In vivo effects of CHOP protocol on onco and suppressor gene expression: follow-up study

OBJECTIVE: To examine tolerance and efficacy of a zidovudine plus lamivudine combination in HIV-infected children without previous exposure to antiretroviral drugs. METHODS: Thirteen vertically infected children (aged 4 months to 10 years) were treated with zidovudine (approximately 100 mg/m2 three times daily) and lamivudine (4 mg/kg twice daily). CD4 T-cell count, plasma HIV RNA concentration, complete blood count and blood chemistry profile were monitored before treatment and at months 1, 3 and 6. RESULTS: In general, treatment was well tolerated. One child developed slight neutropenia in the presence of antineutrophil antibodies. CD4 cell count increased from 851+/-621 x 10(6)/l at baseline to 1073+/-945 x 10(6)/l at month 3 (P < 0.05) and to 1133+/-728 x 10(6)/l at month 6 (P = 0.01). CD4+ cell count increased in 10 patients after 3 months and in 11 patients treated for 6 months. One child showed a continuous decrease of CD4 cells despite treatment. Before treatment the plasma HIV RNA concentration was elevated in nine children (> 4.0 log10 copies/ml) and decreased in all of them: by month 1, the mean reduction was -1.16 log10 copies/ml; by month 3, -1.38 log10 copies/ml; and by month 6, -1.53 log10 copies/ml compared with baseline. However, one child showed steadily increasing viral load from 2.7 log10 copies/ml to a maximum of 4.52 log10 copies/ml, surprisingly in association with increasing numbers of CD4 cells. This child was switched to a new combination regimen after 6 months of treatment. Plasma HIV RNA levels below limit of detection were reached in six patients: after 1 month of treatment in one patient, after 3 months in five patients, and after 6 months in six patients. There was a mean reduction of viral load from 4.56 log10+/-4.63 log10 copies/ml (n = 13) to 3.8 log10+/-3.9 log10 copies/ml (P < 0.05; n = 9) after 1 month, to 3.67 log10+/-3.88 log10 copies/ml (P < 0.01; n = 13) after 3 months, and to 3.64 log10+/-3.95 log10 copies/ml after 6 months of treatment (P < 0.001; n = 13). CONCLUSIONS: This pilot study demonstrates the feasibility of zidovudine-lamivudine combination in children not previously exposed to antiretroviral drugs. This promising combination should therefore be evaluated in larger trials.     

Pilot trial of infusional cyclophosphamide, doxorubicin, and etoposide plus didanosine and filgrastim in patients with human immunodeficiency virus-associated non-Hodgkin's lymphoma

PURPOSE: To determine the following: (1) the feasibility of combining the antiretroviral didanosine (ddl) with a 96-hour continuous intravenous (IV) infusion of cyclophosphamide (800 mg/m2), doxorubicin (50 mg/m2), and etoposide (240 mg/m2) (CDE) plus filgrastim in patients with non-Hodgkin's lymphoma (NHL) associated with human immunodeficiency virus (HIV) infection; (2) the effect of ddl on CDE-induced myelosuppression and CD4 lymphopenia; and (3) the effect of CDE on serum p24 antigen and quantitative HIV blood cultures. METHODS: Twenty-five patients with HIV-related NHL received CDE every 28 or more days. Consecutive patients were assigned in an alternating fashion to group A (ddl given at a standard dose during cycles one, two, five, and six) or group B (ddl given during cycles three, four, five, and six). RESULTS: ddl use was associated with less leukopenia (mean nadir, 3.33 v 1.49 x 10(3)/microL; p = .03), neutropenia (2.38 v 1.07 x 10(3)/microL; p = .03), and thrombocytopenia (76 v 48 x 10(3)/microL; p = .059), and fewer RBC (1.6 v 3.1 per cycle; p < .01) and platelet transfusions (0.7 v 1.5 per cycle; p < .01), but had no significant effect on CD4 lymphopenia. Furthermore, lymphomatous bone marrow involvement and low CD4 count were associated with significantly greater myelosuppression. Although there was no substantial change in serum p24 antigen, the HIV blood culture became quantitatively more positive or converted from negative to positive in seven patients (64%). Complete response (CR) occurred in 58% of patients (95% confidence interval, 38% to 78%), median CR duration exceeded 18 months, tumor-related mortality was 20%, and median survival was 18.4 months. CONCLUSION: Our results suggest that the CDE and filgrastim regimen is tolerable and effective for patients with HIV-associated NHL, and that combination with ddl is feasible and may result in less myelosuppression.     

