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San Francisco AIDS Foundation
News Briefs
Winter 2002/2003
Conference HighlightsSeveral important HIV/AIDS conferences have taken place in the past several months, including the XIV International AIDS Conference (Barcelona, Spain, July 7-12), the 4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV (San Diego, September 22-25), and the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC, San Diego, September 27-30).The International AIDS Conference focused largely on global issues. Topics of note included treatment interruption (see below), short-course treatment, delays in starting therapy (see below), HIV superinfection (see below), new pipeline drugs, heart disease in people with HIV, and drug-resistant HIV. Both former U.S. president Bill Clinton and former South African president Nelson Mandela spoke of the need for increased funding for HIV prevention and treatment in poor countries. The mood of the conference was somber as participants acknowledged the magnitude of the global epidemic and the fact that there is no AIDS cure or vaccine on the horizon. Several studies presented at ICAAC looked at simpler regimens that may help improve adherence. Michael Saag, M.D., of the University of Alabama at Birmingham presented promising results from a trial comparing the experimental once-daily nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine (FTC, Coviracil) with d4T (stavudine, Zerit) in combination regimens. Results for emtricitabine were so good, in fact, that the trial's Data and Safety Monitoring Board (DSMB) decided to end the study early. In September manufacturer Triangle Pharmaceuticals submitted a New Drug Application (NDA) for emtricitabine (see below). Once-daily dosing of 3TC (lamivudine, Epivir) also appears promising. Adding low-dose ritonavir (Norvir) to a regimen containing another protease inhibitor (PI) can help reduce pill burden and frequency of dosing. Gilles Raguin, M.D., from Hôpital Saint-Antoine in Paris and colleagues reported that adding ritonavir increased the effectiveness of regimens containing amprenavir (Agenerase) or lopinavir (Kaletra); Kaletra is already formulated with a small amount of ritonavir. In this study, adding extra ritonavir further boosted PI drug levels without significantly increasing side effects. Several studies looked at new drugs. Kathleen Squires, M.D., of the University of Southern California in Los Angeles presented some promising data on the new PI atazanavir (Zrivada). GlaxoSmithKline's GW433908, or simply 908 -- a prodrug of amprenavir -- appears effective and requires fewer pills each day. In the NEAT trial, after 24 weeks of therapy 54% of participants taking 908 and 40% of those taking nelfinavir (Viracept) achieved viral loads below 50 copies/mL. Other studies looked at anti-HIV drugs that work by novel mechanisms. Data were presented for TMC-125 (a non-nucleoside reverse transcriptase inhibitor, or NNRTI), TMC-114 (a PI), PRO 542 (an entry inhibitor), and S291 and N36E (two new peptide entry inhibitors). CCR5 receptor blockers and integrase inhibitors are further back in the drug development pipeline. (For more information on new drugs, see "The HIV/AIDS Drug Pipeline: A Status Report," BETA, Summer/Autumn 2002). Side effects of antiretroviral therapy were another major theme, especially lipodystrophy, elevated blood lipid (fat) levels (hyperlipidemia), and mitochondrial toxicity. The new PI atazanavir appears less likely than other drugs in its class to cause blood lipid elevations. Several researchers have conducted "switch studies" and tested regimens that "spare" (omit) certain drug classes in the hope of minimizing adverse effects. Many have explored protease-sparing regimens to reduce blood lipid elevations. A report at the Barcelona AIDS conference showed that an initial regimen of efavirenz (Sustiva), AZT (zidovudine, Retrovir), and 3TC was as effective as a regimen of nelfinavir, ddI (didanosine, Videx), and d4T, but was associated with fewer side effects. Many studies have shown that efavirenz (an NNRTI) is associated with less hyperlipidemia than nelfinavir (a PI). But atazanavir may produce even less hyperlipidemia than efavirenz; in one study, triglyceride levels actually decreased in those taking this drug. Switching from PIs to efavirenz reduced blood fat levels in children as well as adults. Several studies at ICAAC looked at treating hyperlipidemia in people using highly active antiretroviral therapy (HAART). In this population, lifestyle changes such as