Epstein-Barr virus (EBV)-mediated lymphomagenesis in the setting of HIV infection has been widely accepted. However, little is known about how EBV impacts prognosis. We investigated the hypothesis that EBV infection is associated with expression of specific B-cell oncogenic markers in HIV-related diffuse large B-cell lymphoma (DLBCL), and examined the prognostic utility of detecting EBV infection.
HIV-related DLBCL cases diagnosed between 1996–2007 within Kaiser Permanente California were identified. Immunohistochemistry staining was used to analyze the expression of selected markers that are cell cycle regulators, B-cell activators, and anti-apoptotic proteins among others. EBV infection was determined by in situ hybridization of EBV RNA. Correlations between EBV and marker expression were examined using Spearman’s correlation coefficient. The prognostic utility of EBV status was examined in multivariable Cox model adjusting for international prognostic index (IPI). Receiver-operating characteristics (ROC) analysis was used to evaluate improvement in model discrimination.
Seventy HIV-related DLBCL cases were included (31% EBV+). EBV+ tumor was associated with increased expression of BLIMP1 and CD30, and reduced expression of BCL6 and LMO2. EBV+ tumor was independently associated with elevated 2-year overall mortality [hazard ratio=3.3 (95% CI: 1.6–6.6)]. Area under the ROC curve demonstrated improved model discrimination when incorporating tumor EBV status with IPI in the prediction model [0.65 vs. 0.74 (IPI only)].
Our results suggest that EBV infection was associated with expression of several tumor markers that are involved in the NF-κB pathway, and that detecting tumor EBV status may have prognostic utility in HIV-related DLBCL.
EBV; Lymphoma; HIV; Diffuse large B-cell lymphoma; Prognosis
Experimental studies suggested that HMG-CoA reductase inhibitors (‘statins’) may have antilymphoma properties. We investigated whether statin use is associated with reduced risk of non-Hodgkin lymphoma (NHL) in HIV-positive persons.
A nested case–control study was conducted among HIV-positive members of Kaiser Permanente California, a large managed care organization.
Cases were incident HIV+NHL diagnosed from 1996 to 2008. Controls were HIV-positive members without NHL matched 5 : 1 to cases by age, sex, race, index year and known duration of HIV infection. Data were collected from Kaiser Permanente’s electronic medical records. Conditional logistic regression was used to examine the effect of statin use on HIV+NHL risk, adjusting for potential confounders (matching factors, prior clinical AIDS diagnosis, antiretroviral use, baseline CD4 cell count, and history of selected co-morbidity) and use of nonstatin lipid-lowering therapy (LLT).
A total of 259 cases and 1295 controls were included. Eight percent of the cases and 14% of the controls had a history of statin use. Statin use was associated with lower risk of HIV+NHL; hazard ratio and 95% confidence intervals for ever use, less than 12, and at least 12 months cumulative use was 0.55 (0.31–0.95), 0.64 (0.31–1.28), and 0.50 (0.23–1.10), respectively. P value for trend for duration of statin use was 0.08. No association between nonstatin LLT use and risk of NHL was observed.
Our results suggested an inverse association between statin use and risk of NHL in HIV-positive persons. Potential limitations include the likelihood of residual confounding by indication and limited study power for some statin use subgroups.
AIDS; HIV; HMG-CoA reductase; inhibitors; lymphoma; non-Hodgkin lymphoma; statins
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 [aORper 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.
Purpose of review
Combination antiretroviral therapy (ART) has turned HIV infection into a complex chronic disease. This article documents cancer risk among HIV-infected persons, reviews immune system effects of HIV infection in relation to cancer risk, discusses implications for cancer prevention, and suggests future research directions.
