Evaluating Treatment Option and Health Care Providers:
by Jeffrey Shouten, MD, Jon Hubert, DDS & Brian Coppedge
HIV/AIDS treatment has entered a new era of optimism as well as a period of daunting complexity. For the first time "eradication" of HIV is being seriously discussed. Almost a dozen anti-HIV drugs are available and many more are in the pipeline. Despite the enthusiasm over advances reported at the XI International Conference on AIDS in Vancouver, people infected with HIV face a significant challenge in making decisions about multiple drug combinations, interpreting viral load tests, as well as issues about how their choices today will effect treatment options tomorrow. If treatment questions seem complex, add to the mix the task of negotiating a rapidly changing U.S. health care system.|
Be As Informed As PossibleNow, more than ever, it is essential to have as much knowledge as possible about HIV treatment options. Even expert panels of researchers have difficulty in making recommendations in today's environment of multiple treatment regiment and rapidly evolving research data. A recent review of AIDS information newsletters demonstrates the range of opinions to be found regarding treatment choices. For a person newly infected with HIV, one doctor recommended no treatment, while another recommended a six drug combination. How can a reader make sense of such a wide disparity in recommendations? How could one person, perhaps consulting these two doctors for recommendations, make a decision? The tremendous value of newsletters lies in the explanation and discussion of the background issues and the context of each approach. The six drug combination was used in a research setting, testing a very aggressive approach for people newly infected with HIV. The " no treatment" approach was discussed by a conservative doctor working in a urban clinic who wanted more research done and was concerned about compliance and medical coverage issues.
When treatment strategies are reported on television, in newspapers, or discussed by friends, often the background information is left out. Reliable treatment newsletters provide information based on interviews and surveys of leading researchers, reports from scientific journal articles and analysis by authors experienced in HIV/AIDS treatment issues. The information in these newsletter is reviewed and cross checked by a number of different people to insure accuracy and reduce bias.
Treatment journals (see end of this article) are an extremely valuable source of state of the art information covering various options as well as putting these options in perspective. They can provide a lifeline for people living in small communities or who otherwise have limited access to up to the date treatment. They also provide information which can be taken to a doctor to help with treatment discussions.
Finding the Right Health Care Provider (HCP)In today's world of PPO's, HMO's, provider lists and other manifestations of managed care, finding a HCP can be a challenge. In some managed care situations HCP choice is restricted, change is difficult and cost constraints limit treatment choices. However, the single most important factor in choosing a HCP is his or her level of clinical experience in treating people with HIV and AIDS. A recently published study conducted at a health care maintenance organization in Seattle found that the level of experience of primary care physicians in the treatment of HIV/AIDS was significantly associated with the survival of their patients. The study was conducted by Kitahata et al, and was report in the New England Journal of Medicine, March, 14, 1996. The study looked at 403 adult males diagnosed between 1984 and 1994 and cared for by 125 primary care physicians. The researchers rated the physicians based on their experience caring for people living with HIV/AIDS during their medical training and the cumulative number of patients with AIDS they had cared for in their individual practices. The median survival of people who had physicians with the least experience was 14 months, as compared to 26 months for patients who had physicians with the most experience. The authors controlled for CD4 count, severity of illness and year of diagnosis. For physicians who saw 5 or more AIDS patients the survival rate improved significantly
The bottom line in insuring the best treatment possible is the combination of an educated client and a knowledgeable and experienced health care provider. It is essential that a HCP has a good understanding of current treatment guidelines as well as a reasonable amount of clinical experience with HIV/AIDS clients. AIDS/HIV Care Access Project (ACAP) is a non-profit organization in Seattle that can provide physicians referrals for people living with HIV/AIDS. They can be reached at: 190 Queen Anne Ave. N (Third Floor), Seattle, WA 98109 206/284-9277
Treatment GuidelinesThe table below outlines basic treatment guidelines as recommended by health care professionals who treat a large number of HIV-positive people, recommendations published by the International AIDS Society, and recommendations made by local and national university-based AIDS experts. As with any general guidelines, each person's unique situation must be factored into any treatment plan. Considerations include drug tolerance, drug interactions, and the person's overall health, including energy level, weight loss, or other symptoms. Another very important consideration is the rate of change of CD4 cells and viral load. Any treatment plan should take into consideration future therapy as well.
Two measurements of viral load a couple of weeks apart are recommended for a baseline for all HIV-positive persons. Subsequently, viral load should be measured about 4 times per year. Additionally, viral load measurements should be obtained 4-8 weeks after initiating a new therapy to assess its efficacy.
Therapy RecommendationsViral Load Non-detectable, CD4 greater than 500 - OBSERVATION
Viral Load Non-detectable, CD4 200-500 - DOUBLE THERAPY
Viral Load Non-detectable, CD4 less than 200 - TRIPLE THERAPY
Viral Load up to 5-10,000 , OBSERVATION OR DOUBLE/TRIPLE THERAPY
Viral Load greater than 5-10,000, CD4 greater than 500, DOUBLE OR TRIPLE THERAPY
Note: Double therapy means a combination of 2 drugs, usually two nucleoside reverse transcriptase inhibitors (AZT, 3TC, ddI, ddC, and d4T). Triple therapy means a combination of 2 nucleoside reverse transcriptase inhibitors and a protease inhibitor (saquinavir, ritonavir, or indinavir) or a non-nucleoside reverse transcriptase inhibitor ( delavirdine or nevirapine). Alternatively, an effective combination of 2 drugs may be 2 protease inhibitors, such as saquinavir and ritonavir. (See STEP Perspective, Summer 1996; Vol. 8, No. 2 for a complete discussion of combination therapy.)
