Fomivirsen for CMV Retinitis
Experimental drug proves effective in Phase III trial
A new drug from Isis Pharmaceuticals, fomivirsen (formerly ISIS 2922), has proven effective in fighting CMV retinitis in a Phase III trial. The study compared two groups: 18 people with HIV and untreated CMV retinitis in one eye who were given three weekly injections of fomivirsen in the affected eye, and 10 people with CMV retinitis who had their treatment deferred. The median time to disease progression was 71 days in the fomivirsen-treated group; for the deferred-treatment group, the median was 14 days. Some patients given the drug experienced a temporary increase in eye pressure and mild-to-moderate inflammation within the eye, but these side effects resolved without lasting consequences.
You may be at heightened risk for this OI when you begin combination therapy
According to researchers at Boston's Beth Israel Deaconess Medical Center, people with HIV and low CD4 counts may be at increased risk of developing a common AIDS-related opportunistic infection, Mycobacterium avium complex (MAC), at the time they begin antiretroviral therapy. The researchers base their observation on five patients, all with CD4 counts below 50, who had to be hospitalized for up to three weeks after starting combination therapy with a regimen that included a protease inhibitor. All five patients were admitted to the hospital with high fever and swollen lymph glands, and all five were found to have local or disseminated MAC infection.
Because of the severity of the symptoms seen in these five patients, the Beth Israel group recommends that all individuals with CD4 counts below 50 be screened for MAC before they begin combination therapy with a regimen that includes one of the protease inhibitors. Patients may also want to consider taking the standard prophylaxis regimen against MAC infection before they begin any therapy that contains a protease inhibitor as one of its components, especially if their CD4 counts are consistently below 25 or they have proved to be particularly susceptible to AIDS-related OIs.
What This Means For You:
Maximally suppressive anti-HIV therapy, which reduces an individual's viral burden below the limits of detection of commercial HIV RNA assays, is the goal of present treatment regimens. This goal is most likely to be achieved by care providers with extensive clinical experience and insight, working with patients who are well informed and highly motivated to comply with their assigned therapy.
Experience has provided us with some important guidelines for initiating antiretroviral therapy. These recommendations apply to all patients, irrespective of background and circumstances, and to all therapeutic regimens, irrespective of complexity:
In the study cited above, the investigators determined that protection against MAC is important for those with low CD4 cell counts. This is not a new observation, but it does remind us that preventing OIs remains an important aspect of the continuing care of people with HIV, especially during the initiation of maximally suppressive anti-HIV therapy.
The explanation for the symptoms observed at Beth Israel in Boston is not clear, but it may relate to the selective nature of immune reconstitution following the initiation of antiretroviral therapy.
Hypersensitivity to Abacavir
Patients are warned not to resume taking the drug if they have an allergic reaction to it
Abacavir, a nucleoside analog that Glaxo Wellcome designated simply as GW1592 during the early stages of its development, has shown considerable promise in clinical trials (see "New nucleoside and nucleotide analogs" in this issue). Although it has yet to receive F.D.A. approval, this new antiretroviral is already being used by people with HIV who have developed resistance to other, older nucleosides. Tested to date in about 2,000 people with HIV, abacavir is generally well tolerated. However, about 3% of people who take abacavir develop an allergic reaction to the drug. This hypersensitivity, which usually develops in the first week of therapy, is characterized by flu-like symptoms -- mild fever, nausea (possibly leading to vomiting), malaise, and rash. These symptoms get progressively worse with each day of continued therapy, but they disappear quickly when treatment is halted.
Individuals who prove to be hypersensitive to abacavir should not resume taking the drug, even if their adverse symptoms resolve promptly and completely. A growing number of case reports indicate that the hypersensitivity reaction will reappear -- within hours and in much more severe form -- if an attempt is made to resume therapy, and the second time around this reaction can be accompanied by dangerously low blood pressure. It appears that the 3% of people who have this allergic reaction to abacavir are simply unable to tolerate the drug, and it is not possible to desensitize such individuals to the compound. On the other hand, people who discontinue abacavir for reasons other than hypersensitivity -- during a hospitalization, for example, or at a care provider's request -- are able to restart the drug without incident or ill effect.
