Charles Gonzalez

Treatment with Indinavir, Zidovudine, and Lamivudine in Adults with Human Immunodeficiency Virus Infection and Prior Antiretroviral Therapy

BACKGROUND The new protease inhibitors are potent inhibitors of the human immunodeficiency virus (HIV), and in combination with other antiretroviral drugs they may be able to cause profound and sustained suppression of HIV replication. METHODS In this double-blind study, 97 HIV-infected patients who had received zidovudine treatment for at least 6 months and had 50 to 400 CD4 cells per cubic millimeter and at least 20,000 copies of HIV RNA per milliliter were randomly assigned to one of three treatments for up to 52 weeks: 800 mg of indinavir every eight hours; 200 mg of zidovudine every eight hours combined with 150 mg of lamivudine twice daily; or all three drugs. The patients were followed to monitor the occurrence of adverse events and changes in viral load and CD4 cell counts. RESULTS The decrease in HIV RNA over the first 24 weeks was greater in the three-drug group than in the other groups (P<0.001 for each comparison). RNA levels decreased to less than 500 copies per milliliter at week 24 in 28 of 31 patients in the three-drug group (90 percent), 12 of 28 patients in the indinavir group (43 percent), and none of 30 patients in the zidovudine-lamivudine group. The increase in CD4 cell counts over the first 24 weeks was greater in the two groups receiving indinavir than in the zidovudine-lamivudine group (P< or =0.01 for each comparison). The changes in the viral load and the CD4 cell count persisted for up to 52 weeks. All the regimens were generally well tolerated. CONCLUSIONS In most HIV-infected patients with prior antiretroviral therapy, the combination of indinavir, zidovudine, and lamivudine reduces levels of HIV RNA to less than 500 copies per milliliter for as long as one year.

Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial

BACKGROUND Raltegravir (MK-0518) is an HIV-1 integrase inhibitor with potent in-vitro activity against HIV-1 strains including those resistant to currently available antiretroviral drugs. The aim of this study was to assess the safety and efficacy of raltegravir when added to optimised background regimens in HIV-infected patients. METHODS HIV-infected patients with HIV-1 RNA viral load over 5000 copies per mL, CD4 cell counts over 50 cells per muL, and documented genotypic and phenotypic resistance to at least one nucleoside reverse transcriptase inhibitor, one non-nucleoside reverse transcriptase inhibitor, and one protease inhibitor were randomly assigned to receive raltegravir (200 mg, 400 mg, or 600 mg) or placebo orally twice daily in this multicentre, triple-blind, dose-ranging, randomised study. The primary endpoints were change in viral load from baseline at week 24 and safety. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, with the number NCT00105157. FINDINGS 179 patients were eligible for randomisation. 44 patients were randomly assigned to receive 200 mg raltegravir, 45 to receive 400 mg raltegravir, and 45 to receive 600 mg raltegravir; 45 patients were randomly assigned to receive placebo. One patient in the 200 mg group did not receive treatment and was therefore excluded from the analyses. For all groups, the median duration of previous antiretroviral therapy was 9.9 years (range 0.4-17.3 years) and the mean baseline viral load was 4.7 (SD 0.5) log10 copies per mL. Four patients discontinued due to adverse experiences, three (2%) of the 133 patients across all raltegravir groups and one (2%) of the 45 patients on placebo. 41 patients discontinued due to lack of efficacy: 14 (11%) of the 133 patients across all raltegravir groups and 27 (60%) of the 45 patients on placebo. At week 24, mean change in viral load from baseline was -1.80 (95% CI -2.10 to -1.50) log10 copies per mL in the 200 mg group, -1.87 (-2.16 to -1.58) log10 copies per mL in the 400 mg group, -1.84 (-2.10 to -1.58) log10 copies per mL in the 600 mg group, and -0.35 (-0.61 to -0.09) log(10) copies per mL for the placebo group. Raltegravir at all doses showed a safety profile much the same as placebo; there were no dose-related toxicities. INTERPRETATION In patients with few remaining treatment options, raltegravir at all doses studied provided better viral suppression than placebo when added to an optimised background regimen. The safety profile of raltegravir is comparable with that of placebo at all doses studied.

