When to Monitor CD4 Cell Count and HIV RNA to Reduce Mortality and AIDS-Defining Illness in Virologically Suppressed HIV-Positive Persons on Antiretroviral Therapy in High-Income Countries: A Prospective Observational Study.

OBJECTIVE: To illustrate an approach to compare CD4 cell count and HIV-RNA monitoring strategies in HIV-positive individuals on antiretroviral therapy (ART). DESIGN: Prospective studies of HIV-positive individuals in Europe and the USA in the HIV-CAUSAL Collaboration and The Center for AIDS Research Network of Integrated Clinical Systems. METHODS: Antiretroviral-naive individuals who initiated ART and became virologically suppressed within 12 months were followed from the date of suppression. We compared 3 CD4 cell count and HIV-RNA monitoring strategies: once every (1) 3 ± 1 months, (2) 6 ± 1 months, and (3) 9-12 ± 1 months. We used inverse-probability weighted models to compare these strategies with respect to clinical, immunologic, and virologic outcomes. RESULTS: In 39,029 eligible individuals, there were 265 deaths and 690 AIDS-defining illnesses or deaths. Compared with the 3-month strategy, the mortality hazard ratios (95% CIs) were 0.86 (0.42 to 1.78) for the 6 months and 0.82 (0.46 to 1.47) for the 9-12 month strategy. The respective 18-month risk ratios (95% CIs) of virologic failure (RNA >200) were 0.74 (0.46 to 1.19) and 2.35 (1.56 to 3.54) and 18-month mean CD4 differences (95% CIs) were -5.3 (-18.6 to 7.9) and -31.7 (-52.0 to -11.3). The estimates for the 2-year risk of AIDS-defining illness or death were similar across strategies. CONCLUSIONS: Our findings suggest that monitoring frequency of virologically suppressed individuals can be decreased from every 3 months to every 6, 9, or 12 months with respect to clinical outcomes. Because effects of different monitoring strategies could take years to materialize, longer follow-up is needed to fully evaluate this question.

Prolongation of life span associated with immunological modification by chronic low-dose-rate irradiation in MRL-lpr/lpr mice.

Chronic low-dose-rate gamma irradiation at 0.35 or 1.2 mGy/h prolonged the life span of MRL-lpr/lpr mice carrying a deletion in the apoptosis-regulating Fas gene that markedly shortens life due to severe autoimmune disease. Immunological modifications as indicated by a significant increase of CD8(+) T cells and a significant decrease of CD3(+) CD45R/B220(+) as well as CD45R/B220(+) CD40(+) cells were found in parallel with amelioration of total-body lymphadenopathy, splenomegaly, proteinuria, and kidney and brain syndromes.

The failure of HAART to cure the HIV-1/AIDS complex. Suggestions to add integrase inhibitors as complementary virostatics, and to replace their continuous long combination applications by short sequences differing by drug rotations.

While the intensive virostatic combinations applied according to the conventional models (such as HAART), based only on the attacks of two HIV-1 targets, retrotranscriptase and protease, and applied in a long and continuous fashion, a) are notably toxic, b) do not correct completely the abnormal immunologic parameters, and c) are followed by particularly severe and poorly sensitive relapses in case of discontinuation, we propose to the 'AIDS treatment headquarters' to include in their failing strategy the two original features which we have included in the treatment of a cohort of a dozen patients, treatment applied at all but one AIDS stage. We attack one more HIV-1 target than the conventional protocols do, by adding inhibitors of integrase; we apply the combinations of virostatics, comprising inhibitors of the three targets, in short sequences (of 3 weeks), between which the analogues are changed inside each series. The first patient of the cohort started his treatment 8.5 years ago, and the entries of the others into it have been at random and not randomized. All patients are alive today and in excellent condition.

Maintenance of high-avidity rubella-specific IgG antibody and titres in recent HIV seroconvertors and in patients progressing to the AIDS-related complex and AIDS.

