RESUMO
OBJECTIVE: The primary objective was to compare the effects of dual or triple combinations of HIV-1 reverse transcriptase inhibitors with respect to survival. The time to new HIV disease progression or death, toxicities, the change in CD4 cells, and plasma HIV-1 RNA concentrations in a subset of study subjects were evaluated. DESIGN: This was a multicenter randomized, double-blind, placebo-controlled study. SETTING: The study was conducted among 42 adult AIDS Clinical Trials Group sites and 7 National Hemophilia Foundation centers. PATIENTS: 1313 HIV-infected patients with CD4 counts < or = 50 cells/mm3 participated in this study, which was conducted from June 1993 to June 1996. INTERVENTION: Patients were randomized to one of four daily regimens containing 600 mg of zidovudine: zidovudine alternating monthly with 400 mg didanosine; zidovudine plus 2.25 mg of zalcitabine; zidovudine plus 400 mg of didanosine; or zidovudine plus 400 mg of didanosine plus 400 mg of nevirapine (triple therapy). MAIN OUTCOME MEASURES: The main outcome was survival (i.e., time to death). RESULTS: A significant difference in survival time was found between the four treatment groups, favoring those assigned to triple therapy (p = .02). A significant difference was also found in the delay of disease progression or death among the four treatment arms favoring the group assigned to triple therapy (p = .002). Baseline CD4 cell counts and plasma HIV-1 RNA concentrations as well as changes of CD4 counts at week 8 predicted survival for subjects in the virology substudy. CONCLUSIONS: In the pre-protease inhibitor era, a combination of triple reverse transcriptase inhibitors prolonged life and delayed disease progression in AIDS patients with advanced immune suppression.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Didanosina/uso terapêutico , Nevirapina/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Zalcitabina/uso terapêutico , Zidovudina/uso terapêutico , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/mortalidade , Adulto , Contagem de Linfócito CD4 , Didanosina/administração & dosagem , Intervalo Livre de Doença , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , HIV/genética , HIV/isolamento & purificação , Humanos , Masculino , Nevirapina/administração & dosagem , Placebos , RNA Viral/sangue , Inibidores da Transcriptase Reversa/administração & dosagem , Taxa de Sobrevida , Fatores de Tempo , Zalcitabina/administração & dosagem , Zidovudina/administração & dosagemRESUMO
OBJECTIVE: To provide recommendations for antiretroviral therapy based on information available in mid-1998. PARTICIPANTS: An international panel of physicians with expertise in antiretroviral research and care of patients with human immunodeficiency virus (HIV) infection, first convened by the International AIDS Society-USA in December 1995. EVIDENCE: The panel reviewed available clinical and basic science study results (including phase 3 controlled trials; clinical, virologic, and immunologic end point data; data presented at research conferences; and studies of HIV pathophysiology); opinions of panel members were also considered. Recommendations were limited to drugs available in mid-1998. CONSENSUS PROCESS: Panel members monitor new clinical research reports and interim results. The full panel meets regularly to discuss how the new information may change treatment recommendations. Updated recommendations are developed through consensus of the entire panel at each stage of development. CONCLUSIONS: Accumulating data from clinical and pathogenesis studies continue to support early institution of potent antiretroviral therapy in patients with HIV infection. A variety of combination regimens show potency, expanding choices for initial regimens for individual patients. Plasma HIV RNA assays with increased sensitivity are important in monitoring therapeutic response; however, more data are needed to determine precisely the HIV RNA levels that define treatment failure. Long-term adverse drug effects are beginning to emerge, requiring ongoing attention. Some issues regarding optimal long-term approaches to antiretroviral management are unresolved. The increased complexity in HIV management requires ongoing monitoring of new data for optimal treatment of HIV infection.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Esquema de Medicação , Quimioterapia Combinada , Feminino , HIV/efeitos dos fármacos , HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Inibidores da Protease de HIV/uso terapêutico , Humanos , Masculino , Exposição Ocupacional , Guias de Prática Clínica como Assunto , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Inibidores da Transcriptase Reversa/uso terapêutico , Falha de Tratamento , Carga Viral , Replicação Viral/efeitos dos fármacosRESUMO
