Decrease In CD4 Cell Count Research Articles

Switch From Enfuvirtide to Raltegravir in Patients With Undetectable Viral Load: Efficacy and Safety at 24 Weeks in a Montreal Cohort

Switch From Enfuvirtide to Raltegravir in Patients With Undetectable Viral Load: Efficacy and Safety at 24 Weeks in a Montreal Cohort

Assessing the immune state of dogs suffering from pituitary gland dependent hyperadrenocorticism by determining changes in peripheral lymphocyte subsets

In order to evaluate the immune state of dogs suffering from pituitary-dependent hyperadrenocorticism (PDH), peripheral lymphocyte subsets were examined. Twenty seven PDH dogs and eight healthy control dogs were used in the current study. Eight healthy dogs served as the control group. Twenty seven PDH dogs were categorized into 4 groups based on their post serum cortisol concentrations by ACTH stimulation test: 2-5, excellent control (n = 8); 5-20, fair control (n = 7); >20, poor control (n = 4); and untreated (n = 8). Cell counts were executed with white blood cells (WBC), lymphocytes, CD3(+) (T lymphocytes), CD4(+) (Helper T lymphocytes), CD8(+) (Cytotoxic T lymphocytes), CD21(+) (B lymphocytes) cells in addition to calculating CD4(+)/CD8(+) ratio. Results indicated a significant difference in lymphocyte numbers and lymphocyte subset populations (CD3(+), CD4(+), CD8(+), and CD21(+) cells) between PDH and control dogs. Moreover, comparison of the PDH groups (excellent control; fair control; poor control; untreated) demonstrated that all groups had a significant decrease in lymphocytes numbers (CD3(+), CD4(+) and CD21(+) cell counts) as compared to control group. Meanwhile, no significant differences were observed in WBC counts and CD4(+)/CD8(+) ratio between groups. Furthermore, lymphocyte subset distribution in excellent control PDH dogs without concurrent disease (n = 4) better resembled that of control dogs as compared to PDH dogs with concurrent disease (n = 4). PDH dogs may be suffering from an immuno-depressed state as evidenced by significant differences in lymphocyte subset populations. Furthermore, treatment of both PDH and concurrent disease might improve lymphocyte subset distribution.

Is HIV becoming more virulent? Initial CD4 cell counts among HIV seroconverters during the course of the HIV epidemic: 1985-2007.

Whether human immunodeficiency virus (HIV) seroconverters have been presenting with progressively lower CD4 cell counts over the course of the HIV epidemic is controversial. Additional data on whether HIV might have become more virulent on a population level (measured by post-seroconversion CD4 cell counts) may provide important insights regarding HIV pathogenesis. To determine whether post-seroconversion CD4 cell counts have changed over time, we evaluated 2174 HIV seroconverters as part of a large cohort study during the period 1985-2007. Participants were documented antiretroviral-naive HIV seroconverters who had a CD4 cell count measured within 6 months after receiving a diagnosis of HIV infection. Multiple linear regression models were used to assess trends in initial CD4 cell counts. The mean initial CD4 cell count decreased during the study period from 632 cells/mm(3) in 1985-1990 to 553 cells/mm(3) in 1991-1995, 493 cells/mm(3) in 1996-2001, and 514 cells/mm(3) in 2002-2007. During those periods, the percentages of seroconverters with an initial CD4 cell count <350 cells/mm(3) were 12%, 21%, 26%, and 25%, respectively. In the multiple linear model, the mean decrease in CD4 cell count from 1985-1990 was 65 cells/mm(3) in 1991-1995 (P < .001)), 107 cells/mm(3) in 1996-2001 (P < .001), and 102 cells/mm(3) in 2002-2007 (P < .001). Similar trends occurred with regard to CD4 cell percentage and total lymphocyte count. Similar decreases in initial CD4 cell counts were observed among African American and white persons during the epidemic. A significant decrease in initial CD4 cell counts among HIV seroconverters in the United States has occurred during the HIV epidemic. These data provide an important clinical correlate to suggestions that HIV may have adapted to the host, resulting in a more virulent infection.

Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies

SummaryBackgroundThe CD4 cell count at which combination antiretroviral therapy should be started is a central, unresolved issue in the care of HIV-1-infected patients. In the absence of randomised trials, we examined this question in prospective cohort studies.MethodsWe analysed data from 18 cohort studies of patients with HIV. Antiretroviral-naive patients from 15 of these studies were eligible for inclusion if they had started combination antiretroviral therapy (while AIDS-free, with a CD4 cell count less than 550 cells per μL, and with no history of injecting drug use) on or after Jan 1, 1998. We used data from patients followed up in seven of the cohorts in the era before the introduction of combination therapy (1989–95) to estimate distributions of lead times (from the first CD4 cell count measurement in an upper range to the upper threshold of a lower range) and unseen AIDS and death events (occurring before the upper threshold of a lower CD4 cell count range is reached) in the absence of treatment. These estimations were used to impute completed datasets in which lead times and unseen AIDS and death events were added to data for treated patients in deferred therapy groups. We compared the effect of deferred initiation of combination therapy with immediate initiation on rates of AIDS and death, and on death alone, in adjacent CD4 cell count ranges of width 100 cells per μL.FindingsData were obtained for 21 247 patients who were followed up during the era before the introduction of combination therapy and 24 444 patients who were followed up from the start of treatment. Deferring combination therapy until a CD4 cell count of 251–350 cells per μL was associated with higher rates of AIDS and death than starting therapy in the range 351–450 cells per μL (hazard ratio [HR] 1·28, 95% CI 1·04–1·57). The adverse effect of deferring treatment increased with decreasing CD4 cell count threshold. Deferred initiation of combination therapy was also associated with higher mortality rates, although effects on mortality were less marked than effects on AIDS and death (HR 1·13, 0·80–1·60, for deferred initiation of treatment at CD4 cell count 251–350 cells per μL compared with initiation at 351–450 cells per μL).InterpretationOur results suggest that 350 cells per μL should be the minimum threshold for initiation of antiretroviral therapy, and should help to guide physicians and patients in deciding when to start treatment.FundingUK Medical Research Council.

The Paradox of Incomplete CD4+Cell Count Restoration Despite Successful Antiretroviral Treatment and the Need to Start Highly Active Antiretroviral Therapy Early

The natural course of HIV infection is characterized by progressive and, ultimately, profound loss of CD4 T lymphocytes, the primary target of this virus that essentially infects the immune system. During peak viremia, in the acute phase of infection, CD4 cells are dramatically depleted in the gut, where the vast majority of them reside [1]. When the HIV load reaches a subsequent quasi–set point, circulating CD4 cells experience a transient recovery. However, over the course of infection, progressive CD4 cell loss leads to increasing immunodeficiency, resulting in opportunistic diseases and, finally, death [2]. CD4 cell counts, therefore, represent the principal surrogate marker for clinical symptoms and AIDSdefining illnesses. With the advent of effective antiretroviral therapy, it became clear that decreases in CD4 cell counts can be drastically reversed. After treatment initiation, the fre-

Substantia nigra hyperechogenicity and CSF dopamine depletion in HIV

Dopaminergic dysfunction is thought to play a pivotal role in human immunodeficiency virus (HIV)-related dementia. Decreased dopamine (DA) levels in the cerebrospinal fluid (CSF) and neuronal loss in the substantia nigra (SN) have been reported in HIV-infected patients, suggesting nigrostriatal damage. Structural changes detectable as hyperechogenicity in transcranial ultrasound (TCS) scans of the SN have been reported in patients with Parkinson's disease (PD) and other neurological conditions. In this study, we assessed the echomorphology of the SN in 40 HIV-positive patients compared to 40 age- and sex-matched healthy controls and correlated these findings with CSF levels of DA and the metabolites homovanillic acid (HVA) and 3,4-dihydroxy phenylacetic acid (DOPAC) and with neuropsychologic performance. We observed that the SN of HIV-infected patients was hyperechogenic relative to that of controls (0.07 +/- 0.05 vs. 0.04 +/- 0.07 cm(2); mean +/- SEM; P < 0.001) and that this SN hyperechogenicity was correlated with decreased DA levels in the CSF, decreased CD4 cell count, and an impaired performance in the psychopathology assessment scale (AMDP) subtest for drive and psychomobility. An association to CDC stage, duration of HIV infection, or presence of HIV dementia was not observed. Our results indicate changes in the nigrostriatal system in HIV-infected patients that are detectable as hyperechogenic SN precede prominent extrapyramidal symptoms and cognitive dysfunction.

