Clinical outcome of HIV-infected antiretroviral-naive patients with discordant immunologic and virologic responses to highly active antiretroviral therapy

BACKGROUND: The prognostic significance of a response to highly active antiretroviral therapy (HAART) that is immunologically and virologically discordant is not well understood. METHODS: Four hundred four antiretroviral-naive patients initiating HAART at an urban HIV outpatient clinic in 1995 to 2004 were analyzed. The association of treatment responses at 3 to 9 months after HAART initiation with time to development of an opportunistic infection (OI) or death was determined using Cox proportional hazards modeling. Logistic regression modeling was used to examine the association between discordant responses and patient characteristics. RESULTS: Of 404 patients, 70.5% experienced favorable concordant responses (CD4 cell count [CD4]+/viral load [VL]+: increase in CD4 count of >or=50 cells/microL and achievement of undetectable plasma HIV RNA level), 15.8% an immunologic response only (CD4+/VL(-)), 8.7% a virologic response only (CD4(-)/VL+), and 5.0% a concordant unfavorable response (CD4(-)/VL(-)). Both types of discordant responses (CD4+/VL(-) and CD4(-)/VL+), nonresponse (CD4(-)/VL(-)), and baseline CD4 cell count were significantly associated with earlier development of an OI or death (relative hazard [RH] = 2.81, 95% confidence interval [CI]: 1.31 to 3.97; RH = 4.83, 95% CI: 2.10 to 11.12; and RH = 0.93, 95% CI: 0.88 to 0.99, respectively). CD4+/VL(-) and CD4(-)/VL(-) were associated with nonwhite race in multivariate logistic regression models (adjusted OR = 2.83, 95% CI: 1.46 to 5.47 and adjusted OR = 6.50, 95% CI: 1.65 to 25.69, respectively). CONCLUSION: Discordant immunologic and virologic responses at 3 to 9 months after HAART initiation play important roles in predicting long-term clinical outcomes in treatment-naive patients.     

The impact of adherence on CD4 cell count responses among HIV-infected patients

BACKGROUND: There have been concerns that irreversible immune damage may result if highly active antiretroviral therapy (HAART) is initiated after the CD4 cell count declines to below 350 cells/microL; however, the role of antiretroviral adherence on CD4 cell count responses has not been well evaluated. METHODS: We evaluated CD4 cell count responses of 1522 antiretroviral-naive patients initiating HAART who were stratified by baseline CD4 cell count (<50, 50-199, and >or=200 cells/microL) and adherence. RESULTS: Among patients starting HAART with <50 cells/microL, during the fifth 15-week period after the initiation of HAART, absolute CD4 cell counts were 200 cells/microL (interquartile range [IQR]: 130-290) for adherent patients versus 60 cells/microL (IQR: 10-130) for nonadherent patients. Similarly, among patients starting HAART with 50 to 199 cells/microL, during the fifth 15-week period after the initiation of HAART, absolute CD4 cell counts were 300 cells/microL (IQR: 180-390) versus 125 cells/microL (IQR: 40-210) for nonadherent patients. In Cox regression analyses, adherence was the strongest independent predictor of the time to a gain of >or=50 cells/microL from baseline (relative hazard [RH] = 2.88, 95% confidence interval [CI]: 2.46-3.37). Among patients with baseline CD4 cell counts <200 cells/microL, adherence was the strongest independent predictor of the time to a CD4 cell count >200 cells/microL (RH = 4.85, 95% CI: 3.15-7.47). CONCLUSIONS: These data demonstrate that substantial CD4 gains are possible among highly advanced adherent patients and should contribute to the ongoing debate over the optimal time to initiate HAART.     

Presence of HIV-specific CD4+ T-cell responses in HIV-infected subjects with sustained virologic control after highly active antiretroviral therapy

HIV-specific CD4+ T-helper cell responses in 40 subjects with chronic infection (CI) who had virus suppression after highly active antiretroviral therapy (HAART) were compared with those in 34 subjects treated during primary infection (PI). A CD4+ T-cell proliferative response to HIV p24 protein was present in 50% of these subjects compared with 79% of subjects treated during PI. The existence of a proliferative response in CI subjects was associated with a higher CD4+ T-cell count at initiation of HAART, a longer duration of virus suppression, and a higher CD4+ T-cell count at the time of analysis. These results show that an HIV-specific proliferative response is preferentially observed in treated CI subjects with CD4+ T-cell counts of >200/microL. However, in treated CI subjects with a significant degree of CD4+ T-cell depletion (<200/microL), it may also be observed in 35% provided that the duration of virus suppression is long enough, which may have implications for future therapeutic strategies.     

