Several recent conferences have featured reports related to HIV/AIDS, most prominently the 13th Conference on Retroviruses and Opportunistic Infections, held February 5-8 in Denver, the 7th International Workshop on Clinical Pharmacology of HIV Therapy, held April 20-22 in Lisbon, and the XV International HIV Drug Resistance Workshop, held June 13-17 in Sitges, Spain. Also in April, the Microbicides 2006 conference showcased the latest scientific and public policy information related to the development of microbicides to prevent sexual transmission of HIV; this meeting is covered in this issue of BETA. Two major liver disease conferences, the 41st European Association for the Study of the Liver (EASL) meeting in Vienna in April and the Digestive Disease Week 2006 conference in Los Angeles in May, covered hepatitis B and C, including some presentations on HIV/hepatitis coinfection.
Due to the large amount of information presented at these meetings, BETA's news summaries are necessarily incomplete; for more in-depth conference coverage, see the Web sites listed below.
an article in this issue of BETA.
In the Hopkins HIV Clinical Cohort (abstract 529), 262 patients who maintained virological suppression on HAART were followed for up to five years. Those who started therapy with higher CD4 cell counts were more likely to eventually achieve normal levels. Among those who started with CD4 counts below 200 cells/mm3, the mean CD4 count attained during follow-up was 423 cells/mm3, compared with 501 cells/mm3 for those starting treatment with 201-350 cells/mm3, and 681 cells/mm3 -- near the normal level -- for those starting with more than 350 cells/mm3.
Kenneth Lichtenstein, MD, of the University of Colorado Health Sciences Center and colleagues (abstract 769) conducted a retrospective analysis of medical records collected between 1996 and 2005 from more than 2300 patients in the HIV Outpatient Study (HOPS). Treatment naive individuals who started therapy with CD4 cell counts above 350 cells/mm3 were significantly less likely to experience peripheral neuropathy, lipoatrophy (fat loss in the face and limbs), or kidney failure compared with patients who started at lower baseline levels; the authors suggested that the higher rate of toxicity in patients with lower baseline CD4 cell counts may be due to a chronic state of inflammation. In this study, starting treatment with higher CD4 counts, staying on therapy continuously, and achieving at least 95% adherence were associated with better outcomes in terms of both reduced toxicity and lower risk of AIDS-defining illness and death.
Current U.S. federal HIV treatment guidelines recommend that people start HAART when their CD4 counts fall below 350 cells/mm3. Taken together, these studies suggest there may be reason to shift back toward the "hit early" treatment philosophy, which fell out of favor due to the unexpected long-term toxicities associated with antiretroviral therapy.
Cardiovascular RiskData from the large international D:A:D studies, following more than 23,000 HIV positive individuals, have shown that antiretroviral therapy is associated with an increased risk of heart attacks and strokes. In 2003, researchers reported that the risk of myocardial infarction increased by 26% per year on HAART; at the 2005 Retrovirus conference, they reported that the rate appeared to have leveled off, to 17%. This year, Nina Friis-Møller, MD (abstract 144) presented the latest data showing that the increase in risk per year has fallen further, to 16%, representing 3.65 heart attacks per 1000 PY of treatment. She also reported that the elevated risk of cardiovascular events was associated with use of PIs, but not NNRTIs; the increased risk associated with PIs was attributable in part to increases in blood lipid (fat) levels.
Lichtenstein (abstract 735) reported that among 1744 HOPS participants seen between 1989 and 2005, 2.8% developed cardiovascular disease; however, as with D:A:D, the incidence of myocardial infarctions decreased in recent years, after peaking in 2000-2001. In this cohort, cardiovascular disease was associated with traditional risk factors, including age over 40 years, elevated blood fats, hypertension, and diabetes. Use of lipid-lowering medications reduced the risk of cardiovascular disease by two thirds, but -- in contrast to other studies -- switching to a PI-sparing regimen or to atazanavir (Reyataz) did not decrease the risk.
