News Briefs

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10th Retrovirus Conference

The 10th Conference on Retroviruses and Opportunistic Infections, the major U.S. scientific meeting on HIV, took place February 10--14, 2003, in Boston. The conference drew nearly 4,000 participants and more than 800 abstracts were presented. The Retrovirus conference covered the full gamut of issues related to HIV, from global treatment access to managing opportunistic illnesses (OIs). But the primary themes were advances in antiretroviral therapy, novel treatment strategies, and treatment-related problems (including resistance and metabolic complications).

When to Start and What to Use

Despite the potential drawbacks of treatment, researchers and physicians agree that the benefits of starting combination anti-HIV therapy before CD4 cell counts fall below 200 cells/mm³ outweigh the disadvantages. Jonathan Sterne, PhD, and colleagues from the ART Cohort Collaboration (abstract 181) reported that CD4 cell counts and viral loads six months after starting therapy predict the development of AIDS-related illnesses and death better than baseline levels. E. Ferrer and colleagues from Barcelona (abstract 910) presented evidence suggesting that it may be better to start therapy before CD4 cell counts fall below 350 cells/mm³ (the recommended level in the current U.S. HIV treatment guidelines), but the exact best time to start treatment remains an open question.

The same is true for which regimen to start with. With many new anti-HIV drugs available, there is much more flexibility than in the past, including several once-daily options. Frank van Leth, MD, from the International Therapy Evaluation Center in Amsterdam and colleagues (abstract 176) presented the long-awaited first results from the multinational "2NN" study comparing the non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz (Sustiva) and nevirapine (Viramune)--both alone and combined--along with d4T (stavudine, Zerit) and 3TC (lamivudine, Epivir). Overall, efavirenz and once- or twice-daily nevirapine performed comparably well, although efavirenz was slightly (about 5%) more likely to suppress HIV--not a statistically significant difference--and appeared to work better in people with high viral loads. Nevirapine was more likely to cause serious side effects including liver toxicity and severe rash (one death due to each), while efavirenz caused more transient central nervous symptoms including bizarre dreams and sleep problems. Importantly, the study failed to demonstrate that using two NNRTIs provided additional benefit compared with just one, although considerably more people who used both NNRTIs together dropped out of the study due to side effects.

On the nucleoside reverse transcriptase inhibitor (NRTI) front, Schlomo Staszewski, MD, of Goethe-Universität in Frankfurt and colleagues (abstract 564b) reported that while tenofovir DF (TDF, Viread) and d4T appear to suppress HIV equally well, d4T is more likely to be associated with elevated blood fat levels and lipoatrophy (fat loss). Brian Kearney and colleagues from Gilead Sciences (abstract 533) presented results of a study of coadministration of tenofovir and once-daily ddI (didanosine, Videx). Because tenofovir increases ddI concentrations, ddI can be taken at a lower dose (250 mg once daily) with a light meal when used with tenofovir. While several presentations touted the benefits of tenofovir, there have been some disturbing reports of kidney toxicity associated with the drug (see news item below).

Treatment Delay and Interruption

Structured treatment interruption (STI) remains a controversial issue, and the conflicting results presented at the Retrovirus conference did little the resolve the debate. Jody Lawrence, MD, from the University of California at San Francisco (UCSF) (abstract 67) reported results from CPCRA 064 comparing immediate use of a new antiretroviral regimen against a four-month interruption prior to starting new therapy. Participants were 270 heavily treated individuals with advanced HIV disease who were experiencing treatment failure. After about a year of follow-up, 22 participants experienced disease progression or death in the deferred therapy arm, compared with 12 in the immediate therapy arm. The deferred group also had poorer CD4 cell responses when they restarted therapy. Because the delayed therapy arm was doing worse, a Data and Safety Monitoring Board halted new enrollments. The researchers recommended that people with multidrug-resistant HIV should not interrupt therapy before switching to a new regimen.

In contrast, Christine Katlama, MD, from Hôpital Pitié-Salpêtrière in Paris and colleagues (abstract 68) studied 68 heavily treated participants with advanced disease in the GIGHAART study who were also experiencing treatment failure. Compared with the CPCRA study, subjects in this trial had lower baseline CD4 cell counts and HIV that was resistant to more drugs. Participants were randomized to start treatment with a six- to eight-drug regimen immediately or after a delay of eight weeks. Unlike in the CPCRA study, viral load reductions were better in the participants who deferred therapy (38% undetectable vs 15% undetectable in the immediate arm) and CD4 cell increases were greater (69 cells/mm³ in the deferred group vs 7 cells/mm³ in the immediate arm).