Pneumocystis pneumonia (PCP), DEFINITELY BENEFICIAL IF CD4 less than 200
Toxoplasmosis, MAY BE BENEFICIAL IF CD4 less than 100 AND Toxo Antibody Positive
CMV, DEFINITELY BENEFICIAL IF CD4 less than 50
Cryptococcus, MAY BE BENEFICIAL IF CD4 less than 100
Mycobacterium Avium Complex, DEFINITELY BENEFICIAL IF CD4 less than 100
Note: Preventative therapy (prophylaxis) for PCP is definitely of benefit to all HIV-positive persons with CD4 values below 200, and some health care providers recommend preventative therapy even in some people with slightly higher CD4 counts. While some studies have shown a benefit for preventative therapy for the other infections in the table above, problems with side-effects, drug interactions, and resistance have resulted in selective use of drugs to prevent these infections. An HIV-infected person with low CD4 counts, (less than 100), should discuss the use of drug therapy to prevent these infections with their health care provider on an individual basis. CMV infection in the eye can cause permanent, irreversible vision loss, even when treated. Therefore, many health care providers recommend that all HIV-infected persons with CD4 counts below 100 be examined regularly for evidence of early CMV infection in the eye (retinitis). Early treatment may prevent vision loss. Screening cannot be done by a quick look into the eye, but requires drops to dilate the eye and a careful examination by a trained professional (fundoscopy). Prophylactic therapy for opportunistic infections should not be discontinued if low CD4 counts increase significantly on antiretroviral therapy. Apparently, the risk of an OI is not significantly decreased when CD4 cell counts increase on antiretroviral therapy.
Self-AdvocacyIn a perfect world, all health care providers would be well-informed and the best and most effective treatment would be offered to all persons who are HIV-positive. However, this is not always the case, and clients must take action and insist that their health care provider and health plan provide them with the opportunity to receive the best possible care. Survival may depend upon it! Sometimes, health care providers are not well-informed about the latest developments concerning protease inhibitors or viral load testing. Other times, the health care plan or health maintenance organization (HMO) may not allow health care providers access to the newest, or best drug, or laboratory tests that he or she wants to prescribe. In either case, each person must become an activist and a treatment advocate on their own behalf.
The first option for a client is to discuss their care with their health care provider and provide him or her with literature supporting any requests, such as the treatment guidelines outlined above. If this approach does not resolve the problem, then the next option is to request to talk to a patient care representative. Most HMO's and clinics have an ombudsman or patient care representative with whom concerns can be addressed, within the group or clinic, if a health care provider has not been responsive.
If the client is still not able to access the care they feel is in their best interest, then a few other options are still available. HMO and some clinics have a restricted formulary, which means that they control the drugs they provide to their members. However, often times these organizations have a mechanism whereby an individual health care provider can prescribe a non-formulary drug. So if a health care provider refuses to administer a drug that has been requested because it is not on the formulary, they should be asked if there is any mechanism whereby approval may be obtained for him or her to prescribe a non-formulary drug.
HMOs and managed care plans often erect "gate-keepers" to limit access to test or drugs, but there are usually appeals or approval processes built in to allow for individual exceptions. Ask your health care provider what mechanisms are available in your HMO or health care plan to make an exception to these rules. Also, most HMOs allow members to switch health care providers if they are not satisfied with their current HCP, although this will not resolve institutional problems.
Lastly, some people have found that the only way to advocate for change within an HMO or managed care group is to form an advocacy group of members within that particular HMO or managed care plan. The most successful of these group have lobbied for changes with the Kaiser-Permanente HMO in California. One person cannot advocate for change as effectively as a group. STEP can assist in forming an advocacy group within health care plans or clinics. If, the above recommendations have been followed, and still not achieved the desired outcome, call STEP and they will attempt to coordinate and facilitate the formation of a consumer advocacy group within a particular health care plan or clinic.
What To Expect When You Are Involved In a Drug Trial Or Research ProjectDrug trials provide the opportunity to start on new or unapproved drugs well before they are available to the general public. Remember: trials are developed and designed to evaluate the effectiveness of a particular treatment and its potential toxicity. Before deciding to take part in a trial special consideration to the possible pro's and con's of each trial should be considered.
In most trials, one arm (group of people who receive identical treatment) includes the unapproved drug and the other arm is a drug or drugs previously shown to have some benefit. Trials may contain several arms which study drugs at different dosage levels. This allows the researchers to compare the results of the new treatment to treatments which have already been approved for use by the Food and Drug Administration (FDA). Currently, many trials compare combinations that include protease inhibitors to combinations of non-protease inhibiting drugs that have already been shown to inhibit HIV replication. People have to decide if they are willing to risk being assigned to an arm that may contain drugs that are not as effective as the ones currently available through their health care provider.
Many health care plans have been slow to offer the viral HIV RNA test. These tests are generally agreed to be the most important test to track the progression of HIV. One way to get a free viral load test is to join a drug trial. Most trails will run these tests because they are the best tool to evaluate the efficacy of the new drugs. Before joining a trial, find out if the researchers will release viral RNA results to clients; also see if the tests will be released in a timely manner, or whether they wait until the end of the trial to release the HIV RNA results. If trials don't provide access to a viral load test, or if the trial is not going to release the results frequently, it may be better not to join the trial.
Some trials may ask participants to stop taking particular medication or may ask them not to start taking other medication. Always find out before starting a trial what restrictions will be place on participants. People who are even slightly uncomfortable with the requirements of the trial, should consult their health care provider before joining. Once in a trial, people should try to be as compliant with trial protocols as possible. If severe side effects appear, the investigators should be notified, and the option to withdraw from the trial should be considered. Trials can provide excellent opportunities for people to access drugs and tests that they would not otherwise have access to. Careful examination of the trial protocols and consultation with a health care provider are crucial when considering new drug trails.
The trial investigators can be contacted directly at:
University of Washington AIDS Clinical Trials Unit
Advanced Research Management
Gay Men's Health Crisis
AIDS Treatment News - available here at The Body
STEP Perspective - available here at The Body
About the Authors
Jeffrey Schouten is a general surgeon and co-chair of STEP's Scientific Review Committee.
Brian Coppedge is the Treatment Information Specialist at STEP.
Jon Hubert is a member of STEP's Scientific Review Committee and is a member of the Board of Directors.
