Important note: Information in this article was accurate in December 1999. The state of the art may have changed since the publication date.
On October 28, the U.S. Food and Drug Administration (FDA) approved once-daily dosing of a new 200 mg formulation of ddI, a nucleoside analog (NRTI) manufactured by Bristol-Myers Squibb. Until now, the standard dose of ddI-which was first approved in October 1991-has been 200 mg (two 100 mg tablets) twice daily. The new ddI tablet will become available in December and is to be used at a dose of 400 mg (two 200 mg tablets) only once per day; all other currently approved NRTIs must be taken at least twice per day. To provide adequate buffering against gastric acid degradation, two tablets of ddI (at any of the prescribed doses) must always be taken together. The FDA will also require Bristol-Myers to emphasize the potential risk of developing pancreatitis (inflammation of the pancreas) in their labeling information. Life-threatening pancreatitis has been observed in both treatment-naive and treatment-experienced persons on ddI therapy.
In late November, the FDA also approved 1,250 mg twice-daily dosing of nelfinavir, a protease inhibitor manufactured by Agouron Pharmaceuticals. Interim results of a pivotal phase III trial had indicated that the standard (750 mg) three-times-daily dose and newer twice-daily dose of nelfinavir (as part of a combination regimen) conferred similar benefits in more than 500 participants. [N. Cheonis]
In late October, researchers from the National Institute of Allergy and Infectious Diseases (NIAID) reported that HIV viral load rises when antiretroviral therapy is discontinued. Some experts had hoped that some people might be able to keep HIV under control if treatment were stopped after viral load was reduced to undetectable levels. The NIAID researchers studied two persons who had no evidence of viral replication, even using sophisticated lymph node culture tests, after prolonged (30-33 months) highly active antiretroviral therapy (HAART) plus interleukin 2 (IL-2).
According to a report published in the October 28, 1999 issue of Nature, the viral load of both persons rebounded within 6-8 weeks after stopping treatment; their viral load returned to undetectable levels when treatment was restarted. The two were part of a study that included 18 persons who had undetectable viral loads on HAART (12 were also receiving IL-2); viral load rebounded in 17 of these people. IL-2 was used in an effort to "flush out" latent virus and render it susceptible to anti-HIV drugs. According to NIAID director Anthony Fauci, MD, "We were hoping that treatment with IL-2 would make it less likely that the virus would rebound. That wasn't the case."
The recent findings add to the evidence that existing drugs are not likely to be able to eradicate HIV from the body, and that the virus can remain in reservoirs even when there is no sign of it in the blood. According to Dr. Fauci, "We need to enhance the immune system response to eradicate the reservoirs." Dr. Fauci characterized the results as "extremely disappointing."
In September, researchers reported that drug-resistant HIV appears to be becoming more common. The study, conducted by Daniel Boden, MD, and colleagues at the Aaron Diamond AIDS Research Center in New York and published in the September 22/29, 1999 issue of the Journal of the American Medical Association (JAMA), looked at 80 men newly infected with HIV. The researchers found that 13 men (about 16%) had HIV strains that were resistant to at least one of the antiretroviral drugs commonly used as part of combination treatment regimens.
Another study, conducted by Susan Little, MD, and colleagues at the University of California at San Diego and published in the same issue of JAMA, found that of 141 newly infected persons examined during the past year, three exhibited a greater than 10-fold reduction in viral sensitivity to at least one drug, and 36 experienced a 2.5-fold to 10-fold reduction in sensitivity. The authors of both studies said their research supported use of resistance testing prior to initiation of therapy. In an editorial in the same issue, Roger Pomerantz, MD, of the Center for Human Virology at Jefferson Medical College in Philadelphia stated that HIV resistance "most likely will accelerate over the next several years," and that "safe sex practices should continue to be stressed to all [HIV positive persons] even those receiving combination antiretroviral therapy."
At the September ICAAC, Abbott Laboratories announced an early access program for ABT-378/r. The new treatment contains Abbott's experimental protease inhibitor ABT-378 plus a small amount of ritonavir (Norvir), which increases the bioavailability of ABT-378. The current supply of the drug is limited, so only up to 350 people will be able to receive it. Eligible persons must have experienced viral rebound on two or more combination regimens that contained an approved protease inhibitor, and either have a CD4 cell count of less than 50 cells/mm3 or have had an opportunistic infection (OI) while taking HAART. A larger supply of the drug is expected to be available by early 2000.
Because changing a single drug in an inadequately suppressive regimen is not recommended, it may be advisable for people who have used all currently approved drugs to wait until other experimental drugs (for example, tenofovir DF or T-20) become available, so that they can start an entirely new combination regimen. Physicians seeking to enroll participants in the study must sign a confidentiality agreement and may enroll only four patients. For information, call 888-711-7193.
