Highly active antiretroviral therapy as the sole treatment for AIDS-related primary central nervous system lymphoma: a case report with implications for treatment

A 40-year-old male presented to medical attention with Pneumocystis jiroveci pneumonia and HIV infection. His CD4+ count was 18 cells per microliter and his HIV viral load (VL) was more than 400,000 copies milliliter. After 3 weeks of antibiotic therapy, he continued to have global cognitive deficits. A brain imaging study showed a right temporal mass, which on biopsy proved to be primary central nervous system lymphoma (PCNSL). He began highly active antiretroviral therapy (HAART) but declined palliative whole-brain radiotherapy (WBRT). Four months later, his CD4+ count had improved to 153 cells per microliter and his HIV VL was less than 75 copies per milliliter. At 36 months follow-up, he remained in complete remission (CR). Through a literature review, we identified 4 additional PCNSL patients who achieved prolonged remission after the initiation of HAART. One patient required WBRT and ventriculo-peritoneal shunting for signs and symptoms of obstructive hydrocephalus. The other 3 patients presented with stable neurologic findings and were treated with HAART alone. The median initial CD4+ count for these patients was 50 cells per microliter (range, 2 to 220 cells per microliter). All 5 remained in CR with a median follow-up of 23.5 (range, 13 to 36) months. For patients who present with PCNSL as their initial AIDS-defining event, stable neurologic findings, and effective HAART options, initial treatment with HAART alone may be possible, reserving WBRT and corticosteroids for those who show signs of impending neurologic demise. Chemotherapy and other novel approaches could also be considered for selected patients with lesser degrees of immune suppression and high baseline functional status.     

Discontinuation of antiretroviral therapy in patients with chronic HIV infection: clinical, virologic, and immunologic consequences

To investigate the clinical, virologic and immunologic consequences of planned treatment interruptions in chronically HIV-infected patients. One hundred forty-one patients with undetectable viral load for at least 6 months and CD4+ T cells count greater than 500 per microliter were recruited. Their antiretroviral therapy was stopped and clinical, analytic, virologic, and immunologic data were recorded at baseline, during discontinuation, and after restarting treatment. Viral load rebound after discontinuation in 137 (97%) patients, and was similar to prehighly active antiretroviral therapy (HAART) levels. A rapid decrease in CD4+ T-cell count (median, 240 cells per microliter), was observed in the first 3 months in all patients, with pronounced differences between them. After a median follow-up of 36 months, 45.5% patients were still without therapy. Factors related to a more severe decline were a prior lower CD4+ T nadir (<200 cells per microliter) before starting HAART, a greater increase (>500 cells per microliter) with it, a higher CD4+ T-cell count before interruption (>800 cells per microliter) and a higher viral load rebound after it. The increase in CD4+ T-cell counts after reinitiation was slower than the decline and only 55% of patients have regained the preinterruption levels at 12 months of follow- up. Twelve infectious events were registered. Treatment failure related to drug resistance was observed in two patients. Planned treatment interruptions may be safe in selected patients with previous CD4+ T cell nadir greater than 200 cells per microliter and pre-HAART VL less than 55.000 copies per milliliter, but should be not recommended in patients with the prognostic factors related to a rapid decline described in this study. Furthermore, there is a considerable concern about the development of drug resistance and the possibility of an incomplete immune reconstitution after the treatment interruption in some patients.     

Development of opportunistic infections after diagnosis of active tuberculosis in HIV-infected patients

