The tragic events of September 11, 2001 have had an effect on the world of HIV/AIDS. AIDS service organizations and other nonprofit groups are feeling financial pressure due to the weakening U.S. economy and because charitable giving has been redirected to victims of the terrorist attacks. The October wave of anthrax exposures drew attention to the poor state of the nation's public health infrastructure, and the high price of Cipro (ciprofloxacin, the most well known antibiotic for the life-threatening disease) has brought renewed attention to drug prices, patents, and generic drugs for HIV/AIDS. In the immediate aftermath of September 11, as travel was thrown into disarray, the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), scheduled for September 22-25 in Chicago, was postponed until December 16-19. BETA will feature news from this conference in the Spring 2002 issue.
2001 USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected With Human Immunodeficiency Virus (PDF), released November 28, are available online at www.hivatis.org.
www.aids2001ias.org (the site also includes abstracts and videos of lectures).
At the IAS conference, David Katzenstein, M.D., presented an interesting report about non-nucleoside reverse transcriptase inhibitor (NNRTI) hypersusceptibility, or increased susceptibility, a condition in which HIV is unusually sensitive to a drug. Dr. Katzenstein and colleagues from Stanford University in Palo Alto, CA, found that HIV that had developed resistance to nucleoside reverse transcriptase inhibitor (NRTI) drugs (with mutations at codons 41, 67, and 215) was more susceptible to NNRTIs. The researchers detected NNRTI hypersusceptibility in 37% of 130 blood samples taken from participants in AIDS Clinical Trials Group (ACTG) study 364. The same research team reported in the June 15, 2001 issue of AIDS that NNRTI hypersusceptibility was associated with improved viral suppression in persons taking efavirenz (Sustiva), which might help explain why the efavirenz arm did considerably better than the nelfinavir arm in this study.
In the October 2001 issue of the Journal of Medical Virology, Helen Devereux and colleagues from the Royal Free and University College Medical School in London reported that wild-type (nonmutated) HIV appears to be more "fit" (able to reproduce) than HIV with drug-resistance mutations. The researchers studied 11 HIV-positive men who had developed resistance to several antiretroviral drugs and had subsequently stopped treatment. The researchers found that certain protease and reverse transcriptase gene mutations were associated with reduced viral fitness, allowing more fit wild-type virus to return when treatment was stopped. They concluded that "the resistant virus population may be reduced to low enough levels to reintroduce [a previously used] drug as part of a new potent regimen."
In the June 15, 2001 issue of the Journal of Infectious Diseases, Susan Eshleman, M.D., and colleagues reported on the largest study to date of antiretroviral drug resistance in children. Dr. Eshleman's team studied 181 HIV-positive children and adolescents aged four months to 17 years as part of Pediatric ACTG (PACTG) study 377. The children received various combinations of d4T (Zerit), 3TC (Epivir), nevirapine (Viramune), nelfinavir (Viracept), and ritonavir (Norvir). The researchers analyzed the presence of drug resistance mutations before treatment and how resistance mutations affected virological response to therapy. They found a "high rate of primary mutations" associated with resistance to AZT, ddI (Videx), and ddC (Hivid); resistance mutations to nelfinavir and ritonavir were detected at "unexpectedly low rates." Resistance to nevirapine and 3TC were "detected frequently" in children who had experienced virological failure. Nevirapine resistance was more common among children receiving three-drug as compared with four-drug regimens. According to the researchers, "Our findings demonstrate that genotypic resistance is frequent in children receiving highly active regimens with less than complete viral suppression."
Researchers from the University of California (UC) have predicted that by 2005 the prevalence of drug-resistant strains of HIV in San Francisco will be 42%. The researchers made their prediction using a mathematical model to extrapolate the development of drug resistance since 1997; the resistance rate was estimated at 29% in 2000. However, transmission of drug-resistant strains is much lower than acquired resistance; the researchers predict that resistant strains will account for 16% of new HIV infections by 2005 (compared with 8% in 2000). "The good news is that transmission of drug-resistant HIV will not become a major public health problem," said researcher Sally Blower, Ph.D., of UC Los Angeles (UCLA). According to James Kahn, M.D., M.P.H., of UC San Francisco (UCSF), "You really need a skilled HIV specialist to prescribe the medications and closely monitor the patient's adherence and response to treatment" in order to avoid the development of resistance. In addition, the researchers recommend delaying treatment as long as possible, developing more effective therapies, establishing specialty centers for state-of-the-art HIV care, and reducing the amount of time a person uses ineffective treatment. The findings appeared in the September 2001 issue of Nature Medicine.
