Twenty Years of AIDS
June 2001 marked the twentieth anniversary of the first medical reports of the disease that would later become known as AIDS. On June 5, 1981, the Centers for Disease Control and Prevention (CDC) published a report in its Morbidity and Mortality Weekly Report describing a cluster of cases of Pneumocystis carinii pneumonia (PCP) occurring in five gay men in Los Angeles. Within months, more cases of PCP and the rare cancer Kaposi's sarcoma (KS) were reported in gay men in New York City and San Francisco. The new syndrome was labeled gay-related immune deficiency (GRID), and KS was called "gay cancer." But soon, cases were also reported in injection drug users, women, infants, and hemophiliacs, and the disease was renamed acquired immune deficiency syndrome, or AIDS. By 1982 it was apparent that the agent that caused the syndrome was transmitted through blood, as well as through sex. In 1983 researchers at the Institut Pasteur in Paris isolated a virus they called lymphadenopathy-associated virus, or LAV; the following year Robert Gallo, M.D., and colleagues in the U.S. discovered a virus they called human T cell lymphotropic virus, or HTLV-III. It later became clear that the two viruses were the same, and it was renamed human immunodeficiency virus, or HIV. Today it is estimated that over 800,000 people in the U.S. and 36 million people worldwide are living with HIV/AIDS and that approximately 22 million have died of the disease.
New Federal HIV Treatment Guidelines
In April the Department of Health and Human Services (DHHS) and the Kaiser Family Foundation released an updated version of the Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. In this version, all changes are in the section "Considerations for Antiretroviral Therapy in the HIV-Infected Pregnant Woman."
In May, the federal government also updated the Public Health Service Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant HIV-1 Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States. The sections on "Antiretroviral Clinical Scenarios," "Recommendations for Monitoring of Women and Their Infants," and "Clinical Research Needs" have all been revised. Both updated sets of guidelines are available online or by calling 800-448-0440.
Also in May, the Health Resources and Services Administration (HRSA) released a new manual entitled A Guide to the Clinical Care of Women with HIV (PDF). The 508-page guide, billed as the "first of its kind," is aimed at primary-care physicians and others caring for women with HIV/AIDS. It includes discussions of gynecologic conditions, child-bearing concerns, and social issues unique to women. The guide's editor, Jean Anderson, M.D., of Johns Hopkins School of Medicine, said that the new manual will help fill gaps in people's understanding of the disease in women, since "people who did a lot of HIV care didn't necessarily know what were the special issues for women, and providers who did a lot of health care for women didn't know much about HIV." The guide is available online.
British Doctors Recommend Longer Treatment Deferral
British physicians are considering whether to recommend that antiretroviral treatment be delayed longer than advised by current treatment guidelines. This past February, the U.S. DHHS updated its antiretroviral therapy guidelines for adults and adolescents, suggesting that treatment should be offered to people with viral load levels greater than 55,000 copies/mL by RT-PCR assay or 30,000 copies/mL by bDNA assay, or CD4 cell counts less than 350 cells/mm3. The previous guidelines (from May 1999) recommended treatment for people with viral load levels above 20,000 copies/mL (RT-PCR) or 10,000 copies/mL (bDNA), or CD4 cell counts below 500 cells/mm3.
At the 7th Annual Conference of the British HIV Association (BHIVA) held in Brighton in April, proposed new guidelines were presented that recommend starting treatment at even later stages of HIV disease. The BHIVA suggests that therapy should be deferred in persons with CD4 cell counts above 350 cells/mm3, regardless of viral load. The guidelines recommend that physicians should consider treatment for people with CD4 cell counts of 200-350 cells/mm3 if they have a high viral load (above 100,000 copies/mL), a rapid CD4 cell decline, or symptoms of opportunistic infections (OIs). Treatment is still recommended for persons with CD4 cell counts of 200 cells/mm3 or less, again regardless of viral load.
As in the U.S., the desire to delay treatment is prompted by factors such as the side effects of aggressive combination therapy, the difficulty of adherence to complex regimens, and the development of drug-resistant HIV that could lead to fewer treatment options at later stages of disease. Some U.S. physicians have expressed concern over the draft British guidelines. According to W. David Hardy, M.D., of the University of California at Los Angeles School of Medicine, for example, the proposed UK guidelines appear "premature and perhaps too avant-garde."