The relative prognostic value of plasma HIV RNA levels and CD4 lymphocyte counts in advanced HIV infection

OBJECTIVE: It has been suggested that the plasma HIV RNA level is a better predictor of AIDS and death than the CD4 lymphocyte count. We assessed whether the prognostic value of plasma virus levels was different according to the CD4 count. DESIGN: Prospective cohort study of HIV-infected patients followed for a median of 2.91 years (range, 0.02-4.54). SETTING: Department of Infectious Diseases at Rigshospitalet, Copenhagen, Denmark. PARTICIPANTS: A group of 255 HIV-infected individuals with an initial measurement of CD4 lymphocyte count and plasma HIV RNA. MAIN OUTCOME MEASURE: Survival time. RESULTS: The plasma HIV RNA (median 101410 copies/ml; range (range 200-7200000) and the CD4 lymphocyte count (median 250 cells x 10(6)/l; range 1-1247) were negatively correlated (Pearson r = -0.53; P < 0.00001). Of the 255 patients, 110 died during follow-up. Overall, a higher HIV RNA level was associated with increased risk of death, but the association was smaller in patients with lower CD4 lymphocyte counts (test for interaction P < 0.0001). In patients with CD4 count below 50 cells x 10(6)/l the association between HIV RNA and risk of death was not statistically significant (relative hazard per 10-fold higher HIV RNA level was 1.53; P = 0.11; adjusted for age and CD4 count) while that between the CD4 count and risk of death was highly significant (relative hazard per 50% lower CD4 count 1.38; P = 0.005; adjusted for age and HIV RNA level). CONCLUSIONS: Patients were relatively lightly treated with antiretroviral drugs both before and during this study. In this situation, it appears that the HIV RNA level has a relatively weak association with risk of death in patients with advanced HIV infection and that the CD4 lymphocyte count is probably more useful in assessing prognosis.     

Suppression of plasma viral load below 20 copies/ml is required to achieve a long-term response to therapy

BACKGROUND: Current guidelines state that the goal of antiretroviral therapy for HIV-infected individuals is to suppress plasma viral load (pVL) to below 400 copies/ml. METHODS: Predictors of achieving and maintaining pVL suppression were examined in a randomized trial of combinations of zidovudine, nevirapine and didanosine in patients with CD4+ T cell counts of between 200 and 600 x 10(6) cells/l who were naive to antiretroviral therapy and AIDS-free at enrolment. RESULTS: One hundred and four patients had pVL > 500 copies/ml at baseline and a pVL nadir below 500 copies/ml. Of these, 77 patients experienced an increase in pVL above 500 copies/ml. The median number of days of pVL suppression to below 500 copies/ml was 285 (42) for patients with pVL nadir < or = (>) 20 copies/ml (P = 00.0001). The relative risk of an increase in pVL above 500 copies/ml associated with a pVL nadir below 20 copies/ml was 0.11 (P = 0.0001). The relative risks of an increase in pVL above 5000 copies/ml associated with a pVL nadir below 20 copies/ml or between 20 and 400 copies/ml were 0.05 [95% confidence interval (CI), 0.02-0.12] and 0.37 (95% CI, 0.23-0.61) respectively, compared with individuals with a pVL nadir > 400 copies/ml. Individuals with a pVL nadir < or = 20 copies/ml were at a significantly lower risk of virologic failure than individuals with a pVL nadir of between 21 and 400 copies/ml (P = 0.0001). CONCLUSIONS: Our results demonstrate that suppression of pVL below 20 copies/ml is necessary to achieve a long-term antiretroviral response. Our data support the need for a revision of current therapeutic guidelines for the management of HIV infection.     