Despite advances in highly active antiretroviral therapy (HAART), its use during tuberculosis (TB) treatment is fraught with challenges, often leading to delayed therapy. This report describes the course of HIV infection and outcomes of 26 consecutive TB/HIV coinfected patients who received TB treatment in Rhode Island. HIV infection was diagnosed in 26 (4%) of 598 TB cases in during a 10-year period. Of these patients, TB was the first indication of HIV infection in 15 patients (58%). Of the 21 patients who were not on antiretrovirals at the time of TB diagnosis, 17 (81%) met criteria for immediate initiation of HAART. The median CD4 cell counts and HIV-1 plasma viral load were 80 cells per microliter (range, 2-800 cells per microliter) and 255,631 copies per milliliter (range, 50,000 to > 500,000 copies per milliliter), respectively, for the patients whose baseline measurements were available. CD4 lymphocyte count was less than 200 cells per microliter in 13 (76%) of the 17 patients whose measurements were available. Three (30%) of the 10 patients whose CD4 cell count was less than 100 cells per microliter developed subsequent AIDS-defining illness prior to the initiation of HAART and a fourth patient, within 30 days of starting HAART. None of the patients who had CD4 cell counts 100 cells per microliter or greater developed subsequent AIDS-defining illness during TB treatment. The median time to starting HAART after starting TB treatment was 12 weeks (range, 3-36 weeks). From our limited experience based on this case series, we recommend early initiation of HAART in coinfected patients with CD4 cell counts less than 100 cells per microliter.     

Oral candidosis as a clinical marker of immune failure in patients with HIV/AIDS on HAART

Oral candidosis (OC) has been proposed as a clinical marker of highly active antiretroviral therapy (HAART) success or failure. The principal objective of this work was to assess whether the presence OC is associated with immunologic or virologic failure in patients with HIV/AIDS undergoing HAART. One hundred fifty-one patients with HIV/AIDS from Regional Hospital "Carlos Haya," Malaga, Spain, were examined orally. All patients had been undergoing HAART for a minimum of 6 months prior to oral examination. OC diagnosis was in accordance with World Health Organization-Centers for Disease Control (WHO-CDC) criteria. Age, gender, route of HIV infection, CD4 lymphocyte counts, and viral load were taken from the medical records. In regard to HAART response the patients were classified as: virologic- responders (viral load < 50 copies per milliliter), virologic nonresponders (viral load >50 copies per milliliter); immunologic responders (CD4 cells counts > 500 per milliliter), and immunologic nonresponders (CD4 cells counts < 500 per milliliter). Prevalence of OC was determined for each group. The presence of OC was closely related to immune failure (p 0.006; odds ratio [OR] 3.38 95% confidence interval [CI] 1.262-12.046) in patients with HIV/AIDS undergoing HAART. The probability of immune failure in the presence of OC was 91% for men who have sex with men, 95.5% for heterosexuals, and 96% for intravenous drug users. In conclusion, OC should be considered a clinical marker of immune failure in patients with HIV/AIDS undergoing HAART.     

Does transient HAART during primary HIV-1 infection lower the virological set-point?

OBJECTIVES: To assess the influence of patient characteristics, treatment precocity (how early) and duration of sustained virological response to highly active antiretroviral therapy (HAART) on HIV RNA levels after withdrawal of treatment started during primary infection and to compare HIV RNA levels after HAART withdrawal with levels reached at the same time point during the natural history of infection in the pre-HAART era. DESIGN: HIV RNA was analysed using linear mixed-effects models for 58 patients from the PRIMO cohort (1996-2003) treated during primary infection (with sustained virological responses until HAART interruption) and 116 untreated patients enrolled in the SEROCO cohort within 6 months following infection (1988-1995). Viral loads were estimated in PRIMO patients 36 months after infection (12 months after treatment interruption) and were estimated for the SEROCO patients 36 months after infection, after adjustment for gender and age. RESULTS: HIV RNA levels 12 months after HAART interruption were independently associated with levels at HAART initiation and with the CD4 cell count at HAART interruption, but not with the precocity of HAART or the duration of virological response to HAART. Thirty-six months after infection, mean HIV RNA levels were 3.95 log10 copies/ml 12 months after stopping HAART and 4.11 log10 copies/ml in never-treated patients. CONCLUSION: Viral load 12 months after withdrawal of transient effective HAART started during primary infection is similar to viral load at the same time after infection in never-treated patients, suggesting that early HAART initiation does not lower the virological set-point.     

