Implications of results and future plans

Before any new and potentially expensive laboratory marker is used for routine patient monitoring, it is important to establish that the information provided by this marker does not simply duplicate information already available from the CD4 count. The markers chosen for analysis in this thesis have already been shown to provide prognostic information in univariate models at fixed time points after seroconversion. However, the amount of additional information that each marker provides when all markers are measured regularly throughout HIV infection has rarely been studied. The results in this thesis suggest that IgA levels, B2M levels and the presence of p24 antigen should be measured routinely in HIV-infected patients. These markers could then be used in combination with the CD4 count, and possibly the rate of CD4 decline, to enable clinicians to make more informed decisions about the prognosis of the patient. For example, the possible long-term adverse effects and the development of resistance to antiretroviral therapies may mean that clinicians wish to delay the initiation of such treatments in patients with low CD4 counts who are clinically well and have relatively low IgA and B2M levels, and who are p24 antigen negative. However, clinicians may wish to consider starting such treatments sooner than usual in individuals who have higher CD4 counts, but who have very high IgA and B2M levels, who may have developed either p24 antigenaemia or a bacterial infection.

With its long incubation period, clinical trials which assess the value of new treatments for HIV infection are often constrained to follow a large group of patients for a long period of time, in order that the number of clinical endpoints (eg. the development of AIDS or death) is sufficiently large for comparisons to be made. The search for suitable surrogate endpoints in clinical trials is, therefore, of key importance. Unfortunately, it appears that the CD4 count is not likely to be useful as a surrogate marker on its own as treatment-induced rises in the CD4 count may not necessarily lead to clinical benefit to the patients. The combined use of the CD4 count, B2M and IgA levels and the development of p24 antigenaemia may improve on the CD4 count alone as a surrogate

endpoint for clinical trials. Further, these markers may also provide a means to restrict clinical trial entry to high-risk patients which may also lead to a reduction in the sample size required for such studies.

With increased follow-up on patients in the cohort it will be possible to further study trends in these prognostic markers throughout infection and to consider the impact of HIV therapies and prophylaxis on these markers. Unfortunately, new developments in laboratory methods mean that some of the markers studied in this thesis have now been superseded by other markers. For example, the development of p24 antigenaemia is now of less clinical importance as it has become possible to directly measure HIV viral load. Other virological markers, such as the development of SI phenotypes, and the number and type of different viral strains, may all be of use when determining patient prognosis. Rather than simply consider the CD4 or CDS count, studies are now underway to identify whether particular subsets of these lymphocytes provide more prognostic information than others. If these markers are demonstrated to provide additional or better prognostic information than that provided by the CD4 count, then it is likely that the routine measurement of these markers in patients remaining alive in the cohort will commence. Where markers are measurable in stored serum, their value can be assessed in all patients in the cohort. However, in many cases, it will only be possible to consider the effect of these markers in living patients.

All haemophilic patients were co-infected with HCV after treatment with unheated clotting factor concentrates. The impact of coinfection with HCV on HIV disease progression is now of interest. As patients survive for longer with HIV they are increasingly likely to develop additional complications as a result of infection with HCV. So far, nine patients have died during liver failure in the cohort (including four patients who died of AIDS). Further, liver function tests are abnormal in the majority of patients who remain alive and AIDS-free. Hence, there is a real possibility of increased morbidity and mortality from HCV infection in these patients. Further, the effect of co-infection with other viruses, such as Epstein-Barr virus, varicella zoster virus, and human herpesviruses 6 and 7 is as yet unknown. It is planned to measure antibodies to these viruses in patients in the cohort in the near future.

In conclusion, therefore, this thesis has presented a selection of work carried out on this well-defined cohort of men with haemophilia. Many of the results presented may be generalised to other groups of HIV-infected patients and, as follow-up continues, it is hoped that the cohort will continue to provide answers to important clinical questions in