On November 1, an FDA advisory panel announced its decision against recommending accelerated approval of Gilead Sciences' adefovir dipivoxil (Preveon, also known as bis-POM PMEA). Adefovir is one of a new class of anti-HIV medications called nucleotide (as opposed to nucleoside) reverse transcriptase inhibitors. It was being developed primarily as a second-line, or salvage, treatment for those who have experienced inadequate HIV suppression with the current antiretroviral drugs. The panel said that the unexpected denial-the first ever for an anti-HIV drug-was due to safety concerns. In a pivotal study of 214 participants who took a 120 mg dose of adefovir, several developed kidney problems and required kidney dialysis. The panel also said that it did not receive sufficient evidence that a 60 mg dose of the drug was safe and effective, in part because a number of participants dropped out of the trial designed to evaluate the lower dose.
The full ramifications of the FDA's decision are not yet known. Approximately 9,000 people who lack other treatment options have received adefovir through an expanded access program. Many advocates feel that with sufficient safeguards, such as monthly monitoring and reporting of renal (kidney) function, the drug arguably might continue to be made available. Adefovir also has displayed significant activity against hepatitis B virus (HBV); greater potency in this context may allow for lower doses of the drug and potentially fewer cases of renal toxicity. Gilead is currently developing a related drug, tenofovir DF (bis-POC PMPA), that appears to be more effective against HIV but causes fewer side effects.
In October, U.S. Biosciences announced it would suspend a phase II trial of its experimental nucleoside analog drug lodenosine after one participant died and others showed signs of possible liver or kidney damage. The trial involved 209 persons in the U.S., U.K., and Brazil; the 176 who were receiving combination regimens containing lodenosine have stopped taking the drug. Favorable preliminary results from the trial had been reported at ICAAC earlier the same month; 55% of participants taking lodenosine as part of a three-drug regimen achieved undetectable viral load levels. A smaller lodenosine study conducted by the National Cancer Institute has also been suspended.
Robert Harrington, MD, from Harborview Medical Center in Seattle and colleagues reported in the October 11, 1999 Archives of Internal Medicine Online that serious drug interactions are possible when combining protease inhibitors with the recreational drugs MDMA (Ecstasy) or gamma-hydroxybutyrate (GHB). Because protease inhibitors are metabolized by the cytochrome P450 enzyme system in the liver, they can interfere with the liver's ability to break down and remove other drugs from the body. The case report involved a single person taking protease inhibitors who experienced prolonged and intensified effects from Ecstasy and GHB. Two years ago, advocates circulated a report of a man in the U.K. who died after mixing ritonavir with a small amount of Ecstasy; on autopsy, the man was revealed to have a much higher blood level of Ecstasy than expected based on the amount he took.
Evidence continues to accumulate suggesting that persons who are experiencing good viral suppression on HAART are less likely to develop OIs (see BETA, January 1999). Paige Williams and colleagues from the Harvard School of Public Health conducted a retrospective study of 842 people with HIV. The researchers found that decreases in HIV RNA viral load were more strongly associated with a reduced risk of OIs than decreases in CD4 cell count. Persons with the highest viral load levels were 3-6 times more likely than those with the lowest viral loads to develop an OI.
Bruno Ledergerber, MD, and colleagues studying the Swiss HIV Cohort reported that the rate of OIs among their study group, which includes most people with HIV in Switzerland, decreased from 157 per 1,000 persons/year in 1992-1994 to 35 per 1,000 persons/year in 1997-1998. Rates of Kaposi's sarcoma (KS) declined dramatically, but there was little change in the rate of non-Hodgkin's lymphoma (NHL). The researchers concluded that "[HIV positive persons] cease to be at risk of KS once immune function has been improved by combination therapy." The results were reported in the July 3, 1999 issue of the British Medical Journal.
In related news, researchers from the Spanish CMV-AIDS Study Group reported in the August 20, 1999 issue of AIDS that the incidence of cytomegalovirus (CMV) retinitis among their study participants was only 5% after a year of taking HAART. NIAID researchers announced in September that in a study of 131 persons taking HAART who discontinued prophylaxis for Mycobacterium avium complex (MAC) for a year, only two developed the disease. Finally, researchers from Denmark presented results in the September 10, 1999 issue of AIDS suggesting that persons taking HAART whose CD4 cell count rises above 200 cells/mm3 can safely discontinue prophylaxis for Pneumocystis carinii pneumonia (PCP). In their study, 219 persons stopped PCP prophylaxis after taking HAART for a median of 18 months; only one person developed the pneumonia.