There has been a shift in the cancer spectrum from AIDS-defining cancers (ADC) to non-ADC, although the burden of ADC remains high. Although a high prevalence of non-HIV cancer risk factors among HIV-infected persons contributes to cancer risk, substantial evidence has accumulated in favor of an independent association between HIV-induced immunodeficiency and elevated risk of many specific cancer types, most of viral cause, although further work is needed to disentangle immunodeficiency and smoking effects for lung cancer, and immunodeficiency and hepatitis virus effects for liver cancer. Relationships between cancer risk and two other immune system hallmarks of HIV infection, chronic inflammation, and immune dysfunction/senescence, remain poorly understood.
Early, sustained ART is a crucial component of cancer prevention. Continued epidemiologic monitoring is needed to detect possible effects on cancer risk of specific ART classes or medications, long-term exposure to systemic inflammation or immune dysfunction, or earlier or more effective ART.
aging; cancer; HIV; immune system; inflammation
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).
Adult HIV-infected and 10:1 age- 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.
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 (aRR) of hepatic dysfunction-related death 59.4; (95% confidence interval [CI]: 39.3–89.7), P< 0.001; hepatic dysfunction, aRR 15.7 (95% CI: 11.4–21.6), 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 co-infection, and diabetes. Longer cumulative exposure to ART did not increase risk, regardless of therapy class.
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.
Hepatic Dysfunction; Hepatic Failure; Liver Failure; Hepatic Dysfunction-Related Death; HIV Infection; Antiretroviral Therapy
Reductions in AIDS-related morbidity and mortality following the advent of combination antiretroviral therapy have coincided with relative increases in chronic non-AIDS end-organ diseases among HIV+ patients.
To examine the association of latest CD4+ counts with risk of non-AIDS diseases in a cohort of 1397 patients who initiate antiretroviral therapy.
CD4+ counts and HIV RNA levels along with fatal, and non-fatal, AIDS and non-AIDS diseases (liver, cardiovascular, renal, and cancer) were assessed over a median follow-up of 5 years. Cox proportional regression models were used to study risk associations.
A total of 227 patients experienced an AIDS event and 80 patients developed a non-AIDS disease event. Both AIDS and non-AIDS diseases rates (events/100 person-years), respectively, declined with higher latest CD4+ counts: 13.8 and 2.1 with latest CD4+ counts less than 200 cells/μl; 2.0 and 1.7 for counts of 200–350 cells/μl; and 0.7 and 0.7 for counts greater than 350 cells/μl. After adjusting for baseline covariates and the latest HIV RNA level, risk of AIDS and non-AIDS diseases were lowered by 44% (95% confidence interval for hazard ratio 0.50–0.62, P <0.01) and 14% (95% confidence interval for hazard ratio 0.77–0.96, P =0.01), respectively, for each 100 cell/μl higher latest CD4+ count.
Higher CD4+ counts on antiretroviral therapy are associated with lower rates of non-AIDS diseases and AIDS. These findings expand our understanding of the implications of HIV-related immunodeficiency and motivate randomized studies to evaluate the effects of antiretroviral therapy on a broad set of clinical outcomes at CD4+ counts greater than 350 cells/μl.
AIDS; antiretroviral therapy; CD4 count; HIV morbidity and mortality; non-AIDS conditions
In a large North American cohort study, anal cancer incidence rates were substantially higher for HIV-infected men who have sex with men, other men, and women compared with HIV-uninfected individuals. Rates increased from 1996–1999 to 2000–2003 but plateaued by 2004–2007.
Background. Anal cancer is one of the most common cancers affecting individuals infected with human immunodeficiency virus (HIV), although few have evaluated rates separately for men who have sex with men (MSM), other men, and women. There are also conflicting data regarding calendar trends.
Methods. In a study involving 13 cohorts from North America with follow-up between 1996 and 2007, we compared anal cancer incidence rates among 34 189 HIV-infected (55% MSM, 19% other men, 26% women) and 114 260 HIV-uninfected individuals (90% men).
