Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy

OBJECTIVE: To determine the extent to which HIV-infected patients, including those with advanced immunodeficiency, can reverse peripheral CD4 T-cell depletion while maintaining long-term viral suppression on highly active antiretroviral therapy. DESIGN: Cohort study. PARTICIPANTS: Four-hundred and twenty-three HIV-infected patients who initiated HAART prior to 1998 and achieved a viral load 1000 copies/ml. MAIN OUTCOME MEASURE: CD4 count changes. RESULTS: Among patients who maintained plasma HIV RNA levels /= 350 x 10(6)/l, respectively (all gains were significantly greater than zero; P < 0.05). Among those with a pre-therapy CD4 count of < 50 x 10(6)/l, 88% achieved a CD4 cell count of >/= 200 x 10(6)/l and 59% achieved a count of >/= 350 x 10(6)/l by year 4. Factors associated with increased CD4 cell count gains from month 3 to year 4 included lower pre-therapy CD4 cell count, younger age, female sex, and infrequent low-level viremia (versus sustained undetectable viremia). CONCLUSIONS: Most patients who achieve and maintain viral suppression on HAART continue to experience CD4 T-cell gains through 4 years of therapy. The immune system's capacity for CD4 T lymphocyte restoration is not limited by low pre-therapy CD4 counts.     

A randomized trial of the impact of multiple micronutrient supplementation on mortality among HIV-infected individuals living in Bangkok

OBJECTIVES: To examine the impact of high-dose multiple micronutrient supplementation on survival and disease progression among HIV-infected individuals in Thailand. DESIGN: Randomized placebo-controlled trial. METHODS: Four-hundred and eighty-one HIV-infected men and women living in and around Bangkok with CD4 cell counts in the range 50 x 10(6)- 550 x 10(6)/l were randomized to receive micronutrients or placebo for a period of 48 weeks. Trial participants were examined clinically 12-weekly and tested for CD4 cell count 24-weekly. A subset were tested for HIV plasma viral load at 48 weeks. RESULTS: Seventy-nine (16%) trial participants were lost to follow-up and 23 (5%) died. The death rate was lower in the micronutrients arm with the mortality hazard ratios [95% confidence interval (CI)] of 0.53 (0.22-1.25; P = 0.1) overall and 0.37 (0.13-1.06; P = 0.052) and 0.26 (0.07-0.97; P = 0.03) among those with CD4 cell counts < 200 x 10(6)/l and < 100 x 10(6)/l respectively. There was no impact on CD4 cell count or plasma viral load. CONCLUSIONS: Multiple micronutrient supplementation may enhance the survival of HIV-infected individuals with CD4 cell counts < 200 x 10(6)/l. This could have important public health implications in the developing world where access to antiretrovirals remains poor. The clinical findings need to be reproduced in other settings and the mechanism, which appears to be independent of change in CD4 cell count, merits further investigation.     

Virologic and immunologic values allowing safe deferral of antiretroviral therapy

OBJECTIVE: To determine how long highly active antiretroviral therapy can be deferred in HIV-1 infected persons. DESIGN: Observational cohort study of HIV-1 infected men at four academic centers in the USA. OUTCOME: Progression to clinical AIDS or to CD4 cell counts < 200 x 10(6)/l in the absence of antiretroviral therapy among HIV-1 infected men. RESULTS: No participant with a CD4 cell count between 201 x 10(6) and 350 x 10(6)/l and having < 20 000 copies/ml of HIV RNA progressed to clinical AIDS within 1 year. In men with > 350 x 10(6) CD4 cells/l and < 60 000 copies of HIV RNA/ml there were also no instances of progression to clinical AIDS within 1 year. No participant with < 10 000 copies HIV RNA/ml and between 201 x 10(6) and 350 x 10(6) CD4 cells/l had a decrease in CD4 cells to < 200 x 10(6)/l within 1 year. In men with baseline CD4 cell counts > 350 x 10(6)/l and HIV RNA < 30 000 copies/ml, only 3% had a decrease in CD4 cell count to < 200 x 10(6)/l within 1 year. CONCLUSION: This analysis supports recommendations to defer therapy in HIV-1 infected individuals with CD4 cell counts > 350 x 10(6)/l and HIV RNA < 60 000 copies/ml and in persons with CD4 cell counts between 201 x 10(6) and 350 x 10(6)/l and < 20 000 copies/ml HIV RNA. Up to 79% of persons with > 350 x 10(6) CD4 cells/l and 29% with CD4 cell counts between 201 x 10(6) and 350 x 10(6)/l may, with close monitoring, safely defer therapy.     

