CD4 percentage is an independent predictor of survival in patients starting antiretroviral therapy with absolute CD4 cell counts between 200 and 350 cells/microL

Objective

To determine the prognostic value of baseline CD4 percentage in terms of patient survival in comparison to absolute CD4 cell counts for HIV‐positive patients initiating highly active antiretroviral therapy (HAART).

Methods

A population‐based cohort study of 1623 antiretroviral therapy‐naïve HIV‐positive individuals who initiated HAART between 1 August 1996 and 30 June 2002 was conducted. Cumulative mortality rates were estimated using Kaplan–Meier methods. Cox proportional hazards regression was used to model the effect of baseline CD4 strata and CD4 percentage strata and other prognostic variables on survival. A subgroup analysis was conducted on 417 AIDS‐free subjects with baseline CD4 counts between 200 and 350 cells/μL.

Results

In multivariate models, low CD4 percentages were associated with increased risk of death [CD4%<5, relative hazard (RH)=4.46; CD4% 5–14, RH=2.43; P<0.01 for both] when compared with those subjects with an initial CD4 fraction of 15% or greater, but had less predictive value than absolute CD4 counts. In subgroup analyses where absolute CD4 strata were not associated with mortality, a baseline CD4 fraction below 15% [RH=2.71; 95% confidence interval (CI) 1.20–6.10], poor adherence to therapy and baseline viral load >100 000 HIV‐1 RNA copies/mL were associated with an increased risk of death.

Conclusion

CD4 percentages below 15% are independent predictors of mortality in AIDS‐free patients starting HAART, including those with CD4 counts between 200 and 350 cells/μL. CD4 percentage should be considered for inclusion in guidelines used to determine when to start therapy.

     

Long-term immunologic response in HIV-infected patients with CD4 cell counts </= 50/mm3 when initiating protease inhibitor therapy

From March to July 1996, 61 patients with CD4<50/mm(3)began a therapy with protease inhibitors. Increase and maintenance of CD4>100/mm(3) was observed in 39/61 patients with a protective effect for occurrence of AIDS or death. This immunological response was correlated with the duration of the virological response. However, 38% of patients with long-term immunological response never had a undetectable viral load.     

Diarrhea,CD4 counts and enteric infections in a community-based cohort of HIV-infected adults in Uganda

OBJECTIVES: To examine relationships between diarrhoea, CD4 cell counts and stool pathogens in a community-based cohort of HIV-infected adults in Uganda. PATIENTS AND METHODS: Stool specimens, obtained between October 1995 and December 1997, were linked to patients' symptoms and laboratory results. The relationship between CD4 counts and symptoms was tested using the Wilcoxon rank-sum test and those between organisms and diarrhoea using first a univariate Mantel-Haenszel analysis and then a logistic regression model adjusted for CD4 count and multiple organisms. RESULTS: 1,213 HIV-infected individuals (70% women, median CD4 cell count at enrollment 215 cells/microl) were followed for 1,224 person years of observation (pyo). 484 stool samples were examined, 357 from patients with diarrhoea. The rate of diarrhoea was 661 episodes per 1,000 pyo. CD4 counts were significantly lower in individuals with diarrhoea than those without (P < 0.001, Wilcoxon rank-sum test). Forty-nine percent of diarrhoeal stools and 39% of stools from asymptomatic patients contained enteric pathogens. The most frequent isolates were helminths (29.5% of all stools), followed by bacteria (19.2%) and then protozoa (8.9%). Rates of isolation of diarrhoea-associated pathogens were 29% from diarrhoeal stools and 17% from asymptomatic stools (P = 0.01, chi(2) test). The association between diarrhoea and infection with bacteria or protozoa was weak and there was no association with helminths.Cryptosporidium parvum infection alone was associated with low CD4 counts. CONCLUSIONS: Diarrhoea was common and most strongly associated with low CD4 counts. Bacteria were frequently found, even in stools from asymptomatic individuals. Over two-thirds of diarrhoeal episodes were undiagnosed, suggesting that unidentified agents or primary HIV enteropathy are important causes of diarrhoea in this population.     

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.     

