Human growth hormone may help combat "buffalo hump" and "protease paunch"
In the February issue of AIDS Care we reported that a surprising number of people on combination antiretroviral regimens that include a protease inhibitor seem to be developing large fatty deposits on their belly, buttocks, neck, and face (see "Combination therapy can lead to unusual fat deposits," Vol. 2, No. 1). Dubbed "protease paunch" when it appears on the lower abdomen and "buffalo hump" when it occurs across the back of the neck, this curious side effect of combination therapy was initially regarded as more unsightly than worrisome. This condition -- for which the technical term is lipodystrophy -- was attributed to unknown metabolic changes; whether it posed significant health problems was unknown.
Researchers subsequently reported a different problem in some of their patients on protease inhibitor therapy -- a loss of fat from places on the body that normally have significant fat pads. These effects were noted after treatment of variable duration, ranging from two months to two years of therapy, and they resulted in an appearance like that commonly associated with the AIDS wasting syndrome. Here too the cause of these physical changes was thought to be a protease-inhibitor-induced alteration in metabolism -- particularly the metabolism of fat.
Concern rose when a team of researchers at the University of Minnesota reported that they were seeing elevated cholesterol and triglyceride levels in patients taking protease inhibitors. Even more worrisome was this team's finding that some of these patients exhibited evidence of premature arteriosclerosis (see "New information on protease inhibitor therapy and unusual fatty deposits," Vol. 2, No. 3). This highly preliminary data suggested that the long-term use of protease inhibitors might be associated with accelerated coronary artery disease in relatively young patients. When the first reports of "protease paunch" began to surface last winter, these unattractive fatty deposits were thought to be more of a cosmetic problem than a matter of clinical concern. However, the possibility that these deposits might pose a real threat to the health of people taking protease inhibitors made research into the causes -- and effective treatment -- of lipodystrophy a high priority. Happily, some progress has been made in this regard.
News of a potential treatment for lipodystrophy was reported at the 12th World AIDS Conference, which drew more than 9,000 clinicians, researchers, epidemiologists, public-health officials, advocates, and activists to Geneva, Switzerland, last summer. In this small study, five patients with HIV who were taking protease inhibitors were given daily doses of a new, genetically-engineered human growth hormone (Serostim®) to combat AIDS-related wasting. The team conducting this clinical trial was pleased to find that the growth hormone not only reversed some of the effects of wasting, it reduced the unusual fatty deposits noted in all five participants. These reductions ranged from approximately 25% to complete resolution of the problem.
What this means for you:
"Protease paunch" and other forms of lipodystrophy would be a matter of concern even if they were not associated with potentially significant changes in fat metabolism. Because lipodystrophy can lead to radical changes in a person's appearance -- sunken cheeks and a protuberant belly, for example -- this side effect of protease-inhibitor-containing therapies affects self-image and quality of life. Although lipodystrophy is as likely to occur in men as in women, women are more likely to report that they are troubled by the fatty accumulations that are the hallmark of lipodystrophy. In extreme cases, affected females appear to be in the late stages of pregnancy.
The accumulating evidence that some people with lipodystrophy also have elevated serum lipid levels increases our concern about this curious side effect of treatment with protease inhibitors. The preliminary report cited above offers some hope that we may be able to reverse the unsightly effects of lipodystrophy with human growth hormone -- welcome news to women (and men) whose bodies have been distorted by this phenomenon.
It should be noted, however, that treatment with growth hormone does not seem to remedy the underlying problem in patients with lipodystrophy; levels of fats such as cholesterol and triglycerides remain elevated in these individuals' blood. Moreover, the five participants in this pilot study reported side effects that where thought to be associated with their hormone therapy. That list included two cases of hyperglycemia, one case of carpal tunnel syndrome, and an elevation of pancreatic enzymes in one patient. Individuals who develop these fatty accumulations as a side effect of protease inhibitor therapy will have to decide, in consultation with their care providers, whether they are willing to risk the potential side effects of growth hormone therapy in order to diminish the size of these fat deposits.