Recent Development In The Treatment And Prevention Of Disseminated Mycobacterium Avium Complex (MAC)by Jeffrey Shouten, MD, Jon Hubert, DDS and Stan Whittemore, MD
Disseminated Mycobacterium avium complex (DMAC) is the third most common opportunistic disease in people with AIDS, ultimately infecting 30-50% of the patients with very low CD4+ counts, and significantly reducing the length and quality of life. MAC is a group of closely related bacteria that grow in water even chlorinated water as hot as 125 degrees F), soil, house dust, and some animals. However, it does not appear that the MAC organisms in the environment are the exact same as those in the infected people, thus there are no recommendations for avoiding exposure. People with CD4 cell counts below 75 who have had a previous AIDS-defining opportunistic infection are at greatest risk for developing DMAC. Symptoms of DMAC include high fever, weight loss, fatigue, diarrhea, poor appetite, night sweats, and anemia (low red blood cell counts). The diagnosis of DMAC is usually made by finding the bacteria present in blood or bone marrow cultures. Prevention of DMAC and the treatment of people with active infection has been very difficult primarily due to drug side effects and resistance. 23% of people on 500m mg of clarithromycin twice daily and about 50% of people using multi-drug regiments have dose limiting drug reactions. 46% of patients receiving clarithromycin alone developed resistance at a median of 16 weeks. Treatment with combinations of 2-4 drugs have serious side effects, often as a result of their complex drug interactions. This article will focus on a few recent favorable reports concerning both the prevention (prophylaxis) and treatment of DMAC.|
Two studies were reported in the New England Journal of Medicine on August 8, 1996 evaluating drug therapy to prevent MAC infection in HIV-infected people with less than 100 CD4+ cells. The first study was a randomized trial in which one half of the participants received an antibiotic, clarithromycin (500 mg twice a day), and one half of the participants received a placebo. After about ten months, MAC infection developed in only six percent of the participants who received the clarithromycin, compared to 16% of the participants who received the placebo ( a 69% risk reduction). 50% of the infections occurred in people with CD 4+ counts in the 0-9 range, and all the infections occurred in people with less than 50 CD4+ cells. In the ten month follow-up period, 32% of the clarithromycin treatment group, and 41% of the placebo group died ( a 26% reduction in mortality). One danger of using a drug to prevent an infection is that people who subsequently develop the infection may have a drug resistant infection, which could be more difficult to treat. In this study, 11 of the 19 people who developed DMAC in the clarithromycin group were resistant to the antibiotic, vs. none in the placebo group. Over the course of the study, the death rate was significantly lower in the group which received clarithromycin ( 32% versus 41%).
The second study compared other antibiotics to prevent MAC. Participants received either azithromycin (1200 mg weekly), rifabutin ( 300 mg daily), or both drugs. All the participants were on either 400 mg fluconazole once a week, or 200 mg daily as well. After one year, the rate of MAC infection was 15.3% with rifabutin, 7.6% with azithromycin, and 2.8% with both drugs. In the group treated with azithromycin who subsequently developed MAC, 11% had azithromycin resistance. Even though the best results were observed in the group which received both drugs, side effects limited tolerance in that group significantly. The most common side effects were gastrointestinal symptoms. However, overall, 23% in the combination group, 16% on rifabutin, and 13% on azithromycin had dose limiting toxic effects. A major advantage of azithromycin is that it only needs to be taken once a week. Once a week azithromycin has been shown to reduce the risk of MAC by 60% when compared to a placebo (19.1% one year rate of DMAC vs. 8.2% with 1200 mg of azithromycin once weekly).There are no data evaluating the concomitant use of azithromycin and protease inhibitors.
What, then, is the preferred choice for the prevention of DMAC? Moreover, when should such prophylactic therapy be initiated? A national panel has recommended considering antimicrobial prophylaxis against M. avium when CD4 lymphocyte count falls below 75 in people who have had opportunistic diseases. Choosing a regimen requires balancing efficacy against tolerability, cost, the potential for drug interaction, and the dangers of resistance to the drug. Administering these drugs together with other medications used to treat people with advanced AIDS has substantial pharmacokinetic implications. Serum levels of both clarithromycin and rifabutin increase when they are taken with fluconazole; HIV-protease inhibitors increase the metabolism of clarithromycin and decrease that of rifabutin. Azithromycin has been less well studied, but has not been reported to interact in these ways. The resistance to clarithromycin and azithromycin is a worrisome development, because resistance to one of the two brings with it resistance to the other, so that people with disease due to resistant organisms have limited options for treatment. The above study by Pierce et al. indicates that the benefit in terms of prevention outweighs the risk of drug-resistant regimens as azithromycin and rifabutin in individuals with CD4 counts less than 10, who have up to a 40% risk of acquiring MAC over the course of one year.
Once M. avium disease occurs, antimycobacterial therapy with a combination of drugs is required. The optimal therapeutic regiment remains to be determined. Current regiments to treat MAC usually include 2-3 drug combinations due to the rapid development of resistance if only a single antibiotic is used. A study of ethambutol (15 mg/kg) added to clarithromycin showed prompt improvement in symptoms and reduction in MAC levels in the blood within several months, and was highly effective in preventing the emergence of resistance to the macrolides. The three drug combination of rifabutin (600 mg daily ), ethambutol ( 15 mg per kg daily), and clarithromycin (1000 mg twice daily) was compared to the four drug combination of rifampin (600 mg daily), ethambutol ( 15 mg per kg daily), clofazimine (100 mg daily ), and ciprofloxacin ( 750 mg twice daily) in a recently published study. A total of 229 individuals with active MAC infection, confirmed by blood culture, were randomized to one of the two regiments.
The study found that people treated with the three drug regimen had a greater chance of removing the bacteria from the blood more rapidly (69% vs. 29%), and their survival rates were better than people treated with the four drug regimen ( 8.6 months vs. 5.2 months). The accompanying editorial, cited above, noted that an earlier study showed that the dose of clarithromycin used in this study ( 1000 mg twice daily) was associated with a decreased survival compared to a lower dose of 500 mg twice daily, and the dose of rifabutin had to be lowered because of a 38% incidence of uveitis (inflammation in the eye). However, it was noted that the treatment of MAC infection once present is inferior to primary prevention. Even though the median survival was around seven months, 20% of the participants in Chaisson's study died in the first 12 weeks of treatment. Other drugs available for use in combination therapy for M. avium disease include, clofazimine, rifampin, ciprofloxacin, and amikacin. Clofazimine, when given with clarithromycin, neither prevents the emergence of resistance to clarithromycin nor prolongs survival. Indeed, recent studies have shown that there was significantly higher mortality when this drug was used in combination with clarithromycin and ethambutol. Rifampin offers on therapeutic advantage over rifabutin and appears to have more potential for drug interactions. Ciprofloxacin is poorly tolerated and has marginal in vitro activity, whereas amikacin adds little to oral regimens. For those persons intolerant to the multi-drug therapies, or who do not respond well to the therapy, steroid administration can reduce symptoms dramatically. Dorman and Sax showed that the addition of 4 mg/day of dexamethasone to their small group of participants who were worsening after a mean of 30.5 days of anti-mycobacterial treatment, had rapid improvement in symptoms. The duration of this benefit varied from a minimum of three months to a maximum of seven months. There was no apparent worsening of baseline prevalent opportunistic infections. Wormser et al. showed that a dose of two mg dexamethasone, in addition to the anti-mycobacterial therapy for people who had progressive weight loss and persistent fever, and an improved sense of well-being.
