Evidence-based, multifactorial approach to addressing non-adherence to antiretroviral therapy and improving standards of care.

BACKGROUND: Near-perfect adherence to antiretroviral therapy over time is critical to achieve viral suppression and recovery of functional immunity in individuals infected with HIV. The concept of adherence as a dynamic behaviour influenced by multiple biopsychosocial factors motivated us to implement an integrated, multifactorial programme in our hospital-based setting. The aims of this study were to survey the scope and determinants of non-adherence in patients attending the Ambulatory HIV Service at Royal Perth Hospital, to develop a method for longitudinal monitoring and to implement measures tailored to support individuals. METHODS: The US Adult AIDS Clinical Trials Group self-report baseline adherence, follow-up and side-effect questionnaires were used to survey 247 patients at two time-points between September 2002 and February 2003. A longitudinal monitoring method was developed and the WA HIV Cohort Study database used to collate results with clinical markers up to December 2005. RESULTS: Adherence was associated with viral suppression and CD4 T-cell recovery and improved over the 3-year period under observation (all P < 0.001). Diminishing adherence was associated with younger age (P = 0.002), substance use (P < 0.01), perceived stress (P = 0.04) and indicators of depression (P = 0.03). The analyses showed relationships between personal experience of side-effects and the depression indicator scale in patients on antiretroviral therapy. CONCLUSION: The programme resulted in an improvement in adherence in our cohort even after adjusting for pill burden, dosing frequency and highly active antiretroviral therapy regimen and has enhanced focus on patients vulnerable to non-adherence while supporting those not currently at risk.

Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on HIV-1 disease progression: An international meta-analysis of individual-patient data.

BACKGROUND: Studies relating certain chemokine and chemokine receptor gene alleles with the outcome of HIV-1 infection have yielded inconsistent results. OBJECTIVE: To examine postulated associations of genetic alleles with HIV-1 disease progression. DESIGN: Meta-analysis of individual-patient data. SETTING: 19 prospective cohort studies and case-control studies from the United States, Europe, and Australia. PATIENTS: Patients with HIV-1 infection who were of European or African descent. MEASUREMENTS: Time to AIDS, death, and death after AIDS and HIV-1 RNA level at study entry or soon after seroconversion. Data were combined with fixed-effects and random-effects models. RESULTS: Both the CCR5-Delta32 and CCR2-64I alleles were associated with a decreased risk for progression to AIDS (relative hazard among seroconverters, 0.74 and 0.76, respectively; P = 0.01 for both), a decreased risk for death (relative hazard among seroconverters, 0.64 and 0.74; P < 0.05 for both), and lower HIV-1 RNA levels after seroconversion (difference, -0.18 log(10) copies/mL and -0.14 log(10) copies/mL; P < 0.05 for both). Having the CCR5-Delta32 or CCR2-64I allele had no clear protective effect on the risk for death after development of AIDS. The results were consistent between seroconverters and seroprevalent patients. In contrast, SDF-1 3'A homozygotes showed no decreased risk for AIDS (relative hazard for seroconverters and seroprevalent patients, 0.99 and 1.03, respectively), death (relative hazard, 0.97 and 1.00), or death after development of AIDS (relative hazard, 0.81 and 0.97; P > 0.5 for all). CONCLUSIONS: The CCR5-Delta32 and CCR2-64I alleles had a strong protective effect on progression of HIV-1 infection, but SDF-1 3'A homozygosity carried no such protection.

Genetics of human complement component C4 and evolution the central MHC.

The two classes of human complement component C4 proteins C4A and C4B manifest differential chemical reactivities and binding affinities towards target surfaces and complement receptor CR1. There are multiple, polymorphic allotypes of C4A and C4B proteins. A complex multiplication pattern of C4A and C4B genes with variations in gene size, gene dosage and flanking genes exists in the population. This is probably driven by the selection pressure to respond to a great variety of parasites efficiently and effectively, which the bony fish achieved through the multiplication and diversification of the related complement C3 proteins. Complement C4, C3 and C5 belong to the alpha2 macroglobulin protein family but acquired specific features that include an anaphylatoxin domain, a netrin (NTR) domain, and stretches of basic residues for proteolytic processings to form multiple chain structures. Complement C3 and C4 are important in the innate immune response as they opsonize parasites for phagocytosis. The emergence of complement C3 predates proteins involved in the adaptive immune response as C3 is present in deuterostome invertebrates such as echinoderms. The human C4 genes are located in the central MHC at chromosome 6p21.3. C3 and C5 are located at chromosome 19 and 9, respectively, with representatives of the other groups of genes paralogous to the MHC at 19p13.1-p13.3, 1q21-25, and 9q33-34. The central MHC also contains genes for complement components C2 and Bf. These genes appear to have similar evolutionary histories to C3/C4/C5 and are used here to illustrate stepwise processes resulting in co-location of diverse domains, chromosomal duplication, local segmental duplication and divergence of sequence and function. This model of evolution is useful in the investigation of innate and acquired immunity and in seeking explanations for diseases associated with MHC ancestral haplotypes.