Results. Among men, the unadjusted anal cancer incidence rates per 100 000 person-years were 131 for HIV-infected MSM, 46 for other HIV-infected men, and 2 for HIV-uninfected men, corresponding to demographically adjusted rate ratios (RRs) of 80.3 (95% confidence interval [CI], 42.7–151.1) for HIV-infected MSM and 26.7 (95% CI, 11.5–61.7) for other HIV-infected men compared with HIV-uninfected men. HIV-infected women had an anal cancer rate of 30/100 000 person-years, and no cases were observed for HIV-uninfected women. In a multivariable Poisson regression model, among HIV-infected individuals, the risk was higher for MSM compared with other men (RR, 3.3; 95% CI, 1.8–6.0), but no difference was observed comparing women with other men (RR, 1.0; 95% CI, 0.5–2.2). In comparison with the period 2000–2003, HIV-infected individuals had an adjusted RR of 0.5 (95% CI, .3–.9) in 1996–1999 and 0.9 (95% CI, .6–1.2) in 2004–2007.
Conclusions. Anal cancer rates were substantially higher for HIV-infected MSM, other men, and women compared with HIV-uninfected individuals, suggesting a need for universal prevention efforts. Rates increased after the early antiretroviral therapy era and then plateaued.
U.S. state AIDS Drug Assistance Programs (ADAPs) are federally funded to provide antiretroviral therapy (ART) as the payer of last resort to eligible persons with HIV infection. States differ regarding their financial contributions to and ways of implementing these programs, and it remains unclear how this interstate variability affects HIV treatment outcomes.
We analyzed data from HIV-infected individuals who were clinically-eligible for ART between 2001 and 2009 (i.e., a first reported CD4+ <350 cells/uL or AIDS-defining illness) from 14 U.S. cohorts of the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). Using propensity score matching and Cox regression, we assessed ART initiation (within 6 months following eligibility) and virologic suppression (within 1 year) based on differences in two state ADAP features: the amount of state funding in annual ADAP budgets and the implementation of waiting lists. We performed an a priori subgroup analysis in persons with a history of injection drug use (IDU).
Among 8,874 persons, 56% initiated ART within six months following eligibility. Persons living in states with no additional state contribution to the ADAP budget initiated ART on a less timely basis (hazard ratio [HR] 0.73, 95% CI 0.60–0.88). Living in a state with an ADAP waiting list was not associated with less timely initiation (HR 1.12, 95% CI 0.87–1.45). Neither additional state contributions nor waiting lists were significantly associated with virologic suppression. Persons with an IDU history initiated ART on a less timely basis (HR 0.67, 95% CI 0.47–0.95).
We found that living in states that did not contribute additionally to the ADAP budget was associated with delayed ART initiation when treatment was clinically indicated. Given the changing healthcare environment, continued assessment of the role of ADAPs and their features that facilitate prompt treatment is needed.
To examine changes in use of prescription opioids for the management of chronic non-cancer pain in HIV-infected patients and to identify patient characteristics associated with long-term use.
Long-term prescription opioid use (i.e. 120+ days supply or 10+ prescriptions during a year) was assessed between 1997 and 2005 among 6,939 HIV-infected Kaiser Permanente members and HIV-uninfected persons in the general health plan memberships.
In 2005, 8% of HIV+ individuals had prevalent long-term opioid use, more than double the prevalence among HIV-uninfected individuals. However, the large increases in use from 1997 to 2005 in the general population were not observed for HIV-infected individuals. The strongest associations with prevalent use among HIV-infected individuals were female gender with a prevalence ratio [PR] of 1.8 (95% CI=1.3, 2.5); Charlson comorbidity score of 2 or more (compared with a score of 0) with a PR of 1.9 (95% CI=1.4, 2.8); injection drug use history with a PR of 1.8 (95% CI=1.3, 2.6); substance use disorders with a PR of 1.8 (95% CI=1.3, 2.5). CD4, HIV RNA, and AIDS diagnoses were associated with prevalent opioid use early in the antiretroviral therapy era (1997), but not in 2005.