Herpes zoster in women with and at risk for HIV: data from the Women's Interagency HIV Study

BACKGROUND: Herpes zoster occurs at all CD4 cell counts in HIV-infected adults. It was hypothesized that even in the era of highly active antiretroviral therapy (HAART), zoster risk is higher in HIV-infected than uninfected women. METHODS: Generalized estimating equations modeled self-reported occurrence of zoster between semiannual visits among 1832 HIV-infected and 489 HIV-uninfected women in the Women's Interagency HIV Study followed for up to 7.5 years. RESULTS: A total of 337 (18.4%) HIV-infected and 7 (1.4%) HIV-uninfected women reported zoster at some time during follow-up. Using HIV-infected women with CD4 >750 cells/microL as the reference category, the odds ratios for reporting zoster since the prior visit were: 1.43 (95% CI 0.86-2.37) for CD4 500-749 cells/microL, 2.07 (95% CI 1.27-3.38) for CD4 350-499 cells/microL, 2.72 (95% CI 1.66-4.46) for CD4 200-349 cells/microL, and 3.16 (95% CI 1.92-5.18) for CD4 <200 cells/microL, compared with 0.11 (95% CI 0.046-0.26) for HIV-uninfected women. In multivariate analyses using visits from all HIV-infected women and only those who initiated HAART, lower CD4 cell count was more strongly associated with zoster incidence than were other clinical indicators. CONCLUSIONS: Herpes zoster is associated with degree of immunosuppression in HIV-infected women, but even women with high CD4 counts are at greater risk of zoster than HIV-uninfected women.     

Short-term CD4 cell response after highly active antiretroviral therapy initiated at different times from seroconversion in 1,500 seroconverters

The effect of HIV infection duration and CD4 cell count on short-term CD4 response was evaluated in treatment-naive seroconverters using logistic regression adjusted for CD4 count before highly active antiretroviral therapy (HAART) as well as for exposure category, age, sex, acute infection, and cohort. This association was also investigated in pretreated seroconverters, further adjusting for prior therapy. CD4 response (increase of >100 cells/microL at 6 months) was more likely if HAART was initiated in the first year following seroconversion (OR = 1.50 [95% CI: 1.07-2.10] compared with 2-5 years). There was no improvement in response from initiating HAART with CD4 count >350 cells/microL compared with 201 to 350 cells/microL. Below 200 cells/microL, however, the chance of a CD4 response appeared to be reduced (OR = 0.72 [95% CI: 0.40-1.28] for 0-200 cells/microL compared with 201-350 cells/microL, P = 0.26). Results were similar for pretreated individuals. Further, in pretreated individuals, a CD4 response was less likely if the CD4 nadir was lower than the pre-HAART CD4 count (OR = 0.18 [95% CI: 0.10-0.36] for >150 cells/microL difference between nadir and pre-HAART CD4 count vs. no difference, P < 0.001). Given the limitations of observational studies, particularly the inability to control for unmeasured confounders, these findings suggest that the initiation of HAART within the first year following seroconversion appears to improve short-term immunologic response. After that time, there is little to be gained in terms of short-term response from initiating HAART before reaching a CD4 count of 200 cells/microL.     

Increased body mass index does not alter response to initial highly active antiretroviral therapy in HIV-1-infected patients

BACKGROUND: Body mass index (BMI) can influence drug metabolism, thus affecting efficacy and risk for toxicities. Hypothesizing that persons with an increased BMI and larger volumes of distribution may experience a suboptimal response to highly active antiretroviral therapy (HAART), we evaluated the effect of BMI on virologic and immunologic response in previously ART-naive patients initiating therapy. METHODS: Using data from the HIV Outpatient Study, we analyzed the statistical association of BMI and other selected demographic variables with achieving an undetectable viral load and experiencing a CD4 cell count increase of more than 100 cell/microL after 3 to 9 months of therapy among antiretroviral-naive patients initiating HAART. RESULTS: Among 711 patients included in analysis, 43% had a BMI of more than 25 (overweight-obese). Higher BMI was associated with being female, having black or Hispanic race/ethnicity, being heterosexual, and using injection drugs (all P<0.001). The patients in BMI groups did not differ significantly by baseline CD4 cell count or the duration of the initial HAART regimen. Although median baseline viral loads were significantly lower in obese participants (P=0.008), overweight or obese BMI did not significantly alter the likelihood of achieving an undetectable viral load and a CD4 cell count increase of more than 100 cells/microL compared with normal weight persons. CONCLUSION: A substantial proportion of HIV-infected outpatients in this cohort were overweight or obese. Increased BMI was not associated with decreased virologic and immunologic responses to initial HAART. Responses were equivalent and within expected ranges between normal weight patients, overweight patients, and obese patients at 3 to 9 months of observation.     

