Stephen Raffanti

Race and Sex Differences in Antiretroviral Therapy Use and Mortality among HIV-Infected Persons in Care

BACKGROUND There are conflicting data regarding race, sex, and mortality among persons infected with human immunodeficiency virus (HIV). We studied all-cause mortality among persons in care during the highly-active antiretroviral therapy (HAART) era. METHODS This retrospective cohort study included patients who made>or=1 clinic visit from January 1998 through December 2005. RESULTS Of 2605 patients (with 6657 person-years of follow-up), 38% were black and 24% were female. The percentage of time in care while receiving HAART was lower for blacks than for nonblacks (47% vs. 76%; P<.001) and for females than for males (57% vs. 71%; P=.01). There were 253 deaths (38 per 1000 person-years). After adjustment for characteristics at baseline, death was associated with black race (hazard ratio [HR], 1.33; P .04), female sex (HR, 1.53; P .007), injection drug use (IDU) as a risk factor for HIV infection (HR, 1.61; P .009), older age (HR, 1.45 per 10 years; P<.001), a lower CD4 cell count (HR, 0.59 for 200 vs. 350 cells/mm3; P<.001) and a higher HIV type 1 RNA level (HR, 1.35; P<.001). After adjustment for the length of time that HAART was received, black race (HR, 1.00; P .99) and IDU (HR, 1.37; P .09) were no longer associated with death, but female sex was (HR, 1.62; P=.002). CONCLUSIONS Race-associated differences in mortality likely resulted from HAART use. Women had an increased risk of death even after adjustment for HAART use. Addressing racial disparities will require improved HAART utilization. Increased mortality among women requires further study.

Drug Transporter and Metabolizing Enzyme Gene Variants and Nonnucleoside Reverse-Transcriptase Inhibitor Hepatotoxicity

This nested case-control study examined relationships between MDR1, CYP2B6, and CYP3A4 variants and hepatotoxicity during antiretroviral therapy with either efavirenz- or nevirapine-containing regimens. Decreased risk of hepatotoxicity was associated with MDR1 3435C-->T (odds ratio, 0.254; P=.021). An interaction between MDR1 and hepatitis B surface antigen status predicted risk with 82% accuracy (P<.001).

Oxidant Stress Is Increased during Treatment of Human Immunodeficiency Virus Infection

Some diseases and environmental exposures, including those that are risk factors for atherosclerosis, are associated with increased oxidant stress. The objective of this cross-sectional, observational study was to determine whether oxidant stress is increased during human immunodeficiency virus type 1 (HIV-1) infection or its therapy. To quantify oxidant stress, plasma F2 isoprostane (F2-IsoP) concentrations were determined by gas chromatography/mass spectroscopy. A total of 120 subjects were enrolled during routine primary care visits. The median CD4+ T cell count was 341 cells/mm3, the median HIV-1 RNA level was 3.4 log10 copies/mL, and 74% of patients were receiving antiretroviral therapy. Plasma F2-IsoP concentrations were 12-149 pg/mL (median, 31 pg/mL). In univariate analysis, higher F2-IsoP concentrations were associated with lower log10 plasma HIV-1 RNA levels (P=.009) and with efavirenz use (P=.02). Both factors remained associated with plasma F2-IsoP concentrations in multivariate analysis. Oxidant stress associated with therapeutic control of viral replication may have important implications for long-term complications of antiretroviral therapy.

Pregnancy and HIV Disease Progression during the Era of Highly Active Antiretroviral Therapy

BACKGROUND Before the availability of highly active antiretroviral therapy (HAART), there was no clear effect of pregnancy on human immunodeficiency virus (HIV) disease progression. This has not been assessed during the HAART era. METHODS We conducted an observational cohort study among HIV-infected women with >or=1 outpatient clinic visit between January 1997 and December 2004. HIV disease progression was defined as the occurrence of an AIDS-defining event or death. RESULTS Of 759 women who met the inclusion criteria, 139 (18%) had had >1 pregnancy, and 540 (71%) had received HAART. There was no difference in HAART duration by pregnancy status. Eleven pregnant (8%) and 149 nonpregnant (24%) women progressed to AIDS or death. After controlling for age, baseline CD4(+) lymphocyte count, baseline HIV-1 RNA level, and durable virologic suppression in a Cox proportional hazards model that included propensity score for pregnancy, pregnancy was associated with a decreased risk of disease progression (hazard ratio [HR], 0.40 [95% confidence interval {CI}, 0.20-0.79]; P=.009]). In a matched-pair analysis of 81 pregnant women matched to 81 nonpregnant women according to age, baseline CD4(+) lymphocyte count, receipt of HAART, and date of cohort entry, pregnant women had a lower risk of disease progression both before (HR, 0.10 [95% CI, 0.01-0.89]; P=.04) and after (HR, 0.44 [95% CI, 0.19-1.00]; P=.05) the pregnancy event. CONCLUSION Pregnancy was associated with a lower risk of HIV disease progression in this HAART-era study. This finding could be the result of the healthier immune status of women who become pregnant or could possibly be related to a beneficial interaction between pregnancy and HAART.