exercise and diet modification led to only modest improvements, and maintaining these changes was a problem. A study comparing the lipid-lowering drugs fenofibrate (TriCor), bezafibrate (Bezalip), pravastatin (Pravachol), and atorvastatin (Lipitor) found that both the fibrates and the statins reduced triglyceride and cholesterol levels by similar amounts, indicating that a variety of drugs can be used successfully to treat hyperlipidemia in people with HIV. At the Workshop on Adverse Drug Reactions and Lipodystrophy, Jeffrey Friedman, M.D., of The Rockefeller University in New York City gave a keynote lecture on the possible role of leptin in treating lipodystrophy. Leptin is a natural hormone produced by adipose (fat) tissue that regulates fat and glucose metabolism. A report by Elif Arioglu Oral, M.D., of the National Institute of Diabetes and Digestive and Kidney Diseases and colleagues in the February 21, 2002 issue of the New England Journal of Medicine described the use of leptin replacement therapy in HIV negative people with lipodystrophy. Two other abstracts at the workshop looked at the role of adiponectin, another hormone produced by fat cells, in people with HIV-related lipodystrophy and insulin resistance. Researchers are just beginning to explore the possibility of using leptin and adiponectin to treat body fat irregularities in people with HIV; study results can be expected at future conferences. Following the early success of protease-sparing regimens, some researchers are now exploring "nucleoside-sparing" regimens that omit NRTIs, the drugs most strongly associated with mitochondrial toxicity (damage to energy-producing organelles within cells). Studies at ICAAC showed that a regimen of lopinavir plus either efavirenz or saquinavir (Fortovase) without NRTIs had good antiretroviral potency. Among the NRTIs, d4T is most clearly associated with numerous side effects including lipoatrophy (loss of body fat, especially in the face and limbs) and mitochondrial toxicity. Researchers reported that people who discontinued antiretroviral therapy due to hyperlactatemia (high lactic acid levels, a symptom of mitochondrial toxicity) could restart treatment with a regimen that contained AZT, 3TC, or abacavir (Ziagen) -- NRTIs that are less likely to cause mitochondrial damage than d4T or ddI. Other studies showed that people who switched from d4T to abacavir, AZT, or tenofovir DF (TDF, Viread) regained some lost fat and showed less evidence of mitochondrial toxicity. Tenofovir is a newly approved nucleotide reverse transcriptase inhibitor (NtRTI) that so far has shown good efficacy and a favorable side effect profile. For conference programs, abstracts, and additional coverage see: XIV International AIDS Conference Workshop on Adverse Drug Reactions and Lipodystrophy www.hivandhepatitis.com/2002conf/adversedrug/main.html 42nd ICAAC
Priority Status for T-20On October 11 the U.S. Food and Drug Administration (FDA) granted priority review status to the first fusion inhibitor, T-20 (known generically as enfuvirtide). T-20 works by preventing HIV from entering cells. The drug -- to be marketed under the brand name Fuzeon -- was jointly developed by Trimeris and Hoffmann-La Roche. The companies submitted an NDA for T-20 in September based on results presented at the Barcelona AIDS conference. The study showed that after 24 weeks T-20 reduced HIV viral loads and increased CD4 cell counts in heavily treatment-experienced people; 37% in one study and 28% in another achieved undetectable viral loads (below 100 copies/mL). Although T-20 is active against HIV that has developed resistance to other antiretroviral drugs, data presented at ICAAC indicate that it is most effective in individuals with less resistance. As reported in the June 2002 issue of Antimicrobial Agents and Chemotherapy, T-20 itself can lead to resistance when used alone, and Roche recommends that it be used as part of a combination regimen. While T-20 has a favorable side effect profile, it requires refrigeration and careful mixing and must be injected under the skin twice daily, which may make adherence difficult.The FDA is expected to make a decision on T-20 by March 2003, and if the outcome is favorable the drug could be available shortly thereafter. Treatment advocates fear that because T-20 is difficult to manufacture, it will be more expensive than other anti-HIV drugs -- possibly $10,000-15,000 per year. Roche warned in August 2002 that supplies of the drug are limited, but said the company is working to increase production capacity.