Steven Deeks, MD, of UCSF (abstract 640) presented data on treatment-experienced people who stopped taking an entire class of drugs. Dr. Deeks had previously shown that when drugs are interrupted, wild-type (nonmutated) HIV usually overcomes less fit drug-resistant strains, which do not replicate as well; when people restart the same treatment, the drug-resistant HIV tends to come back. In Dr. Deeks's latest study, 15 people stopped taking all protease inhibitors (PIs), while five discontinued all NRTIs. Those who stopped PIs and continued NRTIs maintained stable viral loads and CD4 cell counts, while their blood fat levels decreased. Those who stopped NRTIs but continued PIs, however, experienced dramatic and rapid viral load increases (this arm of the study was halted). These intriguing results suggest that staying on "failing" NRTIs can still provide virological benefit. According to Dr. Deeks, such partial treatment interruptions may serve as a "bridge therapy" until better anti-HIV drugs become available.

Mark Dybul, MD, of the National Institute of Allergy and Infectious Diseases (NIAID) (abstract 68LB) reported on long-cycle treatment interruptions. In one study, 52 participants with baseline CD4 cell counts above 300 cells/mm³ and viral loads below 50 copies/mL were randomized to receive continuous therapy or treatment on an eight-weeks-on/four-weeks-off schedule. Study enrollment was halted due to the emergence of drug resistance in those starting and stopping therapy, and there was no significant reduction in blood fat levels in the cycling arm at 48 weeks. Stephano Vella, MD, of the Istituto Superiore di Sanità in Rome and colleagues (abstract 66) compared continuous and intermittent therapy (cycles of three months on followed by one or two months off) in a group of 273 participants. After the first, second, and third interruptions, 88.9%, 96.8%, and 100%, respectively, achieved viral loads below 400 copies/mL (vs 100% in the continuous therapy arm). However, after six months those in the intermittent arm were more likely to develop resistance.

Other researchers presented results from studies of open-ended treatment interruptions guided by CD4 cell count rather than continued for a set period of time. Jintanat Ananworanich, MD, from the Thai Red Cross AIDS Research Center in Bangkok and colleagues (abstract 64) compared continuous treatment, treatment interruptions that lasted as long as CD4 cell counts remained above a predetermined threshold, and one-week-on/one-week-off treatment cycles. After one year, those using the CD4 cell count-guided strategy took drugs for a shorter total time (about one-third of the year) and had better viral suppression. Luis Ruiz, MD, and colleagues from Barcelona (abstract 65) also looked at CD4 cell count-guided treatment interruptions. Participants began with baseline CD4 cell counts above 500 cells/mm³, nadir (lowest ever) CD4 cell counts above 100 cells/mm³, and viral loads below 80 copies/mL. During one year of observation, 57% restarted therapy because their CD4 cell counts fell below 350 cells/mm³ and/or their viral loads increased to more than 100,000 copies/mL, while 43% were able to stay off treatment with no apparent disease progression.

In summary, while timed treatment interruptions appear to yield little benefit, open-ended interruptions based on CD4 cell counts--as well as the new partial treatment interruption strategy--show some promise, but require further study.

Metabolic Complications

Numerous presentations at the Retrovirus conference dealt with metabolic manifestations related to anti-HIV therapy, including lipodystrophy, elevated blood fat levels, diabetes, reduced bone mass, and the potential for increased cardiovascular disease risk (see "HAART and the Heart" news item below). The first results from the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study were presented in three posters (abstracts 732, 733, and 734). FRAM is comparing 1,200 HIV positive men from multiple U.S. sites with 300 HIV negative participants enrolled in the CARDIA heart health study. Based on results to date, lipoatrophy (fat loss in the limbs, buttocks, and face) is the most common manifestation of fat abnormalities in men with HIV, and is not associated with abdominal fat gain. In this study abdominal fat accumulation and "buffalo hump" (fat accumulation at the back of the neck) occurred slightly more often in the HIV negative men, although the HIV positive men had larger "humps." Notably, FRAM is a cross-sectional study that looks at subjects at a single point in time; longitudinal studies that follow patients over time should provide more useful information.

