-morpholinomethyl derivative (4o), both by asymmetric synthesis and X-ray crystallography. Replacing the "Boc-Phe" moiety of inhibitor 4o with a variety of substituents led to subnanomolar inhibitors, one of which (the "3(S)-quinuclidinyl-Phe" derivative 33) lowered blood pressure 20 mmHg and completely inhibited plasma renin activity for 6 h in sodium-depleted rhesus monkeys. This compound proved to have limited bioavailability (1% in rats) due to cleavage of the serine ester bond and rapid hepatic extraction.

Discovery of a potent, orally bioavailable beta(3) adrenergic receptor agonist, (R)-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4 -[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide.

As part of our investigation into the development of orally bioavailable beta(3) adrenergic receptor agonists, we have identified a series of pyridylethanolamine analogues possessing a substituted thiazole benzenesulfonamide pharmacophore that are potent human beta(3) agonists with excellent selectivity against other human beta receptor subtypes. Several of these compounds also exhibited an improved pharmacokinetic profile in dogs. For example, thiazole sulfonamide 2e (R = 4-F(3)C-C(6)H(4)) is a potent full beta(3) agonist (EC(50) = 3.6 nM, 94% activation) with >600-fold selectivity over the human beta(1) and beta(2) receptors, which also displays good oral bioavailability in several mammalian species, as well as an extended duration of action.

Sex trade involvement and rates of human immunodeficiency virus positivity among young gay and bisexual men.

BACKGROUND: Susceptibility to human immunodeficiency virus (HIV) infection is of particular concern for marginalized populations. The objective of this study was to determine risk factors associated with sex trade work among young gay and bisexual men. Further, we aimed to compare HIV prevalence and incidence among men involved and not involved in sex trade work. METHODS: The study is based upon data obtained from a prospective cohort study of young gay and bisexual men. Participants had completed a baseline questionnaire which elicited information on demographic information, sexual behaviours, and substance use. Sex trade involvement was defined as the exchange of money, drugs, goods, clothing, shelter or protection for sex within the one year prior to enrollment. Contingency table and multivariate logistic regression analyses were used to identify risk factors associated with involvement in the sex trade. RESULTS: Of the 761 eligible participants, 126 (16%) reported involvement in sex trade work. Multivariate logistic regression analysis revealed regular alcohol use (Odds Ratio [OR] = 3.6, 95% CI : 1.8-7.2), aboriginal ethnicity (OR = 3.7, 95% CI : 1.6-8.7), unemployment (OR = 3.9, 95% CI : 2.1-7.3), history of residence in a psychiatric ward (OR = 4.2, 95% CI : 1.8-9.8), bisexual activity (OR = 7.0, 95% CI : 3.5-14.1) and the use of crack (OR = 7.4, 95% CI : 3.0-18.7) to be independently associated with sex trade work. Sex trade workers had a significantly higher HIV prevalence at baseline compared with non-sex trade workers (7.3% versus 1.1%, P < 0.001). As well, HIV incidence was found to be significantly higher for sex trade workers compared with non-sex trade workers (4.7% versus 0.9%, P = 0.011). CONCLUSION: Our study reveals that for male sex trade workers in this setting increased vulnerability to HIV infection is related to unfavourable living conditions, substance use and sexual risk behaviour.

L-750355, a human beta3-adrenoceptor agonist; in vitro pharmacology and profile of activity in vivo in the rhesus monkey.

The profile of in vitro and in vivo biology of a human beta3-adrenoceptor agonist, (S)-N-[4-[2-[[3[(2-amino-5-pyridinyl)oxy]-2-hydroxy-propyl]amino]-eth yl]-phenyl]-4-isopropylbenzenesulfonamide, L-750355, is described. Using cloned human and rhesus beta1-, beta2- and beta3-adrenoceptors, expressed in Chinese hamster ovary (CHO) cells, L-750355 was shown to be a potent, albeit partial, agonist for the human (EC(50)=10 nM; % maximal receptor activation=49%) and rhesus (EC(50)=28 nM; % maximal receptor activation=34%) beta3-adrenoceptors. Furthermore, L-750355 stimulates lipolysis in rhesus adipocytes in vitro. L-750355 is a weak partial agonist (EC(50)=3.2 microM; % maximal receptor activation=33% ) for the human beta1-adrenoceptor but exhibits no agonist activity for rhesus beta1- or beta2-adrenoceptors of either human or rhesus origin. Administration of L-750355 to anesthetized rhesus monkeys, as a series of rising dose intravenous infusions, evokes dose-dependent glycerolemia and tachycardia with no change in mean arterial blood pressure or plasma potassium. The dose-response curve for L-750355-induced glycerolemia lies to the left of that for tachycardia. Propranolol, at a dose (0.3 mg/kg, i.v. ) that attenuates isoproterenol-induced changes in heart rate and glycerolemia, abolished L-750355-induced tachycardia but had no effect on L-750355-induced glycerolemia.

