In early February the National Institutes of Health (NIH) updated its guidelines for treating HIV disease. The new guidelines shift emphasis away from the "hit hard, hit early" approach used since 1996, which advocated the use of highly active antiretroviral therapy (HAART) in persons with acute (early) HIV infection, those with symptomatic HIV infection, and asymptomatic persons with fewer than 500 CD4 cells/mm3 and a viral load greater than 10,000 copies/mL. The NIH is now recommending that asymptomatic persons take HAART only if they have fewer than 350 CD4 cells/mm3 and more than 30,000 copies/mL of HIV RNA by bDNA test or 55,000 copies/mL by PCR test.
Side effects and resistance problems associated with anti-HIV medications are among the reasons cited for the government's revision of its official guidelines for physicians. Recent studies have shown that HAART would have to be taken by a person infected with HIV for at least 70 years before the virus is eradicated from the body. Many researchers and AIDS advocates have noted that prolonged use of anti-HIV drugs may diminish the effectiveness of the medications and lead to serious adverse effects, such as liver dysfunction, kidney failure, and sharp increases in blood cholesterol and triglyceride levels. They therefore suggest that only those asymptomatic persons with critically depleted immune systems should start antiretroviral therapy. The guidelines continue to recommend antiretroviral therapy in persons with HIV-related symptoms (regardless of CD4 cell count and viral load) as well as in those with acute HIV infection. Experts believe that beginning a HAART regimen during early HIV infection may lead to more rapid and robust immune reconstitution. The revised guidelines can be viewed at www.hivatis.org. [N. Cheonis]
In October the Food and Drug Administration (FDA) approved a new formulation of ddI, to be marketed as Videx EC. The new enteric-coated capsule is associated with fewer adverse side effects such as diarrhea and gastrointestinal upset. It reportedly tastes less unpleasant and is easier to swallow than the original formulation. Unlike the original tablet, the new capsule does not have to be chewed or dissolved in water. An FDA spokesperson said that the new formulation may be less likely to interact with other drugs because it does not contain the buffering agent contained in the original pill. Videx EC is currently one of only two approved once-daily antiretroviral drugs.
In November the FDA granted accelerated approval to Glaxo Wellcome's new triple-combination antiretroviral drug Trizivir, a combination of 3TC (Epivir), AZT (Retrovir), and abacavir (Ziagen) in a single tablet. The European Commission followed with approval in January. Trizivir may be used alone or in combination regimens with other drugs besides 3TC, AZT, abacavir, or Combivir (Glaxo's two-in-one 3TC/AZT pill). The recommended dose is one pill twice daily; there are no dietary restrictions. Possible adverse side effects of Trizivir include lactic acidosis, liver damage, anemia (low red blood cell count), neutropenia (low white blood cell count), myopathy (muscle damage), nausea, and fatigue. In addition, symptoms such as fever, skin rash, and gastrointestinal symptoms may indicate a potentially fatal hypersensitivity reaction to abacavir, one of Trizivir's component drugs; such a reaction occurs in about 5% of people taking abacavir. Trizivir is not recommended for children or adults weighing less that 90 pounds. Glaxo hopes that the new formulation will improve adherence by reducing the number of pills people with HIV must take. Approval was based on limited studies conducted over a relatively short period of time. The projected price of the new drug is about $26 per day.
On January 4 the Centers for Disease Control and Prevention (CDC) cautioned that the non-nucleoside reverse transcriptase inhibitor (NNRTI) drug nevirapine should not be used for postexposure prophylaxis (PEP) following an accidental needlestick injury or unprotected sex. Between March 1997 and September 2000, the CDC and the FDA identified 22 cases of severe -- in some cases life-threatening -- liver, skin, and muscle damage associated with use of nevirapine for PEP. The adverse effects occurred on average two weeks after starting the drug. Nevirapine is not FDA-approved for PEP; it is still recommended for use in combination anti-HIV regimens for HIV positive people and to prevent transmission from pregnant women to their infants. No serious adverse effects have been seen in three large studies of nevirapine to prevent perinatal transmission, and both the CDC and the United Nations Programme on HIV/AIDS (UNAIDS) maintain that the drug's benefits for this indication outweigh its risks. However, the chances of transmission due to needlesticks is much lower, and thus may not warrant the same risks. The CDC currently recommends a four-week course of PEP with drugs other than nevirapine following accidental HIV exposure.