3-Year suppression of HIV viremia with indinavir, zidovudine, and lamivudine

The use of antiretroviral therapy that includes an HIV protease inhibitor has markedly decreased morbidity and mortality in HIV-infected persons (1-3). In addition, antiretroviral combination therapy that includes a protease inhibitor can suppress viral load levels for up to 2 years (4-8). However, the long-term durability and toxicity of these regimens are unknown. We present results after 3 years of follow-up in patients who received three-drug therapy with indinavir, zidovudine, and lamivudine in a previously reported study (4, 5). Methods Study Design The study was originally designed as a randomized, double-blind comparison of three antiretroviral regimens: indinavir (Crixivan, Merck & Co., Inc., West Point, Pennsylvania), 800 mg every 8 hours; zidovudine (Retrovir, Glaxo Wellcome, Research Triangle Park, North Carolina), 200 mg every 8 hours, with lamivudine (Epivir, Glaxo Wellcome), 150 mg every 12 hours; and all three drugs together at the same specified doses (4, 5). Patients were encouraged to drink at least 1.5 L of fluid per day. We report on the patients who were originally assigned to receive three-drug therapy. Institutional review boards at each site approved the study and amendments, and all patients gave informed consent. Study Participants Eligible patients were HIV-infected adults who had received at least 6 months of zidovudine therapy but had never taken lamivudine or an HIV protease inhibitor. Patients had serum viral load levels of at least 20 000 copies/mL (Amplicor HIV Monitor Test, Roche Diagnostic Systems, Branchburg, New Jersey) and CD4 counts between 50 to 400 cells/mm3 at screening. Assessments Patients had study visits at least every 4 weeks through week 52 and every 8 weeks through week 156. At baseline and at each visit, a history was taken, a physical examination was performed, and standardized laboratory tests were conducted without regard to food intake. Serum was processed, stored at 70 C, and subsequently assayed for HIV RNA by using the Amplicor and ultradirect assays (4, 5). T-lymphocyte subgroups were quantified by using flow cytometry. Genotypic analysis of serum HIV RNA was performed as described elsewhere (5). Individual investigators graded adverse events according to standardized guidelines. A drug-related adverse event was one that the investigator assessed as possibly, probably, or definitely related to the study therapy. Nephrolithiasis was defined as the passing of macroscopic stones or gravel or flank pain with or without associated hematuria. During follow-up, investigators assessed lipodystrophy at one time point from October to December 1998 (after approximately 2.5 to 3.5 years of treatment). Patients were considered to have lipodystrophy if they had one or more of the following features without evidence of hypercortisolemia: truncal or central obesity with or without thinning of the extremities; accumulation of body fat in the abdomen, the neck (buffalo hump), the retroperitoneum, the face, or the breasts; and accumulation or redistribution of body fat in some areas that was out of proportion to other body areas. Statistical Analysis Antiretroviral activity was assessed by calculating 1) the proportions (with 95% CIs) of patients whose HIV RNA levels were less than 500 copies/mL (Amplicor assay) and those whose HIV RNA levels were less than 50 copies/mL [ultradirect assay] and 2) the median changes (plus interquartile ranges) from baseline in log10HIV RNA levels (Amplicor assay) and CD4 cell counts over time. Analyses were performed on an intention-to-treat basis. Patients who withdrew early from the study were considered to have had virologic failure at subsequent time points, except for two patients who withdrew for reasons that were not related to therapy and had HIV RNA levels less than 500 copies/mL at the time of withdrawal, as described elsewhere (5). Because the analyses included patients with observed values and those with imputed values, the term contributing patients is used. Among patients with at least two measurements, those who never achieved an HIV RNA level less than 500 copies/mL were considered to have experienced virologic failure. Those who achieved an HIV RNA level less than 500 copies/mL were considered to have experienced virologic failure if they had two consecutive measurements of HIV RNA levels that were at least 500 copies/mL but did not have subsequent re-suppression while receiving the same three-drug regimen. Role of the Study Sponsor Employees of the industry sponsor participated in the study as co-investigators. After designing the study with the input of the other study investigators, these employees implemented the protocol and coordinated data collection and statistical analyses. All investigators interpreted the data, determined the content of the paper, and decided whether to submit the paper for publication. Results Study Participants Originally, 33 patients were randomly