Slow Acceptance of Universal Antiretroviral Therapy (ART) Among Mothers Enrolled in IMPAACT PROMISE Studies Across the Globe.

The PROMISE trial enrolled asymptomatic HIV-infected pregnant and postpartum women not eligible for antiretroviral treatment (ART) per local guidelines and randomly assigned proven antiretroviral strategies to assess relative efficacy for perinatal prevention plus maternal/infant safety and maternal health. The START study subsequently demonstrated clear benefit in initiating ART regardless of CD4 count. Active PROMISE participants were informed of results and women not receiving ART were strongly recommended to immediately initiate treatment to optimize their own health. We recorded their decision and the primary reason given for accepting or rejecting the universal ART offer after receiving the START information. One-third of participants did not initiate ART after the initial session, wanting more time to consider. Six sessions were required to attain 95% uptake. The slow uptake of universal ART highlights the need to prepare individuals and sensitize communities regarding the personal and population benefits of the "Treat All" strategy.

Performance of the Pooled Cohort atherosclerotic cardiovascular disease risk score in hepatitis C virus-infected persons.

Chronic hepatitis C virus (HCV) infection has been associated with an increased risk for cardiovascular disease (CVD). The recommended Pooled Cohort atherosclerotic cardiovascular disease (ASCVD) risk equation for estimation of 10-year CVD risk has not been validated in HCV-infected populations. We examined the performance of the ASCVD risk score in HCV-infected persons, using the national Electronically Retrieved Cohort of HCV Infected Veterans to derive a cohort of HCV-infected and uninfected subjects without baseline ASCVD, hepatitis B, or HIV infection, and with low-density lipoprotein cholesterol level<190 mg/dL. Performance of the ASCVD risk equation was assessed by Cox proportional hazard regression, C-statistics and Hosmer-Lemeshow statistic. The cohort included 70 490 HCV-infected and 97 766 HCV-uninfected men with mean age of 55 years, 56% White and 29% Black. Incident CVD event rates were similar between the two groups (13.2 and 13.4 events/1000 person-years), with a higher incidence of coronary heart disease events in the HCV-uninfected group and of stroke events in the HCV-infected group. Adjusting for ASCVD risk score, HCV infection was associated with higher risk for an ASCVD event in the subgroup with baseline ASCVD risk ≥7.5% (HR: 1.19, P<.0001). C-statistics were poor in both the HCV-infected and uninfected groups (0.60 and 0.61, respectively). By Hosmer-Lemeshow test, the ASCVD risk equation overestimated risk amongst lower risk patients and underestimated risk amongst higher risk patients in both the HCV-infected and uninfected groups. Further investigation is needed to determine whether a modified equation to accurately predict ASCVD risk in HCV-infected persons is warranted.

Prevalence of coronary artery fistulae after cardiac surgery. Comparison between coronary artery bypass grafting, valve surgery, and orthotopic heart transplantation.

INTRODUCTION: Coronary artery fistulae (CAF) are anomalous connections from a coronary artery to a recipient pulmonary vessel or cardiac chamber, and are reported in 0.2 % of the general population. The prevalence of CAF in the modern orthotopic heart transplant (OHT) population has been demonstrated to be significantly higher. The mechanism is unknown but one proposal is endothelial and vascular growth factor activation from injury. We hypothesize an incremental increase in CAF prevalence with the complexity of surgery, such that patients who have undergone OHT surgery would have an increased prevalence of CAF, as compared with patients who have undergone coronary artery bypass (CABG) surgery with valve surgery and as compared with patients who have undergone CABG surgery only. PATIENTS AND METHODS: Consecutive angiograms of 481 patients after CABG surgery and 432 patients after OHT were reviewed. Patients who had previous valve surgery in addition to CABG were identified. Presence of CAF was determined. The chi-squared test was used for statistical analysis. RESULTS: In all, 436 patients had CABG only (group A), 45 patients had CABG with valve surgery (group B), and 432 patients had OHT (group C). The mean age of patients at the time of surgery for group A, B, and C was 59.0, 66.1, and 55.3 years, respectively. The percentage of male patients was 78.4, 77.8, and 77.1 %, respectively. We found 10 patients (2.3 %) with CAF in group A compared with 4 patients (8.9 %) in group B, and 88 patients (20.4 %) in group C, which was statistically significant (p < 0.001). All CAF were small, were not associated with hemodynamic compromise or significant adverse events, and were managed conservatively. CONCLUSION: There is an increased prevalence of CAF formation both after CABG and OHT compared with the general population. The higher prevalence of CAF in patients who additionally underwent valve surgery or who underwent OHT may be attributed to differences in surgical complexity. The increased prevalence of CAF formation after OHT compared with CABG should be further investigated.