In the area of elevated blood fat and glucose (sugar) levels, several presentations (including the "2NN" study described above and studies of fos-amprenavir described below) looked at how various drugs differentially affect lipid levels and insulin resistance. Research continues to implicate d4T as a major culprit in mitochondrial toxicity (damage to the energy-producing components of cells) and lipoatrophy; several studies have shown that switching from d4T to another NRTI can alleviate peripheral fat loss (in the extremities) (abstracts 133, 727, 728, and 729). Mark Boyd, MD, and colleagues from the HIV Netherlands/ Australia/Thailand Research Collaboration (abstract 738) found that subjects who stopped all NRTIs in favor of an indinavir (Crixivan)/ritonavir (Norvir)/efavirenz regimen gained back lost peripheral fat, but also gained visceral (intra-abdominal) fat and decreased lean body mass (muscle tissue).

In the general population, postmenopausal women are more susceptible to reduced bone mineral density (osteopenia and osteoporosis) compared with men of the same age, but the condition has not been well studied in women with HIV. Two studies presented at the conference did not find lower bone mass to be a major problem in HIV positive women. In one study (abstract 102), bone loss was minimal--0.5% per year--among women with high CD4 cell counts, and no association was seen with anti-HIV therapy. In the other (abstract 103), the rate of osteopenia or osteoporosis in HIV positive women (30%) was not significantly different from that of HIV negative controls (24%). Notably, in both studies a majority of the women were African American, and black women appear to be less susceptible to bone loss than white or Asian women; many of the women were overweight, also a protective factor. In terms of treatment, Pablo Tebas, MD, and colleagues from Washington University in St. Louis (abstract 134) reported that in a small study of 31 participants (mostly men), alendronate (Fosamax) plus calcium and vitamin D improved spinal bone density in HIV positive people with osteopenia or osteoporosis.

As has become clear over the past several years, metabolic abnormalities in people with HIV are a complex phenomenon. The conflicting, and in some cases unexpected, results presented at the Retrovirus conference shed more light on the issue, but do not yet provide definitive answers.

New Drugs

Researchers at the conference presented studies of many new drug candidates that may provide better options both for people just starting treatment and those who have exhausted current therapies. Although many of these experimental candidates will not be available for several years, researchers and people with HIV are encouraged by the fact that the drug pipeline is fuller than it has been in years.

Several new PIs are under study. GlaxoSmithKline's fos-amprenavir, or 908, is a more potent prodrug of amprenavir (Agenerase) that can be taken as two pills once or twice daily and does not require boosting with ritonavir; it is expected to be approved within the year. In the NEAT trial, fos-amprenavir suppressed HIV better than nelfinavir (Viracept) in treatment-naive individuals, and in the CONTEXT trial it worked almost as well as lopinavir (Kaletra) in treatment-experienced people. Bristol-Myers Squibb's atazanavir (Reyataz) provides good viral suppression in treatment-naive individuals and appears less likely to cause elevated blood fat levels or insulin resistance. (Atazanavir was recently approved; see news item below.) Boehringer Ingelheim's tipranavir, now in Phase III trials, is being touted as an option for treatment-experienced individuals. The first nonpeptide PI, it shows activity against HIV that is resistant to many other PIs. Due to its poor bioavailability, tipranavir requires boosting with ritonavir to achieve a reasonable daily pill burden. Other PIs further back in the pipeline include Tibotec's TMC114 and TMC125, and Roche's RO0334649.

Other new drugs in existing classes include emtricitabine (FTC, Emtriva), an NRTI related to 3TC that can be taken once daily; it also works against hepatitis B. While seen by many as a "me too" drug--one that does not offer a major advance--some believe its advantage lies in the creation of a once-daily emtricitabine/tenofovir combination pill. [Ed. note: FTC was approved in early July.] In Phase II studies, Pharmasset's racivir (another NRTI) appears to have a delayed effect that may allow less than once-daily dosing. GW4751 and related drugs are a new type of NNRTI that works against HIV with the K103N NNRTI-resistance mutation.