Researchers at the April BHIVA meeting presented results of studies showing that structured interruptions in antiretroviral therapy may negatively affect immune functioning. Research presented earlier this year in Chicago at the 8th Retrovirus Conference (CROI) suggested that stopping and restarting treatment on a specified schedule (structured treatment interruption [STI] or drug cycling) appeared to cause little or no harm; HIV remained fully suppressed in persons on a seven-days-on/seven-days-off drug schedule, and participants who continued drug cycling for ten months had "no evidence of damage to their immune systems or the development of resistant strains of the virus," according to National Institute of Allergy and Infectious Disease (NIAID) researchers. This research cannot be generalized, since the number of participants was very small.
But studies presented in April show that longer and less carefully monitored treatment interruptions may indeed lead to HIV disease progression. M. Poulton, from the Royal Sussex County Hospital in Brighton, and colleagues presented results of a study of 38 subjects who stopped treatment for two months or longer; the median length of treatment interruption was 289 days, with a range of 77-1,036 days. During treatment interruption, the participants experienced significant increases in viral load and significant drops in CD4 cell count. Those who had lower nadir CD4 counts (the lowest level ever reached) before starting therapy were at the highest risk of disease progression. The 24 participants who had enough data to do the calculation lost a median of 63 CD4 cells/mm3 per year off treatment. Four participants experienced an AIDS-defining illness during their STI, and 29 experienced some type of clinical event.
C. Burton and colleagues from Chelsea and Westminster Hospital in London looked at CD4 cell response during treatment interruption in 15 persons who had temporarily stopped antiretroviral therapy due to side effects, drug toxicity, inability to adhere to the regimen, or other reasons; all had undetectable viral loads when the study started. The researchers used a lymphocyte proliferation assay (LPA) to measure participants' cellular immune response to HIV antigens, and also assessed the production of interferon in response to HIV. After one month without treatment, participants began to experience viral rebound and their CD4 cells showed increased response to HIV antigens. However, after two months without treatment, eight participants experienced viral load rebound to pretreatment levels, decreased CD4 cell counts, and reduced response to HIV antigens. The researchers concluded that while people with HIV may try STIs in an effort to jump-start the body's immune response to HIV, "longer cessation of highly active antiretroviral therapy (HAART) results in loss of regained HIV-1-specific responses." These results help pinpoint what length of treatment interruption is likely to have the most benefit with the least risk. Treatment interruption should only be done under the close supervision of an HIV-experienced physician.
Viral "Blips" Do Not Indicate Treatment Failure
Slight, intermittent increases in viral load in people using HAART do not necessarily indicate that the drugs are not working, according to two studies published in the July 11 issue of the Journal of the American Medical Association. In the first study, Diane Havlir, M.D., and colleagues from the University of California at San Diego analyzed data from 254 HIV-positive persons taking triple combination antiretroviral therapy; 241 people were followed for a median of 84 weeks (101 were on triple therapy for the entire period), and 13 were followed for 4.5 years. Intermittent viremia was defined as an increase in viral load to over 50 copies/mL, followed by a drop back below 50 copies/mL on the subsequent test. Intermittent viremia was seen in 40% of the shorter follow-up group and just under one-half of the longer follow-up group. In the shorter follow-up group, intermittent viral load increases did not predict eventual treatment failure; ten of 96 participants (10%) who had experienced intermittent viremia went on to experience virologic failure, compared with 20 of 145 participants (14%) who had not had viral "blips." In genetic tests of viral DNA from the longer follow-up group, viral material from seven of the 13 did not show drug-resistance mutations.
In the second study, Robert Siliciano, M.D., and colleagues from Johns Hopkins University examined blood samples from 20 HIV-positive persons (seven children and 11 adults) who had been on standard HAART including a protease inhibitor (PI) for two years or more. The researchers found that combination therapy appeared to inhibit viral mutation even in those who experienced intermittent viral load increases.
Physicians often assume that increases in viral load indicate treatment failure and should prompt a switch to new drugs. The new results suggest that this may not always be necessary. According to Dr. Havlir, "Unnecessary regimen switching may result in disruption of a patient's medication routine, toxic effects from new drugs, and premature discarding of useful drugs." Steven Deeks, M.D., of the University of California at San Francisco, who wrote an accompanying editorial in the same issue, said that based on data from the two studies, "it may be argued that 'complete' viral suppression may not be a prerequisite for durable treatment benefit." However, he cautioned that the results were preliminary, and that the findings appear to apply to those whose combination regimen includes a PI.
