AVANTI 3: a randomized, double-blind trial to compare the efficacy and safety of lamivudine plus zidovudine versus lamivudine plus zidovudine plus nelfinavir in HIV-1-infected antiretroviral-naive patients.

The objective of our randomized, multicentre, double-blind, placebo-controlled study was to investigate the safety, tolerability, and antiretroviral and immunological effect of double and triple combination therapy regimens. A total of 105 antiretroviral therapy-naive patients were randomized to receive either zidovudine (300 mg twice per day) plus lamivudine (150 mg twice per day) plus nelfinavir placebo (three times per day) (n=52), or zidovudine/lamivudine (dose as before) plus nelfinavir (750 mg three times per day) (n=53) for 28 weeks. After this time, patients were allowed to switch to open-label zidovudine/lamivudine/nelfinavir. The overall log10 reduction from baseline in plasma HIV-1 RNA was significantly greater in the zidovudine/lamivudine/nelfinavir group than the zidovudine/lamivudine group (P=0.001; median treatment difference, -1.01 log10 copies/ml; 95% confidence interval -1.23 to -0.79), as measured by the average area under the curve minus baseline over 28 weeks. Increases from baseline in CD4 cell counts were statistically significantly greater in the zidovudine/ lamivudine/nelfinavir group (101.5 cells/ml) than the zidovudine/lamivudine group (47.0 cells/ml; P=0.027) at week 28. Of note, the addition of nelfinavir from weeks 28-52 led to an increase in the proportion of subjects with plasma HIV-1 RNA <400 copies/ml from 17% (9/52 patients on zidovudine/lamivudine) to 50% (13/26 patients who switched to zidovudine/lamivudine/nelfinavir). Incidence of drug-related adverse events was similar in the two groups, except for nausea (more common in zidovudine/lamivudine group; 40 versus 17%) and diarrhoea (more common in zidovudine/lamivudine/nelfinavir group; 45 versus 14%). In conclusion, our study confirms the efficacy of triple combination therapy with two nucleoside analogues and a protease inhibitor compared with double-nucleoside therapy. Interestingly, the addition of nelfinavir to zidovudine/lamivudine, even after 6 months of double nucleoside therapy, led to a substantial virological benefit that was sustained over 24weeks in a subset of patients.

The concept of spiritual care in mental health nursing.

AIM: In this paper we aim to clarify the issue of spiritual care in the context of mental health nursing. BACKGROUND: The concept of spirituality in nursing has received a great deal of attention in recent years. However, despite many articles addressed to the issue, spiritual care remains poorly understood amongst nursing professionals and, as a result, spiritual needs are often neglected within the context of health care. METHODS: A series of focus groups was conducted to obtain the views of service users, carers and mental health nursing professionals about the concept of spirituality and the provision of spiritual care in mental health nursing. RESULTS: According to the views expressed in our focus groups, spiritual care relates to the acknowledgement of a person's sense of meaning and purpose to life which may, or may not, be expressed through formal religious beliefs and practices. The concept of spiritual care was also associated with the quality of interpersonal care in terms of the expression of love and compassion towards patients. Concerns were expressed that the ethos of mental health nursing and the atmosphere of care provision were becoming less personal, with increasing emphasis on the 'mechanics of nursing'. CONCLUSIONS: The perceived failure of service providers to attend adequately to this component of care may be symptomatic of a medical culture in which the more readily observable and measurable elements in care practice have assumed a prominence over the more subjective, deeply personal components. In order for staff to acknowledge these issues it is argued that a more holistic approach to care should be adopted, which would entail multidisciplinary education in spiritual care.

Absence of zidovudine resistance in antiretroviral-naive patients following zidovudine/lamivudine/protease inhibitor combination therapy: virological evaluation of the AVANTI 2 and AVANTI 3 studies.

