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News Briefs: Conference Coverage

Winter 2005/2006


On the Web

International AIDS Society Conference (IAS)

European AIDS Clinical Society (EACS)

Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)

American Association for the Study of Liver Disease (AASLD)

Conference Coverage:

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

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

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/mm3 (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/mm3 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 depression and strategies to promote continued use of antiretroviral therapy -- including management of side effects -- might lessen the apparent racial disparities observed in some studies.

HAART Cuts Hospitalizations and Deaths

It is widely recognized that the advent of effective combination therapy in the mid-1990s dramatically reduced the rate of AIDS-related deaths. Now, a new study has shown that HAART has reduced HIV-related hospitalizations in the United States by more than 50%. According to a report from the DHHS Agency for Healthcare Research and Quality (AHRQ), HIV-related hospital admissions fell from a high of 149,000 in 1995 to a low of 70,000 in 2003. The rate of AIDS-related mortality in U.S. hospitals also decreased from 12.5% to 8.5% during this period -- a 32% decline. According to AHRQ director Carolyn Clancy, MD, "This information clearly highlights the benefits of quickly putting new, potentially life-saving medical advances into everyday clinical practice." Another analysis by Jonathan Sterne, PhD, and colleagues, published in the July 30, 2005 issue of The Lancet, found that the use of HAART reduced the risk of progression to AIDS or death among the more than 3,200 participants in the Swiss HIV Cohort by 86%, compared with HIV positive individuals who did not receive antiretroviral treatment.

At the November EACS meeting, Charlotte Lewden and colleagues reported that the rate of death among patients who maintain high CD4 cell counts on therapy was similar to that seen in the HIV negative population as a whole (abstract PE18.4/8). In the French APROCO and Aquitaine cohorts, 24% of the nearly 2,280 participants were "favorable responders," with CD4 counts higher than 500 cells/mm3 and viral loads below 10,000 copies/mL while on HAART. The death rate in this subgroup was 0.7% -- not significantly greater than the rate for age- and sex-matched individuals in the general population. Unsurprisingly, patients with CD4 counts under 200 cells/mm3 were nearly 24 times more likely to die. But even those with CD4 counts of 200-350 cells/mm3 or 350-500 cells/mm3 had mortality rates nearly five times and about three times higher, respectively, than those with more than 500 cells/mm3. Other factors that influenced mortality were sex (with women having a greater risk of death than men), injection drug use, and coinfection with hepatitis C.

Another change in the epidemic is the manner in which HIV causes illness and death. In the early years of the epidemic, most HIV positive patients were hospitalized or died due to opportunistic illnesses (OIs). While AIDS-related illnesses are still a major cause of morbidity and mortality, as HIV positive people receiving HAART live longer, they become more prone to chronic conditions associated with aging, as well as to diseases (such as chronic viral hepatitis) that progress over long periods. As reported in the December 15, 2005 issue of JAIDS, Kelly Gebo, MD, and colleagues conducted a cross-sectional analysis of approximately 317,000 HIV-related hospital admissions in 12 states in 1996, 1998, and 2000. They found that total admissions decreased by more than 30%, from 129,000 to 92,000; the decline was less pronounced among women and African-Americans. There were twice as many admissions for OIs in 1996 compared with 2000 (51,000 vs 25,000, or 40% vs 27%, respectively) and the number of admissions related to injection drug use remained stable at about 6% (6,400 vs 5,200). Liver-related admissions rose from 8% in 1996 to 13% in 2000 (10,500 vs 11,500), with the percentage due to hepatitis C increasing from 1% to 5%. Also on the rise were admissions due to cardiovascular disease (462 vs 800) and diabetes (4,000 vs 4,500). Looking more closely at liver-related deaths among the nearly 12,000 participants in the EuroSIDA cohort, Amanda Mocroft, MD, and colleagues reported in the December 2, 2005 issue of AIDS that the rate of death due to liver disease increased 13% from the pre-1995 to the post-2004 period after adjusting for CD4 cell count. The authors attributed the increase to a longer period of progression of chronic viral hepatitis B and C, liver toxicity due to antiretroviral drugs, and perhaps other unknown factors as well.

While antiretroviral therapy may increase the risk of liver dysfunction and metabolic problems, the profound decrease in hospitalization and death rates since the mid-1990s indicates that, on the whole, the benefits of HAART have outweighed the risks.