Association Between HIV-1 RNA Level and CD4 Cell Count Among Untreated HIV-Infected Individuals

We examined the significance of plasma HIV-1 RNA levels (or viral load alone) in predicting CD4 cell decline in untreated HIV-infected individuals. Data were obtained from the British Columbia Centre for Excellence in HIV/AIDS. Participants included all residents who ever had a viral load determination in the province and who had never taken antiretroviral drugs (N = 890). We analyzed a total of 2074 viral load measurements and 2332 CD4 cell counts. Linear mixed-effects models were used to predict CD4 cell decline over time. Longitudinal viral load was strongly associated with CD4 cell decline over time; an average of 1 log(10) increase in viral load was associated with a 55-cell/mm(3) decrease in CD4 cell count. Our results support the combined use of CD4 cell count and viral load as prognostic markers in HIV-infected individuals before the introduction of antiretroviral therapy.

Estimation of the Predictive Role of Plasma Viral Load on CD4 Decline in HIV-1 Subtype C-Infected Subjects in India

Plasma viral load has been shown to be a meaningful prognostic marker for disease progression in untreated, HIV-1 subtype B-infected subjects in United States and Western Europe and therefore used as a prognostic marker for disease progression. Because of high expenses of commercially available viral load assays, the role of viral load in disease progression has not been evaluated in HIV-1 subtype C-infected patients in India. We developed an inexpensive real-time reverse transcriptase-polymerase chain reaction assay to quantify viral load in plasma of HIV-1 subtype C-infected subjects from India and used it in a longitudinal analysis of viral load and CD4 cell number in HIV-infected subjects from Calcutta, India. The real-time reverse transcriptase-polymerase chain reaction assay can quantify plasma viral load with a linear range of detection from 10 to 10 HIV-1 RNA copies per input. Longitudinal analysis of viral load in a cohort of 39 subjects over an average period of approximately 3 years indicates that 1-log increase in HIV-1 RNA level was associated with a decline of 67 CD4 cell count. Furthermore, HIV-1 RNA level between 500 and 50,000 copies per milliliter would predict a 12.9% decrease in CD4 cell count per year, whereas HIV-1 RNA levels above 50,000 copies HIV-1 RNA per milliliter would predict a 25.3% decrease in CD4 cells per year. In addition, we estimated that the mean incubation period of disease development, as defined by the loss of CD4 below 200, is 8.2 years. Our report on the level of viral load on predicting CD4 decline in Indian subjects with HIV-1 provides an additional important tool to the physicians for treating and planning a therapeutic strategy to control HIV-1 infection in India.

Un cas d’encéphalopathie acquise de l’enfant. À propos d’une cause que l’on croyait disparue

Subacute central nervous system infection must be considered in any infant presenting with progressive encephalopathy. We present the case of an 18-month-old child with normal neuromotor development until the age of 14 months admitted for spastic hypertonia of the legs and arms associated with axial hypotonia. The mother reported that she recently had been found to be HIV-seropositive. HIV antibodies were negative during the first trimester of pregnancy. On the child's blood sample, the HIV test was positive associated with a major decrease in CD4 cell count. Viral load (ARN-PCR) was 720 copies par millilitre. On brain MRI, hypersignals were found in the white matter. HIV related encephalopathy caused by maternal fetal transmission was diagnosed. After 2 months of antiretroviral treatment (azidothymidine, lamivudine, and boosted lopinavir), the child's neurological condition improved. HIV infection must be suspected in all infants with progressive encephalopathy. The HIV test in pregnant women must be proposed at the beginning of pregnancy and repeated during the last trimester.

