Deborah McMahon

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.

Ritonavir and saquinavir combination therapy for the treatment of HIV infection.

OBJECTIVE To evaluate the safety and antiretroviral activity of ritonavir (Norvir) and saquinavir (Invirase) combination therapy in patients with HIV infection. DESIGN A multicenter, randomized, open-label clinical trial. SETTING Seven HIV research units in the USA and Canada. PATIENTS A group of 141 adults with HIV infection, CD4 T lymphocyte counts of 100-500 x 10(6) cells/l, whether treated previously or not with reverse transcriptase inhibitor therapy, but without previous HIV protease inhibitor drug therapy. INTERVENTIONS After discontinuation of prior therapy for 2 weeks, group I patients were randomized to receive either combination (A) ritonavir 400 mg and saquinavir 400 mg twice daily or (B) ritonavir 600 mg and saquinavir 400 mg twice daily. After an initial safety assessment of group I patients, group II patients were randomized to receive either (C) ritonavir 400 mg and saquinavir 400 mg three times daily or (D) ritonavir 600 mg and saquinavir 600 mg twice daily. Investigators were allowed to add up to two reverse transcriptase inhibitors (including at least one with which the patient had not been previously treated) to a patients regimen after week 12 for failure to achieve or maintain an HIV RNA level < or = 200 copies/ml documented on two consecutive occasions. MEASUREMENTS Plasma HIV RNA levels and CD4+ T-lymphocyte counts were measured at baseline, every 2 weeks for 2 months, and monthly thereafter. Safety was assessed through the reporting of adverse events, physical examinations, and the monitoring of routine laboratory tests. RESULTS The 48 weeks of study treatment was completed by 75% (106/141) of the patients. Over 80% of the patients on treatment at week 48 had an HIV RNA level < or = 200 copies/ml. In addition, intent-to-treat and on-treatment analyses revealed comparable results. Suppression of plasma HIV RNA levels was similar for all treatment arms (mean areas under the curve minus baseline through 48 weeks were-1.9, -2.0, -1.6, -1.8 log10 copies/ml in ritonavir-saquinavir 400-400 mg twice daily, 600-400 mg twice daily, 400-400 mg three times daily, and 600-600 mg twice daily, respectively). Median CD4 T-lymphocyte count rose by 128 x 10(6) cells/l from baseline, with an interquartile range (IQR) of 82-221 x 10(6) cells/l. The most common adverse events were diarrhea, circumoral paresthesia, asthenia, and nausea. Reversible elevation of serum transaminases (> 5 x upper limit of normal) occurred in 10% (14/141) of the patients enrolled in this study and was associated with baseline abnormalities in liver function tests, baseline hepatitis B surface antigen positivity, or hepatitis C antibody positivity (relative risk, 5.0; 95% confidence interval 1.5-16.9). Most moderate or severe elevations in liver function tests occurred in patients treated with ritonavir-saquinavir 600-600 mg twice daily. CONCLUSIONS Ritonavir 400 mg combined with saquinavir 400 mg twice daily with the selective addition of reverse transcriptase inhibitors was the best-tolerated regimen of four dose-ranging regimens and was equally as active as the higher dose combinations in HIV-positive patients without previous protease inhibitor treatment.

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

Short-Course Raltegravir Intensification Does Not Reduce Persistent Low-Level Viremia in Patients with HIV-1 Suppression during Receipt of Combination Antiretroviral Therapy

BACKGROUND Combination antiretroviral therapy suppresses but does not eradicate human immunodeficiency virus type 1 (HIV-1) in infected persons, and low-level viremia can be detected despite years of suppressive antiretroviral therapy. Short-course (28-day) intensification of standard antiretroviral combination therapy is a useful approach to determine whether complete rounds of HIV-1 replication in rapidly cycling cells contribute to persistent viremia. We investigated whether intensification with the integrase inhibitor raltegravir decreases plasma HIV-1 RNA levels in patients receiving suppressive antiretroviral therapy. METHODS Subjects (n = 10) with long-term HIV-1 suppression receiving combination antiretroviral regimens had their regimens intensified for 4 weeks with raltegravir. Plasma HIV-1 RNA level was determined before, during, and after the 4-week intensification period, using a sensitive assay (limit of detection, 0.2 copies of HIV-1 RNA/mL of plasma). A 4-week intensification course was chosen to investigate potential HIV-1 replication in cells with relatively short (approximately 1-14-day) half-lives. RESULTS There was no evidence in any subject of a decline in HIV-1 RNA level during the period of raltegravir intensification or of rebound after discontinuation. Median levels of HIV-1 RNA before (0.17 log10 copies/mL), during (0.04 log10 copies/mL), and after (0.04 log10 copies/mL) raltegravir intensification were not significantly different (P > .1 for all comparisons in parametric analyses). High-performance liquid chromatography and mass spectroscopy experiments confirmed that therapeutic levels of raltegravir were achieved in plasma during intensification. CONCLUSIONS Intensification of antiretroviral therapy with a potent HIV-1 integrase inhibitor did not decrease persistent viremia in subjects receiving suppressive regimens, indicating that rapidly cycling cells infected with HIV-1 were not present. Eradication of HIV-1 from infected persons will require new therapeutic approaches. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00618371.

Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing

Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the ability of romidepsin (RMD), a histone deacetylase inhibitor approved for the treatment of T-cell lymphomas, to activate the expression of latent HIV. In an in vitro T-cell model of HIV latency, RMD was the most potent inducer of HIV (EC50 = 4.5 nM) compared with vorinostat (VOR; EC50 = 3,950 nM) and other histone deacetylase (HDAC) inhibitors in clinical development including panobinostat (PNB; EC50 = 10 nM). The HIV induction potencies of RMD, VOR, and PNB paralleled their inhibitory activities against multiple human HDAC isoenzymes. In both resting and memory CD4 T cells isolated from HIV-infected patients on suppressive combination antiretroviral therapy (cART), a 4-hour exposure to 40 nM RMD induced a mean 6-fold increase in intracellular HIV RNA levels, whereas a 24-hour treatment with 1 µM VOR resulted in 2- to 3-fold increases. RMD-induced intracellular HIV RNA expression persisted for 48 hours and correlated with sustained inhibition of cell-associated HDAC activity. By comparison, the induction of HIV RNA by VOR and PNB was transient and diminished after 24 hours. RMD also increased levels of extracellular HIV RNA and virions from both memory and resting CD4 T-cell cultures. The activation of HIV expression was observed at RMD concentrations below the drug plasma levels achieved by doses used in patients treated for T-cell lymphomas. In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART.

Effects of nadir CD4 count and duration of human immunodeficiency virus infection on brain volumes in the highly active antiretroviral therapy era

Cerebral atrophy is a well-described, but poorly understood complication of human immunodeficiency virus (HIV) infection. Despite reduced prevalence of HIV-associated dementia in the highly active antiretroviral therapy (HAART) era, HIV continues to affect the brains of patients with chronic infection. In this study we examine patterns of brain volume loss in HIV-infected patients on HAART, and demographic and clinical factors contributing to brain volume loss. We hypothesized that nadir CD4+ lymphocyte count, duration of HIV infection, and age would be associated with reduced cortical volumes. Volumes of cortical and subcortical regions in 69 HIV-infected neuroasymptomatic (NA) individuals and 13 with at least mild acquired immunodeficiency syndrome (AIDS) dementia complex (ADC) were measured using voxel-based morphometry. Demographic and clinical factors (age, plasma HIV RNA level, current and nadir CD4 counts, duration of infection, central nervous system [CNS] penetration of antiretroviral regimen) along with their interactions were entered into a regression model selection algorithm to determine the final models that best described regional brain volumes. Relative to NA, individuals with ADC exhibited decreased total gray matter and parietal cortex volumes and increased total ventricular volumes. Final regression models showed overall cerebral volume, including gray and white matter volume and volumes of the parietal, temporal, and frontal lobes and the hippocampus, were most strongly associated with disease history factors (nadir CD4 and duration of infection). In contrast, basal ganglia volumes were related most strongly to current disease factors, most notably plasma HIV RNA. These findings indicate that individuals with a history of chronic HIV infection with previous episodes of severely impaired immune function, as reflected by reduced nadir CD4+ lymphocyte count, may be at greatest risk for cerebral atrophy. The pattern of HIV-associated brain loss may be changing from a subcortical to a cortical disease among patients who are largely asymptomatic on HAART.

Prolonged Suppression of Human Immunodeficiency Virus Type 1 (HIV-1) Viremia in Persons with Advanced Disease Results in Enhancement of CD4 T Cell Reactivity to Microbial Antigens but Not to HIV-1 Antigens

CD4 T cell responses were studied for >2 years in 27 zidovudine-experienced patients with advanced human immunodeficiency virus type 1 (HIV-1) infection who received triple combination drug therapy with indinavir, zidovudine and lamivudine or zidovudine plus lamivudine or zidovudine alone for 24-42 weeks before switching to the three-drug therapy. Subjects initially given the three drugs had viremia suppressed to undetectable levels and increases in T cell proliferative and cytokine responses to microbial antigens through 2 years of follow-up. Patients receiving the triple-drug therapy after either indinavir or zidovudine-lamivudine treatment had similar increases in T cell responses only if they also had suppression of virus load. CD4 T cell reactivity to HIV-1 antigens was not restored. Prolonged indinavir-zidovudine-lamivudine treatment has significant but incomplete enhancing effects on CD4 T cell reactivity, which could be important in host control of microbial and persistent HIV-1 infections.