Truvada Versus Combivir

Recent data suggest that Gilead's once-daily fixed-dose combination pill, Truvada (tenofovir/emtricitabine), may work better than GlaxoSmithKline's Combivir (AZT/3TC) when used as a nucleoside reverse transcriptase inhibitor (NRTI) background regimen. In the open-label Gilead 934 study (presented at the IAS meeting [abstract WeOa0202] and published in the January 19, 2006 New England Journal of Medicine), 517 treatment-naive subjects were randomly assigned to receive either once daily tenofovir/emtricitabine or twice-daily Combivir, both in combination with once-daily efavirenz (Sustiva). After 48 weeks, 80% of patients in the tenofovir/emtricitabine arm achieved viral loads below 50 copies/mL, compared with 70% in the AZT/3TC arm. While the virological failure rates were very similar -- and very low -- for both regimens, tenofovir/emtricitabine was better tolerated; discontinuation rates due to adverse events were 4% in that arm, compared with 9% in the Combivir arm. The researchers concluded that tenofovir/emtricitabine "proved superior in terms of virologic suppression, CD4 response, and adverse events resulting in discontinuation of the study drugs." In a January 18 press release, however, Glaxo countered that Combivir has a better long-term safety and efficacy record, having been evaluated in more than 50 randomized clinical trials involving more than 18,000 subjects. The company added that a higher than usual rate of anemia in the Combivir arm contributed to the difference in treatment failure rates seen in the 934 study.

Data from the COMET study presented at ICAAC offered evidence that the Truvada combination pill works at least as well as the separate tenofovir and emtricitabine pills used together. This Phase IV (post-marketing) trial included 411 subjects, about half of whom reached the 24-week analysis point, who switched from Combivir to Truvada while continuing efavirenz. While 59% of participants had viral loads below 50 copies/mL before the switch, that figure increased to 76% by week 24. Regimens taken less often and those containing fewer pills have been shown to improve adherence, which may have contributed to improved virological suppression in this study; 85% of subjects said they made the switch from Combivir to Truvada for the convenience of a complete once-daily regimen (abstract H-517).

While Truvada looks like a win for Gilead, the company has struggled in its joint effort with Bristol-Myers Squibb to combine tenofovir, emtricitabine, and efavirenz into a single three-way combination pill. In April and August 2005, the companies announced that their first two such attempts had failed: the candidate combination pills were not bioequivalent to the three separate drugs used together. In January, however, the companies issued a joint statement that another co-formulation using bi-layer technology did appear to produce blood levels equivalent to those seen with the separate drugs. Gilead and Bristol-Myers Squibb said they plan to file an Investigational New Drug application with the FDA in the second quarter of 2006. If the effort is successful, it will be the first ever complete one-pill, once-daily antiretroviral regimen; this is also the first cross-company collaboration to develop a fixed-dose combination pill consisting of drugs patented by different manufacturers.

One CCR5 Antagonist Praised, Two Buried

CCR5 antagonists, a novel class of HIV entry inhibitors, have featured prominently in recent drug development news. Most strains of HIV use the CCR5 coreceptor to enter cells, and blocking this receptor can interrupt viral replication. At the IAS meeting, Mary McHale from Pfizer reviewed six studies of the company's experimental CCR5 antagonist, maraviroc (UK-427, 857), involving a total of 259 HIV negative volunteers and HIV positive patients. In two Phase I/IIa monotherapy studies with 63 subjects, maraviroc reduced HIV viral load by 1.60-1.84 logs after 10 days; the 300 mg dose was selected for further development (abstract TuOa0204). At the June drug resistance workshop, researchers presented in vitro data showing that HIV that developed resistance to maraviroc remained sensitive to other candidate CCR5 inhibitors. In studies to date, maraviroc appeared well tolerated at doses up to 300 mg twice daily, with adverse events similar to those seen in placebo arms (e.g., headache, nausea, flatulence). The FDA has granted the drug "fast track" status since it potentially fills an unmet need for treatment-experienced patients who have exhausted currently available therapeutic options. Phase IIb/III trials in both treatment-naive and treatment-experienced individuals are currently enrolling (see "Open Clinical Trials" in this issue).

