Early levels of HIV-1 DNA in peripheral blood mononuclear cells are predictive of disease progression independently of HIV-1 RNA levels and CD4+ T cell counts

BACKGROUND: The objective of this work was to assess the role of human immunodeficiency virus (HIV) reservoirs in the risk of disease progression, by studying the relationship between HIV DNA level in peripheral blood mononuclear cells (PBMCs) and progression toward acquired immunodeficiency syndrome (AIDS). METHODS: HIV-1 DNA levels in PBMCs were determined by quantitative polymerase chain reaction for 383 patients enrolled in the SEROCO Cohort Study who had experienced seroconversion and had been followed up for >8 years. We compared the predictive values of HIV DNA level, HIV RNA level, and CD4+ cell count. RESULTS: Between 6 and 24 months after seroconversion, HIV DNA level was a major predictor of progression to AIDS independently of HIV RNA level and CD4+ T cell count (adjusted relative risk [RR] for a 1-log(10) increase, 3.20 [95% confidence interval {CI}, 1.70-6.00]). HIV DNA level was also a major predictor of disease progression during the first 6 months after seroconversion (adjusted RR, 4.16 [95% CI, 1.70-10.21]), when HIV RNA level and CD4+ T cell count were less predictive. Thus, a combination of these 3 markers provides the best estimate of the risk of disease progression for each patient. CONCLUSIONS: Our results suggest that HIV DNA level could be a useful additional marker in clinical practice and could aid in helping to define the best time to initiate treatment for each patient.     

Both serum HIV type 1 RNA levels and CD4+ lymphocyte counts predict clinical outcome in HIV type 1-infected subjects with 200 to 500 CD4+ cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team

To evaluate HIV-1 RNA and CD4+ cell responses to therapy as predictors of clinical progression and to evaluate levels and trends of these markers prior to clinical failure, HIV-1 RNA measurements were retrospectively obtained on subjects who progressed to AIDS or death and a random sample of subjects who did not. Samples were taken from AIDS Clinical Trials Group Study 175, a randomized trial comparing nucleoside analog therapies in subjects with CD4+ cell counts of between 200 and 500 cells/mm3. HIV-1 RNA and CD4+ cell count independently predicted clinical progression. Risk of subsequent progression is best captured by the change to the last measured value for CD4+ cell count and the area under the curve minus baseline, a measure of viral replication over time, for HIV-1 RNA. Subjects who failed had lower CD4+ cell counts, greater rates of CD4+ cell decline, and higher HIV-1 RNA levels, but not greater rates of HIV-1 RNA increase than subjects who did not. Subjects who maintained more than 200 CD4+ cells/mm3 and fewer than 10,000 copies of HIV-1 RNA per milliliter had low risk of progression. During the first few months of therapy, treatments are best monitored by regular HIV-1 RNA and less frequent CD4+ cell measurements. Thereafter, both markers should be monitored on a similar schedule to identify rapidly declining CD4+ cell counts, or adverse levels of either. These results further delineate the prognostic significance of HIV-1 RNA and CD4+ cell count and should help to better define their utility in the practice setting.     

Emergence and persistence of CXCR4-tropic HIV-1 in a population of men from the multicenter AIDS cohort study

We examined the emergence of CXCR4 (i.e., X4) tropism in 67 male human immunodeficiency virus type 1 (HIV-1) seroconverters from the Multicenter AIDS Cohort Study (MACS) who were selected to reflect the full spectrum of rates of HIV-1 disease progression. A mean of 10 serial samples per donor were evaluated by a laboratory-validated, commercially available assay to determine phenotypic coreceptor use. A total of 52% of men had dual- or mixed-tropic HIV-1 detected at 1 or more of the time points tested. Use of X4 by HIV-1 was detected more frequently among men who developed AIDS (defined as a CD4(+) T cell count of <200 cells/muL and/or an AIDS-defining illness) < or =11 years after seroconversion than among those who did not (P = .005), as well as among men who exhibited a total T cell count decline (i.e., a CD3(+) inflection point), compared with those who did not (P = .03). For men in whom both X4 virus and an inflection point were detected, emergence of X4 virus preceded the inflection point by a median of 0.83 years. The median CD4(+) T cell count at first detection of X4 viruses before the onset of AIDS was 475 cells/microL. We conclude that HIV-1 variants that used X4 frequently emerged at high CD4(+) T cell counts and may contribute to the decrease in T cell numbers during late HIV-1 infection.     

