Nelfinavir, efavirenz, or both after the failure of nucleoside treatment of HIV infection.

BACKGROUND: The optimal antiretroviral treatment for patients who have human immunodeficiency virus (HIV) viremia despite treatment with nucleoside reverse-transcriptase inhibitors (nucleoside analogues) remains uncertain. We studied treatment with regimens that combined two nucleoside analogues, at least one of which was new, with the protease inhibitor nelfinavir, the nonnucleoside reverse-transcriptase inhibitor efavirenz, or both. METHODS: The study included 195 patients who had been treated with nucleoside analogues only, and had a plasma HIV type 1 (HIV-1) RNA level of at least 500 copies per milliliter. Patients were randomly assigned to receive, in addition to two nucleoside analogues, nelfinavir, efavirenz, or nelfinavir plus efavirenz. The primary end point was a plasma HIV-1 RNA level of less than 500 copies per milliliter at week 16. A secondary end point was the composite of the HIV-1 RNA levels measured at weeks 40 and 48. RESULTS: At week 16 and at weeks 40 and 48, the proportions of patients in whom a plasma HIV-1 RNA level of less than 500 copies per milliliter was achieved were, respectively, 81 percent and 74 percent in the nelfinavir-plus-efavirenz group, 69 percent and 60 percent in the efavirenz group, and 64 percent and 35 percent in the nelfinavir group. Quadruple therapy resulted in a higher rate of viral suppression in both the short term (P=0.03) and the long term (P=0.001) than did triple therapy with nelfinavir. Triple therapy with efavirenz conferred a higher rate of long-term suppression than triple therapy with nelfinavir (P=0.004). Quadruple therapy also achieved a higher rate of virologic suppression than triple therapy with efavirenz (P=0.008). CONCLUSIONS: In HIV-infected patients previously treated with nucleoside analogues, treatment with nelfinavir plus efavirenz and at least one new nucleoside analogue achieves a higher rate of viral suppression than do regimens with nucleoside analogues and nelfinavir or efavirenz alone.

Highly active antiretroviral therapy decreases mortality and morbidity in patients with advanced HIV disease.

BACKGROUND: Mortality and morbidity related to AIDS have decreased among HIV-infected patients taking highly active anti-retroviral therapy (HAART), but previous studies may have been confounded by other changes in treatment. OBJECTIVE: To assess the benefit of HAART in patients with advanced AIDS and anemia. DESIGN: Prospective, multicenter cohort study. SETTING: The Viral Activation Transfusion Study (VATS), with enrollment from August 1995 through July 1998 and follow-up through June 1999. PATIENTS: 528 HIV-infected patients with cytomegalovirus (CMV) seropositivity or disease who were receiving a first red blood cell transfusion for anemia. MEASUREMENTS: In a person-year analysis of follow-up before and after initiation of HAART, Poisson regression was used to calculate crude rate ratios and rate ratios adjusted for CD4 count, HIV RNA level, calendar period, time on study, sex, ethnicity, and injection drug use. RESULTS: At baseline, patients had a median CD4(+) lymphocyte count of 0.015 x 10(9) cell/L, median plasma HIV RNA level of 4.8 log(10) copies/mL, and median hemoglobin concentration of 73 g/L. Use of HAART increased from 1% of active patients in January 1996 to 79% of active patients in January 1999. The crude death rate was 0.24 event/person-year among patients taking HAART and 0.88 event/person-year among those not taking HAART (rate ratio, 0.26; adjusted rate ratio, 0.38; P < 0.001 for both comparisons). Rates of non-CMV disease were 0.15 event/ person-year after HAART and 0.45 event/person-year before HAART (crude rate ratio, 0.34 [ P < 0.001]; adjusted rate ratio, 0.66 [ P < 0.05]). Rates of CMV disease were 0.10 event/person-year after HAART and 0.25 before HAART (crude rate ratio, 0.42 [ P < 0.01]; adjusted rate ratio, 1.01 [ P > 0.2]). Results were similar in patients with baseline CD4(+) lymphocyte counts less than 0.010 x 10(9) cells/L. CONCLUSIONS: The data support an independent reduction in mortality and opportunistic events attributable to HAART, even in patients with very advanced HIV disease. However, patients with CMV infection or disease may not have a reduction in new CMV events due to HAART.