Finally, Visible Genetics, Inc., announced in late September that the U.S. Food and Drug Administration (FDA) had approved its TruGene genotypic resistance test, the first such test to receive approval. Physicians can send blood samples to one of 130 laboratories that have technicians trained to use the computerized test to determine if a person's HIV strain has any of the more than 70 known resistance mutations. The test, which costs $300-$500, is said to be 98% accurate. FDA officials called the test an important tool for helping physicians determine which drugs to choose when tailoring an HIV treatment regimen.
Because clinical trials of tenofovir were conducted in previously treated persons with a median viral load of less than 5,000 copies/mL, members of the FDA's Antiviral Drugs Advisory Committee debated whether the drug should be labeled for only treatment-experienced persons, or should also include those who are beginning their first anti-HIV regimen. The panel voted 9-7 to limit the indication to those previously treated. However, the FDA -- which typically follows its committee's recommendations -- instead decided to approve tenofovir for both treatment-experienced individuals and those being treated for the first time. Clinical studies of tenofovir in treatment-naive persons are ongoing.
Immune Response officials said results of a study being conducted in Spain appear promising in a subset of subjects with "stronger immune systems," but conceded that Remune "wasn't meeting the study's main goal of reducing levels of HIV in the blood." According to Kim Simon of Pfizer, "Our decision was based on review of the data from several clinical trials." Immune Response would like to continue Remune research, but may not be able to do so without the financial backing of a larger company.
The unbundling allows ribavirin to be used with other brands and types of interferon -- including pegylated interferon, a newly approved, extended-release form of interferon that studies suggest is more effective than standard interferon. Pegylated interferon is typically injected once weekly, compared with three times weekly for standard interferon. In August the FDA approved the combination of ribavirin plus Schering-Plough's Peg-Intron brand of pegylated interferon.
Activists had criticized the Rebetron bundling because it did not allow for flexible dosing or for the use of ribavirin with other brands or types of interferon. While pleased that ribavirin may now be purchased separately, they remain critical of the high cost of treatment. According to the Hepatitis C Action and Advocacy Coalition (HAAC), the average wholesale price for ribavirin ranges from $1,102 to $1,650 per month, depending on the dose -- a 52% increase over the price of bundled Rebetron (i.e., at the higher dose, ribavirin alone costs more than the bundled kit). HAAC says that treatment with ribavirin plus Peg-Intron could cost as much as $25,000 per year. Ribavirin remains available from compounding pharmacies for about one-sixth of Schering-Plough's price.
Overall, 47% of participants experienced adverse clinical events and 27% had abnormal laboratory results that were considered "probably" or "certainly" associated with anti-HIV therapy. Of these, 9% of the clinical events and 16% of the abnormal lab results were rated as serious or severe. Breaking this down by type of regimen, the researchers found that single PI and protease-sparing regimens were associated with a similar risk of adverse events. Participants taking protease-sparing regimens had a higher rate of vomiting, mood disorders, and sleep disturbances, but a lower rate of diarrhea. Participants taking dual-protease regimens had a higher rate of diarrhea, and were more likely to have increased blood levels of cholesterol, triglycerides, and alkaline phosphatase (an enzyme found in various body fluids and tissues; high levels are associated with liver damage). Those taking three-class regimens were also more likely to have diarrhea, as well as increased levels of cholesterol, triglycerides, alkaline phosphatase, and lactate (the salt form of lactic acid, a byproduct of carbohydrate metabolism).
The researchers concluded that "various antiretroviral treatment regimens have comparable efficacy in controlling HIV-1 infection, therefore toxic effects as well as the pill number, pill size, cost, previous medication history, or drug interactions will drive the choice of treatment."
At the July 2001 meeting of the International Association of Physicians in AIDS Care in Chicago, Lawrence Kingsley, Dr.P.H., of the University of Pittsburgh suggested a new definition for HIV-associated lipodystrophy syndrome (HIV-LS). The three-part description includes:
According to Dr. Kingsley, "Because there has been no formal definition of HIV-associated lipodystrophy syndrome up to this point, the prevalence of reported cases of this condition have varied widely -- from less than 10% of HIV-infected persons to more than 80%." He proposed that the new description may lead to more consistent guidelines for diagnosing the syndrome.
At the IAS conference, Massimo Galli, M.D., and colleagues from Milan, Italy, looked at how body shape changes differ between men and women with HIV. The study included 2,258 participants, 30% of whom were women. The researchers found that fat accumulation alone and combined fat accumulation and loss were significantly more common in women than in men; fat loss alone was more common in men, but not significantly so. They reported that gender was a stronger predictor of body shape alterations than age, viral load, or treatment duration. In his presentation, however, Dr. Cooper suggested that because women typically start with higher body fat levels, fat gain is more easily noticed in women, while fat loss is more apparent in men, and thus gender may not truly affect how often these manifestations occur.