In any event, patients with lipodystrophy should consult with their care providers about taking steps to delay or treat arteriosclerosis. Patients and providers may reach the joint decision that it would be wise for the patients to make adjustments in their dietary habits and exercise patterns which are similar to those made by people without HIV who are prone to coronary artery disease due to genetic predisposition or other risk factors. Reducing animal fat in the diet, getting regular exercise, and not smoking may all be advisable precautionary measures for such individuals. In situations where life-style changes alone do not bring about reductions in lipid levels, cholesterol-lowering drugs should be considered as a therapeutic option.
Lower dosage of AZT suggested for preterm infants
A recent study shows that AZT (zidovudine, Retrovir®) stays in the bodies of premature babies longer -- and in stronger concentrations -- than it does in full-term infants. Doctors at Boston University checked blood levels of the drug in 15 babies born prematurely. They discovered that clearance of the drug was slower in the premature babies than in full-term babies and that AZT's half-life was longer. Clearance rates increased, and half-life decreased, as these preemies aged. Even so, the researchers recommend that for preterm infants the dosage of AZT be lowered to 1.5 mg every 12 hours until HIV-positive preemies are two weeks of age, at which time it should be increased to 2 mg per kilogram of body weight every eight hours. They also recommend that similar studies be conducted of other drugs used in HIV-positive infants, because this same combination of reduced clearance and increased half-life may occur when those drugs are given to preterm babies.
Refinement in insemination process may allow HIV-positive men to safely father children
As combination therapy increases life expectancy for people with HIV, some who had abandoned the idea of having children are reconsidering their decision (see "Can I Have Children?" in this issue and "The Toughest Decision I Ever Made," the Personal Perspective column). Now a preliminary study indicates that HIV-positive men who wish to father children but fear infecting their HIV-negative partners in the process may be able to decrease those infection risks with the help of a new insemination technique.
Spanish researchers report that they have developed a means of "washing" semen taken from asymptomatic HIV-positive men, a process that seems to virtually eliminate the virus in the semen samples. Using these screened specimens, the Spanish team then performed intrauterine insemination on 63 HIV-negative women. Of 37 children born to date as a result of the procedure, none have been born with HIV -- and not one of the 63 women has become infected. While these results are promising, the researchers are urging caution in interpreting their findings thus far. They are uncertain as to whether the screening technique they have devised can actually be relied upon to eliminate HIV entirely from donor semen. Further study will be necessary before this method can be recommended to men with HIV who want to father children.
C-section further reduces risk that mothers with HIV will pass the virus to their newborns
We have known since 1994, when the landmark clinical trial known as ACTG 076 was published, that the administration of AZT (zidovudine, Retrovir®) to pregnant women with HIV reduces by almost 70% the likelihood that those women will transmit the virus to their infants. Over the last four years the mother-to-child transmission rate -- which reflects the number of children who are infected with HIV each year -- has dropped from roughly 25% to 8%. Now the results of a study presented at the 12th World AIDS Conference have shown a way to reduce that already low transmission rate even further.
In a study of 8,533 infants born to HIV-positive mothers, researchers from the National Institutes of Health found that when women who were given AZT during pregnancy delivered by cesarean section, the rate of HIV transmission was brought to approximately 2% (range: 0.0% to 4.0%) -- a significant improvement over the transmission rate of 7.3% (range: 5.9% to 8.8%) for HIV-positive mothers who were taking AZT but delivered their newborns vaginally.
It is important to note that these were elective C-sections, performed before the women had begun labor. Some of the women who chose cesarean section over vaginal delivery may have done so to reduce the risk that they would transmit HIV to their offspring, but it is much more likely that those who chose the surgical procedure did so for one of the more common reasons that women have C-sections: because the baby's head was too big to permit vaginal delivery; because the baby was in the wrong position for vaginal delivery (so-called transverse lie); or because the woman had undergone a C-section in the past -- which dictates that all future deliveries be by the cesarean method.
Having a baby is hard work, whether the infant arrives via vaginal delivery or cesarean section. Recovery takes days, and it is generally slower when a woman has had a C-section. Current HMO guidelines call for the rapid discharge of new mothers and their infants regardless of method of delivery, which makes it all the more essential that women with newborns get some help when they get home, especially if they have delivered by cesarean. When pregnant HIV-positive women and their care providers are weighing the merits of vaginal delivery versus C-section -- where either mode is an option -- thought should be given to the increased physical discomfort and delayed time to recovery that are associated with the surgical procedure.