GB virus C during the natural course of HIV-1 infection: viremia at diagnosis does not predict mortality

OBJECTIVE: To investigate whether GBV-C viremia at diagnosis of HIV-1 infection predicts disease outcome in patients not receiving combination antiretroviral therapy (ART), and whether longitudinal changes in GBV-C viremia are associated with disease progression. DESIGN: Prospective cohort study. METHODS: 230 patients with a serum sample available for testing obtained within 2 years of HIV-1 diagnosis were followed until either initiation of ART, death, or their last visit to our clinic (median follow-up 4.3 years). Baseline and follow-up serum samples (available from 163 patients) were tested for GBV-C RNA and antibodies against GBV-C envelope E2 protein (anti-E2; signifying resolved GBV-C viremia). RESULTS: At inclusion, 62 patients (27%) had GBV-C viremia and 69 (30%) had anti-E2. Baseline GBV-C status was not associated with all-cause mortality (P = 0.12), HIV-related mortality (P = 0.18), or development of AIDS (P = 0.84). However, GBV-C RNA was less prevalent in patients with AIDS at inclusion (P = 0.008). Eleven of 44 patients with baseline GBV-C viremia lost GBV-C RNA during follow-up without showing anti-E2 seroconversion. In comparison with anti-E2-negative patients with either persistent absence, persistent presence, or acquisition of GBV-C viremia, these subjects had significantly increased all-cause mortality (P = 0.018), HIV-related mortality (P = 0.007), and AIDS incidence (P < 0.001). CONCLUSIONS: GBV-C status at diagnosis did not predict disease outcome in this HIV cohort. GBV-C viremia was rare in patients with AIDS, and tended to disappear without occurrence of anti-E2 in patients with progressive disease. This suggests that the GBV-C status of HIV-1-infected patients could be a phenomenon secondary to HIV progression, rather than an independent prognostic factor.     

Carriage of GB virus C/hepatitis G virus RNA is associated with a slower immunologic, virologic, and clinical progression of human immunodeficiency virus disease in coinfected persons

The prevalence of GB virus C (GBV-C) infection is high in human immunodeficiency virus (HIV)-infected persons. However, the long-term consequences of coinfection are unknown. HIV-positive persons with a well-defined duration of infection were screened on the basis of their GBV-C/hepatitis G virus (HGV) RNA status and studied. GBV-C/HGV viremia was observed in 23, who carried the virus over a mean of 7.7 years. All parameters (survival, CDC stage B/C, HIV RNA load, CD4 T cell count) showed significant differences in terms of the cumulative progression rate between persons positive and negative for GBV-C/HGV RNA. When GBV-C/HGV RNA-positive and -unexposed subjects were matched by age, sex, baseline HIV RNA load, and baseline CD4 T cell count, HIV disease progression appeared worse in GBV-C/HGV RNA-negative subjects. The carriage of GBV-C/HGV RNA is associated with a slower progression of HIV disease in coinfected persons.     

CD8+CD38+ T cells but not HIV type 1 RNA viral load predict CD4+ T cell loss in a predominantly minority female HIV+ adolescent population

The purpose of this study was to evaluate predictors of HIV-1 disease progression in a cohort of predominantly female and minority adolescents who had acquired their HIV-1 infections through sexual risk behaviors. Subjects were identified from the REACH cohort who were not on antiretroviral therapy for at least 1 year and whose baseline CD4(+) T cells were >300 cells/mm(3). Biomedical and demographic characteristics of the subjects at the start of the study period were evaluated as predictors of CD4(+) T cell loss in univariate and multivariate models. Two-thirds of the 99 subjects meeting the selection criteria were female and 87% were black or Hispanic similar to the REACH cohort as a whole. Higher absolute CD8(+) CD38(+) T cell counts at the start of the assessment period were associated with a greater rate of loss of CD4(+) T cells. HIV-1 RNA viral load was among other potential predictors of HIV-1 disease progression that had no association with the rate of CD4(+) T cell loss in this cohort. This study extends the observed association of higher CD8(+) CD38(+) T cells numbers being predictive of HIV-1 disease progression into predominantly female, minority youth.     