The effect of the partition locus on plasmid stability and expression of a prolonged chemostat culture.

The stability, copy number, and gene expression of the pBR322 plasmid containing the par-locus under prolonged cultivation were studied. In the initial stage of the experiment it was observed that the par-locus had a stabilization effect on plasmid maintenance. This observation was consistent with previously reported results. However, after approximately 225 h, a mixed population of plasmid-containing and plasmid-free cells appeared. The mixed culture was stably maintained for approximately 200 h. In addition, the relative plasmid copy number showed an increase as compared to the par- culture. After 100 h the copy number decreased, reached a minimum, then stabilized. The beta-lactamase activity, was not significantly affected by the par-locus.

Cholesterol granuloma of the petrous apex: MR and CT evaluation.

We reviewed the clinical, CT, and MR findings in seven consecutive patients who had a total of nine cholesterol granulomas. Preoperative MR scans were available for five of the seven patients; two patients were studied with MR after treatment only (one had a recurrent lesion and the other was asymptomatic at the time of study). Preoperative CT scans were available for all patients, except one patient who was examined after developing a symptomatic recurrence. All lesions were detected by both imaging methods. Seven preoperative lesions (five patients) and one symptomatic recurrence (one patient) demonstrated increased signal intensity of both T1- and T2-weighted MR images. Three surgically drained lesions (three patients) showed a marked reduction in signal intensity on T1-weighted images. Pre- and postoperative lesions had different patterns of signal intensity on the chemical-shift images, which were obtained in two instances. The MR appearance of cholesterol granuloma differs from that of most other lesions that occur in the petrous apex. CT did not differentiate between pre- and postoperative lesions in all cases, while MR demonstrated a dramatic change on T1-weighted images and chemical-shift studies. Our findings indicate that MR is more specific than CT in suggesting the correct diagnosis of cholesterol granuloma and that MR appears to be the technique of choice in the follow-up of previously treated patients.

Morbidity and mortality related to human immunodeficiency virus in Canadian men and women, 1987-94.

OBJECTIVE: To assess the impact of HIV/AIDS on hospitalization and mortality patterns in Canada. METHODS: Hospitalizations and deaths due to HIV/AIDS were compared with select causes of morbidity and mortality among men and women across provinces, regions and select cities between 1987-94. Patterns of hospitalization and mortality were characterized by calculating age-specific, standardized rates, rate ratios and potential years of life lost before 65 years. RESULTS: A total of 28,462 hospitalizations (26,153 in men and 2,309 in women) and 8,739 deaths (8,192 in men and 547 in women) were attributed to HIV/AIDS during the study period. Rates of HIV/AIDS hospitalization were highest for men in Ontario, Quebec and British Columbia, and in Montreal, Toronto and Vancouver; while among women they were highest in Quebec and in Montreal, Toronto and Vancouver. Mortality rates followed a pattern similar to the rates found for hospitalization. CONCLUSIONS: Our analysis reveals the considerable impact of HIV/AIDS on patterns of morbidity and mortality in Canada.

PIP: The authors "assess the impact of HIV/AIDS on hospitalization and mortality patterns in Canada...among men and women across provinces, regions and select cities between 1987-94.... This work reveals the considerable impact of HIV/AIDS on patterns of hospitalization and mortality in Canada. When compared with select leading causes of morbidity and mortality, HIV/AIDS was found to be the leading cause of hospitalization and death for men and women, especially during early adulthood." (EXCERPT)

Data analysis of plasmid maintenance in a CSTR.

A simple procedure is developed to process experimental data from plasmid maintenance studies of recombinant cells in a chemostat with nonselective medium. This procedure, based on the model proposed by Imanaka and Aiba, provides quantitative information on the rate of plasmid loss and the difference in the specific growth rate between the plasmid-carrying and plasmid-free cells. The performance of the proposed method is evaluated through simulation studies. In addition, the method is applied to a set of previously reported experimental data. The two-parameter model, together with the estimated parameter values, provides an excellent fit to the experimental data.

