A Comparison of Adherence Timeframes Using Missed Dose Items and Their Associations with Viral Load in Routine Clinical Care: Is Longer Better?

Questions remain regarding optimal timeframes for asking about adherence in clinical care. We compared 4-, 7-, 14-, 30-, and 60-day timeframe missed dose items with viral load levels among 1099 patients on antiretroviral therapy in routine care. We conducted logistic and linear regression analyses examining associations between different timeframes and viral load using Bayesian model averaging (BMA). We conducted sensitivity analyses with subgroups at increased risk for suboptimal adherence (e.g. patients with depression, substance use). The 14-day timeframe had the largest mean difference in adherence levels among those with detectable and undetectable viral loads. BMA estimates suggested the 14-day timeframe was strongest overall and for most subgroups although findings differed somewhat for hazardous alcohol users and those with current depression. Adherence measured by all missed dose timeframes correlated with viral load. Adherence calculated from intermediate timeframes (e.g. 14-day) appeared best able to capture adherence behavior as measured by viral load.

Unannounced telephone-based pill counts: a valid and feasible method for monitoring adherence.

Phone-based unannounced pill counts to measure medication adherence are much more practical and less expensive than home-based unannounced pill counts, but their validity has not been widely assessed. We examined the validity of phone versus home-based pill counts using a simplified protocol streamlined for studies embedded in clinical care settings. A total of 100 paired counts were used to compare concordance between unannounced phone and home-based pill counts using interclass correlations. Discrepancy analyses using χ(2) tests compared demographic and clinical characteristics across patients who were concordant between phone and home-based pill counts and patients who were not concordant. Concordance was high for phone-based and home-based unannounced total pill counts, as well as individual medication counts and calculated adherence. This study demonstrates that a simplified phone-based pill count protocol can be implemented among patients from a routine clinical care setting and is a feasible means of monitoring medication adherence.

Disease-associated prion protein in neural and lymphoid tissues of mink (Mustela vison) inoculated with transmissible mink encephalopathy.

Transmissible spongiform encephalopathies (TSEs) are diagnosed by immunodetection of disease-associated prion protein (PrP(d)). The distribution of PrP(d) within the body varies with the time-course of infection and between species, during interspecies transmission, as well as with prion strain. Mink are susceptible to a form of TSE known as transmissible mink encephalopathy (TME), presumed to arise due to consumption of feed contaminated with a single prion strain of ruminant origin. After extended passage of TME isolates in hamsters, two strains emerge, HY and DY, each of which is associated with unique structural isoforms of PrP(TME) and of which only the HY strain is associated with accumulation of PrP(TME) in lymphoid tissues. Information on the structural nature and lymphoid accumulation of PrP(TME) in mink is limited. In this study, 13 mink were challenged by intracerebral inoculation using late passage TME inoculum, after which brain and lymphoid tissues were collected at preclinical and clinical time points. The distribution and molecular nature of PrP(TME) was investigated by techniques including blotting of paraffin wax-embedded tissue and epitope mapping by western blotting. PrP(TME) was detected readily in the brain and retropharyngeal lymph node during preclinical infection, with delayed progression of accumulation within other lymphoid tissues. For comparison, three mink were inoculated by the oral route and examined during clinical disease. Accumulation of PrP(TME) in these mink was greater and more widespread, including follicles of rectoanal mucosa-associated lymphoid tissue. Western blot analyses revealed that PrP(TME) accumulating in the brain of mink is structurally most similar to that accumulating in the brain of hamsters infected with the DY strain. Collectively, the results of extended passage in mink are consistent with the presence of only a single strain of TME, the DY strain, capable of inducing accumulation of PrP(TME) in the lymphoid tissues of mink but not in hamsters. Thus, mink are a relevant animal model for further study of this unique strain, which ultimately may have been introduced through consumption of a TSE of ruminant origin.

Integrating a web-based, patient-administered assessment into primary care for HIV-infected adults.