Switch to raltegravir decreases soluble CD14 in virologically suppressed overweight women: the Women, Integrase and Fat Accumulation Trial.

OBJECTIVES: Soluble CD14 (sCD14) is a monocyte activation marker associated with increased mortality in HIV infection. We assessed 48-week changes in sCD14 and other inflammatory biomarkers in virologically suppressed, HIV-infected women switching to raltegravir (RAL) from a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI). METHODS: HIV-infected women with central adiposity and HIV-1 RNA < 50 HIV-1 RNA copies/mL continued their thymidine-sparing nucleoside reverse transcriptase inhibitor (NRTI) backbone and were randomized to switch to open-label RAL at week 0 (immediate) or 24 (delayed). In an exploratory analysis, inflammatory biomarkers were measured on stored fasting plasma. RESULTS: Of the 37 evaluable subjects, 78% were non-White; the median age was 43 years, the median body mass index (BMI) was 32 kg/m(2) and the median CD4 count was 558 cells/µL. At baseline, biomarker values were similar between groups. After 24 weeks, median sCD14 significantly declined in subjects switching to RAL [-21% (P < 0.001) vs. PI/NNRTI -5% (P = 0.49); between-group P < 0.01]. After 48 weeks, immediate-switch subjects maintained this decline and delayed-switch subjects experienced a similar decline following the switch to RAL (-10%; within-group P < 0.01). Immediate-switch subjects also experienced an initial increase in tumour necrosis factor (TNF)-α that was neither maintained after 48 weeks nor seen in delayed-switch subjects. After adjustment for multiple testing, only declines in sCD14 remained significant. CONCLUSIONS: In this randomized trial of women with central adiposity, a switch to RAL from a PI or NNRTI was associated with a statistically significant decline in sCD14. Further studies are needed to determine whether integrase inhibitors have improved monocyte activation profiles compared with PIs and/or NNRTIs, and whether measured differences between antiretroviral agents translate to demonstrable clinical benefit.

Performance of serum-supplemented and serum-free media in IFNgamma Elispot Assays for human T cells.

The choice of serum for supplementation of media for T cell assays and in particular, Elispot has been a major challenge for assay performance, standardization, optimization, and reproducibility. The Assay Working Group of the Cancer Vaccine Consortium (CVC-CRI) has recently identified the choice of serum to be the leading cause for variability and suboptimal performance in large international Elispot proficiency panels. Therefore, a serum task force was initiated to compare the performance of commercially available serum-free media to laboratories' own medium/serum combinations. The objective of this project was to investigate whether a serum-free medium exists that performs as well as lab-own serum/media combinations with regard to antigen-specific responses and background reactivity in Elispot. In this way, a straightforward solution could be provided to address the serum challenge. Eleven laboratories tested peripheral blood mononuclear cells (PBMC) from four donors for their reactivity against two peptide pools, following their own Standard Operating Procedure (SOP). Each laboratory performed five simultaneous experiments with the same SOP, the only difference between the experiments was the medium used. The five media were lab-own serum-supplemented medium, AIM-V, CTL, Optmizer, and X-Vivo. The serum task force results demonstrate compellingly that serum-free media perform as well as qualified medium/serum combinations, independent of the applied SOP. Recovery and viability of cells are largely unaffected by serum-free conditions even after overnight resting. Furthermore, one serum-free medium was identified that appears to enhance antigen-specific IFNgamma-secretion.

High-throughput genotyping of KIR2DL2/L3, KIR3DL1/S1, and their HLA class I ligands using real-time PCR.

Killer immunoglobulin-like receptors (KIRs) expressed on natural killer cells are critical components of innate immunity. Interactions between KIRs and their human leukocyte antigen (HLA) ligands have been shown to influence autoimmune and infectious disease course in defined populations. However, the low throughput and high cost of current methods impede confirmation of the universality of these findings. To support large epidemiology surveys, we developed a high-throughput real-time polymerase chain reaction-based assay to identify carriers of KIR3DL1, KIR3DS1, KIR2DL2, and KIR2DL3 and their HLA ligands. The platform performed with 100% sensitivity and specificity in detection of carrier and non-carrier on reference samples. The application of this platform will further clarify the nature and impact of the KIR-HLA epistatic interaction on disease course in large global population-based studies.