Effect of Persistent Moderate Viremia on Disease Progression During HIV Therapy

ObjectiveAlthough highly active antiretroviral therapy has been shown to lower plasma HIV-1 RNA in HIV infection, many patients do not reach the target goal of undetectable viremia. We evaluated whether risk of clinical progression varies by level of viral suppression achieved. DesignPatients in the Collaborations in HIV Outcomes Research/United States cohort who maintained stable HIV-1 RNA levels of either <400, 400 to 20,000, or >20,000 copies/mL during a run-in period of at least 6 months were studied. Baseline was the first day after this period. MethodsProportional hazards models were used to quantify the relation between baseline HIV-1 RNA levels and risk of a new AIDS-defining diagnosis or death after adjusting for CD4 count, age, gender, ethnicity, study site, prior AIDS-defining diagnosis, and antiretroviral therapy history. ResultsPatients (N = 3010) were followed for up to 4.3 years after the 6-month run-in period, with 343 deaths or AIDS-defining diagnoses reported. The risk of a new AIDS-defining diagnosis or death was not significantly different in the 400 to 20,000– and <400-copies/mL groups (6% vs. 7%, hazard ratio [HR] = 1.0, 95% confidence interval [CI]: 0.7–1.4; P = 0.9) but was significantly higher in the >20,000-copies/mL group (26%, HR = 3.3, 95% CI: 2.5–4.4; P < 0.001 vs. the <400-copies/mL group). Median CD4 count changes during the first year of follow-up showed increases of 75 and 13 cells/mm3 for the <400- and 400 to 20,000–copies/mL groups, respectively, whereas the >20,000-copies/mL group had a decrease of 23 cells/mm3. ConclusionsPatients who maintained baseline HIV-1 RNA levels of 400 to 20,000 copies/mL for at least 6 months preserved immunologic status and were no more likely to die or develop a new AIDS-defining diagnosis in the time frame studied than those with baseline levels <400 copies/mL. Patients with HIV-1 RNA levels >20,000 copies/mL at baseline had greater clinical and immunologic deterioration. These data suggest that maintenance of moderate viremia may confer clinical benefit not seen when viremia exceeds 20,000 copies/mL, and this should be taken into account when considering the risks and benefits of continuing failing therapy.

Absolute Count and Percentage of CD4+ Lymphocytes Are Independent Predictors of Disease Progression in HIV-Infected Persons Initiating Highly Active Antiretroviral Therapy

BACKGROUND Highly active antiretroviral therapy (HAART) is recommended when the absolute CD4(+) T lymphocyte count is <200 cells/mm(3), and it should be considered when that count is > or =200, although the optimal timing when it is > or =200 is unclear. Because preliminary data had suggested that a low CD4(+) T lymphocyte percentage (%CD4) is associated with disease progression in persons initiating HAART who have a higher absolute CD4, we sought to further characterize the predictive utility of %CD4. METHODS We conducted an observational study of persons in Collaborations in HIV Outcomes Research/US cohort who initiated their first HAART regimen between 1997 and 2004, received > or =30 days of therapy, and had baseline values of absolute CD4, %CD4, and HIV-1 RNA. Cox proportional-hazards models determined associations between %CD4 and disease progression (to either a new AIDS-defining event [ADE] or death). RESULTS Of 1891 persons, 11% were female and 18% were African American; the median age was 38 years. Median follow-up was 55 months (interquartile range, 23-83 months), and 468 (25%) had disease progression. Multivariable analysis including age, race, sex, HIV-1 RNA, prior antiretroviral therapy, probable route of infection, prior ADE, absolute CD4, and %CD4 was performed; prior ART (P<.0001), injection-drug use (P=.04), lower absolute CD4 (P=.002), and lower %CD4 (P=.002) predicted disease progression. CONCLUSIONS %CD4 at initiation of the first HAART regimen predicted disease progression independent of absolute CD4; %CD4 may be used to determine the timing of HAART.

CD4 Lymphocyte Percentage Predicts Disease Progression in HIV-Infected Patients Initiating Highly Active Antiretroviral Therapy with CD4 Lymphocyte Counts >350 Lymphocytes/mm3

BACKGROUND The optimal timing of highly active antiretroviral therapy (HAART) in human immunodeficiency virus (HIV)-infected patients with > or = 200 absolute CD4 lymphocytes/mm3 is unknown. CD4 lymphocyte percentage could add prognostic information. METHODS Persons who initiated HAART between 1 January 1998 and 1 January 2003, received > or = 30 days of therapy, and had baseline CD4 lymphocyte data available were included in the study. The log-rank test for time to event and Cox proportional hazards models were used to determine predictors of a new acquired immunodeficiency syndrome-defining illness or death. RESULTS A total of 788 patients met the inclusion criteria. At baseline, subjects had a median of 225 CD4 lymphocytes/mm3 and 17% CD4 lymphocytes. Subjects with < 17% CD4 lymphocytes had earlier disease progression, compared with subjects with > or = 17%, both in the entire cohort (P<.0001) and of those subjects with > 350 absolute CD4 lymphocytes/mm3 at baseline (P=.03). CD4 lymphocyte percentage < 17% was the strongest predictor of disease progression among subjects in this latter group (hazard ratio, 3.57; P=.045). CONCLUSIONS In this cohort, CD4 lymphocyte percentage predicted disease progression in HIV-infected subjects who initiated therapy with > 350 CD4 lymphocytes/mm3. This information may help identify persons who will derive the greatest benefit from initiation of HAART.