New Rapid HIV Test ApprovedOn November 7 the FDA approved OraQuick, a long-awaited rapid HIV antibody test that provides results in about 20 minutes. To use the new test, a health-care worker takes a drop of blood using a finger stick (rather than drawing blood from a vein) and places it in a developing solution; the test strip changes color to indicate results. Although OraQuick is effective in ruling out HIV infection, if the results are positive a confirmatory test should be done.Federal officials requested that manufacturer OraSure Technologies apply for a waiver to make the new test more widely available at small clinics and test sites that do not have certified laboratories. To receive the waiver, OraSure must conduct further testing to determine whether providers with less training can accurately administer the test and interpret results. With existing widely used antibody tests, people usually must return to a test site after 1-2 weeks to receive their results; about 50% never do so. Advocates hope the new test will encourage more people to learn their HIV status and begin treatment earlier.
Two New Hepatitis Treatments ApprovedThe FDA recently approved two new treatments for viral hepatitis. On October 16 the agency approved Pegasys brand pegylated interferon-alpha-2a, manufactured by Hoffmann-La Roche, for the treatment of hepatitis C virus (HCV) infection. Pegylated interferon is a chemically altered form of interferon that lasts longer in the body and can be injected once rather than three times per week. Studies have shown that Pegasys in combination with the NRTI ribavirin is more effective than standard interferon plus ribavirin for both HIV/HCV-coinfected persons and those with HCV alone. In December the FDA approved combination therapy with Pegasys and Copegus, Roche's brand of ribavirin.In September the FDA approved adefovir (Hepsera) for the treatment of hepatitis B virus (HBV) infection. Research indicates that adefovir is effective against HBV (including 3TC-resistant strains) in both HIV/HBV-coinfected people and those with HBV alone. Adefovir is active against both HBV and HIV. The drug (then called Preveon) was developed as an anti-HIV medication, but was never approved because it caused kidney toxicity; Hepsera is used in lower doses (about one-tenth as much) to treat hepatitis B and therefore is safer. For more on treatment of viral hepatitis in people with HIV, see "HIV and Hepatitis Coinfection."
NDA Accepted for EmtricitabineIn early November Triangle Pharmaceuticals announced that the FDA had accepted the company's NDA for emtricitabine (FTC, Coviracil), a new NRTI drug. Promising study results for the drug were presented at the September ICAAC (see conference coverage above). The drug may be approved and on the market by the middle of 2003. The company is also applying for approval in Europe.
Amprenavir Label ChangeIn August the FDA announced a change in product labeling for amprenavir (Agenerase). The new precautions concern use of amprenavir with methadone or oral contraceptives. According to the new label information, coadministration of amprenavir and methadone can lead to decreased blood levels of methadone and decreased plasma amprenavir concentrations. Lower methadone levels could result in opiate withdrawal symptoms, and methadone dosages may need to be increased. The label suggests that "alternative antiretroviral therapy should be considered" for people using methadone.Regarding oral contraceptives, the new label advises that women taking amprenavir should not use hormonal contraceptives containing ethinyl estradiol and norethindrone because the pills can lead to decreased concentrations of amprenavir, potentially leading to loss of virological control. "Alternative methods of contraception are recommended" for women taking amprenavir, the label advises.
New Guidelines Recommend Longer Treatment DelaysNew International AIDS Society-USA (IAS-USA) guidelines for HIV treatment published in the July 10, 2002 issue of the Journal of the American Medical Association and announced at the Barcelona AIDS conference suggest that asymptomatic people with HIV can safely wait longer before starting therapy. The panel recommended that treatment should begin when CD4 cell counts fall to between 200 and 350 cells/mm3. The current U.S. Department of Health and Human Services guidelines recommend treatment when CD4 cell counts fall below 350 cells/mm3, and earlier guidelines had set the level at 500 cells/mm3.Recommendations are tending toward later therapy in part due to a greater recognition of and concern about drug side effects and resistance. While HIV treatment may be beneficial for some people with higher CD4 cell counts, the authors said that for this population the risks of therapy generally outweigh the benefits. Later initiation of treatment is supported by two studies presented in Barcelona. Alvaro Munoz, Ph.D., of Johns Hopkins University in Baltimore, Maryland, and colleagues compared people who had started HIV treatment with CD4 cell counts below 200 cells/mm3, between 201 and 350 cells/mm3, or between 351 and 500 cells/mm3. They found no significant differences in outcome between those who started therapy with 201-350 cells/mm3 and those who started with 351-500 cells/mm3. In contrast, those who started with CD4 cell counts below 200 cells/mm3 had greater HIV disease progression.