Imported Malaria in HIV-Infected Patients Enrolled in the ANRS CO4 FHDH Study

To describe episodes of imported malaria in human immunodeficiency virus type 1-infected patients and to study the risk factors for severe Plasmodium falciparum malaria. Patients enrolled in the French Hospital Database on HIV who were diagnosed with a first episode of malaria between 1996 and 2003 were included. The severity of P. falciparum imported malaria was graded with World Health Organization criteria. Geographic areas were classified according to P. falciparum chemoresistance. Risk factors for severe malaria were identified with logistic regression. We studied 190 patients infected by P. falciparum in 178 cases. All but four of the patients were infected in sub-Saharan Africa, and half were returning from a country with a high P. falciparum chloroquine resistance. Their median age was 37.5 years, and 57% came from a country endemic with malaria. The median CD4 cell count was 299/mm, and the median plasma human immunodeficiency virus type 1 RNA load was 4.5 log10 copies/mL. Sixty-five (36.5%) episodes of P. falciparum malaria were severe. Severe imported malaria was associated with CD4 cells/mm <350 (odds ratio = 2.58; 95% confidence interval: 1.19 to 5.57). The risk of severe malaria was lower in patients returning from a country with a high prevalence of chemoresistance (odds ratio = 0.50; 95% confidence interval: 0.25 to 0.99). Severe imported malaria in human immunodeficiency virus type 1-infected patients is associated with decreased CD4 cell count. The risk seems lower when P. falciparum infection was acquired in areas of high prevalence of chemoresistance.

Substantia nigra hyperechogenicity and CSF dopamine depletion in HIV

Abstract Dopaminergic dysfunction is thought to play apivotal role in human immunodeficiency virus (HIV)-related dementia. Decreased dopamine (DA) levels in thecerebrospinal fluid (CSF) and neuronal loss in the sub-stantia nigra (SN) have been reported in HIV-infectedpatients, suggesting nigrostriatal damage. Structural chan-ges detectable as hyperechogenicity in transcranialultrasound (TCS) scans of the SN have been reported inpatients with Parkinson’s disease (PD) and other neuro-logical conditions. In this study, we assessed theechomorphology of the SN in 40 HIV-positive patientscompared to 40 age- and sex-matched healthy controls andcorrelated these findings with CSF levels of DA and themetabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) and with neuropsychologicperformance. We observed that the SN of HIV-infectedpatients was hyperechogenic relative to that of controls(0.07 ± 0.05 vs. 0.04 ± 0.07 cm 2 ; mean ± SEM;P\0.001) and that this SN hyperechogenicity was cor-related with decreased DA levels in the CSF, decreasedCD4 cell count, and an impaired performance in the psy-chopathology assessment scale (AMDP) subtest for driveand psychomobility. An association to CDC stage, durationof HIV infection, or presence of HIV dementia was notobserved. Our results indicate changes in the nigrostriatalsystem in HIV-infected patients that are detectable as hy-perechogenic SN precede prominent extrapyramidalsymptoms and cognitive dysfunction.Keywords AIDS Dopamine HIV dementia Substantia nigra echogenicity Transcranial sonographyIntroductionClinical manifestations of dopaminergic dysfunction areprominent findings in patients with human immunodefi-ciency virus (HIV) infection and consecutive HIVdementia. This symptom-complex consisting of subcorticaldementia and extrapyramidal features, such as bradykine-sia, postural and gait abnormalities, and hypomimia, wasrecognized in the 1980s and represents primary HIV-rela-ted neuronal damage involving the nigrostriatal pathway.Even in the absence of cognitive impairment, HIV-infectedpatients may exhibit subclinical motor disturbances [11].Cerebrospinal fluid (CSF) studies also reflect dopaminergicdysfunction in HIV patients, with HIV-positive patients

Human Immunodeficiency Virus Infection Alters Tumor Necrosis Factor Alpha Production via Toll-Like Receptor-Dependent Pathways in Alveolar Macrophages and U1 Cells