PURPOSE: Kaposi's sarcoma (KS), the most common neoplasm in patients with AIDS, is a significant clinical problem for which current therapies are frequently unsatisfactory. We conducted a randomized phase III clinical trial to compare the efficacy and toxicities of a new form of therapy, pegylated-liposomal doxorubicin, with standard combination chemotherapy in patients with advanced AIDS-related KS (AIDS-KS). PATIENTS AND METHODS: Two hundred fifty-eight patients with advanced AIDS-KS were randomly assigned to receive either pegylated-liposomal doxorubicin (20 mg/m2) or the combination of doxorubicin (20 mg/m2), bleomycin (10 mg/m2) and vincristine (1 mg) (ABV) every 14 days for six cycles. Standard response criteria, toxicity criteria, and predefined indicators of clinical benefit were examined to evaluate outcomes. RESULTS: Among 133 patients randomized to receive pegylated-liposomal doxorubicin, one achieved a complete clinical response and 60 achieved a partial response for an overall response rate of 45.9% (95% confidence interval [CI], 37% to 54%). Among 125 patients randomized to receive ABV, 31 achieved a partial response (24.8%; 95% confidence interval [CI], 17% to 32%). This difference was statistically significant (P < .001). In addition to objective responses, prospectively defined clinical benefits and toxicity outcomes also favored pegylated-liposomal doxorubicin. CONCLUSION: Pegylated-liposomal doxorubicin is more effective and less toxic than the standard combination chemotherapy regimen ABV for treatment of AIDS-KS.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doxorrubicina/administração & dosagem , Sarcoma de Kaposi/tratamento farmacológico , Sarcoma de Kaposi/virologia , Adulto , Bleomicina/administração & dosagem , Portadores de Fármacos , Humanos , Lipossomos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Excipientes Farmacêuticos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Tensoativos/administração & dosagem , Análise de Sobrevida , Resultado do Tratamento , Vimblastina/administração & dosagemRESUMO
We present clinical, bacteriologic, and pathological findings for four patients with AIDS and cutaneous miliary tuberculosis. All patients had generalized tuberculosis with hematogenous dissemination to multiple organs including the skin. Microscopic examination of the skin lesions revealed ill-formed or no granulomata, extensive necrosis, and numerous acid-fast bacilli. Mycobacterium tuberculosis was detected in the skin lesions by cultures for three patients and by polymerase chain reaction for one. Three of the isolates were resistant to at least isoniazid and rifampin, and one was susceptible to these drugs. The outcome was rapidly fatal for the three patients with multidrug-resistant tuberculosis. This report draws attention to the reappearance of a once-rare manifestation of disseminated tuberculosis which, in the setting of advanced human immunodeficiency virus disease, may offer the first indication of infection with multidrug-resistant M. tuberculosis and a poor prognosis.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Tuberculose Cutânea/complicações , Tuberculose Miliar/complicações , Tuberculose Resistente a Múltiplos Medicamentos/complicações , Adulto , Evolução Fatal , HIV-1 , Humanos , Masculino , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose Cutânea/diagnóstico , Tuberculose Miliar/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/diagnósticoRESUMO
BACKGROUND: CD4+ lymphocyte counts and plasma HIV-1 RNA levels predict progression of HIV-related disease, but the relative importance of these and other virological factors in defining response to antiretroviral therapy is not yet clear. OBJECTIVE: To determine the short-term variability of plasma HIV-1 RNA level during stable therapy; the relative importance of pretreatment values and early changes in CD4+ count, HIV-1 RNA levels, and infectious HIV-1 titers in mononuclear cells of peripheral blood and pretreatment syncytium-inducing phenotype of an HIV-1 isolate for prediction of disease progression and decline in CD4+ counts during therapy. DESIGN: Data were collected prospectively in a randomized, clinical trial comparing two combination regimens (ACTG [AIDS Clinical Trials Group] Protocol 241) and pooled across treatments. SETTING: 8 AIDS Clinical Trials Units. PATIENTS: 198 adults with HIV-1 infection and no more than 350 CD4+ lymphocytes/mm3 who had received at least 6 months of nucleoside therapy. INTERVENTIONS: All patients received zidovudine and didanosine; 100 received nevirapine and 98 received placebo. MEASUREMENTS: CD4+ lymphocyte counts, plasma HIV-1 RNA levels, and infectious HIV-1 titers in cells were measured before and 8 and 48 weeks after study treatment. Assay for the syncytium-inducing viral phenotype was done at baseline. Progression was defined as occurrence of opportunistic infection, malignancy, or death during the 48 weeks after treatment began. RESULTS: The difference between two measurements of HIV-1 RNA levels at baseline was within +/-0.39 log10 copies/mL (2.5-fold) for 90% of 167 patients receiving stable therapy. In a multivariate model, risk for disease progression was reduced by 56% (95% CI, 8% to 79% [P = 0.028]) for every 10-fold lower HIV-1 RNA level at baseline, by 52% (CI, 6% increase to 79% reduction [P = 0.071]) for every 10-fold reduction in HIV-1 RNA level at 8 weeks after treatment initiation, and by 67% (CI, 42% to 81% [P < 0.001]) for every 2-fold higher CD4+ count at baseline. These risk factors and syncytium-inducing viral phenotype at baseline, but not infectious HIV-1 titers in circulating cells, were associated with change in CD4+ counts over 48 weeks. CONCLUSIONS: For an individual patient, a change in plasma HIV-1 RNA level of 2.5-fold or more probably indicates a true biological change. Monitoring HIV-1 RNA levels and CD4+ lymphocytes before a change in antiretroviral treatment and monitoring HIV-1 RNA levels shortly thereafter improves prediction of disease progression and decline in CD4+ counts for 1 year compared with monitoring CD4+ counts of HIV-1 RNA levels alone. Additional monitoring of infectious HIV-1 titers in mononuclear cells of peripheral blood is not useful.