OBJECTIVES: To assess the role of resistance mutations in subjects experiencing virological failure on zidovudine (ZDV) and lamivudine (3TC) combined with a protease inhibitor (PI) to those failing on ZDV/3TC alone. DESIGN AND METHODS: Samples were obtained from previously antiretroviral therapy-naive subjects enrolled into two studies, AVANTI 2 and AVANTI 3. Subjects were randomized to receive either: ZDV/3TC or ZDV/3TC plus indinavir (IDV) for 52 weeks (AVANTI 2), and ZDV/3TC or ZDV/3TC and nelfinavir (NFV) for 28 weeks (AVANTI 3). Emergence of viral resistance mutations was monitored by population sequencing and phenotypic resistance was determined by the recombinant virus assay. RESULTS: Genotypic data were obtained for subjects with plasma HIV-1 RNA > 400 copies/ml. In AVANTI 2, ZDV mutations were detected in 27% of ZDV/3TC-treated patients at week 52, but were absent in subjects treated with ZDV/3TC/IDV. No subjects from either arm of AVANTI 3 developed ZDV resistance mutations at week 28. The M184V mutation developed in most ZDV/3TC-treated subjects from both studies. The presence of M184V was, however, associated with significantly lower plasma viral RNA levels when compared with values obtained before initiation of treatment. There was a high frequency (4 of 11) of the protease L10F substitution in ZDV/3TC/IDV-treated patients that was associated with virological failure but did not result in phenotypic resistance to any of the PIs tested. CONCLUSIONS: ZDV mutations were not detected in ZDV/3TC/PI-treated patients and they developed slowly in those treated with ZDV/3TC. Few protease mutations known to confer phenotypic PI resistance developed in the ZDV/3TC/PI arms of either study. The low prevalence of ZDV and PI mutations is encouraging regarding the future treatment options of these patients.

An infectious molecular clone of a Japanese genotype 1b hepatitis C virus.

We describe an infectious molecular clone of a Japanese genotype 1b strain of hepatitis C virus (HCV-N). The molecularly cloned sequence of HCV-N was compared with alignments of other HCV sequences, leading to the identification of 15 unique, nonconservative amino acid substitutions within the HCV-N open reading frame (ORF). These were repaired to the consensus genotype 1b residue, and the infectivity of RNA transcribed from the repaired clone was assessed by intrahepatic inoculation of a chimpanzee. Viral RNA was first detected in the serum of this chimpanzee 3 weeks following inoculation, and was intermittently present over the next 14 weeks. A strong and persistent anti-HCV serological response developed 13 weeks following inoculation, with seroconversion in the recombinant immunoblot assay (RIBA). A weaker, transient serological response, characterized by seroconversion in a third-generation enzyme-linked immunosorbent assay (ELISA) but not RIBA, occurred between weeks 1 and 5. This may have represented an anamnestic response to HCV antigens translated directly from the intrahepatically inoculated RNA, because the animal previously had undergone 2 unsuccessful attempts at rescue of HCV by intrahepatic RNA inoculation. There was neither biochemical nor histological evidence of liver disease. Although this is within the range of expected outcomes in an HCV-naive chimpanzee, prior immunologic priming may have modified the infection in this animal. The HCV-N clone is the first infectious molecular clone of HCV that is comprised entirely of genotype 1b sequence, and it contains an ORF sequence that is significantly divergent from that of a previously described genotype 1a/1b chimera.

AVANTI 1: randomized, double-blind trial to evaluate the efficacy and safety of zidovudine plus lamivudine versus zidovudine plus lamivudine plus loviride in HIV-infected antiretroviral-naive patients. AVANTI Study Group.

The objective of this randomized double-blind, placebo-controlled trial was to investigate the effect of combination antiretroviral therapy on plasma HIV-1 RNA as measured by HIV RNA PCR and to assess the safety and tolerability of such regimens. The trial was carried out in seven European countries, Australia and Canada and involved antiretroviral-naive patients (n = 106) with CD4 counts between 150-300 cells/mm3 (CDC group A) and 150-500 cells/mm3 (CDC group B/C). Patients were randomly assigned to zidovudine (200 mg three times daily) plus lamivudine (300 mg twice daily) or to zidovudine plus lamivudine plus loviride (100 mg three times daily) for 52 weeks. The main outcome measures were degree and duration of reduction of plasma HIV-1 RNA as measured by RNA PCR and the development of drug-related toxicities sufficiently severe to warrant dose modification, interruption or permanent discontinuation. A mild, though statistically significant difference in favour of zidovudine plus lamivudine plus loviride for log10 plasma HIV-1 RNA (P = 0.022), as compared to zidovudine plus lamivudine, was observed using area-under-the-curve minus baseline (AUCMB). An increase in CD4 cell count in the zidovudine plus lamivudine plus loviride group was observed with a median improvement of 124 cells/mm3 at week 52 compared with 70 cells/mm3 in the zidovudine plus lamivudine group (P = 0.06). Both treatment regimens were well tolerated.