Therapeutic Drug Monitoring (TDM)
The issue of therapeutic drug monitoring (TDM) was among the hot topics at the 2nd International Workshop on Clinical Pharmacology of HIV Therapy held in early April in Noordwijk, the Netherlands. In TDM, levels of antiretroviral drugs in the bloodstream are measured in an effort to ensure that an adequate amount is available to suppress HIV, and also to help reduce drug toxicities and side effects. The usefulness of TDM in clinical practice is not yet known; two key studies presented at the conference produced conflicting results.
The PharmAdapt study and the Athena study are the first two prospective comparative trials of TDM versus standard care. Results from the PharmAdapt study were presented by P. Clevenbergh, M.D., from Nice, France. This study included 180 participants who had been unable to maximally suppress HIV on a previous antiretroviral regimen; they were prescribed a second regimen with the help of genotypic resistance testing. Participants were randomized into two groups, one of which received TDM while the other received standard therapy without TDM. In the TDM group, drug levels were measured four weeks after starting the new regimen; if TDM showed that drug levels were too low, a dose modification was recommended (this occurred in less than 15% of the participants). After 12 weeks, the PharmAdapt study could not statistically demonstrate that TDM was beneficial; the decreases in viral load level and the percentages with an undetectable viral load in the two groups did not differ significantly.
Results from the Athena study were presented by David Burger, Pharm.D., from the University Medical Center in Nijmegen, the Netherlands. This study involved 600 participants, half of whom were treatment-naive and half treatment-experienced, who were randomized to a TDM or a non-TDM arm. The TDM group received repeated drug level measurements within four weeks of beginning the study, and repeated dosage adjustments if indicated. Dr. Burger presented early data on treatment-naive participants starting regimens containing either nelfinavir (Viracept) or indinavir (Crixivan). The Athena study showed that TDM could significantly improve treatment outcomes. For persons starting indinavir, after six months, 93% of participants in the TDM group had an undetectable viral load compared with 74% in the non-TDM group (using an intent-to-treat analysis in which everyone who started the study was included). After 12 months, the undetectable viral load percentages were 75% and 48%, respectively. For those starting nelfinavir, the undetectable viral load percentages after six months were 95% in the TDM group and 82% in the non-TDM group; after 12 months, the percentages were 81% and 59%, respectively.
The Athena study, which had a much longer period of follow-up, suggests that the real benefits of TDM are most apparent after extended treatment. More research is needed to determine how best to use TDM, including what dose adjustments should be made when measured drug levels are subtherapeutic (too low to be effective).
Dealing with Drug Interactions
Another popular topic at the Workshop on Clinical Pharmacology concerned interactions among drugs. Eighteen presentations at the conference dealt with drug interactions. Among the most notable studies were those on the once-daily use of nelfinavir plus ritonavir (Norvir), and potentially toxic interactions between rifabutin (a tuberculosis drug) and indinavir. Monique DeMaat, Pharm.D., of Slotervaart Hospital in Amsterdam presented results showing that St. John's wort (an herb often used as an alternative treatment for depression) increased nevirapine (Viramune) clearance by up to 35%, potentially leading to subtherapeutic drug levels. French researchers presented data on how the three drugs in a triple combination regimen interact. For a good overview of HIV/AIDS drug interactions -- including types of interactions; interactions commonly seen with nucleoside analog (NRTI), PI, and OI drugs; and charts of specific drug-drug interactions -- see the article entitled "Interactions among drugs for HIV and opportunistic infections," by Stephen Piscitelli, Pharm.D., and Keith Galliciano in the March 29, 2001 issue of the New England Journal of Medicine.
Also at the workshop, the U.S. National Institutes of Health (NIH) proposed an expanded research effort and a central database for information about drug interactions, due to the fact that people with HIV/AIDS are often taking many different types of drugs (e.g., to treat mental illness, drug addiction, erectile dysfunction, diabetes, high cholesterol) and alternative herbal remedies -- combinations that in many cases have never been tested in laboratory studies or clinical trials.