Assuntos
Síndrome da Imunodeficiência Adquirida/sangue , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Contagem de Linfócito CD4 , HIV-1/genética , Monitorização Fisiológica/métodos , RNA Viral/sangue , Carga Viral , Síndrome da Imunodeficiência Adquirida/virologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Didanosina/uso terapêutico , Progressão da Doença , Quimioterapia Combinada , Humanos , Nevirapina , Fenótipo , Estudos Prospectivos , Piridinas/uso terapêutico , Zidovudina/uso terapêuticoRESUMO
OBJECTIVE: To provide clinical recommendations for antiretroviral therapy for human immunodeficiency virus (HIV) disease with currently (mid 1996) available drugs. When to start therapy, what to start with, when to change, and what to change to were addressed. PARTICIPANTS: A 13-member panel representing international expertise in antiretroviral research and HIV patient care was selected by the international AIDS Society-USA. EVIDENCE: Available clinical and basic science data, including phase 3 controlled trials, clinical endpoint data, virologic and immunologic endpoint data, interim analyses, studies of HIV pathophysiology, and expert opinions of panel members were considered. Recommendations were limited to drugs available in mid 1996. PROCESS: For each question posed, 1 or more member(s) reviewed and presented available data. Recommendations were determined by group consensus (January 1996); revisions as warranted by new data were incorporated by group consensus (February-May 1996). CONCLUSIONS: Recent data on HIV pathogenesis, methods to determine plasma HIV RNA, clinical trial data, and availability of new drugs point to the need for new approaches to treatment. Therapy is recommended based on CD4+ cell count, plasma HIV RNA level, or clinical status. Preferred initial drug regimens include nucleoside combinations; at present protease inhibitors are probably best reserved for patients at higher progression risk. For treatment failure or drug intolerance, subsequent regimen considerations include reasons for changing therapy, available drug options, disease stage, underlying conditions, and concomitant medication(s). Therapy for primary (acute) infection, high-risk exposures to HIV, and maternal-to-fetal transmission are also addressed. Therapeutic approaches need to be updated as new data continue to emerge.
Assuntos
Antivirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Antivirais/administração & dosagem , Contagem de Linfócito CD4 , Quimioprevenção , Quimioterapia Combinada , Tolerância a Medicamentos , Exposição Ambiental/prevenção & controle , HIV/efeitos dos fármacos , HIV/genética , HIV/fisiologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , Inibidores da Protease de HIV/administração & dosagem , Humanos , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , RNA Viral/sangue , Inibidores da Transcriptase Reversa/administração & dosagem , Falha de Tratamento , Replicação ViralRESUMO
To assess safety, antitumor response, and immunological and virological activity of interferon-alpha 2a and zidovudine combination therapy in patients with AIDS-related Kaposi's sarcoma, we conducted an open-label, Phase II, multicenter study. Sixty-three patients with biopsy-proven Kaposi's sarcoma and no previous interferon-alpha therapy received zidovudine 600 mg/day and interferon-alpha 2a 18 x 10(6) U/day. The median duration of follow-up was 49 weeks. Of 62 evaluable patients, 25 (40%; 95% confidence interval, 0.28-0.52) showed a complete (26%) or partial (15%) antitumor response. Eight of 30 patients (27%) with < 100 CD4 cells/mm3 and 17 of 32 patients (53%) with > or = 100 CD4 cells/mm3 had a response. The median time to response was 36 weeks. Of the 25 patients with a response, four developed tumor progression. The median duration of response was 22.4 weeks. Eight patients (13%) developed another AIDS-defining event and 13 (21%) died. The major toxicities included anemia (16%), neutropenia (27%), elevated serum transaminases (16%), weight loss (16%), malaise (14%), fatigue (14%), fever (10%), and headache (6%). Therapy with intermediate-dose interferon-alpha 2a and zidovudine resulted in tumor regression in patients with AIDS-related Kaposi's sarcoma who had a wide range of CD4 cell counts; this therapy was relatively well tolerated.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Antineoplásicos/uso terapêutico , Antivirais/uso terapêutico , Interferon-alfa/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Zidovudina/uso terapêutico , Adulto , Antineoplásicos/administração & dosagem , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Progressão da Doença , Quimioterapia Combinada , Feminino , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Masculino , Proteínas Recombinantes , Sarcoma de Kaposi/complicações , Sarcoma de Kaposi/mortalidade , Taxa de Sobrevida , Zidovudina/administração & dosagem , Zidovudina/efeitos adversosRESUMO