300例艾滋病患者高效抗逆转录病毒治疗后免疫重建规律探讨

目的探讨高效抗逆转录病毒治疗（HAART）对中国南部地区艾滋病患者的免疫重建规律。方法收集近3年来300例患者的完整资料,按基线CD4^＋T细胞数分为A、B、C三组,观察基线及治疗1、3、6、12月末CD4^＋T淋巴细胞数、12月末血浆病毒载量（VL）、临床症状和毒副作用。结果抗病毒治疗12月末300例患者CD4^＋T淋巴细胞计数平均上升127个／1,以治疗3月后增长明显,3、12月末与基线CD4^＋T淋巴细胞计数比较差异有显著性（P〈0．05）;12月末273例（91％）患者血浆病毒载量（VL）〈5copies/ml,27例（9％）患者病毒载量（VL）〉50copies/ml,高病毒载量A组16例,C组4例;A组与C组比较差异有显著性（P〈0．05）;药物不良反应主要是外周神经炎（35．4％）、骨髓抑制（18．2％）、皮疹（15．2％）、肝功能损害（12．1％）、乳酸酸中毒（12．1％）和肾结石（6．1％）。结论HAART治疗对中国南部地区的艾滋病患者有效,能够实现免疫重建,但存在较多毒副作用。     

Immunophenotype of HIV+ patients during CD4 cell-monitored treatment interruption: role of the IL-7/IL-7 receptor system

OBJECTIVE: To investigate immunological changes during CD4-guided therapy interruption in HIV(+) patients who suspended HAART. PATIENTS: Seventeen patients aged > 18 years, who had received HAART for at least 12 months, and had a pre-interruption CD4+ cell count > 500 cells/microl, interrupted treatment. Median nadir CD4(+) cell count was 288 cells/microl. HIV plasma viral load at discontinuation was < 50 or > 50 copies/ml. Criteria for restarting treatment were: a CD4(+) T-lymphocyte count < 350 cells/microl on two separate occasions, a clinical manifestation of AIDS, and the patient's desire to resume HAART. Eleven patients were still off therapy after 12 months (group A); according to the first criterion, six patients restarted therapy within 12 months (group B). METHODS: Haematological, viro-immunological, cytofluorimetic and molecular assays were performed at baseline and every 2 months following standard methods. Statistical analysis was performed under Stata 7.0. RESULTS: In the first 2 months of treatment interruption, a significant increase in viral load and CD8(+) lymphocyte activation occurred. Then such parameters decreased and remained stable. In all patients, a decrease in CD4(+) lymphocytes took place as well, that affected in a similar manner naive, central memory, effector memory and terminally differentiated cells. Group B always presented lower amounts of CD4(+) effector memory lymphocytes. The expression of CD127 was always higher in group A. CONCLUSIONS: The loss of CD4(+) lymphocytes upon viral rebound is equal among naive and memory subsets. Patients with higher expression of CD127, who are likely to exert a better capacity to utilize endogenous interleukin-7 by T cells, could remain off therapy for longer periods.     

Recrudescent Kaposi's sarcoma after initiation of HAART: a manifestation of immune reconstitution syndrome

The objective of this case series and literature review is to characterize the clinical course and prognosis of HIV-infected patients with Kaposi's sarcoma (KS) flare during immune reconstitution inflammatory syndrome (IRIS), a heterogeneous and sometimes fatal disorder of immune perturbation after initiation of highly active antiretroviral therapy (HAART). Medical records of 9 HIV-infected patients with KS flare after virologic and immunologic response to HAART were reviewed from a single institution. An additional 10 cases were abstracted by computerized search of the medical literature. In our single institution series, mean time to onset of KS flare was 5 weeks. Pretreatment mean CD4+ count was 190 cells/mm(3) and mean HIV viral load was 153,934 copies per milliliter. During flare, mean CD4+ count was 256 cells/mm(3) and mean HIV viral load was 1156 copies per milliliter. Similar aggregate results are represented in the literature. Six fatalities are reported, 4 from pulmonary KS and 2 from unrelated causes. Systemic chemotherapy universally led to tumor regression, but was administered in only 10 of 19 cases. In no instance was HAART discontinued. Onset of IRIS-associated KS flare is observed as early as 3 weeks, with most cases diagnosed within 2 months after immunologic and virologic response to HAART. Such a flare does not necessarily portend a poor prognosis. Even for those patients with rapidly symptomatic KS, early systemic chemotherapy is effective in suppressing IRIS-associated flare. Close clinical supervision is warranted for the KS patient initiating, changing, or resuming HAART. Particular vigilance is recommended for pulmonary involvement.     