Providers routinely under diagnose at risk behaviors and outcomes, including depression, suicidal ideation, substance abuse, and poor medication adherence. To address this, we developed a web-based, self-administered patient-reported assessment tool and integrated it into routine primary care for HIV-infected adults. Printed results were delivered to providers and social workers immediately prior to patient appointments. The assessment included brief, validated instruments measuring clinically relevant domains including depression, substance use, medication adherence, and HIV transmission risk behaviors. Utilizing the Institute for Healthcare Improvement's Plan-Do-Study-Act (PDSA) approach to quality improvement, we addressed issues with clinic flow, technology, scheduling, and delivery of assessment results with the support of all levels of clinic staff. We found web-based patient-reported assessments to be a feasible tool that can be integrated into a busy multi-provider HIV primary care clinic. These assessments may improve provider recognition of key patient behaviors and outcomes. Critical factors for successful integration of such assessments into clinical care include: strong top-level /ort from clinic management, provider understanding of patient-reported assessments as a valuable clinical tool, tailoring the assessment to meet provider needs, communication among clinic staff to address flow issues, timeliness of delivery, and sound technological resources.

Hepatitis B vaccination in HIV-infected adults: current evidence, recommendations and practical considerations.

Immunization with hepatitis B (HBV) vaccine is recommended for all HIV-infected individuals without immunity to HBV. This patient population, however, has relatively poor HBV vaccine responses. Factors associated with this impaired HBV vaccine response in HIV-infected individuals may include older age, uncontrolled HIV replication, and low nadir CD4 cell count. Postvaccination testing for HBV surface antibody is recommended and vaccine non-responders should undergo repeat immunization with a full series. The benefit of double dosage, the appropriate strategy for HIV-infected patients with isolated HBV core antibody and the timing and number of vaccinations in persons with advanced immunosuppression on highly active antiretroviral therapy remain controversial areas.

Lipoatrophy and lipohypertrophy are independently associated with hypertension.

OBJECTIVE: Lipoatrophy and lipohypertrophy are associated with metabolic abnormalities, but little is known about their impact on hypertension. We conducted this study to determine the associations of lipoatrophy and lipohypertrophy with hypertension. METHODS: A cross-sectional study of HIV-infected patients who completed a self-report body morphology assessment was performed. We defined hypertension as a clinical diagnosis, or a mean systolic blood pressure (BP) > 140 mmHg or diastolic BP > 90 mmHg in the previous 6 months. We used logistic regression to examine the association between hypertension and body morphology. RESULTS: Among 347 patients, there were 2278 BP readings in 6 months. In adjusted analyses, patients with moderate lipoatrophy [odds ratio (OR) 4.3; P = 0.03] or moderate lipohypertrophy (OR 4.3; P = 0.006) had four times the odds, and patients with mild lipohypertrophy (OR 2.3; P = 0.03) had twice the odds of having hypertension compared with patients without changes. We hypothesized that the impact of lipohypertrophy on hypertension was mediated, in part, through body mass index (BMI). When BMI was included in the analysis, increased BMI was significantly associated with hypertension (OR = 1.1; P < 0.001 per kg/m(2)), and the association between lipohypertrophy and hypertension was no longer present. However, the association between moderate lipoatrophy and hypertension was strengthened (OR = 5.5; P = 0.01). CONCLUSIONS: Lipoatrophy and lipohypertrophy are independently associated with hypertension and there is a dose-response effect with more severe lipoatrophy and lipohypertrophy. The association between lipohypertrophy (but not lipoatrophy) and hypertension appears to be mediated by BMI. Our results suggest that patient-based body morphology assessments are related to hypertension and may have potential implications for cardiovascular disease.

Lipoatrophy among HIV-infected patients is associated with higher levels of depression than lipohypertrophy.

OBJECTIVES: We sought to determine the association between body morphology abnormalities and depression, examining lipoatrophy and lipohypertrophy separately. METHODS: An observational cross-sectional study of 250 patients from the University of Washington HIV Cohort was carried out. Patients completed an assessment including measures of depression and body morphology. We used linear regression analysis to examine the association between lipoatrophy or lipohypertrophy and depression. Analysis of variance was used to examine the relationship between mean depression scores and lipoatrophy and lipohypertrophy in 10 body regions. RESULTS: Of 250 patients, 76 had lipoatrophy and 128 had lipohypertrophy. Mean depression scores were highest among patients with moderate-to-severe lipoatrophy (16.4), intermediate among those with moderate-to-severe lipohypertrophy (11.7), mild lipohypertrophy (9.9) and mild lipoatrophy (8.5), and lowest among those without body morphology abnormalities (7.7) (P=0.002). After adjustment, mean depression scores for subjects reporting moderate-to-severe lipoatrophy were 9.2 points higher (P<0.001), scores for subjects with moderate-to-severe lipohypertrophy were 4.8 points higher (P=0.02), and scores for subjects with mild lipohypertrophy were 2.8 points higher (P=0.03) than those for patients without body morphology abnormalities. Facial lipoatrophy was the body region associated with the most severe depression scores (15.5 vs. 8.9 for controls; P=0.03). CONCLUSIONS: In addition to long-term cardiovascular implications, body morphology has a more immediate effect on depression severity.