BACKGROUND: We conducted a trial to compare treatment with zidovudine or didanosine in patients with advanced human immunodeficiency virus type 1 (HIV-1) infection who had received little or no previous therapy with zidovudine. METHODS: Six hundred seventeen patients with acquired immunodeficiency syndrome (AIDS), advanced AIDS-related complex (CD4 cell count, < or = 0.30 x 10(9)/L [300/microL]), or asymptomatic HIV (CD4 cell count, < or = 0.20 x 10(9)/L) received zidovudine, 500 mg/d of didanosine, or 750 mg/d of didanosine in a randomized, double-blind allocation, with cross-over to alternative medication after development of an end point or serious toxic effect. To be eligible, patients must have received either no or up to 16 weeks of zidovudine therapy before entry into the study. Primary end points were development of a new AIDS-defining event or death. Secondary clinical end points were new or recurrent AIDS-defining events, or death, and survival. RESULTS: In the study as a whole, there were no differences in the relative risks (RRs) of the development of end points between treatment groups. However, there was a strong interaction between the relative efficacies of zidovudine and didanosine and previous experience with zidovudine. Among 380 patients with no previous zidovudine therapy, zidovudine was more effective than 750 mg/d of didanosine (RR, 1.43; 90% confidence interval [CI], 1.02 to 2.00), with a similar trend for zidovudine compared with 500 mg/d of didanosine (RR, 1.21; 90% CI, 0.86 to 1.71). However, among 118 patients with more than 8 weeks but no more than 16 weeks of previous zidovudine therapy, 500 mg/d of didanosine was more effective than zidovudine (RR, 0.48; 90% CI, 0.27 to 0.86); there was a similar trend for increased effectiveness of 750 mg/d of didanosine compared with zidovudine (RR, 0.61; 90% CI, 0.36 to 1.03). Among 119 patients who had some but no more than 8 weeks of previous zidovudine therapy, there were no significant differences among the treatment arms. Similar findings were noted in the analysis of the two secondary clinical end points. No significant differences were found in efficacy between the groups receiving 500 and 750 mg/d of didanosine. The major toxic effect associated with zidovudine was hematopoietic (granulocytopenia) and that associated with didanosine was pancreatitis (dosage, 750 mg/d). CONCLUSIONS: In patients with advanced HIV disease, zidovudine appears to be more effective than didanosine as initial therapy; however, some patients with advanced HIV disease may benefit from a change to didanosine therapy after as little as 8 to 16 weeks of therapy with zidovudine.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Didanosina/uso terapêutico , Zidovudina/uso terapêutico , Infecções Oportunistas Relacionadas com a AIDS/prevenção & controle , Síndrome da Imunodeficiência Adquirida/mortalidade , Adulto , Contagem de Linfócito CD4 , Didanosina/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Cooperação do Paciente , Índice de Gravidade de Doença , Análise de Sobrevida , Resultado do Tratamento , Zidovudina/efeitos adversosRESUMO
To ascertain whether combination therapy with zidovudine (AZT) and zalcitabine (ddC) delayed the emergence of AZT resistance, isolates of human immunodeficiency virus (HIV) were evaluated from 15 previously untreated patients with advanced HIV disease who received combination therapy. Eighteen sequential viral isolates were available from 15 patients who received > or = 6 months of combination therapy. Isolates from eight (73%) of 11 patients obtained between 24 and 48 weeks of therapy were AZT resistant [50% inhibitory concentration (IC50) > or = 0.45 microM; range, 0.45-2.0 microM]. Four of these eight patients yielded virus isolates that were highly AZT resistant (IC50 > 1.0 microM). No changes in ddC susceptibility were discerned. The median IC50 for ddC was 0.2 microM and ranged from 0.07 to 0.5 microM. The CD4 cell counts of patients with AZT-sensitive virus tended to have higher median areas under the curve (AUC) and greater increases compared with patients who had AZT-resistant virus. They also had higher means and ranges of the average CD4 cell counts at week 36 (p = 0.01) and week 48 (p = 0.04). These data would indicate that the previously described more sustained CD4 cell responses conferred by the addition of ddC to AZT therapy cannot be ascribed to delayed emergence of AZT resistance with combination therapy.
