Issues in clinical trials
- In the phase I-II trials the efficacy of a drug
can be assessed in a few days, but monotherapy should not be continued until it fails.
- Phase III trials should include a long-term
follow-up.
Clinical trial design
Randomised clinical trials
Although such trials remain the gold standard for measuring the effect of a new drug or
regimen, issues of toxicity, resistance, viral load monitoring, and combination treatment
make their design increasingly difficult. In addition, questions still exist about what
end-points should be used. The emergence of lipodystrophy with PIs suggests that long-term
clinical end-points, rather than short-term measurements of viral load, should be
considered. The Control arm of any clinical trial must be the "Standard of Care"
– a factor not always present in the work presented at this conference. Finally,
investigators need to work harder to improve the clarity of informed consent forms and the
information provided to trial participants.
Cohort studies
If clinical trials cannot provide all the answers that clinicians need, would cohort
studies help? These designs have already helped in our understanding of viral pathogenesis
and the impacts of drugs in populations. Evidence from other settings – e.g.,
cardiovascular disease – urges caution in analysing cohort data. But the results of
these studies support the idea that they offer useful pointers, if not definitive proof,
abort the values of new agents.
Developing countries
Good trials can be done in difficult settings, with lack of infrastructure for research
and care. HIV-NAT is one example – a collaboration between Thailand, Australia and
the Netherlands. Trials allow to the supply of drugs which otherwise would not be
available, but complex ethical issues remain unresolved – e.g., what constitutes
"Standard-of-care". They raise the issues of the ethics of placebo-controlled
studies, availability of drugs after the end of the studies and clinical monitoring in the
developing country versus in the country responsible for the initiation of the trial.
Highly active antiretroviral therapy :
Complications of treatment.
- Factors involved in lipid abnormalities
- Age;
- Body mass index;
- Genetic disposition;
- Possibly use of ritonavir, as opposed to
nelfinavir.
- Severe complications have been described, such as
acute myocardial infarction. The incidence is not known.
- Early treatments should take into account the
potential for long term complications such as cardio-vascular disease.
HIV in children
Diagnosis and monitoring
No gold standard for diagnosis yet exists. Persistence of HIV antibody beyond 18
months is the current definition of perinatal HIV infection. Monitoring can be by
- Viral markers: PCR is now standardised and the
dried blood spot has clear practical advantages.
- Serological markers : HIV antibody
- Clinical signs : e.g., PCP, lymphoid hyperplasia,
non-suppurative parotiditis, candidiasis, herpes zoster, disseminated mycobacterial
infections
Prognosis can be based on maternal viral load
and, as reported, mutations in HIV-co-receptors. Ideally, viral load and CD4 should be
used together. Growth is also a powerful measure of treatment success.
Management in developed nations
Four issues need to be considered. A key problem is that liquid formulation of drugs often
do not exist.
- Foetus / neonate: AZT is a valuable means of
reducing the risk of MCT, as is C-section before membrane rupture.
- Early treatment is probably important but it is
unknown how big is the window of opportunity.
- Stable and treated: trials are under way to
investigate if the child’s HIV disease state can be improved still further.
- Advanced disease: Triple therapy is superior but
availability is a serious limitation to many regimens.
Management in developing nations
Cost, poor health-care, infrastructures, and poverty all pose serious challenges.
Palliative care
Palliative care – providing comfort and support in a life-threatening illness –
is often forgotten in HIV care. Treatment of symptoms – e.g., PCP, herpes zoster -
may not save life but it can improve substantially quality of life. A particular problem
is effective pain management, a skill that doctors are often poorly trained to administer.
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