Memory Cells and HIV Eradication
In late April, the media widely reported on research by Robert Siliciano, M.D., and colleagues from Johns Hopkins University suggesting that it is unlikely that HIV can be eradicated rather than controlled. In 1997, Dr. Siliciano first found HIV in the memory T cells of HIV-positive people who had an undetectable viral load for two years; fully potent copies of HIV remained in their memory cells even after antiretroviral therapy was started. Memory T cells are long-lived immune cells that "remember" microorganisms that have been previously encountered and allow the immune system to rapidly respond if the same "invader" is encountered again. After five years of follow-up on 50 subjects, Dr. Siliciano reported that their number of memory T cells has remained about the same. The body ordinarily kills HIV-infected cells, but because the latent memory cells appear normal, they are spared. Said Dr. Siliciano, "What HIV has done is tap into the most fundamental aspect of the immune system. ... It's the perfect mechanism for the virus to ensure its survival."
Many scientists are not optimistic that HIV-infected memory T cells -- which die at a very slow rate -- can ever be totally eliminated. Dr. Siliciano estimates that it would take about 73 years for a person's infected memory cells to completely die off, even with anti-HIV treatment. Attempts to "flush out" the hidden HIV by using interleukin 2 (IL-2) to activate the latent memory cells have not been successful. However, David Ho, M.D., of the Aaron Diamond AIDS Research Center in New York, does not believe that the memory cells live that long, but rather that they are constantly replenished. He is currently studying an aggressive four-drug regimen that he hopes will "shut off the supply of newly infected memory cells" and eradicate existing HIV-infected memory cells in a matter of three to four years.
Genetic Variation May Affect AIDS Progression
Research published in the May 31, 2001 issue of the New England Journal of Medicine may help explain why AIDS progression varies so greatly among individuals. Mary Carrington, Ph.D., of the NIH, and colleagues found that a single mutation involving the major histocompatibility complex (MHC) can render a person more susceptible to rapid progression of HIV disease. The MHC is a collection of genes that play an important role in immune defense by determining what microbes a person's immune system can recognize and respond to. The mutation in question is a single amino acid change in the HLA-B*35 molecule that affects viral peptide binding affinity. The researchers examined 850 persons with known HIV seroconversion dates. Those with the HLA-B*35-Px gene variation developed AIDS in about seven years, compared with about 11 years for those with the HLA-B*35-PY variation; the effect was seen in both African-American and European-American persons. The HLA-B*35-Px variation is present in approximately 12% of the population overall. The researchers suggest that the HLA-B*35-Px configuration may be less efficient in presenting HIV to cytotoxic T lymphocytes (CTLs, or killer T cells), since people with this HLA configuration have a poorer CTL response. The discovery could eventually help physicians tailor HIV treatment to specific individuals, with those most likely to progress receiving more aggressive therapy.
Lipodystrophy Syndrome: Uncertainties Remain
Lipodystrophy, lipoatrophy (fat loss), and similar abnormalities related to body fat metabolism and distribution continue to be a major concern for people with HIV/AIDS and their health-care providers. The combined 4th International Conference on Nutrition and HIV Infection and 2nd European Workshop on Lipodystrophy, held April 19-21 in Cannes, France, focused heavily on research in this area.
Conference attendees discussed various theories about the causes of lipodystrophy syndrome and how it is related to antiretroviral drugs, HIV infection, immune restoration, and other factors. Simon Mallal, M.D., from Perth, Australia, reviewed existing data concerning lipodystrophy syndrome, suggesting that various manifestations (such as fat loss, fat gain, abnormal fat metabolism, and abnormal glucose metabolism) should be looked at separately, even though they often occur together in a single person.
An overview of studies to date provides evidence of a strong association between PI drugs and abnormal fat and glucose metabolism; however, the same abnormalities also have been seen in some HIV-positive persons who have never used antiretroviral therapy. Studies of healthy, HIV-negative volunteers have shown that ritonavir can lead to increased cholesterol and triglyceride levels. A study by Mustafa Noor, M.D., and colleagues of the Veterans Affairs Medical Center in San Francisco -- which was reported at the conference and published in the May 4, 2001 issue of AIDS -- showed that hyperglycemia (high blood sugar) and insulin resistance were associated with the use of indinavir in HIV-negative men who took the drug for four weeks. Body fat changes were not seen, leading Dr. Noor to suggest that abnormalities in glucose metabolism may be the earliest manifestation of metabolic changes associated with PI drugs.