In early August, researchers reported new data suggesting that the first case of HIV infection in the U.S. occurred in the 1960s. Researchers found antibodies against the virus in frozen serum and tissue samples from a 15-year-old African-American male prostitute who died in St. Louis in 1969. The youth died with extensive lymph node enlargement and KS. The results were presented by Robert Garry, MD, and colleagues from Tulane University Medical Center in New Orleans at the 11th International Congress of Virology in Sydney, Australia. Dr. Garry's team used polymerase chain reaction (PCR) technology to analyze gene sequences from the boy's frozen serum and tissue. Prior to the recent discovery, the earliest known cases of HIV infection in the U.S. dated from the late 1970s.
The researchers noted that the new finding challenges the widely held theory that HIV evolved from the simian immunodeficiency virus (SIV) by crossing the species barrier from monkeys to humans some time in the late 1970s. The finding also suggests that a different, less virulent, and slower-evolving form of HIV may have been present in humans long before it evolved into the strain that has been linked with widespread illness and death since the early 1980s.
In the October 1, 1999 issue of Cell, Peter Kim, MD, and colleagues from the Whitehead Institute for Biomedical Research in Cambridge, MA, reported they had produced a molecule that can block HIV entry into cells in the laboratory; the new finding may eventually lead to development of a new class of antiviral drugs than can prevent HIV from infecting cells. The potential weakness involves gp41, a hook-like surface protein that the virus uses to enter host cells. Dr. Kim's team devised a chemical that disarms gp41, rendering the virus unable to insert itself into a cell.
The same team reported in the April 18, 1997 issue of the same journal that they had produced an image of gp41 showing that the protein contained a cavity or pocket that is briefly revealed as HIV infects cells. According to Dr. Kim, "a small molecule, one small enough to be used as an oral drug, can bind to this pocket and block the virus from entering the cell"; the researchers call the new chemical a "pocket binder." The researchers suggest that the virus may be unable to develop resistance to drugs that block this stage of infection, unlike currently approved drugs that target later stages of HIV replication after it has already entered a host cell. T-20, a drug now in clinical trials, blocks gp41 at a different point, but must be given by injection.
In July, Robert Neurath, MD, and colleagues from the New York Blood Center reported that a polymer used to coat certain enteric medications to make them last longer in the digestive tract can kill HIV, the human herpesvirus, and the bacteria that cause gonorrhea and chlamydia. The research was reported in the July issue of the British journal Biologicals. The chemical, cellulose acetate phthalate, is designed to survive acid environments like the stomach, and break down in more alkaline environments; the polymer was previously thought to be an inert ingredient, and already has a history of safe use in many drugs. The researchers were working on the development of microbicides, chemicals that can be inserted into the vagina or rectum to prevent the transmission of HIV and other sexually transmitted diseases (STDs). A cream containing the chemical has been shown to prevent STD transmission in mice, with no serious side effects.
Dr. Neurath said that his team was trying to avoid using detergents in microbicides, since they can damage the cells of the mucous membranes. Research reported in the August 20, 1999 issue of AIDS showed that nonoxynol-9, a common detergent microbicide ingredient and condom lubricant, may actually increase the risk of HIV and STD transmission. In a study of 20 female South African sex workers conducted by Roxana Rustomjee, MD, of the University of Natal, women using a film containing 72 mg of nonoxynol-9 experienced more clinically detected genital lesions than those using a placebo film; such lesions are associated with enhanced transmission of disease-causing microorganisms and increased shedding of HIV.
Researchers from the U.S. and Uganda reported in the September 4, 1999 issue of the Lancet that a single dose of the non-nucleoside analog (NNRTI) nevirapine is effective in reducing perinatal (mother-to-infant) HIV transmission. In a study of 618 HIV-infected pregnant Ugandan women, 310 were given a single 200 mg oral dose of nevirapine at the onset of labor and their infants were given a single liquid dose of the drug; 308 other women were given AZT (Retrovir) every three hours during delivery and their newborns were given the same drug twice daily for a week. Four months after birth, 13% of the infants in the nevirapine group were infected with HIV, compared to 25% of the infants in the AZT group.
Nevirapine appears to have a long-lasting effect; moreover, the single dose is excreted in the colostrum (milk secreted by the mother shortly after birth), which may reduce transmission via breast-feeding. Researchers will continue to monitor the infants for possible long-term side effects. The nevirapine regimen is considerably simpler and more practical to implement widely, and is also less expensive-nevirapine costs about $4 per dose compared to about $250 for the short AZT regimen.
Brooks Jackson, MD, of the Johns Hopkins University School of Medicine in Baltimore, said that "in terms of its ability to save lives, this single-dose regimen potentially will save more lives than any other HIV intervention to date in developing countries." Dr. Fauci of NIAID estimated that the new regimen potentially could prevent 300,000-400,000 newborns from becoming infected each year worldwide. The nevirapine regimen is currently being tested in the U.S. and Europe, where a longer AZT regimen is standard therapy to prevent perinatal transmission.