Assuntos
Infecções por HIV/tratamento farmacológico , HIV/efeitos dos fármacos , Zalcitabina/farmacologia , Zidovudina/farmacologia , Linfócitos T CD4-Positivos/citologia , Resistência Microbiana a Medicamentos , Quimioterapia Combinada , Células HeLa , Humanos , Contagem de Leucócitos , Fatores de Tempo , Zalcitabina/uso terapêutico , Zidovudina/uso terapêuticoRESUMO
Despite recent disappointment with antiretroviral agents, investigators continue to examine combination therapy with agents that target the same or different stages of the HIV life cycle. Initial studies suggest that when therapy is started early in the course of infection, certain combinations may be better than single-drug regimens in reducing viral burden and delaying the onset of drug resistance.
Assuntos
Antivirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV/efeitos dos fármacos , Antivirais/classificação , Antivirais/farmacologia , Ensaios Clínicos como Assunto , Resistência Microbiana a Medicamentos , Quimioterapia Combinada , HIV/genética , HIV/crescimento & desenvolvimento , HIV/fisiologia , Humanos , Transcrição Gênica/efeitos dos fármacos , Falha de Tratamento , Integração Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
BACKGROUND: Patients with HIV infection can have recurrent and persistent oral ulcers, not attributable to known infectious agents. OBJECTIVE: Our aim was to evaluate prospectively oral ulcers in patients with HIV infection to determine whether an etiologic agent could be identified. METHODS: Sixteen patients with HIV infection who had oral ulcers not attributable to known causes had culture of the base and a biopsy specimen taken from the ulcer. Cultures were obtained for herpes simplex and varicella-zoster viruses, mycobacteria, and fungi. By polymerase chain reaction (PCR) analysis with primer/probe sets for herpes simplex viruses 1 and 2, varicella-zoster virus, cytomegalovirus, human papillomavirus, and Mycobacterium tuberculosis, each biopsy specimen was analyzed for the presence of DNA from these organisms. Specimens were also evaluated histologically. RESULTS: Histoplasmosis was detected histologically in one biopsy specimen, candidiasis in a second, and herpetic changes in a third. Viral cultures were positive for herpes simplex virus 1 in four cases and herpes simplex virus 2 in one case. PCR analysis detected DNA for herpes simplex virus 1 in one case and herpes simplex virus 2 in another; DNA from other pathogens was not identified. In the remaining eight patients, hematoxylin-and-eosin staining revealed eosinophilic ulcers in five cases and nonspecific changes in three cases. CONCLUSION: The etiologic agent of recurrent or persistent oral ulcers in patients with AIDS and AIDS-related complex was not identified in 50% of patients. PCR analysis was not useful. Herpes simplex virus or other pathogens were not detected in ulcers containing numerous eosinophils.
Assuntos
Complexo Relacionado com a AIDS/complicações , Síndrome da Imunodeficiência Adquirida/complicações , Doenças da Boca/complicações , Adulto , Doença Crônica , DNA Viral/análise , Feminino , Herpesvirus Humano 1/genética , Herpesvirus Humano 2/genética , Humanos , Masculino , Pessoa de Meia-Idade , Doenças da Boca/diagnóstico , Doenças da Boca/microbiologia , Orofaringe , Reação em Cadeia da Polimerase , Estudos Prospectivos , Recidiva , Úlcera/complicações , Úlcera/diagnóstico , Úlcera/microbiologiaRESUMO
Fifty-three patients with AIDS-related Kaposi's sarcoma and no previous treatment with cytotoxic chemotherapy enrolled in a phase II multicenter study to evaluate the safety and efficacy of weekly doxorubicin treatment. Doxorubicin was given intravenously at a dose of 15 mg/m2. Patients were stratified for purposes of analyses by tumor burden and coexistence of HIV-associated signs and symptoms; stratum I included patients with cutaneous disease alone and no symptoms, and stratum II included patients with visceral disease, tumor-associated edema, a previous opportunistic infection, or systemic symptoms. Fifty-one patients were evaluable for toxicity and 50 for tumor response. Five patients had a partial response (10%); 32, a minor response (64%); 12, no change (24%); and one, progression (2%) as the best measurable response. Partial response durations ranged from 4 to 14 weeks. Fifteen patients subsequently showed progression while on treatment. A significantly greater number of patients in stratum I (20.1%) had a partial response compared with those in stratum II (0%, p = 0.009). The major toxicities included nausea (37%), stomatitis (9.8%), mucositis (13.7%), and moderate to severe neutropenia (71%). Neutropenia was dose limiting and resulted in discontinuation of doxorubicin in 18% of the patients. Two patients developed cardiac toxicity. In conclusion, doxorubicin treatment induced relatively few tumor responses and remission durations were short. Treatment was limited by a high rate of toxicity.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Doxorrubicina/administração & dosagem , Sarcoma de Kaposi/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/complicações , Adulto , Doxorrubicina/efeitos adversos , Esquema de Medicação , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Sarcoma de Kaposi/sangue , Sarcoma de Kaposi/etiologiaRESUMO
