News Briefs
Conference Coverage
Introduction
In the summer and fall of 2005, a number of conferences throughout the world presented HIV-related findings. Other HIV news during this time is also reported here.
Several recent medical conferences featured reports related to HIV/AIDS, including the XIV International HIV Drug Resistance Workshop, held June 7-11 in Quebec; the 3rd International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment, held July 24-27 in Rio de Janeiro; the 7th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, November 13-16 in Dublin; the 10th European AIDS Clinical Society (EACS) annual meeting, also in Dublin, November 17-20; and the 1st International Workshop on Targeting HIV Entry, held December 2-3 in Bethesda, Maryland. The 45th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) took place December 16-19 in Washington, DC; ICAAC usually occurs earlier in the fall, but this year was postponed and relocated after Hurricane Katrina struck New Orleans a few weeks before the originally scheduled date. In addition, the 56th Annual Meeting of the American Association for the Study of Liver Disease (AASLD), held November 11-15 in San Francisco, included several presentations on HIV/hepatitis C coinfection.
Highlights from these conferences are included below, organized by topic. Due to the amount of information presented at these meetings, BETA's news summary is necessarily incomplete; for more in-depth reports, see the Web sites in the box to the right.
New Kaletra Formulation Approved
On October 28, the Food and Drug Administration (FDA) approved a new formulation of Kaletra (lopinavir/ritonavir combination pill) that allows patients to take four instead of six pills per day. Each new film-coated "Meltrex" tablet contains 200 mg lopinavir and 50 mg ritonavir. Last April, the agency approved a once-daily Kaletra dosing regimen for some treatment-naive individuals: four of the new tablets once daily, for a total dose of 800 mg lopinavir and 200 mg ritonavir. The dosage remains two tablets twice daily for treatment-experienced patients. The new tablet does not require refrigeration and can be taken on a full or empty stomach (the old soft-gel capsule had to be taken with food). As reported at the IAS meeting, bioavailability of the new formulation is less affected by food (abstract WeOa0206). Studies presented at ICAAC showed that the new pill was 17% more bioavailable, caused fewer gastrointestinal side effects (especially diarrhea), and promoted better adherence over 96 weeks compared with the old formulation (abstracts H-1894 and H-522). The new tablet will cost about 8% more, and Abbott Laboratories has requested an extension of its patent on the drug (due to expire in 2015). For complete prescribing information, see
www.kaletra.com.
Avoid Amevive
People with HIV should avoid the psoriasis drug alefacept (Amevive) since it can reduce CD4 cell counts, the FDA and the drug's manufacturer, Biogen Idec, recently cautioned. In October, Biogen sent a letter to this effect to healthcare providers, warning that the medication "might accelerate disease progression or increase complications of disease" in people with HIV/AIDS.
Updated HIV Treatment Guidelines
Also in October, the U.S. Department of Health and Human Services (DHHS) released an updated version of its "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents." Based on recent worrisome clinical trial data, the new guidelines recommend against regimens that combine ddI (didanosine, Videx) plus tenofovir DF (Viread) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI), due to reports of early virological failure and rapid emergence of NNRTI resistance. The new guidelines also provide information about the new protease inhibitor (PI) tipranavir (Aptivus) and a revised section on medical management of treatment-experienced patients. The new, more aggressive goal in treating this group is to suppress HIV to undetectable levels -- not merely to preserve immune function and delay disease progression -- which may be accomplished (even in patients with multidrug-resistant HIV) using a boosted PI plus T-20 (enfuvirtide, Fuzeon). DHHS also recently updated its pediatric HIV treatment guidelines. For the latest updated guidelines for HIV treatment in adults, adolescents, children, and pregnant women; post-exposure prophylaxis (PEP) for occupational and nonoccupational exposure; and opportunistic illness (OI) prevention, see
www.aidsinfo.nih.gov.
