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
We seek to determine the optimized multidisciplinary care team (MDCT) composition for antiretroviral therapy (ART) adherence.
We analyzed all new regimen starts (n=10,801; 7,071 ART naïve, 3,730 ART experienced) among HIV+ patients in Kaiser Permanente California from 1996–2006. We measured 12-month adherence to ART (pharmacy refill methodology) and medical center-specific patient exposure to HIV/ID specialist (reference group), non-HIV primary care provider (PC), clinical pharmacist, nurse case manager, non-nurse care coordinator, dietician, social worker/benefits coordinator, health educator, and mental health. 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, HCV+, ART regimen class and calendar year) to test which potential MDCT identified had statistically significant association with ART adherence.
We found maximal increase in adherence with pharmacist +coordinator +PC (+8.1% ART adherence difference compared to reference; 95%CI: +2.7–+13.5%). Other MDCT teams with significant (p<0.05) improved adherence compared to specialist only were: nurse +social work +PC (+7.5%; +5.4–+9.7%); specialist +mental health (+6.5%; +2.6–+10.4%); pharmacist +social work +PC (+5.7%; +4.1–+7.4%); pharmacist +PC (+3.3%; +0.8–+5.8%). Among these MDCTs, there were no significant differences in mean adherence, odds maximal viral control, or change CD4+ at 12 months (except pharmacist +PC).
Various MDCTs were associated with improved adherence, including ones that did not include HIV specialist but included primary care plus other health professionals. These findings have application to HIV care team design.
Multidisciplinary Care Team; Antiretroviral Therapy Adherence; Clinical Pharmacist; Patient Centered Medical Home; HIV Specialist; Recursive Partitioning
HIV/AIDS is a worldwide epidemic. Limited evidence suggests that men infected with HIV/AIDS are at increased risk for lower urinary tract symptoms. We determined whether HIV/AIDS status is an independent risk factor for self-reported bothersome lower urinary tract symptoms in a large contemporary cohort.
Materials and Methods
We performed a cross-sectional, Internet based survey of urinary quality of life outcomes in adult HIV infected and HIV uninfected men who have sex with men. The main outcome measure was International Prostate Symptom Score.
Of respondents with complete data 1,507 were HIV uninfected (median age 42 years, mean 43) and 323 HIV infected (median age 45 years, mean 45.1). Of the HIV infected respondents 148 were nonAIDS defining HIV infected and 175 were AIDS defining HIV infected. After adjusting for age and other comorbid conditions, nonAIDS defining HIV infected and AIDS defining HIV infected status increased the odds of severe lower urinary tract symptoms by 2.07 (95% CI 1.04–3.79) and 2.49 (95% CI 1.43–4.33), respectively. HIV infected men had a worse total International Prostate Symptom Score for all domains including quality of life compared to HIV uninfected men. Within the population of men with HIV, those with AIDS had worse mean total International Prostate Symptom Score and all individual International Prostate Symptom Score components relative to nonAIDS defining HIV infected men.
HIV status is an independent risk factor for bothersome lower urinary tract symptoms. The odds of severe lower urinary tract symptoms are greater in HIV infected men with a history of AIDS.
urinary tract; signs and symptoms; HIV
Women with diabetes mellitus who delay pregnancy until glycemic control is achieved experience lower rates of adverse pregnancy outcomes.
To compare rates of provision of contraceptive services among women with diabetes mellitus and women without chronic medical conditions.
A retrospective cohort study of 459,181 women aged 15–44 who had continuous membership and pharmacy benefits in a managed care organization in Northern California between January 2006 and June 2007. Rates of documented provision of contraceptive counseling, prescriptions, and services were compared between women with diabetes and women without chronic medical conditions.
