Jeanne C. Keruly

CD4+ Cell Count 6 Years after Commencement of Highly Active Antiretroviral Therapy in Persons with Sustained Virologic Suppression

BACKGROUND Sustained suppression of the human immunodeficiency virus (HIV) type 1 RNA load with the use of highly active antiretroviral therapy (HAART) results in immunologic improvement, but it is not clear whether the CD4(+) cell count increases to normal levels or whether it reaches a less-than-normal plateau. We characterized the increase in the CD4(+) cell count in patients in clinical practice who maintained sustained viral suppression for up to 6 years. METHODS All patients were from the Johns Hopkins HIV Clinical Cohort, a longitudinal observational study of patients receiving primary HIV care in Baltimore, Maryland, who were observed for >1 year while receiving HAART and who had sustained suppression of the HIV RNA load at <400 copies/mL. We analyzed annual change in the CD4(+) cell count for up to 6 years after the start of HAART, stratified by baseline CD4(+) cell counts of < or =200, 201-350, >350 cells/microL, and we assessed the development of clinical events (death and new acquired immunodeficiency syndrome-defining illness) by Kaplan-Meier analysis. RESULTS A total of 655 patients were observed for a median of 46 months (range, 13-72 months). The median change from baseline to most recent CD4(+) cell count was +274 cells/microL, with 92% of patients having an increase in CD4(+) cell count. By 6 years, the median CD4(+) cell count was 493 cells/microL among patients with baseline CD4(+) cell counts < or =200 cells/microL, 508 cells/microL among those with baseline CD4(+) cell counts of 201-350 cells/microL, and 829 cells/microL among those with baseline CD4(+) cell counts >350 cells/microL. In addition to baseline CD4(+) cell count, injection drug use and older age were associated with a lesser CD4(+) cell count response, and duration of therapy was associated with a greater CD4(+) cell count response. CONCLUSION Only patients with baseline CD4(+) cell counts >350 cells/microL returned to nearly normal CD4(+) cell counts after 6 years of follow-up. Significant increases were observed in all CD4(+) cell count strata during the first year, but there was a lower plateau CD4(+) cell count at lower baseline CD4(+) cell strata. These data suggest that waiting to start HAART at lower CD4(+) cell counts will result in the CD4(+) cell count not returning to normal levels.

Race, Sex, Drug Use, and Progression of Human Immunodeficiency Virus Disease

BACKGROUND The rates of progression of human immunodeficiency virus (HIV) infection and survival have been reported to differ among sociodemographic groups. It is unclear whether these differences reflect biologic differences or differences in access to medical care. METHODS We measured disease progression and survival in a cohort of 1372 patients seropositive for HIV who were treated at a single urban center (median follow-up, 1.6 years). We calculated the rates of survival for the entire cohort and the rates of progression to the acquired immunodeficiency syndrome (AIDS) or death among the 740 patients who presented without AIDS. We used Cox proportional-hazards analysis to examine factors associated with progression to AIDS and death. RESULTS Progression to AIDS or death was associated with a CD4 cell count of 201 to 350 per cubic millimeter (relative risk, 2.0; P < 0.001), the presence of symptoms at base line (relative risk, 2.0; P < 0.001), prior antiretroviral therapy (relative risk, 1.7; P = 0.003), and older age (relative risk per year of age, 1.02; P = 0.03). However, there was no relation between disease progression and sex, race, injection-drug use, income, level of education, or insurance status. In the entire cohort, a lower CD4 cell count, a diagnosis of AIDS, older age, and the receipt of antiretroviral therapy before enrollment were associated with an increased risk of death, whereas the use of prophylaxis against pneumocystis pneumonia, zidovudine use after enrollment, and having a job at base line were associated with lower risks of death. There was no significant difference in survival between men and women, blacks and whites, injection-drug users and those who did not use drugs, or patients whose median annual incomes were

Changes in Renal Function Associated with Tenofovir Disoproxil Fumarate Treatment, Compared with Nucleoside Reverse-Transcriptase Inhibitor Treatment

5,000 or less and those whose incomes were more than

Is the quality of the patient-provider relationship associated with better adherence and health outcomes for patients with HIV?

5,000. CONCLUSIONS Among patients with HIV infection who received medical care from a single urban center, there were no differences in disease progression or survival associated with sex, race, injection-drug use, or socioeconomic status. Differences found in other studies may reflect differences in the use of medical care.

Incidence of neuropathy in HIV-infected patients on monotherapy versus those on combination therapy with didanosine, stavudine and hydroxyurea.

In our large observational cohort, use of tenofovir disoproxil fumarate (n=344) was associated with a greater decline in renal function than was use of alternative nucleoside analogues (n=314). Other associations included a lower CD4 cell count, decreased renal function at baseline, and diabetes. The declines were modest and did not lead to greater rates of discontinuation of therapy.