Human immunodeficiency virus (HIV)-positive persons are predisposed to pulmonary infections, even after receiving effective highly active antiretroviral therapy. The reasons for this are unclear but may involve changes in innate immune function. HIV type 1 infection of macrophages impairs effector functions, including cytokine production. We observed decreased constitutive tumor necrosis factor alpha (TNF-alpha) concentrations and increased soluble tumor necrosis factor receptor type II (sTNFRII) in bronchoalveolar lavage fluid samples from HIV-positive subjects compared to healthy controls. Moreover, net proinflammatory TNF-alpha activity, as measured by the TNF-alpha/sTNFRII ratio, decreased as HIV-related disease progressed, as manifested by decreasing CD4 cell count and increasing HIV RNA (viral load). Since TNF-alpha is an important component of the innate immune system and is produced upon activation of Toll-like receptor (TLR) pathways, we hypothesized that the mechanism associated with deficient TNF-alpha production in the lung involved altered TLR expression or a deficit in the TLR signaling cascade. We found decreased Toll-like receptor 1 (TLR1) and TLR4 surface expression in HIV-infected U1 monocytic cells compared to the uninfected parental U937 cell line and decreased TLR message in alveolar macrophages (AMs) from HIV-positive subjects. In addition, stimulation with TLR1/2 ligand (Pam(3)Cys) or TLR4 ligand (lipopolysaccharide) resulted in decreased intracellular phosphorylated extracellular signal-regulated kinase and subsequent decreased transcription and expression of TNF-alpha in U1 cells compared to U937 cells. AMs from HIV-positive subjects also showed decreased TNF-alpha production in response to these TLR2 and TLR4 ligands. We postulate that HIV infection alters expression of TLRs with subsequent changes in mitogen-activated protein kinase signaling and cytokine production that ultimately leads to deficiencies of innate immune responses that predispose HIV-positive subjects to infection.

The Impact of HIV Tropism on Decreases in CD4 Cell Count, Clinical Progression, and Subsequent Response to a First Antiretroviral Therapy Regimen

Human immunodeficiency virus (HIV) uses 2 distinct chemokine receptors, CCR5 (R5) or CXCR4 (X4), during entry. Viruses may be R5 tropic, X4 tropic, or dual/mixed (D/M) tropic. R5-tropic virus predominates at high CD4 cell counts, with the number of X4-tropic strains increasing as CD4 cell count decreases. We investigated the relationship between tropism and decreases in CD4 cell count before antiretroviral therapy initiation, the frequency of clinical events, and responses to antiretroviral therapy in a cohort of treatment-naive patients. Four hundred two treatment-naive patients underwent tropism determination; 326 harbored R5-tropic virus, and 76 harbored X4- or D/M-tropic virus. After adjustment for baseline characteristics, the rate of decrease in CD4 cell count was significantly greater in patients infected with X4- or D/M-tropic virus at 12 months (P=.026). Two hundred twenty-nine individuals infected with R5-tropic virus and 60 individuals infected with X4- or D/M-tropic virus commenced antiretroviral therapy between tropism testing and the time of data analysis. Time to viral suppression and the proportion of patients achieving viral suppression were similar at 6, 12, and 24 months. CD4 cell count increases were similar. Clinical events were significantly more common in the group infected with X4- or D/M-tropic virus. Multivariate analysis demonstrated a relative risk of experiencing a clinical event of 2.56 (95% confidence interval, 1.37-4.76; P=.003) among patients infected with X4- or D/M-tropic virus. The presence of D/M- or X4-tropic virus has a deleterious effect on CD4 cell count decrease and risk of clinical disease. Response to standard antiretroviral therapy is not affected by viral tropism.

Specific Enfuvirtide‐Associated Mutational Pathways in HIV‐1 Gp41 Are Significantly Correlated With an Increase in CD4+Cell Count, Despite Virological Failure

