Published in the Bulletin of Experimental Treatments for AIDS April 1999 issue, by the San Francisco AIDS Foundation.

Selected Highlights from the 6th Conference on Retroviruses and Opportunistic Infections
-- Main Page
-- Clinical Research
-- Protease Inhibitor Side Effects
-- Anti-HIV Drugs and Combinations
-- HIV Transmission and Origins
-- HIV-Related Conditions

April 1999 Table of Contents

Main Page

beta@sfaf.org

Selected Highlights from the 6th Conference on Retroviruses and Opportunistic Infections

HIV-Related Conditions

By Harvey S. Bartnof, MD

• OIs after HAART
• Kaposi's Sarcoma (KS)
• Pneumocystis carinii Pneumonia (PCP)
• Wasting Syndrome

Better Understanding of OIs after HAART

• New insights could help determine when it is safe to discontinue OI prevention medications.
• Immune responses to Mycobacterium avium complex (MAC) and CMV are measured.

The occurrence of several OIs is now better understood, according to research presented at CROI. These findings could eventually lead to specific tests that can help determine which people with HIV/AIDS need preventive therapy (prophylaxis) for selected OIs (see BETA, January 1999). Such tests could also help determine which persons taking HAART can safely discontinue specific OI prophylaxis.

Diane Havlir, MD, and colleagues from the University of California at San Diego measured immune responses to MAC antigens in three groups: HIV negative persons, HIV positive persons without MAC who were not taking HAART, and people with AIDS who were successfully treated for MAC and had also responded to HAART. Prior to the HAART era, MAC was a common cause of death in people with AIDS. The test used was a research assay that measured lymphocyte cell proliferation in vitro when MAC antigens were added.

The HIV negative persons' lymphocytes showed significant proliferation responses when the MAC antigens were added; this would explain why HIV negative persons rarely develop MAC disease. However, the lymphocytes of the HIV positive persons not taking HAART showed only very minimal proliferation; this would help to explain why MAC disease can occur in people with AIDS. The lymphocytes from the participants on HAART who had recovered from MAC demonstrated nearly normal proliferation in response to MAC antigens, almost to the levels of the HIV negative persons; this would help to explain why persons who respond to HAART usually do not develop MAC disease. The authors concluded that HIV significantly diminishes lymphocyte proliferation responses to MAC, but that responses can potentially be restored by HAART. It is conceivable that a similar commercial test could be developed that would guide physicians in deciding when MAC prophylaxis is necessary, since the current guidelines based on CD4 cell count are somewhat non-specific.

Another group of researchers did a similar lymphocyte function analysis for CMV, a common cause of retinitis that can cause blindness in people with AIDS. F. J. Torriani, MD, and colleagues, also from the University of California at San Diego, followed people with AIDS who had recovered from CMV retinitis, responded to potent anti-HIV therapy, and discontinued CMV maintenance therapy for an average of two years. Those who developed recurrent CMV retinitis had significantly lower lymphocyte responses to CMV antigens in vitro than those who did not develop recurrent retinitis.

As expected, those who developed recurrent retinitis also had CD4 cell counts that had dropped to low levels and HIV RNA viral loads that were significantly higher than in those who did not develop recurrent disease. The authors concluded that people with AIDS who had prior CMV retinitis and who stopped CMV prophylaxis are at high risk for reactivation of CMV disease if their anti-HIV therapy fails, especially if they do not demonstrate restored lymphocyte responses to CMV antigens. As in the MAC report above, one can envision a future commercial test that would better guide physicians in determining when specific anti-CMV preventive therapy is indicated.

Kaposi's Sarcoma (KS)

Receptive Oral Sex Linked to Kaposi's Sarcoma-Associated Herpesvirus (KSHV)

• Receptive oral sex (fellatio) is the likely mechanism for transmission of KSHV (also known as HHV-8) among gay and bisexual men.
• The study included 215 gay/bisexual men in the Amsterdam Cohort study who became KSHV antibody positive.
• Neither anal intercourse nor oral/anal contact were linked with KSHV transmission.

Pneumocystis carinii Pneumonia (PCP)

• Steroid use for severe PCP triples the death rate.
• These findings call into question current CDC guidelines.

Even though rates of PCP have plummeted with the advent of HAART, this OI can still be lethal for people with AIDS. The use of a steroid immune-blocking drug, in addition to an antibiotic, has been part of the standard CDC guidelines for treatment of severe cases of PCP. The guidelines were derived from the results of randomized, controlled clinical trials. The reasoning behind the use of a steroid was that low blood oxygen levels in people with PCP are in part due to an intense inflammatory response to large quantities of Pneumocystis carinii organisms in the lungs, a response that potentially can be reduced with an anti-inflammatory steroid.

A retrospective chart review of 735 patients with severe PCP from 66 hospitals during 1995-97 was conducted by physicians at Northwestern University. The patients met the criteria of severe PCP due to low blood oxygen levels. A total of 73% had a confirmed laboratory diagnosis (PCP organisms detected), while 82% were correctly given an adjunctive course of steroids with an antibiotic.

Surprisingly, the results showed that among those patients with a confirmed PCP diagnosis who received steroids, the mortality rate was three times greater (18%) than among those who did not receive steroids (6%). The abstract did not report an analysis controlling for potential confounding factors. The authors concluded that the CDC guidelines that were based on randomized, controlled trials may not apply in general clinical practice. If these results are confirmed in other studies, the standard practice of steroid therapy with antibiotics for severe PCP may be doing more harm than good.

Wasting Syndrome

Wasting Syndrome is Linked to High Myostatin Levels

• High myostatin levels are also linked to high HIV viral load levels.

Even with the beneficial effects of HAART, wasting syndrome still affects some people with HIV/AIDS. While the exact mechanisms of HIV-related wasting have yet to be fully described, researchers from Washington University in St. Louis have discovered a potential co-factor. Myostatin (also called GDF-8) is a protein that helps regulate muscle growth and differentiation. Specifically, it down-regulates or suppresses muscle growth. When the gene that codes for myostatin is deleted or underexpressed in mice, muscles grow two to three times larger than in control mice.

K.E. Yarasheski and colleagues measured blood levels of myostatin, the rate of muscle protein synthesis, and HIV RNA viral loads in six men with AIDS-related wasting syndrome, ten asymptomatic HIV positive men, and six HIV negative controls. As expected, the results showed that the men with wasting syndrome had the highest HIV viral loads, while the HIV negative controls had the lowest (undetectable) viral loads. Also as expected, the rate of muscle protein synthesis was significantly lower among those with wasting syndrome than the nearly equivalent levels in the other two groups. The researchers also found that blood levels of myostatin were highest among those with wasting syndrome (524 nanograms/mL) and lowest in the HIV negative controls (348 nanograms/mL); the differences were statistically significant.

This study demonstrates a significant correlation between HIV viral load and myostatin blood levels. The exact mechanisms of HIV-related over-expression of myostatin and the resulting low muscle protein growth remain unknown. Further research in this area may lead to new treatments for AIDS-related wasting and weight loss related to cancer.

Page last updated 1 June 1999