NPs, PAs, and MDs Provide Similar Quality Care
As the guidelines for antiretroviral therapy grow ever more complex, it becomes increasingly challenging for medical practitioners to keep abreast of the latest developments. But according to a study published in the November 15, 2005
Annals of Internal Medicine, quality of HIV care is not dependent on type of medical degree. Looking at more than 6,600 patient records from 68 Ryan White CARE Act-funded HIV clinics, Ira Wilson, MD, from Tufts University and colleagues analyzed eight quality of care factors including use of HAART and preventive screenings (e.g., for hepatitis C, cervical cancer, and tuberculosis). They found that nurse practitioners (NPs) and physician assistants (PAs) provided a comparable level of care to physicians (medical doctors or MDs) specializing in HIV/AIDS, and generally performed better than nonspecialist general practitioner MDs. Both NPs and PAs -- but not registered nurses, or RNs -- are trained in how to diagnose patients and select medications (though MDs usually must authorize their prescriptions). The best NP and PA care was delivered by providers who specialize in HIV/AIDS, have practical experience in this field, and work closely with HIV specialist physicians. These results are reassuring for managed care and HMO patients -- as well as those in rural or otherwise underserved areas -- who may have more ready access to NPs or PAs than to MDs.
First Anti-HIV Drug Goes Off Patent
September 17 marked a milestone in the AIDS epidemic: the first expiration of a patent on an antiretroviral drug. In March 1987, GlaxoSmithKline's AZT (zidovudine, Retrovir) was the first drug approved for the treatment of HIV/AIDS; it was initially used as monotherapy which, as soon became apparent, encouraged the rapid development of drug-resistant virus. Today, AZT remains a standard component of HAART "backbone" regimens, though its popularity has faded due to toxicity concerns and more patient-friendly alternatives. The drug is also included in two fixed-dose combination pills, Combivir (AZT/3TC) and Trizivir (AZT/3TC/abacavir). Since its approval, AZT has generated about $4 billion in sales. While AZT alone no longer commands a large market share, Combivir is among the top-selling anti-HIV therapies. The recent patent expiration applies only to AZT itself, not the combination pills. Just days after the patent expired, the FDA approved four generic versions of AZT, produced by three different companies (Aurobindo, Ranbaxy, and Roxane Laboratories) for sale in the United States. Generic versions are expected to cost less than $100 per year, compared with nearly $4,000 annually (wholesale) for brand-name Retrovir. Generic versions of AZT and fixed-dose combination pills containing the drug were already manufactured by several overseas companies, either licensed by Glaxo or produced under World Trade Organization provisions for developing countries with health emergencies.
Unusual New York HIV Case an Anomaly
The Summer 2005 issue of
BETA included a
news item about a gay man in New York City with an unusual multidrug-resistant, dual-tropic (able to use both CCR5 and CXCR4 coreceptors to enter cells) strain of HIV with a high capacity for replication; the case was described in detail in the March 19, 2005 issue of
The Lancet. The report prompted a flurry of media attention last winter, as well as much discussion -- some of it acrimonious -- among medical professionals and HIV prevention workers. Several medical experts and community advocates criticized New York public health officials and researchers at the Aaron Diamond AIDS Research Center (where the case was discovered) for raising the alarm prematurely based on a single patient.
The case prompted a rare special symposium at the February 2005 Conference on Retroviruses and Opportunistic Infections and it was discussed again at the July IAS meeting. While some raised concern that the case might be a harbinger of a new, more aggressive HIV "superstrain," those fears now seem unwarranted, as the New York case appears to be an anomaly. After extensive contact tracing and analysis of stored blood samples, it was determined that the Connecticut man who apparently transmitted HIV to the New York patient is himself experiencing a typical rate of HIV progression, although he also has multidrug-resistant virus. The Connecticut man's physician, Gary Blick, MD, and others have suggested that the aggressive course of disease seen in the New York man might be due to individual genetic factors and/or his heavy use of crystal methamphetamine.