Evaluation of guidelines for initiation of highly active antiretroviral therapy in a longitudinal cohort of HIV-infected individuals

OBJECTIVES: Expert panels have developed several guidelines for initiating highly active antiretroviral therapy (HAART) in patients with HIV infection. To evaluate these guidelines, we simulated their application in a cohort of HIV-infected patients established and followed before HAART was available, and determined how long such patients survived without disease progression in the absence of HAART. METHODS: Longitudinal data was used that had been collected from 1982 to 1995 on a prospective cohort of 133 homosexual men with known or closely approximated dates of HIV-1 seroconversion and negligible antiretroviral exposure. The main definition of disease progression was CD4 cell count < or = 300x10(6)/l or development of clinical AIDS diagnosis within 12 months. RESULTS: The mean number of years between the recommended initiation of therapy and when disease progression occurred in the absence of HAART were as follows: initiation of treatment at first visit, 4.81 years [median, 3.78 years; interquartile range (IQR), 1.85-6.59 years]; CD4 cell count <500x10(6)/l or serum RNA >5000 copies/ml (at least 10000 copies/ml fresh plasma), 4.35 years (median, 3.22 years; IQR, 1.56-6.19 years); CD4 cells <500x10(6)/l or serum RNA >20000 copies/ml (at least 40000 copies/ml fresh plasma), 3.61 years (median, 2.70 years; IQR, 1.40-5.11 years); and CD4 cells <500x10(6)/l, 2.72 years (median, 2.17 years; IQR, 0.81-4.25 years). The percentage of patients who had disease progression before HAART would have been recommended was 0.8, 1.6, 3.2 and 13.6% with each of these four approaches, respectively. CONCLUSIONS: Implementation of recommended treatment guidelines will result in a substantial proportion of patients being treated for long periods before immunologic or clinical disease progression would have occurred in the absence of HAART. These findings should be considered in the clinical care of HIV-infected patients and in future recommendations for the initiation of HAART.     

Quantitative HIV-1 RNA as a marker of clinical stability and survival in a cohort of 302 patients with a mean CD4 cell count of 300 x 10(6)/l

OBJECTIVE: To analyse plasma HIV-1 RNA levels as a marker of clinical stability and survival in a cohort of HIV-infected patients whose time of seroconversion is unknown. DESIGN: Retrospective cohort study. SETTING: Retrovirology laboratory and AIDS Unit in a teaching hospital. PATIENTS: A total of 916 samples from 302 patients, most on antiretroviral therapy, were analysed. Mean initial CD4 cell counts and HIV-1 RNA were 299 x 10(6)/l (range: 0-1600) and 134,261 copies/ml (range: < 200-4,300,000), respectively. Sixty-six cases had been diagnosed previously with AIDS. METHODS: Analysis of progression to AIDS and survival, according to initial and longitudinal viral load (VL) and CD4 cell count measurements was performed by Kaplan-Meier test. Relative risks were calculated by Cox's proportional hazards model. RESULTS: During a mean follow-up of 444 +/- 309 days, 29 patients developed AIDS and 21 died. Relative risk (RR) of progression related to the group with VL < 35,000 was: 10.4 when CD4 > or = 250 x 10(6)/l and VL > or = 35,000 (P = 0.001); and 45.3 when CD4 < 250 x 10(6)/l and VL > or = 35,000 (P < 0.0001). Cumulative probability of progression was: 0%, 0% and 12.3%, at the first, second and third year respectively, for patients with all their sequential VL determinations < 60,000; and 13.3%, 34.7% and 79.3% for patients who did not maintain VL values always < 60,000 (RR = 23; P < 0.0001). The minimum value of VL that reached statistical significance for the survival analysis was 100,000 copies/ml (P < 0.0001). CONCLUSIONS: VL > or = or < 35,000 is a better discriminant for progression than a CD4 cell count > or = or < 250 x 10(6)/l. Sequential VL determinations < 60,000 are associated with a better prognosis.     

