RESUMEN
BACKGROUND: Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1. METHODS: We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, > or = 250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses. RESULTS: A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval [CI], 0.60 to 1.41; P=0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log(10) copies per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2-positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed. CONCLUSIONS: Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log(10) copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.)
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Aciclovir/uso terapéutico , Antivirales/uso terapéutico , Infecciones por VIH/transmisión , VIH-1 , Herpes Genital/tratamiento farmacológico , Herpesvirus Humano 2 , Aciclovir/efectos adversos , Adolescente , Adulto , Antivirales/efectos adversos , Recuento de Linfocito CD4 , Femenino , Estudios de Seguimiento , Infecciones por VIH/complicaciones , VIH-1/genética , VIH-1/aislamiento & purificación , Herpes Genital/complicaciones , Humanos , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Masculino , Cooperación del Paciente , Embarazo , ARN Viral/sangre , Sexo Inseguro/estadística & datos numéricos , Adulto JovenRESUMEN
OBJECTIVES: To assess the feasibility of establishing a pneumococcal vaccine trial among HIV-1-infected adults in Uganda and to characterize their responses to 23-valent pneumococcal polysaccharide vaccine. DESIGN: An open-label pilot trial to assess recruitment and compliance of HIV-1-infected adults in Uganda to vaccination and to determine the immunogenicity of the vaccine. SETTING: A community clinic for HIV-1-infected adults in Entebbe, Uganda. METHODS: Levels of capsule-specific IgG to four common vaccine capsular serotypes were measured before vaccination and 1 month after vaccination. Subsequent rates of disease episodes and deaths, and immunologic responses in two vaccine failures, were followed. RESULTS: One month after-vaccination, both HIV-1-infected (n = 77) and seronegative control subjects (n = 10) demonstrated a significant rise in capsule-specific immunoglobulin G (IgG) for three of four serotypes tested, but levels were significantly lower among HIV-1-infected patients. In 149 patient-years of follow-up, two (2.6%) developed pneumococcal pneumonia, one bacteremic with serotype 1 and one non-bacteremic with serotype 13, a non-vaccine serotype; both patients showed inadequate killing of the organism in vitro. In this same follow-up period, 29 (38%) patients died. CONCLUSION: HIV-1-infected adults in Uganda are at high risk of pneumococcal disease and show a significant but suboptimal response to pneumococcal vaccine. Although reliable recruitment and follow-up of vaccinees is feasible, evaluation of vaccine efficacy may be compromised by limited responses to common vaccine serotypes, an unknown incidence of disease with non-vaccine serotypes, and a high rate of mortality unrelated to Streptococcus pneumoniae infection.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/prevención & control , Vacunas Bacterianas , VIH-1 , Neumonía Neumocócica/prevención & control , Streptococcus pneumoniae/inmunología , Adulto , Anticuerpos Antibacterianos/biosíntesis , Vacunas Bacterianas/inmunología , Actividad Bactericida de la Sangre/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Vacunas Neumococicas , Sinusitis/complicaciones , UgandaRESUMEN
Clear understanding of the natural history of HIV-1 disease is critical for planning and developing appropriate therapeutic strategies for HIV-1-infected populations in the developing world. Present knowledge about Africa is based on very limited data that largely use clinical staging as the prognostic marker; this approach has not been prospectively validated. Our objectives were to compare clinical staging and CD4+ T-cell counts as prognostic tools and to describe survival and cause of death in seroprevalent HIV-1-infected Ugandan adults by means of a prospective cohort study. Consecutive HIV-1-infected adults registering with a community HIV/AIDS clinic in Entebbe, Uganda were enrolled between October 1994 to January 1995 and observed during follow-up until the end of December 1997. Baseline CD4+ T-cell count distribution showed clear and appropriate associations with clinical stage in the 201 participants. Both provided equivalent prognostic information: median survival with CD4+ T-cell count <200 cells/microl was 9 months (95% confidence interval [CI], 7-15 months) compared with 19 and 7 months (95% CI, 10-28 and 0-8 months, respectively) in clinical stages 3 and 4, respectively; survival at 3 years with CD4+ T-cell count > or =200 cells/microl was 68% and for clinical stage 1 and 2, 80% and 60%, respectively. Clinical stage 3 and 4 were 76% sensitive and 65% specific for predicting a CD4+ T-cell count <200 cells/microl, positive predictive value of 56%, negative predictive value 78%. In all, 82 participants died (41%; mortality rate 216 of 1000 person-years) and was strongly associated with low CD4+ T-cell counts. In conclusion, clinical staging is valid and comparable with staging by CD4 T-cell counts for epidemiologic measurements. Mortality with early disease in Entebbe appears equivalent to that found in the developed world but there is poor survival with advanced disease.