We have known since 1994 that the use of AZT results in a sharp drop in mother-to-infant transmission of HIV. In most studies the transmission rate was reduced from 25% to 8% or lower, and in some instances it fell to 3% -- approximately the rate seen in the N.I.H. study of HIV-positive women who elected to deliver by C-section. In 1994 the standard of care for pregnant women with HIV was AZT monotherapy or two-nucleoside therapy. That standard has now evolved to include at least three antiretroviral agents, one of them a protease inhibitor. We do not yet know if these more powerful drug combinations will reduce transmission rates even further, but it is reasonable to think that they will.
Several studies now suggest that HIV-positive women who deliver by cesarean section are less likely to transmit the virus to their newborns than women who deliver vaginally. This benefit occurs in the absence of AZT therapy, and it confers additional protection when combined with AZT therapy. It appears that this benefit is seen in cases of elective C-section -- that is, when the surgical procedure is undertaken prior to the onset of labor and the rupture of the membranes of the uterus. We know that as long as the membranes are intact, all pathogens have a tougher time entering the uterus and infecting the fetus. We presume that the membranes confer this protection against HIV as well, and we assume that the virus gains entry to the womb after the membranes rupture and labor begins.
Cesarean sections performed on HIV-positive women after labor has begun have not been shown to reduce mother-to-child transmission rates. For this reason, women with HIV need to decide whether they want to opt for surgical delivery well before they go into labor, so that the procedure can be scheduled for an appropriate time at the end of gestation but before the onset of labor.
This N.I.H. study, a retrospective meta-analysis of 8,533 deliveries, indicates that elective C-section cuts mother-to-infant transmission of HIV in half. In mothers who were receiving no antiretroviral therapy, the transmission rate was 19% for vaginal delivery versus 10.4% for cesarean delivery. When AZT was administered to the mothers, those rates were 7.3% and 2.0%, respectively. These rates represent medians for the population at large. For individual women on antiretroviral therapy who elect to deliver by C-section, the risk of transmitting HIV can be as high as 4%; for women on therapy who deliver vaginally, the risk can be as low as 5.9%.
Pregnant women with HIV and their primary-care providers will have to consider a number of factors before deciding which mode of delivery to choose. Cesarean section is a surgical procedure, and it is not without risks (although complications are generally minimal with this well-established and widely used procedure). Women who are taking antiretroviral drugs -- especially those who are on maximally suppressive multidrug therapy -- may decide that the modest reduction in mother-to-child transmission that is seen when C-section is added to highly suppressive antiretroviral therapy is outweighed by the added discomfort and potential complications associated with this procedure.
The relationship between HIV disease and vaginal yeast infections becomes clearer
For years the experience of women with HIV has suggested a connection between vaginal yeast infections, a form of candidiasis, and HIV disease itself. (For more information on yeast infections, see "Common Gynecological Infections in Women with HIV," the Pull Out and Save feature in this issue of AIDS Care.) Most women experience yeast infections at some time in their lives regardless of their HIV status, but women with HIV tend to have more of these outbreaks, and they are likely to be more severe. What was not clear, until recently, was whether being HIV-positive actually made a woman more susceptible to candida infection -- and whether the presence of yeast infections, and/or the vaginitis such eruptions often cause, were indicators of HIV disease progression.
Now a group of researchers at Yale Medical School has shed some light on the relationship between these two infections. After studying 184 HIV-positive women for two years, these investigators determined that the presence of candida infection is not, in itself, a significant predictor of HIV disease progression. In this study, as in previous studies, rates of candida infection among women who are HIV-positive ranged between 14% and 62%. Those numbers are only slightly higher than what one would expect to find in the population at large: numerous studies have determined that candida is present in the vaginas of 10% to 55% of all women of child-bearing age.