Randomized, double-blind trial comparing indinavir alone, zidovudine alone and indinavir plus zidovudine in antiretroviral therapy-naive HIV-infected individuals with CD4 cell counts between 50 and 250/mm3

Treatment with indinavir has been shown to result in marked decreases in viral load and increases in CD4 cell counts in HIV-infected individuals. A randomized double-blind study to evaluate the efficacy of indinavir alone (800 mg q8h), zidovidine alone (200 mg q8h) or the combination was performed to evaluate progression to AIDS. 996 antiretroviral therapy-naive patients with CD4 cell counts of 50-250/mm3 were allocated to treatment. During the trial the protocol was amended to add lamivudine to the zidovudine-containing arms. The primary endpoint was time to development of an AIDS-defining illness or death. The study was terminated after a protocol-defined interim analysis demonstrated highly significant reductions in progression to a clinical event in the indinavir-containing arms, compared to the zidovudine arm (p<0. 0001). Over a median follow-up of 52 weeks (up to 99 weeks), percent reductions in hazards for the indinavir plus zidovudine and indinavir groups compared to the zidovudine group were 70% and 61%, respectively. Significant reductions in HIV RNA and increases in CD4 cell counts were also seen in the indinavir-containing groups compared to the zidovudine group. Improvement in both CD4 cell count and HIV RNA were associated with reduced risk of disease progression. All three regimens were generally well tolerated.     

CD4 cell counts in adults with newly diagnosed HIV infection: results of surveillance in England and Wales, 1990-1998. CD4 Surveillance Scheme Advisory Group

OBJECTIVES: To describe the distribution and changes in CD4 cell counts (both initial and subsequent) in HIV-infected persons over time and determine the factors influencing these counts. DESIGN: Reports were requested from laboratories measuring CD4 cell counts in England and Wales. Initial counts were analysed and median counts were followed over time. METHODS: Time trends and the relationship between initial CD4 cell count and age, sex, and HIV risk category were studied using quantile regression methods or chi-square tests. RESULTS: Between 1990 and 1998, 9553 adults were newly diagnosed with HIV infection and had a CD4 cell count within 6 months of HIV diagnosis. Over 50% of initial CD4 cell counts in each major risk category were below 350 cells/mm3. Older age (P < 0.001), male sex (P < 0.013) and heterosexual risk (P < 0.001) were independently associated with lower initial CD4 cell counts. For heterosexually infected adults, the median initial CD4 cell count was significantly negatively associated with the year of diagnosis (P = 0.03) and the median age increased through the time period examined (P < 0.001), whereas for men who have sex with men (MSM), there was no significant change in these values over time. For each year cohort of newly diagnosed individuals, the median CD4 cell count in subsequent years decreased until 1996 and then increased thereafter, consistent with a treatment effect. CONCLUSION: Across all major risk groups, a large proportion of HIV-infected adults are being diagnosed late in the course of HIV disease. For the heterosexually infected, the data suggest an ageing cohort effect, whereas for MSM the data are consistent with continuing transmission.     

Impact of baseline viral load and adherence on survival of HIV-infected adults with baseline CD4 cell counts > or = 200 cells/microl

BACKGROUND: Baseline plasma HIV RNA levels > 100 000 copies/ml have been associated with elevated mortality rates after the initiation of HAART. There is uncertainty regarding the optimal strategy for patients with high plasma HIV RNA but CD4 cell count > or = 200 cells/microl. OBJECTIVE: To evaluate the impact of baseline plasma HIV RNA on survival among patients with CD4 cell counts > or = 200 cells/microl. METHODS: Patients were stratified by plasma HIV RNA, CD4 cell count and adherence level. Mortality rates were evaluated using Kaplan-Meier methods and Cox regression. RESULTS: Among 1166 patients initiating HAART with a CD4 cell count > or = 200 cells/microl, a baseline HIV RNA > or = 100 000 copies/ml was statistically associated with elevated mortality among non-adherent patients (log-rank P = 0.032), but not for adherent patients (log-rank P = 0.690). In a multivariate Cox model comparing patients with a baseline CD4 cell count > or = 200 cells/microl and a baseline plasma HIV RNA < 100 000 copies/ml, the mortality rate was statistically similar among patients with a baseline CD4 cell count > or = 200 cells/microl and a baseline plasma HIV RNA > or = 100 000 copies/ml (relative hazard, 1.21; 95% confidence interval, 0.89-1.65; P = 0.232). CONCLUSION: HIV RNA > or = 100 000 copies/ml was only associated with mortality among HIV-infected patients initiating HAART with CD4 cell counts > or= 200 cells/microl if the patients were non-adherent.     

Correlation between CD4 cell counts and cellular and plasma viral load in HIV-1-seropositive individuals.

We conducted a study of 152 HIV-1-seropositive individuals in order to evaluate the possible correlations between the isolation of HIV from peripheral blood mononuclear cells or from plasma and CD4 cell counts. HIV was isolated from only 36% of plasma samples, and the isolation rate was closely related to CD4 cell counts, increasing gradually from 0% in subjects with greater than 800 x 10(6)/l CD4 cells to 88% in those with less than 100 x 10(6)/l CD4 cells. In contrast, HIV was isolated from 92% of cell samples (99% in subjects with less than 900 x 10(6)/l CD4 cells, 46% in those with CD4 counts greater than or equal to 900 x 10(6)/l). Since most cell samples were positive, a scoring method was designed to quantify the cellular viral load. The results obtained demonstrated that the cellular viral load was closely related to CD4 counts. We also found that the cellular viral load was higher in subjects with either positive plasma isolation or positive p24 antigenaemia. The measurement of the cellular viral load by this scoring method appears to be useful for the management of HIV-seropositive individuals and for the evaluation of therapeutic trials.     