New drug classes also garnered considerable attention at the conference. Based on very preliminary data, Roche/Trimeris' second-generation fusion inhibitor, T-1249, appears to be active against HIV that has developed resistance to the recently approved T-20 (see news item below). Another type of entry inhibitor, CCR5 blockers, interfere with the attachment of HIV to host cell coreceptors; candidates in the pipeline include Pfizer's UK-427,857 (Phase I/II), Ono's AK602 (preclinical studies), and Takeda's TAK-220. Because chemokines such as CCR5 have other functions in the body, CCR5 inhibitors potentially could have serious side effects. Researchers from the Rega Institute in Belgium presented data on a new class of integrase inhibitors (including V-156) that prevent HIV from splicing its genetic material into the host cell's DNA. Panacos' PA-457, a betulinic acid derivative, inhibits assembly and budding of new HIV virions (virus particles).

Two other approaches that received a great deal of attention at the conference were monoclonal antibodies and RNA interference (RNAi). Tanox's monoclonal antibody, TNX-355, inhibits HIV attachment by binding to host cell CD4 receptors. Small interfering RNA (siRNA) are bits of genetic material that can "silence" the expression of genes and the production of certain proteins. Although an interesting concept, it is unclear whether RNAi will provide clinical benefit. For more information on several of the new experimental therapies presented at the Retrovirus conference, see " TMC114 and Other Investigational Drugs for Salvage Therapy."

Atazanavir Approved

On June 20 the U.S. Food and Drug Administration (FDA) approved Bristol-Myers Squibb's new PI, atazanavir (Reyataz). The drug provides good viral suppression in treatment-naive individuals (comparable to that of lopinavir, efavirenz, or nelfinavir) and appears less likely to cause elevated blood fat levels, although it may still contribute to lipodystrophy. Atazanavir is expected to be approved as a once-daily option for first-time therapy, since HIV that develops resistance to the new drug may still be sensitive--perhaps even hypersensitive--to other PIs. When used in treatment-experienced people, atazanavir may need to be boosted with ritonavir to achieve optimal potency. Safety results to date appear positive, although some questions remain about atazanavir's possible liver toxicity (the drug causes elevated bilirubin levels and jaundice in some people, similar to indinavir) and cardiac toxicity (it is associated with heart rhythm abnormalities).

T-20 (Fuzeon) Approved

On March 13 the FDA approved T-20 (enfuvirtide, Fuzeon), the long-awaited first entry inhibitor drug. T-20 works by preventing HIV from fusing with cell membranes and entering host cells. It was developed by Trimeris, and is being produced and marketed in partnership with Roche.

T-20 was approved as salvage therapy for treatment-experienced individuals who have exhausted other anti-HIV therapy options. Two Phase III studies--TORO 1 and TORO 2--showed that T-20 added to an optimized antiretroviral regimen reduced viral load and increased CD4 cell counts in people with multidrug-resistant HIV. At 48 weeks, 30% of participants taking T-20 achieved viral loads below 400 copies/mL, compared with 12% of those on an optimized regimen without T-20. These results were presented at the Retrovirus conference and published in the May 29, 2003 issue of the New England Journal of Medicine (NEJM). T-20 does allow the development of drug resistance in some people. T-1249, an experimental entry inhibitor candidate from the same manufacturer, may work against T-20--resistant HIV (see "TMC114 and Other Investigational Drugs for Salvage Therapy").

Unlike other approved anti-HIV drugs, T-20 powder must be mixed with sterile water and injected under the skin twice daily. People using T-20 are likely to experience reactions at the injection site, including pain, swelling, and hard nodules. People taking T-20 should immediately report to their health-care providers any symptoms that may indicate pneumonia (cough, fever, or difficulty breathing) or a hypersensitivity reaction (rash, fever, chills, vomiting, shortness of breath, or low blood pressure).

T-20 is difficult to produce--requiring more than 100 manufacturing steps--and comes with a correspondingly high price tag. At about $50 per day or $20,000 per year, it is more than twice as expensive as the next most costly anti-HIV drug. Advocates fear that the high price will make it difficult for Medicaid to pay for T-20, and impossible for many AIDS Drug Assistance Programs (ADAPs) to include the drug in their formularies. Several ADAP officials have met with Roche to request deep discounts for the drug. (For more on T-20 and drug pricing issues, see "Paying for Life".)

