News Briefs: Conference Coverage
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.
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.
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.
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.
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.
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.
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.
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.
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 www.hivforum.org/CCR5.
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).
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.
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.
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."
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.
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.
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 citys 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.