For the latest updated treatment guidelines for adults and adolescents, children, and pregnant women; postexposure prophylaxis guidelines for occupational and non-occupational HIV exposure; and opportunistic illness (OI) prevention guidelines, visit www.hivatis.org.
The 9th Conference on Retroviruses and Opportunistic Infections (the Retrovirus conference) took place February 24-28, 2002, in Seattle, Washington. Along with the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), the Retrovirus conference is the major venue for presentations of new medical research on HIV/AIDS. For detailed conference reports, see the following web sites:
A study by Margaret Fischl, MD, of the University of Miami, Florida, and colleagues showed that in people with advanced HIV disease, a four-drug combination regimen containing AZT (zidovudine, Retrovir), 3TC (lamivudine, Epivir), indinavir (Crixivan), and efavirenz (Sustiva) led to better viral suppression (77%) than a regimen containing the same three drugs minus efavirenz (69%) or a four-drug regimen that substituted nelfinavir (Viracept) for efavirenz (52%). Side effects were similar in the efavirenz group and the three-drug group, but toxicity was higher in the nelfinavir group. This trial suggests that a regimen that includes all three of the major available antiretroviral drug classes -- nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) -- may be superior to a two-class regimen, even if the same number of drugs is used.
Other research at the conference showed that people who switch to a protease-sparing regimen may be able to lower blood fat levels. High blood lipid levels are commonly seen in HIV positive people receiving antiretroviral therapy, and are a known risk factor for cardiovascular disease in the general population. Switching to a regimen containing nevirapine (Viramune, an NNRTI) produced the best results, but switching to either efavirenz (another NNRTI) or abacavir (Ziagen, an NRTI) also lowered lipid levels. However, other studies have produced conflicting results, and many physicians are reluctant to switch regimens if a person is otherwise doing well. For more new research related to cardiovascular disease, see Cardiovascular Disease in People With HIV.
The issue of when to begin anti-HIV therapy remains controversial. Despite recently revised federal treatment guidelines that suggest beginning therapy later, researchers from the University of Washington presented results indicating that early treatment may be more beneficial. At their clinic, people who began treatment within the first year of enrollment had less than half the risk of death or serious illness compared with those who waited more than a year to begin therapy. A team from the EuroSIDA study also showed that delaying or interrupting treatment may increase the likelihood of serious illness or death. In this 25-country study of 5,400 participants, those who stopped treatment for three months had a six times greater risk of dying or developing a serious opportunistic illness (OI). However, this increased risk was seen only in people with CD4 cell counts below 200 cells/mm3. The revised federal guidelines recommend treatment for people with fewer than 350 CD4 cells/mm3.
Data on several new drugs -- including atazanavir (Zrivada), tipranavir, T-20, and a new class of entry inhibitor drugs -- were presented at the conference; for an update, see The HIV/AIDS Drug Pipeline: A Status Report.
Mitchell Wolfe, MD, MPH, and colleagues from the Centers for Disease Control and Prevention (CDC) gave an update on causes of death in people with HIV since the advent of highly active antiretroviral therapy (HAART). The overall death rate for HIV positive people has fallen since effective combination therapy became widely available in 1996. Deaths due to OIs such as Pneumocystis carinii pneumonia (PCP) and tuberculosis have declined dramatically. When such OI-related deaths still occur, it is often because people are unaware of their HIV positive status or do not begin antiretroviral treatment or recommended OI prophylaxis. In contrast, rates of deaths due to non-Hodgkins lymphoma, wasting, sepsis (systemic infection), and kidney, heart, and liver disease have risen. The researchers suggested that the increase in liver disease is likely related to adverse effects of antiretroviral drugs, coinfection with hepatitis C virus (HCV), and extended lifespan.