On the other hand, symptomatic candida infections did prove to be a useful marker of HIV disease progression. In the Yale study, women with lower CD4 cell counts were far more likely to have symptomatic yeast infections -- indicating that outbreaks of candida vaginitis, especially serial eruptions and hard-to-treat infections, do correlate with a decline in immune function.
Studies document the importance of good prenatal care for pregnant women with HIV
Doctors from the Harvard School of Public Health who conducted a study of 1,075 HIV-positive pregnant women in Tanzania -- where 13% of all pregnant women test positive for HIV -- have reported that daily doses of multivitamins can improve the health of both seropositive women and their newborns. Given how widespread malnutrition is in Africa, it is not surprising that the women in this study who took daily multivitamins evidenced improved general health when compared with those who did not receive the vitamin supplements. What did come as a surprise to the Harvard team was that study participants who took multivitamins also had significantly fewer preterm births as well as fewer babies with low birth-weights. Moreover, there were fewer fetal deaths in the group that got vitamin supplements. The researchers plan further analyses, to see if multivitamin supplements can also reduce the rate of mother-to-infant transmission of HIV.
While malnutrition is much less of a problem in the United States than it is in developing countries, comprehensive prenatal care -- including nutrition counseling -- can significantly improve the health of pregnant women and their babies, a group that includes HIV-positive expectant mothers, according to a recent study. Doctors from Philadelphia's Thomas Jefferson University and the New York State Department of Health followed the progress of two groups of pregnant IV-drug users with HIV: those who participated in the state's Medicaid Prenatal Care Assistance Program and those who did not.
Over the course of this study, one-third of the women who were not in the prenatal-care program gave birth to infants that were either premature or who weighed less than five pounds at birth, while only one-quarter of those involved in the prenatal care program gave birth early or had underweight babies. This is particularly significant in a group of IV-drug users, since such women are less likely to get prenatal care than the population at large, and they are more likely to have underweight and/or preterm infants.
What this means for you:
All pregnant women should receive good prenatal care, but comprehensive care and adequate counseling are particularly important when the women in question are HIV-positive. The most recent data from the Centers for Disease Control and the Office of AIDS Surveillance of the New York City Department of Health tell us that many of these women are members of minority populations -- which are disproportionately represented at the lower socioeconomic levels. Most of these women are uninsured or underinsured, and a significant number do not speak English as a first language. These are, by and large, inner-city females or the rural poor -- women whose resources are marginal, whose housing (if they have it) is inadequate, and whose struggle to survive often subsumes whatever concerns they may have about their HIV status.
Because such women face so many socioeconomic barriers to adequate medical care, they are more likely than the population at large to experience rapid disease progression -- and they are more likely to transmit HIV to their offspring. What the data from East Africa tell us is that even one multivitamin a day can make a difference in these women's lives, and in the lives of their babies. What the data from ACTG 076 tell us is that AZT can reduce by almost 70% the chances that a woman with HIV will transmit the virus to her newborn.
These are relatively inexpensive and extremely cost-effective interventions, and it makes eminent sense to offer such help to all HIV-positive expectant mothers. Indeed, it strikes me as morally indefensible not to offer such help to every pregnant seropositive woman. Where else can we prevent new HIV infections so cheaply and so certainly?
Loss of the vagina's natural flora may increase the risk of contracting STDs
Parts of the human body, particularly the digestive system and the female genital tract, are normally populated with a host of different flora, primarily bacteria, that are actually helpful -- even necessary -- to the body's normal functioning. In the gastrointestinal tract, these natural flora play an important role in digestion, breaking food down into usable nutrients. In the vagina they play a subtler, but equally important, role. Some of them may actually protect against infection by harmful organisms. Primary among the latter flora are lactobacilli, the same bacteria that turn milk into yogurt -- the "active cultures" that are listed on yogurt containers.
Lactobacilli protect the vagina in two ways: by producing hydrogen peroxide, which kills invading organisms, and by helping to lower the pH level in the vagina, thereby making it a less hospitable environment for foreign organisms. A loss of lactobacilli in the vagina can lower these protective barriers and lead to increased risk of infection.