Dr. Mallal noted that the relationship between lipoatrophy and specific drugs remains unclear. Fat wasting has been seen in persons taking double NRTI regimens, in those taking NRTI/PI combination regimens, and in people who have never taken NRTIs or PIs. Ken Lichtenstein, M.D., presented an analysis of CDC data on fat loss and anti-HIV drug use from eight large U.S. HIV practices. The drugs d4T (Zerit) and indinavir have been most frequently associated with lipoatrophy to date, but Dr. Lichtenstein found that people taking one or both of these drugs who did not have additional contributing factors (e.g., being 40 years of age or older, or being at a later stage of HIV disease) did not develop fat wasting. He concluded that immune restoration may trigger the syndrome in persons predisposed on the basis of age, genetics, or other factors.
Dr. Mallal, Peter Arner, and others reviewed the biology and physiology of adipocytes (fat cells) and discussed how these may be adversely impacted in people with HIV/AIDS. Dr. Mallal noted that adipocytes take in fats and sugar after eating and store them as triglycerides, later releasing them when energy is needed by the body. He suggested that antiretroviral therapy may interfere with the entry of fat into adipocytes, as well as the release of fat from these cells (lipolysis). Arner noted that fat cells not only store nutrients, but also secrete various substances important for normal metabolism; fat tissue in different parts of the body is more or less metabolically active.
Several presenters also looked at mitochondrial toxicity (related to mitochondria, the energy-producing components of cells) -- in particular, how NRTI drugs interfere with mitochondrial DNA (genetic material) -- and how this may contribute to lipodystrophy and related manifestations of the syndrome. Mitochondrial damage is known to be associated with lactic acidosis, in which high levels of lactate (a metabolic byproduct) can lead to organ failure. Kees Brinkman, M.D., Ph.D., from the Department of Internal Medicine at Onze Lieve Vrouwe Gasthuis in Amsterdam, discussed data showing that, while lactic acidosis itself is rare in HIV-infected people taking NRTIs, a more mild condition -- hyperlactatemia (high lactate levels) -- may occur in at least 10%. In related research published in the April 13, 2001 issue of AIDS, a study by Andrew Carr, M.D., and colleagues from St. Vincent's Hospital in Sydney found that lactic acidemia associated with the use of NRTIs was correlated with osteopenia (moderately low bone mineral density) and osteoporosis (very low bone mineral density). (See more on bone mineral disorders in HIV-positive individuals.)
One presentation suggested that the risk of lipodystrophy syndrome is increased in people with HIV and hepatitis C virus (HCV) coinfection. Massimo Galli, M.D., discussed results from an Italian study involving 655 participants, 58% of whom were HIV/HCV-coinfected. The coinfected individuals were almost four times as likely to experience body shape changes than those with HIV alone. This study also showed that women were three times more likely than men to experience fat accumulation, while injection drug users had a decreased risk of body shape changes. Presenters discussed various potential treatments for lipodystrophy and related syndrome manifestations, including human growth hormone (Serostim), anabolic steroids such as oxymethalone (Anadrol) and nandrolone decanoate (Deca Durabolin), antidiabetes drugs such as metformin (Glucophage), and the amino acid acetyl-L-carnitine. Other methods of management include switching antiretroviral drugs and plastic surgery.
PLA Injections for Facial Wasting
For many people with HIV, facial wasting is one of the most disturbing symptoms of lipodystrophy syndrome. A presentation at the 2nd International Workshop on Adverse Drug Reactions and Lipodystrophy, held in September 2000 in Toronto, offered a new option for people with sunken cheeks and temples. The method, developed by French plastic surgeon Patrick Amard, M.D., involves injections of polylactic acid (PLA, or New-Fill), a simple sugar, into the cheeks. In the initial analysis presented last year, 22 of 26 HIV-positive men had successful outcomes using PLA. Follow-up results at 54 weeks were presented at the European lipodystrophy workshop this past April. According to a report by Lark Lands, M.D., in the June 2001 issue of POZ, PLA injections are safe and unlikely to trigger allergic reactions, and give a natural appearance. According to Dr. Amard, the injection of PLA powdered particles triggers the body to produce collagen (a skin protein); direct injections of collagen are also used for facial wasting. People typically require several sessions of injections (depending on the severity of facial wasting), spaced three or more weeks apart. Ice or lidocaine can be used to reduce injection pain, and Dr. Amard says there is no bruising or swelling after the treatment. The new and improved appearance lasts about a year and a half, after which time treatment can be repeated. PLA is currently approved in Europe and Mexico, but not in the U.S. For more information, see www.new-fill.com.