Meanwhile, Roche and Trimeris have established a Reimbursement Assistance Program to help guide patients through the third-party reimbursement process, and a Patient Assistance Program to provide the drug at reduced cost. In addition, the companies announced a Progressive Distribution Program (PDP) to manage the initially limited supply of the drug and help ensure uninterrupted access. T-20 will be available only through the PDP, and will be allocated on a first-come, first-served basis. (This will likely be a disadvantage to those who must wait for a decision from their state ADAPs about whether the drug will be covered.) The companies expect to be able to provide T-20 to 12,000--15,000 people worldwide by the end of 2003--about 10,000 of these in the U.S.--and 32,000 people in 2004.

Physicians may enroll patients by phone, fax, or mail. Enrollment forms are available at www.fuzeon.com. Once enrollment is approved, a 30-day supply of the drug will be shipped to the patient's home, the physician's office, or a local Chronimed/StatScript pharmacy. For more information, including injection instructions, call 866-694-6670 or visit the web site.

New Drug Formulations

In April the FDA approved a new formulation of Agouron/Pfizer's PI nelfinavir (Viracept). The new 625 mg tablet allows a dosage of two pills twice daily, compared with five of the previous 250 mg tablets twice daily. Any reduction in pill burden is likely to have a positive effect on adherence.

Also, this past December the FDA approved a new extended-release formulation of d4T (stavudine, Zerit) that can be taken once daily. Studies have shown that the new formulation--marketed as Zerit XR--is as effective as the older twice-daily version, yet maintains adequate drug concentrations in the blood for a longer period and can suppress HIV replication for 24 hours after dosing. (Note: the original twice-daily formulation should not be taken once per day as a doubled dose of two capsules.) With once-daily drugs, adherence is especially important since more time elapses between doses, potentially allowing resistance to develop if a dose is missed.

Solo Trizivir Study Arm Halted

In March NIAID halted one arm of AIDS Clinical Trials Group (ACTG) study 5095, looking at protease-sparing anti-HIV regimens, after early results showed that Trizivir (a combination pill containing AZT, 3TC, and abacavir) used alone was less effective than two combination regimens. After an average of 32 weeks, 79% of the treatment-naive participants taking only Trizivir achieved viral loads below 200 copies/mL, compared with 90% of those taking either Trizivir plus efavirenz or Combivir (AZT/3TC) plus efavirenz. Treatment failure occurred earlier and more often in the Trizivir-only arm regardless of initial viral load. NIAID issued a letter to health-care providers informing them of the decision to alter the trial. Results to date suggest that a single-class regimen containing only NRTIs may not be sufficiently potent to control HIV over the long term. In related news, the British HIV Association released new draft treatment guidelines at its April conference that recommend avoiding Trizivir alone as a first-line therapy due to its suboptimal efficacy.

Tenofovir Kidney Toxicity

Just over a year after the approval of tenofovir DF (Viread) in October 2001, the first reports of severe kidney toxicity (nephrotoxicity) associated with the drug began to appear in medical journals. Experts have been on the alert for this side effect since a similar drug--adefovir (Preveon)--failed to gain FDA approval as an anti-HIV treatment due to nephrotoxicity. Another related drug--cidofovir (Vistide), used to treat cytomegalovirus (CMV) retinitis--is also known to cause kidney damage. Although high doses of tenofovir caused kidney failure in animal studies, serious kidney toxicity was rare in human clinical trials of the drug.

In the December 2002 issue of the American Journal of Kidney Diseases, David Verhelst from Hôpital Tenon in Paris and colleagues reported on a 45-year-old woman who developed acute renal (kidney) failure and Fanconi syndrome (disruption of the kidneys' normal activity) five months after adding tenofovir to her anti-HIV regimen. In the April 11 edition of AIDS, Caroline Créput and colleagues from France reported a case of kidney damage in a 60-year-old man treated with tenofovir. And the April 15, 2003 issue of Clinical Infectious Diseases contained two articles on tenofovir-related nephrotoxicity. The first, by Alexandre Karras and colleagues from Hôpital Saint-Louis in Paris, concerned three cases of kidney toxicity, including renal failure and proximal tubular dysfunction. The second article, by Melissa Murphy, MD, and colleagues from Oregon Health and Science University in Portland, concerned a 49-year-old man with stable pre-existing impaired kidney function who died due to kidney failure and lactic acidosis several weeks after adding tenofovir to his regimen (which also included ddI).