Resistance Is Futile
First test for HIV resistance to nucleoside analogs is now available
With so many therapeutic options now available to physicians and patients alike, the all-important question is: Which combination of antiretroviral drugs will work best for you? People who are just beginning antiretroviral therapy can be expected to respond well to any of a number of multidrug regimens. People who have tried many drug combinations over the years have fewer options -- because they have, almost certainly, developed resistance to one or more of the drugs they were assigned.
The longer you have been on therapy -- and the more drugs you have tried and abandoned -- the more important it is you know your "resistance profile." Because no one drug has proven effective at suppressing HIV for long, it is crucial to employ a combination of drugs that will reduce viral activity to minimal -- preferably undetectable -- levels. The ideal drug combination is the one that suppresses viral replication as completely as possible for as long as possible with as few side effects as possible.
What is needed is, in essence, a full-court press: each of the chosen drugs must be effective against whatever strains of virus are present in your body. If the team of drugs you and your care-provider have fielded against HIV has even one weak player, the virus will take full advantage of that lone weakness to beat the whole therapeutic team.
A test is now available that can help determine how resistant a viral isolate is to any of the nucleoside analogs. Developed by Murex Technologies, the so-called LiPA HIV-1 RT genotypic resistance assay identifies nucleoside analog-induced mutations in HIV DNA. These mutations indicate whether a patient's viral isolate has developed resistance to AZT, ddI, ddC, or 3TC. Genotypic resistance to d4T is not readily identified.
What this means for you:
Some researchers have cautioned clinicians against attaching too much significance to the information gained from genotypic testing, because these assays read only a small portion of the DNA of HIV. Phenotypic assays, which are still being developed, provide information regarding future treatment options for the viral isolate that is assayed -- but these highly sophisticated tests are difficult to perform, expensive, and labor-intensive. Until a less costly and more widely available phenotypic assay is developed, healthcare providers are limited to the information that genotypic testing provides. This information may only be as good as an accurate history of a patient's prior antiretroviral therapy.
The genotypic assay's main utility is in identifying drugs that will not be effective against the viral strains in a particular person. Often, this information can also be obtained from a thorough history of prior anti-HIV medication combined with knowledge, derived from viral-load monitoring and on-going clinical care, about a patient's response to that treatment. A three-fold increase in viral load is generally accepted as an indicator that antiretroviral therapy is failing.
Genotypic testing does have significant limitations. The treatment information suggested by the genetic mutations that the assay reveals is not conclusive, and the LiPA HIV-1 RT test only identifies possible HIV resistance to nucleoside analogs, not possible future treatment options. Until phenotypic testing can be made faster and easier, and until tests are developed to identify mutations that indicate resistance to the various protease inhibitors and NNRTIs, the information provided by first-generation genotypic assays will be of limited value to healthcare professionals and their patients when they are making decisions about changes in antiretroviral therapy.
Cocktails During Pregnancy
Combination therapy appears to block mother-to-child HIV transmission
Since ACTG 076 showed that giving AZT to pregnant women with HIV (and to their infants immediately after birth) can significantly reduce the incidence of mother-to-child transmission of HIV, this therapy has been universally recommended and widely adopted. Although no one knows precisely why AZT is so effective in blocking transmission from pregnant women to their offspring, some experts believe that it is the presence of this drug in the infant's body at the time of exposure to the virus which suppresses replication and prevents infection.
Mother-to-child transmission may also be a function of maternal viral load: the lower the level of circulating virus, the lower the risk of transmission. If that is indeed the case, then combination therapy -- which produces viral-load reductions considerably greater than those seen with AZT monotherapy -- could provide even better protection for the unborn children of pregnant women. Does it? San Francisco's Bay Area Perinatal AIDS Center -- an early proponent of combination therapy for pregnant women -- recently announced that of the 56 HIV-positive pregnant women treated with such a regimen at the center since April 1995, not a single one has delivered an HIV-positive infant.