Human immunodeficiency virus type 1 (HIV-1) gp41 is a crucial determinant for HIV-1 pathogenicity. We investigated the correlation of enfuvirtide (ENF)-associated gp41 mutational clusters with viroimmunological parameters, as well as the potential underlying mechanisms. A total of 172 gp41 sequences and clinical follow-up data from 73 ENF-treated patients were analyzed monthly, from baseline to week 48. There were 7 novel gp41 mutations positively associated with ENF treatment and correlated with classic ENF mutations. The ENF-associated clusters [V38A + N140I ] and [V 38A +T18A ] significantly correlated with an increase in CD4 cell count at week 48 ( an increase from baseline of 112 and 209 cells/microL, respectively), whereas [Q40H + L45M + 268A] significantly correlated with a decrease in CD4 cell count (-53 cells/microL), without a change in the level of viremia. Residues 38 and 18 are located complementarily to each other in the Rev-responsive element, whereas analysis of molecular dynamics showed that the copresence of [V38A + N140 I] abolishes the interaction between residue 38 and 145 important for stabilization of the 6-helix bundle. In contrast, T268A localizes in the gp41 calmodulin-binding domain responsible for gp41-induced CD4(+) T lymphocyte apoptosis. Specific gp41 mutational clusters associated with ENF treatment significantly correlate with increases in CD4(+) cell count. Structural analysis suggests that this immunological gain is associated with mechanisms that act at both the protein level and the RNA level (even under conditions of virological failure). This result may help in the selection of patients who can benefit most from ENF treatment and represents a driving force for the design of the next generation of entry inhibitors.

Active Tuberculosis Does Not Always Imply the Initiation of Highly Active Antiretroviral Therapy in HIV-Infected Patients

Infection with HIV is an important risk factor for tuberculosis (TB). One-half million cases of TB attributable to HIV infection occur worldwide each year. Since the advent of highly active antiretroviral therapy (HAART) the morbidity and mortality of HIV-infected patients have declined. However concomitant TB treatment and HAART are hampered by a high pill burden complex drug interactions treatment-related adverse events and paradoxic reactions. Studies that have assessed the effect of HAART in the course of TB and HIV coinfection are few. All these retrospective studies suggest that coinfected patients with a CD4 count less than 100 cells/mm/3 would probably benefit from early initiation of HAART. Unlike other HIV-associated opportunistic infections TB may occur at high CD4 cell counts. The indication for HAART in these particular cases has not been assessed and current antiretroviral (ARV) treatment guidelines are based on expert opinion. We evaluated retrospectively 93 episodes of TB diagnosed in 87 HIV-infected patients from January 2000 to February 2004 at Bichat Hospital in an attempt to assess the clinical aspects and outcome of TB according to the level of immunosuppression at TB diagnosis and to the prescription of HAART in the course of TB treatment. (excerpt)

Organizing Pneumonia as a Manifestation of Pneumocystis jiroveci Immune Reconstitution Syndrome in HIV-positive Patients

Organizing pneumonia (OP) is a nonspecific response to various forms of lung injury. Although patients with human immunodeficiency virus (HIV) infection tend to develop several respiratory disorders, especially infections and malignances, the association of HIV infection and OP is unusual. Pneumocystis jiroveci infection is also rarely associated with OP. We describe the radiologic findings in 2 HIV-positive patients who shortly after introduction of highly active antiretroviral therapy, presented with clinical and radiologic deterioration, despite elevation of the CD4 cell count and viral load decrease. In both patients, clinical and radiologic features were consistent with OP and lung biopsy revealed OP associated with P. jiroveci infection. These findings are consistent with immune reconstitution syndrome due to P. jiroveci.

Mycobacterial T Cell Responses in HIV‐Infected Patients with Advanced Immunosuppression

Antimycobacterial T cell reactivity at different stages of HIV infection was investigated. Subjects were screened with purified protein derivative (PPD), early secreted antigenic target (ESAT)-6, and culture filtrate protein (CFP)-10 antigens for interferon (IFN)-gamma-producing effector T cell responses by direct ex vivo enzyme-linked immunospot (ELISpot) assay. The proportion of responders to PPD tuberculin decreased with a reduction in CD4 T cell count, whereas the proportion of responder to ESAT-6 and CFP-10 did not. The main sources of IFN-gamma secretion were CD4 cells, and the relative responses to ESAT-6 and CFP-10 significantly increased in HIV-infected patients with decreasing CD4 cell count. This may reflect early signs of reactivation, reinfection, or a restricted, inefficient immune response to Mycobacterium tuberculosis.