Allergen immunotherapy in a patient with human immunodeficiency virus: effect on T-cell activation and viral replication.

BACKGROUND: Allergen immunotherapy is a major therapeutic modality in the treatment of allergic rhinitis. However, with T-cell activation potential, its role in patients with human immunodeficiency virus (HIV) was theoretically limited. OBJECTIVE: To report the results of allergen immunotherapy in a patient with HIV treated with highly active antiretroviral therapy (HAART). METHODS: A 44-year-old man with a history of HIV did not respond to medical therapy for allergic rhinitis. His HIV status was well controlled with HAART. Owing to the severity of his allergic rhinitis symptoms, he accepted the risk of allergy immunotherapy despite the unknown effect of immunotherapy in patients with HIV. RESULTS: After 6 weeks of weekly immunotherapy injections, his viral load remained undetectable and his CD4 cell count changed from 540 to 570 cells/microL. After 16 weeks of weekly immunotherapy, his viral load increased to 10,900 copies/mL, and his CD4 cell count increased to 665 cells/microL. After 24 weeks of weekly immunotherapy, his viral load returned to an undetectable level, and his CD4 cell count stabilized at 356 cells/microL. Despite his notable change in HIV status, he continues to receive the same HAART. He currently continues en route to maintenance immunotherapy. CONCLUSIONS: The effect of allergen immunotherapy on HIV infection has not been previously reported. A concern remains that any form of immunotherapy may negatively affect HIV disease progression. This case illustrates that weekly allergen immunotherapy may have induced limited T-cell proliferation and a modest increase in RNA viral load, which resolved with continuation of HAART.     

Response to highly active antiretroviral therapy at 6 months and long-term disease progression in HIV-1 infection

OBJECTIVE: To compare the long-term prognostic significance of different definitions of immunologic and virologic responses to highly active antiretroviral therapy (HAART) at 6 months. METHODS: This was a prospective study conducted in 68 French hospitals. HAART was initiated in 2236 protease inhibitor-naive patients included in the French Hospital Database on HIV. Multivariate Cox proportional hazard models measuring time from 6 months after starting HAART were used to compare the strength of the association between different definitions of immunologic and virologic responses at 6 months and subsequent progression to AIDS or death. The Akaike's Information Criteria were used to identify the most appropriate model. RESULTS: During a median follow-up of 58 months, 325 patients experienced an AIDS-defining event or died. The model that fitted best was the model in which the CD4 cell count and plasma HIV-1 RNA values attained at 6 months were considered. The risk of clinical progression at 5 years ranged from 7% (95% confidence interval [CI]: 4-10) in patients whose CD4 cell count at 6 months was >or=350 cells/microL and whose HIV-1 RNA concentration was <3 log10 copies/mL to 63% (95% CI: 52-75) in patients whose CD4 cell count at 6 months was <100 cells/microL and whose HIV-1 RNA concentration was >or=5 log10. CONCLUSIONS: Plasma HIV-1 RNA concentration and CD4 cell count should be taken into account independently when evaluating early response to treatment. The persistent impact of early response on clinical progression at 5 years emphasizes the major importance of the success of first-line HAART.     

Incidence of and risk factors for symptomatic visceral leishmaniasis among human immunodeficiency virus type 1-infected patients from Spain in the era of highly active antiretroviral therapy