New Recommendations for Metabolic ComplicationsIn November the IAS-USA issued the first guidelines concerning metabolic complications related to HIV infection and antiretroviral therapy. The new guidelines -- which cover assessment and management of insulin resistance, abnormal lipid metabolism, abnormal body fat distribution, lactic acid disorders, and bone loss (osteopenia and osteoporosis) -- were published in the November 1, 2002 issue of the Journal of Acquired Immune Deficiency Syndromes.The 12-member IAS-USA panel that compiled the guidelines recommended that fasting glucose and blood lipid levels should be measured before initiating antiretroviral therapy or when a regimen is changed, then again after 3-6 months, then at least annually thereafter. Lactic acid should be measured in people taking NRTIs who show signs of elevated levels and in pregnant women. In terms of management, the panel recommended insulin-sensitizing drugs such as metformin (Glucophage) for insulin resistance, fibrate drugs for elevated triglyceride levels, and pravastatin or atorvastatin to reduce cholesterol levels. In addition, the guidelines suggest that PIs should be avoided if possible in people with preexisting diabetes, high blood fat levels, or cardiovascular risk factors. The panel made no recommendations regarding management of abnormal body fat distribution. According to panel chair Morris Schambelan, M.D., of San Francisco General Hospital, "These recommendations are important for clinicians because significant metabolic complications are affecting as many as half of all HIV-infected patients on antiretroviral regimens," and "are causing some patients to delay initiating therapy and others to reconsider their use of these life-saving medications." Like the federal HIV treatment guidelines, the new recommendations are a "work in progress" and will be modified as new information becomes available.
Structured Treatment InterruptionResearchers are increasingly interested in using structured (or strategic) treatment interruption (STI) -- carefully monitored breaks in antiretroviral therapy -- to help reduce drug side effects, overcome resistance, and possibly boost the immune system's response to HIV.Studies indicate that STI appears to work best in people with low HIV viral loads and relatively high CD4 cell counts. At ICAAC Elana Seminari from Pavia, Italy, and colleagues presented results from an STI study called FROG that used a one-month-on/one-month-off treatment schedule. At the beginning of the study the 62 participants randomized to try STI had viral loads below 50 copies/mL and CD4 cell counts above 300 cells/mm3. In this study, nadir (lowest ever) CD4 cell counts appeared to be more important than CD4 cell counts at the time STI was initiated. Participants who had ever had a CD4 cell count below 200 cells/mm3 (many in this study had nadirs below 50 cells/mm3) were at risk of having their counts once again fall below 200 cells/mm3 during off-treatment months. When CD4 cell counts fall to this level, people are at greater risk for opportunistic illnesses (OIs). Participants in this study were restarted on antiretroviral therapy if their CD4 cell counts fell to dangerous levels, but those with the lowest nadir tended to have poor CD4 cell recovery after resuming treatment. The results of this study suggest that people who have ever had a CD4 cell count below 200 cells/mm3 may not be good candidates for STI. Manuel Fernández-Guerrero and colleagues from Madrid, Spain, offered more promising results for people with higher CD4 cell counts. In this study, also presented at ICAAC, 49 participants who had started HAART with CD4 cell counts of 300-500 cells/mm3 were taken off therapy. At the time of treatment discontinuation the average CD4 cell count was about 750 cells/mm3 and the average viral load was approximately 700 copies/mL. After 16 months without HAART, the average CD4 cell count was about 500 cells/mm3 and the average viral load was 45,000 copies/mL -- still within the safe range based on the latest federal treatment guidelines, which recommend antiretroviral therapy for people with fewer than 350 CD4 cells/mm3 and viral loads above 55,000 copies/mL. Participants were able to regain virological control when they restarted HAART. The authors concluded that for asymptomatic people with baseline CD4 cell counts greater than 350 cells/mm3 and low viral loads, STI is "a safe practice that may improve quality of life, avoid drug side effects, and save money." In an article published in the September 15, 2002 issue of the Journal of Infectious Diseases, Pablo Tebas, M.D., of Washington University in St. Louis, Missouri, and colleagues similarly concluded that STI can be safe as long as CD4 cell counts remain above 200 cells/mm3. Because CD4 cell counts can drop rapidly in some people, however, frequent and careful monitoring is necessary. Another potential benefit of STI is reduced drug resistance and a reversion of mutated HIV to more drug-susceptible wild-type strains. At the Barcelona AIDS conference Christine Katlama, M.D., of Hôpital Pitié-Salpêtrière in Paris and colleagues reported on over 30 people with viral loads of at least 50,000 copies/mL and CD4 cell counts below 200 cells/mm3. The researchers found that after stopping HAART for eight weeks, more than one-half of the participants again became responsive to at least one class of antiretroviral drugs to which they had previously developed resistance. Viral load levels dropped ten-fold when the subjects resumed HAART. And in the October 2002 issue of the Journal of Acquired Immune Deficiency Syndromes, Walter Hauke, M.D., from Erlangen, Germany, and