Ronald Reisler, MD, MPH, from the National Institute of Allergy and Infectious Diseases (NIAID) and colleagues studied the incidence of life-threatening (grade 4) adverse events in over 3,000 people receiving HAART in five large Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) trials. Overall, about one-quarter experienced a grade 4 event after 30 months on therapy. The most common serious side effects were liver damage (6.1%), neutropenia (low white blood cell count, 3.9%), pancreatitis (inflammation of the pancreas, 2.2%), anemia (low red blood cell count, 2.1%), psychiatric conditions (2.1%), heart and cardiovascular conditions (1.6% each), kidney damage (1.5%), thrombocytopenia (low platelet count, 1.2%), and hemorrhage (bleeding, 0.9%). The 30-month rate of AIDS-defining illnesses was 13.4% and the 30-month mortality rate was 10.6%. The researchers concluded, In this large U.S. HIV cohort treated with HAART, the rate of grade 4 events is higher than the rate of AIDS; and the risk of death associated with a grade 4 event and the risk of death associated with AIDS were similarly high.
Preliminary results from a study by Michelle Roland, MD, and colleagues from the University of California at San Francisco (UCSF) indicate that rates of successful organ transplants in people with HIV are comparable to those in HIV negative persons; 95% of HIV positive people in the study with kidney transplants and 84% of those with liver transplants were still alive after one year.
Finally, researchers from Brazil presented data showing that the availability of postexposure prophylaxis (PEP) for HIV does not appear to lead to an increase in risky sexual behavior.
In mid-May GlaxoSmithKline (GSK) warned people with HIV and their health-care providers to be alert for counterfeit drug labels. The company reported that fake labels for Combivir (AZT/3TC) had been found on some sealed bottles that actually contained abacavir; both drugs are produced by GSK. Suspect labels were found on four bottles of abacavir in California, Connecticut, Maryland, and Florida. It is recommended that people examine the contents of drug bottles labeled as Combivir. Combivir is a white tablet marked GX FC3 (as depicted on the label), while abacavir is a yellow tablet marked GX 623. People who have suspicions about their medications should contact their pharmacists; suspected tampering can be reported to GSK at 888-825-5249.
The mix-up could be dangerous because about 5% of individuals who take abacavir develop a potentially life-threatening hypersensitivity reaction; persons who experience such a reaction should stop the drug and not use it again. An unintended medication switch also could interfere with the effectiveness of therapy. A spokesperson for GSK said the label switch appeared to be financially motivated, since Combivir sells for considerably more than abacavir. The company said the tampering appeared to be isolated and limited in scope, and that no related adverse reactions had been reported. The Food and Drug Administration (FDA) is investigating the situation.
In March the product label for d4T (stavudine, Zerit) was changed to reflect the possible side effect of lactic acidosis and associated neuromuscular toxicity. The action comes after the drugs manufacturer, Bristol-Myers Squibb, issued a letter to health-care providers in February warning of the possible adverse reaction. Lactic acidosis is a build-up of lactic acid in the body, and is known to be associated with NRTI drugs. The FDAs Adverse Event Reporting System has received reports of 25 cases of neuromuscular weakness resembling Guillain-Barré syndrome in people taking the drug; six of these individuals died. Fatal lactic acidosis previously has been reported in pregnant women who took d4T plus ddI (didanosine, Videx). The revised d4T label includes symptomatic hyperlactatemia syndrome among the drugs adverse effects. Symptoms may include abdominal pain, nausea, vomiting, fatigue, and respiratory difficulty in addition to muscular weakness, especially in the arms and legs. Most severe cases occurred in people who continued the drug despite early symptoms. Persons who experience such symptoms while taking d4T should consult their health-care providers. If lactic acidosis is suspected, the label recommends that all antiretroviral medications should be discontinued. If the condition is confirmed, permanent discontinuation of d4T should be considered.
In May the FDA gave preliminary approval to a rapid HIV-1 antibody test called OraQuick, produced by OraSure Technologies. The new test requires a drop of blood from a finger stick and can yield results in 20 minutes; in contrast, traditional HIV antibody tests require a vial of blood to be drawn from a vein and take several days to yield results. Public health officials have eagerly awaited a rapid HIV test that can provide on-the-spot results because as many as one-third of people tested in public clinics do not come back after their blood draw to obtain their results.