Also in early January, Bristol-Myers Squibb warned against the use of two of its nucleoside analog drugs, d4T and ddI, in pregnant women with HIV. The caution followed the deaths of three pregnant women taking antiretroviral regimens that included the drugs. The women died of lactic acidosis, a condition in which lactic acid (lactate) accumulates in the blood, leading to a dangerously low pH level that may damage organs such as the liver or pancreas. In postmarketing studies, several cases of nonfatal lactic acidosis have also been seen in pregnant women taking combination regimens containing d4T plus ddI, d4T plus 3TC, or ddI alone. The company recommended that the drugs should only be used by pregnant women in cases in which the "potential benefit clearly outweighs the potential risk," for example, in women who have exhausted other treatment options. Pregnant women who use d4T and/or ddI should be closely monitored for signs of lactic acidosis and liver toxicity. The FDA will require a stronger "black box" warning on the drugs' packaging. Labels for the drugs had previously noted that lactic acidosis was a possible adverse side effect, but the recent results suggest that the risk is greater in pregnant women.
On January 24 the federal government released its updated Recommendations for 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 guidelines, prepared by a U.S. Public Health Service (USPHS) task force, set forth the latest standard of care for pregnant women and thinking about how best to prevent mother-to-child (perinatal) transmission of HIV, which feature a few major changes from the previous version. Among these are an expanded section on antiviral drug side effects in pregnant women, including mitochondrial toxicity and lactic acidosis related to nucleoside analog drugs (see the "d4T and ddI during Pregnancy" brief). There is also a new section on preconception counseling and care for HIV positive women. Specific treatment recommendations include: use of AZT (Retrovir) after the first trimester for all HIV positive pregnant women who have not previously received antiretroviral therapy, use of AZT within 6 to 12 hours after birth for HIV positive infants, and use of resistance testing during acute (early) HIV infection or in the case of treatment failure. The updated guidelines are available on the HIV/AIDS Treatment Information Service Web site at www.hivatis.org.
In December researchers at the University of Colorado Health Sciences Center reported the discovery of a blood protein that can prevent HIV from spreading. The protein -- known as alpha-1 antitrypsin, or AAT -- is a naturally occurring protein in the blood. In test tube studies, it blocked the production and release of new HIV particles from infected cells and reduced the infection of healthy cells by nearly 80%. According to lead investigator Leland Shapiro, MD, "I think this could be a significant new way of approaching HIV with a great potential for applications in therapy." AAT is currently synthesized through genetic engineering and is used to treat cystic fibrosis. Researchers hope that a synthetic version could be developed that would have the same effect as the natural protein. Shapiro said that more laboratory and animal studies are needed before human trials can begin, a process which could take five years. The study results were published in the January issue of the Federation of the American Societies of Experimental Biology Journal.
In related news, scientists recently published research about proteasomes, a group of proteins that normally perform a "housekeeping" function by destroying old and unneeded proteins. HIV uses proteasomes to assemble and release new viral particles; drugs that block proteasomes could thus inhibit the spread of the virus. Ulrich Schubert, PhD, of the National Institute of Allergy and Infectious Diseases (NIAID), lead author of one of the research papers, said that in test tube studies, inhibiting proteasomes reduced the replication and spread of HIV by 98%. However, coauthor Jonathan Yewdell, MD, PhD, cautioned that "it is possible that [proteasomes] may not have any effect [against HIV] at all." In addition, because proteasomes are essential to the normal activities of healthy cells, any therapy that interferes with their action could "affect every cell in the body," said Yewdell. In addition, two research teams -- Akash Patnaik, MD, PhD, and colleagues from Pennsylvania State University, and Bettina Strack, PhD, and colleagues from the Dana-Farber Cancer Institute, Harvard Medical School, and the University of Padua in Italy -- reported on a molecule called ubiquitin (a type of proteasome) that HIV uses to complete the assembly and subsequent "budding" of new viral particles from an infected cell. All three papers were published in the November 21 issue of the Proceedings of the National Academy of Sciences.