Heat-denatured human immunodeficiency virus type 1 protein 24 antigen: prognostic value in adults with early-stage disease

CD4(+) lymphocyte count and human immunodeficiency virus (HIV) type 1 RNA level are useful for determining when to initiate antiretroviral therapy but are not used widely in developing countries due to the high cost. Heat-denatured protein 24 (p24) antigen is an inexpensive assay that predicts disease progression among persons with advanced disease but has not been assessed among persons with early-stage disease. Plasma levels of heat-denatured p24 antigen were quantified in baseline study-visit specimens obtained from injection drug users enrolled in a longitudinal cohort study of HIV-1 infection. Of the 494 study participants (median initial CD4(+) lymphocyte count, 518 lymphocytes/mm(3)), 90 (18%) progressed to acquired immunodeficiency syndrome within 5 years. p24 antigen level correlated with both CD4(+) lymphocyte count (r=-0.34; P<.0001) and HIV-1 RNA level (r=0.55; P<.0001). p24 antigen level >5 pg/mL predicted disease progression, comparable with that of cutoff CD4(+) lymphocyte count <350 lymphocytes/mm(3) and HIV-1 RNA level >30,000 copies/mL. Heat-denatured p24 antigen level predicted subsequent clinical disease progression in early-stage HIV-1 infection and correlated with both CD4(+) lymphocyte count and HIV-1 RNA level.     

Natural history of serum HIV-1 RNA levels in 330 patients with a known date of infection. The SEROCO Study Group

OBJECTIVE: To describe the spontaneous course, before the introduction of highly active antiretroviral therapy (HAART), of HIV-1 RNA during the AIDS-free period of the disease. To assess the predictive value of changes in HIV-1 RNA levels. DESIGN: A total of 330 patients with a known date of infection followed in the SEROCO cohort. METHODS: HIV-1 RNA levels (threshold, 200 copies/ml) were evaluated from 2243 frozen sera obtained from enrolment until the onset of AIDS or until February 1996. Lowess curves were used to describe the variations of viraemia during follow-up. A Cox regression model was used to assess the predictive value of early and updated CD4 cell count and viral load. RESULTS: In addition to a lower early viral load, patients who remained AIDS-free had, on average, a longer period of viral load decrease after infection (36 versus 18 months), followed by a slower viral load increase compared with those who progressed to AIDS. A true plateau-phase after the seroconversion period, lasting approximately 4 years, was identified only in patients who remained AIDS-free for at least 90 months. In multivariate analysis, both early viral load and later changes were significant predictors of progression to AIDS. A decrease in the CD4 cell count to less than 200 cells/microl and the onset of a group B condition remained significant predictors of progression. CONCLUSION: Our study extends to the early post-seroconversion phase the prognostic value of extracellular HIV-1 RNA levels. Moreover, our data suggest that, in most HIV-infected individuals, a progressive loss of control of viral replication arises during the early years of HIV-1 infection.     

Reduced mother-to-child transmission of HIV associated with infant but not maternal GB virus C infection

BACKGROUND: Prolonged coinfection with GB virus C (GBV-C) has been associated with improved survival in human immunodeficiency virus (HIV)-infected adults. We investigated whether maternal or infant GBV-C infection was associated with mother-to-child transmission (MTCT) of HIV-1 infection. METHODS: The study population included 1364 HIV-infected pregnant women enrolled in 3 studies of MTCT of HIV in Bangkok, Thailand (the studies were conducted from 1992-1994, 1996-1997, and 1999-2004, respectively). We tested plasma collected from pregnant women at delivery for GBV-C RNA, GBV-C antibody, and GBV-C viral genotype. If GBV-C RNA was detected in the maternal samples, the 4- or 6-month infant sample was tested for GBV-C RNA. The rates of MTCT of HIV among GBV-C-infected women and infants were compared with the rates among women and infants without GBV-C infection. RESULTS: The prevalence of GBV-C RNA in maternal samples was 19%. Of 245 women who were GBV-C RNA positive, 101 (41%) transmitted GBV-C to their infants. Of 101 infants who were GBV-C RNA positive, 2 (2%) were infected with HIV, compared with 162 (13%) of 1232 infants who were GBV-C RNA negative (odds ratio [OR] adjusted for study, 0.13 [95% confidence interval {CI}, 0.03-0.54]). This association remained after adjustment for maternal HIV viral load, receipt of antiretroviral prophylaxis, CD4(+) count, and other covariates. MTCT of HIV was not associated with the presence of GBV-C RNA (adjusted OR [aOR], 0.94 [95% CI, 0.62-1.42]) or GBV-C antibody (aOR, 0.90 [95% CI, 0.54-1.50]) in maternal samples. CONCLUSIONS: Reduced MTCT of HIV was significantly associated with infant acquisition of GBV-C but not with maternal GBV-C infection. The mechanism for this association remains unknown.     