AZT/3TC and Vertical Transmission
According to a study published in the April 25, 2001 issue of the Journal of the American Medical Association, combination therapy with AZT (Retrovir) and 3TC (Epivir) reduces perinatal transmission from HIV-infected women to their infants, but leads to more side effects in newborns than AZT alone. Laurent Mandelbrot, M.D. and colleagues from the French National Agency for AIDS Research studied 899 HIV-positive women who received AZT monotherapy administered beginning at a median of 23 weeks of gestation and 445 women who received 3TC orally in addition to AZT beginning at 32 weeks; the drugs were also given to the infants after birth. Women receiving AZT plus 3TC had a transmission rate of 1.6% compared with a rate of 6.8% for women receiving AZT alone. The researchers called the 1.6% rate the "lowest rate reported to date in a large prospective study." Controlling for Cesarean sections, the transmission rate with combination therapy was five times lower than the rate with AZT monotherapy.
Blood cell abnormalities -- including anemia (low red blood cell counts) and neutropenia (low white blood cell counts) -- were seen with similar frequency in infants in both groups, but were more severe in the AZT/3TC group. Two infants in the combination therapy group experienced suspected mitochondrial damage and died during their first year. Dr. Mandelbrot and colleagues also noted that 3TC resistance was seen in women taking the two-drug regimen, which may "compromise the future efficacy" of this drug for these women. The researchers concluded that the implications of their study were "unclear," because "the precise relationship between incremental benefit and incremental risk remains to be determined."
Nathan Shaffer, M.D., in an editorial in the same publication, called the AZT/3TC results "impressive," but emphasized the need for close monitoring when the combination regimen is used. Lynne Mofenson, M.D., of the NIH said that current guidelines for pregnant women -- as for most people treated with antiretrovirals -- call for a three-drug regimen. The two-drug regimen under study may have the most relevance for resource-poor areas where treatment to prevent perinatal transmission is started later in pregnancy.
Breast-Feeding May Increase Maternal Mortality
A randomized study of women in Nairobi, Kenya, suggests that breast-feeding by women with HIV may increase the risk of both maternal and infant death. The study results were reported in the May 26, 2001 issue of the Lancet. Ruth Nduati, M.D., and colleagues from the University of Nairobi and the University of Washington studied 425 HIV-infected pregnant women, 212 of whom were randomly assigned to breast-feed their newborn infants and 213 of whom were assigned to feed them formula. Most of the women did not have access to running water or the ability to sterilize infant formula. The women were followed up every month for a year after delivery, then quarterly for a second year. Several of the women in the study were lost to follow-up for various reasons. Of the remaining women, 18 breast-feeding women (11%) died during the two-year follow-up period, compared with six formula-feeding women (4%). The breast-feeding women were more than three times as likely to die, a significant difference in mortality rate. The infants of the women who died were eight times more likely to have died themselves, even after controlling for the infants' HIV infection status.
The researchers suggested various possible reasons for greater mortality among breast-feeding women. The metabolic burden of breast-feeding in women who are poorly nourished may lead to weight loss and "maternal depletion syndrome," a condition in which women do not replenish nutrients lost during pregnancy and breast-feeding. Also, higher levels of the hormone prolactin in women who breast-feed may increase immunosuppression. Further research is needed, especially in light of the fact that an earlier study of over 500 HIV-positive women in Durban, South Africa, did not find an association between breast-feeding and clinical problems in mothers.
Cesarean Section Morbidity
A study by Elisa Josefina Rodriguez, M.D., and colleagues from Emory University School of Medicine in Atlanta looked at morbidity (illness) related to Cesarean sections in HIV-infected women. The researchers studied 86 HIV-positive and 86 HIV-negative women matched for age and race who had a Cesarean delivery between 1992 and 2000. Minor postoperative complications were seen significantly more often in HIV-positive women (66%) compared with HIV-negative controls (42%); the most common complication was fever. There were also more major postoperative complications in HIV-infected women (9%) than in uninfected controls (3%), but this difference was not statistically significant. Among HIV-positive women, those with higher viral loads were more likely to experience complications than those with undetectable viral loads. The results of the study were published in the May 31, 2001 issue of the American Journal of Obstetrics and Gynecology. Dr. Rodriguez concluded, "Despite our reassuring findings that Cesarean delivery was not associated with major maternal morbidity, caution should be maintained in advocating Cesarean delivery as the standard of care for HIV seropositive mothers."