colleagues reported on a case in which the amount of multidrug-resistant HIV was greatly reduced after a seven-month treatment interruption. The man was able to successfully reinitiate therapy with previously used medications, leading the authors to conclude that STI may allow for drug "recycling." A similar study from Spain, however, showed no such benefits from stopping drugs for eight weeks. While STI may have certain benefits, improved immune response to HIV does not appear to be among them. In the October 7, 2002 online edition of the Proceedings of the National Academy of Sciences, Annette Oxenius, M.D., from Zurich, Switzerland, and colleagues reported that supervised breaks from antiretroviral therapy did not affect levels of HIV-targeting CD8 cells and were "generally unable" to reduce the HIV viral load set-point (the level at which the immune system initially holds viral replication, without treatment, at the end of acute infection) in the 97 participants studied. In contrast with some small previous studies, the authors concluded that STI does not appear to "train" the immune system to keep HIV under control.
New Findings on Long-Term NonprogressorsThe existence of long-term nonprogressors (LTNPs) -- people who remain asymptomatic without treatment long after they become infected with HIV -- has puzzled scientists for years. LTNPs, who make up an estimated 1%-5% of people with HIV, generally maintain relatively intact immune function, high CD4 cell counts, and low viral loads, sometimes after having the virus for 20 years or more.In 1986 Jay Levy, M.D., of the University of California at San Francisco (UCSF) discovered that the CD8 cells of LTNPs produce a protective chemical, which he called CD8 antiviral factor, or CAF. Since then, researchers have been unable to pinpoint what exactly the factor is. In 1995 Robert Gallo, M.D., now director of the Institute for Human Virology in Baltimore, identified a group of beta-chemokines (MIP-1a, MIP-1b, and RANTES) that appeared to block HIV replication; however, these proved ineffective against HIV strains that utilize CXCR4 rather than CCR5 coreceptors. This fall two research teams proposed new candidates as the elusive CAF. David Ho, M.D., of the Aaron Diamond AIDS Research Center in New York City and colleagues reported in the September 27, 2002 online issue of Science, and also at ICAAC, that they had uncovered a family of proteins -- called alpha-defensins -- that may protect cells from HIV infection. Alpha-defensins act as "natural antibiotics" and are produced by immune system white blood cells called neutrophils. Dr. Ho now suggests that the chemicals are also produced by CD8 cells and are active against viruses. Dr. Ho's team cultured CD8 cells from three LTNPs. When they introduced CD4 cells and HIV into the cultures, the virus did not infect the CD4 cells. After the researchers added antibodies that inactivated the alpha-defensins, however, HIV easily infected the CD4 cells. The team also used new protein chip technology to identify alpha-defensins based on their weight. On the heels of Dr. Ho, Mark Connors, M.D., of the National Institute of Allergy and Infectious Diseases (NIAID) and colleagues reported in the October 7, 2002 online edition of Nature Immunology that when the CD8 cells of LTNPs are exposed to HIV-infected cells, they proliferate rapidly and produce large amounts of a protein called perforin that kills virus-infected cells. Dr. Connors' team compared CD8 cells from 15 LTNPs and 25 progressors. Many researchers remain skeptical about the recent findings. "This is not it," said Dr. Levy of Dr. Ho's discovery. Dr. Levy maintains that CAF -- whatever it is -- blocks replication of HIV after it infects cells rather than preventing infection in the first place. Dr. Gallo suggested that there are probably multiple protective mechanisms operating in different LTNPs. "There is no single answer," he said. Ultimately, researchers hope the new findings might lead to the development of effective novel HIV vaccines or drugs. But even if one or both of the newest candidates proves protective against HIV in larger studies, such a prospect is many years in the future. Looking at long-term nonprogression from a different angle, Mary Carrington, M.D., of the National Cancer Institute and colleagues reported in the July 22 online edition of Nature Genetics that they had uncovered a genetic pattern associated with slower progression to AIDS. The genetic pattern includes two genes, one of which codes for a receptor on the surface of natural killer cells and the other of which codes for an HLA protein on the surface of white blood cells and other tissues. HLA markers are individualized identifiers that help the immune system distinguish the body's own cells from foreign invaders. Dr. Carrington's team analyzed the genetic blueprints of over 900 people with HIV and found that about 10% of European Americans carry the two protective genes; the gene pattern was less common among African Americans. People who carry both genes -- but not either one by itself -- were shown to experience slower HIV disease progression. Dr. Carrington speculated that when the specific HLA protein and receptor are both present, natural killer cells can more easily recognize and destroy HIV-infected cells, thus keeping the virus in check. She emphasized, however, that not everyone with the newly discovered gene pattern will experience slower HIV disease progression, and that others who do not possess the gene pattern are nevertheless LTNPs -- validating Dr. Gallo's contention that multiple factors are likely involved in delayed progression to AIDS.