The way in which the extensive use of highly active antiretroviral therapy (HAART) has influenced the incidence of visceral leishmaniasis (VL) among human immunodeficiency type 1 (HIV-1)-infected patients is not yet understood. The present study assessed whether the incidence of symptomatic VL in HIV-infected patients has decreased since the introduction of HAART. Likewise, the role of other potential risk factors for VL was also analyzed. Therefore, 479 HIV-1-infected patients receiving antiretroviral treatment, according to the available drugs at each moment, were prospectively followed from April 1989 to June 2000 in two university hospitals in southern Spain. A bone marrow aspiration was performed when patients showed symptoms suggestive of kala-azar. A diagnosis of VL was made when Leishmania amastigotes were seen in Giemsa-stained samples or promastigotes were cultured in specific media. The median follow-up time was 1,380 [8 to 4,536] days. Twenty-one patients were diagnosed with symptomatic VL. The density of incidence of VL has decreased 64.8% as of January 1997, when HAART began to be used extensively in our area. The use of HAART was the main independent factor associated with VL; this therapy was a protective factor (adjusted hazard ratio [HR], 0.05; 95% confidence interval [CI], 0.02 to 0.15). CDC clinical category C at entry in the cohort (HR, 4.08; 95% CI, 1.46 to 11.35) and CD4(+) cell counts below 300 cells/mm(3) during the follow-up (HR, 3.96; 95% CI, 1.56 to 10.01) were also independently associated with kala-azar. A VL diagnosis prior to follow-up and low compliance with antiretroviral therapy were not independently associated with symptomatic VL, although statistical significance was almost reached (P = 0.1 and P = 0.08, respectively). In summary, the use of HAART has led to a fall in the incidence of symptomatic VL in HIV-infected patients. The main risk factor associated with kala-azar emergence in patients infected with HIV is deep immunosuppression.     

Prognostic factors of combined viral load and CD4+ cell count responses under triple antiretroviral therapy, Aquitaine cohort, 1996-1998

OBJECTIVE: To describe the viroimmunologic response and its prognostic factors 6 months after initiating triple antiretroviral therapy in a cohort of HIV-1-infected patients. METHODS: Positive virologic response during follow-up (VL+) was defined as plasma HIV RNA level <500 copies/ml and positive immunologic response (CD4+) as an increase of CD4+ count of at least 50 cells/mm3. Four categories of response were defined: VL+/CD4+; VL+/CD4-; VL-/CD4+ and VL-/CD4-. Prognostic factors were studied through a polytomous logistic regression (VL-/CD4-, as reference). RESULTS: Baseline characteristics of the 478 studied patients were: 22% at AIDS stage, 77% pretreated, median CD4+ cell count 195/mm3 and HIV RNA level 4.42 log. At 6 months 37.5% were VL+/CD4+; 15.7% VL+/CD4-; 23.8% VL-/CD4+ and 23.0% VL-/CD4-. Baseline HIV RNA level was associated to a higher risk of VL-/CD4+ response. More advanced age was associated with a higher risk of isolated immunologic failure (VL+/CD4-), whereas pretreatment and saquinavir therapy were associated with a lower frequency of positive virologic response independently of immunologic response. CONCLUSION: HIV-RNA level, pretreatment, and saquinavir therapy were already known to be linked to therapeutic response. Based on our results, a high baseline HIV-RNA level is associated with isolated immunologic response; moreover, age should be of importance in treatment decision.     

Characteristics and outcome of AIDS-related Hodgkin lymphoma before and after the introduction of highly active antiretroviral therapy

OBJECTIVES: We analyzed survival, therapeutic response, and prognostic factors in patients with HIV-related Hodgkin lymphoma (HL) treated or not with highly active antiretroviral therapy (HAART). METHODS: This study included 104 patients with HL, treated (n = 83) or not (n = 21) with HAART. Outcomes and prognostic factors of complete remission (CR), overall survival (OS), and disease-free survival (DFS) were assessed by an intention-to-treat analysis of all patients who received at least 1 chemotherapy course. RESULTS: No differences were found between groups at baseline in the specific characteristics of HIV and HL. The proportion of patients receiving appropriate-for-stage therapy for HL was similar for both groups. The CR rates in the HAART (-) and HAART (+) groups were 14 (70%) of 20 versus 71 (91%) of 78 (P = 0.023). The median OS in the HAART (-) group was 39 months (95% confidence interval [CI]: 0 to 89) and was not reached in the HAART (+) group (P = 0.0089). The median DFS in the HAART (-) group was 85 months (95% CI: 73 to 97) and was not reached in the HAART (+) group (P = 0.129). Factors independently associated with CR by logistic regression analysis were appropriate-for-stage therapy of HL, HAART, and baseline CD4 count > or =100 cells/microL. CR was the only factor independently associated with OS by Cox regression analysis. CONCLUSIONS: The achievement of CR was independently associated with appropriate-for-stage therapy for HL, with HAART, and with a baseline CD4 count > or =100 cells/microL. The only variable independently associated with OS was the achievement of CR.     