Evidence of a Source of HIV Type 1 within the Central Nervous System by Ultraintensive Sampling of Cerebrospinal Fluid and Plasma

Defining the source of HIV-1 RNA in cerebrospinal fluid (CSF) will facilitate studies of treatment efficacy in the brain. Four antiretroviral drug-naive adults underwent two 48-hr ultraintensive CSF sampling procedures, once at baseline and again beginning on day 4 after initiating three-drug therapy with stavudine, lamivudine, and nelfinavir. At baseline, constant CSF HIV-1 RNA concentrations were maintained by daily entry of at least 10(4) to 10(6) HIV-1 RNA copies into CSF. Change from baseline to day 5 ranged from -0.38 to -1.18 log(10) HIV-1 RNA copies/ml in CSF, and from -0.80 to -1.33 log(10) HIV-1 RNA copies/ml in plasma, with no correlation between CSF and plasma changes. There was no evidence of genotypic or phenotypic viral resistance in either CSF or plasma. With regard to pharmacokinetics, mean CSF-to-plasma area-under-the-curve (AUC) ratios were 38.9% for stavudine and 15.3% for lamivudine. Nelfinavir and its active M8 metabolite could not be accurately quantified in CSF, although plasma M8 peak level and AUC(0-8hr) correlated with CSF HIV-1 RNA decline. This study supports the utility of ultraintensive CSF sampling for studying HIV-1 pathogenesis and therapy in the CNS, and provides strong evidence that HIV-1 RNA in CSF arises, at least in part, from a source other than plasma.

Steady-state pharmacokinetics of indinavir in cerebrospinal fluid and plasma among adults with human immunodeficiency virus type 1 infection

To characterize steady‐state indinavir pharmacokinetics in cerebrospinal fluid and plasma, 8 adults infected with human immunodeficiency virus underwent intensive cerebrospinal fluid sampling while receiving indinavir (800 mg every 8 hours) plus nucleoside reverse transcriptase inhibitors. Nine and 11 serial cerebrospinal fluid and plasma samples, respectively, were obtained from each subject. Free indinavir accounted for 94.3% of the drug in cerebrospinal fluid and 41.7% in plasma. Mean values of cerebrospinal fluid peak concentration, concentration at 8 hours, and area under the concentration‐time profile calculated over the interval 0 to 8 hours [AUC(0‐8)] for free indinavir were 294 nmol/L, 122 nmol/L, and 1616 nmol/L · h, respectively. The cerebrospinal fluid‐to‐plasma AUC(0‐8) ratio for free indinavir was 14.7% ± 2.6% and did not correlate with indexes of blood‐brain barrier integrity or intrathecal immune activation. Indinavir achieves levels in cerebrospinal fluid that should contribute to control of human immunodeficiency virus type 1 replication in this compartment. The cerebrospinal fluid‐to‐plasma AUC(0‐8) ratio suggests clearance mechanisms in addition to passive diffusion across the blood‐cerebrospinal fluid barrier, perhaps by P‐glycoprotein–mediated efflux. (Clin Pharmacol Ther 2000;68:367‐74.)

Factors That Predict Incomplete Virological Response to Protease Inhibitor—Based Antiretroviral Therapy

Many patients infected with human immunodeficiency virus type 1 (HIV-1) have suboptimal responses to protease inhibitor-based therapy. We retrospectively evaluated a cohort of 104 HIV-positive adults, most of whom had previously received antiretrovirals, to identify the frequency and clinical predictors of incomplete response to potent HIV-1 protease inhibitors. Sixty-two (60%) of the patients had an incomplete response, defined as a plasma HIV-1 RNA level of >400 copies/mL after 20 weeks of therapy. Logistic regression analysis identified the following independent risk factors for incomplete response: elevated baseline plasma HIV-1 RNA level (P = .03), low baseline weight (P = .01), chemoprophylaxis for Pneumocystis carinii pneumonia (P = .04), and active illicit drug use (P = .04). Regular prescription of narcotics or benzodiazepine anxiolytics (P = .01) and use of any Internet site (P = .01) predicted a more favorable response. Identifying factors that predict suboptimal response to protease inhibitors improves our understanding of interpatient variability in response to therapy and should foster strategies that enhance the effectiveness of current and future regimens.