Bisphosphonate Drug Holiday and Fracture Risk: A Population-Based Cohort Study.

Holidays from bisphosphonates (BPs) may help to prevent rare adverse events such as atypical femoral fractures, but may be appropriate only if risk of osteoporosis-related fractures does not increase. Our objective was to compare the incidence of osteoporosis-related fractures among women who had a BP holiday to those who continued to use BPs. This retrospective cohort study, conducted within four Kaiser Permanente integrated health system regions, included 39,502 women aged ≥45 years with ≥3 years exposure to BP. Participants with a BP holiday (≥12 months with no use) were compared to persistent (use with ≥50% adherence) and nonpersistent (use with <50% adherence) users for incident osteoporosis-related fractures. The BP holiday (n = 11,497), nonpersistent user (n = 10,882), and persistent user groups (n = 17,123) were observed for 156,657 person-years. A total of 5199 osteoporosis-related fractures (including 1515 hip fractures and 2147 vertebral fractures) were observed. Compared to the persistent use group, there was a slight difference in overall osteoporosis-related fracture risk (HR 0.92; 95% CI, 0.84 to 0.99)and no difference in hip fracture risk (HR 0.95; 95% CI, 0.83 to 1.10) for the BP holiday group. A slight reduction in risk of vertebral fracture was observed (HR 0.83; 95% CI, 0.74 to 0.95). Compared to the nonpersistent user group, the BP holiday group was at decreased risk for osteoporosis-related fractures (HR 0.71; 95% CI, 0.65 to 0.79), vertebral fractures (HR 0.68; 95% CI, 0.59 to 0.78), and hip fractures (HR 0.59; 95% CI, 0.50 to 0.70). Women who undertake a BP holiday from BP of ≥12 months duration for any reason after ≥3 years of BP use do not appear to be at greater risk of osteoporosis-related fragility fracture, hip, or vertebral fractures compared to ongoing BP users. In our cohort, BP holiday remains a viable strategy for balancing the benefits and potential harms associated with long-term BP use. © 2018 American Society for Bone and Mineral Research.

Influence of provider experience on antiretroviral adherence and viral suppression.

BACKGROUND AND AIM: Early in the combination antiretroviral therapy (cART) era, provider experience (as measured by panel size) was associated with improved outcomes. We explored that association and other characteristics of provider experience. METHODS: We performed a retrospective cohort analysis in Kaiser Permanente California (an integrated health care system in the United States), examining all human immunodeficiency virus seropositive (HIV+) patients initiating a first cART regimen (antiretroviral therapy [ART]-naïve, N = 7071) or initiating a second or later cART regimen (ART-experienced, N = 3730) from 1996-2006. We measured ART adherence through 12 months (pharmacy fill and refill records) and determined HIV viral load levels below limits of quantification at 12 months. Provider experience, updated annually, was measured as (1) HIV panel size (0-10 patients as reference strata), (2) years treating HIV (less than 1 year as reference), and (3) specialty ( noninfectious disease specialty, non-HIV expert as reference). We assessed associations by utilizing mixed modeling analyses (clustered by provider and medical center), controlling for patient age, sex, race/ethnicity, HIV risk behavior, hepatitis C coinfection, ART regimen class, and calendar year. RESULTS: Among the ART-experienced, improved adherence was associated with greater years experience (mean increase 3.1% 2-5 years experience; 3.7% 5-10 years; 2.7% 11-20 years; P = 0.07, categorical). In adjusted analyses, viral suppression among ART-naïve was positively associated with panel size (odds ratio 26-50 patients: 1.31, P = 0.03, categorical), but negatively associated with years experience (18% less for greater than 100 patients; P = 0.003). No provider characteristic was significantly associated with improved adherence among ART-naïve or odds of maximal viral suppression among ART-experienced in adjusted analysis. CONCLUSIONS: Except for panel size and years experience among ART-naïve, provider characteristics did not significantly influence ART adherence or likelihood of viral suppression.

Risk factors for short-term virologic outcomes among HIV-infected patients undergoing regimen switch of combination antiretroviral therapy.