Dynamics of plasmid maintenance in a CSTR upon square-wave perturbations in the dilution rate.

The effects of forced oscillations in the dilution rate on a population of Escherichia coli K12 harboring the plasmid pBR322 in a chemostat with a nonselective medium were studied. In the constant dilution rate control experiments, the percentage of plasmid-containing cells decreased after a long lag time. Eventually, the culture approached a population consisting of 100% plasmid-free ells. However, under forced perturbations of the dilution rate, the culture maintained a mixed population of plasmid-free and plasmid-carrying cells for a longer period of ime. An unstructured model was developed to describe the above observations. Our results indicate that transient conditions created by dilution-rate perturbations provide a favorable environment for the plasmid-carrying population. In addition, experiments with different cycling frequencies suggest that adaptation by the culture to these transient conditions will reduce or totally eliminate such an advantage.

Population dynamics of a recombinant culture in a chemostat under prolonged cultivation.

The dynamics of a chemostat culture of Escherichia coli K12 harboring plasmid pBR322 under prolonged cultivation with a nonselective complex medium were studied. The ability of the culture to form colonies on plates supplemented with different ampicillin concentrations was monitored. It was observed that almost all cells sampled were able to grow on a high concentration of ampicillin at the beginning of the experiment. However, a subpopulation which formed colonies on intermediate-concentration (500-1000 mg/L) plates, but not on a high-concentration (2000 mg/L) plate, was detected just before the appearance of the plasmid-free cells. As time progressed, the percentage of this subpopulation increased, reached a maximum, then decreased toward the end of experiment. At this time the culture was dominated by a subpopulation which could not form colonies on the 100 mg/L ampicillin plates. These results indicate that three major processes may occur in the chemostat: a gradual shift of the higher plasmid copy number population toward a relatively lower copy number population; the complete shedding of the plasmid due to faulty segregation of plasmids during cell division; and growth competition among the subpopulations. A previously derived model is extended to account for all subpopulations. The model agrees qualitatively with the experimental results.

Recording sexual behavior: comparison of recall questionnaires with a coital diary.

OBJECTIVE: To compare sexual behavior data obtained using a weekly-recall questionnaire, a daily-recall questionnaire, and a coital diary. DESIGN: Cross-sectional survey of female sex workers from KwaZulu-Natal, South Africa between August and October 1998. METHODS: In this study, 52 weekly-recall questionnaires, 27 daily-recall questionnaires, and 79 coital diaries for dates corresponding to the questionnaires were obtained from female sex workers. Variables examined included: number of clients, number of condoms used with clients and partners, and number and type of sexual acts with clients and partners. Statistical analyses were conducted to examine the degree of agreement between the data collection methods and to assess differences between the mean values of the variables in the questionnaires versus the diary. RESULTS: Comparison of weekly-recall questionnaires with coital diaries indicated a significantly greater mean number of clients (P < 0.001), number of condoms used (P < 0.001), vaginal acts (P < 0.001), and anal acts (P = 0.044) reported in the diary versus the questionnaire. On comparison of daily-recall questionnaire with coital diary, significant differences were revealed between the means detected for the number of clients (P = 0.027), number of days worked (0.009), and anal acts with clients (P = 0.004). CONCLUSIONS: The use of coital diaries for the collection of sexual behavior data may be limited to cross-sectional community surveys. A recall questionnaire may provide more reliable and a better quality of data for longitudinal studies and for human immunodeficiency virus/sexually transmitted disease evaluation programs.

PIP: This study aimed to compare data obtained from coital diaries (CD) with those collected using weekly recall (WR) and daily recall (DR) questionnaires. 79 female sex workers aged 18-44 coming from KwaZulu-Natal, South Africa, were studied. They were followed up every month with clinical examination and treatment of STDs, provision of condoms, and CD collection. There were 52 WR, 27 DR, and 79 CD records collected from the participants. Results showed that CD records showed a significantly greater mean number of clients compared to the questionnaires (23.3 vs. 13.6, P 0.001), number of condoms used (2.7 vs. 0.5, P 0.001), vaginal acts (6.8 vs. 2.9, P 0.001), and anal acts (1.9 vs. 0.7, P = 0.044). Daily accounts of weekly sexual activity showed significant differences in 1) the number of days worked (6.2 vs. 5.2, P = 0.009), 2) the number of clients (21.7 vs. 17.4, P = 0.027), and 3) the number of anal acts with clients (3.9 vs. 0.8, P = 0.004), with higher means reported in the CD records for all cases. The CD records are an important instrument for gathering preliminary sexual behavioral information; however, their use is limited to long-term data collection. Therefore, a comprehensive recall questionnaire is recommended for future trials.