In March the FDA approved a nucleic acid test called Procleix that can detect small amounts of HIV-1 and hepatitis C virus genetic material in the blood. The genetic fingerprinting assay, manufactured by Chiron, works by amplifying viral genetic material to a detectable level. Because it can detect smaller amounts of HIV and HCV RNA, Procleix can register the presence of the viruses sooner after infection. The assay will allow blood banks to more rapidly test donated blood for the viruses. Procleix has been tested worldwide and already is in use in about two-thirds of U.S. blood banks. Some experts question the cost-effectiveness of the new test since the risk of contracting HIV from donated blood in the U.S. is already very low. The assay is expected to cost about $15 per pint of blood. In a three-year study at U.S. blood banks, Procleix detected seven HIV and 88 HCV infections that were not revealed by older blood screening tests. Roche Diagnostics also is seeking FDA approval for its own nucleic acid test, which is currently undergoing trials.
As noted above, about 5% of people taking abacavir develop a hypersensitivity reaction, which may be characterized by fever, skin rash, vomiting, abdominal pain, muscle aches, and/or shortness of breath. Abacavir should be discontinued in people who experience such symptoms; restarting the drug can be fatal.
A new genetic test may help predict who is likely to experience this life-threatening reaction. Researchers from the Royal Perth Hospital in Australia examined DNA from 200 people taking abacavir and discovered three genetic variants associated with drug hypersensitivity. The results were presented at the February Retrovirus conference and published in the March 2, 2002 issue of The Lancet. Eighteen persons developed hypersensitivity; of these, 72% had a combination of the HLA-B*5701, HLA-DR7, and HLA-DQ3 gene variants. People with the HLA-B*5701 variant were over 100 times more likely to experience the reaction than those without the variant. Researchers from GSK have found that 46% of people who experience abacavir hypersensitivity have the HLA-B*5701 variant; this is considerably lower than the percentage reported by the Perth team, perhaps due to different frequencies of the gene in the two populations studied. Simon Mallal, MD, one of the authors of the Perth study, reported that he now routinely tests for the gene variants before prescribing abacavir, and has reduced the occurrence of hypersensitivity reactions among his patients from 9% to 2.5%. Such genetic tests are currently expensive -- about $500 -- making the cost per case of hypersensitivity detected between $10,000 and $50,000.
A new test has been developed to measure mitochondrial toxicity in people receiving antiretroviral therapy. Mitochondria are organelles within cells that play a role in energy production. NRTI drugs have been associated with mitochondrial dysfunction. The new blood test, developed by Julio Montaner, MD, of the University of British Columbia in Vancouver and colleagues, can detect mitochondrial damage early, giving physicians a chance to change drug regimens before symptoms -- including fatigue, shortness of breath, and rapid heartbeat -- occur. The test measures the level of mitochondrial DNA circulating in the bloodstream. Although mitochondrial damage is associated with lactic acidosis, measurement of lactic acid in the blood is not a reliable indicator of mitochondrial dysfunction. The researchers found that mitochondrial DNA was significantly depleted in people taking antiretroviral drugs who experienced symptoms associated with mitochondrial toxicity. Once the offending drugs were discontinued, mitochondrial DNA levels again increased. The test is currently in the research stage and is not yet commercially available. Study results were reported in the March 14, 2002 issue of the New England Journal of Medicine.
In March the FDA warned that kava kava, a popular herbal supplement, may cause serious liver damage. Kava kava often is used to relieve anxiety and as a sleep aid. Problems may be especially likely in people with existing liver damage (such as those with chronic hepatitis) and those taking anti-HIV drugs that can affect the liver. The FDA began to investigate the supplement after a previously healthy woman experienced liver failure and required a transplant after using it. Similar cases have been reported in other countries. Regulatory agencies in Europe, Canada, and Australia also have issued warnings. Advisors to the German government have recommended that the herb be available only by prescription. People who experience early symptoms of liver damage -- which may include fatigue, nausea, abdominal pain, loss of appetite, and jaundice (yellowing of the skin and whites of the eyes) -- should consult their health-care providers promptly.
Researchers reported in the May 14, 2002 issue of the Proceedings of the National Academy of Sciences that natural killer (NK) cells, a type of immune system white blood cell, can be infected by HIV and may be reservoirs for the virus. NK cells are lymphocytes that contain chemical granules and act as a first line of defense, destroying cells that are cancerous or infected with microorganisms. George Pavlakis, MD, from the National Cancer Institute and colleagues examined ten treatment-naive HIV positive persons who had been taking HAART for 1-2 years. While combination therapy reduced HIV viral load, viral material still could be detected in NK cells as well as in CD4 helper T cells. Not only do these cells get infected, said Dr. Pavlakis, they stay infected even with antiretroviral therapy.