One of the most potentially serious toxicities of rifabutin is an inflammation in the eye called uveitis. This condition began to show up when rifabutin was used at very high doses (1200+ mg), and when combined with clarithromycin and fluconazole (with rifabutin doses in the 600 mg range). This has occurred in non-HIV patients infected with MAC as well, but only in conjunction with clarithromycin or fluconazole. Before this condition was well known, a group of opthamologists treated the affected people with intensive topical corticosteroid therapy, and were able to continue rifabutin, sometimes without a dose reduction. This condition developed at a range of 51 to 393 days (median, 79 days) after starting rifabutin, clarithromycin and fluconazole. The interaction of these drugs has been discussed above, showing marked elevations of rifabutin levels when combined with either of these other two drugs. These authors felt it was potentially safe to continue rifabutin at lower doses under close supervision if the clinical situation indicated the need. Horsburgh, in his editorial in the New England Journal of Medicine, states that "there is now strong evidence that primary prophylaxis against M. avium disease has a substantial clinical benefit, and such prophylaxis should be considered the standard of care." The question remains: when to begin therapy, but it appears that azithromycin has the least toxic effects and least drug interactions and equal efficacy. Chaisson suggests that treatment of DMAC initially should be with clarithromycin 500 mg twice daily (or azithromycin 600 mg daily) plus ethambutol 15 mg/kg/daily (maximum 1000 mg) with or without rifabutin (300-450 mg daily). In people who may have antibiotic resistant disease, the three drug combination should be used. Treatment of relapsed disease due to resistance is difficult, as there are no additional agents with proven activity. One option is to add two new agents such as amikacin and ciprofloxacin, though the efficacy of such maneuvers is unknown.
About The Authors
Jeffrey Schouten is a general surgeon and co-chair of STEP's Scientific Review Committee.
Stan Whittmore is on STEP's Scientific Review Committee and is a member of the Board of Directors.
New Recommendations On Health Care Workers Exposure To HIVby Jane Woodward, Pharm.D.
Human Immunodeficiency Virus (HIV) has always drawn vast media attention and study, probably due to its lethality and agility in evading the immune system. Recently, there has been an explosion of knowledge about the dynamics of its life cycle, especially in measuring the velocity and magnitude of its replication. Although frightening, this knowledge has also come at a time when new ways of treating the infection have emerged which have given new hope to people infected with HIV and those responsible for their care.
Health care workers who administer care to people living with HIV are highly trained in universal precautions and procedures to prevent possible transmission of the virus. When an unfortunate contact with blood or body fluid occurs, the risk of seroconversion is low but decidedly present. In the most risky esposures, there has always been interest in finding something to offer these affected workers, either to prevent transmission or possibly eradicate infection once it occurs. Knowledge of the viral life cycle and highly aggressive, potent antiretroviral regiments have completely altered our perceptions of how to treat these exposures.
New Findings in Viral DynamicsOne of the most important advances in HIV/AIDS care is the ability to measure the amount of viral particles in the blood stream. More commonly known as "viral load,"the measurement gives a more complete picture of immune system. At high viral levels, it is a sensitive marker of those who are at risk to progress rapidly to AIDS. Viral measurements have also given us a better idea of the velocity of replication and the damage that can occur to the immune system when replication is allowed to continue unchecked. It has now been estimated that the half life of an infected CD4 cell that is rapidly producing viral particles is about 1.6 days and for a free virion in plasma it is 0.3 days. Thus, the number of virions produced daily is at least 10.3 x 109. It is estimated that up to two billion immune cells are destroyed daily (Science).
Protease inhibitors are a new class of drugs designed to block viral replication. They work late in the life cycle and thus are effective in newly and chronically infected cells. When used in combination with nucleoside analogs such as zidovudine (AZT) and lamivudine (3TC) it is possible to block viral replication within the bloodstream. When this occurs viral levels decline rapidly - an initial lag is followed by exponential decay. This phase of decay is due to clearance of free virions and productively infected cells. The half life of this phase is estimated at 2.1 days. Once the plasma is cleared of infecting virus, a second elimination phase begins that is due to the drugs' effect on macrophages and latently infected CD4 cells. This is a much slower phase with the average cell life span of 13.3 days. In theory, administering potent antiretroviral medications over an extended period of time would allow all compartments to burn out cells that have been infected with HIV (XI Int AIDS Conf (ThB930 Ho, David).
While these are exciting theories, there are many questions left to be answered. It is not known how long these potent antiretroviral regimens would have to be administered to completely clear virus particles and infected cells. It has been estimated that at least 1.5-3 years will be required (XI Int AIDS Conf (ThB930 Ho, David). Antiretroviral regimens have always lost their efficacy over time. The reasons for this are unknown, but considerable evidence has pointed to development of resistance. Thus, there is some skepticism that these regimens will remain effective or will be tolerated for the time required to eradicate the virus. Previous regiments were never able to completely stop replication in the bloodstream and thus, viral replication occurred in the presence of the drug, driving resistance mutations. Completely stopping replication may result in resistance being avoided altogether. However, even if the regimen was successful, it is unknown if the immune system would be able to recover.
Post Exposure Prophylaxis (PEP)Theories on viral dynamics and aggressive antiretroviral regiments both play a role in the decision of how to treat someone exposed to HIV in the health care setting. Potent antiretroviral drugs, if introduced early after exposure, could theoretically block the first cycle of replication, preventing infection of multiple cells lines. It has also been hypothesized that they may also be used to eradicate infection, again, if introduced soon enough after exposure. Even if they do not completely eradicate the virus, they could potentially alter the natural history of the disease by lowering the set point of initial viremia after infection has occurred ( Gerberding NEJM 1995).