HIV in Fat CellsFrance Pietri-Rouxel, M.D., of the Institut Cochin in Paris, and Jacques Leibowich of Hôpital Foch in Suresnes, France, reported at a meeting of the Institute for Human Virology in September that HIV can infect fat cells. In particular, the virus was found in the abnormal fat deposits of HIV positive people with lipodystrophy (unusual body fat distribution). Dr. Pietri-Rouxel conducts operations in which she removes accumulated abdominal fat and transplants it to fill out the sunken cheeks of people with lipoatrophy. Dr. Leibowich detected HIV genetic material in samples of fat he had requested from Dr. Pietri-Rouxel for an unrelated study. Dr. Pietri-Rouxel then sought and found HIV in the fat of seven of her patients who were taking HAART and had undetectable blood viral loads. The researchers next plan to look for HIV in the fat cells of people without lipodystrophy.HIV has long been known to infect immune cells, especially those that carry the CD4 and CCR5 cell surface receptors. As it turns out, fat cells also carry CCR5. Institute for Human Virology director Dr. Gallo said the finding might help explain why HIV is so difficult to eradicate. "That could be a major contributor to the reservoir," he suggested. "It could also be the reason that some people with HIV lose fat."
Male Sexual Dysfunction and HAARTAs if bone disease, body fat irregularities, and an increased risk of heart attacks were not enough, two new studies show that HIV positive men taking antiretroviral drugs are also more likely to experience sexual dysfunction.Amy Colson, M.D., from Harvard Medical School in Boston and colleagues conducted a retrospective survey of the medical records of 254 HIV positive men receiving care from a large New England health maintenance organization (HMO) between 1993 and 1998. The results were reported in the May 2002 issue of the Journal of Acquired Immune Deficiency Syndromes. All of the men received antiretroviral regimens that included a PI at some point during this period: indinavir (62%), nelfinavir (46%), ritonavir (46%), or saquinavir (41%); in many cases more than one of these drugs were used concurrently. At least three-quarters also received NRTIs. Only 27% used NNRTIs. Eighty cases of either loss of libido or erectile dysfunction were found in a search of the men's records. The rate of sexual dysfunction was highest in those taking ritonavir, followed by indinavir, nelfinavir, and saquinavir. NRTIs and NNRTIs as a class were not associated with sexual problems. On the whole, the men had advanced HIV disease -- not surprising since the survey time frame included years before the advent of PIs in 1996. The men also had a variety of other conditions often associated with sexual dysfunction including depression (35%), high blood pressure (14%), alcoholism (12%), and diabetes (7%). There were no significant differences in testosterone levels between men with and without sexual difficulties. Given the general ill health of the men in the early years of the survey period, the researchers said they expected to see a decrease in sexual dysfunction as more effective treatment with PIs became available. However, the opposite trend was seen, supporting an association between PIs and increased sexual dysfunction. Francis Lallemand of INSERM in Paris and colleagues reported results from a more recent prospective study in the June 2002 issue of the same journal. The researchers looked at 156 gay and bisexual men with HIV with a median age of just over 40 years. One hundred and eleven men reported some degree of sexual dysfunction since they began taking antiretroviral therapy. The rates were similar in men who had taken HAART regimens containing a PI for at least a month, those who had stopped treatment more than one month prior to the study, and those who had never taken a PI (71%, 73%, and 65%, respectively). Altogether, 89% reported reduced or absent libido, 86% reported erectile dysfunction, and 59% reported ejaculatory difficulties. Only 18% said they had experienced sexual dysfunction before they tested positive for HIV, and 32% said they had experienced sexual problems after becoming HIV positive but before starting antiretroviral therapy. While some previous studies have suggested that PIs may be associated with sexual dysfunction, this study found no differences related to whether or not the men were taking regimens that included a PI. "Given the increased life expectancy of HIV-infected patients since the advent of HAART, their sexuality should no longer be considered only in terms of prevention of transmission," wrote the authors. "Sexual dysfunction in these patients should be specifically diagnosed and treated as in patients with other chronic diseases such as diabetes, hypertension, and depression."