Value of HIV-1 viral load and CD4 lymphocyte count as determinants of progression to AIDS and survival

BACKGROUND: HIV-1 viral load is regarded as a better surrogate marker for progression and death than CD4+ cell counts. Both markers are analysed in a cohort of patients with unknown seroconversion date and advanced HIV infection. PATIENTS AND METHODS: Retrospective cohort analysis of 421 patients, most on antiretroviral therapy, with a median initial CD4+ cell count of 209 x 10(6)/l and a median initial viral load of 4.7 log copies/ml. One thousand two hundred and eighty-six samples were analysed. Univariate and bivariate analysis were performed with initial and sequential CD4+ cell counts and viral load values to estimate the risk of progression and death by Cox regression models. RESULTS: After a median follow up of 763 days, 124 patients developed AIDS and 117 died. Relative risks of progression related to the group that maintained viral load values always < 35,000 copies/ml were: 5-fold (95% CI: 1.4-17.0; p < 0.05) for patients with any viral load value > 35,000 copies/ml but always < 200,000 copies/ml; and 13.6 fold (95% CI: 5.4-34.2; p < 0.0001) for patients who could not maintain viral load < 200.000 copies/ml. CD4+ counts = 100 x 10(6)/l and viral load = 220,000 copies/ml were the threshold values that best fitted to estimate the probability of survival by a bivariate analysis. CONCLUSIONS: The maintenance of sequential viral load values < 35.000 copies/ml is associated with a lower risk of progression. The maintenance of sequential viral load values < 150,000 copies/ml is associated with higher short-term survival rates.     

Treatment response and durability of a double protease inhibitor therapy with saquinavir and ritonavir in an observational cohort of HIV-1-infected individuals

OBJECTIVE: To evaluate treatment response, durability and tolerance of a four-drug regimen including saquinavir and ritonavir in combination with either zidovudine/lamivudine or stavudine/lamivudine. DESIGN: Observational cohort of HIV-positive individuals. METHODS: Viral load, CD4+ and CD8+ T lymphocyte counts were assessed at intervals of 1-3 months in subjects commencing therapy between July 1996 and November 1996. Adverse events were evaluated as well as risk factors for therapeutic failures. RESULTS: A group of 56 male patients were included and followed for 48 weeks. Of these, 66% had already taken a protease inhibitor. Viral load dropped by a median 1.98 log10 HIV RNA copies/ml from baseline (interquartile range: 1.49-2.46) and became undetectable (< 400 copies/ml) in 68% of patients. Response varied: 9% were non-responders (HIV RNA reduction < 0.5 log10 copies/ml) and 23% were incomplete responders (nadir of HIV RNA > 400 copies/ml). After 48 weeks, viral load remained undetectable in 49%. Median CD4+ T lymphocyte count increased from 191 x 10(6) to 418 x 10(6) cells/l (range, 241-537 x 10(6) cells/l). Although protease inhibitor and nucleoside pretreatment selected for drug-resistant viral mutants, only the protease inhibitor experience was identified as a risk factor for therapeutic failure. Adverse events occurred in 73% of patients and led to a change of therapy in 9%. CONCLUSION: Despite advanced HIV disease and pretreatment with multiple antiretroviral drugs, a strong initial treatment response to this drug regimen was observed. However, virological failure occurred in 51% of patients after 48 weeks and frequent adverse events complicated therapy.     