Among 8,182 women with diabetes and 122,921 women without any chronic conditions, women with diabetes were less likely than women without a chronic condition to have documented receipt of any contraceptive counseling, prescriptions, or services (47.8% vs 62.0%, p < 0.001). After controlling for age and race, women with diabetes were more likely to have undergone tubal sterilization compared to women without a chronic condition (OR = 1.41, 95% CI 1.30–1.54), but less likely to have received highly effective, reversible methods of contraception such as intrauterine contraception (OR = 0.68, 95% CI 0.61–0.75). In addition, more women with diabetes had undergone hysterectomy, which is rarely performed solely for contraceptive purposes.
Women with diabetes were less likely to receive highly effective reversible contraception and more likely to undergo sterilization procedures. Increasing the use of highly effective reversible contraceptives may help diabetic women who want to retain their fertility to delay pregnancy until glycemic control is achieved.
diabetes mellitus; pregnancy; contraception; preconception counseling; women
The U.S. National HIV/AIDS Strategy targets for 2015 include increasing access to care and improving health outcomes for persons living with HIV in the United States (PLWH-US).
To demonstrate the utility of the NA-ACCORD (North American AIDS Cohort Collaboration on Research and Design) for monitoring trends in the HIV epidemic in the United States and to present trends in HIV treatment and related health outcomes.
Trends from annual cross-sectional analyses comparing patients from pooled, multicenter, prospective, clinical HIV cohort studies with PLWH-US, as reported to national surveillance systems in 40 states.
U.S. HIV outpatient clinics.
HIV-infected adults with 1 or more HIV RNA plasma viral load (HIV VL) or CD4 T-lymphocyte (CD4) cell count measured in any calendar year from 1 January 2000 to 31 December 2008.
Annual rates of antiretroviral therapy use, HIV VL, and CD4 cell count at death.
45 529 HIV-infected persons received care in an NA-ACCORD–participating U.S. clinical cohort from 2000 to 2008. In 2008, the 26 030 NA-ACCORD participants in care and the 655 966 PLWH-US had qualitatively similar demographic characteristics. From 2000 to 2008, the proportion of participants prescribed highly active antiretroviral therapy increased by 9 percentage points to 83% (P < 0.001), whereas the proportion with suppressed HIV VL (≤2.7 log10 copies/mL) increased by 26 percentage points to 72% (P < 0.001). Median CD4 cell count at death more than tripled to 0.209 × 109 cells/L (P < 0.001).
The usual limitations of observational data apply.
The NA-ACCORD is the largest cohort of HIV-infected adults in clinical care in the United States that is demographically similar to PLWH-US in 2008. From 2000 to 2008, increases were observed in the percentage of prescribed HAART, the percentage who achieved a suppressed HIV VL, and the median CD4 cell count at death.
Primary Funding Source
National Institutes of Health, Centers for Disease Control and Prevention, Canadian Institutes of Health Research, Canadian HIV Trials Network, and the government of British Columbia, Canada.
Human immunodeficiency virus (HIV) antiretroviral agents and effective HIV care management transformed HIV disease from a death sentence to a chronic condition for many in the United States. A comprehensive HIV care model was developed to meet the complex needs of HIV patients, with support from the Ryan White program, the Veterans Administration, and others. This paper identifies the essential components of an effective HIV care model. As access to health care expands under the National HIV/AIDS Strategy and the Patient Protection and Affordable Care Act, it will be critical to build upon the HIV care model to realize positive health outcomes for people with HIV infection.
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. Screening for tuberculosis prior to highly active antiretroviral therapy (HAART) initiation is not routinely performed in low-incidence settings. Identifying factors associated with developing tuberculosis after HAART initiation could focus screening efforts.
Methods. Sixteen cohorts in the United States and Canada contributed data on persons infected with human immunodeficiency virus (HIV) who initiated HAART December 1995–August 2009. Parametric survival models identified factors associated with tuberculosis occurrence.