British Man's "Cure" Questionable
Just as the hype surrounding the New York "superstrain" later proved unfounded, the recent excitement over a British man's reported HIV "cure" appears equally unjustified. This past November, Andrew Stimpson gave interviews to two U.K. newspapers, the
News of the World and
Mail on Sunday, suggesting he cured his HIV with vitamin supplements. Stimpson said that in 2003 and 2004 he received multiple negative HIV antibody tests and undetectable viral load tests, after previously receiving one indeterminate and two positive antibody tests, as well as a very low but detectable viral load test, in 2002. After receiving the positive results, Stimpson reported, he began having unprotected sex with his HIV positive partner. People truly infected with HIV may have viral loads below the limit of detection of a specific test (typically 50 copies/mL), but it would be unusual for an infected person to have both undetectable viral load and a negative antibody test. While "seroreversion" from HIV positive to HIV negative is rare, it has been observed in a few individuals treated early with antiretroviral therapy during acute infection (as reported in the March 5, 2005 issue of
Clinical Infectious Diseases [
CID]) and in some children who acquired HIV through mother-to-child transmission (as reported in a letter in the December 15, 2005 issue of
CID); Stimpson, however, says he never received anti-HIV treatment. Stimpson sued the Chelsea and Westminster Health Trust, alleging that its sexual health clinic must have mixed up his and another person's blood samples. The British National Health Service Litigation Authority confirmed that all tests were done using Stimpson's blood, but asked him to undergo further testing -- a request he declined. Even if the blood samples were not mixed up, false-positive results could have resulted from laboratory errors, problems with the tests, or unusual viral or host factors that have yet to be determined.
Rapid Oral HIV Test Gives False-Positive Results
In December, several U.S. agencies stopped using the OraQuick Advance rapid oral HIV antibody test after unexpectedly large numbers of false-positive results were reported at certain sites in a few cities; however, most agencies nationwide have not seen similar clusters of false positives. The test, which uses a sample of oral fluid taken from around the gums, was approved in March 2004. According to the test manufacturer, OraSure Technologies, there were 107 false-positive results out of more than 28,400 tests conducted between January and November 2005, for a specificity rate of 99.6%. But in San Francisco, there were 49 false-positives out of about 9,400 tests performed that year. The New York City health department reported 30 false-positives in November alone, while the Los Angeles Gay and Lesbian Center reported 13. Similar problems have not been seen with OraSure's rapid fingerstick blood test. On December 16, the Centers for Disease Control and Prevention (CDC) issued an advisory stating that positive rapid oral HIV test results should always be confirmed using a supplemental test such as a Western blot or immunofluorescent assay. OraSure, CDC, FDA, and local health officials are investigating the cause of the erroneous results. Program directors can call 800-672-7873 to report further problems. Despite the recent spate of false positives, many public health experts believe the rapid oral HIV test remains useful because it allows individuals to avoid needlesticks and to receive their results in 20 minutes, rather than having to return after 1-2 weeks.
Is HIV Becoming Weaker?
According to a report by Belgian researchers in the October 14 issue of
AIDS, HIV may be getting progressively weaker. Kevin Ariën and colleagues analyzed HIV-1 isolates from 24 treatment-naive individuals, half of which were collected during the 1986-1989 period and half during 2002-2003; isolates were matched for subtype and coreceptor tropism (use of the CCR5 or CXCR4 coreceptors). The researchers found that the earlier isolates were more effective at entering and killing CD4 cells compared with the more recent strains. In 176 out of 238 head-to-head tests, the older isolate infected cells more readily than the newer one. Ariën's team calculated that the more recent virus isolates had a replicative fitness about 55% of that seen in the older isolates. They noted that this reduction in fitness may be a consequence of mutations the virus must undergo to evade the human immune response. In addition, pathogens commonly evolve to become less virulent over time, since they have more opportunities to replicate -- and to be transmitted to new bodies -- if they do not kill their hosts too quickly. These data suggest that the gains in health and longevity among people with HIV/AIDS over the past two decades may be due in part to weaker virus, in addition to the development of better antiretroviral therapies.