Evaluation of the World Health Organization staging system for HIV infection and disease in Ethiopia: association between clinical stages and laboratory markers

OBJECTIVE: To study the association between the clinical axis of the World Health Organization (WHO) staging system of HIV infection and disease and laboratory markers in HIV-infected Ethiopians. DESIGN: Cross-sectional study. METHODS: Clinical manifestations and stage of HIV-positive individuals participating in a cohort study of HIV infection progression, and of HIV-positive patients hospitalized with suspicion of AIDS, were compared to CD4+ T-cell count and viral load. RESULTS: Of the 86 HIV-positive participants of the cohort study, 53 (62%), 16 (19%), 16 (19%), and one (1.2%) were in stage 1, 2, 3 and 4, respectively. Minor weight loss (n = 15) and pulmonary tuberculosis (n = 9) were the most commonly diagnosed conditions among the 38 (44%) symptomatic HIV-positive individuals. Although 23 (27%) HIV-positive participants had CD4+ T-cell counts less than 200 x 10(6)/l, only one was in clinical stage 4. Among 79 hospitalized HIV-positive patients, 15 (19%) and 64 (81%) were in stage 3 and 4, respectively. The majority (83.5%) had CD4+ T-cell counts < 200 x 10(6)/l. Individuals at stage 3 had lower CD4+ T-cell counts and higher viral loads when seen in hospital as compared to cohort participants (P = 0.06 and 0.008, respectively). When grouping the two study populations, the median CD4+ T-cell count decreased (337, 262, 225, 126, and 78 x 10(6)/l, P< 0.01), and the median viral load increased (4.08, 3.89, 4.47, 5.65, and 5.65 log10 copies/ml, P < 0.01), with increasing clinical stage of HIV infection (1, 2, 3 cohort, 3 hospital, and 4, respectively). Median CD4+ T-cell counts were remarkably low in HIV-negative participants (749 x 10(6)/l), and in HIV-positive participants at stage 1 and 2 (337 and 262 x 10(6)/l, respectively). CONCLUSIONS: There was a good correlation between WHO clinical stages and biological markers. CD4+ T-cell counts were low in Ethiopians, particularly during early stages of HIV-1 infection, and preliminary reference values at different stages of HIV-1 infection were determined. In HIV-infected Ethiopians, lymphocyte counts less than 1,000 x 10(6)/l in non-hospitalized individuals, and less than 2,000 x 10(6)/l in hospitalized patients, had high positive predictive value, but low sensitivity, in identifying subjects with low CD4+ T-cell counts (< 200 x 10(6)/l) who would benefit from chemoprophylaxis of opportunistic infections. The on-going longitudinal study will be useful to confirm the prognostic value of the WHO staging system.     

Relative preservation of natural killer cell cytotoxicity and number in healthy AIDS patients with low CD4 cell counts.