Researchers at IAS also presented data on Schering-Plough's CCR5 inhibitor candidate, vicriviroc (SCH-D or SCH 417690). D. Schuermann and colleagues conducted a randomized, dose-ranging study in which 48 HIV positive subjects were randomly assigned to receive one of three doses of vicriviroc or placebo. After 14 days, the mean reduction in HIV viral load was 1.62 logs in subjects receiving the 50 mg dose. Vicriviroc was generally well tolerated in doses up to 100 mg daily, but a few patients experienced seizures and some developed transient liver enzyme elevations (abstract TuOa0205). Schering researchers reported at ICAAC that vicriviroc exhibited potent antiviral activity against drug-resistant HIV and that no more clinically relevant heart rhythm disturbances were observed than with placebo (abstracts H-1096 and H-1095). The company, however, announced in October that it was halting Phase II trials of vicriviroc in treatment-naive subjects due to early virological breakthrough. After several weeks of therapy, study participants receiving vicriviroc plus AZT/3TC were more likely to experience viral load rebound than subjects taking efavirenz plus AZT/3TC. A study of the drug in treatment-experienced individuals is ongoing, and the company said it would continue to evaluate the potential use of vicriviroc in combination with other treatment regimens.

Schering's announcement came just two days after GlaxoSmithKline announced that it was stopping all trials of its CCR5 candidate, aplaviroc (GSK-873,140), because some study participants developed serious liver toxicity. The company first halted a Phase IIb trial in treatment-naive individuals in September, after two subjects (out of about 250) developed severe liver enzyme elevations. On October 25, a Phase III study in treatment-experienced patients (just started in July, with about 50 enrollees) was also stopped for the same reason. Glaxo's Helen Steele discussed these toxicity cases -- plus a fourth -- at the EACS conference. She said all four patients had alanine aminotransferase (ALT, a liver enzyme) levels more than three times the upper limit of normal -- 70 times in one case -- plus transiently elevated bilirubin. While these patients all recovered after the drug was discontinued, this type of complication is potentially life-threatening. According to the company, "No further clinical studies of the compound are planned at this time."

While the demise of two CCR5 inhibitor candidates is disappointing, it does not mean the entire class is doomed. Schering said its decision to abandon vicriviroc was not related to liver toxicity or other significant safety issues. In July and September, an independent Data Safety Monitoring Board (DSMB) reviewed the safety data on maraviroc, concluding that trials should continue without major design changes. But at the EACS meeting two months later, a Pfizer representative announced that the company had recently learned of a single case of severe liver toxicity in an individual taking the drug in a clinical trial. Pfizer's Howard Mayer, MD, reviewed the case at the Targeting HIV Entry workshop in December. The treatment-naive patient -- who was coinfected with hepatitis C and had pre-existing liver damage -- began to experience rising liver enzyme levels during the pretreatment study screening period. He developed a fever and skin rash after taking four doses of maraviroc plus Combivir. His ALT level continued to rise after maraviroc was replaced with lopinavir/ritonavir, ultimately necessitating a liver transplant. The patient was also taking acetaminophen, isoniazid, and trimethoprim/sulfamethoxazole (TMP/SMX), any of which may have contributed to his liver toxicity. The DSMB suggested that the other medications were more likely the cause of liver injury, but maraviroc's role could not be ruled out. They recommended that trials continue, but use of isoniazid has been added as an exclusion criterion. Anyone currently enrolled in clinical trails of maraviroc (or any other CCR5 antagonist) should undergo careful liver function monitoring.

The FDA has scheduled an open public meeting to discuss development of CCR5 antagonists in February or March 2006 and is currently seeking public input from the patient and advocacy communities and from researchers. For more information, see

TMC114 Looks Powerful

TMC114 (now named darunavir), a novel nonpeptide PI, is among the most promising experimental agents moving along the development pipeline. At the IAS meeting, Christine Katlama, MD, presented data from a multicenter Phase IIb trial (POWER 1) in which 318 treatment-experienced individuals with resistance to other PIs were randomly assigned to receive one of four doses of ritonavir-boosted TMC114 or a currently approved PI, all with an optimized "backbone" of two NRTIs and possibly T-20 (abstract WeOaLB0102). After 24 weeks, 53% of patients in the arm taking 600/100 mg TMC114/ritonavir twice daily (the most effective dose) achieved HIV viral loads below 50 copies/mL, compared with 18% of subjects taking other PIs; 77% and 25%, respectively, experienced at least a 1 log drop in HIV RNA. The corresponding mean CD4 cell increases were 124 and 20 cells/mm3. Katlama and colleagues concluded that TMC114/ritonavir "demonstrated unprecedented efficacy" in treatment-experienced patients with limited therapeutic options." TMC114 was well tolerated overall, according to a safety analysis by Beatriz Grinsztejn, MD, and colleagues (abstract WePeLB6.2C01); just 10% of subjects discontinued TMC114 prematurely, compared with 62% in the control arm, mostly due to virological failure.