Relationship between herpes simplex virus ulceration and CD4+ cell counts in patients with HIV infection.

OBJECTIVE: To establish the incidence of herpes simplex virus (HSV) ulceration in relation to CD4+ cell counts in HIV-infected patients. DESIGN: Swabs were taken from all ulcerated lesions in HIV-infected patients and cultured for HSV. CD4+ cell counts were performed at regular intervals. SETTING: The HIV unit at a London teaching hospital (the Royal Free Hospital, London, UK). PATIENTS: All HIV-infected patients (n = 500) attending the HIV unit. RESULTS: Two hundred and twenty-three swabs were obtained from 118 patients; 83 (37.2%) swabs from 62 (52.5%) patients were positive for HSV. Of 96 swabs taken from patients with CD4+ cell counts < 50 x 10(6)/l, 56 (58.3%) were positive for HSV, compared with 27 of 127 (21.2%) swabs from patients with higher CD4+ cell counts (P < 0.0001). Of patients with CD4+ cell counts < 50 x 10(6)/l, 37 of 47 (78.7%) had positive cultures compared with 25 of 71 (35.2%) of patients with higher counts (P < 0.0001). This trend was observed with swabs from all body sites; sufficient samples were available from oral and perianal lesions to demonstrate statistical significance (P < 0.0001 and P = 0.007, respectively). CONCLUSIONS: These results show a sharp rise in the incidence of HSV with CD4+ cell counts < 50 x 10(6)/l and thus provide important data for the design of studies of anti-HSV prophylaxis. Furthermore, since nearly 60% of all ulcers in patients with such low CD4+ counts are HSV-positive, we suggest appropriate empirical therapy on presentation.     

HIV co-infection, CD4 cell counts and clinical correlates of bacillary density in pulmonary tuberculosis.

BACKGROUND: Sputum microscopy for acid-fast bacilli (AFB) is the commonest diagnostic method for pulmonary tuberculosis (PTB) in developing countries. The method is reported to be less sensitive in human immunodeficiency virus (HIV) positive compared to negative patients. We determined the bacillary density in sputum of smear-positive PTB patients and related it to the patients' HIV status, CD4 cell count, clinical and demographic characteristics. METHODS: Three sputum samples per patient were examined using microscopy before initiating therapy. The AFB density was graded according to World Health Organization recommendations. The smear with the highest density was used. High bacillary density was defined as >10 AFB/field. HIV status and CD4 cell count were determined according to the national guidelines. RESULTS: Of 844 patients, 433 (51.3%) were HIV-positive. High bacillary density was significantly less common among HIV-positive (39.0%) than -negative (75.7%) patients (prevalence ratio 0.52; 95%CI 0.45-0.59, P < 0.0001). Among HIV-positive patients, the proportion of those with high bacillary density increased progressively with CD4 cell counts (P = 0.003). CONCLUSION: HIV is associated with lower AFB concentration in sputum. The AFB density falls with falling CD4 cell count. Microscopy for AFB in sputum may be less sensitive in diagnosing PTB when HIV infection is present, especially in severely immunocompromised patients.     

Phase III study of granulocyte-macrophage colony-stimulating factor in advanced HIV disease: effect on infections, CD4 cell counts and HIV suppression. Leukine/HIV Study Group