OBJECTIVE: This study examines whether there may be an immune component that protects a relatively rare group of HIV-infected people with very low CD4 cell counts (< or = 50 x 10(6)/l) who have prolonged asymptomatic periods. DESIGN/METHODS: Three groups were recruited in Miami: (i) healthy low CD4 cell count patients (HLC; n = 30) who, for 9 months had < 50 x 10(6) CD4 cells/l, were asymptomatic and were not on protease inhibitors during that time; (ii) HIV comparison group (Comp; n = 60) who had CD4 cell counts predominantly 150 x 10(6) to 400 x 10(6)/l and never had AIDS Category C symptoms; this group was also followed for CD4 cell count and viral load change over 6 months; and (iii) healthy community controls (n = 33). The study was replicated at the University of California at Los Angeles (UCLA) with HLC (n = 31) versus HIV-negative laboratory controls (n = 28). RESULTS: The HLC patients were significantly higher than the Comp group on natural killer cell cytotoxicity (NKCC) and natural killer cell number (NK#) despite their lower CD4 cell numbers and higher viral loads. In fact, there was no difference between the HLC group and the healthy community control group in NK# or NKCC. The NK findings were replicated at UCLA. A retrospective analysis showing that higher NKCC was related to fewer prior symptoms in the HLC group, and prospective analysis in the Comp group showing that NK# predicted a lower increase in viral load over 6 months further supported the importance of NK# and NKCC. CONCLUSIONS: Non-specific cellular immunity may be a factor protecting the health of HIV sero-positive individuals with very low CD4 cell counts.     

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.     

Long-term immunological response in HIV-1-infected subjects receiving potent antiretroviral therapy

OBJECTIVE: To determine the long-term T-lymphocyte response to highly active antiretroviral therapy (HAART) and to define predictors of the immunological response. DESIGN: Cohort study, including 135 HIV-1-infected subjects at a city general practice who commenced HAART between 1996 and 1998. METHODS: Collection of plasma HIV-1 RNA, CD4+ and CD8+ T-lymphocyte data at 3-6 monthly time intervals over 2 years. RESULTS: Seventy-three subjects (54%) achieved suppression of plasma HIV-1 RNA to levels below 400 copies/ml during the observation period, 31 individuals (23%) had detectable plasma HIV-1 RNA below 10,000 copies/ml and 31 subjects (23%) had virological failures with viral loads above 10,000 copies/mL. Median CD4+ T lymphocytes increased from 246 to 463 x 10(6) cells/l, showing a median rise of 20 x 10(6) cells/l per month in the first 3 months and 7 x 10(6) cells/l per month thereafter. The proportion of individuals who reached CD4+ cell counts above 500 x 10(6) cells/l increased from 8% at baseline to 54% at 2 years. Treatment-na?ve individuals, subjects with a large reduction of HIV-1 RNA or a large early CD8+ increase had better early CD4+ responses. Long-term CD4+ T-cell increases were inversely correlated with mean plasma HIV-1 RNA levels. Baseline CD4+ T-cell count was the most important determinant of reaching CD4+ cell counts above 500 x 10(6) cells/l. Nineteen per cent of subjects had no further CD4+ T-cell increases in the second year of therapy despite undetectable viral load. CONCLUSIONS: Immune reconstitution is a slow process, showing a large individual variability. The virological response to HAART was the most important determinant of the immunological short- and long-term response.     

Lung CD4 lymphocytes predict survival in asymptomatic HIV infection

BACKGROUND: Plasma viral load and blood CD4 counts are accepted indicators of severity of illness in patients with HIV-1. Lung CD4 counts have not been evaluated in asymptomatic HIV-1 patients as indicators of disease severity. OBJECTIVE: To determine if lung lymphocyte counts in asymptomatic subjects with HIV compare with plasma viral loads and blood CD4 counts in predicting survival. DESIGN: Retrospective, cross-sectional analysis. SETTING: Midwestern urban community, December 1996 to August 1998. PARTICIPANTS: HIV-seropositive subjects (n = 95) without AIDS-related pulmonary complications. MEASUREMENTS: Plasma viral load, blood hemoglobin and blood lymphocyte subtypes, lung lymphocyte subtypes from BAL, body mass index, and mortality. RESULTS: Eight of the 95 subjects (8.4%) had died at the 4-year follow-up. Lung CD4 counts were significantly related to mortality by univariable analysis (2.5 x 10(3)/mL vs 0.9 x 10(3)/mL, median values for survivors vs nonsurvivors, respectively, p = 0.010). Modeling using exact methods further showed lung CD4 counts to be a significant predictor of survival after individually adjusting for potential confounders, including plasma viral load and blood CD4 count. CONCLUSIONS: Lung CD4 counts in patients with HIV-1 infection may provide an independent predictor of survival.     

