A common problem among HIV-infected people is the HIV wasting syndrome, defined as unintended and progressive weight loss often accompanied by weakness, fever, nutritional deficiencies and diarrhea. The syndrome, also known as cachexia, can diminish the quality of life, exacerbate illness and increase the risk of death for people with HIV.

Wasting can occur as a result of HIV infection itself but also is commonly associated with HIV-related opportunistic infections and cancers. HIV wasting syndrome is diagnosed in HIV-infected people who have unintentionally lost more than 10 percent of their body weight. Most patients with advanced HIV disease and AIDS eventually experience some degree of wasting.

The National Institute of Allergy and Infectious Diseases (NIAID) supports basic and clinical research aimed at better understanding and improving treatments for this debilitating condition. Several studies of therapies and nutrition for HIV wasting are being conducted in NIAID’s AIDS clinical trials research network. The AIDS Clinical Trials Group (ACTG), one component of this network, has established the Wasting Pathogen Study Group. Monthly, this group of preclinical and clinical investigators discusses research ideas and priorities as well as ongoing and planned clinical trials.

Many approaches have been used to reverse weight loss in HIV-infected people, including appetite stimulants, anabolic agents, cytokine inhibitors and hormones. Goals of therapy include both increase in body weight and increase in lean body mass (muscle).

Currently, the precise causes of the HIV wasting syndrome are not well known, and probably vary among individuals. However, a growing body of evidence suggests that many factors may contribute to wasting including inadequate dietary intake, malabsorption of nutrients, abnormalities in metabolism and energy expenditure, and HIV-related infections.

Reduced caloric intake among HIV-infected people is often the result of a loss of appetite, frequently because of nausea. A number of agents to enhance dietary intake have been evaluated in NIAID clinical trials; two of them -- megestrol acetate (megace) and dronabinol (marinol, which contains the active ingredient of marijuana, THC) -- are currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV wasting syndrome. Nutritional supplements also have a role in boosting caloric intake and currently are being assessed in NIAID's clinical trials research network.

Many HIV-infected people suffer from aphthous ulcers of the mouth or esophagus that make eating difficult. A recent NIAID-supported study demonstrated that the drug thalidomide can safely and effectively heal these ulcers. This finding promises to remove a major impediment to adequate nutrition for HIV-infected people who suffer from these painful sores.

Despite ingesting sufficient calories, many people with HIV lose nutrients because of diarrhea, vomiting or malabsorption of nutrients in their intestines. Malabsorption may be caused by HIV itself as well as by enteric infections associated with HIV disease. Research into HIV's effects on the gastrointestinal tract and into diseases such as cryptosporidiosis and microsporidiosis may help explain the causes of HIV-associated diarrhea and wasting.

Increased calorie usage, and in some cases the breakdown of muscle and other tissues, also contributes to HIV wasting. Agents that reverse metabolic abnormalities, such as testosterone and growth hormones, have been studied by NIAID-supported investigators and others. One such drug, a growth factor known as somatropin (Serostim), was approved by the FDA in 1996 for the treatment of HIV-associated wasting. Researchers also have found that increased levels of immune-signalling molecules (cytokines) such as interleukin-6 and tumor necrosis factor-alpha (TNF-alpha) are associated with HIV wasting. Drugs that block TNF-alpha may have a role in the treatment of this condition.

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High HIV RNA Levels Major Risk Factor for Mother-to-Child HIV Transmission

Two studies supported by the National Institutes of Health (NIH) provide compelling evidence that the amount of HIV in a pregnant woman's blood, known as the maternal HIV viral load, is the prime risk factor for transmitting the virus to her baby.

Women who had high levels of HIV in their blood -- whether they received the anti-HIV drug AZT or not -- transmitted the virus to their infants more often than women with low levels of HIV. The studies, which appear in the August 5 issue of The New England Journal of Medicine, underscore the importance of treatment strategies aimed at reducing viral load in HIV-infected pregnant women.

"Although we know that various factors can contribute to perinatal HIV transmission," says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), which co-sponsored the studies, "these findings suggest that maternal viral load is the most important one."

The first report analyzed data from a clinical trial conducted by the Pediatric AIDS Clinical Trials Group. The second report comes from the Women and Infants Transmission Study.

"Despite the use of anti-HIV therapy during pregnancy, some infants continue to be infected," says Duane Alexander, M.D., director of the National Institute of Child Health and Human Development (NICHD), which also co-sponsored the studies. "These results suggest that reducing HIV viral levels in women during pregnancy may further reduce the risk of transmission of HIV to their infants."

"The studies also emphasize the importance of developing novel techniques for monitoring viral load in these women," adds National Heart, Lung and Blood Institute (NHLBI) Director Claude Lenfant, M.D.

The Pediatric AIDS Clinical Trials Group (PACTG) Study

In this report, researchers measured HIV levels in stored blood samples from HIV-infected pregnant women enrolled in a clinical trial known as PACTG 185, says the study's principal author, Lynne Mofenson, M.D., of NICHD's Pediatric, Adolescent and Maternal AIDS Branch. This study was supported by NICHD, NIAID and NHLBI.

