Identification of genotypic changes in human immunodeficiency virus protease that correlate with reduced susceptibility to the protease inhibitor lopinavir among viral isolates from protease inhibitor-experienced patients.

The association of genotypic changes in human immunodeficiency virus (HIV) protease with reduced in vitro susceptibility to the new protease inhibitor lopinavir (previously ABT-378) was explored using a panel of viral isolates from subjects failing therapy with other protease inhibitors. Two statistical tests showed that specific mutations at 11 amino acid positions in protease (L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V, and L90M) were associated with reduced susceptibility. Mutations at positions 82, 54, 10, 63, 71, and 84 were most closely associated with relatively modest (4- and 10-fold) changes in phenotype, while the K20M/R and F53L mutations, in conjunction with multiple other mutations, were associated with >20- and >40-fold-reduced susceptibility, respectively. The median 50% inhibitory concentrations (IC(50)) of lopinavir against isolates with 0 to 3, 4 or 5, 6 or 7, and 8 to 10 of the above 11 mutations were 0.8-, 2.7-, 13.5-, and 44.0-fold higher, respectively, than the IC(50) against wild-type HIV. On average, the IC(50) of lopinavir increased by 1.74-fold per mutation in isolates containing three or more mutations. Each of the 16 viruses that displayed a >20-fold change in susceptibility contained mutations at residues 10, 54, 63, and 82 and/or 84, along with a median of three mutations at residues 20, 24, 46, 53, 71, and 90. The number of protease mutations from the 11 identified in these analyses (the lopinavir mutation score) may be useful for the interpretation of HIV genotypic resistance testing with respect to lopinavir-ritonavir (Kaletra) regimens and may provide insight into the genetic barrier to resistance to lopinavir-ritonavir in both antiretroviral therapy-naive and protease inhibitor-experienced patients.

Longitudinal evaluation of adrenocortical function in patients infected with the human immunodeficiency virus.

Adrenal dysfunction has been reported in patients infected with the human immunodeficiency virus (HIV). To evaluate the prevalence and degree of adrenal dysfunction in HIV-infected patients, we performed a longitudinal study in 53 ambulatory HIV patients. The plasma cortisol, aldosterone, and dehydroepiandrosterone (DHEA) responses to cosyntropin (250 micrograms, i.v.) were evaluated at 6-month intervals for 24 months and compared to those of normal subjects. The basal and peak cortisol responses to cosyntropin were normal in all HIV patients during the study. There was no difference in the mean basal or stimulated cortisol measurements between Center for Disease Control (CDC) class II-III and CDC class IV patients. Although the mean peak aldosterone response to cosyntropin in HIV patients did not differ from that in normal subjects during the study, the aldosterone secretory capacity was significantly less in CDC class IV than CDC class II-III patients at 6- and 18-month intervals. In addition, there was an impaired aldosterone response to cosyntropin in 31-53% of CDC class IV patients and in only 0-26% of CDC class II-III patients. The mean peak DHEA response to cosyntropin in HIV patients was significantly less than that in normal subjects during the entire study. Basal plasma aldosterone, PRA, cortisol, and DHEA levels did not change in 25 HIV patients who were followed for the entire 24-month period. However, plasma ACTH in these 25 patients was significantly increased at 24 months (9.7 +/- 0.9 pmol/L) compared to that at study entry (7.0 +/- 0.7 pmol/L). Of these 25 patients, 8 had plasma ACTH concentrations that exceeded the normal range at 24 months. The subnormal aldosterone and DHEA secretion with normal cortisol production in these HIV patients is similar to the alterations in adrenal function reported in seriously ill patients without HIV infection. Although we found that clinically significant adrenal insufficiency is uncommon, the elevations in plasma ACTH in several patients at the end of our 2-yr study suggest that adrenocortical capacity may become compromised.

Didanosine compared with continuation of zidovudine in HIV-infected patients with signs of clinical deterioration while receiving zidovudine. A randomized, double-blind clinical trial. The Bristol-Myers Squibb AI454-010 Study Group.

OBJECTIVE: To determine the benefits of switching to didanosine compared with continuing zidovudine among patients infected with human immunodeficiency virus (HIV) who have previously used zidovudine and have signs of clinical deterioration. DESIGN: Randomized, double-blind, two-armed, parallel, comparative clinical trial with a blinded, compassionate crossover provision at 12 weeks. SETTING: Outpatient clinics at 19 tertiary care medical centers. PATIENTS: 312 patients infected with HIV who had received zidovudine for 6 months or more, had CD4 cell counts of 300/mm3 or less, and had signs of clinical deterioration within 12 weeks before study entry. INTERVENTION: Peroral didanosine tablets (600 mg/d adjusted for weight, "high dose") or zidovudine capsules (600 mg/d). MEASUREMENTS: Primary study end points were death, a new acquired immunodeficiency syndrome (AIDS)--defining event, or the combination of two new or recurrent HIV-related diagnoses with a 50% decrease in CD4 cells. RESULTS: Switching to didanosine was associated with fewer end points than continuing zidovudine (relative risk [RR] for zidovudine:didanosine = 1.5; 95% Cl, 1.1 to 2.0). This benefit was consistent across subgroups of patients with either AIDS-related complex or AIDS and was most apparent among those with a CD4 count at entry of 100/mm3 or more (RR = 2.2; Cl, 1.1 to 4.4). CONCLUSIONS: This study shows a positive treatment effect for switching from zidovudine to didanosine among patients with either AIDS-related complex or AIDS and validates the common practice of using clinical signs or a decrease in the CD4 count as an indication for changing therapy.