We investigated risk factors for unfavorable virologic responses among HIV-infected patients who recently switched antiretroviral regimens. We identified HIV-infected patients who switched antiretroviral regimens (defined as adding ≥2 new medications) between 2001 and 2008 at Kaiser Permanente California. Virological response, measured after 6 months on the new regimen, was classified as (1) maximal viral suppression (HIV RNA <75/ml), (2) low-level viremia (LLV; 75-5000/ml), or (3) advanced virologic failure (>5000/ml). Potential risk factors examined included (1) HIV disease factors, e.g., prior AIDS, CD4 cell count; (2) history of antiretroviral use, e.g., therapy classes of the newly switched regimen, medication adherence, and virologic failure at previous regimens; and (3) novel patient-level factors including comorbidities and healthcare utilization. Adjusted odds ratios (aOR) for LLV and advanced virologic failure were obtained from multivariable nominal logistic regression models. A total of 3447 patients were included; 2608 (76%) achieved maximal viral suppression, 420 (12%) had LLV, and 419 (12%) developed advanced virologic failure. Factors positively associated with LLV and advanced virologic failure included number of regimens prior to switch [aOR(per regimen)=1.38 (1.17-1.62) and 1.77 (1.50-2.08), respectively], nucleotide reverse transcriptase inhibitor-only regimens (vs. protease inhibitor-based) [aOR=2.78 (1.28-6.04) and 5.10 (2.38-10.90), respectively], and virologic failure at previous regimens [aOR=3.15 (2.17-4.57) and 4.71 (2.84-7.81), respectively]. Older age, higher CD4 cell count, and medication adherence were protective for unfavorable virologic outcomes. Antiretroviral regimen-level factors and immunodeficiency were significantly associated with virologic failure after a recent therapy switch and should be considered when making treatment change decisions.

The effect of HIV infection, immunodeficiency, and antiretroviral therapy on the risk of hepatic dysfunction.

BACKGROUND: Limited data exists regarding the effect of chronic HIV infection on the liver. We sought to characterize the hepatic risks of HIV infection, immunodeficiency, and cumulative use of antiretroviral therapy (ART). METHODS: Adult HIV infected and 10:1 age-matched and sex-matched HIV-uninfected individuals were followed for incident hepatic dysfunction or hepatic dysfunction-related death. Multivariable Poisson regression models were used to obtain incident rate ratios, adjusting for multiple hepatic risk factors including alcohol/drug abuse, hepatitis B and C, and diabetes. RESULTS: We identified 20,775 HIV-infected and 215,158 HIV-uninfected individuals. HIV-infected individuals had a significantly greater overall risk compared with HIV-uninfected individuals of both hepatic dysfunction and hepatic dysfunction-related death. The highest risk was seen in patients with low CD4 cell counts not on ART [adjusted rate ratio of hepatic dysfunction-related death 59.4; (95% confidence interval: 39.3 to 89.7), P < 0.001; hepatic dysfunction, adjusted rate ratio 15.7 (95% confidence interval: 11.4 to 21.6), P < 0.001]. In an HIV-infected only model, factors that increased risk included low CD4 cell count, high HIV RNA level, alcohol/drug abuse, hepatitis B or C coinfection, and diabetes. Longer cumulative exposure to ART did not increase risk, regardless of therapy class. CONCLUSIONS: HIV-infected individuals have a higher risk of hepatic dysfunction and hepatic dysfunction-related death compared with HIV-uninfected individuals, even with adjustment for known hepatic risk factors. Hepatic outcomes were associated with lower CD4+ T-cell counts but not with longer cumulative ART exposure. These findings provide indirect evidence supporting early use of ART to reduce the risk for hepatic-related complications.

Determination of optimized multidisciplinary care team for maximal antiretroviral therapy adherence.