Among the more than 5400 HIV positive patients treated at Kaiser Permanente of Northern California (abstract 737), the rate of cardiovascular events was twice that seen among the health plan's HIV negative members (2.9 vs. 6.0 cases of cardiovascular disease per 1000 PY; 2.2 vs. 3.6 heart attacks per 1000 PY). Like D:A:D, this study also found a 16% increase in cardiovascular risk per year of HAART use; here, too, the annual rate leveled off, after peaking at 4-6 years' use of antiretroviral therapy. Unlike D:A:D, however, the risk of cardiovascular events did not differ significantly between patients taking PIs or NNRTIs (though there was a trend toward higher rates with PIs).
The recent decrease in cardiovascular events in these studies may be in part due to more aggressive use of adjunct medications to manage elevated blood lipids (increasing from 1% in 2001 to 27% in 2005 in the Kaiser study), hypertension, and blood glucose abnormalities, as well as wider use of the newer PI, atazanavir (increasing from 6% to 35% at Kaiser), which is less likely to cause blood-lipid elevation.
Managing Metabolic ManifestationsSeveral presentations covered strategies for managing HAART-related metabolic manifestations, including peripheral fat loss, central fat accumulation, and elevated blood lipids. One study looked at whether pioglitazone (Actos), a medication used to manage type 2 diabetes, can help restore lost limb fat. A related agent, rosiglitazone (Avandia), offers minimal or no benefit, according to several past studies. In this double-blind, placebo-controlled study of 130 heavily treatment-experienced participants with lipoatrophy (abstract 151LB), patients in the pioglitazone arm experienced a significant increase in limb fat as assessed by DEXA scans -- unless they were taking d4T (stavudine, Zerit) -- but the improvement was too subtle for patients to notice.
Moving on to fat accumulation, Rakhi Kohli, MD, from Tufts University and colleagues (abstract 148) reported that in a placebo-controlled trial of 48 participants with normal glucose tolerance, another diabetes drug, metformin (Glucophage), did not significantly reduce visceral fat after 24 weeks (again, assessed by DEXA scans). Patients also experienced no improvement in blood lipid levels, but did show an overall reduction in body mass index (BMI). Kathleen Mulligan, PhD, of the University of California at San Francisco and colleagues (abstract 147) reported data from a study of 105 HIV positive individuals with insulin resistance randomly assigned to receive metformin alone or metformin plus rosiglitazone. After 16 weeks, no significant changes in either visceral abdominal fat or subcutaneous fat were observed in either arm.
Study ACTG 5079 (abstract 149) included 88 men with abdominal fat accumulation and moderate hypogonadism (low testosterone); half were randomly assigned to use a 1% testosterone gel, while the rest used an inactive placebo gel. After 24 weeks, no significant difference was observed in terms of visceral fat reduction (as measured by CT scans), although the men in the testosterone arm lost significantly more subcutaneous and total abdominal fat, as well as trunk, limb, and whole-body fat. These results suggest that testosterone replacement should be used with caution in patents with lipoatrophy.
Finally, another study showed that a combination of fish oil (which contains omega-3 fatty acids) plus fenofibrate reduced triglyceride levels more than either alone. In the ACTG 5186 study (abstract 146), 100 HIV positive individuals with triglyceride levels above 400 mg/dL were randomly assigned to received either fish oil or fenofibrate; those who did not show improvement after eight weeks (about 90%) added the second therapy. After an additional 12 weeks, triglycerides decreased by 65%, although three quarters of the patients still did not reach values below 200 mg/dL (150-200 mg/dL is considered "borderline high").
Taken together, these studies produced disappointing results overall, pointing to the need for more potent adjunct therapies for managing lipodystrophy or -- better yet -- antiretroviral medications that cause less metabolic toxicity.
Tenofovir Kidney ToxicityKidney toxicity has long been a concern with tenofovir (and the combination pills that contain it, Truvada and Atripla), and various studies have produced conflicting data -- including several presented at the Retrovirus conference. Mark Nelson, MD, and colleagues (abstract 781) analyzed data from 10,343 patients in the tenofovir expanded access programs (EAPs) and from post-marketing safety reports received through April 2005. In the EAPs, only 0.57% experienced serious kidney problems. In the post marketing database (which included some patients with pre-existing kidney impairment), the rate of kidney failure was 43 per 100,000 PY.