Correlates of change in cytomegalovirus viremia in patients with advanced human immunodeficiency virus infection who require transfusion.

The Viral Activation Transfusion Study compared leukocyte-reduced to unfiltered red blood cell transfusions in human immunodeficiency virus (HIV)- and cytomegalovirus (CMV)-coinfected patients. Relationships between serially measured plasma CMV load and clinical and laboratory outcomes over a median of 12 months were examined in 511 subjects. At baseline, subjects had a median of 15 CD4(+) cells/mm(3), 25% had CMV disease, and 21.5% were viremic. No relationship was found between changes in CMV viremia and changes in HIV RNA. Increased CMV viremia was associated with a concomitant fall in Karnofsky score. Highly active antiretroviral therapy (HAART) led to a decrease in CMV viremia after a 90-day delay. After adjustment for HIV load and CD4(+) cell count, CMV viremia remained associated with an increased risk of CMV disease (relative hazard, 5.78). In late-stage HIV-infected patients, CMV viremia was associated with lower functional status and increased risk of CMV disease. HAART suppressed CMV viremia only after a delay of several months.

Aerobic exercise: effects on parameters related to fatigue, dyspnea, weight and body composition in HIV-infected adults.

OBJECTIVES: The purpose of the study was to examine the effects of aerobic exercise on physiological fatigue (time on treadmill), dyspnea [rate of perceived exertion (RPE) and forced expiratory volume at 1 s (FEV1)], weight, and body composition in HIV-1-infected adults (200-499 x 106 CD4+ cells/l). DESIGN: The study was a randomized, wait-listed, controlled clinical trial of aerobic exercise in HIV-1-infected adults on signs and symptoms associated with HIV-1 infection or its treatment. METHODS: Sixty subjects were recruited and randomized to two groups. Experimental subjects completed a 12-week supervised exercise program. Control subjects continued usual activity from baseline to week 12 and were then were enrolled in the exercise program. RESULTS: At baseline, the groups were similar in age, weight, body mass index [mean body mass index (BMI) > 27], time since diagnosis, number of symptoms, CD4+ cell count, and number on protease inhibitor therapy (n = 7). Despite disproportionate attrition from the exercise group (38%), exercise subjects were able to remain on the treadmill longer, lost weight, decreased BMI, subcutaneous fat, and abdominal girth when compared to controls. The improvement in weight and body composition occurred without a decrease in kilocalories consumed. Exercise did not seem to have an effect on RPE, a surrogate for dyspnea, and FEV1. There was no significant difference in either the change in CD4+ cell count, percentage or copies of plasma HIV-1 RNA between groups. CONCLUSIONS: We conclude that supervised aerobic exercise training safely decreases fatigue, weight, BMI, subcutaneous fat and abdominal girth (central fat) in HIV-1-infected individuals. It did not appear to have an effect on dyspnea.

Qualitative and quantitative PCR measures of cytomegalovirus in patients with advanced HIV infection who require transfusions.

The Viral Activation Transfusion Study (VATS) was a randomized trial that compared leukocyte-reduced transfusions with unfiltered red blood cell transfusions in HIV and cytomegalovirus (CMV) antibody-positive patients with anemia who were undergoing their first blood transfusion. The relations of the baseline qualitative and quantitative polymerase chain reaction (PCR) measures of plasma CMV viremia, HIV RNA, CD4(+) cell counts, and quality of life in these study subjects were examined. The 511 study subjects had a median CD4(+) cell count equal to 15 cells/mm3, and 110 (21.5%) had CMV viremia by qualitative assay. In multivariate models, frequency of positive qualitative CMV increased with decreasing CD4(+) cell counts (p =.04 trend), higher HIV RNA (p <.001), and a history of CMV disease (p <.001). Quantitative CMV PCR were performed on the 110 qualitative assay-positive study subjects. Median CMV viral load was 1780 copies/ml. In multivariate regression models, lower CD4(+) cell count (p =.03), and a history of CMV disease (p <.001) correlated with the level of CMV load. HIV RNA load and CMV load were not correlated. A lower Karnofsky score was associated with both the presence and quantity of CMV DNA.