What is the Risk?Needlestick exposures are thought to be the most risky, yet seroconversion rates are only 0.2-0.3%. Factors which increase the risk of seroconversion are deep injuries, devices visibly contaminated with blood, procedures involving a needle placed directly in a vein or artery and advanced AIDS in the source patient (probably indicative of high viral load or syncytium inducing virus) (MMWR 1995). Injuries with hollow core needles and injuries that do not occur through gloved skin are thought to be more risky as well.
Mucocutaneous exposures resulting in seroconversion have never occurred in studies, but the risk has been estimated at 0.08% ( XI Int AIDS Conf 1996 TuC120). Higher risk is associated with large volumes of blood, prolonged duration of contact and a potential portal of entry such as non-intact skin (Gerberding NEJM 1995). Host defense may also play a role since evidence of cellular immune response has been found in exposed but uninfected health care workers. Treatment of HIV exposure has been hampered with concern over lack of efficacy of available treatments and also high toxicity rates. Zidovudine (AZT) is the only antiretroviral agent formally studied for this indication and there have been well documented failures despite early administration. The Center for Disease Control (CDC) surveillance data found AZT used in 31% of exposures overall and 31% of patients did not complete the course. Adverse events occurred in 75% of those treated. Failure of AZT occurred in at least nine cases, although five failures had exposures greater than a needle stick ( Annals of Int Med 1993;118(12) 913-19). Failure can occur because of inadequate control of replication, timing, lack of penetration into target tissues, compliance with the regimen and resistance.
Interest in post exposure prophylaxis was renewed recently with the results of a study reported in 1995 (MMWR 1995). A case-control study was reported of 31 workers who seroconverted after occupational percutaneous exposure to HIV. Results found a significant reduction in seroconversion in those who took AZT early after exposure. Taking AZT reduced the risk 79% (MMWR Dec 22, 1995 vol 44 no 50:929-933). Although a prospective, placebo-controlled trial would have given more reliable results, such a study is not feasible at this time, (given the very low seroconversion rate and the participants' understandable hesitation at being randomized to the placebo arm).
Although AZT alone has proven efficacy in reducing the risk of seroconversion after exposure to HIV, failures have kept investigators searching for better regimens. As previously discussed, potent combinations of antiretrovirals that include protease inhibitors afford much better control of viral replication and will probably be more effective at preventing seroconversion. Using the knowledge of viral dynamics and the properties of these medications, the United States Public Health Service (USPHS) has published new recommendations for post exposure prophylaxis (see table 1). If possible, these drugs should be started within 1-2 hours of exposure, preferably as soon as possible, and continued for four weeks. The University of Washington and Harborview Medical Centers have adopted these recommendations and are prepared to provide these medications quickly following accidental exposure.
Careful evaluation of the severity of the exposure is necessary, as these medications are not innocuous. There is not much information of the incidence of adverse events in people not already infected with HIV, but considerable toxicity does occur. Zidovudine, when used for this indication, is hampered by nausea (61%), vomiting (15%), fatigue (49%), abdominal pain (15%), headache (12%), myalgias (12%), anemia (12%) and neutropenia (8%) (Int Con AIDS TuC122). All serious exposures should receive three medications - zidovudine (ZDV or AZT), lamivudine (3TC) and the protease inhibitor indinavir (IDV). Please see table 2 for details regarding dose, adverse reactions and possible drug interactions. Changes may be made to this regimen on a case-by-case basis, particularly if the source patient is known to be taking any of these medications. Some providers may elect to use a loading dose (high initial dose) to achieve therapeutic drug levels as quickly as possible. It is unknown whether a loading dose will offer additional prophylactic benefit, but will possibly cause more transient side effects. Compliance with the medication regimen is of paramount importance. Resistance can develop quickly if the regimen is not adhered to, and efficacy may compromised.
Prophylaxis Following Risky BehaviorsIt has become a concern that antiretroviral medications are being used by some people following potential exposure to HIV, especially following unsafe sex and needle sharing. This "morning after" use of these medications is fraught with problems. If these drugs are not taken in combination, very soon after exposure, at correct dosages, and at least for four weeks, incomplete viral suppression will occur, thus potentially breeding resistance. AZT alone will not prevent HIV infection when used in this setting. These medications are anything but innocuous, and require frequent monitoring by someone well-versed in HIV care to avoid toxicities that may be irreversible. "Morning after" therapy should not be used in place of well-accepted methods to prevent HIV transmission.
About The Author
Jane Woodward, Pharm.D, is a pharmacist currently in practice at the University of Washington.
Dietary Consideration And Protease InhibitorsBy Brad S. Lichtenstein, ND
Drug therapy is becoming increasingly more complex every day. New combinations offer a great deal of promise, yet it is important to remember that these drugs are still in their infancy. More needs to be learned before we have all the answers. The new protease inhibitors are a case in point. The drug ritonavir (Norvir or ABT - 538) has been studied for its numerous drug interactions due to its effects on the liver.|
One of the key roles of the liver is detoxification. Detoxification is the process of neutralizing and eliminating toxins from the body. External sources of toxins include smoke, fumes, pesticides, drugs, pathogenic microorganisms, food additives and dyes, and excessive hormones found in animal products. Oddly, our body generates its own source of internal toxins during the detoxification process. For this reason, maximum liver function must be maintained in order to prevent destruction of liver cells (hepatocytes) and other bodily tissues. The liver deals with toxins in a variety of ways. In the healthy, optimally functioning liver, approximately two liters ( half a gallon) of blood flow through it each minute before returning to general circulation. While in the liver the hepatocytes filter out toxins and bacteria. Special liver cells, called Kupffer cells, engulf foreign particles (bacteria and toxins), ingest them, and remove them from the bloodstream. This filtration is the first step in the detoxification process.