Two studies published in October related to levels of sexually transmitted organisms in genital fluids. The first, by Ann Anderson Kiessling, PhD, and colleagues from Beth Israel Deaconess Medical Center in Boston, showed that HIV viral load levels in semen had little relation to HIV levels in the blood. The researchers measured HIV levels in the semen and blood of twelve men with HIV, all but two of whom were taking antiretroviral therapy. Some men who had undetectable blood viral load levels had detectable HIV in their semen, leading the researchers to conclude that semen and blood are differently affected by anti-HIV therapy. Anderson Kiessling's findings were reported at the annual meeting of the American Society for Reproductive Medicine.
The second study, conducted by Sara Mostad and colleagues at the University of Washington at Seattle and reported in the October issue of the American Journal of Obstetrics and Gynecology, showed that levels of cytomegalovirus (CMV) and herpes simplex virus (HSV) were higher than expected in 450 samples collected daily for one month from 17 women coinfected with HIV, HSV, and CMV. Polymerase chain reaction (PCR) tests revealed detectable levels of HSV at least once in samples from 71% of the women and in 10% of the total 450 samples; 52% of the 450 samples showed evidence of CMV. Levels of HSV shedding were higher in women with lower CD4 cell counts (below 200 cells/mm3), while CMV shedding was significantly higher during the luteal phase of the menstrual cycle. Asymptomatic shedding of CMV and HSV is known to transmit these infections, and may also be implicated in mother-to-child transmission during birth. The results of both studies support safer sex precautions regardless of the presence of symptoms or antiviral treatment.
According to CDC researchers, the influenza vaccine does not lead to accelerated HIV disease progression. On the contrary, the records review conducted by Patrick Sullivan, DVM, PhD, and colleagues showed a slight decrease in progression to AIDS-defining opportunistic infections (OIs) among HIV positive persons who received the flu vaccine. The review included records from over 25,000 participants in the Adult and Adolescent Spectrum of HIV Disease Surveillance Project collected between 1990 and 1999 at 113 clinics in ten U.S. cities. Forty-two percent of the subjects had received a flu vaccine. No changes in CD4 cell counts or HIV RNA viral load were seen in vaccinated compared to unvaccinated subjects. Some previous studies have shown CD4 cell count decreases and/or viral load increases following flu vaccination. The larger sample size and longer follow-up time of this study suggest that there is no increased progression risk associated with flu vaccination of people with HIV. According to the researchers, "Physicians should not withhold influenza vaccine from HIV-infected persons because of concerns about long-term detrimental effects of increased viral replication." The study results were published in the December 1 issue of AIDS.
Researchers at the Academic Medical Center in Amsterdam reported in the December 22 edition of AIDS that HIV positive people with chronic hepatitis B (HBV) and hepatitis C (HCV) infection who begin taking a PI-based HAART regimen appear to be 2.5 to 3 times more likely to experience serious elevations in liver enzyme levels (hepatotoxicity) than are HIV positive people without hepatitis. In their study of 394 HIV positive subjects, Joep Lange, MD, and his Dutch colleagues defined elevated liver enzyme levels as ALT (alanine aminotransferase) or AST (aspartate aminotransferase) plasma concentrations no less than five times the upper limit of normal values, and absolute enzyme level increases of at least 100 U/L (units/liter). Although hepatotoxicity is a serious side effect, liver enzyme levels improved in the study subjects whether or not treatment with PIs was discontinued. The researchers therefore recommend that HAART not be stopped to reverse the liver enzyme abnormalities seen in persons coinfected with HIV and hepatitis. [N. Cheonis]
According to a study reported in October, HIV positive people with tuberculosis are more likely to experience TB relapses than are HIV negative people. However, people with HIV were not more likely to relapse if they took the drug isoniazid (INH). The study was conducted in Port-au-Prince, Haiti, by Daniel Fitzgerald and colleagues from Cornell University Medical College and published in the October 28 issue of the Lancet. After receiving successful six-month treatment for active TB, the 142 HIV positive and 91 HIV negative participants received either isoniazid or a placebo for one year. HIV positive participants were over ten times more likely to experience a TB recurrence than HIV negative participants. There were 7.8 recurrences of active TB per 100 HIV positive persons per year who were not taking isoniazid, compared to 1.4 relapses per 100 HIV positive persons per year who took the drug; HIV negative persons experienced just 0.4 recurrences per 100 persons per year. Among people with HIV, isoniazid reduced the TB recurrence rate from 13.4 to 2.9 cases per 100 person-years. The researchers concluded that long-term secondary prophylaxis with isoniazid could help prevent TB relapse among people with HIV.
