presentations represented many of the most perplexing issues of clinical management of
- Hydroxyurea (observations collected from three
studies presented) :
- Modest anti-HIV effect with ddI/d4T;
- Lymphopenia produces decrease in absolute CD4+ cell
count but not in the CD4+/CD8+ ratio;
- Very significant hematological toxicity if baseline
CD4+ < 100 cells/mm3.
- Observations from other antiretroviral studies:
- Maximal suppression to <5 copies/mL plasma may
take at least 48 weeks which may have implications for maintenance therapy.
- CD4+ rise with potent suppression in early HIV
infection (CD4+ >500) was mostly of na´ve CD4+ cells (as opposed to memory cells in
late HIV infection). Analysis of lymph nodes indicate a CD4+/CD8+ ratio comparable to
normal HIV-negative individuals.
- Starting with two protease inhibitors (PI) may be
more beneficial then a single protease inhibitor for patients with either high plasma HIV
RNA or prior reverse transcriptase inhibitor therapy.
- Intensification of therapy with a second PI for
patients who fail with highly antiretroviral therapy active (HAART) (2 nucleoside reverse
transcriptase inhibitors NRTIs + 1 protease inhibitor PI) virologically may lead to
medium-term viral suppression for a substantial minority of patients (approximately
The following lines are a summary
of a workshop on resistance/treatment strategies (Lago Maggiore).
- Second generation protease inhibitors are active and
headed for Phase III studies
- RNA decline of 1.0-1.3 logs (when added to a stable
but failing double NRTI regimen);
- Diarrhea which requires use of over-the-counter
anti-diarrheal medications for 37% of patients;
- Three times daily dosing
- Excellent pharmacokinetic profile in humans when
used in combination with low dose (100 mg twice daily) of ritonavir;
- The combination of ABT-378 and ritonavir resulted in
plasma HIV RNA < 400 copies in 100% of patients.
- Multiple new mechanisms of resistance to all classes
- e.g., 67/70 mutations which remove the AZT-MP and
215/219 mutations which restore reverse transcriptase (RT) processivity.
- e.g. S-S-S amino acid insertion between codons 68
and 69 of the HIV RT induces multi-nucleoside resistance including d4T and abacavir.
- K103N NNRTI (non-nucleoside reverse transcriptase
inhibitor) mutation results in a "closed pocket" and prevents binding.
- In vitro resistance testing can predict responses to
Resistant phenotype/genotype means poor
antiviral effect likely;
Sensitive phenotype/genotype means good
antiviral effect likely.
- Transmission of PI-resistant HIV occurs.
- Methods of analysis alter measurement of response
Intent to treat vs. "as-treated"
analysis: ITT would report a 50-60% response rate in AVANTI-2 whereas an
"as-treated" analysis would report a 80-90% response rate.
- Common with persons who receive PI and possibly with
those who receive reverse transcriptase inhibitors.
- Often associated with hyperlipidemia and insulin
- Reported more frequently in persons receiving the
ritonavir/saquinavir (RTV/SQV) protease combination therapy than indinavir or nelfinavir.
Reported frequency of the lipodystrophy syndrome among persons receiving indinavir or
nelfinavir alone were equivalent.
- No long-term data.
- Similar changes in women to those previously
reported in men.
- No consensus in diagnostic criteria.
- It seems paradoxical to invest large sums of money
into new drugs only to fail to focus on how these drugs are accepted or not
by those taking them. Non-adherence in Western countries is common: in one study, a third
of patients had missed a dose during the previous 3 days.
- Doctors will often say that the reasons for
non-adherence are the number of tablets which need to be taken and the side effects. But
patients point out the difficulty of adhering to meal instructions and the overall
complexity of the dosing schedule. The need for privacy is also important for some
patients with regard to taking their medications and this cannot always be
- Securing adherence can only be achieved by
considering the context of life and needs of the patient before anything else. Each person
has his/her own particular set of concerns, for example, being able to work; developing
resistance; impact on quality of life.
- Improving the climate for adherence demands a
trusting doctor-patient relationship based on full disclosure of information and
- Non-adherence is not inevitable. It is important to
take time to explain why drugs are needed, so that the person feels supported and knows
how to take them. In the developing world, the same difficulties exist but often in an
entirely different context. There are few drug monitoring facilities; little health care
infrastructure; erratic transport networks; poor water and sanitation systems; fears about
loss of employment; a more influential role for traditional healers; and different health
beliefs (e.g., the power of spirits).
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