Human Papillomavirus Genotypes and Anal-Related Lesions Among HIV-1-Infected Men in Milan, Italy

Human Papillomavirus Genotypes and Anal-Related Lesions Among HIV-1-Infected Men in Milan, Italy

Predictors of Stillbirth in Sub-Saharan Africa

To describe the incidence and predictors of stillbirth in a predominantly human immunodeficiency virus (HIV)-infected African cohort. Human Immunodeficiency Virus (HIV) Prevention Trials Network (HPTN) 024 was a randomized controlled trial of empiric antibiotics to reduce chorioamnionitis-related perinatal HIV transmission. A proportion of HIV-uninfected individuals were enrolled to reduce community-based stigma surrounding the trial. For this analysis, only women who gave birth to singleton infants were included. Of 2,659 women enrolled, 2,434 (92%) mother- child pairs met inclusion criteria. Of these, 2,099 (86%) infants were born to HIV-infected women, and 335 (14%) were born to HIV-uninfected women. The overall stillbirth rate was 32.9 per 1,000 deliveries (95% confidence interval [CI] 26.1-40.7). In univariable analyses, predictors for stillbirth included previous stillbirth (odds ratio [OR] 2.3, 95% CI 1.2-4.3), antenatal hemorrhage (OR 14.4, 95% CI 4.3-47.9), clinical chorioamnionitis (OR 20.9, 95% CI 5.1-86.2), and marked polymorphonuclear infiltration on placental histology (OR 2.9, 95% CI 1.7-5.2). When compared with pregnancies longer than 37 weeks, those at 34-37 weeks (OR 1.7, 95% CI 0.8-3.4) and those at less than 34 weeks (OR 22.8, 95% CI 13.6-38.2) appeared more likely to result in stillborn delivery. Human immunodeficiency virus infection was not associated with a greater risk for stillbirth in either univariable (OR 1.5, 95% CI 0.7-3.0) or multivariable (adjusted OR 1.11, 95% CI 0.38-3.26) analysis. Among HIV-infected women, however, decreasing CD4 cell count was inversely related to stillbirth risk (P=.009). In this large cohort, HIV infection was not associated with increased stillbirth risk. Further work is needed to elucidate the relationship between chorioamnionitis and stillbirth in African populations. ClinicalTrials.gov, www.clinicaltrials.gov, NCT00021671 II.

Reduced mortality and CD4 cell loss among carriers of the interleukin-10 −1082G allele in a Zimbabwean cohort of HIV-1-infected adults

To evaluate the effect on HIV progression of single nucleotide polymorphisms in promoters of the genes for tumour necrosis factor (TNF)-alpha and interleukin (IL)-10 and known to influence cytokine production. Survival was documented for 4.3 years after baseline for 198 HIV-1-infected and 180 HIV-uninfected individuals from the Mupfure Schistosomiasis and HIV Cohort in rural Zimbabwe. Polymorphisms determined were -592C>A and -1082A>G for IL-10 and -238G>A and -308G>A for TNF-alpha. CD4 cell counts, plasma HIV RNA, soluble TNF receptor II (sTNF-rII), IL-8 and IL-10 were also measured. Mortality was lower in carriers of the IL-10 -1082G high-producer allele (hazard ratio, 0.47; P < 0.01). CD4 cell count decrease in participants reporting for the follow-up at 3 years was attenuated in carriers of this allele (P < 0.01). In univariate analysis, plasma IL-10, IL-8, and sTNF-rII correlated negatively with CD4 cell count, positively with HIV RNA, and higher levels predicted mortality. In multivariate analysis only sTNF-rII was an independent predictor of HIV progression markers and mortality. Indeed, sTNF-rII predicted mortality (P < 0.01) at a level of significance comparable to HIV RNA (P < 0.01) and CD4 cell count (P < 0.05). In carriers of IL-10 -1082G, an allele linked to increased IL-10 production, survival was doubled and CD4 cell decrease was attenuated compared with noncarriers. Only sTNF-rII and not plasma IL-10 was an independent predictor of HIV progression markers and mortality. This study supports immune activation as a driving force in HIV pathogenesis and indicates a protective role of IL-10 -1082G that should be evaluated in other cohorts.