OBJECTIVE: To determine the clinical manifestations of patients with human immunodeficiency virus (HIV) infection and tuberculosis caused by multiple-drug-resistant bacilli compared with those with single-drug-resistant or susceptible bacilli. DESIGN: Descriptive, case-control, and cohort studies. SETTING: A large urban teaching hospital. PATIENTS: Sixty-two patients with tuberculosis caused by multiple-drug-resistant bacilli (cases) and 55 patients with tuberculosis caused by single-drug-resistant or susceptible bacilli (controls). MEASUREMENTS: Characteristics of clinical presentation, radiographs, pathologic abnormalities, antituberculosis treatment, and clinical course. RESULTS: Twenty cases (32%) had concomitant pulmonary and extrapulmonary disease at presentation compared with 9 controls (16%; odds ratio, 2.4; 95% CI, 1.0 to 5.9). More cases had alveolar infiltrates (76%; odds ratio, 3.6; CI, 1.2 to 11.4), interstitial infiltrates with a reticular pattern (67%; odds ratio, 7.8; CI, 1.0 to 83.5), and cavitations (18%; odds ratio, 6.6; CI, 0.8 to 315.3) on initial chest radiographs compared with controls (49%, 19%, and 3%, respectively). Pathologic specimens from cases showed extensive necrosis, poor granuloma formation, marked inflammatory changes with a predominance of neutrophils, and abundant acid-fast bacilli. Twenty-five cases received two or more effective antituberculosis drugs for more than 2 months. Only 2 cases had three consecutive negative cultures for Mycobacterium tuberculosis; one patient died within 1 day of the last negative culture, and the other had positive cultures 496 days later. The remaining 23 cases had persistently or intermittently positive cultures despite therapy. The clinical course of these cases suggested overwhelming miliary tuberculosis with involvement of the lungs (77%), pleura (15%), stool (34%), meninges (13%), bone marrow (16%), blood (10%), lymph nodes (10%), and skin (8%). The median survival time was 2.1 months for cases compared with 14.6 months for controls (P = 0.001, log-rank test). CONCLUSIONS: Tuberculosis caused by multiple-drug-resistant bacilli in patients with HIV infection is associated with widely disseminated disease, poor treatment response with an inability to eradicate the organism, and substantial mortality.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Pulmonar/microbiologia , Adulto , Antituberculosos/administração & dosagem , Estudos de Casos e Controles , Estudos de Coortes , Resistência Microbiana a Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Modelos de Riscos Proporcionais , Análise de Sobrevida , Resultado do Tratamento , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/patologiaRESUMO
In vitro studies have shown that 3'-azido-3'-deoxythymidine (zidovudine, AZT) and interferon synergistically inhibit the replication of the human immunodeficiency virus type 1 (HIV) in peripheral blood mononuclear cells at concentrations achievable in patients. Interferon alfa can cause lesions to regress in patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma (KS). Although zidovudine has no significant effect on the regression of these lesions, it does have antiviral activity in these patients as manifested by a decline in serum HIV antigen. However, when used separately, the two drugs can have serious side effects in some patients. In addition, the development of zidovudine-resistant strains has been noted in patients with advanced HIV disease receiving zidovudine for nine months or longer. Three in vivo trials have been initiated to assess possible advantages of combination therapy with zidovudine and interferon alfa in patients with AIDS-related KS. The incidence of serious adverse reactions, therapeutic efficacy, and the rate of emergence of zidovudine-resistant strains of HIV were evaluated. Preliminary results indicate that combination therapy with interferon alfa and zidovudine can safely be administered to patients with AIDS-related KS in doses that elicit antitumor and antiviral responses and discourage the potential emergence of zidovudine-resistant HIV strains.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Interferon Tipo I/administração & dosagem , Sarcoma de Kaposi/tratamento farmacológico , Zidovudina/administração & dosagem , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Antígenos HIV/isolamento & purificação , Humanos , Interferon Tipo I/uso terapêutico , Proteínas Recombinantes , Sarcoma de Kaposi/complicações , Zidovudina/efeitos adversosRESUMO
