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CLINICAL SCIENCE AND CARE - TRACK B
Summary of Tuesday, 30 June, 1998

Tuesday's presentations represented many of the most perplexing issues of clinical management of HIV-infected individuals.

Antiretroviral Therapy

• 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 naïve 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 40-50%).

Resistance

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

Tipranavir

• 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

ABT-378

• 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 of antiretrovirals

Biochemical mechanisms

• e.g., 67/70 mutations which remove the AZT-MP and 215/219 mutations which restore reverse transcriptase (RT) processivity.

Genetic mechanisms

• 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.

Structural mechanisms

• K103N NNRTI (non-nucleoside reverse transcriptase inhibitor) mutation results in a "closed pocket" and prevents binding.

• In vitro resistance testing can predict responses to antiretroviral therapy

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.

Lipodystrophy syndromes

• Common with persons who receive PI and possibly with those who receive reverse transcriptase inhibitors.
• Often associated with hyperlipidemia and insulin resistance.
• 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.

Adherence

• 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 achieved.
• 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 individualized management.
• 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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