Research published in the July/August 2001 issue of HIV Clinical Trials lends more weight to a multifactorial explanation for lipodystrophy. Faroudy Boufassa, M.D., and colleagues studied 685 HIV-positive men and women receiving outpatient antiretroviral treatment at six Paris hospitals during the first half of 1999. Lipodystrophy was diagnosed in 59% of the participants, 64% of whom were receiving regimens that included a PI and 49% of whom had never taken a PI. In a multivariate analysis, the researchers found that older age, lower HIV viral load, longer treatment duration, and regimens that included PIs or d4T all independently predicted lipodystrophy. According to a study by Stephen Arpadi, M.D., and colleagues from the Columbia University College of Physicians and Surgeons, published in the May 1, 2001 issue of the Journal of Acquired Immune Deficiency Syndromes (JAIDS), use of PIs and d4T were also associated with lipodystrophy in prepubertal children, although children with lipodystrophy had higher rather than lower HIV viral loads. Also, Michel Duong, M.D., from Hôpital du Bocage in Dijon, France, reported in the July 1, 2001 issue JAIDS that coinfection with HIV and HCV is associated with higher rates of body fat redistribution, elevated blood lipids, and insulin resistance.
Colleen Hadigan, M.D., of Massachusetts General Hospital in Boston and colleagues reported in the September 1, 2001 issue of Clinical Infectious Diseases that alcohol, fat, and fiber in the diet may affect abnormal body fat distribution. The researchers studied 62 men and 23 women with HIV who had body fat redistribution, measuring levels of blood glucose, insulin, and lipids. In a multivariate analysis, age, duration of PI use, and higher polyunsaturated fat intake were associated with more insulin resistance. Higher fiber intake was associated with less insulin resistance. Higher alcohol consumption was associated with elevated levels of low-density lipoprotein ("bad") cholesterol. Dr. Hadigan and colleagues recommended more research to determine whether dietary modification could reduce the risk of insulin resistance and other manifestations of lipodystrophy syndrome in people with HIV.
Finally, in July 2001 the FDA sent a letter to pharmaceutical companies requiring them to include information about lipodystrophy syndrome in their package inserts for all antiretroviral drugs. Previously, such information was required only for PIs. According to the letter, "Based on publications in the literature, conference abstracts, and postmarketing reports, it is difficult to determine if fat redistribution is related to any particular antiretroviral drug or drug class. Therefore, the Division of Antiviral Drug Products feels that all approved antiretrovirals should include information on fat redistribution in their package and patient package inserts."
In the first study, Jinhua Xiang, M.D., and colleagues from the Iowa City Veterans Affairs Medical Center and the University of Iowa College of Medicine tested 362 HIV-positive persons for GBV-C between 1998 and 2000; 144 (39%) had detectable GBV-C in their blood. During an average of four years of follow-up -- and controlling for other factors such as baseline CD4 cell count, age, race, sex, mode of HIV transmission, and antiretroviral treatment -- 41 (28%) coinfected persons died, compared with 123 (56%) of those without GBV-C. In laboratory tests, HIV replication appeared to be slower in cell cultures that were simultaneously infected with GBV-C; after six days, HIV replication was inhibited by nearly 50% in the coinfected cells. In addition, the subsequent introduction of GBV-C inhibited HIV replication by 58% after six days in cell cultures that were infected with HIV 24 hours earlier. However, the presence of GBV-C in cell cultures did not prevent HIV infection of cells.
In the second study, Hans Tillmann, M.D., and colleagues from the Medizinische Hochschule in Hannover, Germany, tested 197 HIV-positive persons for GBV-C in 1993 and 1994; 33 (16%) had detectable GBV-C RNA (genetic material), while 112 (56%) had GBV-C antibodies. The researchers found that the subjects with detectable GBV-C RNA survived "significantly longer" than those with only GBV-C antibodies and those not exposed to GBV-C, while the GBV-C antibody positive group lived longer than the unexposed group. Dr. Tillmann and colleagues attributed the survival difference to a longer time to progression to AIDS in those with GBV-C antibodies or detectable GBV-C viral load. Persons with higher GBV-C viral loads tended to have lower HIV viral loads, but no correlation was found between GBV-C and CD4 cell counts. The researchers hope that "identification of mechanisms by which GBV-C inhibits HIV replication might lead to the development of new therapeutic approaches for HIV infection." Dr. Tillmann also suggested that physicians should test HIVHCV coinfected persons for GBV-C, since interferon treatment for HCV could potentially eliminate GBV-C as well.