Fumagillin for MicrosporidiosisJean-Michel Molina, M.D., of Hôpital Pitié-Salpêtrière in Paris and colleagues reported in the June 20, 2002 issue of the New England Journal of Medicine that the fungal antibiotic fumagillin (Fumidil B) can effectively treat microsporidiosis caused by the parasite Enterocytozoon bieneusi in people with immune dysfunction. Microsporidiosis is an intestinal infection characterized by chronic diarrhea, malabsorption, and wasting. Fumagillin is the first therapy that effectively clears the parasite. Study participants included ten people with AIDS and two organ transplant recipients (transplant recipients are given drugs that suppress immune function in order to prevent organ rejection). One-half received fumagillin and one-half were given a placebo. After two weeks, all six taking fumagillin achieved E. bieneusi clearance, compared with none of those taking placebo; the placebo recipients were then switched to open-label fumagillin and they too all cleared the parasite. Three of those taking fumagillin developed bone marrow toxicity and low blood cell counts; two later relapsed.
Companies Heed Call for Nonoxynol-9 DiscontinuationMajor manufacturers of sexual lubricants have responded to activist pressure to remove nonoxynol-9 (N-9) from their products. N-9 is a detergent that kills sperm and many microorganisms. Long used as a contraceptive, N-9 was added to several brands of lubricants and condoms in the mid-1980s in the hope that it would help prevent HIV transmission. But research has shown that N-9 can cause vaginal and anal irritation that may promote the spread of HIV and other sexually transmitted infections (STIs).Studies found that female sex workers who frequently used N-9 had a higher risk of HIV infection. More recently, research showed that N-9 caused shedding of the sheets of protective epithelial cells that line the anus. Both the U.S. Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) have issued cautions about the rectal use of N-9. According to a WHO report, there is no evidence that N-9-lubricated condoms provide any additional protection against pregnancy or STIs (although it is better to use a condom with N-9 than no condom at all). These study findings and warnings were not widely disseminated, however, and a recent survey showed that over 40% of gay men preferred lubricants containing N-9, believing they offered extra protection. In September a coalition of scientists and health groups -- including the San Francisco AIDS Foundation, the Global Campaign for Microbicides, the American Foundation for AIDS Research, the Gay and Lesbian Medical Association, the National Women's Health Network, and Planned Parenthood -- issued a letter calling on manufacturers to stop adding N-9 to sexual lubricants and condoms. (The call did not include contraceptive products designed exclusively for vaginal use.) The letter, along with an investigative series in San Francisco's Bay Area Reporter newspaper, led several stores to agree to discontinue sales of products containing N-9 and led manufacturers to agree to stop adding the ingredient to their lubricants. However, some manufacturers continue to add N-9 to condoms. Advocates are concerned that N-9 on condoms could potentially increase the risk of HIV transmission if a condom breaks.