Timothy Wilkin, MD, presented data from the companion POWER 2 study at ICAAC (abstract H-413). In this trial, 62% of treatment-experienced subjects with PI-resistance mutations receiving 600/100 mg TMC114/ritonavir achieved at least a 1 log viral load decrease at 24 weeks, compared with 14% in the comparator PI arm; percentages achieving undetectable viral loads were 39% and 7%, respectively. Adverse event rates were similar across all arms.

Based on the results of these two studies, Tibotec Pharmaceuticals submitted a new drug application to the FDA on December 27. A Phase III clinical trial of TMC114 in treatment-naive individuals is currently enrolling, and in October Tibotec announced an expanded access program for treatment-experienced patients with advanced HIV disease who are ineligible for ongoing trials (see "Open Clinical Trials" in this issue).

New Drugs in Existing Classes

Preliminary data on another new PI, brecanavir (GW640385 or VX-385, jointly developed by GlaxoSmithKline and Vertex) were presented at ICAAC by Douglas Ward, MD (abstract H-412). Like other nonpeptide PIs, brecanavir binds tightly to HIV's protease enzyme and demonstrated activity against virus resistant to conventional PIs. In this open-label study, 31 subjects (six of them treatment-experienced with resistant virus) received 300 mg brecanavir twice daily boosted with 100 mg ritonavir, plus two NRTIs (excluding tenofovir). At 24 weeks, 81% achieved viral loads less than 400 copies/mL (77% less than 50 copies/mL); the median CD4 count increase was 84 cells/mm3. Two patients experienced severe triglyceride elevations; one discontinued due to liver toxicity and another due to gastrointestinal symptoms. Phase III trials are planned for 2006.

Data from study TMC125-C223, a Phase IIb trial of Tibotec's new NNRTI, TMC125 (now called etravirine), were presented at both EACS and ICAAC (EACS abstracts LSPS3/7A and 7B; ICAAC abstract H-416c). In the ICAAC report by Jeffrey Nadler, MD, 199 heavily treatment-experienced subjects with NNRTI- and PI-resistant HIV were randomly assigned to receive 400 or 800 mg TMC125 twice daily or an active control drug, plus an optimized background regimen. After 24 weeks, mean viral load reductions were 1.04, 1.18, and 0.19 logs, respectively; the corresponding percentages with viral load below 50 copies/mL were 21.3%, 17.7%, and 7.5%. The most common TMC125 side effects were diarrhea and skin rash; no common neuropsychiatric side effects (as seen with efavirenz) were reported. Severe (grade 3 or 4) side effects (about 40%) and laboratory abnormalities (about 30%) were common in the TMC125 and control arms alike. Tibotec is currently enrolling two Phase III studies of TMC125 plus TMC114 in treatment-experienced patients (see "Open Clinical Trials" in this issue). However, in December the company stopped a Phase II trial of TMC125 in PI-naive subjects with prior NNRTI failure after preliminary data showed that the drug did not suppress HIV as well as approved PIs.

In the NRTI class, Paul Colucci presented data at ICAAC on elvucitabine, an experimental agent being developed by Achillion Pharmaceuticals (abstract LB-27/Z). With a half-life of more than 90 hours, the drug may potentially be administered just once weekly. In this study, 24 subjects received Kaletra plus either 5 or 10 mg elvucitabine once daily or 20 mg every 48 hours. After 21 days, viral load decreases were similar in the three arms: 1.8, 1.9, and 2.0 logs, respectively. Every-other-day dosing suppressed HIV as effectively as daily dosing. A potential limitation is that the drug can cause bone marrow toxicity with decreased white blood cell counts at higher doses.

At the IAS meeting, Cal Cohen, MD, presented data on a new cytidine analog NRTI, Reverset (D-d4FC), being developed by Incyte (abstract WeOaLB0103). In a multicenter Phase IIb trial, 199 subjects resistant to other NRTIs were randomly assigned to receive one of three doses of Reverset or placebo as part of an optimized regimen. After two weeks, subjects in the 200 mg once-daily Reverset arm (the most effective dose) saw a 0.7 log reduction in HIV viral load, while HIV levels increased slightly in the placebo arm. Even subjects with 4-6 thymidine analog resistance mutations achieved a 0.6 log reduction. After four months, 54% of subjects experienced a greater than 90% decrease in HIV viral load, compared with 40% of those receiving placebo. Reverset was generally well tolerated and most side effects were mild. However, 12 subjects (34%) who took Reverset plus ddI developed severe (grade 4) pancreas enzyme elevations, and three who took Reverset plus ddI plus tenofovir developed frank pancreatitis. In addition, the data suggested that Reverset plus 3TC (lamivudine, Epivir) -- also a cytidine analog -- is not a potent pairing. On September 28, Incyte announced that the FDA did not approve its plan to begin a Phase III trial of Reverset by the end of 2005, instead requesting an additional Phase II study.