In an editorial in the same issue, Valentina Stosor, M.D., and Steven Wolinsky, M.D., of Northwestern University Medical School in Chicago emphasized that "any suggestion that the intentional infection of persons with GBV-C be explored as a therapeutic approach for HIV infection is premature."
CDC researchers reported that the dramatic decline in AIDS cases and deaths that has been seen over the past several years appears to have reached a plateau. After falling in the mid-1990s, the quarterly number of AIDS deaths remained stable between mid-1998 and mid-2000. Also, the CDC's estimate of new HIV infections remains stable at 40,000 per year; this figure is based on a mathematical model rather than epidemiological surveys. But health officials expressed concern that the rate of infection seems to be increasing in certain groups, notably young gay and bisexual men of color and low-income African-American women. Of the estimated new infections, 42% were in gay men, 33% were sexually transmitted infections in heterosexuals, and 25% were in injection drug users (IDUs). The racial disparity in gay men's infection rates does not appear to be due to differences in the frequency of high-risk sexual activity, given that African-American gay men were somewhat less likely to report unprotected sex or multiple partners; the higher infection rate may be explained by the fact that gay men of color may select their sexual partners from a pool of men with a higher HIV prevalence. According to Helene Gayle, M.D., M.P.H., former director of the CDC's National Center for HIV, STD, and TB Prevention, "The latest data suggest that the era of dramatic declines [in AIDS deaths] is over. There are a number of signs indicating that our progress in fighting the disease is in serious jeopardy."
In more encouraging news, Dr. Gayle said that only 156 cases of mother-to-child HIV transmission were reported in 1999 -- a record low since the start of the epidemic -- and that HIV rates appear to have declined among IDUs. In New York City, for example, the rate of HIV infection in IDUs fell from 50% in 1990 to 20% in 2000. According to Don Des Jarlais, M.D., of Beth Israel Medical Center, needle exchange programs were the major reason for the decrease in new infections among this population.
In contrast, a recent San Francisco study suggests that the rate of HIV infection among IDUs in that city may be increasing. Timothy Kellogg and colleagues from the San Francisco Department of Public Health conducted a retrospective study of 2,893 people tested for HIV between 1993 and 1999. Eighty-four people contracted HIV during this period, the majority of whom were IDUs. (Since HIV reporting is not required in San Francisco, this number does not represent all new HIV infections.) Among male IDUs who had sex with men, the infection rate increased from 2.9 per 100 person-years in 1996 to 4.7 per 100 person-years in 1998. The researchers could not say whether the men were infected through contaminated injection equipment or through sexual activity. The research was published in the September 1, 2001 issue of JAIDS.
Two studies presented at the prevention conference indicate that approximately 40% of people with HIV do not learn of their positive status until they develop symptoms; these people may live with HIV for years or even decades without treatment before they become ill. According to a CDC survey, 40% of people with HIV learned of their infection one year or less before being diagnosed with AIDS (that is, before their CD4 cell count fell below 200 cells/mm3 or they developed an OI). The survey found that African-Americans and Latinos are more likely than European-Americans to delay HIV testing, and heterosexuals were more likely to get tested late than gay men. A study by Kaiser Permanente produced similar results. Said Leo Hurley, M.P.H., of Kaiser, "These data show that even among persons with reasonable access to quality health care, HIV may go undetected for several years." To encourage timely testing, public health officials have suggested mobile testing sites and rapid-response oral HIV tests that return results faster than traditional testing methods. In the June 29, 2001 issue of Morbidity and Mortality Weekly Report, the CDC recommended routine HIV testing in areas of high prevalence, based on study results showing that such testing could identify people at earlier stages of infection.
Finally, Kimberly Page-Shafer, Ph.D., M.P.H., and colleagues from UCSF presented results at the prevention conference showing that the risk of contracting HIV through receptive oral sex on a man (fellatio) is extremely low. In a study of 198 gay and bisexual people (98% men), of whom 20% reported receptive oral sex with a man known to be HIV positive, only one infection occurred. This infection was not recent and "could not be attributed to the period of exclusive oral receptive intercourse," according to the researchers. "The most important thing we found out is that none of the people that we've been studying or have studied have gotten HIV," Dr. Page-Shafer told National Public Radio. "Our results suggest that oral sex is safer sex." However, Ronald Valdiserri, M.D., M.P.H., of the CDC said, "We know it's possible to transmit HIV through oral sex, but it is not a common event. We want to stress that low risk is not the same as no risk."
Liz Highleyman is a freelance medical writer based in San Francisco.
Back to the SFAF BETA Winter 2002 contents page.