Finally, in April researchers from Vancouver reported at the 12th Annual Canadian Conference on HIV/AIDS Research the results of a study of kidney toxicity in patients attending local HIV clinics, 322 of whom received tenofovir and 430 of whom received abacavir (Ziagen). In this study, the researchers reported kidney dysfunction if a person had a creatinine level 1.5 times normal (as opposed to the severe grade 3 or 4 creatinine elevations counted in tenofovir clinical trials). The researchers found that the tenofovir users were about three times more likely to develop elevated creatinine levels compared with those taking abacavir. Overall, about 7% of the participants receiving tenofovir in this study showed some degree of kidney dysfunction, and six stopped the drug due to nephrotoxicity.

These data indicate that it is important for people taking tenofovir to have their kidney function monitored regularly, including measurements of serum creatinine, electrolytes, and sugar and protein in the urine. Symptoms of kidney dysfunction--including unusual thirst, frequent urination, edema (swelling), fatigue, and muscle weakness--should be reported immediately to a health-care provider.

Controversial AIDSVAX Vaccine Results

On February 24 researchers from VaxGen announced initial results from a three-year randomized, controlled Phase III trial of its recombinant vaccine candidate, AIDSVAX. The vaccine is designed to stimulate the production of antibodies that attach to HIV's gp120 envelope protein, thus preventing the virus from binding to and entering cells. The vaccine did not significantly decrease the risk of HIV infection overall, but data suggest that it may be effective in certain racial groups.

The analysis included 5,009 high-risk volunteers in the U.S., Canada, and the Netherlands who received at least three doses of either AIDSVAX or a placebo; 4,185 were white, 326 were Hispanic, 314 were black, and 184 were Asian, mixed race, or other. Overall, the infection rate was 3.8% lower in vaccine recipients than in those who received the placebo--not a statistically significant difference. However, the rate was 67% lower among all non-white/non-Hispanic vaccine recipients, and 78% lower among black vaccine recipients; non-whites seemed to produce more antibodies in response to the vaccine. Statistical analysis showed that in the non-white volunteers, the vaccine appeared to reduce the risk of infection by between 30% and 84%, a result the company said was extremely unlikely to be due to chance alone.

The results are controversial because few non-white/non-Hispanic participants were included in the study: four of the 203 black volunteers (1.9%) and two of the 53 Asian participants (3.7%) who received the vaccine contracted HIV, compared with nine of the 111 blacks (8.1%) and two of the 20 Asians (10%) who received the placebo. "The company is claiming that this vaccine works better in African Americans and other non-Hispanic racial subgroups based on a difference of five people," noted Project Inform founding director Martin Delaney.

Reactions to the study results were mixed. "Last week, no human had ever been protected from HIV infection," said VaxGen president Donald Francis, MD. "This week, they have." Said UNAIDS director Peter Piot, MD, PhD, "These results are promising. The trial provides clear evidence that a vaccine can work." But Seth Berkley, MD, of the International AIDS Vaccine Initiative (IAVI) called the results "disappointing," and Phill Wilson of the Black AIDS Institute said, "However promising this vaccine may look for black people, it is a promise for tomorrow."

NIAID director Anthony Fauci, MD, called the results "quite provocative, unexplained, and surprising." He said the federal government would perform laboratory tests on blood samples from trial volunteers to look for immune or genetic factors that may help explain why the vaccine seemed to work better in certain people of color. AIDS advocates have called on the National Institutes of Health (NIH) to conduct an independent review of the study data. VaxGen expects that results from a similar Phase III trial in injection drug users in Thailand will be available later this year.

Palliative Care

In March the federal government issued new guidelines for palliative care for people with HIV disease. Palliative care refers to supportive measures aimed at preventing or easing pain and suffering. The document, "A Clinical Guide to Supportive and Palliative Care for HIV/AIDS," covers management of advanced HIV disease; psychosocial, cultural, and ethical issues; and end-of-life care. "This guide urges clinicians to treat not just the symptoms of this terrible disease, but to provide care that meets the physical, emotional, and spiritual needs of the individual," said Secretary of Health and Human Services Tommy Thompson. The guide is available at www.hab.hrsa.gov/tools/palliative.