HLA class I allele and haplotype diversity in Ugandans supports the presence of a major east African genetic cluster.

The objective of this study was to characterize the class I human leukocyte antigen (HLA) genetic composition of the Ugandan population to better define its relationship with other African groups. Samples from 175 individuals from Kampala (Uganda) were subjected to class I HLA-A, -B, and -C sequence-based typing. The high concordance between the major alleles and haplotypes found in the current and Kenyan populations and interpopulation genetic distance analysis strongly supported the presence of an East African cluster that contained the current Ugandan population along with Kenyan Luo and Nandi populations. The congruence of major alleles in different populations would permit consideration of East Africa as an integrated setting when designing and evaluating much needed malaria, tuberculosis, and AIDS vaccines.

Evaluation of aldrithiol-2-inactivated preparations of HIV type 1 subtypes A, B, and D as reagents to monitor T cell responses.

The development of HIV vaccines is an urgent priority and there is need to generate reagents representing multiple subtypes that can be used to screen HIV-1-specific responses. We used Aldrithiol-2 (AT-2), a mild oxidizing reagent, to eliminate the infectivity of HIV while maintaining its structure and ability to be processed for presentation to T cells. Inactivated subtype A, B, and D viruses were evaluated for their ability to stimulate T cell responses in PBMC samples from 18 U.S. subjects infected with HIV-1 subtype B and 32 Ugandan subjects infected with subtypes A and D or recombinants AC and AD. Five HIV-1-negative samples were also analyzed. T cell responses to AT-2-inactivated viral isolates were monitored by interferon-gamma (IFN-gamma) intracellular cytokine secretion (ICS) analysis; matched microvesicle preparations served as negative controls. Among the 18 subtype B infected subjects, 39% had CD3(+) CD4 (+) IFN-gamma responses and 67% had CD3(+) CD8(+) IFN-gamma responses. Of the 32 Ugandan subjects, 34% demonstrated CD3(+) CD4(+) IFN-gamma responses and 78% demonstrated CD3(+) CD8(+) IFN-gamma responses. Both subtype-specific and cross-reactive responses were observed. Responses to the AT-2 viruses tended to be lower in magnitude than those detected by a set of overlapping gag peptides. Robust lymphoproliferative responses to AT-2 viruses were seen in a subset of subjects. In conclusion, AT-2-inactivated HIV-1 virions stimulated both CD4 and CD8 HIV-1-specific responses and may provide an additional reagent for screening HIV-1-specific responses in HIV seropositives and vaccinees.

Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy.

Changes in fat distribution, dyslipidemia, disordered glucose metabolism, and lactic acidosis have emerged as significant challenges to the treatment of human immunodeficiency virus (HIV) infection. Over the past decade, numerous investigations have been conducted to better define these conditions, identify risk factors associated with their development, and test potential therapeutic interventions. The lack of standardized diagnostic criteria, as well as disparate study populations and research methods, have led to conflicting data regarding the diagnosis and treatment of metabolic and body shape disorders associated with HIV infection. On the basis of a review of the medical literature published and/or data presented before April 2006, we have prepared a guide to assist the clinician in the detection and management of these complications.

Effects of chronic heparin administration on coronary vascular adaptation to hypertension and ventricular hypertrophy in sheep.

BACKGROUND: Hypertension decreases myocardial perfusion capacity in adults for several reasons, including insufficient coronary angiogenesis with left ventricular (LV) hypertrophy, arteriolar hypertrophy, and altered vasomotion. Heparin influences growth factors that promote angiogenesis and vasodilation and inhibit arteriolar wall thickening. METHODS AND RESULTS: Adult sheep were given heparin 200 U/kg body wt SC twice daily throughout 6 weeks of LV and coronary hypertension from a progressively constricted ascending aortic band (n=14). They were compared with untreated sheep with (n=13) and without (n=13) aortic stenosis. After 6 weeks, maximum myocardial perfusion was measured during adenosine infusion in the conscious state by the microsphere method. Sheep with aortic stenosis had less maximum coronary flow per gram, less conductance reserve, and thicker arteriolar walls in the LV and nonhypertrophied right ventricle. Capillary density decreased in the LV endomyocardium and remained unchanged in the right ventricle. Heparin-treated sheep had significant partial normalization of coronary conductance reserve and maximum perfusion in both ventricles and capillary density in the LV endomyocardium. Arteriolar wall thickness was unchanged. Compared with untreated sheep with aortic stenosis, in heparin-treated sheep LV FGF-2 protein increased 2-fold, whereas FGF-2 mRNA remained unchanged. VEGF mRNA and protein increased 3-fold and 1.4-fold, respectively, whereas TGF-beta(1) mRNA declined 3-fold. CONCLUSIONS: Heparin administration during LV hypertension increases heparin-binding angiogenic factors FGF-2 and VEGF in the LV and ameliorates decreases in LV perfusion capacity and capillary density.