The effect of a multidisciplinary program on HAART adherence

Although emerging evidence suggests differing interventions may improve antiretroviral adherence, there has not been a formal evaluation to identify the impact of a clinic-based multidisciplinary program designed to provide education and identify and correct potential adherence barriers prior to the initiation of highly active antiretroviral therapy (HAART). A retrospective cohort study utilizing a historical control group was conducted to compare duration on antiretrovirals, clinical indicators, and adherence rates, as captured by pharmacy refill records. Two hundred sixty-one patients met criteria for inclusion (109 subjects, 152 controls). Time to stopping antiretrovirals, as evidenced by Kaplan-Meier plot, was significantly higher in Protocol group than Controls (log-rank p = 0.023): the median duration on HAART for the intervention group was greater than 360 days but only 210 days for the control group. Thus, more subjects in the protocol group continued on therapy for the full year: 60 (55%) versus 65 (43%) for the control group. The mean reduction in log10 viral loads between HAART initiation and 12 months was greatest for the intervention group with viral load at HAART initiation 100,000 copies per milliliter or more, -3.57 versus -1.78 for controls with viral load less than 100,000 copies per milliliter (p < 0.001). For the intervention group, the mean number of adherence barriers identified per person was 4% and 72% were found to have three or more barriers. Patients at high risk for poor adherence benefit from multidisciplinary education and proactive identification of adherence barriers by exhibiting prolonged duration on therapy and greater reduction in log10 viral loads.     

Immunological and virological responses to highly active antiretroviral therapy in a non-clinical trial setting in a developing Caribbean country

OBJECTIVE: Few data exist on the efficacy of antiretroviral therapy in individuals infected with HIV in the Caribbean. We evaluated the virological and immunological responses of HIV-infected adults starting highly active antiretroviral therapy (HAART). DESIGN: This was a prospective observational cohort study. METHODS: A total of 158 antiretroviral-naive patients who initiated HAART between January 2002 and March 2003, and completed at least 6 months of treatment and follow up, were included in the analysis. The response to therapy was assessed by changes in CD4 cell counts and viral loads from baseline. The mean increase in CD4 cell count, the rate of virological success (a viral load of <50 HIV-1 RNA copies/mL) and the rate of immunological success (an increase in CD4 cell count of > or =50 cells/microL over the baseline value) after commencing HAART were measured. RESULTS: In total, 82% of patients (123 of 150) achieved viral loads of <50 copies/mL after 6 months of therapy. Viral success rate after 6 months of HAART was similar irrespective of gender, pre-HAART CD4 cell count and pre-HAART viral load. However, patients older than 40 years were significantly more likely to achieve virological success than those younger than 40 years. At 6 months after starting HAART, 79.5% of patients were estimated to have achieved immunological success and 17.9% had an increase in CD4 cell count of > or =200 cells/microL over the baseline value. The median increase in CD4 cell count for the 156 patients who had CD4 cell counts at baseline and at 6 months of therapy was 122 cells/microL. CONCLUSION: In this cohort of antiretroviral-naive HIV-infected adults, there was a high rate of virological and immunological success after 6 months of HAART, irrespective of the pre-HAART viral load and CD4 cell count.     