Aerobic Exercise Helps People with HIV
According to a study in the April 13, 2001 issue of AIDS, HIV-positive persons who exercise regularly experience increased endurance and improved body composition. The study by Barbara Smith, Ph.D., of the University of Alabama at Birmingham School of Nursing and colleagues involved 60 HIV-infected adults. Participants who did aerobic exercise for 12 weeks increased their treadmill endurance time by a minute, lost a mean 3.3 pounds, reduced their fat consumption from 35% to 30% of their total caloric intake, and had improved body mass index (BMI), subcutaneous fat, and waist circumference measurements. They had no significant changes in viral load or CD4 cell count. Concluded Dr. Smith, "Exercise is safe; it will increase endurance, and it will help improve body composition." She said further research should be done to determine the relationship between exercise and lipodystrophy and mitochondrial damage to the muscles. Previous research indicates that aerobic exercise in people with HIV-related wasting can actually accelerate weight loss.
Advances in Hepatitis Care
Two recent announcements heralded advances in hepatitis care. In May, the U.S. Food and Drug Administration (FDA) approved a combination vaccine for hepatitis A virus (HAV) and hepatitis B virus (HBV). The combination will be marketed under the name Twinrix. In several studies, the combined vaccine was shown to be as effective as the individual vaccines administered separately; use of the combination reduces the number of injections needed from five to three (given on three separate occasions). HAV causes acute liver inflammation, which later resolves, while HBV resolves in most cases but in some people leads to chronic liver disease and liver damage. HAV vaccination is recommended for travelers to developing countries and those who have household contact with HAV-infected persons. HBV vaccination is recommended for sexually active adults and health-care workers; it is now routinely given to all children in the U.S. Although there is no vaccine for hepatitis C virus (HCV), people with chronic HCV are advised to receive HAV and HBV vaccines.
On the hepatitis C front, new study results show that combination treatment with long-acting pegylated interferon (Pegasys or Peg-Intron) plus ribavirin (Rebetol) is more effective than standard interferon plus ribavirin, which is the current standard of care (Intron-A brand standard interferon and ribavirin are sold as a bundled kit called Rebetron). Michael Fried, M.D., and colleagues from the University of North Carolina at Chapel Hill studied over 1,000 HCV-positive people in 18 countries. People receiving the pegylated interferon combination had a sustained viral response (undetectable HCV viral load six months following 12 months of therapy) rate of 56%, compared with a 45% response rate for those receiving the standard interferon combination. In addition, the side effects of depression and flu-like illness were less frequent in people receiving pegylated interferon. The research was presented at the Digestive Disease Week 2001 conference in Atlanta in May.
Liver Transplants Successful in HIV-Positive People
According to study results presented at the Transplant 2001 conference in Chicago in May, liver transplants can be successfully performed in selected people with HIV. It was previously believed that the immunosuppressive drugs that must be taken following an organ transplant would further damage the immune systems of HIV-positive people. John Fung, M.D., and colleagues from the University of Pittsburgh assessed six HIV-infected people who had had liver transplants since March 1997. The subjects had viral loads ranging from undetectable to over 175,000 copies/mL and CD4 cell counts ranging from 108 to 660 cells/mm3. None had active opportunistic illnesses, and all were on antiretroviral therapy. Two subjects died following transplantation, one from a bacterial infection unrelated to HIV and the other due to liver failure related to chronic organ rejection. The other four did well, with liver function tests returning to normal after starting HAART; because PIs and transplant-related medications can interact, dose reductions were needed in some cases. Said Dr. Fung, "HIV-infected patients can do well after transplantation and they are at no additional risk for opportunistic infection or exacerbating their HIV disease."