OBJECTIVE: We seek to determine the optimized multidisciplinary care team (MDCT) composition for antiretroviral therapy (ART) adherence. METHODS: We analyzed all new regimen starts (n = 10,801; 7071 ART naive, 3730 ART experienced) among HIV-positive patients in Kaiser Permanente California from 1996 to 2006. We measured 12-month adherence to ART (pharmacy refill methodology) and medical center-specific patient exposure to HIV/infectious disease specialist (reference group), non-HIV primary care provider, clinical pharmacist, nurse case manager, non-nurse care coordinator, dietician, social worker/benefits coordinator, health educator, and mental health worker. We used recursive partitioning to ascertain potential MDCT compositions associated with maximal mean ART adherence. We then employed mixed linear regression with clustering by provider and medical center (adjusting for ART experience, age, gender, race/ethnicity, HIV risk, hepatitis C virus coinfection, ART regimen class, and calendar year) to test which potential MDCT combination identified had statistically significant association with ART adherence. RESULTS: We found maximal increase in adherence with pharmacist plus coordinator plus primary care provider combination (8.1% ART adherence difference compared with reference; 95% confidence interval: 2.7% to 13.5%). Other MDCT teams with significantly (P < 0.05) improved adherence compared with specialist only were nurse plus social worker with primary care provider (7.5%; 5.4% to 9.7%), specialist plus mental health worker (6.5%; 2.6% to 10.4%), pharmacist plus social worker plus primary care provider (5.7%; 4.1% to 7.4%), and pharmacist plus primary care provider (3.3%; 0.8% to 5.8%). Among these MDCTs, there were no significant differences in mean adherence, odds of maximal viral control, or CD4+ changes at 12 months (except pharmacist plus primary care provider). CONCLUSIONS: Various MDCTs were associated with improved adherence, including ones that did not include the HIV specialist but included primary care plus other health professionals. These findings have application to the HIV care team design.

Survival of non-Hodgkin lymphoma patients with and without HIV infection in the era of combined antiretroviral therapy.

OBJECTIVE: To investigate the survival outcomes for non-Hodgkin lymphoma (NHL) in HIV-infected vs. uninfected patients from the same integrated healthcare system, and to identify prognostic factors for HIV-related NHL in the era of combined antiretroviral therapy. DESIGN: A cohort study. METHODS: Incident NHL diagnosed between 1996 and 2005 were identified from members of Kaiser Permanente California Health Plans. Two-year all-cause and lymphoma-specific mortality by HIV status were examined using multivariable Poisson regression. Among HIV-infected patients, prognostic factors of demographics, lymphoma, and HIV-related characteristics for the same outcomes were also examined. RESULTS: A total of 259 HIV-infected and 8230 HIV-uninfected incident NHL patients were evaluated. Fifty-nine percent of HIV-infected patients died within 2 years after NHL diagnosis as compared with 30% of HIV-uninfected patients. HIV status was independently associated with a doubling of 2-year all-cause mortality (relative risk = 2.0, 95% confidence interval 1.7-2.3). This elevated mortality risk for HIV-infected patients was similar for all race groups, lymphoma stages, and histologic subtypes. HIV-infected patients with CD4 cell count below 200 cells/microl, prior AIDS-defining illness, or both were also at increased risk for lymphoma-specific mortality as compared with HIV-uninfected patients. Among HIV-infected NHL patients, significant prognostic factors for overall mortality included prior AIDS-defining illness and Burkitt's subtype. CONCLUSION: HIV-infected patients with NHL in the combined antiretroviral therapy era continue to endure substantially higher mortality compared with HIV-uninfected patients with NHL. Better management and therapeutic approaches to extend survival time for HIV-related NHL are needed.

Impact of tenofovir on renal function in HIV-infected, antiretroviral-naive patients.

OBJECTIVE: To better characterize the long-term effects of tenofovir on renal function in a large managed care organization. METHODS: We performed a retrospective cohort analysis in Kaiser Permanente for years 2002 to 2005 comparing renal function among antiretroviral naïve patients initiating a tenofovir-containing regimen (964 patients) or tenofovir-sparing regimens (683 patients). We evaluated glomerular filtration rate (GFR, [Modification of Diet in Renal Disease equation]), serum creatinine, and the development of renal proximal tubular dysfunction. We report multivariable hazard ratios (HR, Cox modeling) and linear outcomes (repeated measures) with predictors retained if P < 0.10 (backward selection). Potential predictor variables included in multivariate models were age, sex, Black race, baseline laboratories (including CD4 count), history of diabetes mellitus, hypertension, malignancy, hepatitis, and concurrent medications. RESULTS: Overall, tenofovir-exposed patients had a larger relative decline in GFR through 104 weeks (-7.6 mL/min/1.73 m(2) relative to tenofovir-sparing, P < 0.001); the degree of the difference varied by baseline GFR, with the greatest effect seen in those patients with GFR greater than 80 mL/min/1.73 m(2). Tenofovir-exposed patients had greater development of proximal tubular dysfunction over time (at 52 wk: HR(adjusted) = 1.95 [P = 0.01] and at 104 wk: HR(adjusted) = 5.23 [P = 0.0004]) and had greater risk of medication discontinuation (HR(adjusted) = 1.21, P = 0.02), especially as renal function worsened. Viral control and CD4 count changes were similar between the two groups. CONCLUSIONS: Tenofovir is associated with greater effect on decline in renal function and a higher risk of proximal tubular dysfunction in antiretroviral naïve patients initiating antiretroviral therapy.