What This Means For You:
If reducing maternal viral burden is one aspect of interrupting vertical transmission of HIV, then administering combination antiretroviral therapy for at least four to six weeks before delivery may prove even more effective than a similar period of AZT monotherapy in reducing transmission rates. In this small study, such therapy appears to be at least as effective as monotherapy in preventing infections in newborns. However, this study involved far too few women to tell us if combination therapy is indeed superior to AZT alone.
In some ways the data from the San Francisco Perinatal AIDS Center are like data that the pediatric department at Duke collected during the early years of the epidemic, before AZT was available. Not one of the 44 infected women we saw that first year passed HIV to her child, even though these pregnant women received no antiretroviral therapy. By the time our caseload reached several hundred women, however, the transmission rate had risen from zero to 20%. What this experience tells us is that until we have much more information on many more patients, we will not know which antiretroviral regimen is most effective in blocking vertical transmission of HIV. For the present, the best advice we can give HIV-positive pregnant women is that AZT should be a component of whatever regimen they choose.
What is important to remember here is that all pregnant women, regardless of age, marital status, or socioeconomic circumstances, should be strongly encouraged to have an HIV test during the early stages of each pregnancy, should be offered the test at no cost if they cannot afford it, and should receive appropriate counseling and support if they test positive. Those who do test positive should be urged to begin antiretroviral therapy during the last trimester of pregnancy, to reduce the likelihood that they will pass HIV to their offspring. In these special circumstances AZT alone reduces the risk of vertical transmission by 67% compared with no therapy.
Another Therapeutic Option: d4T Plus 3TC
Combination proves effective in patients whose previous antiretroviral treatment has made them resistant to AZT
Many people with HIV have been on some form of antiretroviral therapy for a decade or longer. They took AZT as soon as it became available, then switched to ddC or ddI, then moved on to various two- and three-drug combinations of those agents, adding d4T or 3TC (and subtracting older, less effective drugs) along the way. In the process, these long-term survivors developed some degree of resistance to most of these compounds.
A new generation of antiretroviral agents will soon be available to these extensively treated patients. In the interim, new combinations of existing drugs can provide such patients with therapeutic options. One such combination is d4T plus 3TC.
Researchers at the University of British Columbia have announced results of a recent small trial studying the effectiveness of combining d4T (stavudine, Zerit) with 3TC (lamivudine, Epivir) to treat people with advanced HIV disease who failed therapy with AZT (zidovudine, Retrovir).
What the Canadian team found is that the combination of d4T and 3TC produced modest increases in CD4 counts and decreases in viral load. Unsurprisingly, patients who had higher CD4 counts at the beginning of the study, no previous AIDS-defining illnesses, and no previous exposure to either of the two drugs used had the best response. But, interestingly enough, even those who had been previously exposed to one or both of these agents experienced reductions in viral load and increases in CD4 counts, suggesting that this combination overcomes some degree of therapy-induced resistance. Moreover, the combination was found to be safe and generally well tolerated.
What This Means For You:
Although the current standard of care for people with HIV is therapy with a combination of at least three antiretroviral agents -- usually two nucleoside analogs plus a protease inhibitor; less often two nucleoside analogs plus an NNRTI -- a significant number of patients are still being treated with a combination of two nucleosides, and a distressing number remain on monotherapy. For patients who have not begun triple-drug therapy, d4T plus 3TC is a safe and moderately effective therapeutic combination. It will not consistently suppress viral load to undetectable levels, but it does leave patients with the option of switching to more potent combinations at a later date.
Crixivan on the Brain
Protease inhibitor appears to cross blood-brain barrier
Samples of blood and cerebrospinal fluid, taken from 13 people with HIV undergoing treatment with indinavir (Crixivan®), reveal that levels of this protease inhibitor are fairly constant in the central nervous system over the course of the drug's dosing schedule. While on average the concentration of the drug in the cerebrospinal fluid was only one-sixth of that in the blood, CNS levels remained much more constant than blood levels. The Swedish researchers who conducted this small study note that more work had to be done to determine how effective indinavir is against HIV infection within the central nervous system.