Anemia and survival in HIV infection

PURPOSE: Patient-centeredness, originally defined as understanding each patient as a unique person, is widely considered the standard for high-quality interpersonal care. The purpose of our study was to examine the association between patient perception of being “known as a person” and receipt of highly active antiretroviral therapy (HAART), adherence to HAART, and health outcomes among patients with HIV. STUDY DESIGN: Cross-sectional analysis. SUBJECTS: One thousand seven hundred and forty-three patients with HIV. MEASUREMENTS: Patient reports that their HIV provider “knows me as a person” and 3 outcomes: receipt of HAART, adherence to HAART, and undetectable serum HIV RNA. RESULTS: Patients who reported that their provider knows them “as a person” were more likely to receive HAART (60% vs 47%, P<.001), be adherent to HAART (76% vs 67%, P=.007), and have undetectable serum HIV RNA (49% vs 39%, P<.001). Patients who reported their provider knows them “as a person” were also older (mean 38.0 vs 36.6 years, P<.001), reported higher quality-of-life (mean LASA score 71.1 vs 64.8, P<.001), had been followed in clinic longer (mean 64.4 vs 61.7 months, P=.008), missed fewer appointments (mean proportion missed appointments 0.124 vs 0.144, P<.001), reported more positive beliefs about HAART therapy (39% vs 28% strongly believed HIV medications could help them live longer, P<.008), reported less social stress (50% vs 62% did not eat regular meals, P<.001) and were less likely to use illicit drugs or alcohol (22% vs 33% used drugs, P<.001; 42% vs 53% used alcohol, P<.001). Controlling for patient age, sex, race/ethnicity, quality-of-life, length of time in clinic, missed appointments, health beliefs, social stress, and illicit drug and alcohol use, patients who reported their provider knows them “as a person” had higher odds of receiving HAART (odds ratio [OR] 1.41, 95% confidence interval [CI] 1.19 to 1.65), adhering to HAART (OR 1.33, 95% CI 1.02 to 1.72), and having undetectable serum HIV RNA (1.20, 95% CI 1.02 to 1.41). CONCLUSIONS: We found that a single item measuring the essence of patient-centeredness—the patients’ perception of being “known as a person”—is significantly and independently associated with receiving HAART, adhering to HAART, and having undetectable serum HIV RNA. These results support the hypothesis that the quality of patient-physician relationship is directly related to the health of patients.

Impact of opportunistic disease on survival in patients with HIV infection.

BackgroundSensory neuropathy is a common adverse effect of the nucleoside analogue anti-retroviral drugs didanosine (ddI) and stauvudine (d4T). These drugs are increasingly being used in combination, and it is not currently known whether the incidence of neuropathy is higher with combination compared to individual drug use. It is also not known if hydroxyurea, used to potentiate the antiviral efficacy of these drugs, may also increase the risk of neuropathy. The purpose of this analysis is to investigate if the combination of ddI and d4T, with or without hydroxyurea, has a higher incidence of neuropathy than a single drug regimen. MethodsData were obtained from patients followed longitudinally by the Johns Hopkins AIDS Services. Incidence rates of development of neuropathy were calculated for each of five regimens: ddI (± hydroxyurea), ddI + d4T (± hydroxyurea), and d4T. Cox proportional hazard regression was used to compare the relative risk of neuropathy for each regimen adjusting for CD4 cell count, other drugs received, and time on therapy. ResultsA total of 1116 patients received at least one of the five regimens. There were 117 cases of neuropathy. The crude incidence rate of neuropathy ranged from 6.8 cases per 100 person-years for ddI to 28.6 cases per 100 person-years for ddI + d4T + hydroxyurea. Compared with ddI alone, and adjusting for CD4 cell counts and other variables, the relative risk of neuropathy was 1.39 [95% confidence interval (CI): 0.84–2.32] for d4T alone, 2.35 (95% CI: 0.69–8.07) for ddI + hydroxurea, 3.50 (95% CI: 1.81–6.77) for ddI + d4T, and 7.80 (95% CI: 3.92–15.5) for ddI + d4T + hydroxyurea. ConclusionsBased on the data, the risk of neuropathy is additive or even synergistic for ddI + d4T + hydroxyurea compared with ddI or d4T alone. The combination of ddI + d4T also increases the risk of neuropathy but less than when hydroxyurea is included.