The virological and immunological consequences of structured treatment interruptions in chronic HIV-1 infection.

BACKGROUND: Some individuals with chronic HIV-1 infection have discontinued their drug therapy with consequent plasma virus rebound. In a small number of patients, a delayed or absent rebound in plasma virus load has been noted after drug cessation, apparently associated with prior drug interruptions and autologous boosting of HIV-1 specific immune responses. We hypothesized that cyclic structured treatment interruptions structured treatment interruptions (STI) could augment HIV-1 specific immune responses in chronic HIV-1 infection, which might help to control HIV-1 replication off therapy. METHODS: We initiated an STI pilot study in 10 antiretroviral treatment-naive HIV-1 chronically infected subjects with baseline CD4 T-cell counts > 500 x 10(6) cells/l and plasma viral load > 5000 copies/ml who received highly active antiretroviral therapy (HAART) for 1 year with good response (plasma viral load < 20 copies/ml for at least 32 weeks). Three cycles of HAART interruption were performed. RESULTS: In all of the patients viral load rebounded, but doubling times increased significantly between the first and third stops (P = 0.008), and by the third stop, six out of nine subjects had a virological set-point after a median 12 months off therapy that was lower than baseline before starting HAART (ranging from 0.6 log(10) to 1.3 log(10) lower than baseline) and in four it remained stable below 5000 copies/ml. Those subjects who controlled viral replication developed significantly stronger HIV-1 specific cellular immune responses than subjects lacking spontaneous decline (P < 0.05). During viral rebounds no genotypic or phenotypic changes conferring resistance to reverse trancriptase inhibitors or protease inhibitors was detected, but mean absolute CD4 T-cell counts declined significantly, although never below 450 x 10(6)/l and the mean value at 12 months off therapy was significantly higher than the pre-treatment level (P = 0.004). CONCLUSIONS: Our findings suggest that STI in chronic HIV-1 infection might augment HIV-1-specific cellular immune responses associated with a spontaneous and sustained drop in plasma viral load in some subjects but at the potential cost of lower CD4 T-cell counts.     

Short-term risk of AIDS according to current CD4 cell count and viral load in antiretroviral drug-naive individuals and those treated in the monotherapy era

BACKGROUND: One key piece of information required when deciding whether to initiate antiretroviral therapy is the risk of AIDS before the next clinic visit. Information on the short-term (6-month) risk of AIDS according to the current viral load and CD4 cell count in untreated individuals and those treated in the zidovudine monotherapy era (i.e., pre-September 1995), especially in those with CD4 cell count > 200 x 10 cells/l, is lacking. METHODS: Risk of AIDS was assessed in 3226 subjects with viral load and CD4 cell count known before initiation of antiretroviral therapy or during the zidovudine monotherapy era. These were from CASCADE Collaboration in which data from 20 cohorts of individuals with known dates of seroconversion to HIV, based in clinics in Europe and Australia, have been combined. RESULTS: During a total 5126.0 person-years of follow-up, 219 individuals developed AIDS. In those with current CD4 cell count < 200 x 10 cells/l, 6-month risks were 4.9, 12.7, 17.7 and 22.4% for viral load groups < 10 000, 10 000-29 999, 30 000- 99 999 and > or = 100 000 copies/ml, respectively. For CD4 cell counts 200-349 x 10 cells/l risks were 0.5, 1.6, 3.2 and 4.7%, respectively, for the four viral load groups while the corresponding values for group with CD4 cell count > or = 350 x 10 cells/l were 0.2%, 0.5%, 0.9% and 2.2%, respectively. Results were similar when analysis was restricted to those with no antiretroviral drug experience. Older people had a higher risk of AIDS for a given CD4 cell count and viral load than younger people. CONCLUSION: Combined with consideration of other issues, these estimates should prove useful information when deciding whether to initiate antiretroviral therapy in HIV-infected individuals.     