OBJECTIVE: To evaluate the effect of adjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF) (sargramostim, yeast-derived recombinant human GM-CSF) on incidence and time to opportunistic infection or death, plasma HIV-RNA, and CD4 cell count in patients with advanced HIV disease. METHODS: This Phase III randomized, double-blind, placebo-controlled trial enrolled subjects with CD4 cell counts < or = 50 x 10(6)/l or < or = 100 x 10(6)/l with a prior AIDS-defining illness on stable antiretroviral therapy. Subjects were stratified by baseline HIV-RNA level (> or = or < 30,000 copies/ml) and randomized to receive subcutaneous injections of GM-CSF 250 microg or placebo three times per week for 24 weeks. Subjects were permitted to continue on blinded drug for up to 20 months. Subjects were evaluated for infections, plasma HIV-RNA, lymphocyte counts, changes in antiretroviral therapy, toxicity, and survival. RESULTS: Three-hundred and nine subjects received at least one dose of study drug, 70% completed 24 weeks of therapy. Groups were well matched at baseline. Significant increases in CD4 cell and neutrophil counts were observed at 1, 3, and 6 months in the GM-CSF group. GM-CSF significantly reduced the incidence of overall infections (78% placebo versus 67% GM-CSF; P = 0.03) and delayed time to first infection (56 days placebo versus 97 days GM-CSF; P = 0.04). No statistical difference in cumulative opportunistic infections was observed between groups; however, among subjects without an opportunistic infection prior to study, the GM-CSF group demonstrated a trend towards fewer subjects with an opportunistic infection on study (26% placebo versus 8% GM-CSF; P = 0.08). Change in HIV-RNA was not significantly different between groups, but significantly fewer GM-CSF subjects with baseline viral load < 30,000 copies/ml had changes in antiretroviral therapy for increased viral load (42% placebo versus 21% GM-CSF; P = 0.01). In patients with HIV-RNA levels below the limit of detection at baseline, more GM-CSF patients maintained an undetectable viral load at 24 weeks (54% placebo versus 83% GM-CSF; P = 0.02). GM-CSF was well tolerated. CONCLUSIONS: GM-CSF significantly increased CD4 cell count and decreased virological breakthrough and overall infection rate in subjects with advanced HIV disease.     

Discontinuation of potent antiretroviral therapy: predictive value of and impact on CD4 cell counts and HIV RNA levels.

OBJECTIVE: To characterize predictors and consequences of discontinuing antiretroviral therapy (ART) in terms of CD4 cell count, HIV RNA, and reported side-effects in a large cohort of HIV-infected women. DESIGN: Cohort study. METHODS: A total of 1058 HIV-infected women initiated potent ART before September 1999. For each 6 month period after October 1996 we determined the proportion of potent ART users who downshifted to non-potent ART and who discontinued all ART. We examined the role of CD4 cell count and HIV RNA with regard to ART discontinuation. RESULTS: Between October 1996 and September 1999, 1058 individuals contributed 3362 visits at which potent ART was reported in the previous 6 months. Overall rates of 6 month downshifting and discontinuation were 10.0% and 6.7%. The proportion of individuals discontinuing all ART increased from 2.9% in late 1996 to 9.1% in mid 1999 (P < 0.001). Individuals with high HIV RNA levels were more likely to discontinue (P < 0.05). Compared to those who continued on potent ART, individuals who discontinued experienced large declines (P < 0.001) in CD4 cell counts and were more than three times more likely (P < 0.001) to experience HIV RNA increases. However, over one-third of those discontinuing ART reported side-effects and this subset had smaller CD4 cell count declines as compared to discontinuers not reporting side-effects (P = 0.147). CONCLUSIONS: In a large cohort of HIV-infected women, an increasing proportion of potent ART users discontinued ART over 3 years. Higher HIV RNA levels predicted discontinuation. Immediate immunological/virological deleterious consequences were observed. Side-effects were the most common reason for discontinuation and CD4 cell count declines were larger among those who did not cite side-effects as the reason for discontinuation.     

The values of quantitative serum HIV-1 RNA levels and CD4 cell counts for predicting survival time among HIV-positive individuals with CD4 counts of < or = 50 x 10(6) cells/l

OBJECTIVE: To evaluate the HIV-1 RNA level as a predictor of survival time among individuals with advanced AIDS. METHODS: The serum HIV-1 RNA level, the CD4 cell count, and other clinical variables were evaluated at baseline, as predictors of survival time, among 56 retrospectively identified HIV-1 positive individuals with < or = 50 x 10(6) CD4 cells/l who attended the Beth Israel Deaconess Medical Center, Division of Infectious Diseases, between 1 July 1989 and 30 September 1993. RESULTS: During follow-up, 55 of these 56 patients died. The median survival time was 20.5 months. In univariate Cox proportional hazard modeling neither the baseline HIV-1 RNA level nor the CD4 cell count were predictive of survival time. However, in multivariate models longer survival time was associated with the use of trimethoprim-sulphamethoxazole at entry [hazard ratio (HR), 0.42; P = 0.007], whereas shorter survival time was associated with a history of an AIDS-defining illness other than Pneumocystis carinii pneumonia (HR, 2.87; P = 0.007). Correlative analysis revealed a modest correlation of the baseline CD4 cell count with survival time (Spearman p = 0.41; P = 0.002). However, no correlation was found between HIV RNA levels and survival time (P = 0.5). CONCLUSIONS: In this population with very advanced disease, the HIV-1 RNA level was a poor discriminator of survival time, being inferior to the CD4 cell count and to specific clinical variables such as the nature of the prior AIDS-defining illness and the type of Pneumocystis carinii pneumonia prophylaxis employed. Among individuals with advanced AIDS, these data emphasize the relative importance of the CD4 cell count and of specific clinical factors, over the HIV-1 RNA level in predicting survival time.