The avidity (functional affinity) and titre of rubella-specific IgG antibodies were examined in sequential and cross-sectional sera from 38 adult HIV-infected patients, whose HIV status ranged from pre- and recent HIV seroconversion to the AIDS-related complex (ARC) and AIDS, in order to determine whether a preexisting mature antibody response to rubella is maintained or if there is a need for rubella (re)vaccination. Thirty-five patients were already rubella-seropositive and one became rubella-seropositive during the time in which sera were collected. Although the avidity of rubella-specific IgG was higher in HIV-positive patients than in their age-and sex-matched HIV-negative counterparts, the difference was not significant. The titres of this antibody, however, were significantly higher in the HIV-positive patients. No significant decrease in antibody avidity or titre were seen in sequential sera from individual HIV-positive patients except when the titres in pre-HIV-seroconversion sera were compared with the titres in sera from patients with AIDS, where a significant decrease was observed. This would suggest that preexisting humoral immunity to rubella in HIV-infected patients is not compromised with HIV disease progression and there should be no need to revaccinate.

Cardiovascular autonomic neuropathy in HIV infected patients.

OBJECTIVE: To evaluate the presence and extent of autonomic dysfunction in HIV infected individuals of one ethnic group. DESIGN: Prospective, age-sex matched study. METHODS: 25 patients (seven asymptomatic (HIV), eight AIDS related complex (ARC), 10 AIDS) and 25 controls were recruited from patients and staff at the Aga Khan Hospital, Nairobi. Autonomic function was assessed by measurement of pulse rate variability on standing, rest, deep breathing, Valsalva manoeuvre, isometric exercise, cold face test, and mental stress. Blood pressure was measured during standing, supine resting, and on Valsalva manoeuvre. CD4 count was correlated with number of abnormal test results. RESULTS: 21 patients had at least one abnormal test of autonomic function compared with one control (p < 0.0001). There were significant differences between AIDS patients and controls for supine heart rate (p < 0.001), Valsalva ratio (p = 0.05), and cold face test (p = 0.05), and almost significant results for mental stress (p = 0.051). Evidence of autonomic hypersensitivity was found in response to exercise and/or mental stress in some patients with HIV or ARC. No difference was found in blood pressure measurements. Abnormalities in autonomic function occurred at all CD4 counts and all patients with four abnormal tests of heart rate variation had a CD4 count less than 300 x 10(6)/l. CONCLUSIONS: There is evidence of substantial autonomic dysfunction in AIDS patients compared with controls and mild abnormalities in the majority of HIV infected patients studied irrespective of CD4 count. Autonomic hypersensitivity may precede loss of function in some cases.

A comparison of smoothing techniques for CD4 data measured with error in a time-dependent Cox proportional hazards model.

The use of CD4+ T-lymphocyte counts as a covariate presents some unique challenges in survivorship analyses due to the variability of this marker. If one does not account for the measurement error component of this variability in some manner, the estimate of the relative risk parameter in a time-dependent Cox model is biased towards zero, and coverage levels of confidence intervals may be seriously incorrect. We use a two-stage approach to reduce the variability in the observed CD4 counts in order to obtain a more accurate estimate of the relative risk parameter and more valid summary statistics. In the first stage, population based smoothing methods derived from a random-effects model plus a stochastic process or individual based smoothing methods are used to replace the observed longitudinal CD4 counts with less variable imputes at each failure time. In the second stage, we use the imputes in a time-dependent Cox model to estimate the risk parameter and its associated summary statistics. We compare the smoothing methods in simulation studies and find that the use of these smoothing methods results in a substantial reduction in bias for the true risk parameter estimate, better efficiency, and more accurate coverage rates in confidence intervals. We apply our two-stage smoothing methods to the marker CD4 in the ACTG-019 clinical trial part B.

Alteration of T-cell subsets in the lymph nodes from cats infected with feline immunodeficiency virus.

Alterations of T-cell subsets in the lymph nodes from FIV-infected cats in various clinical disease stages were examined histologically. In the early stage of infection (AP stage), follicular hyperplasia accompanied by expansion of the paracortical area was observed. Follicular involution and depletion with reduced paracortical area was observed in the ARC and AIDS stage nodes. The maximum section area of the entire popliteal lymph node was expanded significantly in the AP nodes. The paracortical area expanded in the AP nodes and decreased in the ARC and AIDS stage nodes. The cell density in the paracortical area in the AP nodes did not show a significant increase, while there was a significant reduction in the ARC and AIDS stage nodes. The lymph node CD4/CD8 ratio in the AP and ARC stages significantly decreased as compared with that of uninfected control cats, but conversion of the ratio was not seen. The estimated total numbers of CD4+ and CD8+ cells in the maximum section were increased in the AP stage but significantly decreased in the ARC and AIDS stages. Our study indicated that the lymphocyte depletion in the terminal ARC and AIDS stages of FIV infection was associated with both CD4+ cells and CD8+ cells. Findings obtained in this study might provide useful information for studying the pathophysiology of FIV infection.