Long-term opioid use for chronic pain has remained stable over time for HIV patients, while use increased in the general population. The prevalence of prescribed opioids in HIV patients was highest for certain subgroups, including women, and those with a comorbidity and substance abuse history.
HIV/AIDS; chronic pain; prescription opioids; substance use disorders
Few studies have compared cancer risk between HIV-infected individuals and a demographically-similar HIV-uninfected internal comparison group, adjusting for cancer risk factors.
We followed 20,775 HIV-infected and 215,158 HIV-uninfected individuals enrolled in Kaiser Permanente (KP) California for incident cancer from 1996–2008. Rate ratios (RR) were obtained from Poisson models comparing HIV-infected (overall and stratified by recent CD4 count and HIV RNA) with HIV-uninfected individuals, adjusted for age, sex, race/ethnicity, calendar period, KP region, smoking, alcohol/drug abuse, and overweight/obesity.
We observed elevated RRs for Kaposi sarcoma (KS) (RR=199; P<0.001), non-Hodgkin lymphoma (NHL) (RR=15; P<0.001), anal cancer (RR=55; P<0.001), Hodgkin lymphoma (HL) (RR=19; P<0.001), melanoma (RR=1.8; P=0.001), and liver cancer (RR=1.8; P=0.013), a reduced RR for prostate cancer (RR=0.8; P=0.012), and no increased risk for oral cavity/pharynx (RR=1.4; P=0.14), lung (RR=1.2; P=0.15), or colorectal (RR=0.9; P=0.34) cancers. Lung and oral cavity/pharynx cancers were elevated for HIV-infected subjects in models adjusted only for demographics. KS, NHL, anal cancer, HL, and colorectal cancer had significant (P<0.05) trends for increasing RRs with decreasing recent CD4. The RRs for lung and oral cavity/pharynx cancer were significantly elevated with CD4 <200 cells/µL and for melanoma and liver cancer with CD4 <500 cells/µL. Only KS and NHL were associated with HIV RNA.
Immunodeficiency was positively associated with all cancers examined except prostate cancer among HIV-infected compared with HIV-uninfected individuals, after adjustment for several cancer risk factors.
Earlier antiretroviral therapy initiation to maintain high CD4 levels might reduce the burden of cancer in this population.
HIV/AIDS; cancer; immunodeficiency; viral replication; epidemiology
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.
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.
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.
Except for panel size and years experience among ART-naïve, provider characteristics did not significantly influence ART adherence or likelihood of viral suppression.
antiretroviral therapy; adherence; provider-level factors; HIV-related outcomes
Prior studies evaluating racial/ethnic differences in responses to antiretroviral therapy (ART) among HIV-infected patients have not adequately accounted for many potential confounders, and few have included Hispanic patients.
To identify racial/ethnic differences in ART adherence, and risk of AIDS and death after ART initiation for HIV patients with similar access to care.
Retrospective cohort study.
4,686 HIV-infected patients (66% White, 20% Black, and 14% Hispanic) initiating ART and who were enrolled in an integrated healthcare system.
Main outcomes evaluated were ART adherence, new AIDS clinical events, and all-cause mortality. The potential confounding effects of demographics, socioeconomic status, ART parameters, HIV disease stage, and other clinical parameters were considered in multivariable models.
Adjusted mean adherence levels were higher among White (70.1%; ref) compared with Black (64.2%; < 0.001) and Hispanic patients (65.2%; < 0.001). Adjusted hazard ratios (HR) for the risk of new AIDS events (White patients as reference) were 1.3 ( = 0.09) for Black and 0.9 ( = 0.64) for Hispanic patients. The adjusted HR for AIDS comparing Hispanic to Black patients was 0.7 ( = 0.11). Hispanic patients had fewer deaths compared with other racial/ethnic groups, particularly cancer and cardiovascular-related. However, adjusted HRs for death were 1.2 ( = 0.37) and 0.9 ( = 0.62) for Black and Hispanic patients, respectively, compared with White patients and 0.9 ( = 0.63) for Hispanic compared with Black patients. Adjustment for adherence did not change inferences for AIDS or death.