The psychosocial impact of serological herpes simplex type 2 testing in an urban HIV clinic.

BACKGROUND/OBJECTIVES: Herpes simplex virus type 2 (HSV-2) is a common infection among HIV infected people. HSV type specific serologies permit the diagnosis of previously unrecognised HSV-2 infection. While substantial psychosocial morbidity has been associated with a clinical diagnosis of genital herpes, the burden associated with a serological diagnosis of HSV-2 is unclear. This study prospectively measured the psychosocial response to a new serological HSV-2 diagnosis in patients receiving care at an urban HIV clinic. METHODS: At entry, sera were tested for HSV-1 and HSV-2 antibodies by western blot. Participants completed a 90 item psychosocial and life quality questionnaire at enrollment, and at 2 weeks, 3 months, and 6 months after receiving test results. RESULTS: Of 248 HIV infected participants, 172 (69.4%) were HSV-2 seropositive and 116 (67.4%) seropositive people did not have a previous history of genital herpes. After correction for multiple comparisons, no statistically significant differences were detected on the psychosocial and life quality scales between those who received a new HSV-2 serological diagnosis compared with those who were HSV-2 seropositive with a history of genital herpes, or those who tested HSV-2 seronegative. Additionally, no significant changes in scores were observed during follow up. CONCLUSIONS: HSV-2 was a common but often unrecognised infection in this urban HIV clinic and participants coped well with a positive HSV-2 result. Concerns about psychosocial burden should not deter serological testing for HSV-2. Given the epidemiological and clinical interaction between HSV-2 and HIV, these data support routine HSV-2 testing of HIV infected people.

Retroviral rebound syndrome after cessation of suppressive antiretroviral therapy in three patients with chronic HIV infection.

BACKGROUND: Although viral rebound follows cessation of suppressive antiretroviral therapy in chronic HIV infection, a viremic clinical syndrome has not been described. OBJECTIVE: To describe a retroviral syndrome associated with cessation of effective antiretroviral therapy in chronic HIV infection. DESIGN: Case reports. SETTING: Outpatient HIV specialty clinics in Seattle, Washington, and Boston, Massachusetts. PATIENTS: Three patients with chronic HIV infection who discontinued suppressive antiretroviral therapy. MEASUREMENTS: Clinical course, plasma HIV RNA levels, and CD4 cell counts before, during, and after cessation of antiretroviral therapy. RESULTS: Within 6 weeks after stopping antiretroviral therapy, each patient experienced a clinical illness that resembled a primary HIV syndrome. This coincided with a marked increase in HIV RNA level and, in two of three patients, a decrease in CD4 cell count. After antiretroviral therapy was restarted, each patient's symptoms rapidly resolved in association with resuppression of HIV RNA and increase in CD4 cell count or percentage. CONCLUSION: A retroviral rebound syndrome similar to that seen in primary HIV syndrome can occur in patients with chronic HIV infection after cessation of suppressive antiretroviral therapy.

Urinary tract infection risk factors and gender.

Urinary tract infections (UTIs) are more common among women than men, although the prevalence in elderly men and women is similar. Most of the research on UTI has focused on young, sexually active women who are at high risk for developing an infection. The predominant UTI risk factors in young women are sexual intercourse and the use of spermicidal contraceptives. Other important UTI risk determinants in selected age groups include anatomic and physiologic factors, such as obstructing lesions and estrogen deficiency; genetic factors, such as blood group secretor status; antibiotic exposure; functional status; and possibly receptive anal intercourse and HIV infection.

Life-threatening interactions between HIV-1 protease inhibitors and the illicit drugs MDMA and gamma-hydroxybutyrate.

Human immunodeficiency virus 1 (HIV-1) protease inhibitors have dramatically reduced the morbidity and mortality due to HIV-1 infection. However, most of these antiretrovirals are also potent inhibitors (and occasionally inducers) of hepatic and intestinal cytochrome P450 systems and, therefore, have the potential to alter the elimination of any substance that utilizes these metabolic pathways. We describe a patient infected with HIV-1 who was treated with ritonavir and saquinavir and then experienced a prolonged effect from a small dose of methylenedioxymetamphetamine (MDMA or ecstacy) and a nearly fatal reaction from a small dose of gamma-hydroxybutyrate (GHB). We also discuss the potential for HIV-1 protease inhibitors to alter the metabolism of other abusable prescribed and illicit substances.