Pipeline Agents Work in New Ways

While improvements in existing drug classes are welcome, agents that work by entirely novel mechanisms often generate the most excitement at medical conferences. At the EACS meeting, Javier Morales-Ramirez, MD, presented initial Phase II data on MK-0518, Merck's experimental integrase inhibitor (abstract LBPS1/6). After 10 days, 28 treatment-naive subjects receiving various doses of MK-0518 twice daily experienced viral load decreases of 1.7-2.2 logs (about a 98% reduction), and about half achieved HIV viral loads below 400 copies/mL. There were no serious adverse events or discontinuations due to side effects. A longer 48-week dose-ranging trial is now underway.

Also at ICAAC, George Beatty, MD (a member of BETA's Scientific Advisory Committee) reported late-breaking data on Panacos' PA-457, the first HIV maturation inhibitor, which causes the virus to produce noninfectious progeny (abstract H-416d). In this 10-day Phase IIa study, 33 participants, about one-third of them treatment-experienced, were randomly assigned to receive one of four doses of PA-457 monotherapy or placebo. Subjects who received the highest tested dose (200 mg) achieved a median 1.03 log (90%) reduction in viral load. The agent appeared safe and well tolerated, with no observed dose-limiting toxicities and no evidence of resistance. Because it targets a different stage of the HIV lifecycle, PA-457 should work against virus that is resistant to other drug classes, and due to its long half-life (60 hours), it may potentially be administered less than once daily. A Phase IIb trial is expected to begin this year.

Stanley Lewis, MD, of Tanox reported at ICAAC interim 24-week data on TNX-355, an investigational monoclonal antibody entry inhibitor (LB-26). In a Phase II study of 82 heavily treatment-experienced subjects with virological failure, those who added 10 mg TNX-355 to their optimized background regimens achieved better virological suppression than those who added placebo (mean viral load reduction of 1.19 vs 0.32 logs, respectively). No serious adverse events were attributed to the study drug and it did not cause CD4 cell depletion. Unlike CCR5 antagonists, TNX-355 works against HIV that uses either CCR5 or CXCR4 coreceptors (or both) to enter cells (ICAAC abstract LB2-26). Tanox plans to start a Phase III trial later this year.

Finally, further back in the pipeline, researchers from Sangamo BioSciences presented proof-of-concept data at ICAAC showing that human cells with genetically modified CCR5 coreceptors were protected from HIV infection in laboratory studies (abstract H-1084). The new gene therapy employs zinc finger nuclease enzymes designed to disrupt the CCR5 gene. When CCR5 expression was restored, cells were again susceptible to HIV entry. The company plans to file an Investigational New Drug application with the FDA in the second half of 2006.

Valproic Acid: A Potential "Cure"?

Can a common epilepsy drug help eradicate latent viral reservoirs in the body -- the key to the elusive "cure" for HIV? As Mario Stevenson, PhD, and Tae-Wook Chun, PhD, explained in a forum at the July IAS meeting (debate TuDe04), HIV (or its genetic material) remains dormant in long-lived immune cells, safe from antiretroviral therapy, which is active only against replicating virus. While HIV is thought to persist in latent (resting) cells, Chun and colleagues reported in the November 2005 Journal of Clinical Investigation that all 11 subjects analyzed in a recent study retained proviral HIV genetic material in both active and resting CD4 cells, even after as many as nine years of successful antiretroviral therapy with undetectable viral loads. Stevenson and Chun agreed that current anti-HIV therapies -- which suppress but do not completely arrest HIV replication -- are unable to eradicate the virus. However, new treatments could conceivably accomplish this goal, including immune-based therapies, agents that activate latent cells (such as interleukin-2), drugs that better penetrate resting cells, or agents that target different HIV replicative enzymes (such as integrase or RNase).