In the setting of similar access to care, we did not observe a disparity for the risk of clinical events for racial/ethnic minorities, despite lower ART adherence.
race; ethnicity; AIDS; survival
To report trends and characteristics of long-term opioid use for non-cancer pain.
CONSORT (CONsortium to Study Opioid Risks and Trends) includes adult enrollees of two health plans serving over one-percent of the US population. Using automated data, we constructed episodes of opioid use between 1997 and 2005. We estimated age-sex standardized rates of opioid use episodes beginning in each year (incident) and on-going in each year (prevalent), and the percent change in rates annualized (PCA) over the 9 year period. Long-term episodes were defined as > 90 days with 120+ days supply or 10+ opioid prescriptions in a given year.
Over the study period, incident long-term use increased from 8.5 to 12.1 per 1,000 at Group Health (GH) (6.0% PCA), and 6.3 to 8.6 per 1,000 at Kaiser Permanente of Northern California (KPNC) (5.5% PCA). Prevalent long-term use doubled from 23.9 to 46.8 per 1,000 at GH (8.5% PCA), and 21.5 to 39.2 per 1,000 at KPNC (8.1% PCA). Non-Schedule II opioids were the most commonly used opioid among patients engaged in long-term opioid therapy, particularly at KPNC. Long-term use of Schedule II opioids also increased substantially at both health plans. Among prevalent long-term users in 2005, 28.6% at GH and 30.2% at KPNC were also regular users of sedative hypnotics.
Long-term opioid therapy for non-cancer pain is increasingly prevalent, but the benefits and risks associated with such therapy are inadequately understood. Concurrent use of opioids and sedative-hypnotics was unexpectedly common and deserves further study.
pain; opioids; trends; analgesic
Purpose of review
There is an increasing burden of non-AIDS-defining malignancies (NADM) in the antiretroviral therapy (ART) era. The recent literature is reviewed with respect to NADM risk, ART use, and immune function.
Recent studies have increasingly focused on individual ART use, CD4 T-cell counts and the risk of NADMs. Certain NADMs have been shown to have a reduced risk with ART use including liver, breast, colorectal, and lung cancers. NADMs associated with immunosuppression included Hodgkin’s lymphoma, oral/pharynx, lung, anal, and colorectal cancers. Despite the potential protective effect of ART on some NADMs, recent studies evaluating calendar era trends have noted an increased risk of Hodgkin’s lymphoma and anal cancer, and no change in risk for lung cancer in the ART era.
Successful ART use and improvements in immune function for HIV-infected persons may reduce the risk of certain NADMs. However, a continued high risk in the ART era for certain cancers have been observed, including Hodgkin’s lymphoma and anal cancers. Future studies should monitor trends in NADMs in HIV-infected persons in the ART era, as well as changes in the prevalence of risk factors, co-infections, and screening practices in this population.
HIV; antiretroviral therapy; immunodeficiency; malignancy
To determine the impact of age and initial HAART regimen class on virologic and immunologic response within 24 months after initiation.
Pooled analysis of data from 19 prospective cohort studies in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).
Twelve thousand, one hundred and ninety-six antiretroviral-naive adults who initiated HAART between 1998 and 2008 using a boosted protease inhibitor-based regimen or a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen were included in our study. Discrete time-to-event models estimated adjusted hazard odds ratios (aHOR) and 95% confidence intervals (CIs) for suppressed viral load (≤500 copies/ml) and, separately, at least 100 cells/μl increase in CD4 cell count. Truncated, stabilized inverse probability weights accounted for selection biases from discontinuation of initial regimen class.