Restenosis after percutaneous transluminal coronary angioplasty: have we been aiming at the wrong target?

Restenosis after percutaneous coronary balloon angioplasty remains a significant problem. Despite success with a variety of agents in animal models, no agent has proved clearly successful in reducing restenosis in humans. There are many potential reasons for this, but one possibility is that because of our incomplete understanding of the restenotic process, therapy has been directed at the wrong target. Arterial remodeling (changes in total vessel area or changes in area circumscribed by the internal elastic lamina) is well described in de novo atherosclerosis, and there is increasing evidence that this process occurs after angioplasty. Thus, restenosis can be thought of not merely as neointimal formation in response to balloon injury, but as arterial remodeling in response to balloon injury and neointimal formation. Arterial remodeling may consist of actual constriction of the artery, as has been described in some animal models and in preliminary fashion in humans, or of compensatory enlargement as has been described in de novo atherosclerosis and in the hypercholesterolemic rabbit iliac artery model. Arterial constriction can result in restenosis with minimal neointimal formation. Compensatory enlargement accommodates significant amounts of neointimal formation, with preservation of lumen area despite an increase in neointimal area adequate to cause restenosis in a noncompensated artery. This expanded paradigm of arterial remodeling and intimal formation may in part account for the lack of success in clinical trials to date, and therapy directed at arterial remodeling as well as intimal formation may be required to reduce restenosis after coronary interventions.

Low molecular weight heparin (enoxaparin) reduces restenosis after iliac angioplasty in the hypercholesterolemic rabbit.

Smooth muscle cell proliferation is central to the process of restenosis. Attempts to inhibit the events leading to this proliferation have met with little success. In addition to its known antithrombotic effects, heparin also has inhibitory effects on smooth muscle cell proliferation. These effects appear to be unrelated to its anticoagulant properties and are retained in low molecular weight heparin derivatives. Although the use of heparin for as long as 18 to 24 h after coronary angioplasty in humans has not prevented restenosis, longer treatment periods have not been assessed. This study examines the effect of treatment with a low molecular weight heparin (enoxaparin) in a hypercholesterolemic rabbit iliac artery model. Control rabbits had a mean iliac artery diameter of 0.70 +/- 0.06 mm, which increased to 1.73 +/- 0.09 mm after balloon angioplasty. At follow-up angiography 4 weeks later, the mean vessel diameter was 0.56 +/- 0.12 mm. Animals treated with low dose enoxaparin (1 mg/kg per day) for 4 weeks and high dose enoxaparin (10 mg/kg per day) for either 2 or 4 weeks had similar mean luminal diameters before and immediately after angioplasty. At follow-up angiography, the mean luminal diameter was 0.82 +/- 0.17 mm for low dose enoxaparin, 1.04 +/- 0.20 mm for 2 week high dose enoxaparin (p = 0.03 versus control) and 1.19 +/- 0.09 mm for 4 week high dose enoxaparin (p = 0.001 versus control). When defined as loss of 50% of the initial gain achieved with angioplasty, restenosis was found in all control vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of young age on coronary adaptations to left ventricular pressure overload hypertrophy in sheep.