The second step occurs during the liver's daily production of bile. Bile is necessary for digestion and absorption of all fats. This includes the fat soluble vitamins, vitamins A, K, E, and O. Without bile, deficiencies in the fat soluble antioxidants (vitamins A, K, E and 0) would ensue. For detoxification purposes, toxins in the liver bind to bile to be excreted from the body. Fiber, from the diet, is necessary in order for this toxic bile to be excreted through the feces. If bile, or fiber for that matter, is not present, these toxins will become reabsorbed in the intestines and re-enter the bloodstream, allowing them another chance at destruction. The last step in the detoxification process involves a series of enzyme systems which help remove chemicals from the bloodstream by neutralizing them. The two pathways required in this operation are known as the Phase I and Phase II detoxification systems. Phase I directly alters the structure of chemical compounds. This initial phase involves a series of enzymes collectively known as the mixed function oxidase system (MFOS0, which includes approximately 100 different enzymes perform the following role during Phase I detoxification:
When this last step occurs, a new chemical intermediate is formed that is more toxic than the original substance. Smoking is an example of this process. When the chemicals from tobacco or charcoaled foods (polycyclic hydrocarbons) are taken into the body, they are not carcinogenic until they pass through Phase I detoxification. The intermediates formed during this process are more chemically toxic than the original substance. On an unfortunate note, every time the Phase I system is invoked, free radicals are generated which can, in turn, produce more free radicals and result in serious injury and stress to the body. Therefore, despite the perceived benefits of Phase I detoxification, activation of the system is not always desired, as we will discuss below.
The body deals with the intermediates of Phase I by shuttling them to Phase II. In Phase II, another group of enzymes, the conjugating enzymes, are involved. Not only do these enzymes conjugate (attach particles) to the intermediates, (which inactivates them in order to be safely excreted in urine or bile), but they may also conjugate chemicals which never passed through Phase I. In order to deal effectively with toxins, the Phase II system must be kept working properly. If Phase I is working well, yet Phase II is not, build up and the Phase I induced, chemically altered, toxic intermediates will have no means of being removed from the body. They will continue to circulate in the blood stream causing more damage. Ritonavir affects the liver's ability to perform optimally. Ritonavir affects the MFOS by keeping the cP450 enzymes busy and unavailable. In other words, ritonavir inactivates the cP450 enzymes. As a result, many drug interactions can occur when taking this protease inhibitor. First, the liver's ability to clear drugs such as antihistamines and benzodiazepine antidepressants can pose life-threatening complications when taken in conjunction with ritonavir. The majority of drugs taken orally undergo a process known as the "first pass effects." This process occurs when the drug enters the bloodstream and goes to the liver to be metabolized, or inactivated, by the cP450 enzymes. The dosages for oral medications take this into consideration. Since ritonavir ties up the enzymes essential for this to occur, chemicals and drugs are unable to be metabolized properly. Therefore, they stay in the bloodstream longer and at higher concentrations. What was once a standard dose now becomes a toxic one, since they are not fully inactivated by the liver.
Second, ritonavir affects the liver's ability to activate many chemicals and drugs in order for them to be converted into substances the body can use. This is the reason why many drugs lose their effectiveness in conjunction with ritonavir; oral birth control pills are an example of this. Since these drugs need to be converted by the c P540 enzymes, an increased dose is necessary in order to obtain the desired effects.
Diet and food can play a role in influencing the liver and the Phase I and Phase II detoxification systems. Although no studies exist as of this date regarding the interaction between food and ritonavir, much has been written describing the role of diet and lifestyle on basic drug metabolism. Once again, we find that common sense and basic nutrition cannot be overlooked when the goal is to stimulate the body's natural ability to stay healthy and maintain a strong functioning immune system.
The goal for healing with food is to ensure that Phase II detoxification is working properly. Although the cP450 system (Phase I) is inactivated by ritonavir, attempts at activating these enzymes is not necessarily the objective. By activating these enzymes, we decrease the effectiveness and concentration of ritonavir in the body. This is seen in tobacco smoke. Tobacco and other smoked products contain chemicals (nitrosamines) which must be activated by the cP540 enzymes in order for their toxic and carcinogenic effects to take place in the body, i.e., they must be converted to toxic intermediates. These nitrosamines activate the cP450 enzymes. The same thing occurs with charcoaled food which yields polycyclic hydrocarbons. Theses hydrocarbons are produced by incomplete combustion when drippings contact hot coals and are redeposited on the foods. Hydrocarbons activate cP450 enzymes as well. Studies show that those who smoke have an 18% reduction in their blood levels of ritonavir. This is due to the fact that activated cP450 enzymes begin clearing ritonavir from the body. Alcohol also increases the cP450 activity and may have the same effects on blood levels of this drug as does tobacco. Stimulating cP450 enzymes has another hazard; activating Phase I detoxification without an intact Phase II can result in an increase in circulating toxic intermediates which can be life-threatening.
In addition to these effects, both smoking and alcohol consumption lead to deficiencies in nutrients essential for virtually all enzymatic pathways in the body, especially Phase II detoxification. The consequences of such deficiencies can be more problematic for maintaining a healthy immune system and functioning liver that the actual activation of cP450 enzymes. Therefore, as a rule, avoidance of tobacco, alcohol and charcoaled foods is advisable. If cooking with charcoal, tightly wrap foods in aluminum foil in order to prevent the formation of hydrocarbons.