Discontinuation of primary prophylaxis in HIV-infected patients at high risk of Pneumocystis carinii pneumonia: prospective multicentre study

OBJECTIVES: To assess the safety of discontinuation of primary prophylaxis in HIV-infected patients on antiretroviral combination therapy at high risk of developing Pneumocystis carinii pneumonia. DESIGN: Prospective multicentre study. PATIENTS AND METHODS: The incidence of P. carinii pneumonia after discontinuation of primary prophylaxis was studied in 396 HIV-infected patients on antiretroviral combination therapy who experienced an increase in their CD4 cell count to at least 200 x 10(6)/l and 14% of total lymphocytes; the study population included 191 patients with a history of CD4 cell counts below 100 x 10(6)/l (245 person-years) and 144 patients with plasma HIV RNA above 200 copies/ml (215 person-years). RESULTS: There was one case of Pneumocystis pneumonia, an incidence of 0.18 per 100 person-years [95% confidence interval (CI), 0.005--1.0 per 100 person-years]. No case was diagnosed in groups with low nadir CD4 cell counts (95% CI, 0--1.2 per 100 person-years) or detectable plasma HIV RNA (95% CI, 0--1.4 per 100 person-years). CONCLUSIONS: Discontinuation of primary prophylaxis against Pneumocystis pneumonia is safe in patients who have responded with a sustained increase in their CD4 cell count to antiretroviral combination therapy, irrespective of the CD4 cell count nadir and the viral load at the time of stopping prophylaxis.     

Detection and quantification of HIV-1 in semen: identification of a subpopulation of men at high potential risk of viral sexual transmission.

BACKGROUND: To assess HIV burden in both acellular and cellular fractions of semen in men with different levels of blood plasma HIV RNA by a cross-sectional study. PATIENTS: Fifty-two HIV-1-seropositive men (21 receiving antiretroviral therapy) with CD4 cell counts ranging from 1 to 1170 x 10(6)/l. METHODS: Semen was separated into seminal plasma and fractions enriched in motile spermatozoa or non-spermatozoal cells. HIV RNA was quantified by the HIV-Monitor technique (Roche) in blood plasma, seminal plasma and spermatozoa fractions. HIV DNA or infectious virions in cellular fractions were detected by either PCR or qualitative viral culture. RESULTS: HIV RNA was detected in 86.5% of seminal plasma specimens and in 14.6% of spermatozoa fractions; HIV DNA was detected in 57.1% of non-spermatozoal cell fractions. HIV RNA levels in blood plasma and seminal plasma were correlated (r5 = 0.56, P < 0.0001, Spearman's rank test). A majority of men had lower levels in seminal plasma than in blood plasma: one-third had HIV-positive seminal cell fractions. However, 20 men (38.5%) with HIV RNA levels in seminal plasma (median: 4.65 log10 copies/ml) comparable to or higher than those in blood plasma had all HIV-positive non-spermatozoal cells or spermatozoa fractions with a high frequency of positive cultures. CONCLUSION: A high frequency of men had detectable HIV in semen. We identified a subpopulation demonstrating high levels of HIV RNA in seminal plasma, comparable to or higher than those in blood plasma, frequently associated with a substantial viral shedding in seminal cells, raising the possibility of viral production within the genital tract and suggesting heterogeneity in the potential of HIV sexual transmission among infected men.     

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-seropositive thrombocytopenia: the action of zidovudine.