OBJECTIVES: This study attempted to determine the effect of young age on changes in coronary conductance and capillary density with left ventricular pressure overload hypertrophy. Mechanisms responsible for age differences in perfusion capacity were examined. BACKGROUND: Hypertension in adults causes alterations in the coronary vasculature, resulting in diminished coronary perfusion capacity and myocardial ischemia. These processes are worsened in adults by advanced age. Young age may provide advantages in coronary adaptation to hypertension. METHODS: Coronary conductance was examined in conscious chronically instrumented 10-week old lambs and adult sheep with progressive ascending aortic stenosis of 6-week's duration and age-matched control sheep by means of the microsphere technique and vasodilators. Capillary density was measured post-mortem. RESULTS: Adult sheep with aortic stenosis had a decrease in left ventricular subendomyocardial capillary density by 17% and maximal coronary conductance with adenosine by 67%. In the nonhypertrophied right ventricle, maximal coronary conductance was depressed by 47%, whereas capillary density was normal, implying an effect of coronary hypertension on resistance vessels. In contrast, lambs with aortic stenosis maintained normal left ventricular capillary density, maximal coronary conductance and coronary reserve and had relatively little impairment of conductance in the right ventricular coronary bed (-15%, p = NS). Similar responses were found with other vasodilators, isoproterenol and chromonar. CONCLUSIONS: Young age confers advantages to coronary adaptation to left ventricular pressure overload, including angiogenesis proportionate to hypertrophy, resulting in normal capillary density and coronary conductance. There is also less hypertension-induced impairment of coronary conductance distinct from the effects of hypertrophy.

Microwave balloon angioplasty effectively seals arterial dissections in an atherosclerotic rabbit model.

OBJECTIVES: The purpose of this study was to determine the effectiveness of microwave balloon angioplasty in sealing arterial dissections and to characterize the histologic features associated with this intervention. BACKGROUND: Coronary dissection accompanying balloon dilation is frequently associated with abrupt closure and acute ischemic complications. Effective management of this complication remains an active area of investigation. Because thermal energy is effective in welding separated atherosclerotic plaques, a microwave-based catheter system that provides controlled local heating was utilized in vessels with angioplasty-induced dissections. METHODS: Iliac artery dissections were induced in ahypercholesterolemic rabbit model. Vessels were randomly assigned to treatment with standard balloon angioplasty (control vessels) or microwave balloon angioplasty using an average temperature of 80 degrees C. The response of the artery was assessed angiographically and histologically. RESULTS: Angiographic success, defined as a reduction of dissection length by > 50% or the resolution of lumen haziness, was achieved in 63% of microwave-treated vessels and in 16% of control vessels (p < 0.005). Dissection length (mean +/- SD) was reduced 8.0 +/- 4.8 mm in microwave-treated vessels compared with 0.1 +/- 7.9 mm in vessels receiving standard balloon inflations (p < 0.005). Cellular necrosis was more commonly observed in microwave-treated vessels than in control vessels (73% vs. 17%, p < 0.05), but less intraluminal thrombus was seen in vessels exposed to microwave energy (p < 0.05). CONCLUSIONS: Microwave balloon angioplasty is more effective than routine balloon inflations in sealing arterial dissections in this model and appears to be less thrombogenic in these markedly disrupted vessels.

Optimizing stent expansion with new stent delivery systems.

OBJECTIVES: The purpose of this study was to assess whether the newer stent delivery systems provide a stented lumen cross-sectional area (CSA) that is equal to the delivery balloon nominal dimensions. BACKGROUND: First generation stents were often not adequately expanded with their delivery system and frequently required higher pressure or a larger balloon after deployment. Newer stents were designed to optimize expansion with noncompliant, high-pressure balloons provided as the delivery systems. METHODS: Intravascular ultrasound (IVUS) was used to evaluate 38 stents in 32 patients after deployment at 14 to 16 atm with their delivery balloon system. Minimum stent lumen CSA and stent minimum lumen diameter (MLD) were measured by IVUS imaging. The manufacturer's expected stent diameter was defined as the balloon diameter measured by the company at the maximum pressure used. The manufacturer's expected stent area was calculated based on the manufacturer's expected stent diameter. RESULTS: The MLD (2.5 +/- 0.5 mm) and minimum stent CSA (6.0 +/- 1.7 mm(2)) by IVUS were significantly smaller than the manufacturer's expected stent diameter (3.5 +/- 0.4 mm) and area (9.5 +/- 1.9 mm(2)) (p < 0.0001, respectively). The mean MLD by IVUS was 72 +/- 8% of the expected stent diameter, and the mean minimum stent CSA by IVUS was 62 +/- 10% of the expected stent area. CONCLUSIONS: Despite moderately high-pressure inflations, the mean minimum stent CSA actually achieved was, on average, only 62% of the manufacturer's expected stent area. To optimize stent deployment, these IVUS observations should be considered during coronary artery stenting.

The safety of discontinuation of maintenance therapy for cytomegalovirus (CMV) retinitis and incidence of immune recovery uveitis following potent antiretroviral therapy.