The anticonvulsant drug valproic acid (also known as divalproex; brand names include Depakote and Depakene) may be such an agent, according to a proof-of-concept study described in the August 13, 2005 issue of The Lancet. Noting that an enzyme called histone deacetylase 1 (HDAC1) is necessary to maintain HIV in its dormant state within resting cells, David Margolis, MD, Ginger Lehrman and colleagues hypothesized that agents that inhibit HDAC1 might deplete latent virus; past laboratory studies have demonstrated that valproic acid can flush out HIV from resting CD4 cells. Four HIV positive subjects who had viral loads below 50 copies/mL for at least two years were given intensified antiretroviral therapy with T-20 for 4-6 weeks, then 500-750 mg valproic acid twice daily was added to their regimens for three months. The researchers found that the amount of replication-competent HIV hidden in resting CD4 cells declined by 68%-84% in three of the four subjects after the addition of valproic acid (the fourth experienced a smaller response), and that the treatment was well tolerated. While this study was small and brief, it suggests that new techniques for eradicating HIV are feasible. The authors concluded that intensified HAART plus an HDAC1 inhibitor safely accelerates HIV clearance from resting cells, stating, "This finding, though not definitive, suggests that new approaches will allow the cure of HIV in the future."

Some experts sounded a less optimistic note, however, recalling that while previous attempts using similar methods appeared promising initially, patients did not remain virus-free over the long term. Robert Siliciano, MD, told the Associated Press that it was premature to talk about a potential cure for HIV, arguing that "even if you had one latently infected cell left, in a matter of days you would be back to where you started from."

HAART and Fat Accumulation

Everyone knows protease inhibitors cause abdominal fat accumulation, right? Not so, according to the latest results from the large Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study, reported in the October 1 issue of JAIDS. Peter Bacchetti, PhD, Carl Grunfeld, MD, and colleagues conducted a cross-sectional analysis of data from 425 HIV positive and 152 HIV negative gay and bisexual men aged 33-45, including MRI results, clinical assessments, and patient self-reports. They found that central lipohypertrophy (accumulation of visceral abdominal fat) was not associated with HIV infection or use of PIs; 40.2% of HIV positive men reported increased abdominal fat, compared with 55.9% of HIV negative control subjects. Peripheral lipoatrophy (fat loss in the face, limbs, and buttocks) was more common among HIV positive men, reported by 38.3% of this group versus just 4.6% of HIV negative men. The researchers suggested that whatever weight gain occurred among men with HIV was likely due to aging and/or improved health (e.g., a lower rate of severe AIDS wasting syndrome in the HAART era), rather than HIV infection itself or antiretroviral therapy. Grunfeld acknowledged, though, that normal weight gain may appear excessive on a person with wasted limbs. Lipoatrophy was linked to use of d4T (stavudine, Zerit), as expected, but also to indinavir (Crixivan), which has more commonly been blamed for fat gain; nevirapine (Viramune) was associated with less central fat. Peripheral fat loss and central fat accumulation were not closely associated with each other -- men who lost fat in their faces and limbs lost abdominal fat as well -- adding to the evidence that lipoatrophy and lipohypertrophy are two separate processes, rather than "redistribution" of fat from one site to another.

Insulin Resistance and Diabetes

Another recent study suggests that PIs also might not be responsible -- or solely responsible -- for blood glucose abnormalities seen in people with HIV. As reported in the September 2, 2005 issue of AIDS, Todd Brown, MD, and colleagues analyzed prospective data from 533 HIV positive and 755 HIV negative gay and bisexual men in the Multicenter AIDS Cohort Study (MACS) collected at six-month intervals between 1999 and 2003. The researchers found that HIV positive men as a group were more likely to have higher fasting blood glucose levels, higher blood insulin levels, and greater insulin resistance compared with HIV negative men, regardless of what type of antiretroviral therapy they were taking; 36% of HIV positive men had insulin levels above 15 µU/mL vs 22% of HIV negative men. Even HIV positive men not taking any antiretroviral therapy had a higher rate of insulin resistance compared with HIV negative subjects. In addition, individuals with lower nadir (lowest ever) CD4 cell counts were also more likely to develop insulin resistance. Cumulative use of either PIs or NNRTIs was not associated with greater rates of insulin resistance. However, each additional year of NRTI use upped the odds of having an elevated insulin level and -- as with lipoatrophy -- d4T was the most common culprit; 3TC (but not AZT or ddI) was also associated with increased risk of insulin resistance.