HIV antiretroviral treatment: early versus later

OBJECTIVES: Cohort studies indicate that starting highly active antiretroviral therapy (HAART) when the CD4+ T-cell count is less than 200 cells/muL is associated with poor outcomes. These studies have been unable to address how early HAART should be initiated, however. This report uses a modeling approach to compare starting HAART at a mean CD4+ T-cell count greater than 350 cells/microL (early) versus less than 350 cells/microL but greater than 200 cells/microL (later). METHODS: A Markov model tracks people with HIV infection through 6 disease stages defined by CD4+ T-cell count ranges over a 25-year period. Transition probabilities between the disease stages for 6-month periods vary according to initial viral load. Sequences of different first-line, second-line, and "salvage" antiretroviral regimens are defined, and their impact on transition probabilities is estimated. HAART effectiveness is based on data from an urban hospital-based HIV clinic, supplemented by clinical trial data. The model computes the incremental cost-effectiveness of alternative treatment patterns and includes sensitivity analyses for a range of plausible alternative input values. RESULTS: Starting HAART earlier rather than later increases total lifetime costs by $19,074, increases years of life by 1.21 years, increases discounted quality-adjusted life-years by 0.61, and has an incremental cost-effectiveness ratio of $31,266 per quality-adjusted life-year. Early therapy is more cost-effective when the impact of HAART on well-being is smaller. CONCLUSIONS: Initiation of HAART at a CD4+ T-cell count greater than 350 cells/microL may be cost-effective (less than $50,000 per quality-adjusted life-year) compared with initiating HAART at a CD4+ T-cell count less than 350 cells/microL but greater than 200 cells/muL and may result in longer quality-adjusted survival.     

Impact of weight on immune cell counts among HIV-infected persons

Prior studies have shown that weight may impact immune cell counts. However, few data exist about the relationship of weight and immune cell counts among HIV-infected patients. We examined documented HIV seroconverters (mean window, 15.7 months) in a prospective U.S. Military HIV Natural History Study (1 January 1986 to 20 January 2010). We estimated the association of the time-updated body mass index (BMI) category with changes in immune cell counts from HIV diagnosis across time (mean follow-up of 5.1 years) using multiply adjusted longitudinal linear mixed-effects models. Of 1,097 HIV seroconverters, 448 (41%) were overweight and 93 (8%) were obese at HIV diagnosis. Immune cell counts at HIV diagnosis did not significantly differ by BMI category. In the longitudinal models for those diagnosed before the advent of the highly active antiretroviral therapy (HAART) era, mean postdiagnosis decreases in the white cell count, total lymphocyte count, CD4 count, CD4 percentage, and CD4/CD8 ratio were less as the BMI category increased (all with P values of <0.05). Among HIV seroconverters diagnosed in the HAART era, obese compared to normal-weight patients had significantly smaller increases in CD4 counts, CD4 percentages, and the CD4/CD8 ratio (all with P values of <0.05). Similar findings were also noted among underweight versus normal-weight patients. In conclusion, although BMI was not associated with immune cell levels at the time of HIV diagnosis, weight appears to affect immune cells counts over the course of infection. In the HAART era, being either underweight or obese was associated with smaller increases in several important immune cell levels, including the CD4/CD8 ratio.     

Micronutrient levels and HIV disease status in HIV-infected patients on highly active antiretroviral therapy in the Nutrition for Healthy Living cohort

