# Presentation: 545184

## Need for New Therapies

- Lawrence Fox, MD, Ph.D.
- Division of AIDS

## Highly Active Antiretroviral Therapy (HAART) alone is not adequate therapy for HIV disease.

- The benefits of HAART
- The limitations of HAART
- Virologic failure
- Immunologic failure
- Toxicity
- End organ disease

## Benefits of HAART

- Suppression of viremia and virus shedding in semen and vaginal secretions
- Increased CD4+ T cell count
- Reduced immune activation
- Restoration of lymph node architecture
- Clinical improvement
- Prolonged survival
- Fewer O.I.s and HIV-associated malignancies
- Ability to discontinue O.I. prophylaxis and maintenance therapy

## Annual Deaths in the CWRU John Carey Special Immunology Unit

## HAART does not:

- Work in all cases
- Clear the latently infected cell pool
- Restore HIV-specific immunity
- Prevent relapse
- Offer an affordable therapy for 95% of HIV-infected people in the world

## Slide 6

## Virologic failure

- Within one year after initial good response to HAART, 20-30% of patients experience viral break-through.
- Those maintaining viral suppression for one year experience 8-15% failure the following year.
- 		Abst. 12294, 22349 and 22353
- 		12th World AIDS Conference, 1998

## Treatment failure in the clinic(53% at 1 yr,   n = 310)

**CD4+ cell nadir**
**Peak plasma HIV-1-RNA**
**Women**
**Earlier PI start date**
**# of missed clinic visits in yr. prior**
**CCR5 wt/wt (vs d32/wt)**

**Valdez: Arch Int Med 99**
**JAMA 99**

## Correlation Between Adherence* and Virologic Suppression† (N = 84)

- 70

- 60

- 50

- 40

- 30

- 20

- 10

- 0

- % Patients WithHIV-1 RNA<400 copies/mL

- >95

- 90–95

- 80–90

- Level of Adherence, %

- *Adherence was measured by MEMScaps electronic pill monitoring device.
- †*P* = .00001.
- Data from Paterson et al. Poster presented at: 6th Conference on Retroviruses and OpportunisticInfections; January 31–February 4, 1999; Chicago, Ill. Poster 92.

- 80

- 90

- 70–80

- <70

## Immunologic failure

- Despite successful suppression of plasma HIV below levels of detection, 9-15% of patients fail to increase their CD4+ cell count enough to reduce their risk of opportunistic infections.
- 		AIDS 1998;12:745-750
- 		Abst. 330 Conf Retroviruses and OI
- 			1999

## Toxicities associated with HAART

- Lipoatrophy
- Abnormal fat accumulation
- Hyperlipidemia
- Insulin resistance
- Bone loss
- Marrow suppression
- Pancreatitis
- Hepatitis
- Nephropathy
- Neuropathy
- Many others

## Slide 12

## End organ disease

- The combined effects of HIV, HCV,HBV, immune restoration syndrome and drug toxicity has led to an increasing incidence of liver and renal failure.
- New therapies are needed to treat or forestall this end organ disease.
- Protocols to test the safety and efficacy of liver and kidney transplantation into HIV+ recipients are under development.

## The frequent toxicity and failure of HAART to eradicate HIV is forcing a paradigm shift

- Patients are unwilling to tolerate HAART for life.
- STI and cycles of HAART are increasingly popular.
- Patients wish to defer therapy.
- Younger patients are even more reluctant to accept HAART.
- 50% of new HIV infections occur in people _<_25 years old in the U.S.