The latest results from the large ongoing D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) study reveal about a 6% rate of new-onset diabetes mellitus. As reported at the IAS meeting, Caroline Sabin and an international group of colleagues analyzed data from 22,749 HIV positive individuals on HAART who did not have diabetes at study entry. Within this cohort, 435 patients received a new diabetes diagnosis, for an incidence rate of 5.89 cases per 1,000 PY. Risk factors included older age, male sex, black race, higher body weight, and smoking. In contrast to Brown's findings, in the D:A:D study use of PIs was associated with a slight -- but significant -- increase in the risk of diabetes; the researchers suggested that this link may be related to the effect of PIs on triglyceride levels.

On the other hand, a study by Clara Jones, MD, and colleagues from Tufts (published in the October 1, 2005 issue of JAIDS) found that among HIV positive individuals in the Nutrition for Healthy Living cohort, CD4 cell count, viral load, and number of years living with HIV were not associated with degree of insulin sensitivity. However, insulin resistance was associated with both PI-based and NNRTI-based HAART in HIV positive men. These results conflict with a Women's Interagency Study analysis (published in the May 1, 2005 issue of the same journal), which found that insulin sensitivity was not affected by either HIV or HAART. Further longer-term research is needed to determine why different studies find inconsistent links between blood glucose abnormalities, HIV infection, and antiretroviral therapy.

Lipodystrophy Treatment

Several recent conference presentations and journal articles have covered treatments for lipodystrophy and dyslipidemia (blood lipid abnormalities). Data from the RAVE study presented at ICAAC by Graeme Moyle, MD, showed that patients who switched from the thymidine analogs d4T or AZT to abacavir (Ziagen) or tenofovir experienced modest improvements in lipoatrophy -- gaining limb fat -- but tenofovir was associated with fewer side effects and greater reductions in triglyceride and LDL ("bad") cholesterol levels (abstract H-340). In another study, treatment-naive individuals who took the newer PI atazanavir (Reyataz) were less likely to experience elevated blood lipids than those taking nelfinavir (Viracept); as a consequence, researchers estimated that the atazanavir group had a significantly lower 10-year risk of developing cardiovascular disease (abstract H-348). Also, Eugenia Negredo, MD, and colleagues from Spain presented data from a study of 22 HIV positive individuals on HAART with elevated baseline LDL cholesterol and normal triglyceride levels who added ezetimibe (Zetia), an agent that inhibits cholesterol absorption in the gut, to their existing pravastatin (Pravachol). At 24 weeks, total cholesterol levels were down by 5%, LDL by 7%, and triglycerides by 8%; interestingly, lipid levels were lower at six weeks, then rebounded. No interactions between ezetimibe and Kaletra or nevirapine were observed (abstract H-336).

According to a study published in the July 1, 2005 issue of AIDS, lipid-lowering medications work better than switching antiretroviral drugs when it comes to dyslipidemia. In this open-label study, Leonardo Calza, MD, and colleagues from Italy randomly assigned 132 HIV positive subjects with elevated blood lipids to either switch from their PIs to efavirenz or nevirapine -- since NNRTIs are less associated with lipid abnormalities -- or to stay on their PIs and add pravastatin or bezafibrate (a fenofibrate drug, in the same class as gemfibrozil [Lopid], that is not approved by the FDA). After 12 months, subjects who switched to NNRTIs experienced an average 19% decrease in total cholesterol, compared with an average 41% drop among those taking lipid-lowering medications; the corresponding decreases in triglyceride levels were 18% and 44%. At the Dublin lipodystrophy workshop, Patrick Mallon, MD, and colleagues from Australia reported that in a 33-person study, pravastatin -- in addition to its lipid-lowering effect -- improved lipoatrophy (average limb fat gain of 0.72 kg) more than discontinuing d4T or AZT (abstract 23). Based on another small study of 16 subjects, Calza's team found that the most recently approved statin drug, rosuvastatin (Crestor), was safe and effective in reducing lipids at 24 weeks, with a 31% decrease in total cholesterol and a 21% decrease in triglycerides; until larger studies are conducted, however, rosuvastatin should be used with caution since it can cause rhabdomyolysis, a serious form of muscle toxicity.