Chronic Kidney Disease Incidence, and Progression to End-Stage Renal Disease, in HIV-Infected Individuals: A Tale of Two Races

Several clinical studies have suggested that anemia is an independent risk factor for dying in patients with HIV disease. We analyzed data from a large urban HIV clinical practice in Baltimore to assess the annual incidence of anemia, the risk of dying in patients who develop anemia, and the association between recombinant human erythropoietin use to treat anemia and subsequent survival. In 2348 patients observed between 1989 and 1996, 498 (21%) developed at least grade 1 anemia (hemoglobin <9.4 g/dl); 95 (4%) developed grade 4 anemia (hemoglobin <6.9 g/dl). Development of anemia was associated with decreased survival, independent of other prognostic factors. Use of erythropoietin was more likely in patients of nonminority race, those who did not inject drugs, those with a lower CD4 count or AIDS, and those being treated for cytomegalovirus disease (p < .05). Adjusting for these factors as well as severity of anemia, age, diagnosis of opportunistic disease, blood transfusion, and antiretroviral therapy in a time-dependent Cox proportional hazards analysis, erythropoietin use (n=91) was associated with a decreased hazard of dying (relative hazard [RH]=0.57; 95% confidence interval [CII, 0.40-0.81; p=.002). Although we cannot rule out a treatment selection bias, adjusting for available prognostic factors and factors potentially associated with a decision to use erythropoietin suggests that erythropoietin for treatment of anemia is associated with improved survival in HIV disease.

Measuring Retention in HIV Care: The Elusive Gold Standard

Objective:To assess the impact of opportunistic diseases on survival in patients with HIV disease. Methods:A cohort of 2081 patients followed for a mean of 30 months was studied. Time-dependent Cox proportional hazards analyses were performed using incident opportunistic diseases and CD4 cell counts as independent variables. Results:During follow-up, 730 (35%) patients died. The occurrence of Pneumocystis carinii pneumonia (PCP), cytomegalovirus (CMV) disease, Mycobacterium avium complex (MAC) disease, Candida esophagitis, Kaposis sarcoma, lymphoma, progressive multifocal leukoencephalopathy (PML), dementia, wasting, toxoplasmosis, and cryptosporidiosis were all significantly associated with death, independently of CD4 cell count (all P < 0.001 for opportunistic diseases controlling for CD4 cell count). The magnitude of increased risk was greatest for lymphoma [relative hazard (RH), 7.2], PML (RH, 3.9), MAC (RH, 3.0) and CMV (RH, 2.2). Cryptococcosis (RH, 0.94) and herpes zoster (RH, 0.85) were not associated with death. In a multivariate Cox proportional hazards analysis, MAC [RH, 2.56; 95% confidence interval (CI), 2.1–3.1], CMV (RH, 1.63; 95% CI, 1.3–2.1), toxoplasmosis (RH, 1.85; 95% CI, 1.3–2.6), PCP (RH, 1.29; 95% CI, 1.1–1.5), and CD4 cell count were significantly associated with death. Patients who had opportunistic diseases had significantly greatly monthly declines in CD4 counts (−11 × 106/l per month) than those who did not (−6 × 106/l per month; P < 0.001). Conclusion:Most opportunistic diseases increase the risk of death independently of CD4 cell count. These data support the hypothesis that opportunistic diseases enhance HIV pathogenesis and further underscore the importance of prophylaxis.

Improved Outcomes with Earlier Initiation of Highly Active Antiretroviral Therapy Among Human Immunodeficiency Virus–Infected Patients Who Achieve Durable Virologic Suppression: Longer Follow-Up of an Observational Cohort Study

BACKGROUND Little is known about the racial differences in the incidence and progression of HIV-related chronic kidney disease (CKD) that underlie African American-white disparities in HIV-related end-stage renal disease (ESRD). METHODS In a cohort in Baltimore, Maryland, we measured CKD incidence, glomerular filtration rate (GFR) slope, and progression to ESRD in 3332 African American and 927 white HIV-infected subjects. RESULTS A total of 284 subjects developed CKD, 100 (35%) of whom subsequently developed ESRD. African American subjects were at slightly increased risk for incident CKD, compared with white subjects (hazard ratio [HR], 1.9 [95% confidence interval {CI}, 1.2-2.8]). However, once CKD had commenced, the African American subjects developed ESRD markedly faster than did the white subjects (HR, 17.7 [95% CI, 2.5-127.0]), and, correspondingly, their GFR decline after diagnosis of CKD was 6-fold more rapid (P < .001). In the subset of African American subjects for whom kidney-biopsy data were available, progression to ESRD was significantly faster than that in white subjects with CKD, irrespective of the presence of HIV-associated nephropathy. CONCLUSIONS The results of this study suggest that African American-white disparities in HIV-related ESRD are explained predominantly by a more aggressive natural disease history in African Americans and less by racial differences in CKD incidence.