Herpes zoster and HIV-1 infection in a rural Ugandan cohort

OBJECTIVE: To compare the rates and clinical features of herpes zoster in HIV-positive and HIV-negative individuals in a cohort in rural Uganda; to report the incidence of herpes zoster in the HIV-positive group in relation to seroconversion and CD4 cell counts and to determine whether it is indicative of a more rapid progression to death. DESIGN: A prospective population-based cohort. METHODS: The cohort comprised 107 prevalent and 144 incident (with documented dates of seroconversion) participants with HIV infection and 231 HIV-negative controls who were reviewed routinely every 3 months. RESULTS: The mean rate of herpes zoster was 53.6/1000 person-years in HIV-positive and 4.4 in HIV-negative participants. The cumulative incidence of a first episode of herpes zoster was 7.6% at 2 years, 12.6% at 4 years and 24.0% at 6 years after seroconversion; the incidence rate was 35.6/1000 person-years. There was no evidence of a significant effect of age, gender, period from seroconversion or CD4 cell count on this incidence rate. Herpes zoster was an indicator of HIV-1 infection in this population but not an indicator of more rapid progression to death after adjusting for CD4 cell count and age. CONCLUSIONS: The rates, including the cumulative incidence after seroconversion and the clinical presentation of herpes zoster, were similar to those reported from industrialized countries. Although an indicator of HIV-1 infection in this population, herpes zoster was unrelated to CD4 cell count or period from seroconversion and did not lead to a faster disease progression.     

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.     

Persistent immune activation in HIV-1 infection is associated with progression to AIDS

BACKGROUND: HIV-1 infection is characterized by chronic generalized CD8 and CD4 T cell hyperactivation, the biological effect of which is not understood. OBJECTIVE: To study the relation between chronic immune activation and CD4 T cell depletion in HIV-1 infection. DESIGN: Prospective cohort study among participants of the Amsterdam Cohort Studies on HIV-1 infection and AIDS who have a known seroconversion date (n = 102). METHODS: CD4 and CD8 T cell activation marker expression was analysed by FACScan before and after seroconversion (1 and 5 years after seroconversion); T cell proliferation and T cell numbers were also measured. Cox proportional hazard analyses were used to study the predictive value of these parameters for progression to AIDS. RESULTS: Preseroconversion low CD4 T cell numbers or elevated levels of CD4 T cell activation were associated with increased risk for development of AIDS after HIV-1 seroconversion. Progression to AIDS was associated with loss of both CD4 and CD8 naive T cells. The predictive value of CD8 T cell activation was confirmed and, in addition, in the course of infection low CD4 T cell counts and increasing proportions of dividing CD4 T cells, dividing CD8 T cells or elevated CD4 T cell activation marker expression became independent predictors of progression to AIDS. CONCLUSIONS: Increased T cell activation has predictive value for HIV-1 disease progression even before seroconversion. These data support the hypothesis that persistent hyperactivation of the immune system may lead to erosion of the naive T cell pool and CD4 T cell depletion.     

Predictors of virologic and clinical outcomes in HIV-1-infected patients receiving concurrent treatment with indinavir, zidovudine, and lamivudine. AIDS Clinical Trials Group Protocol 320.

BACKGROUND: A substantial proportion of patients with HIV infection will not respond to antiretroviral therapy. Early predictors of response to treatment are needed to identify patients who are at risk for treatment failure. OBJECTIVE: To determine predictors of virologic and clinical response to indinavir, zidovudine, and lamivudine therapy. DESIGN: Observational analysis of one treatment group in a phase III trial. SETTING: 40 AIDS Clinical Trials units. PATIENTS: 489 patients receiving indinavir, zidovudine, and lamivudine who had 1) a CD4 count of 0.200 x 10(9) cells/L or less after 8 or more weeks of study therapy and 2) plasma HIV-1 RNA measurements obtained at baseline and week 8. MEASUREMENTS: HIV-1 RNA level and CD4 cell count at weeks 0, 4, 8, 24, and 40. Clinical progression was defined as a new AIDS-defining illness or death. RESULTS: Patients' levels of HIV-1 RNA at the 8th study week of therapy predicted whether patients would achieve virologic suppression to below 500 (or 50) copies/mL at study week 24. An HIV-1 RNA level less than 500 copies/mL at week 24 was achieved in 71% of patients whose level at week 8 had been less than 500 copies/mL, 53% of those with a level of 500 copies/mL or more and at least 2-log(10) copies/mL reduction since baseline, 29% of those with a level of 500 copies/mL or more with a 1- to 1.99-log(10) copies/mL reduction, and 9% of those with a level of 500 copies/mL or greater and less than 1-log(10) copies/mL reduction since baseline (P < 0.001). HIV-1 RNA level at week 8 also predicted clinical progression. HIV-1 disease progressed in 2.2% of the patients with a week-8 HIV-1 RNA level less than 500 copies/mL, 2.3% of patients with 500 copies/mL or greater and at least 2-log(10) copies/mL reduction since baseline, 4.9% of patients with 500 copies/mL or greater and 1- to 1.99-log(10) copies/mL reduction since baseline, and 10.6% of patients with 500 copies/mL or greater and less than 1-log(10) copies/mL decrease since baseline (P = 0.009). After adjustment for HIV-1 RNA level, patients with a higher week-8 CD4 cell count were more likely to have a week-24 HIV-1 RNA level less than 500 copies/mL (relative risk for patients with a week-8 CD4 count >/= 0.10 x 10(9) cells/L, 1.47 [95% CI, 1.00 to 2.16] compared with <0.050 x 10(9) cells/L; relative risk for patients with a week-8 CD4 count of 0.05 to 0.099 x 10(9) cells/L, 0.98 [CI, 0.61 to 1.57] compared with <0.050 x 10(9) cells/L). After adjustment for HIV-1 RNA level, patients with a week-8 CD4 count of 0.05 x 10(9) cells/L or greater (compared with <0.05 x 10(9) cells/L) had a decreased hazard for clinical progression (hazard ratio, 0.25 [CI, 0.09 to 0.67]). CONCLUSIONS: The HIV-1 RNA level and CD4 cell count achieved at 8 weeks of treatment are important predictors of subsequent virologic and clinical outcomes.     