Recent Studies Explore HIV Progression
Several recent studies have focused on HIV disease progression. At the ICAAC meeting (abstract H-515) and in the January 1, 2006 issue of
CID, Nicolai Lohse and colleagues from Denmark reported that short-term virological suppression after starting a course of HAART is associated with long-term HIV suppression and survival. They analyzed data from 2,046 HIV positive subjects divided into three groups: those with continuous viral suppression (viral load below 400 copies/mL), those whose HIV was suppressed some of the time, and those who never had undetectable virus during the 6-18 months after HAART initiation. Subjects in the 100% suppression group were more likely to be alive after 72 months than those in the 1%-99% suppression group or the no suppression group (survival rates of 92.7%, 85.6%, and 76.1%, respectively), and were more likely to have undetectable viral load at the end of follow-up (96%, 83%, and 57%, respectively). They were also less likely to die of AIDS-related causes and had slightly larger CD4 cell count increases. However, compared with the 100% suppressed subjects, patients in the 1%-99% suppression and no suppression groups were more likely to be injection drug users, had lower pretreatment CD4 cell counts, were more likely to have previously tried antiretroviral therapy (especially suboptimal pre-HAART therapy), and had more prior treatment interruptions -- all factors linked to worse outcomes. Thus, while the data indicate that viral breakthrough during early treatment predicts disease progression, they do not explain why. The negative outcomes seen in this study may, for example, be due to prior treatment history and resulting resistance, rather than early virological breakthrough per se.
In another recent study, primary drug resistance did not predict worse overall outcomes. As reported in the January 2, 2006 issue of AIDS, researchers with the international CASCADE Virology Collaboration analyzed 300 treatment-naive individuals who received drug-resistance tests within 18 months after HIV infection; 10% (29 subjects) showed evidence of intermediate or high-level resistance to at least one antiretroviral agent. They found that patients initially infected with HIV that had one or more drug-resistance mutations did not progress more rapidly over five years. While patients with primary drug resistance experienced greater CD4 cell declines during the first year after infection than subjects infected with non-resistant HIV, both groups had similar CD4 cell counts after five years. In addition, primary drug resistance did not appear to impair response to first-line treatment. The authors concluded that the study provided no evidence of a long-term effect of transmitted drug resistance on the natural history of HIV disease, but cautioned that the negative impact of primary resistance may emerge even later in the course of disease if salvage therapy should become necessary.
These findings, if confirmed, are welcome news, since the prevalence of primary drug resistance appears to be on the rise, according to a report in the December 15, 2005 Journal of Acquired Immune Deficiency Syndromes (JAIDS). Looking at data from the CASCADE cohort, Bernard Masquelier, PharmD, and colleagues reported that 45 out of 438 of patients (10.3%) who seroconverted between 1987 and 2003 were infected with drug-resistant strains of HIV. The prevalence of resistance was higher among men who have sex with men (11.6%) than among injection drug users (6.7%) or individuals infected through heterosexual contact (5.6%). The overall resistance rate increased between 1996-1999 and 2000-2003, leading the authors to conclude that transmitted drug resistance is rising over time and to emphasize the importance of developing new antiretroviral agents and novel drug classes.
SMART Study Cancelled
The SMART (Strategies for Management of Anti-Retroviral Therapy) study, a large international trial comparing two HIV treatment strategies, discontinued enrollment in January after data showed that continuous HAART is superior to episodic treatment guided by CD4 cell counts; in the United States, the trial was conducted by the Community Programs for Clinical Research on AIDS (CPCRA). The study, begun in 2002, was designed to determine whether patients at low risk of HIV disease progression could safely reduce their use of antiretroviral therapy in the hope of minimizing side effects, slowing the development of drug resistance, and preserving future treatment options. Participants -- nearly 5,500 to date -- were randomly assigned to either continue (or start) treatment in an attempt to keep their viral loads as low as possible, regardless of CD4 cell count (the viral suppression arm), or to stop anti-HIV therapy (or not start) until their CD4 cell counts fell below 250 cells/mm
3 (the drug conservation arm).