assigned to receive three-drug therapy with zidovudine, lamivudine, and indinavir. Median age was 40 years (range, 30 to 62 years). Thirty-one patients (94%) were men, and 2 (6%) were women; 26 (79%) were white, 2 (6%) were African American, 3 (9%) were Latin American, and 2 (6%) were members of other racial or ethnic groups. At study entry, patients had taken zidovudine for a median of 28 months (range, 6 to 92 months) and had a median baseline serum HIV RNA level of 41 900 copies/mL (range, 7550 to 219 040 copies/mL) and a median baseline CD4 count of 133 cells/mm3 (range, 35 to 433 cells/mm3). Of the 33 patients, 12 (36%) discontinued therapy within 3 years: 7 because of increased viral load levels; 2 because of need for contraindicated medications (rifampin and cytotoxic chemotherapy); and 1 each because of nausea, patient request, and investigator recommendation after resolution of urinary tract obstruction. Nine patients experienced virologic failure (6 in the first year, 0 in the second year, and 3 in the third year). Antiretroviral Activity The percentages of contributing patients whose HIV RNA level decreased from baseline to less than 500 copies/mL and less than 50 copies/mL, respectively, were 78% (95% CI, 60% to 90%) and 75% (CI, 56% to 88%) at 1 year, 78% (CI, 60% to 90%) and 66% (CI, 47% to 81%) at 2 years, and 68% (CI, 49% to 83%) (21 of 31 patients) and 65% (CI, 45% to 80%) (20 of 31 patients) at 3 years (Figure 1). Patients experienced a median change in HIV RNA level from baseline of 2.07 log10 copies/mL (interquartile range, 2.39 to 1.61 log10 copies/mL) at 1 year, 2.07 log10 copies/mL (interquartile range, 2.40 to 1.61 log10 copies/mL) at 2 years, and 1.99 log10 copies/mL (interquartile range, 2.32 to 1.31 log10 copies/mL) at 3 years (Figure 2). The median increase in CD4 counts from baseline was 155 cells/mm3 (interquartile range, 95 to 230 cells/mm3) at 1 year, 209 cells/mm3 (interquartile range, 117 to 339 cells/mm3) at 2 years, and 230 cells/mm3 (interquartile range, 150 to 316 cells/mm3) at 3 years (Figure 2). Figure 1. Proportion of patients with serum HIV RNA levels less than 500 copies/mL and less than 50 copies/mL during 3 years of treatment with indinavir, zidovudine, and lamivudine. Figure 2. Median changes in serum HIV RNA level and CD4 cell count from baseline during 3 years of treatment with indinavir, zidovudine, and lamivudine. Genotypic Analysis of Viral Resistance For the nine patients who experienced virologic failure by year 3, results of genotypic analyses performed at baseline and at the time of virologic failure were similar to the results of the 2-year analysis (5). Briefly, six patients had preexisting zidovudine resistance, as evidenced by the presence of the reverse transcriptase T215Y substitution combined with M41L (four patients), K70R (one patient), or D67N/K70R/K219Q (one patient). One patient developed zidovudine resistance (M41L), and all nine developed lamivudine resistance (M184V). Five patients acquired protease substitutions that were previously associated with indinavir resistance (9): M46L/V82A (four patients) and L90M (one patient). In two additional patients, evidence of new protease substitutions (L10V or L63P/S/A) appeared during treatment; however, the significance of substitutions at these two naturally occurring polymorphic sites is unclear. Adverse Events Four patients experienced a serious drug-related adverse event related to nephrolithiasis. Two of these patients experienced urinary tract obstruction, and one withdrew from the study 2 months after the adverse event resolved. Two of these patients also had other serious drug-related adverse events (pain and abdominal pain). In total, 12 of 33 patients (36%) had at least one episode of clinical nephrolithiasis during 3 years of treatment and 7 of 33 patients (21%) had more than one episode. Initial episodes of nephrolithiasis occurred from 24 weeks to 3 years of treatment. A total of 64.6 person-years of follow-up occurred before the first episode of nephrolithiasis or before censoring at 3 years. Therefore, the incidence of nephrolithiasis was 1.86 per 10 person-years of follow-up. Of the 21 patients in active follow-up, 4 (19%) fulfilled the clinical definition of lipodystrophy. When random, nonfasting specimens obtained throughout the study were used, serum triglyceride levels greater than 8.47 mmol/L (750 mg/dL) were documented at least once in 8 of 33 patients (24%) and levels greater than 13.55 mmol/L (1200 mg/dL) were documented in 2 of 33 patients (6%). Serum glucose levels greater than 13.88 mmol/L (250 mg/dL) occurred at least once in 1 of 33 patients (3%). Total serum cholesterol level was measured retrospectively in frozen samples obtained after 0.5, 1, 2, and 3 years of follow-up. Seven of 30 patients (23%) had total serum cholesterol levels of at least 6.21 mmol/L (240 mg/dL), and 1 of 30 patients (3%) had a level of at least 7.76 mmol/L (300 mg/dL) at least once. Discussion Evidence shows that it will be difficult