HIV-1 DNA Decay Dynamics in Blood During More Than a Decade of Suppressive Antiretroviral Therapy

BACKGROUND Human immunodeficiency virus type 1 (HIV-1) DNA dynamics during long-term antiretroviral therapy (ART) are not defined. METHODS Blood mononuclear cells obtained during 7-12 years of effective ART were assayed for total HIV-1 DNA and 2-long terminal repeat (LTR) circles by quantitative polymerase chain reaction (qPCR). Slopes of HIV-1 DNA were estimated by participant-specific linear regressions. Plasma was assayed for residual viremia (HIV-1 RNA) by qPCR. RESULTS Thirty participants were studied. HIV-1 DNA decreased significantly from years 0-1 and 1-4 of ART with median decay slopes of -0.86 (interquartile range, -1.05, -0.59) and -0.11 (-0.17, -0.06) log10(copies/10(6) CD4+ T-cells)/year, respectively (P < .001). Decay was not significant for years 4-7 (-0.02 [-0.06, 0.02]; P = .09) or after year 7 of ART (-0.006 [-0.030, 0.015]; P = .17). All participants had detectable HIV-1 DNA after 10 years (median 439 copies/10(6) CD4+ T-cells; range: 7-2074). Pre-ART HIV-1 DNA levels were positively associated with pre-ART HIV-1 RNA levels (Spearman = 0.71, P < .001) and with HIV-1 DNA at years 4, 7, and 10 on ART (Spearman ≥ 0.75, P < .001). No associations were found (P ≥ .25) between HIV-1 DNA slopes or levels and % activated CD8+ T-cells (average during years 1-4) or residual viremia (n = 18). 2-LTR circles were detected pre-ART in 20/29 and in 8/30 participants at last follow-up. CONCLUSIONS Decay of HIV-1 DNA in blood is rapid in the first year after ART initiation (86% decline), slows during years 1-4 (23% decline/year), and subsequently plateaus. HIV-1 DNA decay is not associated with the levels of CD8+ T-cell activation or persistent viremia. The determinants of stable HIV-1 DNA persistence require further elucidation. Clinical Trials Registration. NCT00001137.

Extragenital Mycoplasma hominis infections in adults

PURPOSE To heighten awareness of the role of Mycoplasma hominis as an extragenital pathogen in adults. PATIENTS AND METHODS AND RESULTS Patients ranged in age from 14 to 76 years. Thirteen patients were immunosuppressed, including nine organ transplant recipients; three were receiving steroids, and two had an underlying malignancy. The remainder were immunocompetent. Thirteen patients had prior surgery at or near the site of infection. M. hominis was isolated from normally sterile sites such as blood or cerebrospinal, pleural, abdominal and joint fluids, and bone. Non-sterile sites of isolation included surgical wounds and pulmonary secretions. The organism was detected in anaerobic cultures of clinical specimens sent to the laboratory for routine bacteriologic culture. Gram stains of fluids or wound drainage revealed neutrophils but no bacteria. Anti-mycoplasmal therapy was effective in eradicating the organism in 13 of 15 patients who were treated. Of those in whom treatment failed, one patient had an antibiotic-resistant isolate and the other had M. hominis isolated from the lung at postmortem after just 2 days of therapy. CONCLUSION Our experience suggests that significant infections due to M. hominis, although uncommon, are not rare, and methods to isolate and identify this organism should be available for general adult medical and surgical populations.

Anti-Human Immunodeficiency Virus Type 1 (HIV-1) CD8+ T-Lymphocyte Reactivity during Combination Antiretroviral Therapy in HIV-1-Infected Patients with Advanced Immunodeficiency

ABSTRACT The long-term efficacy of combination antiretroviral therapy may relate to augmentation of anti-human immunodeficiency virus type 1 (HIV-1) CD8+ T-cell responses. We found that prolonged treatment of late-stage HIV-1-infected patients with a protease inhibitor and two nucleoside reverse transcriptase inhibitors failed to restore sustained, high levels of HIV-1-specific, HLA class I-restricted, cytotoxic-T-lymphocyte precursors and gamma interferon (IFN-γ) production by CD8+ T cells. In some patients, particularly those initiating three-drug combination therapy simultaneously rather than sequentially, there were early, transient increases in the frequency of anti-HIV-1 CD8+ T cells that correlated with decreases in HIV-1 RNA and increases in T-cell counts. In the other patients, HIV-1-specific T-cell functions either failed to increase or declined from baseline during triple-drug therapy, even though some of these patients showed suppression of plasma HIV-1 RNA. These effects of combination therapy were not unique to HIV-1 specific T-cell responses, since similar effects were noted for CD8+T cells specific for the cytomegalovirus pp65 matrix protein. The level and breadth of CD8+ cell reactivity to HLA A*02 HIV-1 epitopes, as determined by IFN-γ production and HLA tetramer staining after combination therapy, were related to the corresponding responses prior to treatment. There was, however, a stable, residual population of potentially immunocompetent HIV-1-specific T cells remaining after therapy, as shown by tetramer staining of CD8+CD45RO+ cells. These results indicate that new strategies will be needed to target residual, immunocompetent HIV-1-specific CD8+ T cells to enhance the effectiveness of antiretroviral therapy in patients with advanced immunodeficiency.