Results. Of 37845 persons in the study, 145 were diagnosed with tuberculosis after HAART initiation. Tuberculosis risk was highest in the first 3 months of HAART (20 cases; 215 cases per 100000 person-years; 95% confidence interval [CI]: 131–333 per 100000 person-years). In a multivariate Weibull proportional hazards model, baseline CD4+ lymphocyte count <200, black race, other nonwhite race, Hispanic ethnicity, and history of injection drug use were independently associated with tuberculosis risk. In addition, in a piece-wise Weibull model, increased baseline HIV-1 RNA was associated with increased tuberculosis risk in the first 3 months; male sex tended to be associated with increased risk.
Conclusions. Screening for active tuberculosis prior to HAART initiation should be targeted to persons with baseline CD4 <200 lymphocytes/mm3 or increased HIV-1 RNA, persons of nonwhite race or Hispanic ethnicity, history of injection drug use, and possibly male sex.
Determination of the prevalence of accumulated antiretroviral drug resistance among persons infected with human immunodeficiency virus (HIV) is complicated by the lack of routine measurement in clinical care. By using data from 8 clinic-based cohorts from the North American AIDS Cohort Collaboration on Research and Design, drug-resistance mutations from those with genotype tests were determined and scored using the Genotypic Resistance Interpretation Algorithm developed at Stanford University. For each year from 2000 through 2005, the prevalence was calculated using data from the tested subset, assumptions that incorporated clinical knowledge, and multiple imputation methods to yield a complete data set. A total of 9,289 patients contributed data to the analysis; 3,959 had at least 1 viral load above 1,000 copies/mL, of whom 2,962 (75%) had undergone at least 1 genotype test. Using these methods, the authors estimated that the prevalence of accumulated resistance to 2 or more antiretroviral drug classes had increased from 14% in 2000 to 17% in 2005 (P < 0.001). In contrast, the prevalence of resistance in the tested subset declined from 57% to 36% for 2 or more classes. The authors’ use of clinical knowledge and multiple imputation methods revealed trends in HIV drug resistance among patients in care that were markedly different from those observed using only data from patients who had undergone genotype tests.
antiretroviral therapy, highly active; drug resistance; genotype; HIV
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
HIV infection is associated with sexual dysfunction. Using validated instruments, we investigated the relationship between HIV/AIDS and sexual function in a contemporary cohort of men who have sex with men (MSM). An anonymous Internet-based survey was disseminated to MSM via organizations and social networking sites that cater to this population. Information on ethnodemographic variables, health status (including HIV status, disease stage, and other health conditions), and sexual behavior was collected. Men were categorized as HIV-negative, HIV-positive/AIDS-negative, or HIV-positive /AIDS-positive. A modified validated version of the International Index of Erectile Function (IIEF) for use in MSM and the Premature Ejaculation Diagnostic Tool (PEDT) were used to stratify risk of sexual dysfunction. The study cohort included 1361 men (236 of whom were HIV-positive) who provided complete data on HIV status, IIEF, and PEDT. There was a significant trend toward greater prevalence of erectile dysfunction (ED) in men with progressive HIV infection 40–59 years of age relative to age matched HIV-negative men (p=0.02). In a logistic regression model controlling for other variables, HIV infection without AIDS was not associated with greater odds of ED; however, HIV infection with AIDS was associated with greater odds of ED (p=0.006). In a separate logistic regression model, HIV infection with or without AIDS was not significantly associated with greater odds of premature ejaculation (p>0.05). Use of phosphodiesterase 5 (PDE5) inhibitor drugs was much more common in HIV-infected men. HIV infection is a risk factor for poorer sexual function primarily due to higher risk of erectile dysfunction in men with AIDS.
To investigate the survival outcomes for non-Hodgkin lymphoma (NHL) in HIV-infected vs. -uninfected patients from the same integrated health care system, and to identify prognostic factors for HIV-related NHL in the era of combined antiretroviral therapy (cART).
Incident NHL diagnosed between 1996–2005 were identified from members of Kaiser Permanente (KP) 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.