Immune system dysregulation in adolescent major depressive disorder

BACKGROUND A large body of evidence suggests that immune system dysregulation is associated with Major Depressive Disorder (MDD) in adults. This study extends this work to adolescent MDD to examine the hypotheses of immune system dysregulation in adolescents with MDD, as manifested by significantly: (i) elevated plasma levels of cytokines (interferon [IFN]-gamma, tumor necrosis factor-alpha, interleukin [IL]-6, IL-1beta, and IL-4); and (ii) Th1/Th2 cytokine imbalance shifted toward Th1 as indexed by increased IFN-gamma/IL-4. METHOD Thirty adolescents with MDD (19 females; 13 medication-free/naïve; ages 12-19) of at least 6 weeks duration and a minimum severity score of 40 on the Childrens Depression Rating Scale-Revised, and 15 healthy comparisons (8 females), group-matched for age, were enrolled. Plasma cytokines were examined using enzyme-linked immunosorbent assay. Mann-Whitney test was used to compare subjects with MDD and controls. RESULTS Adolescents with MDD had significantly elevated plasma IFN-gamma levels (3.38+/-11.8 pg/ml versus 0.37+/-0.64 pg/ml; p<0.003), and IFN-gamma/IL-4 ratio (16.6+/-56.5 versus 1.76+/-2.28; p=0.007). A trend for IL-6 to be elevated in the MDD group was also observed (1.52+/-2.88 pg/ml versus 0.49+/-0.90 pg/ml; p=0.09). Importantly, findings remained evident when medicated subjects were excluded. CONCLUSIONS Findings suggest that immune system dysregulation may be associated with adolescent MDD, with an imbalance of Th1/Th2 shifted toward Th1, as documented in adult MDD. Larger studies with medication-free adolescents should follow.

Six-year follow-up of HIV-1-infected adults in a clinical trial of antiretroviral therapy with indinavir, zidovudine, and lamivudine.

Objective: To assess virological and immunological responses and toxicity in subjects receiving combination antiretroviral therapy. Design: Six-year follow-up of a single arm of a randomized study of combination antiretroviral therapy. Methods: HIV-infected, zidovudine-experienced patients originally randomized to receive indinavir, zidovudine, and lamivudine had HIV RNA levels and CD4 cell counts assessed over 6 years. Information was collected by questionnaire from subjects who discontinued the study regimen before 6 years. Both on-study and post-study responses were assessed. Results: Of 33 subjects, 16 (48%) discontinued before 6 years of follow-up. After 6 years, 16 (53%) and 14 (47%) of 30 contributing subjects had HIV RNA levels < 500 and < 50 copies/ml, respectively, and the median increase in CD4 cell count from baseline for 28 contributing subjects was 268 × 106 cells/l. Treatment-limiting nephrolithiasis occurred in four subjects. Of the 16 subjects who discontinued the study, 12 had post-study questionnaire data available and seven had HIV RNA < 500 copies/ml on a post-study regimen. In an exploratory analysis combining both on-study and post-study data at approximately 6 years, 26 (79%) and 19 (58%) of 33 had HIV RNA levels < 500 and < 50 copies/ml, respectively, and the median increase in CD4 cell count from baseline was 344 × 106 cells/l. Conclusions: Antiretroviral therapy with indinavir, zidovudine, and lamivudine suppressed HIV viremia and produced continued CD4 cell increases in a majority of subjects for 6 years. Most subjects who discontinued study medications had HIV RNA levels suppressed on post-study therapy. Though based on a small group, this study demonstrates the durable effects of antiretroviral therapy.

A Preliminary Study of Cytokines in Suicidal and Nonsuicidal Adolescents with Major Depression