The action of zidovudine when administered to individuals with severe HIV thrombocytopenia was investigated. Four individuals with platelets less than 50 x 10(9)/l and CD4 cells greater than 200 x 10(6)/l were treated with 600 mg zidovudine per day for 6 weeks, no drug for 6 weeks, 1200 mg zidovudine per day for 6 weeks, then no drug for 6 weeks. Glycocalicin, a platelet protein which correlates inversely with platelet survival, was assayed before and after treatment. Glycocalicin indices were also measured in four additional individuals with HIV thrombocytopenia. Platelet counts rose 2.5-fold [95% confidence interval (Cl), 2.0-3.0)] for four subjects who received 600 mg zidovudine per day and 4.9-fold (95% Cl, 4.0-5.8) for three subjects receiving 1200 mg zidovudine per day. Platelet counts declined during drug-free intervals. Plasma glycocalicin indices were elevated in all with untreated HIV thrombocytopenia. Indices fell after zidovudine treatment in six of seven individuals, suggesting that zidovudine prolonged platelet survival. Analysis of 170 HIV-seropositive asymptomatic individuals [mean CD4 count 474 x x 10(6)/l, standard deviation (s.d.) 245 x 10(6)/l] revealed that 14 (8%) had less than 125 x 10(9)/l platelets but only 2 (1%) had less than 50 x 10(9)/l platelets. Platelet counts increased spontaneously in eight individuals with mild HIV thrombocytopenia among the 10 for whom repeat counts were available.     

Virological and immunological responses to HAART in asymptomatic therapy-naive HIV-1-infected subjects according to CD4 cell count

OBJECTIVE: When to start highly active antiretroviral therapy (HAART) in asymptomatic chronically HIV-1-infected subjects with CD4 cell counts of 300 x 10(6)-500 x 10(6)/l is debated extensively. Retrospective analyses of virological and immunological responses following HAART have been evaluated in both blood and lymph nodes according to pre-treatment levels of CD4 cells either above or below 500 x 10(6)/l. DESIGN: Open-label, observational, non-randomized, prospective study. SETTING: Outpatients attending the Centre of Clinical Investigation in Infectious Diseases, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland. PARTICIPANTS: Fifty-four HIV-1-infected antiretroviral-naive subjects with CD4 cell count > or = 250 x 10(6)/l and plasma viraemia > or = 5000 copies/ml who had been treated with HAART for at least 48 weeks. Controls were 49 HIV-negative subjects. INTERVENTIONS: All patients received abacavir, nelfinavir, saquinavir soft gel capsules, and amprenavir in varying combinations for 72 weeks. MAIN OUTCOME MEASURES: The extent of immune reconstitution following HAART in 43 and 11 subjects with either more or fewer than 500 x 10(6) CD4 cells/l at baseline was evaluated in blood and lymph node, and compared with immunological measures observed in 49 HIV-negative controls. RESULTS: After 48 weeks of therapy, plasma viraemia was suppressed effectively in both groups of patients. Normalization of both CD4 cell count in blood, divided equally between memory and naive cells, and percentage of CD4 cells in lymph nodes occurred in the two groups. Consistently, the net increase over baseline in CD4 cell count and in memory and naive CD4 subsets was greater in patients with fewer than 500 x 10(6) CD4 cells/l at baseline. Recovery of HIV-specific responses was similar in the two groups. CONCLUSIONS: This study suggests that virological and immunological responses are comparable in asymptomatic therapy-naive HIV-1-infected subjects with CD4 cell counts above or below 500 x 10(6)/l.     

Impact of pulmonary tuberculosis on survival of HIV-infected adults: a prospective epidemiologic study in Uganda