As mentioned above, adequate nutrition is paramount. In order for the Phase II detoxification to perform optimally, it must have all the basic building blocks. The proper vitamins and minerals must be available; without them, detoxification cannot occur. Vitamin deficiencies can lead to an increased conversion of procarcinogenic substances to toxins and carcinogens by the cP450 system, and an increased level of circulating toxic intermediates from Phase I. Providing the body with the essential nutrients, either through supplementation, or diet, helps restore balance. All the B vitamins, (thiamin, riboflavin, niacin, pantothenic acid pyridoxine, folic acid and cobalamin), are needed at some level for the Phase II system to function properly. Emphasis should be given to these nutrients of the antioxidant family as well, namely vitamin C and E, beta carotene and selenium. Both vitamin C and E can block the formation of nitrosamines which can prevent activation of cP450 enzymes and inhibit tumor formation. Furthermore, when levels of selenium and B vitamins decrease, glutathione decreases. Glutathione is a major antioxidant in both of the Phase I and Phase II systems. Stores of glutathione must be maintained to prevent free radical damage and ensure adequate detoxification. The amino acid N-acetylcysteine (NAC) can protect glutathione levels from dropping in the body. NAC supplementation has been studied for its ability to successfully treat and prevent liver toxicity by such drugs as acetaminophen (Tylenol). All in all, supplementation with a good multivitamin is a start and can ensue the body with B vitamins, antioxidants and NAC is warranted when taking ritonavir. However, supplementation does not preclude the fundamental necessity for proper diet. Like the effects of tobacco and alcohol, methylxanthines, such as caffeine, theophylline, and cola induce the cP450 enzymes of Phase I. Rather than further stimulate this system, it would be best to decrease consumption of foods containing theses substance. Such foods would include coffee, black teas, chocolate, and sodas. As with all parts of our lives, balance is the key; complete avoidance to the point of fanaticism is not necessary. If you are taking a protease inhibitor, rather than continue to stress the liver, allow it time to balance and recharge. Although these protease inhibitors are extremely potent, becoming obsessed with everything you do (including everything you eat and drink) does not promote healing and wellness. If you find yourself drinking many cups of coffee per day, explore your need for coffee. If you find yourself addicted to the caffeine, now would be and excellent time to do something about it. This does not mean coffee can never be consumed again. It simply suggests that moderation, without addiction, is key.
Cruciferous vegetables, such as broccoli, cabbage, and brussel sprouts, contain a chemical known as indole-3-carbinol which is a potent activator of Phase I and Phase II detoxification. While diets high in these vegetables have anti-tumor producing effects, they induce cP450 enzymes. Remember activation of Phase I is problematic with out Phase II. Since cruciferous vegetables do both, simply be cautious. Even though your mother may have had good motives, feel comforted in knowing that it is not always beneficial to eat your brussel sprouts! So what to eat or drink? One class of chemical compounds, flavonoids, phenolic compounds abundant in fruits and vegetable, have potent action on Phase I and Phase II systems. Not all flavonoids are the same. Flavonoids containing multiple hydroxyl groups appear to be more effective inhibitors. Fruits such as lemons, limes, and grapefruits possess the highest amounts of these polyhydroxylated flavonoids, while tangerines and oranges do not. Ingestion of lemons, limes, and grapefruits inactivate Phase I even more. Since ritonavir is already performing this action, there is no need to provoke the situation any further. Oranges and tangerines, on the other hand , activate Phase I, which we do not want to do either. As a rule, avoidance of citrus fruits and juices is wise. The inhibition of Phase I detoxification is the reason why people are told to take their saquinivir (invirase) with an 8 once glass of grapefruit juice. If the cP450 enzymes are inactivated, then the drug (saquinivir) will not be cleared from the system as readily. Ritonavir's inhibition of cP450 enzymes is the rationale behind taking both of these protease inhibitors simultaneously. Ritonavir will increase circulating saquinivir in the bloodstream. Unfortunately, without an understanding of proper dosage, this combination can be lethal. Studies are being conducted to determine the levels and concentration necessary for these two drugs to be taken together.
Consuming the following foods daily would be helpful to ensure proper Phase II detoxification; foods high in glutathione, sulfur containing amino acids, protein, and vitamins, especially B and C. Glutathione rich foods include asparagus, walnuts and avocados. Foods high in sulfur containing amino acids include red peppers, onions and garlic, and cruciferous vegetables (to be eaten moderately). Some foods with B vitamins are yeast, whole grains, animal products and beans. Vitamin C are peppers and cabbage. Again, supplementation is useful to ensure no deficiencies are occurring. Yet, supplementation should never be used as a means of ignoring healthy eating habits.
Included in a healthy diet for the liver would be herbs and vegetables that are known to stimulate liver detoxification and cleansing. Such vegetables that are known to stimulate liver detoxification and cleansing. Such vegetables are beets, artichokes, radishes, carrots and baby dandelion greens. As a rule of thumb, dark leafy green and yellow vegetables have healing properties for the liver and should be consumed often. Licorice root contains the chemical compound glycyrrthitinic acid which accords protection for the liver. Licorice prevents destruction of the liver cells by toxins, decreases the production of free radicals and helps restore balance to the adrenal glands (helping those suffering from fatigue due to over exertion and stress). This herb can be added to the diet through teas made from the fresh root. A word of warning: Licorice root should not be used by those with pre-existing condition of hypertension as glycyrrhitinic acid is known to exacerbate this condition. Glycyrrhitinic acid does not raise the blood pressure of those individuals with normal levels. Deglycyrrhinated licorice root (DGL), however, does not provide the benefits for the liver listed above, and therefore should not be used with these goals in mind. The herb milk thistle (silybum marianum) contains the chemical silymarin which has been studied for its many healthy effects of the liver. Milk thistle is known to prevent liver cell destruction, enhance liver function, inhibit free radical damage in the liver, inhibit synthesis of inflammatory chemicals (prostaglandins) and promote protein synthesis of new liver cells. Studies have demonstrated milk thistle's ability to prevent liver necrosis (destruction of liver cells) from toxic chemicals, such as carbon tetrachloride, when administered intravenously. On the whole, adding milk thistle to your daily regime can have a major effect in preserving your liver cells and minimizing the toxic effects of many medications in addition to ritonavir. Milk thistle can be found in capsules as well as the seeds. If using capsules or tincture, look for standardized extract with at least 70% silymarin content. When using the seeds, these can be soaked in water or apple juice overnight, then crushed or blended in order to be consumed.
Drug therapy, regardless of its benefits, can be harsh on the body, especially the liver. Taking steps towards healing requires an examination of our behaviors, including our eating habits. Avoiding known carcinogens and stimulators of the MFOS, (smoking, alcohol, and charcoal foods), will only promote our well-being and health. The choices we make in our diets can positively affect our liver. Supplementation with antioxidants and B vitamins supports Phase II detoxification system. Adequate fiber in the diet ensures that toxins in the bile are removed effectively. As a basic rule, a diet high in fresh vegetables and fruits (particularly yellow-green vegetables and fruits),and whole grains has a protective affect on the liver. The goal is balance.
About The Author
Dr. Brad S. Lichtenstein is a licensed naturopathic physician in private practice in Seattle and is a member of STEP's Scientific Review Committee.