Effect of lamivudine in HIV-infected persons with prior exposure to zidovudine/didanosine or zidovudine/zalcitabine.

Nucleoside analog-based regimens remain an integral component of combination therapy for use in both antiretroviral treatment-naive and experienced HIV-infected patients. To further define treatment responses to new antiretroviral therapy in patients with long-term experience to dual nucleoside analog therapy (zidovudine [ZDV] plus didanosine [ddI] or ZDV plus zalcitabine [ddC]), 325 subjects derived from the AIDS Clinical Trials Group (ACTG) 175 trial were randomized to three different combination regimens: (1) continuation of ZDV + ddI or ZDV + ddC (continuation arm), (2) addition of 3TC to ZDV + ddI or ZDV + ddC (addition arm), or (3) a switch to ZDV + 3TC therapy (switch arm). Both the addition and switch arms sustained significantly greater short-term (baseline to week 4) mean CD4+ cell count increases compared with the continuation arm (+36, +28 versus -4 cells/mm3; p = 0.012) and long-term CD4+ cell count responses (baseline to weeks 40/48: +32, +19 versus -9 cells/mm3; p = 0.003). Superior short-term (baseline to week 8) mean decreases in plasma HIV RNA (p < 0.001) were achieved by both the addition and switch arms (0.53 log10 and 0.54 log10 copies/ml, respectively) compared with the continuation arm (0.13 copies/ml) whereas no differences in long-term virologic suppression were observed (p = 0.30). At week 48, no differences were observed in the proportions of subjects who had HIV RNA levels below 500 copies/mL: 18% of subjects in each treatment arm (3-way p = 1.0). Overall, the treatments were well tolerated and only nine subjects (3%) died or developed one or more AIDS-defining events. While this study confirms the intrinsic antiretroviral activity of 3TC, only modest marker changes and limited short-term viral suppression are seen with incremental addition of the drug. The current approach of using 3TC in maximally suppressive regimens is preferred.

Reduced toxicity with gradual initiation of trimethoprim-sulfamethoxazole as primary prophylaxis for Pneumocystis carinii pneumonia: AIDS Clinical Trials Group 268.

Trimethoprim-sulfamethoxazole (TMP/SMX) is recognized as the superior agent for Pneumocystis carinii pneumonia (PCP) prophylaxis but a high incidence of adverse drug reactions, which may be due to toxic drug metabolites, limits its use. AIDS Clinical Trials Group protocol 268 was a randomized, double-blind, controlled two-arm trial designed to determine whether gradual initiation of TMP/SMX suspension reduced the incidence of treatment-limiting adverse drug reactions compared with routine initiation of double-strength (DS; 160 mg/800 mg) tablets. In all, 372 HIV-1-infected study subjects with a CD4+ cell count <250 x 10 cells/mm3 who had not previously received TMP/SMX for PCP prophylaxis were randomized to receive either daily TMP/SMX DS tablets or a gradually increasing dose of TMP/SMX suspension. The suspension dose was increased to reach the equivalent of a DS tablet by study day 13. During the first 2 weeks, study subjects also received a matching placebo tablet/suspension. After week 2, all study subjects received TMP/SMX tablets for the next 10 weeks. There were significantly fewer study subjects who discontinued prophylaxis during the first 12 weeks when TMP/SMX therapy was initiated gradually (17%) than when initiated in DS tablet formulation (33%) (p =.0002). Gradual initiation was also associated with significantly fewer adverse drug reactions. Gradual initiation of TMP/SMX for primary PCP prophylaxis reduces the incidence of its treatment-limiting adverse effects.

Baseline human immunodeficiency virus type 1 phenotype, genotype, and RNA response after switching from long-term hard-capsule saquinavir to indinavir or soft-gel-capsule saquinavir in AIDS clinical trials group protocol 333.