The CDC's Adult/Adolescent Spectrum of Disease database (abstract 779) collected safety information on 11,362 HIV positive individuals without pre-existing kidney disease. Here, the rates of kidney impairment among patients taking tenofovir were 35.1%, 6.4%, and 2.6%, respectively, for mild, moderate, and severe dysfunction. Tenofovir use increased the overall risk of kidney impairment by 60%, although there was no significant association with severe impairment. Kidney problems were associated with older age (over 50 years), lower CD4 cell count, diabetes, high blood pressure, and anemia.
In the University of Washington HIV cohort (abstract 780), 17.5% of the nearly 500 patients taking tenofovir showed evidence of kidney impairment. Here, kidney problems were associated with age over 50 years, low body weight, and use of ddI (didanosine, Videx). Jodie Guest, PhD, of the Atlanta Veterans Administration Medical Center and colleagues (abstract 778) reported that in a group of 222 heavily treatment-experienced patients with advanced HIV disease, 17.1% developed nephrotoxicity (damage to the kidney tubules), 13% developed hypophosphatemia low blood phosphate), and 4% had impaired creatinine clearance during the first year on tenofovir.
While interpretation of these studies is complicated by the varying measures of kidney impairment, the take home message is that the overall rate of kidney toxicity is low among patients taking tenofovir, and that it typically occurs in people with other risk factors, such as pre-existing kidney dysfunction or concurrent use of other nephrotoxic drugs. Gilead recommends that people with severe kidney impairment should not take tenofovir, and that those with mild-to-moderate impairment may require dose-interval adjustment because they clear the drug from their kidneys more slowly; additional caution is warranted with the fixed-dose combination pills because the tenofovir dose cannot be independently adjusted.
Four studies offered conflicting data about interactions between PIs and tenofovir. Certain ritonavir-boosted PIs can slow tenofovir clearance and thereby increase concentrations in the kidneys -- potentially raising the risk of toxicity -- by interfering with the activity of the transporter proteins MPR2 and/or MPR4 (abstracts 34, 38, 39, 49). Another drug interaction study showed that efavirenz reduces blood levels of the PI darunavir, while darunavir increases efavirenz concentrations (abstract 55). Several other studies looked at the pharmacokinetics and pharmacodynamics of various antiretroviral agents, as well as new methods of therapeutic drug monitoring. One study that generated considerable interest (abstract 82) found that in 45 healthy volunteers, the recently approved fixed-dose tenofovir/emtricitabine/efavirenz combination pill, Atripla, is bioequivalent to the three separate drugs taken together (see news item).
At the Clinical Pharmacology Workshop, Elizabeth Phillips, MD, and colleagues (abstract 33) presented data showing that a genetic patch test can be used to detect the HLA-B*5701 variant. Among 46 patients at four international sites, all 23 participants with positive patch test results carried HLA-B*5701, compared with only two of 23 individuals with negative patch test results. Six people with previous suspected hypersensitivity reactions who had negative patch tests and lacked HLA-B*5701 did not experience hypersensitivity after abacavir was carefully reintroduced, suggesting that their former symptoms were not truly indicative of a reaction.
Similar results were reported by Australian researchers in the July 1, 2006 issue of Clinical Infectious Diseases. Andri Rauch, MD, and colleagues conducted a prospective study in which 260 abacavir-naive individuals were given a genetic test for hypersensitivity; 7.7% tested positive for the HLA-B*5701 gene. Among 148 subjects who tested negative for HLA-B*5701, none experienced hypersensitivity reactions after they started abacavir; however, among patients who tested positive, three developed hypersensitivity symptoms.
If verified in planned randomized controlled trials, genetic testing could help identify patients who have been falsely identified as hypersensitive to abacavir, potentially allowing them to try the drug again with careful monitoring.
The recently approved PI tipranavir (Aptivus) continued to show superior efficacy over comparator PIs in heavily treatment-experienced patients who had virological failure on previous regimens (abstract 520). However, manufacturer Boehringer Ingelheim announced in June that it would discontinue a study comparing ritonavir-boosted tipranavir against lopinavir/ritonavir in treatment naive patients due to poor efficacy and concerns about liver toxicity (see earlier news item).
In the NNRTI class, Tibotec's TMC125 (etravirine) in combination with an optimized background regimen was active against HIV in patients with extensive NNRTI and PI resistance (abstracts 154, 575b, 583).