Bordetella bronchiseptica infection in human immunodeficiency virus-infected patients.

Bordetella bronchiseptica is a pleomorphic gram-negative coccobacillus that commonly causes respiratory tract infections in dogs. We identified nine human immunodeficiency virus (HIV)-infected persons with culture-confirmed B. bronchiseptica infections (eight respiratory tract and one disseminated infection). The respiratory illnesses ranged in severity from mild upper respiratory tract infection to pneumonia. All nine patients had had at least one AIDS-defining condition before the B. bronchiseptica infection. Two patients had household contact with dogs before their illnesses, and one had household contact with cats. Infection due to B. bronchiseptica is uncommon in HIV-infected persons. Additional data are needed to fully define the spectrum of disease due to B. bronchiseptica infections and to evaluate the possibility that this infection may be acquired from pets. Treatment of B. bronchiseptica infection should be tailored to the patient and should be based on the results of susceptibility testing.

An indicator cell assay for T-cell tropic, macrophage-tropic, and primary isolates of HIV-1 based on green fluorescent protein.

Quantitation of HIV-1 in blood is now widely used by clinicians to manage antiviral therapy. Current methods to detect viral RNA are expensive, have slow turnaround times, and do not directly quantitate infectious particles. Indicator cell assay (ICA) methods for titering HIV-1 rely on the activation of HIV-1 long terminal repeat (LTR)-driven expression of a reporter gene by the viral tat gene product, which is expressed early in the course of infection. The Aequorea victoriana green fluorescent protein (GFP) has proven to be a useful reporter gene for detecting tat-mediated HIV-LTR activation. A general approach to developing a clinically useful ICA required a method of introducing the LTR-GFP expression cassette into various HIV1-infectable cell lines. The LTR-GFP expression cassette was inserted into the LXSN retrovector in a reverse orientation with respect to transcription from the 5' LTR. In cells transduced by the RH5 retrovector, GFP expression was tightly dependent on expression of HIV-1 tat. The PM1 human T-cell line was transduced with RH5 and was further engineered to express the CCR5 HIV-1 CD4 coreceptor constitutively. The resulting cell line, D5-R5, was susceptible to infection by primary HIV-1 strains, macrophage-tropic (M-tropic) and T-cell tropic (T-tropic) laboratory strains, and syncytium-inducing (SI) and and non-SI (NSI) variants. Four days after HIV-1 infection of the indicator cells, GFP expression was detected and quantitated by fluorescence activated cell sorter (FACS), without any false-positive signals. This GFP-based ICA method is of potential use in clinical management of HIV-1, especially in the detection and recovery of drug-resistant virus and the direct determination of antiviral drug sensitivities.

Hyposplenism from Mycobacterium avium complex infection in a patient with AIDS and immune thrombocytopenia.

We describe a patient with HIV-related immune thrombocytopenic purpura with known Mycobacterium avium complex (MAC) infection presenting with intracerebral hemorrhage associated with severe thrombocytopenia who failed splenectomy following unsuccessful trials of corticosteroids and intravenous immunoglobulin. His presplenectomy peripheral blood smear showed Howell-Jolly bodies and microscopic examination of his spleen demonstrated multiple granulomas with numerous acid-fast organisms replacing the normal splenic tissue. We postulate that splenic hypofunction secondary to overwhelming MAC infection contributed to the failure of the thrombocytopenia to promptly respond to splenectomy.

Detection of HIV-1 infection with a green fluorescent protein reporter system.