To determine the safety, maximum tolerated dose, and preliminary efficacy of concomitant interferon-alpha and zidovudine therapy in AIDS-related Kaposi's sarcoma (KS), 56 patients with biopsy-proven KS and documented human immunodeficiency virus type 1 (HIV) infection were enrolled into a phase I study. Interferon-alpha was given intramuscularly at a dose of 9, 18, or 27 mu once a day and zidovudine was administered as 100 or 200 mg every 4 h for 8 weeks followed by a 48-week maintenance period. The major toxicities were anemia, neutropenia, and hepatotoxicity. Neutropenia was dose limiting with 1,200 mg of zidovudine/day and the lowest dose of interferon-alpha (9 mu/day). Hepatotoxicity was dose limiting with 27 mu of interferon and 600 mg of zidovudine/day. Cumulative dose-related anemia or neutropenia was not seen during long-term follow-up. The maximum tolerated doses for the combination were defined as 18 mu daily for interferon-alpha and 600 mg daily for zidovudine. Variable changes in CD4 lymphocytes occurred during the first 8 weeks of therapy. At higher doses of the combination, sustained increases in median CD4 lymphocyte numbers were noted (p less than 0.001). In HIV antigenemic patients, progressive antigen suppression was seen with increasing doses of the combination (p less than 0.005). The overall antitumor response rate was 47%. Tumor regression was associated with better survival benefits (p less than 0.001) and a pretreatment CD4 cell count greater than or equal to 200 cells/mm3 (p = 0.01). In conclusion, intermediate doses of interferon-alpha and lower doses of zidovudine appear to be relatively well tolerated and associated with disease improvement, including survival benefits.
Assuntos
Síndrome da Imunodeficiência Adquirida/terapia , Interferon Tipo I/uso terapêutico , Interferon-alfa/uso terapêutico , Sarcoma de Kaposi/terapia , Zidovudina/uso terapêutico , Síndrome da Imunodeficiência Adquirida/complicações , Adulto , Anemia/induzido quimicamente , Bissexualidade , Linfócitos T CD4-Positivos , Terapia Combinada , Avaliação de Medicamentos , Seguimentos , Antígenos HIV/análise , HIV-1/imunologia , Homossexualidade , Humanos , Injeções Intramusculares , Interferon Tipo I/administração & dosagem , Interferon Tipo I/efeitos adversos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Contagem de Leucócitos , Fígado/efeitos dos fármacos , Masculino , Neutropenia/induzido quimicamente , Infecções Oportunistas/complicações , Proteínas Recombinantes , Sarcoma de Kaposi/etiologia , Zidovudina/administração & dosagem , Zidovudina/efeitos adversosRESUMO
Thirty-six patients with AIDS and culture-proven nontuberculous mycobacteriosis were compared to 20 patients with acquired immunodeficiency syndrome (AIDS) and tuberculosis with regard to clinical signs, symptoms, and diagnostic methods. Patients with nontuberculous mycobacteriosis were more often younger and homosexuals, while patients with tuberculosis were usually Haitian-American or users of intravenous drugs. A majority of patients with tuberculosis presented with fever and weight loss. These symptoms were seen in approximately 50 percent of the patients with nontuberculous mycobacteriosis. A distinct syndrome of dyspnea, chills, hemoptysis, and chest pain was seen in a significant minority of patients with nontuberculous mycobacteriosis. Lymphadenopathy was seen almost exclusively in patients with tuberculosis. Pulmonary sources (expectorated sputum or bronchoscopy specimens) were the most common source of diagnosis in both groups. Patients in both groups in whom the diagnosis was obtained from pulmonary sources frequently had negative chest x-ray films on presentation. Cavitary disease was absent from both groups.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Infecções por Mycobacterium não Tuberculosas/etiologia , Infecções por Mycobacterium/etiologia , Infecções Oportunistas/etiologia , Tuberculose Pulmonar/etiologia , Adulto , Fatores Etários , Broncoscopia , Feminino , Haiti/etnologia , Homossexualidade , Humanos , Masculino , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Fatores de Risco , Escarro/microbiologia , Transtornos Relacionados ao Uso de Substâncias , Tuberculose Pulmonar/diagnóstico , Estados UnidosRESUMO
The safety and efficacy of sulfamethoxazole and trimethoprim in the prevention of Pneumocystis carinii pneumonia associated with the acquired immunodeficiency syndrome (AIDS) were evaluated. Sixty patients with a new diagnosis of Kaposi's sarcoma and no history of opportunistic infections were randomly assigned to receive 800 mg of sulfamethoxazole and 160 mg of trimethoprim twice per day or no therapy. None of the 30 patients receiving sulfamethoxazole and trimethoprim developed P carinii pneumonia. Sixteen of the 30 patients receiving no suppressive therapy developed P carinii pneumonia. Development of P carinii pneumonia was associated with the stage of Kaposi's sarcoma, B subtype disease, and the presence of 0.20 X 10(9)/L (200/mm3) or fewer CD4 cells at study entry. The proportion of patients surviving and the mean length of survival were significantly greater in the treatment group compared with the control group. Adverse reactions occurred in 15 patients (50%).