In a related study published in the same issue, E. Francis Bowen and colleagues from St. George's Hospital in London studied blood samples from people with TB at three London chest clinics. The researchers found that over 11% of 202 persons with TB were also HIV positive, nearly double the rate found in previous surveys. The authors suggested that all persons diagnosed with TB should be routinely tested for HIV.
Finally, researchers from Case Western Reserve University in Cleveland reported in the August 15 issue of the Journal of Acquired Immune Deficiency Syndromes that coinfection with TB is associated with an increase in the diversity of HIV "quasispecies," or variants; increased diversity correlates with HIV disease progression. Eric Arts and colleagues examined samples from 16 HIV-infected persons, seven of whom also had active TB. They found that the coinfected samples showed more genetic variation in the HIV env (envelope) gene and a higher rate of mutations. According to Arts, "An increase in HIV-1 heterogeneity [variation] with the advent of TB could have a profound effect on disease progression," and thus, "earlier diagnosis and treatment of TB in HIV-1-infected individuals may abrogate long-term effects on HIV-1 disease progression."
Research published in the October issue of the journal Blood showed that rates of AIDS-related lymphoma (cancer of the lymphoid tissue) have not declined despite the widespread use of HAART in the developed world. Mark Bower, MD, PhD, and colleagues from Chelsea and Westminster Hospital in London studied data from 7,840 people with HIV. While rates of other OIs decreased, rates of lymphoma remained steady. Non-Hodgkin's lymphoma rates ranged from 3% to 7%, the same as before HAART was widely used.
A related study, published in the December issue of the same journal, showed that HAART has also not improved the survival rates of people with HIV newly infected with lymphoma. Alexandra Levine, MD, and colleagues from the University of Southern California (USC) in Los Angeles looked at data from 369 cases of AIDS-related lymphoma and population-based data from Los Angeles county collected from 1982 to 1998. Although rates of small, non-cleaved lymphoma (or SNCL, an aggressive B-cell lymphoma that occurs more often in children) fell, rates of diffuse large-cell lymphoma (or LCL, one of the most common types of aggressive lymphoma) increased during the study period. The researchers also found that the median CD4 cell count at the time of lymphoma diagnosis had decreased significantly during this time, suggesting, according to the authors, that since the advent of HAART, "these patients may simply have lived long enough to eventually develop lymphoma as a long-term complication of HIV infection." Although HAART was not shown to significantly decrease the median survival rate, the data did suggest a possible improvement in survival rates in the later years of the study, indicating that indeed "HAART may have a substantial beneficial effect on the outcome of patients receiving chemotherapy for [lymphoma], as has been suggested in other studies."
Research published in the November 9 issue of the New England Journal of Medicine showed that human herpesvirus type 8 (HHV-8), which is associated with Kaposi's sarcoma (KS), is present in saliva and may be transmitted through deep kissing. KS is a type of cancer that affects people with weakened immune systems; it was commonly seen in people with AIDS in the early years of the epidemic. Several studies have shown that KS is more common in the U.S. among men who have sex with men (MSM) than among other HIV-infected populations such as women and injection drug users. HHV-8 was previously believed to be sexually transmitted. However, John Pauk, MD, MPH, and colleagues at the University of Washington and the Fred Hutchinson Cancer Research Center, who studied 880 samples from 27 HHV-8 positive MSM who had not developed symptoms of KS, found evidence of HHV-8 in 30% of saliva and mouth swab samples compared to only 1% of anal and genital samples. Positive HHV-8 samples were associated with more male sex partners, deep kissing with an HHV-8 infected partner, sex with a partner with KS, use of nitrite inhalants ("poppers"), and a history of hepatitis B, gonorrhea, genital warts, or herpes simplex virus type 2 infection. According to the researchers, MSM who engaged in deep kissing "appeared to be at substantially higher risk of catching [HHV-8]." According to Ronald Valdiserri of the CDC, while the finding "definitely has public health implications for people infected with HIV," there are not enough data to recommend that HIV positive people avoid deep kissing.
Liz Highleyman is a freelance medical writer.
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