Several systems for the detection of HIV-1 have been described in which HIV-1-susceptible cells contain a reporter gene (chloramphenicol acetyltransferase, beta-galactosidase, or alkaline phosphatase) under the control of the HIV-1 long terminal repeat (LTR). Upon infection by HIV-1, the expression of the viral tat product increases transcription from the HIV-1 LTR promoter, leading to high-level expression of the reporter gene product. Previously described reporter systems require processing of the cells by lysis, fixation, or other steps following infection to detect the reporter gene product. In the present study, the Aequorea green fluorescent protein S65T variant (GFP-S65T) was used in a reporter system for detecting HIV-1. HeLa-CD4 cells transfected with the plasmid pRH1, which encodes GFP-S65T under the control of the HIV-1 LTR promoter, and either co-transfected with a plasmid encoding the HIV-1 tat product or superinfected with HIV-1, expressed high levels of GFP-S65T, which was readily detected by fluorescence microscopy and fluorescence-activated cell-sorting analysis. The advantages of this system include its simplicity, sensitivity, and ability to detect and sort live HIV-1-infected cells using readily available instruments. The construction of cell lines stably transfected with pRH1 will provide a tool for titering HIV-1 and sorting HIV-1-infected cells.

Human immunodeficiency virus type-1 susceptible whole cell and microcell hybrids.

Expression of CD4, the principle receptor for HIV-1, is not sufficient for viral entry into most non-human and rare human cell lines. Construction of HIV-1 susceptible heterokaryons and a hybrid cone by fusion of HeLa cells and the HIV-1 resistant human cell line U373-CD4 were previously reported by us. These results suggested that U373-CD4 lack a cofactor(s) which is essential for HIV-1 entry and can be supplied by HeLa cells. Now the construction of multiple stable U373-CD4/HeLa whole cell and microcell hybrid clones are described, two of which are highly susceptible to HIV-1. Using these hybrids it is demonstrated that expression of CD4 and CD26, the T cell activation antigen dipeptidyl peptidase IV recently proposed as a CD4 cofactor necessary for HIV-1 infection, are not sufficient for HIV-1 entry. This panel of HIV-1 resistant and susceptible hybrids provides a rapid, simple assay for testing the role of other candidate cofactor molecules (e.g., fusin) that may be required for HIV-1 entry into human cells. Further, the method described by us for constructing HeLa microcells should permit the construction of murine-HeLa microcell hybrids, thus providing ideal reagents for determining which human chromosome(s) are needed to confer HIV-1 susceptibility onto non-human cells.

Legionellosis in a bone marrow transplant center.

We reviewed 10 cases of culture proven legionellosis that occurred at a marrow transplant center (Fred Hutchinson Cancer Research Center, Seattle, WA, USA) over a 6-year period ending in 1993. Infections were caused by four species of Legionella with no apparent clustering of cases. Detection of Legionella using direct fluorescent antibody assays proved unreliable due to the high proportion of rare Legionella species isolated. The clinical presentation, course and outcome of patients varied and did not correlate with underlying disease, type of transplant, transplant day or engraftment status. However, five of the seven patients infected with non-pneumophila species recovered from their pneumonia compared to none of the three patients infected with L. pneumophila. Persistent or relapsed infection after 3 weeks of appropriate therapy was documented in one case suggesting that prolonged antibiotic treatment is indicated in these patients.

Oerskovia xanthineolytica infection of a prosthetic joint: case report and review.

Oerskovia spp. are gram-positive, Nocardia-like bacilli which inhabit the soil and rarely cause human infections. Previously reported cases of Oerskovia infection have been characterized by a nonaggressive course and an association with foreign bodies. We report the first case of a patient with a prosthetic joint infection due to Oerskovia xanthineolytica. Our patient presented with a prolonged, indolent course and was thought to have aseptic loosening of his prosthesis until the time of surgery. He was cured of his infection by removal of the prosthesis, antibiotic therapy, and delayed reimplantation. Review of the previous 10 reported cases of Oerskovia infection in humans supports the recommendation that foreign-body-associated infections should be treated with a strategy that includes removal of the foreign material.

Cofactor requirement for human immunodeficiency virus type 1 entry into a CD4-expressing human cell line.

Expression of the human immunodeficiency virus type 1 (HIV-1) receptor CD4 on many nonhuman and some human cell lines is not sufficient to permit HIV-1 infection. We describe a human glioblastoma cell line (U373-MG) which remains resistant to HIV-1 despite the added expression of an authentic CD4 molecule. The block to HIV-1 infection of these cells is strain independent and appears to be at viral entry. Heterokaryons of CD4-expressing U373-MG (U373-CD4) cells fused to HeLa cells allow HIV-1 entry. A U373-CD4/HeLa hybrid clone allows efficient HIV-1 replication. These results suggest that HeLa cells express a factor(s) that can complement the viral entry defect of U373-CD4 cells and is necessary for efficient CD4-mediated HIV-1 infection.