A total of 259 HIV-infected and 8,230 HIV-uninfected incident NHL cases were evaluated. Fifty-nine percent of HIV-infected patients died within 2 years after NHL diagnosis, compared to 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 <200/mm3 and/or prior AIDS-defining illness were also at increased risk for lymphoma-specific mortality compared to HIV-uninfected patients. Among HIV-infected NHL cases, significant prognostic factors for overall mortality included prior AIDS-defining illness and Burkitt’s subtype.
HIV-infected patients with NHL in the cART 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.
HIV infection; non-Hodgkin lymphoma; prognostic factors; antiretroviral therapy; mortality
Initiatives to improve early detection and access to HIV services have increased over time. We assessed the immune status of patients at initial presentation for HIV care from 1997-2007 in 13 US and Canadian clinical cohorts.
We analyzed data from 44,491 HIV-infected patients enrolled in the North American – AIDS Cohort Collaboration on Research and Design. We identified first presentation for HIV care as the time of first CD4+ T-lymphocyte (CD4) measurement and excluded patients who prior to this date had HIV RNA measurements, evidence of antiretroviral exposure, or a history of AIDS-defining illness. Trends in mean CD4 count (measured as cells/mm3) and 95% confidence intervals ([,]) were determined using linear regression adjusted for age, gender, race/ethnicity, HIV transmission risk and cohort.
Median age at first presentation for HIV care increased over time (range 40-43 years, p<0.01), while the proportion of patients with injection drug use HIV transmission risk decreased (26% to 14%, p<0.01) and heterosexual transmission risk increased (16% to 23%, p<0.01). Median CD4 at presentation increased from 256 (IQR: 96-455) to 317 (IQR: 135-517) in 1997 to 2007 (p<0.01). The proportion with a CD4 count ≥350 at first presentation also increased from 1997 to 2007 (38% to 46%, p=<0.01). The estimated adjusted mean CD4 count increased at a rate of 6 [5, 7] per year.
CD4 count at first presentation for HIV care has increased annually over the past 11 years, but has remained <350 cells/mm3, suggesting the urgent need for earlier HIV diagnosis and treatment.
CD4 Lymphocyte Count; Delivery of Health Care / statistics & numerical data; HIV Infections / therapy; United States; Canada
We assessed CD4 count at initial presentation for HIV care among ≥50-year-olds from 1997-2007 in 13 US and Canadian clinical cohorts and compared to <50-year-olds. 44,491 HIV-infected individuals in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) were included in our study. Trends in mean CD4 count (measured as cells/mm3) and 95% confidence intervals ([,]) were determined using linear regression stratified by age category and adjusted for gender, race/ethnicity, HIV transmission risk and cohort. From 1997-2007, the proportion of individuals presenting for HIV care who were ≥50-years-old increased from 17% to 27% (p-value < 0.01). The median CD4 count among ≥50 year-olds was consistently lower than younger adults. The interaction of age group and calendar year was significant (p-value <0.01) with both age groups experiencing modest annual improvements over time (< 50-year-olds: 5
[4 , 6] cells/mm3; ≥50-year-olds: 7
[5 , 9] cells/mm3), after adjusting for sex, race/ethnicity, HIV transmission risk group and cohort; however, increases in the two groups were similar after 2000. A greater proportion of older individuals had an AIDS-defining diagnosis at, or within three months prior to, first presentation for HIV care compared to younger individuals (13% vs. 10%, respectively). Due to the increasing proportion, consistently lower CD4 counts, and more advanced HIV disease in adults ≥50-year-old at first presentation for HIV care, renewed HIV testing efforts are needed.