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Pneumonia por Pneumocystis/prevenção & controle , Sulfametoxazol/uso terapêutico , Trimetoprima/uso terapêutico , Síndrome da Imunodeficiência Adquirida/mortalidade , Adulto , Quimioterapia Combinada , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia por Pneumocystis/etiologia , Estudos Prospectivos , Distribuição Aleatória , Sarcoma de Kaposi/complicações , Sulfametoxazol/efeitos adversos , Trimetoprima/efeitos adversosRESUMO
Five dose regimens of 2',3'-dideoxycytidine (ddC) were administered, intravenously for 2 weeks then orally for 4 or more weeks, to 20 patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). ddC was well absorbed from the gut and crossed the blood-brain barrier. 10 of the 15 patients who received 0.03-0.09 mg/kg every 4 h had increases in their absolute number of T4+ T cells at week 2 (p less than 0.05), though in many these rises were not sustained. 11 of 13 evaluable patients had a fall in their serum human immunodeficiency virus (HIV)p24 antigen by week 2 of therapy (p less than 0.01); in 4 patients the p24 antigen subsequently rose to baseline while in others the decline was sustained. Dose-related toxic effects included cutaneous eruptions, fever, mouth sores, thrombocytopenia, and neutropenia. A reversible painful peripheral neuropathy developed in 10 patients after 6-14 weeks' treatment. These results suggest that ddC has activity against HIV in vivo and has a different toxicity profile from that of zidovudine (AZT). 6 patients with AIDS or ARC were given an alternating regimen of oral AZT (200 mg every 4 h for 7 days) and oral ddC (0.03 mg/kg every 4 h for 7 days). The regimen was well tolerated, and the 5 patients who completed 9 or more weeks of treatment had sustained rises in their T4+ T cells and/or falls in p24 antigen.
Assuntos
Complexo Relacionado com a AIDS/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Desoxicitidina/análogos & derivados , Timidina/análogos & derivados , Adulto , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Esquema de Medicação , Avaliação de Medicamentos , Quimioterapia Combinada , HIV/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Timidina/administração & dosagem , Timidina/uso terapêutico , Zalcitabina , ZidovudinaRESUMO
We conducted a double-blind, placebo-controlled trial of the efficacy of oral azidothymidine (AZT) in 282 patients with the acquired immunodeficiency syndrome (AIDS) manifested by Pneumocystis carinii pneumonia alone, or with advanced AIDS-related complex. The subjects were stratified according to numbers of T cells with CD4 surface markers and were randomly assigned to receive either 250 mg of AZT or placebo by mouth every four hours for a total of 24 weeks. One hundred forty-five subjects received AZT, and 137 received placebo. When the study was terminated, 27 subjects had completed 24 weeks of the study, 152 had completed 16 weeks, and the remainder had completed at least 8 weeks. Nineteen placebo recipients and 1 AZT recipient died during the study (P less than 0.001). Opportunistic infections developed in 45 subjects receiving placebo, as compared with 24 receiving AZT. The base-line Karnofsky performance score and weight increased significantly among AZT recipients (P less than 0.001). A statistically significant increase in the number of CD4 cells was noted in subjects receiving AZT (P less than 0.001). After 12 weeks, the number of CD4 cells declined to pretreatment values among AZT recipients with AIDS but not amonG AZT recipients with AIDS-related complex. Skin-test anergy was partially reversed in 29 percent of subjects receiving AZT, as compared with 9 percent of those receiving placebo (P less than 0.001). These data demonstrate that AZT administration can decrease mortality and the frequency of opportunistic infections in a selected group of subjects with AIDS or AIDS-related complex, at least over the 8 to 24 weeks of observation in this study.