Outcome of cognitive-behavioral and support group brief therapies for depressed, HIV-infected persons.

OBJECTIVE: Although many studies have documented patterns of emotional distress in persons with HIV disease, there have been few controlled evaluations of therapy outcomes with these individuals. This research evaluated the effects of brief cognitive-behavioral or social support group therapy with this population. METHOD: Sixty-eight depressed men with HIV infection were randomly assigned to one of three conditions: eight-session cognitive-behavioral groups, eight-session social support groups, or a comparison condition. Before and after intervention and at 3-month follow-up, all participants were individually assessed by using measures of symptoms of distress as well as substance use and sexual practices. RESULTS: Relative to the comparison group, both the cognitive-behavioral and social support group therapies produced reductions in depression, hostility, and somatization. The social support intervention also produced reductions in overall psychiatric symptoms and tended to reduce maladaptive interpersonal sensitivity, anxiety, and frequency of unprotected receptive anal intercourse, while the cognitive-behavioral intervention resulted in less frequent illicit drug use during the follow-up period. Tests for clinical significance of change particularly underscored benefits of the social support group intervention both at postintervention and at long-term follow-up. CONCLUSIONS: Brief group therapy for depressed persons with HIV infection produced reductions in symptoms of distress. The two forms of therapy resulted in shared and unique improvements in functioning, although social support groups focused on emotional coping presented greater evidence of clinically significant change. As more persons contract HIV infection and live longer with HIV disease, further research is needed to evaluate outcomes of mental health services with these individuals.

Factors associated with severity of depression and high-risk sexual behavior among persons diagnosed with human immunodeficiency virus (HIV) infection.

Whereas some people appear to cope after learning that they have human immunodeficiency virus (HIV) infection, others experience depression and suicidal ideation. In this study, 142 persons with HIV infection were administered the Center for Epidemiological Studies Depression Scale (CES-D). High levels of depression were predicted by lower perceived social support, attributions that health was influenced more by chance, high-risk sexual behavior practices, and greater number of HIV illness symptoms and greater duration of time knowing of one's own positive serostatus. Ongoing high-risk sexual behavior practices were predicted by higher levels of recreational drug use and of depression. These findings highlight the need for improved mental health services for persons with HIV conditions.

A needs assessment survey of HIV-infected patients.

Few studies have surveyed HIV-infected patients to determine how adequately medical, legal, psychological, social service, and financial needs are being met through current treatment services. Fifty HIV-infected men seen at a county medical facility were surveyed to determine which of 17 needs were being met and the importance rating attributed to those needs. Five needs were reported by more than 30% of the sample as not being met: 1) being able to talk about fears of the future, illness, or death; 2) being occupied and having things to do; 3) having up-to-date information about HIV; 4) having someone to help them with their feelings of depression, helplessness, anxiety, or anger; and 5) help for the patient's family. Three of these five needs involve better access to psychological services. Although patients felt they had knowledgeable medical staff and good health care, they wanted more up-to-date information on HIV treatment.

Treatment of osteomyelitis and septic arthritis with cefamandole.

Fourteen patients with bone and joint infections caused by a variety of bacterial pathogens were treated with intravenous cefamandole, 4 to 12 g/day; ten received additional therapy with 2 g/day of cefaclor and one with 2 g/day of cephalexin. Ten of 14 patients were cured. Of those cured, infecting pathogens had minimal inhibitory concentrations of cefamandole of 4 micrograms or less/ml. Of those who were not cured, two had recurrent infections that had not responded to other previously administered antibiotics, one had a mixed infection with resistant strains, and one had positive bone cultures five months after a favorable clinical response. Peak and valley cefamandole serum concentrations were 48.0 to 173.0 micrograms/ml and 23.4 micrograms or less/ml, respectively. Synovial fluid concentrations were 11.1 to 16.7 micrograms/ml and bone concentrations were 0.2 to 20.4 micrograms/g. Adverse effects included leukopenia in one and hepatic enzyme elevations in four patients. Cefamandole, with and without cefaclor, was efficacious in therapy of bone and joint infections caused by susceptible organisms.