It has long been known that CD4 cells and macrophages also serve as HIV reservoirs. In the May 2, 2002 issue of Nature researchers confirmed a long-standing suspicion that HIV specifically targets CD4 cells that are programmed to attack the virus. Daniel Douek, MD, of NIAID and colleagues studied immune cells from 12 HIV positive individuals and found that HIV-specific memory CD4 cells contained 2-5 times more HIV genetic material than non-HIV-specific memory CD4 cells. The research team also looked at four individuals who underwent structured treatment interruptions (STIs). They found that stopping antiretroviral drugs led to a rebound in HIV viral load, which in turn spurred an increase in HIV-specific CD4 cells, thus providing the virus with more potential cells to infect. The researchers noted that their results imply that treatment interruptions should be done with extreme caution. The results also suggest that stimulating HIV-specific CD4 cell production may be a risky HIV vaccine strategy.
Researchers from Johns Hopkins University in Baltimore, Maryland, reported in the April 15, 2002 issue of the Journal of Infectious Diseases that measles appears to suppress HIV. The research team looked at 93 HIV positive children in Zambia infected with the measles virus. They found that while the measles virus was most active, HIV replication was inhibited. William Moss, MD, said that the researchers were surprised by the results; they had expected that, because measles usually suppresses the immune system, HIV replication would increase during measles infection. Instead, immune system activation in response to measles led to increased CD8 killer T cell counts and a temporary suppression of HIV. After the children recovered from measles, their HIV viral loads once again increased. A similar effect has been seen with scrub typhus, a bacterial infection that is much less common than measles.
Harold Burger, MD, of the Wadsworth Laboratory in Albany, New York, and colleagues reported results at the February Retrovirus conference that may shed light on why the rate of heterosexual HIV transmission in the U.S. and Europe is lower than the rates in Asia and Africa. Dr. Burgers team compared 2,047 HIV positive U.S. women and 558 HIV negative women matched for race and age. They found a statistically significant difference in the frequency of the delta-32 gene mutation, which has been shown to be protective against HIV infection. People with two delta-32 alleles (a persons has two alleles for each gene, one from each parent) produce abnormal CCR5 cell surface receptors; because HIV does not recognize the receptor, it cannot infect the cell. People with one delta-32 allele appear to be partially protected. The researchers found that HIV negative women were about twice as likely to have the protective gene mutation. Among white women, 1.2% of HIV negative women had at least one delta-32 allele compared with 0.6% of HIV positive women. In addition, they found that white women had a considerably higher frequency of the delta-32 mutation than African-American women (1.2% vs 0.2% for HIV negative women; 0.6% vs 0.1% for HIV positive women). The researchers suggested that the lower frequency of the genetic mutation in non-Caucasians may increase their susceptibility to HIV infection.
Older people with HIV respond at least as well to antiretroviral therapy as their younger counterparts, according to research published in the April 2002 issue of the Journal of the American Geriatrics Society. Kenneth Schmader, MD, of Duke University in Durham, North Carolina, and colleagues looked at the effectiveness of antiretroviral therapy in 101 HIV positive persons aged 50 years or older and in 202 people aged 18-39. The two groups experienced similar CD4 cell count increases, and the older participants were more likely to achieve an undetectable viral load (47% in the older group vs 34% in the younger group). The new research contradicts a prevalent belief that older people do not benefit as much as younger people from anti-HIV therapy. Past research has shown that older HIV positive people progress more rapidly to AIDS than do younger individuals, but those studies were conducted before the advent of HAART. Dr. Schmader and colleagues suggested that older people may be more likely than younger people to adhere to complex anti-HIV regimens.
While older and younger people derive similar benefit from HAART, it appears that older people face a greater risk from foregoing antiretroviral therapy. At the February Retrovirus conference researchers from Johns Hopkins presented results showing that HIV positive people over age 50 with CD4 cell counts below 200 cells/mm3 who did not take HAART had twice the mortality rate of younger people who were not treated.