BACKGROUND: Low serum micronutrient levels were common before widespread use of highly active antiretroviral therapy (HAART) and were associated with adverse outcomes. Few data are available on micronutrient levels in subjects taking HAART. OBJECTIVE: To determine the prevalence of low serum retinol, alpha-tocopherol, zinc, and selenium in HIV-infected subjects taking HAART and to assess the association of micronutrient levels with HIV disease status. DESIGN: Cross-sectional. SETTING: Nutrition for Healthy Living (NFHL) study. PARTICIPANTS: HIV-infected subjects on HAART. METHODS: Retinol, alpha-tocopherol, zinc, and selenium were determined in frozen serum samples from 171 men and 117 women. Low serum levels were defined as retinol <30 microg/dL, selenium <85 microg/L, alpha-tocopherol <500 microg/dL, and zinc <670 microg/L. Association of micronutrient quartiles with CD4 cell count, CD4 count <200 cells/mm, HIV viral load (VL), and undetectable VL was assessed using adjusted multivariate regression. RESULTS: Five percent of men and 14% of women had low retinol, 8% of men and 3% of women had low selenium, and 7% of men and no women had low alpha-tocopherol. Forty percent of men and 36% of women had low zinc, however. Subjects in the upper quartiles of zinc had lower log VL levels than those in the lowest quartile (significant for women). Subjects in the upper quartiles of selenium also tended to have lower VL levels compared with those in the lowest quartile. Surprisingly, women in the upper quartiles of retinol had higher log VLs than those in the lowest quartile. There was no significant association of any micronutrient with CD4 cell count or likelihood of CD4 count <200 cells/mm. The level of CD4 cell count influenced the association of retinol with log VL in men, however. In men with CD4 counts >350 cells/mm, those with higher retinol had higher log VLs compared with the lowest quartile, whereas in men with CD4 counts <350, those with higher retinol levels had lower log VLs compared with the lowest quartile. CONCLUSIONS: Low retinol, alpha-tocopherol, and selenium are uncommon in HIV-infected subjects on HAART. Zinc deficiency remains common, however. Decreased retinol levels in women and in men with CD4 counts >350 cells/mm and increased zinc and selenium levels in both genders may be associated with improved virologic control.     

Long-term CD4+ lymphocyte response following HAART initiation in a U.S. Military prospective cohort

Background

Among HIV-infected persons initiating highly active antiretroviral therapy (HAART), early CD4+ lymphocyte count increases are well described. However, whether CD4+ levels continue to increase or plateau after 4-6 years is controversial.

Methods

To address this question and identify other determinants of CD4+ response, we analyzed data for 1,846 persons from a prospective HIV military cohort study who initiated HAART, who had post-HAART CD4+ measurements, and for whom HIV seroconversion (SC) date was estimated.

Results

CD4+ count at HAART initiation was ≤ 200 cells/mm³ for 23%, 201-349 for 31%, 350-499 for 27%, and ≥500 for 19%. The first 6 months post-HAART, the greatest CD4+ increases (93-151 cells) occurred, with lesser increases (22-36 cells/year) through the first four years. Although CD4+ changes for the entire cohort were relatively flat thereafter, HIV viral load (VL) suppressors showed continued increases of 12-16 cells/year. In multivariate analysis adjusting for baseline CD4+ and post-HAART time interval, CD4+ responses were poorer in those with: longer time from HIV SC to HAART start, lower pre-HAART CD4+ nadir, higher pre-HAART VL, and clinical AIDS before HAART (P < 0.05).

Conclusions

Small but positive long-term increases in CD4+ count in virally suppressed patients were observed. CD4+ response to HAART is influenced by multiple factors including duration of preceding HIV infection, and optimized if treatment is started with virally suppressive therapy as early as possible.     

Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study

BACKGROUND: AIDS-related death and disease rates have declined in the highly active antiretroviral therapy (HAART) era and remain low; however, current causes of death in HAART-treated patients remain ill defined. OBJECTIVE: To describe mortality trends and causes of death among HIV-infected patients in the HAART era. DESIGN: Prospective, multicenter, observational cohort study of participants in the HIV Outpatient Study who were treated from January 1996 through December 2004. MEASUREMENTS: Rates of death, opportunistic disease, and other non-AIDS-defining illnesses (NADIs) determined to be primary or secondary causes of death. RESULTS: Among 6945 HIV-infected patients followed for a median of 39.2 months, death rates fell from 7.0 deaths/100 person-years of observation in 1996 to 1.3 deaths/100 person-years in 2004 (P=0.008 for trend). Deaths that included AIDS-related causes decreased from 3.79/100 person-years in 1996 to 0.32/100 person-years in 2004 (P=0.008). Proportional increases in deaths involving liver disease, bacteremia/sepsis, gastrointestinal disease, non-AIDS malignancies, and renal disease also occurred (P=or<0.001, 0.017, 0.006, <0.001, and 0.037, respectively.) Hepatic disease was the only reported cause of death for which absolute rates increased over time, albeit not significantly, from 0.09/100 person-years in 1996 to 0.16/100 person-years in 2004 (P=0.10). The percentage of deaths due exclusively to NADI rose from 13.1% in 1996 to 42.5% in 2004 (P<0.001 for trend), the most frequent of which were cardiovascular, hepatic, and pulmonary disease, and non-AIDS malignancies in 2004. Mean CD4 cell counts closest to death (n=486 deaths) increased from 59 cells/microL in 1996 to 287 cells/microL in 2004 (P<0.001 for trend). Patients dying of NADI causes were more HAART experienced and initiated HAART at higher CD4 cell counts than those who died with AIDS (34.5% vs 16.8%, respectively, received HAART for 4 of more years, P<0.0001; 22.4% vs 7.8%, respectively, initiated HAART with CD4 cell counts of more than 350 cells/microL, P<0.001). CONCLUSIONS: Although overall death rates remained low through 2004, the proportion of deaths attributable to non-AIDS diseases increased and prominently included hepatic, cardiovascular, and pulmonary diseases, as well as non-AIDS malignancies. Longer time spent receiving HAART and higher CD4 cell counts at HAART initiation were associated with death from non-AIDS causes. CD4 cell count at time of death increased over time.     