Jeroen van Wijk, MD, and colleagues from the Netherlands presented results from a trial comparing rosiglitazone (Avandia) versus metformin (Glucophage) at ICAAC (abstract H-339) and in the September 6, 2005 Annals of Internal Medicine. In this open-label study, 39 HIV positive men with lipodystrophy were randomly assigned to receive one of the two agents for six months. Rosiglitazone was associated with increases in body weight and both subcutaneous (under the skin) and visceral (internal) abdominal fat; fat loss did not improve, however, in patients taking d4T. Metformin, in contrast, was linked to decreases in body weight, total body fat, subcutaneous and visceral abdominal fat, and greater reductions in fasting lipid levels. Changes in insulin sensitivity were similar in both groups, but only rosiglitazone was associated with increased levels of adiponectin (a hormone produced by fat cells that helps regulate glucose metabolism). About one-third of patients taking metformin experienced gastrointestinal side effects, while rosiglitazone was well tolerated; liver toxicity was not seen in either group. The authors concluded that while rosiglitazone may partially correct fat loss, metformin improved visceral fat accumulation, fasting lipid profiles, and endothelial (blood vessel) function. Thus, they recommended that treatment should be individualized based on the specific nature of a patient's lipodystrophy-related symptoms.

HAART Reduces Transmission Among Heterosexual Couples

Combination antiretroviral therapy dramatically reduced the risk of HIV transmission among heterosexual couples in a Spanish study reported in the September 1, 2005 issue of JAIDS. Jesus Castilla, PhD, and colleagues studied 393 steady serodiscordant (mixed-status) heterosexual couples in which the uninfected partner reported no other risk factors. Before the advent of HAART, the HIV transmission rate was 10.3%, compared with 1.9% after the use of combination therapy was well established -- a decline of about 80%. Looking at the data another way, the transmission rate was 8.6% among couples in which the HIV positive partner was not taking HAART, while none of the HIV negative individuals contracted the virus if their HIV positive partners were using effective combination therapy. In contrast to some past research, the presence of sexually transmitted infections in the HIV positive partner was not significantly associated with increased risk of HIV transmission. The reduction in transmission risk is likely attributable to low or undetectable viral load in individuals on effective treatment. The authors warned, however, that transmission remains possible and mixed-status couples should continue to practice safer sex even if the HIV positive partner is taking HAART.

Crystal Methamphetamine and HIV

Increasing attention has focused lately on the use of crystal methamphetamine -- especially among gay men -- and its connection to HIV/AIDS. This past August, more than 900 public health officials, care providers, and patient advocates gathered in Salt Lake City for the first National Conference on Methamphetamine, HIV and Hepatitis, sponsored by the Salt Lake City Harm Reduction Project and the New York City-based Harm Reduction Coalition. In her keynote address, Patricia Case, PhD, from Harvard Medical School questioned whether methamphetamine use is, as many have asserted, a new "epidemic," arguing that stimulant use has long been widespread in the United States. Conference attendees discussed the physiology of methamphetamine use, its sociological impact, its effects on sexual desire and behavior, harm reduction and addiction treatment, and the current state of research, as well as the need for more funding and better collaborative efforts to address crystal use and its impact on the transmission of HIV and viral hepatitis. Much remains to be learned about the impact of crystal on HIV transmission, disease progression, and treatment. For a comprehensive overview of the conference, see Bob Huff's report in the July/August 2005 issue of GMHC Treatment Issues.

Gay and bisexual men who use crystal may triple their risk of HIV infection, according to a report in the September 2, 2005 issue of AIDS. Kate Buchacz, PhD, and colleagues examined the link between amphetamine use and HIV incidence among nearly 3,000 men who have sex with men (MSM) visiting AIDS Health Project anonymous test sites in San Francisco. They found that the HIV incidence rate was 6.3% per year among the 290 amphetamine users (10% of the total), compared with 2.1% per year among the 2,701 non-users. Among the 34 men who were infected with HIV in the previous six months, eight (24%) reported using amphetamine. The effect of crystal use was still apparent even after controlling for the use of alcohol and other recreational drugs. The increase is likely attributable, at least in part, to the fact that amphetamine users were more likely to engage in unprotected anal sex and more likely to report having 10 or more sexual partners in the past year.

Fortunately, education and prevention efforts in San Francisco may be having the intended effect. According to a survey by the Stop AIDS Project, methamphetamine use declined by 8% between the last six months of 2003 and the first six months of 2005; while 18% of 1,305 men surveyed during the first period said they used crystal in the past six months, this figure dropped to 10% among the 809 men surveyed during the second period. Willi McFarland, MD, of the San Francisco Department of Public Health (SFDPH) said this was the first time such a downward trend has been seen, and suggested it might help explain why the city’s rate of HIV infection among MSM has recently declined. H. Fisher Raymond of the SFDPH AIDS Office, however, said the decrease in crystal use is probably too recent to have contributed to the reduced HIV incidence rate.

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This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.