In more disappointing news, Incyte Corporation announced in April that it would discontinue development of its NRTI candidate, DFC (dexelvucitabine, Reverset), after an "unacceptably high" number of participants (about 40%) in a long-term extension of the Phase IIb Study 203 developed severe lipase elevations, a sign of pancreatitis. The rate of lipase elevation was much lower among patients who also took 3TC (lamivudine, Epivir) or emtricitabine, but DFC did not work as well in these patients.
News Briefs"). Shering-Plough previously announced that it would halt development of vicriviroc due to virological breakthrough, but decided, based on the latest safety data, to continue a Phase II trial using higher doses.
PRO 140, a monoclonal antibody targeting CCR5, was granted FDA "fast track" status in February; a poster at the Retrovirus conference (abstract 515) reported that PRO 140 had "favorable tolerability, pharmacokinetic, and pharmacodynamic profiles" in an initial study, and remained bound to CCR5 for more than 60 days. Researchers from Tanox reported that the monoclonal antibody TNX-355 was active against HIV that uses either CCR5 or CXCR4 coreceptors (abstract 158LB). Pharmacokinetic and resistance data were presented on two other monoclonal antibodies in earlier stages of development, mAb004 (abstract 505) and KD-247 (abstract 506).
Researchers from Trimeris and Roche offered preclinical data showing that two next-generation peptide fusion inhibitors, TR-290999 and TR-291144 (abstract 48), had potent and long-lasting in vitro activity against HIV, including drug-resistant strains. These agents may require injection just once per week -- as opposed to twice daily for the sole approved fusion inhibitor, T-20 (enfuvirtide, Fuzeon). Researchers from Japan's Kureha Corporation reported on two orally available CXCR4 antagonist candidates, KRH-3955 and KRH-3140, which demonstrated potent antiviral activity in vitro and favorable pharmacokinetic and toxicity profiles in rats (abstract 49LB).
Another recent study by Manoli Vourvahis, PharmD, and colleagues (abstract 569) found that oral tenofovir reaches high extracellular and intracellular concentrations -- higher than plasma levels -- in men's genital tracts, and high extracellular concentrations in women's genital tracts, after 14 days of use as monotherapy or more than 20 days after being added to an existing antiretroviral regimen. Tenofovir monotherapy significantly reduced HIV viral load in the blood and genital tract over a period of 14 days in both men and women.
However, other data presented at the Retrovirus conference suggest that a combination of tenofovir plus emtricitabine (the drugs in the Truvada pill) is more effective than either used alone. J. Gerardo Garcia-Lerma, PhD, and colleagues from the CDC (abstract 32LB) administered daily subcutaneous injections of tenofovir plus emtricitabine to six rhesus macaque monkeys. After nine days, the animals were repeatedly challenged with weekly rectal exposures to a recombinant simian/human immunodeficiency virus (SHIV), in amounts similar to those present during sexual intercourse. None of the monkeys receiving combination PREP became infected after 14 exposures, compared with five out of six untreated control animals. In a third arm, two out of six monkeys became infected after receiving PREP using emtricitabine alone. In a study reported at the 2005 Retrovirus conference, all four monkeys who received PREP with tenofovir alone became infected.
Based on these results, some advocates have called for further studies of the feasibility of combination PREP in humans. "Project T" is currently looking at the safety of oral tenofovir monotherapy as PREP, but may add emtricitabine based on the latest study data (see "Open Clinical Trials"); similar studies are taking pace in Botswana and Thailand, but tenofovir PREP trials in Cambodia and Cameroon were cancelled due to ethical concerns about inadequate prevention counseling and provision of care to participants who happen to become infected.
Other concerns remain, including the fear that availability of a prophylactic medication (which may not be completely protective) might discourage people from practicing safer sex, and the possibility of the development and dissemination of tenofovir-resistant virus. Indeed, Garcia-Lerma's team (abstract 609) also presented data showing that within nine weeks, all 11 monkeys who received tenofovir monotherapy as PREP showed evidence of the K65R mutation, which confers resistance to tenofovir and other NRTIs.
Liz Highleyman is a freelance medical writer and editor based in San Francisco.
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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.