We evaluated the therapeutic outcomes of all antiretroviral-naive HIV-1-infected patients with fewer than 100 CD4 cells/μl, who received efavirenz-based highly active antiretroviral therapy (HAART). Sixty-one percent suffered AIDS-defining diseases, and after a median follow-up of 45 weeks there were three deaths and five AIDS-related conditions (two relapses, three new). Efavirenz-based HAART was found to be effective in profoundly immunosuppressed HIV-1-infected patients.
The efficacy of efavirenz-based highly active antiretroviral therapy (EFV–HAART) in advanced HIV- infected patients suffering opportunistic diseases is at present unknown. The pivotal phase III trial of efavirenz (study 006) enrolled only patients with a CD4 cell count of more than 50 cells/μl. The mean baseline CD4 cell count of the 1266 patients included in the 006 trial was 341 cells/μl, and only 129 patients (10%) had baseline CD4 cell counts of between 50 and 100 cells/μl . None of the patients included in study 006 had suffered an AIDS-defining condition shortly before entering the trial. Given the lack of data on the efficacy of non-nucleosides in profoundly immunosupressed patients, the latest expert guidelines issued by official agencies in Spain, recommend protease inhibitor (PI)-based HAART as the preferred regimen for naive patients with fewer than 100 CD4 cells/μl .
In this retrospective study, we determined the effectiveness of EFV–HAART in profoundly immunosupressed HIV-infected patients who were followed in three HIV clinics in Spain. Patients were eligible to be included in the study if they were naive for antiretroviral therapy, had fewer than 100 CD4 cells/μl, received treatment with efavirenz and two nucleosides, and had had at least one follow-up visit.
Ninety-two patients (83% male, mean age 36 years) who met the inclusion criteria were identified. Forty-four patients (48%) received stavudine and lamivudine, 42 (46%) received zidovudine and lamivudine, five received stavudine and didanosine, and one received didanosine and lamivudine along with efavirenz. The median CD4 cell count and HIV-RNA level were 34 cells/μl and 350 000 copies/ml, respectively. Fifty-seven patients (62%) had fewer than 50 cell/μl before they started EFV–HAART, and 77 (84%) had a baseline HIV-1-RNA level of more than 100 000 copies/ml. Forty-four patients (48%) had been diagnosed with an AIDS-defining condition before starting EFV–HAART (18 tuberculosis, 16 Pneumocystis carinii pneumonia, 14 oesophageal candidiasis, six cytomegalovirus end-organ diseases, five intestinal cryptosporidiosis, four cerebral toxoplasmosis, four cryptococosis, four Kaposi′s sarcoma, three disseminated Mycobacterium avium disease, and one progressive multifocal leukoencephalopathy). The median time from the diagnosis of AIDS-defining or HIV-related diseases and the beginning of EFV–HAART was 36 days. The median follow-up time after starting EFV–HAART was 45 weeks. During the study, 13 patients (14%) discontinued efavirenz because of virological failure (one), adverse events (two), death (three), or other reasons (seven). The percentages of patients reaching more than 100 CD4 cells/μl at 12, 24 and 48 weeks are shown in Fig. 1. Of the 48 patients with follow-ups of longer than one year who remained ‘on treatment', only five maintained a CD4 cell count below 100 cells/ml (all of them with viral load under the limit of detection). Mean increases in CD4 cell counts over baseline values at weeks 12, 24 and 48 were 80, 115 and 173 cells/μl, respectively. The percentage of patients with virological response (HIV-1-RNA level lower than 50 copies/ml) are shown in Fig. 1.