An independent Data and Safety Monitoring Board halted enrollment because patients in the drug conservation group had twice the risk of progression to AIDS or death after an average follow-up period of about 15 months. Subjects in that arm also had a higher incidence of cardiovascular, kidney, and liver problems -- contrary to the hypothesis that episodic therapy might reduce the rate of adverse events. "We were surprised to learn that in the short term, episodic antiretroviral therapy carries such an increased risk without evidence of sparing patients the known side effects associated with [antiretroviral therapy]," said Wafaa El-Sadr, MD, one of the study's principal investigators. After reviewing the data, the committee overseeing the trial recommended that treatment-experienced subjects currently in the drug conservation arm should restart HAART; follow-up will continue for all currently enrolled participants.
Do Some Groups Benefit More From Treatment?
According to a study published in the November 18, 2005 issue of
AIDS, some people seem to benefit more from anti-HIV therapy than others. Caroline Sabin and colleagues with the Antiretroviral Therapy Cohort Collaboration analyzed changing patterns of HIV/AIDS morbidity and mortality as antiretroviral therapy evolved. Looking at data from more than 22,000 patients, they found that the rate of new AIDS-defining illnesses declined more steeply among gay men compared with other risk groups. While the incidence of AIDS-related events decreased overall after starting HAART, the reduction was not the same across all populations. During the first year of treatment, the researchers recorded 1,521 AIDS-defining events and 414 deaths, with the vast majority occurring during the first six months. Between the first and the second six-month periods, the combined event rate fell by 68%, from 12 to 4 per 100 person-years (PY). Among gay men, however, the decrease was 77%, compared with 59% among injection drug users. Patients who were already diagnosed with AIDS and those who had CD4 cell counts below 350 cells/mm
3 or viral loads above 100,000 copies/mL when they started antiretroviral therapy derived less benefit, as did those who started treatment after 2001.
But, according to researchers in Amsterdam, women using antiretroviral therapy appear to benefit as much as men. As reported in the March 4, 2005 issue of AIDS, Maria Prins, PhD, and colleagues conducted a review of the medical literature on sex differences in the rate of HIV disease progression before and after the advent of HAART. They found little evidence for sex differences in the rate of progression or the beneficial effects of anti-HIV therapy, even though some studies showed women were more likely to experience adverse side effects. Pregnancy also did not seem to worsen HIV disease progression. Given the complex effects of metabolic and hormonal factors, the authors emphasized the importance of including an adequate number of women in clinical trials of experimental anti-HIV therapies.
A related study found that among U.S. women, the benefits of antiretroviral therapy are not directly impacted by race/ethnicity. As reported in the August 15, 2005 issue of JAIDS, Kathryn Anastos, MD, and colleagues analyzed prospective data from 961 HIV positive women in the Women's Interagency HIV Study (WIHS) who started HAART between July 1995 and September 2003. After a median five years of follow-up, survival rates were 80% for white women, 77% for Hispanic/Latino women, and 70% for African-American women. While white women on the whole were more likely to achieve and maintain virological suppression and less likely to die, these differences disappeared after adjusting for factors such as use of antiretroviral therapy, treatment discontinuation, pretreatment CD4 cell count and HIV viral load, route of HIV exposure, history of AIDS-defining illnesses, use of illegal drugs, and depression. But the likelihood of treatment response was not related to genetic differences between racial/ethnic groups. Although African-American and Hispanic/Latino women were more likely to discontinue treatment and suffer from depression, the researchers concluded that "[n]o significant differences by race were found in virologic, immunologic, or clinical outcomes after adjustment for continued HAART use and depression." They added that treatment of d