Scientists now recognize that the central nervous system can serve as a reservoir of HIV infection long after the virus has been all but eliminated from the circulatory system. Indeed, replicating HIV can be recovered from lymph nodes, brain tissue, and other body sites in patients who have had no detectable virus in their blood for two years or more.
Once HIV sequesters itself in these remote locations, it can be eradicated only by drugs that enter the central nervous system and cross the so-called blood-brain barrier. Unfortunately, many drugs that are highly effective against HIV in the circulatory system have only limited efficacy in the CNS. As a result, one aim of multidrug antiretroviral therapy is to combine drugs that are very good at killing HIV in the blood (protease inhibitors) with drugs that are very good at killing HIV in the CNS and other remote sites (AZT, abacavir, nevirapine).
What This Means For You:
Many factors need to be considered when combination therapy is initiated or changed. These factors include potency, possible side effects, drug-drug interactions, resistance patterns, and ease of compliance. But patients and their care providers should also consider whether the chosen antiretroviral regimen contains at least one drug that is known to penetrate the central nervous system. Given what we now know about the virus's ability to escape immune surveillance by insinuating itself into lymph and brain tissue, it seems clear that truly suppressive therapy must include an agent or agents that can penetrate these remote sites.
Combination therapy can lead to unusual fat deposits
A surprising number of people on combination antiretroviral therapy seem to be developing unusual fatty accumulations on their belly, buttocks, neck, and face. Dubbed "protease paunch" when it appears on the lower abdomen and "buffalo hump" when it occurs across the back of the neck, this curious side effect of combination therapy is, at this point, more unsightly than worrisome.
More than a dozen poster presentations at the 5th Conference on Retroviruses and Opportunistic Infections, which convened in Chicago in early February, dealt with this little-understood phenomenon. The incidence of unusual fat accumulations ranges from 5% (in studies where healthcare providers reported these physiological changes) to as high as 64% (in the only study that asked patients if they had noticed changes in their body shape).
Because these fatty deposits are unattractive -- they cause some women to appear to be pregnant, and they are hard to conceal when they appear on the face and neck -- the researchers who reported these findings are worried that some affected individuals will abandon their antiretroviral regimens. There have, in fact, been reports that a few people with HIV stopped taking their drugs when therapy-induced changes in their appearance tipped others off that they were on anti-HIV treatment.
In some patients these changes in body shape resemble Cushing syndrome, which results from the overproduction of adrenal hormones, but it appears that adrenal disorders are not the cause of "protease paunch." At this point, no one knows what causes this unwanted but apparently benign side effect of combination therapy. But as one researcher observed, more than vanity is involved here. "This is a metabolic issue," he declared, "and we need to investigate it."
Efavirenz now available to anyone with a CD4 count below 400
The experimental non-nucleoside reverse-transcriptase inhibitor efavirenz (Sustiva®) has demonstrated particular potency against strains of HIV that are resistant to nucleoside analogs and/or Crixivan® (see "Newer NNRTIs" in this issue). Merck and DuPont, joint developers of this compound, recently eased the inclusion criteria for those wishing to obtain the drug through a pre-existing expanded-access program. The drug, once known as DMP-266, is now available to people with HIV whose CD4 count has ever been below 400 and are failing, or cannot tolerate, their current drug regimen. Sustiva, which is taken in combination with one or more antiretroviral drugs, is not being recommended for people who have become resistant to either of the F.D.A.-approved NNRTIs, nevirapine (Viramune®) and delavirdine (Rescriptor®). Individuals who are resistant to one of these three drugs are likely to be resistant to all of them, and in such individuals Sustiva therapy would be pointless. For more information on enrollment in the Merck-DuPont expanded-access program, call: 1-800-998-6854.
Undermining the A.D.A.
Think the law protects you against discrimination? Think again
Most of us, healthcare providers, patients, and advocates alike, thought that the issue of discrimination against people with HIV was resolved when Congress passed the Americans with Disabilities Act in 1990 -- a statute that was intended to include HIV infection as a disability. We were wrong. The Supreme Court is currently considering whether the A.D.A. protects people with asymptomatic HIV against discrimination.