PACTG 185 compared the effectiveness of AZT alone versus AZT plus immune globulin containing HIV-1 antibodies in preventing perinatal HIV transmission. The trial was designed to learn if the spread of HIV from mother to child could be reduced further by the addition of immune globulin. PACTG 185 was stopped early after the rate of mother-to-infant transmission was found to be only 5 percent for both groups.

As reported in the current issue of NEJM, Dr. Mofenson and her colleagues investigated the factors associated with transmission of HIV in this study.

The researchers measured HIV levels in blood samples from 497 HIV-infected pregnant women, all of whom received AZT or AZT in combination with other drugs. Their infants were tested for HIV at birth, and at ages 6 weeks, 6 months and 1 year.

The investigators found that women who had higher levels of HIV-1 RNA in their blood were most likely to bear a child who was infected with the virus.

They also measured other factors that might increase the chances for transmitting HIV from mother to child. These included the numbers of CD4+ T cells, the amount of virus that could be cultured from blood, and the presence of an infection of the membrane containing amniotic fluid at delivery, called chorioamnionitis. Many of these factors were found to increase the risk of HIV transmission when considered alone. However, when all factors were evaluated together, only levels of HIV RNA were found to predict the likelihood of HIV infection.

The risk of transmission was lowest in women with undetectable viral RNA (fewer than 500 copies of viral RNA per ml of blood). None of the 84 women who had undetectable RNA levels at entry into the study and none of the 107 women who had undetectable RNA levels at delivery transmitted HIV to their infants. However, transmission did occur at all levels of detectable RNA. Six percent of infants born to 395 women who had detectable levels of RNA in their blood when they entered the study and 7 percent of those born to 344 women who had detectable RNA levels when they gave birth became infected with HIV.

The finding suggests that the current standard of treating pregnant women with a combination of AZT together with other anti-HIV drugs, such as protease inhibitors, is likely to also effectively reduce transmission of HIV to their infants because the therapy reduces viral RNA levels greatly, Dr. Mofenson says.

"In addition to improving a woman's overall health, reducing the level of HIV-1 RNA may also reduce a woman's chance of giving birth to a child with HIV infection," says Dr. Mofenson. However, she cautions that although none of the women in the study who had undetectable levels of the virus in the blood transmitted virus to their children, there have been reports of transmission even from women who had undetectable viral levels.

Dr. Mofenson adds that there is limited experience with use of these drugs during pregnancy and that their possible benefits must be weighed against the lack of information on potential long-term effects on the children exposed to them. She also recommends that uninfected children whose mothers received anti-HIV drugs during pregnancy continue to have careful medical follow-up into adulthood.

The Women and Infants Transmission Study (WITS)

In a separate study, researchers report that viral load predicts the risk, but not the timing, of transmission of HIV from pregnant women to their infants.

Lead author Patricia M. Garcia, M.D., of Northwestern University in Chicago, and colleagues analyzed data from 552 mother-infant pairs who enrolled in the WITS between 1990 and 1995. Sponsored by NIAID, NICHD and the National Institute on Drug Abuse (NIDA), the WITS is an ongoing, multicenter investigation of HIV infection in pregnant women and their infants.

"We wanted to learn whether higher HIV levels in the mother could by itself increase the risk of infecting her baby," explains Dr. Garcia. "We also wanted to assess whether the risk of transmission correlated more closely with high viral loads earlier in pregnancy rather than later."

Slightly more than 20 percent (114 of 552) of the infants in the study became infected with HIV. The average HIV level in women who transmitted the virus to their babies was nearly three times higher than the average HIV level in women who did not. None of the 57 women in the study with fewer than 1,000 copies of HIV RNA per milliliter of blood transmitted the virus to their infants, although other studies have reported mother-to-infant transmission among women with similarly low viral loads.

Viral load was a strong predictor of perinatal transmission even after accounting for other known risk factors, such as low infant birth weight and lack of prenatal AZT treatment. However, the researchers found no relationship between a woman's viral load at any time during pregnancy and the time at which her baby becomes infected.

Since most of the study period predated the 1994 publication of ACTG 076, the NIH-supported study that showed that AZT could reduce perinatal HIV transmission by two-thirds, many women (321 of 552) in the WITS study had not received prenatal AZT. The rest of the women in the study had been treated with AZT either according to the ACTG 076 protocol or for other indications. The WITS study data reflect the reduction in perinatal HIV transmission rates seen in ACTG 076 -- before 1994, the transmission rate among women in the WITS study was 24 percent; thereafter, it was 9 percent.

"The receipt of any type of AZT therapy in general was significantly associated with a lower rate of perinatal HIV transmission," notes Dr. Garcia, "although treatment with AZT was not associated with maternal HIV viral load. This supports previous studies that found that AZT therapy during pregnancy reduces the risk of perinatal transmission, but not solely as a result of reduction in maternal HIV levels. The same may not be true for combinations of potent antiretroviral drugs that are capable of reducing maternal viral load to undetectable levels."

The researchers conclude that of all the independent factors related to the risk of perinatal HIV transmission, viral load, and the use of antiretroviral drug therapy are perhaps the most modifiable.

"Yet, women with low or undetectable viral loads should not be falsely reassured," they caution, "but instead should be offered AZT therapy because of its demonstrated efficacy in reducing the risk of transmission regardless of maternal HIV levels."