No association between GB virus C infection and disease progression in HIV-2-infected patients from the French ANRS HIV-2 cohort

Out of 183 HIV-2-infected patients tested in the ANRS CO8 HIV-2 cohort, 69 were exposed to GB virus C (GBV-C), yielding a prevalence of 38% (95% CI 30.7, 45.2). There was no significant difference between the CD4 cell count and HIV-2-RNA plasma viral load in patients exposed and not exposed to GBV-C. After adjusting for age and CD4 cell count, co-infection with GBV-C was not associated with clinical progression (hazard ratio 0.78; 95% CI 0.24-2.56, 16 clinical events).     

CD8(+) T cell activation in women coinfected with human immunodeficiency virus type 1 and hepatitis C virus

Immune activation is a hallmark of human immunodeficiency virus type 1 (HIV-1) infection and impacts innate and adaptive immunity. Individuals coinfected with HIV-1 and hepatitis C virus (HCV) may have increased immune activation early in HIV disease because of a high HCV antigen load in tissues such as the liver. We evaluated T cell markers of activation and maturation in women with or without HIV-1 infection, by HCV antibody and HCV RNA status. We found increased percentages of activated CD8(+) T cells (i.e., CD8(+)HLA-DR(+)38(+) cells and CD8(+)CD28(+)HLA-DR(+) cells) but not of CD4(+) T cells among women who tested positive for HIV-1, HCV antibody, and HCV RNA, compared with HIV-1-positive women who tested negative for HCV antibody. Because CD8(+) T cell activation is related to HIV-1 disease progression, these data may have implications for the medical management of patients coinfected with HIV-1 and HCV.     

Acquisition of GB Virus Type C and Lower Mortality in Patients With Advanced HIV Disease

Background.?GB virus type C (GBV-C) is transmitted by sexual or parenteral exposure and is prevalent among patients receiving blood products. GBV-C is associated with lower human immunodeficiency virus (HIV) RNA and better survival among HIV-infected patients. Open questions are the presence and the direction of any causal relationship between GBV-C infection and HIV disease markers in the context of highly active antiretroviral therapy (HAART). Methods.?We used a limited access database obtained from the National Heart, Lung, and Blood Institute's Viral Activation Transfusion Study (VATS), a randomized controlled trial of leukoreduced vs nonleukoreduced transfusions to HIV-infected transfusion-naive patients. Blood samples from 489 subjects were tested for GBV-C markers. Cox regression models and inverse probability of treatment weights were used to examine the association between GBV-C coinfection and mortality in the VATS cohort. Results.?We found a significant reduction in mortality among GBV-C coinfected VATS subjects, after adjusting for HAART status, HIV RNA level, and CD4 cell count at baseline. Acquisition of GBV-C RNA (n?=?39) was associated with lower mortality in 294 subjects who were GBV-C negative at baseline, adjusting for baseline covariates (hazard ratio?=?0.22, 95% confidence interval [CI]: .08-.58) and in models in which weights were used to control for time-updated covariates (odds ratio?=?0.21, 95% CI: .08-.60). Conclusions.?GBV-C viremia is associated with lower mortality, and GBV-C acquisition via transfusion is associated with a significant reduction in mortality in HIV-infected individuals, controlling for HIV disease markers. These findings provide the first evidence that incident GBV-C infection alters mortality in HIV-infected patients.