In late August, the Centers for Disease Control and Prevention (CDC) sponsored its first National HIV Prevention Conference in Atlanta. Among the most widely reported news from the conference was new CDC data showing that the decline in the number of U.S. deaths due to AIDS is no longer as steep as it has been in recent years. New epidemiological data show that the number of AIDS-related deaths decreased by 20% from 1997 to 1998, nearly half the 42% decline seen from 1996 to 1997. There were 17,047 U.S. deaths due to AIDS in 1998, compared to 21,222 in 1997 and 36,792 in 1996. In San Francisco, there were 304 deaths due to AIDS in 1998, compared to 360 in 1997 and 1,118 in 1996.
The decline in AIDS deaths in the mid-1990s has been attributed in part to the widespread use of combination anti-HIV therapy including protease inhibitors. The reduced decline in the death rate suggests that the drugs may not be as effective as hoped over long periods for many people with HIV disease; resistance, side effects, and adherence problems all impact the drugs' effectiveness. According to Helene Gayle, MD, director of the CDC's National Center for HIV, STD, and Tuberculosis (TB) Prevention, "For the time being, it appears that much of the benefit of these new therapies has been realized." Steven Fisher of AIDS Action in Washington, DC, commented that "AIDS drugs don't work for everyone and they aren't a cure for anyone."
Researchers at the conference also reported on HIV/AIDS rates among African-Americans. In 1998, the number of AIDS deaths and the rate of new AIDS cases as a proportion of population was ten times higher among African-Americans than among whites. U.S. Surgeon General David Satcher, MD, reported that relative proportions of AIDS-related deaths in 1997-1998 were 49% among African-Americans (who make up 13% of the U.S. population), 32% among whites, and 18% among Latinos. Forty-five percent of new AIDS cases occurred in African-Americans, 22% in Latinos, and 23% in women (compared to 25%, 14%, and 8%, respectively, in the mid-1980s). Public health officials estimated that the overall U.S. rate of new HIV infections is holding steady at approximately 40,000 per year. According to Dr. Gayle, "Despite a growing complacency about the need for HIV prevention, HIV remains a serious disease that is still very much with us, and there is a greater need for HIV prevention today more than ever."
In October, the CDC released its annual report entitled Births and Deaths: Preliminary Data for 1998, which examines U.S. deaths from all causes. According to the report, AIDS accounted for 4.6 deaths per 100,000 people last year. For the first time since 1987, AIDS was not among the top 15 causes of death in the U.S. population as a whole, although it remains the leading cause of death for African-American men aged 25-44, the third leading cause for African-American women in the same age group, and the fifth leading cause for all people aged 25-44.
Researchers at the Atlanta conference also presented results from the National Commission on Correctional Health Care that indicated that AIDS rates are high in U.S. prisons. Approximately 8,900 incarcerated persons had AIDS in 1997, five times higher than the rate in the nonincarcerated population. Rates of HIV infection are estimated to be up to ten times higher among prisoners than among the population as a whole. Recently released prisoners may account for about 17% of U.S. AIDS cases, and they also have high rates of hepatitis C, TB, and STDs. Study author Theodore Hammett attributed the figures to high rates of injection drug use before entering prison, rather than a high rate of transmission within prisons.
At the Atlanta conference, the CDC unveiled a new testing strategy it hopes will give a more complete picture of the HIV epidemic and will allow for better targeting of prevention initiatives to the populations most at risk. The Serologic Testing Algorithm for Recent HIV Seroconversions (STAHRS) strategy uses the recently developed detuned ELISA HIV antibody test. While the standard ELISA typically detects HIV antibodies in the blood after 3-4 weeks, the less sensitive detuned version can detect infection only after about 120 days. Thus, a person who tests HIV positive using the standard ELISA but HIV negative using the detuned ELISA most likely was infected within the past four months. [Ed. note: In some cases, antibodies may take longer than 3-4 weeks to develop and therefore to be detected, which is why the official "window period"-the time from initial infection to seroconversion-is six months.]
The standard ELISA gives information about HIV prevalence (total number of infections) only; the detuned assay also provides information about HIV incidence (new infections). In San Francisco, public HIV test sites began using the detuned ELISA in September 1998. According to Willi McFarland of the San Francisco Department of Public Health, approximately 20% of those who tested HIV positive since the new assay has been in use have been detected during the first four months of infection. Public health officials hope the test can be used to better track the transmission of HIV, since individuals likely will be better able to remember their sexual partners over a shorter period of time. Currently, contact tracing and partner notification are not widely done for HIV due to strong confidentiality regulations, although they are standard practice for STDs such as gonorrhea and syphilis.
Liz Highleyman is a freelance writer based in San Francisco and a former member of the BETA editorial staff.
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