Among 12 196 eligible participants (mean age = 42 years), 50% changed regimen classes after initiation (57 and 48% of whom initiated protease inhibitor and NNRTI-based regimens, respectively). Mean CD4 cell count at initiation was similar by age. Virologic response to treatment was less likely in those initiating using a boosted protease inhibitor [aHOR = 0.77 (0.73, 0.82)], regardless of age. Immunologic response decreased with increasing age [18–<30: ref; 30–<40: aHOR 0.92 (0.85, 1.00); 40–<50: aHOR = 0.85 (0.78, 0.92); 50–<60: aHOR = 0.82 (0.74, 0.90); ≥60: aHOR=0.74 (0.65, 0.85)], regardless of initial regimen.
We found no evidence of an interaction between age and initial anti-retroviral regimen on virologic or immunologic response to HAART; however, decreased immunologic response with increasing age may have implications for age-specific when-to-start guidelines.
age; CD4 lymphocyte count; HAART; HIV; viral load
The extended use of antiretroviral drugs among human immunodeficiency virus (HIV)–seropositive individuals underscores the need for a comprehensive evaluation of therapy-associated clinical symptoms.
Beginning in April 2000, 364 HIV-seronegative and 1256 HIV-seropositive women enrolled in a multicenter cohort study reported clinical symptoms that included abdominal pain, diarrhea, anorexia, nausea and/or vomiting, myalgias, fatigue, fever, body fat redistribution, dizziness, headaches, paresthesias, xerostomia, nephrolithiasis, and rash. We examined the prevalence of symptoms with respect to HIV infection and the use of highly active antiretroviral therapy (HAART), using data-correlation models.
In the 6 months before a study visit, 49% of HIV-seronegative women, 67% of HIV-seropositive women not receiving therapy, and 69% of HIV-seropositive women receiving HAART reported any clinical symptom. The odds ratios (ORs) for reporting any symptom were 1.4 (95% confidence interval [CI], 1.1–1.8) for women who changed HAART regimens and 0.9 (95% CI, 0.7–1.1) for women reporting stable HAART use, compared with those reporting no therapy use. Significant findings (P < .05) for particular symptoms were an increased odds of diarrhea, nausea and/or vomiting, body fat redistribution, myalgias, and paresthesias, when data for women who changed HAART regimens were compared with those for women not receiving therapy. The OR for reporting any symptom was 1.5 (95% CI, 1.2–1.9) for women who switched HAART regimens and 1.6 (95% CI, 1.3–1.9) for women who discontinued HAART, compared with those reporting stable HAART use.
Our findings confirm the high prevalence of clinical symptoms among HIV-seropositive women who changed HAART regimens. The high prevalence of symptoms among HIV-seronegative women and HIV-seropositive women not receiving therapy demonstrates that caution should be used when attributing the occurrence of symptoms entirely to HAART.
To determine if the concomitant use of nelfinavir (NFV) and proton pump inhibitors (PPIs) among HIV-positive individuals results in the loss of virologic control.
Kaiser Permanente Northern California (KPNC).
A total of 1,147 HIV-positive adults initiating NFV between November 1998 and June 2003 were included. The earlier date corresponds to the availability of the branched-DNA HIV viral load assay at KPNC and the later date corresponds to over-the-counter availability of PPIs.
Measurements and Main Results
The effect on two virologic outcomes, achieving undetectable HIV viral load and subsequent virologic rebound, were compared between subjects receiving NFV alone and NFV with PPIs. Cox proportional hazard models were utilized with adjustment for age, sex, race, HIV risk factors, hepatitis B or C co-infection, and other concurrent medications known to affect the metabolism of NFV. The use of PPIs had little effect on the ability to achieve an undetectable HIV viral load (adjusted hazard ratio (HR) = 0.82; 95% confidence interval (95% CI) = 0.58, 1.19; p = 0.29), but there was an approximate 50% increased risk of virologic rebound with the use of PPIs (adjusted HR = 1.53; 95% CI = 1.06, 2.19; p = 0.02). Short-term use of PPIs (defined as within 30 days of initial PPI dispensation) was not associated with increased risk of virologic rebound (HR = 1.07; 95% CI = 0.26, 4.41; p = 0.93) in comparison to no use.