New Clues about HIV Mutation and Antibodies

HIV mutates more rapidly than previously thought, according to research reported in the March 18, 2003 issue of the Proceedings of the National Academy of Sciences. Douglas Richman, MD, of the University of California at San Diego and colleagues found that the outer coat of HIV changes at an "incredibly rapid rate" in response to human antibodies. The researchers combined virus from HIV-infected individuals with luciferase (the light-emitting enzyme in fireflies) in order to visualize the virus as it replicates in antibody-containing blood plasma. They found that antibodies exert a "very strong selective pressure" on the virus, and that HIV mutates faster than the immune response can control it. "The bad news is that the virus is always staying a step ahead," said Dr. Richman.

In related news, George Shaw, MD, from Howard Hughes Medical Institute in Chevy Chase, Maryland, and colleagues reported in the March 20, 2003 edition of Nature that HIV continually changes the arrangement of sugar molecules in its outer envelope, which effectively blocks antibody attachment sites. This "glycan shield" helps the virus evade recognition and attack by antibodies, which can alter their own structure in response to a changing target but have trouble keeping up. Rapid viral evolution is the main impediment to developing effective anti-HIV treatments and vaccines.

Finally, Mario Clerici, MD, of the University of Milan and colleagues reported in the March 7, 2003 issue of AIDS that men who regularly have sex with HIV positive female partners yet remain uninfected have high levels of HIV-fighting antibodies in their semen. The study looked at 14 HIV negative men who had been having sex with an HIV positive woman partner for at least four years. Eleven of these men had relatively high levels of HIV-targeting IgA--a type of antibody found in bodily fluids that protects the entrances to the body--and antibody concentrations tended to be highest in the men who had recently had unprotected sex with their infected partners.

Viral Hepatitis

Several reports at the Retrovirus conference looked at hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection in people with HIV. Kelly Gebo, MD, from Johns Hopkins University in Baltimore (abstract 827) confirmed that HCV-related liver failure is now one of the major causes of death among people with HIV.

Results from a European multicenter study of 492 HIV/HCV-coinfected people (abstract 830) presented further evidence that HIV accelerates liver disease progression in people with hepatitis C. Shedding further light on this phenomenon, Jennifer Babik, MD, and colleagues from Stanford University in Palo Alto, California, reported in the February 2003 issue of the Journal of Virology that prolonged use of combination anti-HIV therapy in HIV/HCV-coinfected people is associated with a more genetically diverse population of HCV and higher HCV viral loads, both of which may accelerate hepatitis C disease progression.

For HIV/HBV-coinfected people, tenofovir continues to yield promising results. David Cooper, MD, of the University of New South Wales in Sydney and colleagues (abstract 825) presented data from Gilead study 903 showing that adding both tenofovir and 3TC to an existing anti-HIV regimen suppresses HBV replication better than 3TC alone.

Finally, new data were presented confirming that liver transplants can be successfully performed in people with HIV. Margaret Ragni, MD, from the University of Pittsburgh and colleagues from several transplant centers (abstract 155) found that HIV positive liver recipients have post-transplant survival rates similar to those of HIV negative recipients. Survival rates were 90.9%, 75.9%, and 75.9% at 12, 24, and 36 months, respectively. This study adds to the evidence that HIV status should no longer be considered a reason to deny someone a liver transplant.

GBV-C and HIV

Several presentations at the Retrovirus conference confirmed that GB virus type C, or GBV-C (formerly known as hepatitis G virus) may help prevent HIV infection and slow the progression of HIV disease. GBV-C is structurally related to the hepatitis C virus, but does not appear to cause disease. Carolyn Williams, PhD, of NIAID and colleagues looked at the effect of GBV-C coinfection in 271 men in the Multicenter AIDS Cohort Study (MACS). Analysis of blood samples from an early clinic visit (1--1.5 years after HIV infection) showed that 39% of the men had detectable GBV-C viral load and 46% showed evidence of past GBV-C infection and clearance. Looking at samples from a second visit 4--5 years later, men who had cleared GBV-C between the two visits were nearly six times more likely to have died, and men who were never infected with GBV-C were over two times more likely to have died, com