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
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
Atripla® (Gilead Sciences Inc, Foster City, CA, USA and Bristol-Myers Squibb, New York City, NY, USA) is a coformulated single pill composed of efavirenz, emtricitabine, and tenofovir disoproxil, intended as a once-daily potent combination antiretroviral therapeutic agent. Its efficacy is equivalent to the 3 component drugs taken in a combination as single medications. The coformulated antiretroviral regimen can be quite effective in patients whose human immunodeficiency virus is sensitive to all 3 components of Atripla. However, women at risk of pregnancy, already pregnant, or nursing mothers should not take Atripla, due to the teratogenic potential of the efavirenz moiety. Adverse effects are similar to those seen with the constituent medications, including potential central nervous system effects and renal toxicity. Since its US Food and Drug administration approval, prescriptions for Atripla have increased steadily.
tenofovir; efavirenz; emtricitabine; antiretroviral therapy
Although combination antiretroviral therapy continues to evolve, with potentially more effective options emerging each year, the ability of therapy to prevent multiple regimen failure and mortality in clinical practice remains poorly defined.
Sixteen cohorts representing over 60 sites contributed data on all individuals who initiated combination antiretroviral therapy. We identified those individuals who experienced virologic failure (defined as a human immunodeficiency virus [HIV] RNA level >1000 copies/mL), received modified therapy, and subsequently had a second episode of virologic failure. Multivariate Cox regression was used to assess factors associated with time to second regimen failure and the time to death after the onset of second regimen failure.
Of the 42,790 individuals who received therapy, 7159 experienced a second virologic failure. The risk of second virologic failure decreased from 1996 (56 cases per 100 person-years) through 2005 (16 cases per 100 person-years; P < .001). The cumulative mortality after onset of second virologic failure was 26% at 5 years and decreased over time. A history of AIDS, a lower CD4+ T cell count, and a higher plasma HIV RNA level were each independently associated with mortality. Similar trends were observed when analysis was limited to the subset of previously treatment-naive patients
Although the rates of multiple regimen failure have decreased dramatically over the past decade, mortality rates for those who have experienced failure of at least 2 regimens have remained high. Plasma HIV RNA levels, CD4+ T cell counts at time of treatment failure, and a history of AIDS remain independent risk factors for death, which emphasizes that these factors remain important targets for those in need of more-aggressive therapeutic interventions.
The optimal time for the initiation of antiretroviral therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection is uncertain.
We conducted two parallel analyses involving a total of 17,517 asymptomatic patients with HIV infection in the United States and Canada who received medical care during the period from 1996 through 2005. None of the patients had undergone previous antiretroviral therapy. In each group, we stratified the patients according to the CD4+ count (351 to 500 cells per cubic millimeter or >500 cells per cubic millimeter) at the initiation of antiretroviral therapy. In each group, we compared the relative risk of death for patients who initiated therapy when the CD4+ count was above each of the two thresholds of interest (early-therapy group) with that of patients who deferred therapy until the CD4+ count fell below these thresholds (deferred-therapy group).
In the first analysis, which involved 8362 patients, 2084 (25%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimeter, and 6278 (75%) deferred therapy. After adjustment for calendar year, cohort of patients, and demographic and clinical characteristics, among patients in the deferred-therapy group there was an increase in the risk of death of 69%, as compared with that in the early-therapy group (relative risk in the deferred-therapy group, 1.69; 95% confidence interval [CI], 1.26 to 2.26; P<0.001). In the second analysis involving 9155 patients, 2220 (24%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimeter and 6935 (76%) deferred therapy. Among patients in the deferred-therapy group, there was an increase in the risk of death of 94% (relative risk, 1.94; 95% CI, 1.37 to 2.79; P<0.001).
The early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds significantly improved survival, as compared with deferred therapy.
Combination antiretroviral therapy (cART) is associated with increased survival among HIV-infected persons. Yet, no research to date has examined whether introduction of once-daily fixed-dosed combinations (FDC) affects the likelihood of cART initiation. We aimed to determine whether implementation of once-daily FDC regimens was associated with changes to cART initiation. We also identified clinical, treatment regimen, and provider characteristics possibly associated with cART initiation.
Retrospective observational analysis.