AIDS Clinical Trials Group protocol 333 was an open-label trial of a switch from saquinavir (SQV) hard capsules (SQVhc) to indinavir (IDV) or saquinavir soft-gel capsules (SQVsgc) after >48 weeks of prior treatment with SQVhc. Eighty-nine subjects received IDV or SQVsgc or continued to receive SQVhc and continued unchanged treatment with non-protease-inhibitor antivirals for 8 weeks. Subjects receiving SQVhc then switched treatment to IDV. Baseline drug susceptibility and protease gene sequencing were done; 12 codons related to IDV and SQV resistance were analyzed. After 112 weeks (median) of SQVhc, the fall in human immunodeficiency virus (HIV) type 1 RNA level from baseline was significantly greater with IDV and was inversely correlated with the number of protease substitutions. The number of substitutions also correlated with baseline CD4 cell count, HIV-1 RNA level, SQV experience, and drug susceptibility. Substitution at codon 10, which occurred only in isolates with >/=2 substitutions, was associated with blunted RNA response. IDV IC(50) correlated with HIV-1 RNA response after the switch to IDV but added little predictive power once the genotype was considered.

Methods for investigation of the relationship between drug-susceptibility phenotype and human immunodeficiency virus type 1 genotype with applications to AIDS clinical trials group 333.

Use of human immunodeficiency virus (HIV) drug-resistance testing in therapeutic decision making may be aided by understanding the relationship between results of genotypic and drug-susceptibility phenotypic assays. We investigated this relationship by applying 3 different statistical methods-cluster analysis, recursive partitioning, and linear discriminant analysis-to results for 72 patients followed in the Adult AIDS Clinical Trials Group (ACTG) protocol 333. ACTG 333 was a multicenter, randomized trial comparing 2 formulations of saquinavir (SQV) to indinavir (IDV) in patients with extensive hard-gel SQV experience. Data include protease amino acid sequences and 50% inhibitory concentrations for SQV and IDV at baseline. The 3 methods give similar results showing the association of mutations at codons 10, 63, 71, and 90 with in vitro resistance to IDV and SQV. Recursive partitioning is especially useful because it can identify interactions among mutations at different codons and accommodates many types of data as well as missing observations.

Delavirdine susceptibilities and associated reverse transcriptase mutations in human immunodeficiency virus type 1 isolates from patients in a phase I/II trial of delavirdine monotherapy (ACTG 260).

The development of human immunodeficiency virus type 1 resistance to delavirdine (DLV) was studied in subjects receiving DLV monotherapy. Phenotypic resistance developed in 28 of 30 subjects within 8 weeks. K103N and Y181C, which confer nonnucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance, were the predominant reverse transcriptase mutations. P236L, which confers DLV resistance but hypersensitivity to other NNRTIs, developed in <10% of isolates.

ACTG 260: a randomized, phase I-II, dose-ranging trial of the anti-human immunodeficiency virus activity of delavirdine monotherapy. The AIDS Clinical Trials Group Protocol 260 Team.

ACTG 260 was an open-label, four-arm trial designed to study the safety and anti-human immunodeficiency virus (anti-HIV) activity of delavirdine monotherapy at three ranges of concentrations in plasma compared to those of control therapy with zidovudine or didanosine. Delavirdine doses were adjusted weekly until subjects were within their target trough concentration range (3 to 10, 11 to 30, or 31 to 50 microM). A total of 113 subjects were analyzed. At week 2, the mean HIV type 1 (HIV-1) RNA level declines among the subjects in the three delavirdine arms were similar (0.87, 1.08, and 1.02 log10 for the low, middle, and high target arms, respectively), but by week 8, the subjects in the pooled delavirdine arms showed only a 0.10 log10 reduction. In the subjects in the nucleoside arm, mean HIV-1 RNA level reductions at weeks 2 and 8 were 0.67 and 0.55 log10, respectively. Because viral suppression by delavirdine was not maintained, the trial was stopped early. Rash, which was usually self-limited, developed in 36% of subjects who received delavirdine. Delavirdine monotherapy has potent anti-HIV activity at 2 weeks, but its activity is time limited due to the rapid emergence of drug resistance.