BACKGROUND Increased systemic cytokine levels, modulators of the immune system, have been repeatedly documented in adult and adolescent major depressive disorder (MDD). This preliminary study extends this work to test the role of cytokines in suicidal symptomatology in adolescent MDD. Hypotheses were that acutely suicidal depressed adolescents would have: (1) increased plasma levels of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1beta, and (2) a proinflammatory/antiinflammatory cytokine imbalance (indexed by plasma IFN-gamma/IL-4), compared to nonsuicidal depressed adolescents and healthy controls. METHODS Twelve suicidal adolescents with MDD (7 females [58%]; 5 medication-free/naïve), 18 nonsuicidal adolescents with MDD (12 females [67%]; 8 medication-free/naïve), and 15 controls (8 females [53%]) were enrolled. MDD had to be of at least 6 weeks duration, with a minimum severity score of 40 on the Childrens Depression Rating Scale-Revised. Plasma cytokines were examined using enzyme-linked immunosorbent assays. Nonparametric tests were used to compare subject groups. RESULTS Unexpectedly, suicidal adolescents with MDD had significantly decreased plasma TNF-alpha concentrations compared to nonsuicidal adolescents with MDD (1.33 +/- 2.95 pg/mL versus 30.9 +/- 110.9 pg/mL; p = 0.03). IFN-gamma was increased in both suicidal and nonsuicidal adolescents with MDD compared to controls (2.14 +/- 6.22 and 4.20 +/- 14.48 versus 0.37 +/- 0.64; p < 0.02, p = 0.005). Findings remained evident when controlled for age and gender. CONCLUSIONS Our preliminary findings suggest that immune system dysregulation may be associated with suicidal symptomatology in adolescent MDD. These findings should be replicated in larger samples with medication-free adolescents.

Long-Term Efficacy and Safety of the HIV Integrase Inhibitor Raltegravir in Patients With Limited Treatment Options in a Phase II Study

Background:Raltegravir in combination therapy has demonstrated potent suppression of HIV-1 with a favorable safety profile. This report provides 96-week efficacy and safety data from Protocol 005, a Phase II study. Methods:HIV-infected patients with very limited treatment options and failing antiretroviral therapy were randomized to raltegravir 200, 400, or 600 mg or placebo b.i.d., plus optimized background therapy for ≥24 weeks; all patients were then offered open-label raltegravir 400 mg b.i.d. Efficacy measurements included changes in viral load and CD4 count from baseline and percent of patients with HIV-1 RNA <400 and <50 copies/mL. Results:One hundred and thirty-three patients received raltegravir and 45 received placebo. No dose-dependent differentiation in the safety or antiviral activity of raltegravir was observed during the double-blind phase. For the combined raltegravir groups, mean change in viral load from baseline was −1.60 log10 copies/mL at week 48 and −1.38 log10 copies/mL at week 96 (observed failure approach). At week 48, HIV-1 RNA levels were <400 copies/mL in 68% of raltegravir recipients and <50 copies/mL in 55%; these levels were maintained in 55% and 48% of raltegravir recipients, respectively, at week 96 (noncompleter = failure). There were few discontinuations of raltegravir (4%) due to adverse events. Conclusions:In patients with limited treatment options, raltegravir with OBT had a potent and sustained antiretroviral effect and was generally well tolerated through 96 weeks.

A cytokine study in children and adolescents with Tourette's disorder

BACKGROUND While immune system dysregulation has been postulated to play a role in Tourettes disorder (TD), most research has focused on the hypothesis of an autoimmune process similar to rheumatic fever. This study examined the potential role of cytokines, modulators of the immune system. We hypothesized that children with TD would have increased levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-12, IL-1 beta and IL-6, and decreased IL-2. We also explored whether comorbid obsessive compulsive disorder (OCD) had an effect on the cytokine profile of TD patients. METHOD Thirty-two children and adolescents with TD (27 males, ages 7-18 years), 17 with comorbid OCD (14 males), and 16 healthy comparison subjects (7 males, ages 9-19), were enrolled. Plasma cytokines were examined using an enzyme-linked immunosorbent assay. The Mann-Whitney and binary logistic regression tests were used to compare the groups. RESULTS Only patients with comorbid OCD (TD+OCD; n=17) had significantly elevated IL-12 plasma levels compared to controls (2.73+/-5.12 pg/ml vs. 0.55+/-0.88 pg/ml, rank statistic=222.5; p<0.04). IL-2 was significantly higher in the TD+OCD subgroup compared to the non-OCD TD subgroup (0.74+/-0.29 pg/ml vs. 0.49+/-0.24 pg/ml, rank statistics=108.5; p<0.03). There were no other significant cytokine differences between groups. CONCLUSIONS Findings suggest a role for IL-12 and IL-2 in TD, and that the TD+OCD subgroup may involve different neuroimmunological functions than the TD-OCD subgroup. Larger studies with medication-free patients should follow.

Daily low-dose subcutaneous interleukin-2 added to single- or dual-nucleoside therapy in HIV infection does not protect against CD4+ T-cell decline or improve other indices of immune function: results of a randomized controlled clinical trial (ACTG 248).