Further characterization of MHC haplotypes demonstrates conservation telomeric of HLA-A: update of the 4AOH and 10IHW cell panels.

Cell panels have been used extensively in studies of polymorphism and disease associations within the major histocompatibility complex (MHC), but the results from these panels require continuous updates with the increasing availability of novel data. We present here an updated table of the typings of the 10IHW and 4AOH panels. Local data included are HFE, HERV-K(C4) and six microsatellites telomeric of HLA-A. Typings for class I, MICA (PERB11.1), MICB (PERB11.2), XA, XB, LMP2 and 10 microsatellites reported by others have also been consolidated in this table. The tabulation shows that the length of conservation in the human MHC is even more extensive than previously thought. Human MHC ancestral haplotypes are inherited as a conserved region of genomic sequence spanning some 6-8 megabases from the HLA class II region and beyond the HLA class I region up to and including the HFE gene. Numerous examples of historical recombinations were also observed.

PERB11 (MIC): a polymorphic MHC gene is expressed in skin and single nucleotide polymorphisms are associated with psoriasis.

The susceptibility genes for psoriasis remain to be identified. At least one of these must be in the major histocompatibility complex (MHC) to explain associations with alleles at human leucocyte antigen (HLA)-A, -B, -C, -DR, -DQ and C4. In fact, most of these alleles are components of just two ancestral haplotypes (AHs) designated 13.1 and 57.1. Although relevant MHC gene(s) could be within a region of at least 4 Mb, most studies have favoured the area near HLA-B and -C. This region contains a large number of non-HLA genes, many of which are duplicated and polymorphic. Members of one such gene family, PERB11.1 and PERB11.2, are expressed in the skin and are encoded in the region between tumour necrosis factor and HLA-B. To investigate the relationship of PERB11.1 alleles to psoriasis, sequence based typing was performed on 97 patients classified according to age of onset and family history. The frequency of the PERB11.1*06 allele is 44% in type I psoriasis but only 7% in controls (Pc = 0.003 by Fisher's exact test, two-tailed). The major determinant of this association is a single nucleotide polymorphism (SNP) within intron 4. In normal and affected skin, expression of PERB11 is mainly in the basal layer of the epidermis including ducts and follicles. PERB11 is also present in the upper keratin layers but there is relative deficiency in the intermediate layers. These findings suggest a possible role for PERB11 and other MHC genes in the pathogenesis of psoriasis.

Immunogenetic analysis of successful and rejected bone marrow grafts within one family.

We report the case of an Indonesian patient who required urgent bone marrow transplantation for acute leukaemia and who received successive transplants from two siblings. The first transplant failed while the second was successful. There were some uncertainties in serological typing due to the presence of cross-reacting HLA-B alleles, lack of paternal typing and the use of Caucasoid sera for Indonesian patients. Distinction between the two donors was also difficult. Interestingly, the use of a new DNA technique identified the presence of differences between the patient and the first unsuccessful donor but not the second successful donor.

Severity and outcome of Pneumocystis carinii pneumonia (PCP) in patients of known and unknown HIV status.

Of 170 Western Australian patients who had their first AIDS-defining illness between 1 January 1983 and 31 December 1991, 61 (36%) were of unknown HIV antibody status (AIDS presenters), while 109 (64%) were of known HIV antibody status (HIV presenters). Pneumocystis carinii pneumonia (PCP) was less common as the AIDS-defining illness in HIV presenters (41% versus 62%, p = 0.005). In this study of 70 patients with PCP as the index AIDS diagnosis, 36 were HIV presenters and 34 were AIDS presenters. Ten HIV presenters were taking prophylaxis at the time PCP manifested. The duration of symptoms of cough or dyspnea before the diagnosis of PCP was shorter, and the arterial PO2 measurement on admission was higher in those on prophylaxis, and a lower proportion of patients on prophylaxis required hospital admission (p < or = 0.05 for all comparisons). Furthermore, the CD4 counts at diagnosis of PCP were lower in patients taking PCP prophylaxis (mean 26 x 10(6)/L) than in patients who were not (mean 94 x 10(6)/L, p = 0.007). Of seven patients who died of PCP, none were receiving treatment for HIV disease before AIDS presentation. These findings suggest that PCP is prevented or deferred in patients receiving care for HIV disease and is less severe as a result of early diagnosis and treatment.