Cellular immunotherapy of advanced human immunodeficiency virus type 1 infection using autologous lymph node lymphocytes: effects on chemokine production.

A pilot study was undertaken in patients with human immunodeficiency virus type 1 (HIV-1) infection to examine the effects of infusing autologous lymph node lymphocytes that had been cultured ex vivo in conditions designed to maximize the specific secretion of HIV-1-suppressive factors, including beta chemokines. Ten patients with CD4 cell counts between 119 and 436/microliter on antiretroviral drugs received a single infusion of CD4 and CD8 lymph node lymphocytes. There were no serious acute or chronic adverse clinical effects. Increases in serum levels of macrophage inflammatory protein 1beta (MIP-1beta) and increases in the production of MIP-1beta by peripheral blood lymphocytes in response to HIV-1 env were observed. Increases in CD4 and CD8 cell counts and skin test reactivity to recall antigens and decreases in HIV-1 virus load were also observed. This cellular immunotherapy can modulate beta chemokine production in patients with advanced HIV-1 infection and may contribute immunorestorative and antiviral activities.

Phase I/II study of the toxicity, pharmacokinetics, and activity of the HIV protease inhibitor SC-52151.

SC-52151, an HIV-1 protease inhibitor, was developed as an ethanol-based elixir and subsequently as a self-emulsifying drug delivery system (SEDDS) to improve bioavailability. To evaluate formulation and treatment regimen effects, we conducted a four-arm, phase I/II study using the highest previously tested daily dose, 2250 mg. Forty-nine patients received the elixir or SEDDS at a dosage of 750 mg three times daily or 1125 mg twice daily for 14 days. One patient developed hypertriglyceridemia, and one had fever and dyspnea. The SEDDS formulation compared with the elixir resulted in a larger area under the concentration-time curve (AUC, p < 0.001), peak (Cmax, p = 0.041) and trough (Cmin, p = 0.025). Twice-daily administration compared with administration three times daily produced a higher cumulative AUC (p = 0.008). Both SEDDS regimens produced mean plasma concentrations above the 90% inhibitory concentration (IC90) for HIV. A mean decline of 0.03 log10 RNA copies (SEDDS) and an increase of 0.15 log10 (elixir) were observed. Although SC-52151 was well tolerated and the SEDDS formulation resulted in plasma concentrations above the IC90 for viral replication, no antiviral activity was produced.

Neuropsychological performance and CD4 levels in HIV-1 asymptomatic infection.

The performance of 68 HIV-1 seropositive asymptomatic (HIV+) subjects stratified on CD4 levels were compared with 82 HIV-1 seronegative (HIV-) subjects on a battery of neuropsychological, mood state, and perceived health status measures. The neuropsychological test battery included measures of attention, reaction time, memory, intellectual ability, psychomotor speed, frontal lobe or "executive" function, and decision time. None of the HIV+ subjects were taking antiviral agents. The groups did not differ for age, mood state, or WAIS-R Verbal and Performance IQ scores. Due to group differences for education and weekly ethanol consumption, both variables were used as covariates in multivariate analyses of variance. Relatively few differences were observed between subgroups of HIV+ patients or between these subgroups and control subjects. These data suggest that factors other than absolute levels of immunosuppression as expressed by CD4 levels alone, appear to be responsible for the deficits observed in HIV+ asymptomatic patients.

Foscarnet for suppression of human immunodeficiency virus replication.

The effect of foscarnet against human immunodeficiency virus (HIV) was evaluated in nine HIV-infected individuals; six completed 28 days of induction therapy. The overall mean increase in CD4+ lymphocytes was 64 cells per mm3. The mean decline in the HIV antigen concentration was 108 pg/ml (P = 0.03), and suppression was related to systemic foscarnet exposure by a maximum-effect pharmacodynamic model.

Duration of illness and neuropsychological performance in asymptomatic HIV infection.