[A report on 8 seronegative converted HIV/AIDS patients with traditional Chinese medicine].

OBJECTIVE: For the first time, serum anti-HIV antibody negative conversion was being reported. METHODS: Eight confirmed HIV/AIDS patients (AC1, ARC 6, AIDS 1) were treated with TCM recipes (802, 806, 809, 810, Shengmaiyin, ZY-1), recheck the serum antibody and immunological function and intranuclear HIV-DNA was investigated with PCR amplifying assay and were long-term followed-up. RESULTS: After medication for 87-463 days, seronegative conversion occurred, PCR assay revealed that 5 cases were PCR(+), 2 of them(-), 1 turned seropositive again in the early stage. Observed continuously for 11-49 months, the "serum negative and intranuclear positive" state maintained. These patients belonged to immunosilent HIV-infection. The immunological function of all seronegative converted patients were good. CONCLUSIONS: AIDS is a reversible disease. Using medicinal herbs to enhance the immune function will facilitate the appearance of seronegative conversion, which has not been reported before. If it could be further confirmed, its mechanism elucidated, this may greatly strengthen the confidence of the patients.

A pooled analysis of CD4 response to zidovudine and zalcitabine treatment in patients with AIDS and AIDS-related complex.

INTRODUCTION: This article reports a meta-analysis focused on the efficacy of zalcitabine and zidovudine alone or in combination as reported by three AIDS Clinical Trial Group trials. We analyzed the log CD4 count (LCD4) response to therapy up to 1 year after the beginning of therapy. One of the purposes of this article was to illustrate a meta-analysis method that permits pooling of original data from trials with different designs. METHODS: To effectively eliminate obvious differences due to design, we first estimated complete (1 year) individual LCD4 versus time curves using a sophisticated smoothing technique. Then several summary descriptors were computed from the completed LCD4 curves. Those descriptors were corrected for baseline covariate differences, and the corrected values were then related to measures of drug exposure. RESULTS: Significant baseline covariates were LCD4 baseline count and AIDS-related complex or AIDS diagnosis. The predictor, corrected for baseline covariates, that correlated best with drug exposure was intensity, the initial rate of rise of LCD4, estimated as the slope of LCD4 between pretreatment and peak LCD4. CONCLUSION: Using intensity as a single response measure, we found weak evidence for synergism of zalcitabine and zidovudine: combination therapy increased response by 20% over that expected from a purely additive interaction.

Combinations of three or four HIV virostatics applied in short sequences which differ from each other by drug rotation. Preliminary results of the viral loads and CD4 numbers.

This paper presents the evolution during its follow-up of a virostatic combination study of the type I-II trial conducted on ten AIDS-related complex (ARC) or acquired immunodeficiency syndrome (AIDS) patients [1, 9, respectively]. Its concept is based on the following original notions: a) it is not the number of the virostatics applied to each patient at any phase which determines their effect; it is the number of affected virus targets which determines the effect. Thus, the so called "tritherapies", imposed by the "AIDS Command" to thousands of patients selected at random, to be compared to the same number of subjects receiving only "bi" or "monotherapies", might be beginning to face failure because they attack only two targets: retro-transcriptase and HIV1 protease. Having discovered, owing to our experimental screening, original HIV1 virostatics, acriflavine (ACF) and several ellipticine analogues among which we have used methyl-hydroxy-ellipticine (MHE), we are able to attack two virus targets unaffected by classical virostatics: ACF attacks DNA, from its integrated double branched stage to the provirus one, and MHE inhibits topoisomerase II. We experimentally combined these two agents with AZT, which inhibits retro-transcriptase, thus we realized a combination affecting three targets. This three agent combination was able to eradicate Friend's virus from infected mice. Clinically, combinations of three drugs affecting four targets (as they are selected among the ten virostatics available today) give a stronger result than three drug combinations affecting only three targets, because they were selected from the five virostatics which were the only ones available at the beginning of the present study. Five patients out of five who received the combinations of four virostatics chosen among the ten currently available (thus affecting four targets) from the beginning of their treatment to the present have all reduced their viral load (VL) and maintained it below the detectable level (< 200 RNA copies/mL then 20 copies/mL); b) as the toxicities of virostatics and as HIV1 resistances may happen as soon as 12 weeks of treatment, the combinations have been, in our study, applied in shorter (3 week) sequences, differing from each other due to drug rotation; c) neither toxicity nor resistance occurred; d) curiously, the CD4 numbers, even when they increased rapidly, has never attained their normal count, and their curve may be a Gombertzian one. This CD4 restoration limitation can be due to persisting virus, as indicated in some patients by small peaks which may appear on some VL plateaus, though they disappear without treatment change.