Methadone Stimulates HIV Infection in Lab Studies
According to new laboratory studies, methadone can increase the infectivity of certain strains of HIV. Methadone is an oral opiate drug used as maintenance therapy for people addicted to heroin. Wen-Zhe Ho, M.D., of the Children's Hospital of Philadelphia and colleagues exposed human fetal microglia and macrophages (two types of immune cells that are susceptible to HIV infection) to methadone, then tried to infect the cells with HIV. The researchers found that methadone enhanced infection with R5 strains of HIV -- those that use the CCR5 coreceptor -- apparently because methadone upregulates, or increases, CCR5 expression on cell surfaces, as well as inhibiting the production of beta chemokines that decrease infectivity. The researchers also exposed peripheral blood mononuclear cells (PBMCs) from opiate users to methadone in the laboratory, and found that methadone enhanced the activation and replication of the latently infected cells. Dr. Ho and colleagues concluded that physicians should closely monitor the viral load and CD4 cell counts of persons taking methadone. Dr. Ho presented the study results at the PsychoNeuroImmunology Research Society meeting in May in Utrecht, the Netherlands.
Sexual Risk Factors Among IDUs
A study published in the May 5, 2001 issue of the Lancet showed that HIV transmission in injection drug users (IDUs) was "strongly associated" with sexual behavior. It has long been known that sharing needles and other injection equipment can spread HIV through direct blood-to-blood contact, but the recent study suggests that sexual activity plays a major role in the high rates of HIV infection among IDUs. Alex Kral, Ph.D., of the University of California at San Francisco and colleagues administered questionnaires to 1,192 street-recruited San Francisco IDUs. The researchers found that men who have sex with men and inject drugs are almost nine times more likely than heterosexual IDUs to become infected with HIV, and that women IDUs who have traded sex for money are more than five times more likely to contract HIV than other women IDUs. "There has been a tendency for IDU prevention programming to be needle-obsessed, and here in San Francisco that has worked to a certain degree," said Dr. Kral. "Now we need to focus new energy on sexual risk reduction among IDUs, while continuing current programs that address needleborne risks."
In related news, a study presented at the 12th International Conference on Harm Reduction held in April in New Delhi, India, showed that young female IDUs who have sex with other women are more likely to contract HIV than other young female IDUs. The study by Samuel R. Friedman and colleagues of the Institute for AIDS Research in New York City involved 803 women IDUs aged 18-20 in five U.S. cities. Participants were classified as women who have sex with women if they had had sex with a woman in the past six months or self-identified as lesbian or bisexual. Woman-to-woman sex itself is not associated with a high risk of HIV transmission (although there are a few documented cases in the medical literature). However, female IDUs who had sex with women were also more likely to share needles, to trade sex (with men) for money, to be homeless, to have ever been incarcerated, and to have been in a mental health facility. According to Friedman, the researchers believe that "stigmatization and social marginalization" contribute to the higher HIV rates among female IDUs who have sex with women.
Supreme Court Rules Against Medical Marijuana
On May 14, the U.S. Supreme Court ruled 8-0 against an Oakland, CA, cannabis (marijuana) buyers club that provided medicinal marijuana to people with a physician's recommendation. Many people use medical marijuana to relieve AIDS-related wasting and to combat nausea caused by anti-HIV drugs and cancer chemotherapy. The case is the outcome of a 1998 federal injunction against the Oakland Cannabis Buyers Cooperative and five other Northern California cannabis clubs. Overruling the 9th Circuit Court of Appeals, the Supreme Court ruled that a medical necessity defense could not be used by organizations dispensing medical cannabis, although a minority of the justices left open the possibility that such a defense might be used by individual patients. The court said that because it is a Schedule I drug (substances that have a high potential for abuse, have no currently acceptable medical use, and lack any accepted safe use under medical supervision), marijuana by definition has "no currently accepted medical use." Justice Clarence Thomas said it would be up to the legislature, not the courts, to change the drug's scheduling. Representative Barney Frank (D-MA) currently has a bill pending to reduce marijuana from Schedule I to Schedule II (substances that have a high potential for abuse with a severe liability to cause psychic or physical dependence, but have some approved medical use). The court did not rule on the issue of whether federal law unconstitutionally impinges on the right of states to pass medical marijuana laws; for now, state and federal law remain at odds in the eight states that have passed initiatives allowing for medicinal cannabis.
Liz Highleyman is a freelance medical writer and editor based in San Francisco.
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