BACKGROUND: Retrospective cohort studies of tuberculosis suggest that active tuberculosis accelerates the progression of HIV infection. The validity of these findings has been questioned because of their retrospective design, diverse study populations, variable compliance with anti-tuberculous therapy and use of anti-retroviral medication. To assess the impact of tuberculosis on survival in HIV infection we performed a prospective study among HIV-infected Ugandan adults with and without tuberculosis. METHODS: In a prospective cohort study, 230 patients with HIV-associated tuberculosis and 442 HIV-infected subjects without tuberculosis were followed for a mean duration of 19 months for survival. To assess changes in viral load over 1 year, 20 pairs of tuberculosis cases and controls were selected and matched according to baseline CD4 lymphocyte count, age, sex and tuberculin skin test status. RESULTS: During the follow-up period, 63 out of of 230 tuberculosis cases (28%) died compared with 85 out of 442 controls (19%), with a crude risk ratio of 1.4 [95% confidence interval (CI), 1.07-1.87]. Most deaths occurred in patients with CD4 lymphocyte counts < 200 x 10(6) cells/l at baseline (n = 99) and occurred with similar frequency in the tuberculosis cases (46%) and the controls (44%). When the CD4 lymphocyte count was > 200 x 10(6)/l, however, the relative risk of death in HIV-associated tuberculosis was 2.1 (95% CI, 1.27-3.62) compared with subjects without tuberculosis. For subjects with a CD4 lymphocyte count > 200 x 10(6)/l, the 1-year survival proportion was slightly lower in the cases than in the controls (0.91 versus 0.96), but by 2 years the survival proportion was significantly lower in the cases than in the controls (0.84 versus 0.91; P < 0.02; log-rank test). For subjects with a CD4 lymphocyte count of 200 x 10(6) cells/l or fewer, the survival proportion at 1 year for the controls was lower than cases (0.59 versus 0.64), but this difference was not statistically significant (P = 0.53; logrank test). After adjusting for age, sex, tuberculin skin test status, CD4 lymphocyte count, and history of HIV-related infections, the overall relative hazard for death associated with tuberculosis was 1.81 (95% CI, 1.24-2.65). In a nested Cox regression model, the relative hazard for death was 3.0 (95% CI, 1.62-5.63) for subjects with CD4 lymphocyte counts > 200 x 10(6)/l and 1.5 (95% CI, 0.99-2.40) for subjects with a CD4 lymphocyte count of 200 x 10(6)/l or fewer. CONCLUSION: The findings from this prospective study indicate that active tuberculosis exerts its greatest effect on survival in the early stages of HIV infection, when there is a reserve capacity of the host immune response. These observations provide a theoretical basis for the treatment of latent tuberculous infection in HIV-infected persons.     

Efficacy of a five-drug combination including ritonavir, saquinavir and efavirenz in patients who failed on a conventional triple-drug regimen: phenotypic resistance to protease inhibitors predicts outcome of therapy.

OBJECTIVE: to assess the safety and efficacy of a combination of ritonavir, efavirenz and two recycled nucleosides in patients who failed on a conventional triple-drug regimen including indinavir or ritonavir. METHODS: An open label study of ritonavir (100 mg twice daily), saquinavir (1000 mg twice daily), efavirenz (600 mg per day) and nucleoside analogues in 32 saquinavir- and efavirenz-naive protease inhibitor-experienced patients. Patients were included on the basis of plasma levels of HIV RNA above 5000 copies/ml while on conventional antiretroviral therapy. Phenotypic resistance and genotypic resistance mutations to saquinavir were assessed at baseline. Peak and trough plasma levels of saquinavir were monitored throughout the study. RESULTS: Median CD4 cell counts and median plasma HIV RNA at baseline were 258 x 10(6)/l and 4.31 log10 copies/ml, respectively. The plasma viral load decreased by a median of 1.20 log10 copies/ml and the CD4 cell count increased by a median 60 x 10(6) cells/l at week 24 of therapy. Seventy-one per cent of the patients achieved a plasma viral load < 500 copies/ml and 45% achieved a viral load < 50 copies/ml. Patients exhibiting phenotypic resistance to saquinavir at baseline experienced a median decrease in HIV RNA of 0.91 log10 copies/ml at week 24 of therapy, as compared with a decrease of 1.52 log10 copies/ml in those exhibiting sensitive viral strains (P = 0.03). Genotypic resistance to saquinavir was not predictive of virologic failure. CONCLUSION: Our results indicate that the combination of ritonavir, saquinavir and efavirenz is safe and effective at 24 weeks in over two-thirds of patients who previously failed on highly active antiretroviral therapy, and that the determination of phenotypic resistance may be of greater value than the detection of resistance mutations to predict the outcome of salvage therapy in this setting.     