Use of PPIs should be minimized or avoided in individuals who have attained an undetectable HIV viral load on a NFV-based antiretroviral regimen. However, concomitant use of these medications may be acceptable for indications where PPIs are required for < 30 days.
nelfinavir; proton pump inhibitors; omeprazole; interaction; HIV; virologic rebound
Chronic opioid therapy for chronic non-cancer pain (CNCP) is increasingly common in community practice. Concomitant with this practice change, rates of fatal opioid overdose have increased. It is not known to what extent overdose risks are elevated among patients receiving medically prescribed chronic opioid therapy.
To estimate rates of opioid overdose and their association with average prescribed daily opioid dose among patients receiving medically prescribed chronic opioid therapy.
Cox proportional hazards models were used to estimate overdose risk as a function of average daily opioid dose (morphine equivalents) received at time of overdose.
Health maintenance organization.
Individuals (n=9940) who received 3+ opioid prescriptions within 90-days for CNCP between 1997 and 2005.
Average daily opioid dose over the previous 90 days from automated pharmacy data. Primary outcomes, non-fatal and fatal overdoses, were identified through diagnostic codes from inpatient and outpatient care and death certificates and confirmed by medical record review.
Fifty-one opioid-related overdoses were identified, including six deaths. Compared to patients receiving 1-20mg of opioids per day (0.2% annual overdose rate), patients receiving 50-99 mg had a 3.7 fold increase in overdose risk (95% C.I. 1.5, 9.5) and a 0.7% annual overdose rate. Patients receiving 100mg or more per day had an 8.9 fold increase in overdose risk (95% C.I. 4.0, 19.7) and a 1.8% annual overdose rate.
Increased overdose risk among patients on higher dose regimens may be due to confounding by patient differences and by use of opioids in ways not intended by prescribing physicians. The small number of overdoses in the study cohort is also a limitation.
Patients receiving higher doses of prescribed opioids are at increased risk of opioid overdose, underscoring the need for close supervision of these patients.
To evaluate the risk of cancers with and without a known infectious cause in HIV-infected persons.
Retrospective cohort study.
Adult HIV-infected and matched HIV-uninfected members of Kaiser Permanente followed between 1996 and 2007 for incident AIDS-defining cancers (ADC), infection-related non-AIDS-defining cancers (NADC) (anal squamous cell, vagina/vulva, Hodgkin’s lymphoma, penis, liver, HPV-related oral cavity/pharynx, stomach) and infection-unrelated NADC (all other NADC).
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 3,418 infection-unrelated NADC. The rate ratio (RR) comparing HIV-infected and HIV-uninfected persons for ADC was 37.7 (95% CI: 31.7–44.8), with decreases in the RR over time (p<0.001). The RR for infection-related NADC was 9.2 (95% CI: 7.7–11.1), also with decreases in the RR over time (p<0.001). These results were largely influenced by anal squamous cell cancer and Hodgkin’s lymphoma. The RR for infection-unrelated NADC was 1.3 (95% CI: 1.2–1.4), with no change in the RR over time (p=0.44). Among infection-unrelated NADC, 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 NADC, the RR decreased over time only for lung cancer (p=0.007).
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.
HIV; cancer; incidence; coinfection; cohort
We report trends in long-term opioid use among patients from two large health plans with a history of depression.
Using claims data, age and gender-adjusted rates for long-term (>90 days) opioid use episodes were calculated for 1997–2005, comparing those with and without a depression diagnosis in the prior two years. Opioid use characteristics were calculated for those with a long-term episode in 2005.