Context:Approaches to preserve or enhance immune function in HIV-1 infection are needed. Objectives:To examine the ability of daily low-dose interleukin-2 (IL-2) in combination with antiretroviral therapy to preserve circulating CD4+ T-cell counts, the clinical safety and tolerability of this treatment, and safety with respect to changes in plasma HIV-1 RNA levels. Design:Twenty-four–week, phase 2, multicenter, randomized, open-label trial conducted at 12 AIDS Clinical Trials Units between September 1995 and May 1997. Participants:A total of 115 HIV-infected persons with screening CD4+ T-cell counts between 300 and 700 cells/mm3 who were on stable single- or dual-nucleoside therapy for at least 2 months, 11% of whom were also on a protease inhibitor at study entry. Interventions:Patients were randomly assigned to receive IL-2 at a dose of 1 million IU subcutaneously once daily plus continued anti-retroviral therapy (ART + IL-2, n = 57) vs. continued ART alone (ART alone, n = 58). IL-2 dose reductions were made for objective or subjective toxicities. All subjects randomly assigned to the IL-2 arm who interrupted ART were also required to discontinue IL-2 for the same period. Main Outcome Measures:The primary endpoint was a decrease in CD4+ T-cell count from baseline; the safety analysis was based on change in plasma HIV RNA by bDNA; and clinical safety and tolerability were analyzed by standard clinical criteria. Results:Of the patients with a baseline CD4+ T-cell count recorded, 15 (27%) of 55 patients randomly assigned to ART alone had a drop of ≥25% in their CD4+ T-cell count and 23 (41%) of 56 patients randomly assigned to ART + IL-2 had a drop of ≥25% in their CD4+ T-cell count at some time over the 24 weeks of the study. This difference was not statistically significant. There was a statistically significant greater variance in CD4+ T-cell counts in the IL–2-treated group. More patients in the IL-2 group had at least a 25% increase in CD4+ T-cell counts over baseline (34 vs. 13%, P = 0.007). A comparison of grade 3 or worse toxicity showed no differences between the arms, but IL-2 was associated with significantly more grade 2 or worse general body symptoms, primarily discomfort and fatigue. There was no significant difference between the groups with regard to changes in plasma HIV RNA, lymphocyte proliferation, natural killer cell activity, skin test responses to recall antigens, or antibody responses to immunization. Plasma markers of immune activation all increased significantly in IL-2 recipients. Conclusions:In patients with baseline CD4+ T-cell counts ≥300 cells/mm3 primarily treated with single- or dual-nucleoside ART, subcutaneously administered IL-2 at a dose of 1 million IU daily for up to 24 weeks had low toxicity but showed no consistent benefit in preventing decline in CD4+ T-cell counts and minimal evidence of immunologic improvement vs. continued ART alone.

HIV-1-Infected Patients with Envelope-Specific Lymphoproliferation or Long-Term Nonprogression Lack Antibodies Suppressing Glycoprotein 120 Antigen Presentation

BACKGROUND Antibodies to the CD4-binding domain (CD4bd) of human immunodeficiency virus type 1 (HIV-1) glycoprotein 120 (gp120) inhibit gp120 antigen presentation to CD4 T cells. These findings imply that the presence of anti-CD4bd antibodies might contribute to the dearth of envelope-specific T helper responses observed in most HIV-1-positive patients. In the absence of these antibodies, however, anti-envelope T helper responses might be maintained. METHODS We used ELISA to evaluate the levels of anti-CD4bd antibodies in rare HIV-1-positive patients who exhibit envelope-specific lymphoproliferation. Subsequently, we examined the contribution of anti-CD4bd antibodies to disease progression by comparing anti-CD4bd antibody levels in 3 cohorts of HIV-1-positive patients with distinct rates of disease progression. RESULTS Although most HIV-1-positive individuals produce anti-CD4bd antibodies, 77% of patients with envelope-specific lymphoproliferation have undetectable anti-CD4bd antibody levels. Moreover, comparison of the 3 HIV-1-positive cohorts revealed that individuals with long-term nonprogression have significantly lower anti-CD4bd antibody titers than do those with rapid or slow progression. Unlike immunoglobulin G (IgG) from rapid progressors, IgG from nonprogressors had no suppressive effects on glycoprotein (gp) 120-specific T cell proliferation. CONCLUSIONS Low anti-CD4bd antibody levels are associated with the absence of disease progression. A number of HIV-1-positive individuals without these antibodies also appear to sustain gp120-specific T helper responses needed to help control the infection.