Pregnancy outcomes in women with advanced HIV infection in Italy

Pregnancy has been associated with a low risk of HIV disease progression. Most pregnancies with HIV currently involve women who have not experienced AIDS-defining events, and are clinically classified as Centers for Disease Control and Prevention (CDC) groups A or B. We evaluated the main maternal outcomes among pregnant women with more advanced HIV disease, defined by CDC-C disease stage. Data from the Italian National Program on Surveillance on Antiretroviral Treatment in Pregnancy were used. A total of 566 HIV-infected mothers, 515 in stage A or B (CDC-AB group) and 51 in stage C (CDC-C group) were evaluated. The two groups had similar baseline characteristics. No differences were found in the main maternal and neonatal outcomes. Most of the women achieved viral suppression at end of pregnancy (>1000 copies per milliliter: CDC-C: 17.2%; CDC-AB: 13.7%). One year after delivery, HIV replication (HIV-RNA >1000 copies per milliliter) was present in 11.5% of CDC-AB women and 30.0% CDC-C women. Despite lower initial CD4 counts (300 versus 481 cells per microliter), CDC-C women maintained stable CD4 levels during pregnancy, and 1 year after delivery, a significant increase in CD4 count from preconception values was observed in both groups (CDC-C: +72 cells per microliter, p=0.031; CDC-AB: +43 cells per microliter, p<0.001). Only one AIDS event occurred in a woman with a previous diagnosis of AIDS. In CDC-C women, pregnancy is not associated with an increased rate of adverse maternal or neonatal outcomes, and a good immunovirologic response can be expected. During postpartum care, women with more advanced HIV infection should receive particular care to prevent loss of virologic suppression.     

Hospitalized HIV-infected patients in the HAART era: a view from the inner city

To evaluate hospitalizations of HIV-infected patients in the highly active antiretroviral therapy (HAART) era, we analyzed 2736 admissions of 1562 HIV-infected patients to Cook County Hospital from September 20, 1999 to July 10, 2002. Patients were predominantly African American (81%), male (72%), and active substance abusers (74%). Only 48% of patients with a prior HIV diagnosis were taking HAART and 37% of them had a viral load less than 1000 copies per milliliter. Patients on protease inhibitor (PI)-sparing regimens more frequently achieved a viral load less than 1000 copies per milliliter than those on a PI-containing regimens (41% vs. 34% p = 0.036). For patients with CD4 cell counts less than 200 cells per milliliter, those not taking HAART were more likely African American (83% vs. 76%, p < 0.031), homeless (13% vs. 5%, p < 0.001), active substance abusers (79% vs. 65%, p < 0.001), female (28% vs. 22%, p = 0.001), new to the hospital system (19% vs. 6%, p < 0.001), or not recently seen in the outpatient clinic (42% vs. 17%, p < 0.001). In our population, active substance abuse was prevalent and only a minority of patients was taking HAART. Women were receiving HAART less often, independent of race and substance abuse. Aggressive programs are needed in high-risk populations to address substance abuse issues and to improve patient use of HAART.     

CD4 cell-monitored treatment interruption in patients with a CD4 cell count > 500 x 106 cells/l

BACKGROUND: Little is known about CD4 cell count changes in patients with high CD4 cell counts who interrupt antiretroviral therapy, especially in those with a nadir of 250-350 x 10 cells/l. METHODS: Data derived from 139 patients from seven prospective cohorts who had > 12 months highly active antiretroviral therapy (HAART), CD4 cell count nadir of > 250 x 10 cells/l and at pre-interruption of > 500 x 10 cells/l. Endpoint was time to CD4 cell count < 350 x 10 cells/l or reinitiation of treatment. RESULTS: At interruption, the median CD4 cell count was 800 x 10 cells/l, median viral load was 1.7 log10 copies/ml. At the time of analysis, 63 (45.3%) had resumed therapy or experienced < 350 x 10 cells/l CD4 cells over a median interruption of 75 weeks. Of these, 33 (52.4%) experienced a decline to < 350 x 10 cells/l and 30 (47.6%) restarted therapy before their CD4 cell count had fallen below this level. In 43 patients with CD4 cell nadir of 251-350 x 10 cells/l, median time to therapy resumption or CD4 cell count < 350 x 10 cells/l was 61 weeks. Higher CD4 cell count nadir, longer duration of viral load suppression on therapy, and higher viral load level at interruption were independently associated with longer time to restart therapy. The risk of clinical events was 5 per 1000 person-years of follow-up. CONCLUSIONS: Patients who started therapy with CD4 cell count of 250-350 x 10 cells/l and who later interrupted therapy appear able to remain off therapy with a CD4 cell count > 350 x 10 cells/l for a substantial period of time.     