The case in question was initiated when a dentist named Randon Bragdon refused to perform oral surgery on a woman with asymptomatic HIV infection. He demanded that she check into a nearby emergency room for the procedure, so that "appropriate precautions" could be taken. Because the procedure was a simple one that required no special precautions other than those all dentists now routinely take, the patient insisted that Dr. Bragdon undertake it. When he again refused, she sued.
The issue, as it is being put to the high court in Bragdon v. Abbott, is whether asymptomatic HIV infection qualifies one for protection under the A.D.A., or whether that protection begins only when one develops full-blown AIDS. This distinction is an immensely significant one for all people living with HIV. As every one of these Americans knows, discrimination is something that infected individuals live with, or live in fear of, from the moment they learn their HIV status. It is not a function of CD4 count.
Dr. Catherine M. Wilfert, a member of the editorial advisory board of AIDS Care, is particularly concerned about the potential impact of a decision in favor of Bragdon -- because she recognizes that such a ruling would make it even harder to persuade pregnant women to undergo HIV testing, and that, it turn, would lead to higher rates of mother-to-infant transmission.
As Scientific Director of the Elizabeth Glaser Pediatric AIDS Foundation, Dr. Wilfert helped draft the amicus curiae brief that the foundation filed with the high court in support of Abbott. That brief says, in part, that Congress specifically intended the A.D.A. "to protect all HIV-infected individuals from invidious discrimination, in part to ensure that the fear of such discrimination would not deter these people from seeking needed testing and treatment."
This public-health goal would be severely compromised if the Act were interpreted to protect only those who have manifested outward symptoms of infection. All of us appreciate the logic of that argument. Let's hope the Justices do, too.
HAART Therapy Leads to Resolution of MAC Infection
Another apparent benefit of maximally suppressive antiretroviral regimens
Prior to the introduction of highly-active antiretroviral therapy, disseminated MAC infection was one of the most common life-threatening opportunistic infections seen in people with advanced HIV infection. DMAC occurred almost exclusively in patients with CD4 counts below 50, and prognosis was poor: even with optimal anti-mycobacterial treatment, median survival was only eight to nine months from the time of diagnosis. Despite the widespread use of a multidrug macrolide-based regimen, relapses were common. There were no reports of microbiologic cure of MAC on this regimen, so the standard of care was to continue treatment for the rest of the patient's life.
The advent of HAART has changed this picture, as it has changed so much about the treatment of HIV infection and AIDS-related opportunistic infections. A group at San Francisco General Hospital reports that four of their patients who developed disseminated infection when their CD4 counts fell below 50 have apparently been cured by a combination of anti-mycobacterial therapy for MAC plus HAART. After more than a year of treatment all four were asymptomatic and medically stable. MAC therapy was therefore discontinued, and up to ten months later these patients still have no evidence of Mycobacterium avium in their blood or bone marrow, and they remain clinically asymptomatic.
What This Means For You:
This is the first report of the successful discontinuation of antimycobacterial therapy for MAC in patients with AIDS who have responded well to combination therapy. Although median survival with optimal anti-mycobacterial therapy in the pre-HAART era was less than one year, these four patients are asymptomatic after one year of combined antimycobacterial therapy and potent antiretroviral therapy, and they have no clinical or microbiologic evidence of MAC relapse up to ten months after discontinuing antimycobacterial therapy. This suggests that AIDS-related MAC can be cured in patients whose CD4 counts rise on combination antiretroviral therapy.
Evidence continues to accumulate that HAART has a significant impact on AIDS-related OIs. There have been a number of reports that HAART has a positive therapeutic impact on such previously untreatable OIs as progressive multifocal leukoencephalopathy, cryptosporidiosis, and microsporidiosis. Recently, eight patients were able to discontinue CMV maintenance therapy after they began combination antiretroviral therapy.
None of these individuals experienced progression of CMV disease after a mean follow-up of 146 days. CD4 counts remained elevated even though six out of the eight patients had detectable viral load. These findings suggest that HAART may restore CMV-specific immunity even in patients who do not achieve complete suppression of viral load.
Judith A. Aberg, M.D.
San Francisco General Hospital