Immunity to human immunodeficiency virus (HIV) in children with chronic HIV infection receiving highly active antiretroviral therapy

Our objective was to describe the CD4-mediated human immunodeficiency virus (HIV)-specific cell-mediated immunity (CMI) and its virologic and immunologic correlates in children with chronic HIV infection on highly active antiretroviral therapy (HAART). Twelve HIV-infected children on stable antiretroviral therapy with a median level of CD4+ lymphocytes (CD4%) of 25.5% and a median viral load (VL) of 786 HIV RNA copies/ml were enrolled in this study. Nine of these children were also cytomegalovirus (CMV) seropositive. Blood mononuclear cells, stimulated with HIV and CMV antigens, were used to measure lymphocyte proliferation and to enumerate gamma interferon (IFN-gamma)-producing CD4+ cells. HIV CMI and CMV CMI were detected in similar proportions of patients and correlated with each other, although the HIV responses were less robust. HIV lymphocyte proliferation significantly increased with lower HIV VL and showed a trend to increase with higher CD4% and longer time on HAART. The in vitro IFN-gamma response to HIV or CMV was not affected by CD4%, VL, or HAART. Pediatric patients with established HIV infection on HAART frequently exhibit HIV CMI despite undetectable HIV replication. We concluded that the association between HIV CMI and CMV CMI indicates that the same factors govern responsiveness to either antigen.     

Determinants of HIV progression and assessment of the optimal time to initiate highly active antiretroviral therapy: PISCIS Cohort (Spain)

OBJECTIVE: We analyze the factors related to progression to AIDS or death in HIV-infected patients from the Proyecto para la Informatización del Seguimiento Clínico epidemiológico de los pacientes con Infección por VIH/SIDA (PISCIS) Cohort and we assess the optimal time to initiate highly active antiretroviral therapy (HAART) taking lead time into account. METHODS: We selected naive patients who were AIDS-free and initiated HAART after January 1998. Statistical analyses were performed using Cox proportional hazards models. Lead time was defined as the time it took the deferred group with an early disease stage to reach the later stage. The analysis accounting for lead time was performed using multiple imputation methods based on estimates from the pre-HAART period as described elsewhere. RESULTS: Multivariate analysis on 2035 patients (median follow-up = 34.3 months) showed significantly higher hazard ratios (HRs) for a CD4 count <200 cells/microL (HR = 3.79, 95% confidence interval [CI]: 2.18 to 6.57), HIV-1 RNA level >100,000 copies/mL (HR = 1.84, 95% CI: 1.26 to 2.69), and hepatitis C virus (HCV) coinfection (HR = 2.40, 95% CI: 1.65 to 3.49), whereas a lower risk was found for those who started HAART between January 2001 and June 2004 (HR = 0.55, 95% CI: 0.30 to 0.90). When lead time and unseen events were included, we found a higher risk of progression to AIDS among patients who deferred treatment when the CD4 count reached <200 cells/microL (HR = 2.97, 95% CI: 1.91 to 4.63) and 200 to 350 cells/microL (HR = 1.85, 95% CI: 1.03 to 3.33) compared with those who started treatment with CD4 counts from 200 to 350 cells/microL and >350 cells/microL, respectively. CONCLUSIONS: Advanced HIV disease, HCV coinfection, and early HAART period were determinants of AIDS progression or death. Lead-time analysis in asymptomatic HIV-infected patients suggests that the best time to start HAART is before the CD4 count falls to lower than 350 cells/microL.