The relationship between duration of illness and neuropsychological performance was examined in 25 asymptomatic HIV-infected men with an estimated date of seroconversion. Mean duration of illness was approximately 2 years. After controlling for CD4 level at the time of neuropsychological examination, duration of illness was correlated with measures of visual attention, mental flexibility, dexterity, auditory information processing, and response fluency, as well as an overall measure of neuropsychological performance. Although these patients performed within normal limits, these data suggest that duration of infection may be related to subtle alterations in neuropsychological performance. These results are discussed with regard to possible mechanisms that implicate gradual accumulation of neurotoxins.

Change in neuropsychological performance in asymptomatic HIV infection: 1-year follow-up.

OBJECTIVE: To examine the stability of cognitive function in patients with asymptomatic HIV infection. DESIGN: Previous longitudinal studies of cognitive function have focused on patients who progress in terms of disease stage. The present study avoided this potential confounding factor by including only subjects who remained in the asymptomatic stage of infection over the follow-up period. METHOD: Subjects were administered an extensive neuropsychological test battery at baseline and 1 year follow-up. Overall performance was characterized as normal or abnormal based on the performance of a well-matched HIV-negative control group. RESULTS: A significantly higher proportion of HIV-positive subjects became abnormal at the follow-up examination. Comparison of the seropositive subjects who remained normal with those who became abnormal revealed no differences at baseline on age, education, depression or CD4 levels. Subjects who became abnormal had worse performance at baseline on measures of information processing, verbal learning and memory, and reaction time. CONCLUSIONS: These data indicate that cognitive function may decline in some patients who continue to be in the asymptomatic stage of infection. Patients with a pattern of cognitive abnormalities at baseline, which includes information processing and reaction time deficits, may be at increased risk for declines in function during early stages of infection.

Depression and neuropsychological performance in asymptomatic HIV infection.

OBJECTIVE: The authors examined the effect of depression on neuropsychological performance in HIV-infected men. Previous studies have suggested that depression may account for the neuropsychological abnormalities observed in some patients with HIV infection, but few studies have specifically examined this question. METHOD: An extensive neuropsychological test battery was administered to 121 HIV-seropositive asymptomatic men and 42 HIV-seronegative comparison subjects. The seropositive subjects were grouped into depressed and non-depressed groups on the basis of scores on the Beck Depression Inventory, Hamilton Rating Scale for Depression, and Structured Clinical Interview for DSM-III-R. RESULTS: Statistical comparisons revealed very few measures on which the depressed seropositive subjects scored significantly worse than either of the nondepressed comparison groups. The nondepressed seropositive group differed consistently from the seronegative comparison subjects on measures of verbal memory and dexterity. CONCLUSIONS: These data indicate that the subtle neuropsychological abnormalities observed in some asymptomatic HIV-seropositive subjects cannot be attributed to depression. These data also indicate the advantages of a multifaceted approach to assessment of depression.

Psychopathology in human immunodeficiency virus infection: lifetime and current assessment.

The present study determined lifetime and current psychiatric functioning in a sample of homosexual or bisexual men at various stages of human immunodeficiency virus (HIV) infection in order to address several questions regarding the relationship between psychopathology and HIV infection. HIV+ asymptomatic or symptomatic and HIV- homosexual or bisexual men completed self-report measures of psychological and health functioning and participated in structured diagnostic interviews. Additional information regarding HIV-related life events and their potential relationship to onset of disorder and family history of psychiatric disorder were obtained. A high lifetime prevalence of affective and substance use disorder was found, with almost one half of the sample meeting criteria for both disorders. Lifetime affective disorder diagnosis was associated with a positive family history of affective disorder. HIV-related events were most closely associated with onset or recurrence of affective disorder compared with other disorders. Low current rates of psychiatric disorder and levels of emotional distress were found, with no differences in degree of psychiatric adjustment across stage of infection. We conclude that the lifetime prevalence of certain categories of psychiatric disorder is high in both HIV+ and HIV- homosexual samples. Increased rates of psychiatric disorders do not appear to be a consequence of HIV infection. However, episodes of illness, particularly affective disorder, may develop following an HIV-related event such as confirmation of infection. Although symptomatic subjects have more somatic difficulties, there appears to be no relationship between stage of illness and level of emotional distress.