At a recent meeting of the American Society of Microbiology in Atlanta, several teams of researchers reported that loss of lactobacilli can leave women at increased risk of contracting a number of sexually-transmitted diseases. A study conducted in Thailand among 144 female sex-workers found that those with a loss of vaginal flora were twice as likely as those with a normal balance of vaginal organisms to contract HIV. In addition, a study of 657 female sex-workers in Kenya showed that the risk of contracting gonorrhea rose by 78% in women who had low levels of lactobacilli.
What this means for you:
Clearly, maintaining the natural, healthy balance of flora in the vagina -- especially lactobacilli -- can be beneficial to all women. Any natural defense against STDs should be promoted, and if this one can help protect against HIV, then women who are HIV-negative should listen up. But women living with HIV should pay even closer attention, since their weakened immune systems make them more susceptible to infections of all kinds.
There are a number of conditions and circumstances that can upset the balance of vaginal flora, and HIV-positive women and their healthcare providers should always be on guard against anything that may cause such an imbalance. In particular, they should be aware of two practices that can have a strong negative impact on vaginal flora -- the use of antibiotics and douching.
It is often necessary for women with HIV to take a course of antibiotics to combat an infection somewhere in the body, and the right antibiotic can quickly wipe out the microorganisms responsible for that infection. Unfortunately, antibiotics can also wipe out many microorganisms in the vagina -- including lactobacilli -- and this can lead to an imbalance in the vaginal flora, one that often manifests first as a yeast infection.
Some antibiotics are more damaging to vaginal flora than others, but as a general rule any time a woman begins taking an antibiotic she should also begin taking an acidophilus supplement (or eating plain yogurt several times a day) in order to replace lactobacilli that are killed by the antibiotic. This will often prevent the sort of imbalance that leads to yeast infections -- and to other, more serious infections that can result from an antibiotic-induced imbalance in vaginal flora.
The other thing that women with HIV can do to help maintain the natural balance of flora in the vagina is avoid all douching. A number of studies have identified douching as a risk factor in the loss of helpful vaginal flora. Dr. Sharon Hillier of the University of Pittsburgh, a founder of vaginal lactobacilli research, has made her feelings on the subject quite clear: "Douching has no known medical benefit, but there is a $100-million industry out there selling perfumed water to women, and they fall for the advertising." Women living with HIV should heed Dr. Hillier's advice and avoid douching.
Studies reveal some early indicators of disease progression in infants and toddlers
As we noted in the June issue of AIDS Care, most of the early clinical studies of HIV infection were open only to adults, and as a result we often had a good idea about how adults would respond to a given drug or drug combination long before we had any data on how pediatric patients might respond to these treatments (see "CD4 count and viral load do predict HIV progression in pediatric patients," Vol. 2, No. 3). During the early years of the epidemic, those who provided care to infants, toddlers, and preadolescents with HIV were therefore obliged to extrapolate standards of care and parameters of success or failure from data gathered in trials that involved no children.
As we also noted in our June issue, the F.D.A. now routinely approves the use of new antiretroviral drugs in pediatric patients -- if the pharmacokinetic data are available in children and efficacy has been shown in adults. Furthermore, a new F.D.A. regulation requires that all new anti-HIV drugs be studied simultaneously in adults and children.
Because so much of the early care of children with HIV was seat-of-the-pants -- especially when it came to deciding when to initiate or switch antiretroviral therapies -- the identification of reliable indicators of disease progression in children with HIV is cause for celebration. Recently, two studies have yielded more information in this important area. Researchers at the University of Puerto Rico, who studied 128 infants with HIV over two years, noted a factor that seems to correlate with high risk of disease progression.
Newborns who had positive HIV cultures within 48 hours of birth proved to be just as likely to experience rapid disease progression as infants who showed actual physical signs of infection within three months of birth. In this study, 21% of the newborns who had positive cultures developed symptomatic disease by their first birthday. This information suggests that such infants may benefit from early, aggressive antiretroviral treatment.