Anderson, K. E. and Kappas, A. Dietary Regulation of Cytochrome P450. 1991. Annual Review Nutrition, 11: 141-167.
by Brian Coppedge
The 36th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) was held September 15-18, 1996 in New Orleans. Following so closely after the XI International AIDS Conference, there was speculation that very little new information about HIV/AIDS would be presented in New Orleans; this proved not to be true. New information about the clinical benefits of lamivudine (3TC), the use of ritonavir and saquinavir in combination, and information about a promising new protease inhibitor were all presented at ICAAC.
Clinical Benefit of 3TC StudiedDr. Julio Montaner of Saint Paul's Hospital in Vancouver B.C. presented results of the CAESAR (Canada, Australia, Europe and South Africa) study which sought to compare the efficacy and safety of adding 3TC, 3TC plus Loviride, (an experimental non-nucleoside reverse transcriptase inhibitor under development in Europe but not yet available in the US), or a placebo to the participants current antiretroviral regimen. The CAESAR trial was a large trial of 1800 participants with CD4 counts between 25 and 250. All trial participants were already receiving either zidovudine (AZT) monotherapy, or AZT plus didanosine (ddI), AZT plus zalcitabine (ddC). Trial participants were separated into three separate arms. After 52 weeks of the trial all participants were offered open-label 3TC plus Loviride.
The study was stopped and unblinded following a Data Safety Monitoring Board analysis on July 5, 1996, because the trial data showed a significant difference between the three arms and it was determined no further data would change the results. The rate of disease progression to an AIDS-defining illness was: 17% for the placebo arm; 9% for the 3TC group, and 8% for the 3TC plus loviride group. Death rates in the trial were: 4.6% for the placebo arm: 2.4% for the 3TC arm, and 2.7% for the 3TC plus loviride group. This study determined that adding 3TC to these existing treatments led to a 54% reduction in AIDS-defining illnesses, and a 53% reduction in the risk of death for the trial participants. Adding 3TC to already existing combination therapy did not appear to increase toxicity and seemed to be well-tolerated by the participants. The addition of loviride did not appear to add any benefit to the 3TC enhanced treatments. The purpose of this trial was not to measure the clinical benefit of loviride. Further trials are necessary to evaluate loviride's efficacy.
Ritonavir and Saquinavir in CombinationIn Vancouver, early data (only six weeks on trial) was presented that hinted to the possible advantages of using ritonavir and saquinavir in combination. The two protease inhibitors are being studied in combination because ritonavir can increase the blood levels of saquinavir up to 40 times. Additionally they have different toxicity's, and may have different resistance mutation patterns.
The study was an uncontrolled, open-label study which allowed participants to know which therapy they were receiving. Participants had CD4 counts between 100 and 500 and none were allowed to have taken any protease inhibitors previously. In addition, to be included in the trial, people had to discontinue all antiretroviral therapy for at least two weeks before starting on the new combination. The study divided the 136 volunteers into four arms: 400 mg ritonavir plus 400 mg saquinavir twice daily; 600 mg ritonavir plus 400 mg saquinavir twice daily; 400 mg of ritonavir plus 400 mg of saquinavir three times a day; 600 mg of ritonavir plus 600 mg of saquinavir twice daily.
After 12 weeks, the first two arms had a combined median reduction in viral load of 2.97 logs (a 99.9% reduction) and CD4 increase of 95. 75% of the participants in the first two arms saw their viral loads decrease to undetectable level ( below 200 copies). This same group of participants had been reported as having a 2.4 log (99.6%) drop after six weeks of the combination therapy. Only four people from these two arms had to discontinue therapy because of side effects ( one in the first arm and three in the second).
The third and fourth arms of the trial (which used high dosages) were started only after the initial lower dosage trials proved to be safe. After 6 weeks of the higher dosages, the median viral load dropped by 2.14 logs (99.3) and the median CD4 counts increased by 75 cells. The arm which received 400 mg of both ritonavir and saquinavir three times a day was not well-tolerated; eight of the participants in this arm had to discontinue treatment due to adverse side effects. The arm with 600 mg of ritonavir plus 600 mg of saquinavir was well tolerated and none of the participants in this arm had to discontinue therapy.
141W94 (Glaxo Wellcome): A New Protease InhibitorGlaxo Wellcome is developing a new protease inhibitor, 141W94, which it has licensed from the biotech firm Vertex. The initial study was aimed at determining the safety and maximal antiviral activity of different dosages of 141W94. This new drug seems quite promising for a few reasons: Initial data shows that it is synergistic with reverse transcriptase inhibitors, it is water soluble and therefore quite well-absorbed into the blood system, and in animals models, higher levels of the drug were seen in brain tissue than in the blood.
Antiretroviral activity was seen in the trial which was relatively small, enrolling 42 people in four separate arms. Participants CD4 counts ranged from 150 to 400 cells/ mm3 and had a median viral load of 483,000 viral copies/ml. Each arm consisted of about ten people who received either 300 mg of 141W94 twice a day, 300 mg three times a day, 900 mg twice a day or 1,200 mg twice a day. The study offered 141W94 monotherapy only, and none of the participants were allowed to have taken any protease inhibitors previously. The highest dose group saw a median increase in CD4 counts of 110 cells and a decrease in viral load of 1.95 log. The 900 mg group had a median CD4 increase of only 35 cells, had a decrease in viral load of 1.69 logs. The results of the lower dose arms were not quite as impressive. Volunteers taking 300 mg of 141W94 twice a day experienced only a .53 log reduction in viral load and an increase of 64 CD4 cells. Those who took 300 mg three times a day had CD4 increases of 84 cells and a viral load reduction of 1 log. 141W94 was generally well-tolerated, although about 10% of the participants reported side effects which included, headaches, loose stools and nausea.
Information presented at ICAAC continues to provide encouragement for people living with HIV/AIDS. The CAESAR study results confirm the clinical benefits of adding 3TC to existing antiretroviral treatments, ritonavir and saquinavir appear to be another strong combination that can be used to slow the replication of the virus and 141W94 is just one of many anticipated new protease inhibitors in development. Although the news from New Orleans was not as dramatic as that from Vancouver, important new information was made available.
Brian Coppedge is the Treatment Information Specialist for STEP.