Serum and secretory IgA from HIV-infected individuals mediate antibody-dependent cellular cytotoxicity.

The potential function of IgA anti-HIV antibodies in mediation of antibody-dependent cellular cytotoxicity (ADCC) was investigated in this study. Serum IgA isolated from HIV-seropositive subjects in stage B3 or C3 and from healthy seronegative individuals was compared to IgG and whole serum for the ability to mediate ADCC. Peripheral blood mononuclear cells isolated from uninfected donors were used as effectors against CEM-NKr cells chronically infected with the HTLV-IIIB strain of HIV-1. Whole sera, isolated IgA, and IgG from both groups of seropositive individuals were capable of significant ADCC lysis against infected CEM-NKr cells compared to identical preparations from seronegative individuals. In comparing ADCC activity between the two seropositive groups, IgG mediated higher mean ADCC levels in the C3 group at the two highest concentrations of antibody assayed (P < 0.03), whereas IgA mediated the highest mean ADCC levels in the B3 group at all concentrations. Secretory IgA (S-IgA) isolated from colostrum of HIV-infected women was also examined for ADCC capabilities against infected CEM-NKr cells. Significant differences were observed between ADCC mediated by S-IgA from seropositive mothers compared to seronegative mothers (P < 0.04), but the amount of lysis detected was not as great as that seen with serum IgA. The presence of IgG, serum IgA, and secretory IgA antibodies capable of mediating ADCC may be critical in maintaining a functional immune response in all stages of HIV infection.

Switching from zidovudine to didanosine in patients with symptomatic HIV infection and disease progression. ddI Iberian Study Group.

This study evaluated the efficacy of switching to didanosine in patients who were clinically or immunologically progressing despite zidovudine therapy. This multicenter, open-label study involved 400 patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC), who had tolerated zidovudine for at least 12 weeks and had signs of clinical or immunological disease progression. They were randomly assigned to receive 600 mg/d of zidovudine (n=133), 500 mg/d of didanosine (n=131), or 200 mg/d of didanosine (n=136). The primary end point was a new AIDS-defining event or death. The study was prematurely terminated, after the first interim analysis, mainly owing to results of two controlled studies demonstrating that a change to didanosine was associated with an improved outcome in patients with advanced HIV-1 disease. The median duration of follow-up was 53 weeks. The primary end point rates were 41, 58, and 59 (per 100 person-years) in the didanosine 500 mg, didanosine 200 mg, and zidovudine groups (zidovudine vs. didanosine 500 mg, relative risk 1.28, 95% confidence interval, 0.88-1.86, p = 0.19; didanosine 200 vs. 500 mg, relative risk 1.24, 95% confidence interval, 0.85-1.79, p = 0.26). In subjects with a baseline CD4 count of 100/mm3 or more, the primary end point rates were 8, 29, and 25 (per 100 person-years) in the didanosine 500 mg, didanosine 200 mg, and zidovudine groups, respectively (zidovudine vs. didanosine 500 mg, relative risk 2.96, 95% confidence interval 0.91-9.62, p = 0.07). No difference was seen in survival. In the didanosine 500 mg group, more patients had a 50% increase in CD4 cells (10% vs. 1% in zidovudine group, p = 0.01) and an increase of > or = 2.5 kg in body weight (2% versus 3%). Fatal pancreatitis developed in one patient assigned to didanosine 500 mg and in one to zidovudine. Our data suggest that switching from zidovudine to currently recommended doses of didanosine in subjects with ARC or AIDS who show evidence of clinical and laboratory disease progression can be associated with improvements in clinical outcome as well as in surrogate markers of HIV disease progression. This effect tended to be greater among individuals with higher CD4 counts (>100/mm3).

Preliminary results in HIV-1-infected patients treated with transfer factor (TF) and zidovudine (ZDV).