Incident and prevalent long-term opioid use rates were three times higher in those with a history of depression. Prevalent long-term use per 1,000 in patients with a history of depression increased from 69.8 to 125.9 at Group Health, and from 84.3 to 117.5 at Kaiser Permanente of Northern California between 1997 and 2005. Those with a history of depression were more likely to receive a higher average daily dose, greater days supply, and Schedule II opioids than non-depressed persons.
Persons with a history of depression are more likely to receive long-term opioid therapy for non-cancer pain than those without a history of depression. Results suggest that long-term opioid therapy for non-cancer pain is being prescribed to a different population in clinical practice than the clinical trial populations where opioid efficacy has been established.
opioid; pain; depression; pharmacoepidemiology
Long-term opioid therapy for non-cancer pain has increased. Caution is advised in prescribing for persons with substance use disorders, but little is known about actual health plan practices. This paper reports trends and characteristics of long-term opioid use in persons with non-cancer pain and a substance abuse history. Using health plan data (1997–2005), the study compared age–sex-standardized rates of incident, incident long-term and prevalent long-term prescription opioid use, and medication use profiles in those with and without substance use disorder histories. The CONsortium to Study Opioid Risks and Trends study included adult enrollees of two health plans, Kaiser Permanente of Northern California (KPNC) and Group Health Cooperative (GH) of Seattle, Washington. At KPNC (1999–2005), prevalence of long-term use increased from 11.6% to 17.0% for those with substance use disorder histories and from 2.6% to 3.9% for those without substance use disorder histories. Respective GH rates (1997–2005), increased from 7.6% to 18.6% and from 2.7% to 4.2%. Among persons with an opioid disorder, KPNC rates increased from 44.1% to 51.1%, and GH rates increased from 15.7% to 52.4%. Long-term opioid users with a prior substance abuse diagnosis received higher dosage levels, were more likely to use Schedule II and long-acting opioids, and were more often frequent users of sedative-hypnotic medications in addition to their opioid use. Since these patients are viewed as higher risk, the increased use of long-term opioid therapy suggests the importance of improved understanding of the benefits and risks of opioid therapy among persons with a history of substance abuse, and the need for more careful screening for substance abuse history than is the usual practice.
Prescription opioid episodes; Substance use disorders; Chronic pain management in managed care
Few studies have evaluated age and racial/ethnic differences in the prevalence of symptoms in HIV infection. Thus, the objective of this study was to compare the prevalence of gastrointestinal, metabolic, general malaise, neurologic, or other self-reported symptoms by age and race/ethnicity among 1,574 HIV-infected women enrolled in the Women’s Interagency HIV Study and 955 HIV-infected men who have sex with men (MSM) enrolled in the Multicenter AIDS Cohort Study. All patients had known dates of initiation of highly-active antiretroviral therapy. It was observed that women ≥50 years were less likely to experience gastrointestinal symptoms (24% vs. 27%, multivariable p=0.024), but more likely to experience general malaise (47% vs. 37%; multivariable p=0.004), neurologic (44% vs. 38%; multivariable p=0.048), or other symptoms (40% vs. 28%; multivariable P<0.001) compared to women <40 years of age. Only neurologic symptoms had a higher prevalence among older MSM (52% vs. 37%; multivariable P=0.002), largely driven by paresthesias (48% vs. 31%; multivariable p=0.004), the most common individual symptom reported by men. Caucasian women generally had the highest prevalence of symptoms and African-American women had the lowest prevalence. Few racial/ethnic differences were noted for MSM. Depression and a prior diagnosis of AIDS were the strongest and most consistent predictors of clinical symptoms in both cohorts. In summary, the prevalence of reported symptoms varies with patient race/ethnicity, age, and modifiable factors such as depression and HIV disease stage. Clinicians should consider these factors when counseling patients regarding potential adverse effects of antiretrovirals or symptoms associated with HIV disease.
Highly active antiretroviral therapy; symptoms; gender; race/ethnicity; aging