Immunologic and clinical responses to highly active antiretroviral therapy over 50 years of age. Results from the French Hospital Database on HIV

OBJECTIVE: To study immunologic and clinical responses to HAART in patients over 50 years old. DESIGN AND METHODS: A prospective cohort study which included 68 hospitals in France. A total of 3015 antiretroviral-naive patients, 401 of whom were aged 50 years or over, were enrolled following initiation of HAART. The influence of age on the mean CD4 cell count increase on HAART was studied by using a two-slope mixed model. Progression, defined by the occurrence of a new AIDS-defining event (ADE) or death, was studied by Cox multivariate analyses. RESULTS: Among patients with baseline HIV RNA above 5 log copies/ml, CD4 mean increase during the first 6 months on HAART was +42.9 x 10(6) cells/l per month in patients under 50 years and +36.9 x 10(6) cells/l per month in patients over 50 years (P < 0.0001); subsequently, the respective monthly changes were +17.9 and +15.6 x 10(6) cells/l per month (P < 0.0001). Similar trends were observed in patients with baseline HIV RNA below 5 log copies/ml, and also after stratification for the baseline CD4 cell count. After a median follow-up of 31.5 months, 263 patients had a new ADE and 44 patients died. After adjustment for baseline characteristics, older patients had a significantly higher risk of clinical progression (hazard ratio (HR) = 1.52 [95% confidence interval (CI), 1.15-2.00]) and were more likely to achieve a viral load below 500 copies/ml [HR = 1.23, (95% CI, 1.11-1.38)]. CONCLUSION: Patients over 50 years of age have an immunologic response to HAART. However, their CD4 cell reconstitution is significantly slower than in younger patients, despite a better virologic response. This impaired immunologic response may explain their higher risk of clinical progression.     

HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression

Identifying the immunologic and virologic consequences of discontinuing antiretroviral therapy in HIV-infected patients is of major importance in developing long-term treatment strategies for patients with HIV-1 infection. We designed a trial to characterize these parameters after interruption of highly active antiretroviral therapy (HAART) in patients who had maintained prolonged viral suppression on antiretroviral drugs. Eighteen patients with CD4(+) T cell counts >/= 350 cells/microliter and viral load below the limits of detection for >/=1 year while on HAART were enrolled prospectively in a trial in which HAART was discontinued. Twelve of these patients had received prior IL-2 therapy and had low frequencies of resting, latently infected CD4 cells. Viral load relapse to >50 copies/ml occurred in all 18 patients independent of prior IL-2 treatment, beginning most commonly during weeks 2-3 after cessation of HAART. The mean relapse rate constant was 0.45 (0.20 log(10) copies) day(-1), which was very similar to the mean viral clearance rate constant after drug resumption of 0.35 (0.15 log(10) copies) day(-1) (P = 0.28). One patient experienced a relapse delay to week 7. All patients except one experienced a relapse burden to >5,000 RNA copies/ml. Ex vivo labeling with BrdUrd showed that CD4 and CD8 cell turnover increased after withdrawal of HAART and correlated with viral load whereas lymphocyte turnover decreased after reinitiation of drug treatment. Virologic relapse occurs rapidly in patients who discontinue suppressive drug therapy, even in patients with a markedly diminished pool of resting, latently infected CD4(+) T cells.     

Five-year immunological outcome of highly active antiretroviral treatment in a clinical setting: results from a single HIV treatment centre

Our objective was to study the evolution of CD4 cell count five years after starting highly active antiretroviral treatment (HAART) in a clinical setting. The study was performed at the HIV outpatient clinic, Institute of Tropical Medicine, Antwerp. All patients (n = 225) who started HAART in 1997, who had a CD4 cell count within six months prior to starting HAART and who were subsequently followed for at least two years were included. Change in CD4 cell count after start of HAART and the influence of patient and clinical factors were investigated using graphical exploration, endpoint analysis and mixed-effects linear regression. The mean CD4 cell count at start of HAART was 280 cells/mm(3). At the five-year endpoint of the study the mean increase in CD4 cell count was 333 cells/mm(3), while 79% of the patients had a viral load less than 400 copies/mL. There was a significant negative correlation between increase in CD4 cell count at five years and time since first positive HIV test at start of HAART (P = 0.021). Patients who ever had a HAART interruption of more than seven days had a significantly lower increase in CD4 cell count than those who did not (225 cells/mm(3) compared with 438 cells/mm(3); P < 0.001). A mixed-effects linear regression model additionally suggested a significant impact of exposure to antiretrovirals prior to HAART (P = 0.03). Overall, the recovery of CD4 cell count after five years of HAART is good, although therapy interruptions have an important negative impact.     