BACKGROUND: Reconstitution of immune function during potent antiretroviral therapy can prompt discontinuation of maintenance cytomegalovirus (CMV) therapy but has also been associated with sight-threatening inflammatory conditions including immune recovery uveitis (IRU). METHOD: Patients with inactive CMV retinitis and a CD4+ cell count above 100/mm3, receiving CMV therapy and stable combination antiretroviral therapy, were assigned to one of two groups based on willingness to discontinue CMV therapy. RESULTS: Thirty-eight participants were enrolled: 28 discontinued anti-CMV therapy (Group 1) and 10 continued CMV treatment (Group 2). Median on-study follow-up was 16 months. One Group 1 participant who experienced an increase in plasma HIV viral load and a decline in CD4+ cell count developed confirmed progression of CMV retinitis. Progression or reactivation CMV retinitis was not observed among Group 2. IRU was present at study entry in 3 participants. Six participants in Group 1 and 3 participants in Group 2 developed IRU on-study. CMV viremia was not detected in any participants, and urinary shedding of CMV was intermittent. CONCLUSION: Recurrence of CMV retinitis following discontinuation of anti-CMV therapy among patients with antiretroviral-induced increases in CD4+ cell count was rare. However, IRU was common in both those who maintained and discontinued anti-CMV therapy.

Monoclonal antibodies that bind to the My23 human myeloid cell surface molecule: epitope analysis and antigen modulation studies.

It has previously been shown that the AML-2-23 monoclonal antibody (MoAb) reacts with a glycoprotein on differentiated myeloid cells. The antigen, My23, is released from these cells in culture and is also detectable in normal human plasma. We have now raised a panel of MoAbs against the soluble form of the antigen which reacts with monocytes and calcitriol-treated U937 and HL-60 myeloid cell lines, but not with lymphocytes or undifferentiated U937 and HL-60 cells. As with the AML-2-23 MoAb, the anti-My23 MoAbs immunoprecipitated a 50,000-55,000 protein from calcitriol treated HL-60 cells. Besides binding to cell surface My23, all eight MoAbs as well as the 63D3 MoAb reacted with crude and purified forms of soluble My23. A novel ELISA epitope analysis assay was developed to identify four distinct antigenic determinants on My23. Thus, the soluble and cell surface forms of My23 share several antigenic determinants and are biochemically very similar. Pooled anti-My23 caused selective patching, capping and clearing of My23 from the cell surface. My23 was not associated with cell surface, HLA-DR, HLA-A,B,C, beta 2-microglobulin or the Fc receptors for IgG or IgA. These anti-My23 MoAbs should be of importance in antigen functional studies and in clinical treatment protocols for patients with acute myelogenous leukemia. Furthermore, we have shown that a soluble myeloid differentiation antigen can serve as an effective immunogen for the preparation of MoAbs against important cell surface molecules thus obviating many problems inherent in the use of whole cells or detergent lysate-derived immunoprecipitates as immunogens.

Joint effects of HIV-1 RNA levels and CD4 lymphocyte cells on the risk of specific opportunistic infections.

OBJECTIVES: To evaluate the predictive value of baseline plasma HIV-1 RNA levels and CD4 lymphocyte counts and early changes in these markers after initiating antiretroviral therapy on the risk of development of specific opportunistic infections (OIs). DESIGN: Patient data from four antiretroviral therapy studies were combined for a retrospective analysis. The analysis included 842 participants from the virology substudies of these trials who had baseline measurements for both HIV-1 RNA levels and CD4 cell counts. METHODS: Cox proportional hazards models were used to assess the joint effects of baseline CD4 cell count and HIV-1 RNA level and early treatment-associated changes in these values on the risk of development of Pneumocystis carinii pneumonia (PCP), cytomegalovirus (CMV), or Mycobacterium avium complex (MAC). The effects of potential confounders such as prior prophylaxis and previous OIs were also addressed. RESULTS: Baseline CD4 cell counts and HIV-1 RNA measurements showed significant associations with the risk of PCP, CMV, and MAC. Patients with higher levels of HIV-1 RNA were estimated to have three to six times the risk of these OIs than those with lower levels. Reductions in viral load were linked to significantly reduced risks of PCP, CMV, and MAC. Early decreases in RNA were generally more predictive of risk than were early increases in CD4 cell counts. CONCLUSIONS: Baseline viral load and reductions in viral load during therapy appeared to influence the risk of these OIs independently of the CD4 cell count. Future guidelines for the initiation of prophylaxis for these OIs may be improved by incorporating information on viral load.