Visual responses and connectivity in the turtle pretectum.

1. Using an isolated turtle brain preparation, we made extracellular spike recordings in the dorsal midbrain during visual stimulation. Single units were isolated by their response to a slow-moving full-field visual pattern imaged on the contralateral retina. This stimulus elicits responses from the basal optic nucleus (BON) and the cerebellar cortex using a similar preparation. Direction and speed tuning were then analyzed, as well as the size and position of the receptive field. 2. In one brain stem region, anterior to the optic tectum and deep to the dorsal surface, all of the visually responsive neurons were direction sensitive (DS) to contralateral retinal stimulation. The location and properties of these cells indicate that they are in the mesencephalic lentiform nucleus (nLM). Anterograde transport of intravitreally injected horseradish peroxidase revealed that this pretectal nucleus receives direct input from the contralateral eye. 3. All but 2 of the 48 cells of the nLM were strongly DS. The most effective stimulus was a slowly moving complex visual pattern that drifted nasally in the contralateral visual field. Brief flashes of spots, patterns, or diffuse light were much less effective. Receptive fields were large and usually (9 of 13 cells) centered in the superior visual field near the horizon and nasal to the blind spot. 4. The visual responses of nLM cells were compared to those of cells in the superficial layers of the optic tectum. In contrast to nLM, the responses of tectal cells were heterogeneous and frequently not DS. Neither tectum or nLM cells had much spontaneous spike activity during darkness or stationary patterns. On the other hand, visual responses of nLM cells were very similar to those of the BON, where neurons also had low spontaneous activity, preferred slow-moving patterns, and were DS. However, nLM and BON exhibit different distributions of preferred directions. Most nLM cells preferred temporal-to-nasal motion, whereas BON cells preferred almost any direction, although few preferred the nasal direction. nLM cell responses were not affected by removal of the ventral brain stem including the BON. 5. The visual properties of nLM cells recorded in vitro were very similar to those that were recorded in intact turtles.(ABSTRACT TRUNCATED AT 400 WORDS)

Determinants of hospital admission among HIV-positive people in British Columbia.

BACKGROUND: This study was initiated to evaluate the demographic and clinical determinants of admission to hospital among HIV-positive men and women receiving antiretroviral therapy in British Columbia. METHODS: The analysis was restricted to participants enrolled in the HIV/AIDS Drug Treatment Program between September 1992 and March 1997 who had completed an annual participant survey, had a viral load determination and had signed a consent form allowing electronic access to their inpatient hospital records. A record linkage was conducted with the BC Ministry of Health to obtain all records of hospital admissions from April 1991 to March 1997. Statistical analyses were carried out using parametric and nonparametric methods and multivariate logistic analyses. RESULTS: The study sample comprised 947 participants (859 men, 88 women). Of these, 165 (17%) were admitted to hospital during the study period from May 1, 1996, to Mar. 31, 1997. The median number of admissions was 1 (interquartile range [IQR] 1-2 admissions), and the median length of stay per admission was 3 days (IQR 1-8 days). Admission to hospital was associated with being unemployed (82% of those admitted v. 58% of those not admitted), being an injection drug user (24% v. 17%), reporting a fair or poor health status (46% v. 29%) and having a physician experienced in the management of HIV/AIDS (31% v. 24%). Examination of clinical determinants demonstrated that hospital admission was associated with a previous admission (72% v. 46%), a high viral load (median 74,000 v. 14,000 HIV-1 RNA copies/mL), a low CD4 count (median 0.16 v. 0.27 x 10(9)/L) and an AIDS diagnosis (44% v. 24%). Multivariate logistic regression analysis revealed that being admitted to hospital was independently associated with being unemployed (odds ratio [OR] 2.64, 95% confidence interval [CI] 1.66-4.20), having been previously admitted to hospital (OR 2.30, 95% CI 1.53-3.46), having a high viral load at baseline (OR 1.45, 95% CI 1.16-1.80), being an injection drug user (OR 1.63, 95% CI 1.02-2.62) and having an experienced physician (OR 1.98, 95% CI 1.29-3.03). INTERPRETATION: Hospital admission among participants in this study was found to be associated with marginalization and poor health status.