A small study conducted by researchers at the State University of New York at Syracuse should also aid providers in making treatment decisions about young patients. By comparing language development in nine toddlers with HIV and 69 children who were exposed to HIV in the womb but were not infected, these investigators showed that the toddlers with HIV consistently scored lower on language tests. As a result, they are recommending that language-assessment tests should be added to other developmental tests used to detect possible disease progression in toddlers with HIV. As a bonus, the tests may also be able to indicate whether a toddler's assigned antiretroviral treatment is proving effective, since three of the youngsters with HIV who began combination antiretroviral therapy during the course of this study demonstrated improved language development -- as well as improved sensory and motor skills -- after treatment was initiated.
Is nonoxynol-9 helping or hurting in the fight against HIV transmission?
Almost from the moment researchers and AIDS activists first began promoting safer sex to prevent the spread of HIV, the condom -- the foot-soldier of the prevention war -- has been accompanied by a chemical weapon: lubricants containing the spermicide nonoxynol-9. Studies had shown nonoxynol-9 to be active against HIV in the test tube, and since this compound was already in use in some lubricants as a spermicide, it was assumed that using a lubricant containing nonoxynol-9 might help prevent transmission of HIV -- and certainly wouldn't do any harm.
However, a decade and a half later there is still no evidence that lubricants containing nonoxynol-9 do help protect against HIV transmission. In fact, several studies have suggested that because the spermicide often irritates the delicate skin of the genitals, nonoxynol-9 may actually promote HIV infection.
Recently, a large-scale trial of nonoxynol-9 was conducted by Family Health International and the Cameroon Ministry of Health. In this study 1,300 female sex-workers in Cameroon were supplied with condoms and either a lubricant containing 70 mg of nonoxynol-9 or one containing a placebo. The participants, who were instructed to use the condoms and lube with all of their sexual partners, reported a 90% rate of condom use during the study.
The researchers discovered no difference in rates of new HIV infections -- or of new chlamydia or gonorrhea infections -- between the two test groups. The HIV transmission rate was 6.7 infections per 100 woman-years among the sex-workers who used nonoxynol-9, and 6.6 per 100 woman-years among those using placebo. However, the women using nonoxynol-9 did have more cases of genital lesions during the trial: 42.2 cases per 100 woman-years versus 33.5 cases for placebo. And because genital lesions are associated with heightened risk of HIV infection, it can be argued that the use of nonoxynol-9 actually increases a woman's risk of acquiring HIV.
Meanwhile, Population Council researchers in New York were studying the usefulness of nonoxynol-9 to prevent the spread of herpes simplex virus 2 (HSV-2). Specifically, they were studying whether the spermicide could prevent anal transmission of HSV-2 in mice. They were surprised to discover that mice who were treated with nonoxynol-9 were actually more likely to become infected with HSV-2 than those who were not.
Closer analysis of the tissues involved revealed that nonoxynol-9 temporarily weakened rectal tissue, which may have been responsible for the increased rate of transmission. While these researchers were working only with mice and studying only HSV-2, their findings led them to suggest that the results of their study might be generalized to other sexually transmitted diseases, including HIV. They recommended that, pending human studies, people avoid use of lubricants containing nonoxynol-9 for anal intercourse.
What this means for you:
The jury is still out on whether the use of lubricants containing nonoxynol-9 helps to prevent, or actually promotes, HIV infection. At this point we have no conclusive evidence that nonoxynol-9 does prevent the transmission of HIV during sexual relations -- and we do know that this lubricant can irritate the mucous membranes of the vagina, rectum and penis, and can even cause lesions or genital ulcers. Moreover, we know that the presence of genital lesions or ulcers can significantly increase the risk of contracting any STD, including HIV.
Pending the jury's return, it may be prudent to reverse the standard wisdom on safer sex and nonoxynol-9. We have long assumed that using a lubricant containing nonoxynol-9 might help prevent transmission of HIV -- and certainly wouldn't do any harm. It is now clear that this matter is more complicated than we originally thought. At the very least, the evidence we now have suggests that the risks of infection associated with using the spermicide may outweigh its possible benefits as a microbicide. Women with HIV should be aware of this when using lubricants containing nonoxynol-9 for vaginal or anal sex.
Back to the October 1998 AIDS Care contents page.
This article was provided by San Francisco General Hospital. It is a part of the publication AIDS Care.