CD4+ cell-count-guided treatment interruptions in chronic HIV-infected patients with good response to highly active antiretroviral therapy

OBJECTIVE: To evaluate the safety of treatment interruption guided by CD4+ cell count in HIV-infected patients followed up prospectively. METHODS: Patients on highly active antiretroviral therapy with CD4+ cell counts > 500 x 10(6) cells/l discontinued therapy with instructions to start therapy again before their CD4+ count dropped below 200 x 10(6) cells/l. Any patients who resumed therapy would be eligible to interrupt treatment again once their CD4+ cell count increased above 500 x 10(6) cells/l. RESULTS: Data on 71 HIV infected patients is reported. Their median nadir CD4+ cell count before antiretroviral treatment was 352 x 10(6) cells/l [interquartile range (IQR), 294-445 x 10(6) cells/l]. The median CD4+ cell count at the time of first interruption was 790 x 10(6) cells/l (IQR, 657-1041 x 10(6) cells/l). The median follow-up after starting the first treatment interruption was 28.3 months (IQR, 21.4-37.0 months). During the follow-up 49 patients restarted therapy and 22 patients remain off therapy; 24 patients have interrupted therapy twice, nine patients have interrupted therapy three times and six patients four times. No AIDS-defining illnesses occurred during the follow-up. The median duration of the first interruption was 15 months (IQR, 6-26 months). The overall reduction of time on therapy was 71.1%. The duration of the first interruption and the reduction of time on therapy were related to nadir CD4+ cell count. The patients who resumed HAART rapidly regained CD4+ cells and achieved viral suppression. CONCLUSION: If carefully monitored, treatment interruptions guided by CD4+ cell count in patients with an initially high CD4+ cell counts are clinically safe, decrease exposure to the drugs and do not reduce the efficacy of therapy when this is re-started.     

A controlled trial of granulocyte macrophage-colony stimulating factor during interruption of HAART

OBJECTIVES: To explore the effect of granulocyte macrophage colony stimulating factor (GM-CSF) on viral load and CD4 cell count during interruption of highly active antiretroviral therapy (HAART). METHODS: Patients on effective HAART (CD4 cell count > 400 x 10(6)/l; viral load < 50 HIV RNA copies/ml) were randomized to one of two groups: 12 weeks' treatment interruption plus, during the first 4 weeks, 300 microg GM-CSF (Leucomax-Novartis) by subcutaneous injection three times weekly (GM-CSF group); 12 weeks' scheduled treatment interruption (STI-only group). Viral load, CD4 cell count, clinical events and side effects of treatment were monitored. RESULTS: Thirty-three patients, 15 in the GM-CSF group and 18 in the STI-only group, were evaluated according to the intention-to-treat principle. The two groups were well matched with regard to pre-HAART viral loads and CD4 cell counts. During STI, viraemia was approximately two to three times lower in the group receiving GM-CSF (max 4.97 versus 5.45 in STI-only group; P = 0.03). Fifteen out of 17 patients in the STI-only group showed a decrease in their CD4 cell count between weeks 0 and 4 (median decrease 231 x 10(6) cells/l; P < 0.001); there was no such tendency in the GM-CSF group (P = non-significant when comparing CD4 cell counts at weeks 0 and 4). The median CD4 cell AUC (area under the curve) from week 0 to week 12 was higher in the GM-CSF group (9166 cells.week) than in patients without GM-CSF (7257), P = 0.02. GM-CSF produced local reactions in 88% of patients, and generalized symptoms such as fever, back pain or headache in 82% of patients. Seventy-six percent of patients completed the planned course of 12 injections. CONCLUSIONS: The administration of GM-CSF blunted the viral rebound following interruption of HAART, and largely prevented a decrease of CD4 cell counts during a 12-weeks-treatment interruption. A better understanding of the underlying mechanism(s) may help to identify synergistic treatment targets and improved administration protocols to enhance control of chronic HIV infection.