The efficiency of HIV-1 specific transfer factor (TF) administration, combined with Zidovudine (ZDV), in asymptomatic persistent generalised lymphadenopaty, or AIDS related complex (ARC) patients was evaluated. Twenty patients were randomly assigned to receive only ZDV (1st group) or ZDV together with HIV-1-specific TF (2nd group). HIV-1-specific TF was administered orally at 2 x 10(7) cell equivalent daily for 15 days, and thereafter once a week for up to 6 months. There were no significant differences between the two groups in clinical evolution, red blood cells, haemoglobin, lymphocytes, CD20 subset, transaminases, beta-2-microglobulin, p24 antigen. White blood cells, CD8 lymphocytes as well as IL-2 levels increased in the second group, while the CD4 subset increased in the first group. The combination treatment with ZDV and TF appeared to be safe and well tolerated. Furthermore, levels of serum cytokines were investigated in 10 patients (8 asymptomatic and 2 ARC) treated with ZDV, and compared with 5 patients of the 2nd group (3 asymptomatic and 2 ARC) treated with ZDV plus HIV-1-specific TF. Peripheral lymphocytes, CD4, CD8 subsets, IL-2, TNF alpha, IL-6, p24 antigen, IL-2 soluble lymphocyte receptors (sR), CD4sR, CD8sR and beta-2-microglobulin were evaluated at the baseline and at the 3rd month. The CD4 subset was not significantly different in the two groups, whilst IL-2 increased in the 2nd group receiving ZDV plus TF, suggesting an activation of the Th1 secretion pattern.

Antigen/antibody content of circulating immune complexes in HIV-infected patients.

Dual infection with HIV and hepatitis B virus (HBV) is not an uncommon feature. Immunity impairment due to HIV infection can be the cause of a higher rate of HBV replication with less intensive liver damage and less effective immune response to HBV. Many HIV-infected patients have an elevated level of circulating immune complexes (CIC) in serum, throughout all stages of illness evolution. The aim of our study was to estimate p24 and HBsAg content of CIC in dually infected patients, and the prevalence of major classes of complexed antibodies (IgM and IgG). We examined 146 samples of sera from 105 HIV positive patients of the Institute for Infectious and Tropical Diseases during 1992 and 1993. On those sera we performed p24Ag and HbsAg detection, with and without prior dissociation of CIC, we determined serum level of CIC and immunoglobulin classes IgM and IgG level in sera and in polyethilenglycol (PEG) precipitates of sera. Acid dissociation of immune complexes revealed a high proportion of HIV antigen positive sera in all stages of HIV disease progression. HbsAg in serum of HIV positive patients was also found coupled in immune complexes much more frequently than in the HIV negative control group. In many instances both antigens were simultaneously found coupled in CIC. Immune complexes detected have been shown to contain both IgM and IgG immunoglobulins, while IgM antibodies were associated to immune complexes in higher proportion than IgG, compared to total serum immunoglobulins.

Hyponatremia in pediatric patients with HIV-1 infection.

Hyponatremia has been recognized as a complication in adults with acquired immunodeficiency syndrome (AIDS). We did a retrospective study evaluating the medical records of 86 children (age 4 months to 21 years) with human immunodeficiency virus (HIV-1) infection to determine the frequency and clinical associations of hyponatremia. Twenty-two children (26%) developed hyponatremia (serum sodium < 135 mEq/L; range 104 to 134 mEq/L; mean 130 mEq/L). Fourteen were male; 18 of the 22 patients were black and 4 were white. At the time of hyponatremia, the children frequently had comorbid associations, including 8 (35%) with AIDS encephalopathy; 3 (14%) with cardiomyopathy; 3 (14%) using diuretics; 1 (5%) using pentamidine; 3 (14%) with bacterial pneumonia; 2 (9%) requiring gastric lavage feedings; 2 (9%) with tuberculosis meningitis; 2 (9%) with gastroenteritis; 1 (5%) with infection caused by Mycobacterium avium-intracellulare; 1 (5%) each with brain tumor and tumor metastasis to brain. The cause of hyponatremia was attributed to syndrome of inappropriate antidiuretic hormone in 8 children; poor sodium intake and/or excessive diarrheal losses in 5; and the use of diuretics in 3 patients. Mild hyponatremia with no identifiable cause was found in 5 patients.

Safety, pharmacokinetics, and antiviral response of CD4-immunoglobulin G by intravenous bolus in AIDS and AIDS-related complex.