Predictive value of Toxoplasma gondii antibody titres on the occurrence of toxoplasmic encephalitis in HIV-infected patients. ANRS 005/ACTG 154 Trial Group

OBJECTIVE: To study the predictive value of anti-Toxoplasma gondii antibody titres for the occurrence of toxoplasmic encephalitis (TE) in HIV-infected patients. METHODS: Data from the placebo arm of a trial of primary prophylaxis for TE (ANRS 005/ACTG 154) were analysed. Patients included had CD4+ cell counts < 200 x 10(6)/l and a positive Toxoplasma serology. Immunoglobulin (Ig) G and IgM Toxoplasma antibody titres at entry were retrospectively determined by enzyme-linked immunosorbent assay and agglutination on serum samples in a single laboratory. Incidence of TE was estimated by Kaplan-Meier method and a Cox model was used to study the predictive value of antibody titres, adjusted for other covariates. RESULTS: All 164 patients studied were positive for IgG antibodies and one had IgM antibodies. After a mean follow-up of 16 months, 31 cases of TE were documented. One-year incidence of TE was significantly higher in patients with IgG titres > or = 150 IU/ml (23.7%) than in patients with titres < 150 IU/ml (7.7%; relative risk, 3.1; P < 0.003). IgG titres remained significantly associated with the occurrence of TE (relative risk, 3.3; P < 0.005) in the Cox model. Predictive value of IgG titres did not differ according to baseline CD4+ cell counts. CONCLUSIONS: In patients with CD4+ cell counts < 200 x 10(6)/l, IgG anti-Toxoplasma antibody titre is a prognostic factor of occurrence of TE, with a higher risk for titres > or = 150 IU/ml. This finding should reinforce the recommendation of specific prophylaxis in these patients.     

Clinical utility of cytomegalovirus urine cultures for ophthalmic care in patients with HIV

BACKGROUND: The utility of cytomegalovirus (CMV) urine cultures was checked in patients with HIV (a) to identify those at risk for CMV retinitis and (b) to guide clinical decisions on treatment and prophylaxis of CMV retinitis. METHODS: HIV infected patients were tested for CMVuria by shell vial cell cultures. The prevalence of CMVuria was related to CD4 count, HIV risk group, and time before and after diagnosis of CMV retinitis. RESULTS: A total of 639 shell vial cell cultures were obtained from 266 HIV infected ophthalmic patients. Only 4% of all patients with a CD4 count > 400 x 10(6)/l shed CMV in their urine compared with 42% with a CD4 count < or = 50 x 10(6)/l. Twenty three of 25 patients with CMV retinitis had a CD4 count < or = 50 x 10(6)/l. Among 130 patients with a CD4 count < or = 50 x 10(6)/l (a) those who were CMVuric had a nearly sevenfold risk (p < 0.0001) of developing CMV retinitis (35%) compared with those who did not shed CMV in their urine (5%), and (b) CMVuria and CMV retinitis were more frequent in homosexuals (58%/25%) than in intravenous drug users (23%/15%). More than 1 year before diagnosis of CMV retinitis 18% of patients were CMVuric compared with 83% of patients who were CMV culture positive in the last 3 months. CMVuria under virustatic maintenance therapy is associated with worsening of retinitis in two thirds of cases. CONCLUSION: Ophthalmic screening of patients with HIV should include those with a CD4 count < or = 50 x 10(6)/l and focus on the subgroup with additional CMVuria. Screening of other patients can be dropped without undue risk in order to spare AIDS patients unnecessary hospital visits. CMVuria as a single finding, however, does not justify antiviral prophylaxis of CMV retinitis.     

Randomized placebo-controlled trial of granulocyte-macrophage colony-stimulating factor in patients with chemotherapy-related febrile neutropenia