Two relapses of previously diagnosed opportunistic infections were diagnosed during the first 48 weeks of follow-up. One patient suffered disseminated M. avium complex infection several weeks after having discontinued antimycobacterial and antiretroviral therapies. One patient was diagnosed with relapsing cytomegalovirus retinitis 12 weeks after starting EFV–HAART. This relapse of cytomegalovirus retinitis was considered to be related to immune reconstitution, and was satisfactorily controlled with intravitreal ganciclovir. One patient who was receiving antituberculous therapy suffered a paradoxical worsening of tuberculous disease (abdominal pain and marked increase in abdominal lymph nodes on a computed tomography scan) 3 weeks after starting EFV–HAART. Seven new opportunistic diseases were diagnosed after EFV–HAART: cutaneous Herpes Zoster in four patients, tuberculosis disease in two (one patient after having been imprisoned, and one patient who had received corticosteroids for the treatment of P. carinii pneumonia), and cutaneous Kaposi's sarcoma in one (in a patient treated with corticosteroids during toxoplasmosis therapy), which completely resolved without specific treatment. Five patients diagnosed with intestinal cryptosporidiosis experienced complete clinical and parasitological resolution after starting EFV–HAART. Four patients were diagnosed with cutaneous Kaposi's sarcoma before starting EFV–HAART. None of these four patients received chemotherapy, and all experienced a resolution of the Kaposi's sarcoma lesions after starting EFV–HAART. One patient diagnosed with progressive multifocal leukoencephalopathy experienced a stabilization of neurological deficits. P. carinii prophylaxis was discontinued in 12 patients who fulfilled the criteria for discontinuation . There were no episodes of P. carinii pneumonia, either in the 10 patients who discontinued primary prophylaxis or in the two patients who discontinued secondary prophylaxis after a median follow-up time of 33 and 23 weeks, respectively. Three patients died during the first 48 weeks of follow-up. Only one death was considered to be AIDS-related (progressive wasting syndrome). The other causes of death were hepatic failure (in a patient previously diagnosed with hepatitis C and cirrhosis) and complications of epithelial lung carcinoma.
Despite the extreme immunosuppression suffered by patients included in our study, virological responses were similar to the virological responses reported for advanced HIV-1-infected patients in clinical trials of EFV–HAART [4,5]. The fact that only one of the 92 patients included in our cohort suffered confirmed virological failure further supports the effectiveness of EFV–HAART in patients with very high viral loads. Most of the patients treated with EFV–HAART experienced substantial, clinically significant, immunological reconstitution. Quantitative increases in CD4 cell counts were comparable to the CD4 cell count increases reported in clinical trials and cohort studies of patients treated with EFV–HAART [5,6]. Quantitative CD4 cell recovery after 48 weeks of EFV–HAART was also within the range described in non-advanced HIV-infected patients treated with PI-based HAART. In 15 trials of antiretroviral-naive patients treated with PI–HAART, the geometric mean of the CD4 cell count increase at 48 weeks was 153 cells/μl , which is comparable to the result obtained in our study (170 cells/μl).
In this cohort of advanced AIDS patients, immune recovery after EFV–HAART closely resembled the immune recovery described after PI–HAART. We observed four cases of herpes zoster, one case of inflammatory cytomegalovirus retinitis, and one case of paradoxical worsening of intra-abdominal tuberculous lymphadenitis after treatment with EFV–HAART. Interestingly, herpes zoster , inflammatory cytomegalovirus retintis , and paradoxical worsening of tuberculous disease  have all been described previously as part of the ‘immune restoration syndrome’ associated with PI–HAART .
Six patients in our study suffered opportunistic diseases for which there is no confirmed beneficial specific therapy. These six patients experienced either complete resolution (five cases of intestinal cryptosporidiosis) or stabilization (one case of progressive multifocal leukoencephalopathy) after treatment with EFV–HAART. Spontaneous regression or an improvement in Kaposi's sarcoma lesions were observed in five patients after EFV–HAART. Finally, 12 patients successfully discontinued primary or secondary prophylaxis against P. carinii pneumonia after EFV–HAART . In our opinion, all of these observations suggest that, from the clinical point of view, there seems to be very little difference between immune reconstitution occurring after PI–HAART or EFV–HAART.
In summary, our study shows that EFV–HAART is effective in profoundly immunosuppressed HIV-1- infected patients. These results support the use of efavirenz in PI-sparing regimens, even in patients with very low CD4 cell counts and recently diagnosed AIDS-defining conditions.
Jose R. Arribasa
Jose M. Miróc
María A. Costab
Jose M. Peñaa
Angel del Palaciob
Juan José Vázqueza
Jose M. Gatellc
and the EfaVIP Cohort Study Group
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EfaVIP Cohort Study members:
Hospital La Paz: Susana Hernández, Maria Luisa Montes.
Hospital 12 de Octubre: Concepción Cepeda, José R. Costa.
Hospital Clinic-Idibaps: Esteban Martínez, Felipe García, Elisa de Lazzari, Jose Mallolas.