To assess the safety, pharmacokinetics, and antiviral effects of intravenous recombinant CD4 immunoglobulin G (CD4-IgG), a 12-week Phase One study with an optional maintenance phase was performed. Twenty-two subjects with advanced human immunodeficiency virus (HIV) infection were enrolled; 15 subjects completed the initial 12 weeks. CD4-IgG doses were 30, 100, or 300 micrograms/kg weekly; 1,000 micrograms/kg once, twice, or three times per week; or 3,000 micrograms/kg twice weekly. Serum concentrations of CD4-IgG increased linearly with dose, with average peak serum concentrations of 22 micrograms/ml with 1,000 micrograms/kg. CD4-IgG was well tolerated; one patient had self-limited tachycardia and flushing associated with CD4-IgG therapy. No changes were seen in CD4 cell counts, hematologic or coagulation studies, serum chemistries, HIV p24 antigen titers, or plasma HIV titers. No subject developed anti-CD4 antibodies. HIV isolates from five patients had IC90 values that were higher than the peak concentrations of CD4-IgG achieved in those patients. Additional studies that achieve higher CD4-IgG concentrations are necessary to evaluate the antiviral activity of this compound.

Difference in clinical implications of CD4 counts among HIV-infected homosexual men and injection drug using men and women.

While the relationship between CD4 counts and clinical symptoms is well established among homosexual men, the same is not true for injection drug using men and women (IDUM and IDUW). In this paper we investigate whether CD4 counts have the same clinical implications for IDUM and IDUW as for homosexual men. We estimated the CD4 counts at which 50 per cent of the HIV-infected but AIDS-free population has AIDS related complex (ARC) based on three biannually measured CD4 counts. The analyses involve interval, right and left censored threshold data. We took the parametric approach, assuming that the threshold values for ARC arise from a family of distributions that includes symmetric, left or right skewed distributions, in which the logistic and extreme value distributions are embedded as special cases. The resulting estimates of median thresholds of CD4 counts for ARC were 249, 424 and 755 for homosexual men, IDUM, and IDUW, respectively. The results were robust with respect to the assumptions on the underlying distribution.

Immunologic aspects of hyperimmunoglobulinemia E-like syndrome in patients with AIDS.

In this study we describe a series of nine patients affected by acquired immunodeficiency syndrome (AIDS) or AIDS-related complex who had hypereosinophilia and hyperimmunoglobulinemia E (hyper-IgE) with chronic dermatitis and recurrent staphylococcal infections. These patients had features similar to those present in hyper-IgE syndrome, a primary immunodeficiency disease. In addition, immunologic characterization of these patients with human immunodeficiency virus (HIV) infection, compared with 51 HIV-positive patients without hyper-IgE, both atopic and nonatopic, and three patients affected by the primary hyper-IgE syndrome, also revealed an increase in IgA and a severe decrease in B and CD4+ lymphocytes. Spontaneous in vitro synthesis of IgE by peripheral blood mononuclear cells was confirmed in both hyper-IgE conditions, together with increased levels of circulating eosinophil cationic protein. Serum-soluble CD23, usually increased in atopic conditions and hyper-IgE, was similar to that of normal control subjects in the HIV-positive patients with hyper-IgE. On the basis of our findings, we conclude that a hyper-IgE-like syndrome represents a distinct aspect of the clinical manifestations associated with HIV infection and that the immunologic mechanisms in this condition seem to differ from those known in primary hyper-IgE syndrome, because CD4+ TH2 type cells, which are currently believed to have a role in IgE production, are severely depleted in HIV-positive patients.

Stavudine in patients with AIDS and AIDS-related complex: AIDS clinical trials group 089.

In a phase I trial of stavudine in AIDS or AIDS-related complex (ARC), antiviral effects and safety were assessed in 41 patients treated with dosages of 0.5-12.0 mg/kg/day. Among evaluable patients, 10% increases in CD4 lymphocyte counts were sustained in 24 (60%) of 40 during treatment; an NAUC response (normalized area under the CD4 cell count-versus-time curve > 1.0) was observed in 31 (91%) of 34 at 10 weeks and in 20 (80%) of 25 at 24 weeks; 15 (83%) of 18 had decreases in p24 antigenemia; and 24 (60%) of 40 gained > or = 2.5 kg body weight. Median CD4 lymphocyte levels remained above baseline for 6 months in patients receiving > 0.5 mg/kg/day. Median serum p24 antigen levels remained below baseline for > or = 1 year in patients with p24 antigen responses. The principal toxicity was peripheral neuropathy, which generally resolved after drug discontinuation but limited the dosage to < or = 2.0 mg/kg/day. Additional trials assessing the effect of stavudine on overall morbidity and mortality are ongoing.