PURPOSE: To determine whether granulocyte-macrophage colony-stimulating factor (GM-CSF) used in addition to standard inpatient antibiotic therapy shortens the period of hospitalization due to chemotherapy-induced neutropenic fever. PATIENTS AND METHODS: One hundred thirty-four patients with a hematologic (n = 47) or solid tumor (n = 87) who had severe neutropenia (< 0.5 x 10(9)/L) and fever (> 38.5 degrees C once or > 38 degrees C twice over a 12-hour observation period) were randomly assigned to receive GM-CSF 5 micrograms/kg/d (n = 65) or placebo (n = 69) in conjunction with broad-spectrum antibiotics for a minimum of 4 days and a maximum of 14 days. GM-CSF/placebo and antibiotics were stopped if the neutrophil count was greater than 1.0 x 10(9)/L and temperature less than 37.5 degrees C during 2 consecutive days, or for a leukocyte count > or = 10 x 10(9)/L, both followed by a 24-hour observation period (hospitalization period). RESULTS: Compared with placebo, GM-CSF enhanced neutrophil recovery. Median neutrophil counts at day 4 were 2.5 x 10(9)/L (range, 0 to 25) in the GM-CSF arm and 1.3 x 10(9)/L (range, 0 to 9) in the placebo arm (P < .001). No significant difference was observed with regard to median number of days with less than 1.0 x 10(9)/L neutrophils (4 v 4) or days of fever (3 v 3). The median number of days patients were hospitalized while on study was comparable in the GM-CSF and placebo groups at 6 (range, 3 to 14) versus 7 (range, 4 to 14), respectively, according to an intention-to-treat analysis (P = .27). Quality-of-life scores in 90 patients demonstrated significant differences in favor of the placebo group. Hospital costs were significantly higher for GM-CSF-treated patients if GM-CSF was included in the price (median costs, $4,140 [US] for GM-CSF v $590 for placebo; P < .05). CONCLUSION: These results indicate that GM-CSF does not affect the number of days for resolution of fever or the hospitalization period for this patient group, although a significant effect of GM-CSF was observed on neutrophil recovery.     

Evaluation of two staging systems for HIV infection for use in developing countries

OBJECTIVE: To evaluate the clinical axis of the World Health Organization (WHO) clinical staging system and the modified WHO staging system proposed by Montaner et al. using the lymphocyte strata > 1500, 1500-1000 and < 1000 cells x 10(6)/l. DESIGN: Cross-sectional study. PATIENTS: Four hundred and fifteen consecutive patients with HIV infection attending three HIV reference centres in Belgium. METHODS: Absolute CD4 lymphocyte counts were compared between stages within the two staging systems. RESULTS: Median CD4 lymphocyte counts decreased with increasing stage of disease in both staging systems. Differences in median CD4 lymphocyte counts between stages of each staging system were statistically significant (Kruskal-Wallis one-way analysis of variance, P < 0.001). The WHO clinical stage 1 and the modified WHO stage I had positive predictive values of 56 and 58%, respectively, for identifying patients with CD4 lymphocyte levels > 500 cells x 10(6)/l. The WHO clinical stage 4 and the modified WHO stage IV had positive predictive values of 79 and 80%, respectively, for identifying patients with CD4 lymphocyte levels < 200 cells x 10(6)/l. CONCLUSIONS: The WHO clinical staging system or a modified version of this system using lymphocytes stratification may be a good alternative in developing countries to the CD4 lymphocyte count-based HIV staging system used in the developed world. Cohort studies in developing countries are needed to assess their prognostic value.     

A pilot study of hydroxyurea among patients with advanced human immunodeficiency virus (HIV) disease receiving chronic didanosine therapy: Canadian HIV trials network protocol 080

To assess the in vivo short-term antiretroviral effect of hydroxyurea in human immunodeficiency virus (HIV)-infected persons chronically treated with didanosine (ddI), 26 patients with CD4 cell counts between 100 and 350 were enrolled in a 12-week, open-label pilot study and randomly assigned to receive 500 or 1000 mg/day hydroxyurea. Clinical status, laboratory toxicities, CD4 lymphocyte count, and HIV RNA plasma virus load were assessed weekly. Median declines from baseline of 0.02 and 0.63 log10 HIV-1 RNA copies/mL of plasma were observed for the 500- and 1000-mg/day groups, respectively (P = .02). CD4 cell counts did not change significantly with the addition of hydroxyurea; however, a small but statistically significant decrease in counts was observed during the washout phase. Both doses of hydroxyurea were well-tolerated. These results demonstrate a substantial decrease in plasma virus load when 1000 mg of hydroxyurea is administered over 1 month as adjunctive therapy to ddI among HIV-infected persons with 100-350 CD4 cells/mm3.     