New research in Africa suggests that women who use hormonal contraceptives may be more likely to develop what researchers call more aggressive HIV infection. The research team, from the Fred Hutchinson Cancer Research Center in Seattle, Washington, studied 115 HIV positive female sex workers in Mombassa, Kenya. Women who were taking hormonal contraceptives -- primarily birth control pills or injectable progesterone (Depo-Provera) -- were 5-7 times more likely than women not taking such contraceptives to become infected with multiple strains of HIV, which appears to lead to more rapid disease progression. Julie Overbaugh, PhD, an author of the study, suggested that hormonal contraceptives may cause thinning of the vaginal lining and also may increase the number of cells in the genital tract that are susceptible to HIV infection. The research was presented at the February Retrovirus conference.
A French research team reported in the February 16, 2002 issue of The Lancet that use of anti-HIV drugs by pregnant women appears to increase their babies risk of febrile seizures. Such seizures, which typically occur in children under five years of age, are associated with high fevers; they are not linked to epilepsy. The researchers looked at data from over 4,400 infants in the French Perinatal Cohort. Most of the children were HIV negative; a majority had been exposed to anti-HIV drugs in the womb, during delivery, or after birth. Overall, febrile seizures were uncommon, occurring in just 30 children. However, children who had been exposed to anti-HIV drugs were twice as likely as unexposed children to experience seizures. There were no significant differences in seizure rates based on which specific drugs children had received. Febrile seizures generally are not life-threatening, but may affect brain function. The researchers are conducting follow-up studies to see if these children exhibit mental development problems. Study author Stephane Blanche said these results should not discourage women with HIV from using antiretroviral medications during pregnancy because the risk of seizures is small and the drugs have been shown to greatly reduce the risk of mother-to-child HIV transmission.
According to a study published in the March 1, 2002 issue of the Journal of Infectious Diseases, cocaine use accelerates the progression of HIV disease in mice. Researchers from the University of California at Los Angeles AIDS Institute studied specially bred HIV-infected laboratory mice with human CD4 cells. The mice were administered injected cocaine or a saline solution placebo. The mice exposed to cocaine experienced a greater CD4 cell decline and higher HIV viral loads. After ten days the cocaine-exposed mice had nine times fewer CD4 cells and 200-fold higher viral loads than unexposed mice. It is not known how cocaine stimulates HIV, although cell surface receptors or cytokines may play a role. Study author Gayle Baldwin, MD, suggested that the effect would likely be similar in humans. Previous research has shown that HIV disease progresses more rapidly in cocaine users, although this may be related to other factors such as poor diet or repeated exposure to different strains of HIV. While other experts maintain that more research is needed before Dr. Baldwins conclusion can be verified, most nevertheless recommend that people with HIV should avoid cocaine.
Studies to date have shown that pegylated interferon is superior to standard interferon in people coinfected with HCV and HIV; however, response rates are lower than in people with HCV alone. At the February Retrovirus conference Ray Chung, MD, of Massachusetts General Hospital in Boston and colleagues reported results from a controlled trial comparing the safety and effectiveness of combination therapy with ribavirin plus either Pegasys or standard interferon in 133 people coinfected with HCV and HIV (ACTG 5071). After 24 weeks, 44% of those in the pegylated interferon group achieved an undetectable HCV viral load compared with 15% in the standard interferon group. Among those with genotype 1 HCV, the response rates were 33% for pegylated interferon and 7% for standard interferon; among those with genotypes 2 or 3, the respective response rates were 80% and 40%. CD4 cell counts declined in both groups (more so in the pegylated interferon group), but HIV viral load did not increase. Also, in an uncontrolled study using Peg-Intron in HIV/HCV-coinfected persons, a research team from Madrid found that 54% of 65 participants achieved an undetectable HCV viral load at the end of treatment (37% for genotype 1 and 63% for genotypes 2 or 3).
Several researchers at the Retrovirus conference presented promising results of treatment for hepatitis B virus (HBV) infection. Yves Benhamou, MD, and colleagues from Paris studied 35 HIV/HBV-coinfected subjects who were receiving combination anti-HIV therapy that included 3TC, an antiretroviral drug that is active against HBV as well as HIV. Adefovir (Preveon) was added to participants existing antiretroviral regimens. After 72 weeks participants experienced a nearly 5-log drop in HBV viral load, and four achieved an undetectable HBV viral load. Adefovir failed to win FDA approval for use as an anti-HIV therapy in part due to its potential for kidney toxicity; toxicity was less of a problem in this study, which used doses about ten times lower than those used for HIV. Data from two studies of tenofovir DF (Viread), a successor to adefovir that can be taken once daily, showed that the drug was effective against HBV. A forthcoming trial (ACTG 5127) will compare adefovir and tenofovir DF in people with HIV/HBV coinfection.