HIV infection and the risk of cancers with and without a known infectious cause.

OBJECTIVE: To evaluate the risk of cancers with and without a known infectious cause in HIV-infected persons. DESIGN: Retrospective cohort study. METHODS: Adult HIV-infected and matched HIV-uninfected members of Kaiser Permanente followed between 1996 and 2007 for incident AIDS-defining cancers (ADCs), infection-related non-AIDS-defining cancers (NADCs; anal squamous cell, vagina/vulva, Hodgkin's lymphoma, penis, liver, human papillomavirus-related oral cavity/pharynx, stomach) and infection-unrelated NADC (all other NADCs). RESULTS: We identified 20 277 HIV-infected and 202 313 HIV-uninfected persons. HIV-infected persons experienced 552 ADC, 221 infection-related NADC, and 388 infection-unrelated NADC. HIV-uninfected persons experienced 179 ADC, 284 infection-related NADC, and 3418 infection-unrelated NADC. The rate ratio comparing HIV-infected and HIV-uninfected persons for ADC was 37.7 [95% confidence interval (CI): 31.7-44.8], with decreases in the rate ratio over time (P < 0.001). The rate ratio for infection-related NADC was 9.2 (95% CI: 7.7-11.1), also with decreases in the rate ratio over time (P < 0.001). These results were largely influenced by anal squamous cell cancer and Hodgkin's lymphoma. The rate ratio for infection-unrelated NADC was 1.3 (95% CI: 1.2-1.4), with no change in the rate ratio over time (P = 0.44). Among infection-unrelated NADCs, other anal, skin, other head and neck, and lung cancer rates were higher and prostate cancer rates lower in HIV-infected persons. Among all infection-unrelated NADCs, the rate ratio decreased over time only for lung cancer (P = 0.007). CONCLUSION: In comparison with those without HIV infection, HIV-infected persons are at particular risk for cancers with a known infectious cause, although the higher risk has decreased in the antiretroviral therapy era. Cancers without a known infectious cause are modestly increased in HIV-infected persons compared with HIV-uninfected persons.

Depression and role impairment among adolescents in primary care clinics.

PURPOSE: To evaluate the association between depression and role impairment in a primary care sample, with and without controlling for the effects of general medical conditions. METHODS: Cross-sectional survey of consecutive primary care patients, ages 13-21 years (n = 3471), drawn from six sites including public health, managed care, and academic health center clinics. We assessed probable depressive disorder, depressive symptoms, and common medical problems using youth self-report on a brief screening questionnaire. Main outcome measures were two indicators of role impairment: (a) decrement in productivity/role activity, defined as not in school or working full time; and (b) low educational attainment, defined as more than 2 years behind in school or > or = 20 years of age and failed to complete high school. RESULTS: Adolescents screening positive for probable depressive disorder had elevated rates of productivity/role activity decrements (19% vs. 13%; OR 1.69; 95% confidence interval [CI] 1.39-2.06; p < 0.001) and low educational attainment (20% vs. 15%; OR 1.47; 95% CI 1.21-1.78; p < 0.001). Probable depressive disorder made a unique contribution to the prediction of these impairment indicators after adjusting for the effect of having a general medical condition; controlling for depression, the presence of a general medical condition did not contribute to role impairment. CONCLUSIONS: Adolescent primary care patients screening positive for depression are at increased risk for impairment in school/work productivity and educational attainment. These findings emphasize the importance of primary care clinicians' attention to depression and role limitations.