Spectrum of disease among HIV-infected adults hospitalised in a respiratory medicine unit in Abidjan, C?te d'Ivoire

SETTING: Respiratory medicine wards of the University Teaching Hospital, Abidjan, C?te d'Ivoire. OBJECTIVES: To describe the spectrum of opportunistic infection among human immunodeficiency virus (HIV) infected adults hospitalised in the respiratory medicine unit in Abidjan, and the level of immunosuppression at which these diseases occur. DESIGN: Cross-sectional study. RESULTS: Overall, 75% of patients were HIV-positive: among these patients, the most frequent diagnosis was tuberculosis, in 61%, followed by bacterial pneumonia (15%), Gram-negative septicaemia (particularly non-typhoid Salmonella) (9%) and empyema (5%). Atypical pneumonias appeared to be rare. Most HIV-positive patients had CD4 counts indicative of advanced immunosuppression: 36% had CD4 counts below 100 x 10(6)/l, 19% between 100 and 199 x 10(6)/l, 29% between 200 and 499 x 10(6)/l, and 16% above 500 x 10(6)/l. Overall in-hospital mortality was 27% for HIV-positive patients and 22% for HIV-negative patients (P = 0.5). In a multivariate analysis, the strongest independent risk factors for death were cachexia (odds ratio [OR] 7.4, 95% confidence interval [CI] 2.1-26.3), male sex (OR 4.5, 95% CI 1.2-17.4) and age over 40 (OR 4.1, 95% CI 1.0-17.2). CONCLUSIONS: Tuberculosis and bacterial infections are the major causes of respiratory morbidity in immunosuppressed HIV-infected adults in this population. Efforts to improve the management of HIV-related disease need to focus on prevention and treatment of these infections.     

Changes in CD4+ cell count and the risk of opportunistic infection or death after highly active antiretroviral treatment. Groupe d'Epidémiologie Clinique du SIDA en Aquitaine

OBJECTIVE: To study the relationship between the CD4+ cell response after initiation of protease inhibitors and the occurrence of opportunistic infections and survival. DESIGN: Prospective observational cohort study. METHODS: HIV-1-seropositive subjects followed-up in HIV centres of Bordeaux University Hospital, Southwest France who were prescribed at least one available protease inhibitor between January and December 1996 were included in this analysis. A Cox model estimated the independent effect of baseline covariates and CD4+ cell response, considered as a time-dependent covariate, on the occurrence of new AIDS-defining opportunistic infection, new AIDS-defining events, new AIDS-defining opportunistic infection or death. RESULTS: A total of 556 HIV-positive patients were prescribed at least one protease inhibitor: 34% saquinavir, 52% indinavir, and 14% ritonavir. Median CD4+ cell count at baseline was 95 x 10(6)/l and mean plasma HIV RNA was 5.0 log10 copies/ml. After a median follow-up of 230 days, 65 patients experienced a new episode of opportunistic infection, 79 patients experienced at least one AIDS-defining event, and 24 had died. On average, the increase in CD4+ cell count was 42 x 10(6)/l (SD, 74) after a median of 49 days. In the multivariate analysis of opportunistic infection or death, each 50% higher CD4+ cell count at baseline was associated with a 23% reduction [95% confidence interval (CI), 14-30] of risk. Each 50% increase in CD4+ cell count during follow-up was associated with a 9% reduction (95% CI, 2-15) of risk, adjusted for the presence of AIDS prior to protease inhibitor therapy (hazard ratio, 3.76 versus absence of AIDS; P < 0.01) and haemoglobin level (hazard ratio, 0.48 if > 11 g/dl versus <11 g/dl; P < 0.01). CONCLUSION: Our results show, at least indirectly, how protease inhibitors might produce clinical stabilization. This result may be due to improved functionality of CD4+ cells in patients started on protease inhibitors.