HAART Not Associated With Adverse Birth OutcomesAccording to a report in the June 13, 2002 issue of the New England Journal of Medicine, use of antiretroviral therapy during pregnancy does not appear to increase the risk of stillbirth or premature birth. Ruth Tuomala, M.D., of Brigham and Women's Hospital in Boston and colleagues looked at the pregnancy outcomes of 2,123 HIV positive women who received antiretroviral therapy in seven clinical trials and 1,143 women with HIV who did not receive treatment. The women gave birth between 1990 and 1998. Because much of the time frame of the study covered years before the advent of PIs, only about 6% received combination regimens that included a PI. Nineteen percent used combination regimens without a PI and 74% received monotherapy. The study was initiated by the National Institutes of Health after some earlier studies suggested that anti-HIV therapy might be associated with poor birth outcomes.After controlling for factors such as CD4 cell count and alcohol, tobacco, or illegal drug use, the researchers found that rates of stillbirth, premature birth, low birth weight, and abnormal APGAR scores (a measure of newborn viability that includes pulse, skin color, and respiration) did not differ significantly between the women receiving antiretroviral therapy and those not on treatment. Sixteen percent of treated women and 17% of untreated women delivered prematurely, and 16% in both groups gave birth to low birth weight infants (less than 2,500 grams). Outcomes were comparable between the women who received monotherapy and those who received combination therapy, and between those who did and did not use PIs. Seven women (5%) who received PIs delivered very low birth weight infants (less than 1,500 grams) compared with 34 women (2%) who received non-PI monotherapy and nine women (2%) who received combination therapy without a PI. This trend was not significant, and the number of women receiving PIs was small. The researchers suggested that women with the most advanced HIV disease were most likely to receive PIs when they first became available, and that severity of illness might help explain the difference. Dr. Tuomala concluded, "Our data provide reassurance that the risks of adverse outcomes of pregnancy that are attributable to antiretroviral therapy are low and are likely to be outweighed by the recognized benefits of such therapy during pregnancy."
HIV Superinfection DocumentedIn news that has implications for prevention and vaccine development, different research groups have recently reported cases of HIV superinfection.The first case was reported at the Barcelona AIDS conference by Bruce Walker, M.D., of Massachusetts General Hospital in Boston. The Boston man was one of 14 undergoing experimental STI under Dr. Walker's supervision. The man began treatment soon after his initial infection with HIV, and was taken off therapy periodically in the hope of boosting his immune response to the virus. He was doing well after two rounds of on again/off again treatment, but then -- soon after having unprotected sex -- experienced a dramatic increase in HIV replication. Researchers genetically sequenced the man's virus and found a new strain of HIV that was 12% different from his initial strain. The man was restarted on antiretroviral therapy, but responded poorly and experienced a decline in his condition. Two more cases of superinfection were reported in the August 1, 2002 issue of the Journal of Virology. These cases, reported by Artur Ramos of the CDC and colleagues, occurred in injection drug users in Thailand. In both cases the second infections were detected several weeks after the individuals had apparently developed good antiviral responses to their initial infections. Another case was also reported at the Barcelona conference and published in the September 5, 2002 issue of the New England Journal of Medicine. Bernard Hirschel, M.D., Stephanie Jost, and colleagues from the University of Geneva reported on a 38-year-old HIV positive man who contracted a second strain of HIV more than two years after his initial infection in 1998. As part of a study of early HIV treatment, after two years of successful therapy the man received an experimental immune-boosting vaccine and was taken off therapy. Soon thereafter, in April 2001 -- after having unprotected sex while on vacation in Brazil -- the man experienced a steep increase in viral load, leading to the recognition of a second infection with a new strain of HIV. The new strain was one that is common in Brazil but uncommon in Europe. The man resumed antiretroviral therapy and has responded well. Researchers are concerned that the recent case reports suggest that developing a vaccine that stimulates an effective immune response to HIV may be even more difficult than previously assumed. Dr. Walker's case indicates that a person who apparently has developed a good natural immune response to HIV is still susceptible to reinfection, even with a similar strain. Dr. Hirschel's case -- in which the man was infected with a distinct strain from a different part of the world -- emphasizes the difficulty of developing a vaccine that will be effective worldwide. Said Dr. Hirschel, "It just shows how little we understand what's happening with HIV-related immunity." Although superinfection remains rare, the new findings lend weight to safer sex messages for people with HIV. Some individuals have concluded that since they are already infected, they can safely have unprotected sex with other HIV positive people. But as Dr. Walker's case illustrates, superinfection can lead to HIV disease progression and poor response to antiretroviral therapy. "With sexual activity seemingly increasing among persons with HIV-1 infection," Dr. Walker wrote in an editorial accompanying Dr. Hirschel's findings, "this is a public health message that needs to be broadcast loud and clear." Liz Highleyman (liz@black-rose.com) is a freelance medical writer and editor based in San Francisco.
This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. |
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