At the February Retrovirus conference researchers from the CDC reported that two-thirds of people with HIV do not start antiretroviral therapy in a timely manner. A.D. McNaughton, MD, and colleagues examined the medical records of over 4,000 people at 100 clinics in ten U.S. cities. They found that during the five-year period from 1996 to 2000, 33% of people began antiretroviral therapy early (with CD4 cell counts of 350 or more cells/mm3), 26% initiated HAART at the generally recommended time (with 250-350 CD4 cells/mm3), and 40% began treatment late (with 250 or fewer CD4 cells/mm3). African-Americans, Latinos, heterosexuals, and injection drug users were more likely not to receive treatment until they had advanced disease. Latinos were 1.8 times more likely and African-Americans were 1.7 times more likely to initiate HAART late. Women and people under age 25, in contrast, were less likely to start treatment late. Dr. McNaughton said it was unclear whether untreated individuals were being diagnosed with HIV disease later, were accessing care later, or were waiting until CD4 cell levels fell before starting therapy.
Patricia Flemming, MD, also of the CDC, reported at the same conference that as many as one-half of people with HIV in the U.S. either do not know they have the virus or are not receiving therapy. Dr. Flemmings team looked at HIV data from 25 states and used these figures to extrapolate numbers for states that do not report HIV infections. The researchers estimated that 180,000-280,000 Americans do not know they are HIV positive and 223,000 know they are infected but are not receiving treatment.
In a reflection of the increasing attention devoted to the global AIDS epidemic, several studies at the Retrovirus conference showed that triple combination antiretroviral therapy is feasible and can be effective in developing countries. Paul Weidle, PharmD, of the CDC and colleagues looked at the used of triple combination therapy in over 200 Kenyans with advanced HIV disease. Sixty percent had undetectable viral loads after six months, 47% maintained viral suppression after one year, and 32% still had undetectable viral loads after two years. Notably, the subjects in this study attended private medical practices and could afford to pay for their drugs, so were not representative of the poorest people who must rely on public health resources. Other studies in Senegal and India found that treatment success rates were similar to those in developed countries. Although many have argued that the complexity of antiretroviral regimens and the lack of health-care infrastructure and resources in poor countries would make use of anti-HIV drugs difficult or even dangerous, the main roadblock appears to be the cost of the drugs.
In related news, the World Health Organization (WHO) in April released guidelines for HIV treatment in developing countries. The guidelines recommend triple combination regimens and include information about when to start therapy, how to determine whether treatment is working, how to alter failing regimens, and what laboratory tests should be done. While the recommendations are similar to standards of care in the U.S. and Europe, there are some differences. For example, the WHO guidelines recommend treatment for people with CD4 cell counts below 200 cells/mm3 rather than below 350 cells/mm3 as in the most recently revised U.S. federal HIV treatment guidelines. The WHO recommendations also allow for starting treatment on the basis of clinical condition when laboratory tests are not available. In addition, the WHO added ten new antiretroviral drugs to its essential medications list; nevirapine and AZT previously were included for reducing mother-to-child transmission. The list, updated every two years, includes drugs that the agency identifies as essential to treat major diseases and that governments are encouraged to make available.
Meanwhile, at its April board meeting in New York City, the Global Fund to Fight AIDS, Tuberculosis, and Malaria awarded its first grants. In the first round of funding $378 million was distributed to 40 programs in 31 countries. Over 50% of the money will fund projects in Africa. Eighteen additional proposals were slated for fast-track approval, which will bring the total amount awarded to $616 million. At the same meeting the board also announced the appointment of Richard Feachem, MD, as executive director of the Fund. Dr. Feachem is director of the Institute for Global Health, a joint initiative of UCSF and UC Berkeley.
Liz Highleyman is a freelance medical writer and editor based in San Francisco.
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