We queried electronic medical records between July 1999–June 2006 to identify incident cases of detectable HIV infection in antiretroviral-naïve adults. Cox regression with time-dependent covariates was used to examine the effects of once-daily FDC era, clinical, provider, and treatment regimen characteristics on cART initiation.
Once-daily FDC availability did not change the likelihood of cART initiation, but other characteristics were associated with an increased likelihood: AIDS diagnosis, above-median daily pill consumption, and 16+ yrs of physician HIV experience. Decreased likelihood of cART initiation was associated with CD4 201–350 cells/μL, HIV RNA < 100,000 copies/mL, and with CD4 > 350 cells/μL (any HIV RNA level), compared to CD4 ≤ 200 cells/μL.
Availability of once-daily FDC-based regimens did not affect likelihood of cART initiation. Patient clinical characteristics appear to be more important predictors of cART initiation.
ARV treatment; once-daily FDC therapies; ARV-naïve
HIV; AIDS; cohorts; epidemiology
It is important, for drug-resistance surveillance, to identify human immunodeficiency virus type 1 (HIV-1) strains that have undergone antiretroviral drug selection.
We compared the prevalence of protease and reverse-transcriptase (RT) mutations in HIV-1 sequences from persons with and without previous treatment with protease inhibitors (PIs), nucleoside RT inhibitors (NRTIs), and nonnucleoside RT inhibitors (NNRTIs). Treatment-associated mutations in protease isolates from 5867 persons and RT isolates from 6247 persons were categorized by whether they were polymorphic (prevalence, >0.5%) in untreated individuals and whether they were established drug-resistance mutations. New methods were introduced to minimize misclassification from transmitted resistance, population stratification, sequencing artifacts, and multiple hypothesis testing.
Some 36 established and 24 additional nonpolymorphic protease mutations at 34 positions were related to PI treatment, 21 established and 22 additional nonpolymorphic RT mutations at 24 positions with NRTI treatment, and 15 established and 11 additional nonpolymorphic RT mutations at 15 positions with NNRTI treatment. In addition, 11 PI-associated and 1 NRTI-associated established mutations were polymorphic in viruses from untreated persons.
Established drug-resistance mutations encompass only a subset of treatment-associated mutations; some of these are polymorphic in untreated persons. In contrast, nonpolymorphic treatment-associated mutations may be more sensitive and specific markers of transmitted HIV-1 drug resistance.
Nelfinavir was once one of the most commonly used protease inhibitors (PIs). To investigate the genetic mechanisms of multidrug resistance in protease isolates with the primary nelfinavir resistance mutation D30N, we analyzed patterns of protease mutations in 582 viruses with D30N from 460 persons undergoing HIV-1 genotypic resistance testing at Stanford University Hospital from 1997 to 2005. Three patterns of mutational associations were identified. First, D30N was positively associated with N88D but negatively associated with N88S. Second, D30N and L90M were negatively associated except in the presence of N88D, which facilitated the cooccurrence of D30N and L90M. Third, D30N + N88D + L90M formed a stable genetic backbone for the accumulation of additional protease inhibitor (PI) resistance mutations. In 16 patients having isolates with more than one combination of mutations at positions 30, 88, and 90, all exhibited one of the steps in the following progression: D30N → D30N + N88D → D30N + N88D + L90M → D30N + N88D + L90M + (L33F ± I84V or M46I/L ± I54V). Although nelfinavir is now used less frequently than other PIs, the well-delineated mutational pathway we describe is likely to influence patterns of cross-resistance in viruses from persons who experience virologic failure while receiving this PI.
HIV-1 genotypic resistance test results were obtained on clinical samples from 116 patients with plasma HIV-1 RNA levels of less than 75 copies/mL. Genotype validity was confirmed in 49 of 50 patients with a previous or follow-up genotype. The belief that genotypic resistance testing is unreliable in samples with low-level viremia should be reassessed.
genotypic testing; population-based sequencing; low viral load