Immunologic and virologic responses to HAART in severely immunocompromised HIV-1-infected children

OBJECTIVE: To determine the long-term immunologic and virologic effects of highly active antiretroviral therapy (HAART) in children with AIDS. DESIGN: A prospective observational study. SETTING: Two pediatric HIV clinics. PARTICIPANTS: Twenty-five protease-inhibitor naive HIV-infected children (aged 2-18 years) with advanced disease (CD4 < or =6%). INTERVENTION: HAART (one protease inhibitor and one or more nucleoside analogs). Diphtheria and tetanus immunization in six patients after 18 months of therapy. MAIN OUTCOME MEASURES: Changes in percentage of CD4 cells and plasma HIV-1 RNA levels; post-treatment assays of lymphoproliferative responses to recall antigens; CD4 cell memory phenotype. RESULTS: Median duration of follow-up was 18.8 months (range, 7.5-28 months). At baseline the CD4 cell percentage was 2% (range, 0-6%), this increased significantly to 16% (range, 3-48%) above baseline at 12 months (P = 0.002). The mean maximum CD4 cell increase was 20.7% (range 4-48%) which corresponds to 657x10(6) cells/l (range, 30-2240x10(6) cells/l) above baseline. By contrast, the median viral load was not significantly lower at 12 months than at baseline (P = 0.34), and only 25% of the patients had sustained undetectable viral load. Of the reconstituted CD4 cells 70% were naive, and none of the subjects had lymphoproliferative responses to tetanus and diphtheria although 40% did develop responses to Candida, an environmental antigen. A single immunization with diphtheria and tetanus toxoid produced lymphoproliferative responses to tetanus in three out of six patients. CONCLUSIONS: HAART was associated with sustained increases in CD4 cell counts, despite a high incidence of 'virologic failure'. CD4 counts and the proportion of naive cells were higher than have been reported in adults, which may be a reflection of greater thymic activity in children. Memory cell clones for antigens encountered in the past which are not prevalent before therapy could not be expanded without additional antigenic exposure.     

Interleukin-2 accelerates CD4 cell reconstitution in HIV-infected patients with severe immunosuppression despite highly active antiretroviral therapy: the ILSTIM study--ANRS 082

BACKGROUND: Despite effective highly active antiretroviral therapy (HAART), some patients infected with HIV have persistently low CD4 cell counts with risk of HIV disease progression. The addition of interleukin-2, a cytokine that stimulates CD4 T lymphocyte helper cells, may benefit patients with discordant responses. METHODS: A total of 72 HIV-infected patients with CD4 cell counts of 25-200 x 10(6) cells/l (median 145) and plasma HIV RNA < 1000 copies/ml were randomized in a multicentre study to receive open-label 4.5 x 10(6) IU interleukin-2 subcutaneously twice daily for 5 days every 6 weeks plus their ongoing HAART or were maintained on HAART alone (control group). After 24 weeks, all patients received interleukin-2 therapy plus HAART up to week 80. Primary end-point was the CD4 T cell area under the curve minus baseline up to week 24. RESULTS: After four cycles of interleukin-2, in an intent-to-treat analysis, the respective median CD4 cell area under the curve minus baseline values were +51 and +11 cells in the interleukin-2 (n = 34) and the control group (n = 36) (P < 0.0001). The percentage of patients in the two groups with CD4 cell counts > 200 x 10(6) cells/l was 81% and 33%, respectively (P < 0.0001). At week 80, the median CD4 cell counts in the two groups were 380 and 270 x 10(6) cells/l, respectively. Interleukin-2 treatment was reasonably well tolerated and did not result in sustained increases in plasma HIV RNA levels. CONCLUSIONS: Administration of interleukin-2 produces significant and sustained increase in CD4 cell counts in HAART-treated patients with persistent CD4 cell counts < 200 x 10(6) cells/l.