Current HIV Treatmentsby Terri Ferreira, R.Ph.
Earlier detection of HIV along with increasingly effective prophylaxis and treatment of opportunistic infections helps increase the life span of persons with AIDS.
Acquired Immunodeficiency Syndrome (AIDS) was first identified in this country in 1981. Since then, the estimated number of AIDS cases worldwide has reached 4 million - an overall increase of 60% over last year,1 despite exhaustive education efforts. With no cure in sight or vaccine in the near future, the pharmacist's expertise in this complex and changing pharmacotherapy field is vital to both people living with human immunodeficiency virus (HIV)/AIDS and members of the health care team. This article reviews the epidemiology and pathogenesis of AIDS as well as current treatment strategies both for the management of HIV and the treatment and prophylaxis of opportunistic infections.
Between the years 1981 and 1989, the first 100,000 cases of AIDS were reported in the United States. The second 100,000 cases were reported slightly more than two years later.2 In 1994 alone, 80,691 cases of AIDS were reported to the Centers for Disease Control and Prevention (CDC).3
AIDS is now the number one killer of persons aged 25 up to 44 years in the United States,4 and since its recognition has killed over 270,000 Americans.5 At the Tenth International Conference on AIDS in Yokohama, Dr. Mike Merson reported shocking estimates that 17 million people have been infected with HIV, with 6,000 persons becoming infected daily.6
AIDS reported cases in 1994 continued to rise from 1993 data in women (16% to 18%) and heterosexual contact (9% to 10%) while the percentage of cases from same-sex contact decreased from 47% to 43%. Blacks and Hispanics made up more of the caseload than in 1993 with 39% vs. 36% and 19% vs. 18% respectively, while cases in whites decreased to 41% from 45%.7
In January, 1993, the CDC broadened the AIDS case definition (replacing the 1987 classification) to more accurately reflect the numbers of individuals with AIDS.8 People with CD4 cell counts less than 200 are now classified as having AIDS. The new classification system recognizes a broader spectrum of clinical condition that occur in severely immuno-compromised individuals and emphasizes the importance of CD-4+ T-cell count. Therefore, data collected since its introduction may be somewhat skewed as universal adoption is probably incomplete.
The human immunodeficiency virus is of the Lentivirinae sub-family of retroviruses.9 There have been two strains of HIV identified: HIV-1 (prevalent in the US) and HIV-2 (most often found in Africa).10
HIV-1 binds primarily to the CD4+ receptor on the T-lymphocyte and then enters the cytoplasm of the cell where the virus is uncoated and reverse transcription of viral RNA begins. This results in the production of the double stranded DNA form of the virus if appropriate host factors are present. The viral DNA duplex is then inserted into the host genome, thereby giving rise to the HIV-1 provirus. HIV-1 may remain dormant or replicate (HIV-1 does not replicate in resting T-cells). After T-cell activation by host factors (i.e., antigens, cytokines, mitogens, etc.), proviral DNA is incorporated in the manufacturing process of viral proteins, which are assembled to form a new virus.10,11
Antiretroviral therapy is targeted at different steps in the replication cycle of HIV-1. Until recently only agents that inhibit reverse transcriptase, the enzyme responsible for converting viral RNA into DNA are FDA approved. These agents are called dideoxynucleosides (or simply nucleosides) and include zidovudine (Retrovir, AZT, ZDV), ddI (Videx, dideoxycytidene), ddC (Hivid, dideoxycytidine), d4t (Zerit, stavudine), and 3TC (Epivir, lamivudine). However, due to the toxicity and lack of clinical durability of the nucleosides, the current focus has shifted to non-nucleosides reverse transcriptase inhibitors and protease inhibitors. Nevertheless, nucleosides remain the mainstay of HIV therapy.12 (Author's addition February, 1996: Since the original publication of this article, three protease inhibitors, have been approved by the FDA. See FDA Approves Two New Protease Inhibitors: Ritonavir (Norvir®) and Crixivan® (Indinavir Sulfate) in this issue of STEP Perspective)
On-going antiretroviral clinical trials are charged with the task of determining: a) when to initiate antiretroviral therapy, b) whether monotherapy or combination therapy is more effective, and c) when to change antiretroviral therapy. As new data from clinical trials emerge, it is becoming more difficult to establish simple guidelines for antiretroviral therapy that apply to all groups of people.13 In addition to antiretroviral therapy, it is important to maintain adequate nutrition to help prevent wasting syndrome.
The most recent general recommendations by an expert panel convened by the National Institute of Allergy and Infectious Disease (NIAID) were published in JAMA, December 1993 (see Table 1).14 3TC and d4t were not included in the recommendations since they were not yet FDA approved. Current ongoing trials show impressive results when 3TC (Lamivudine) or Invirase (Saquinavir) is used in combination therapy with other nucleosides.
Zidovudine (Retrovir, AZT, ZDV):
AZT (commonly known as ZDV) was the first antiretroviral agent approved by the FDA and remains the initial drug of choice for the treatment of adult persons with CD4+ cell counts of 500 cells/mm3 or less who have not yet received any prior anti-HIV therapy. AZT is also indicated for HIV-infected children over three months of age who are asymptomatic with abnormal laboratory values indicating significant HIV-related immunosuppression. The most recent indication is for the prevention of maternal fetal HIV transmission.15
AZT is rapidly absorbed by the GI tract with a peak serum concentration in approximately 0.5 hours to 1.5 hours. AZT undergoes first-pass metabolism and is renally excreted. The elimination half-life of AZT is one hour; however, the intracellular half-life of the active metabolite, 5'-triphosphate approaches three hours.16 Food does not significantly affect AZT absorption.
Based on recent clinical data, the current recommended dose of AZT is 100 mg orally, every 4 hours (600 mg daily dose) for symptomatic HIV infection and 100 mg orally, every 4 hours while awake (500 mg total daily dose) for patients with asymptomatic infections. These doses are lower than the original test dose of 250 mg orally every 4 hours as studies have shown less toxicity with no difference in progression rates to AIDS with the lower doses.16 The dose for children greater than three months of age is 180-200 mg/mm of body surface area every six hours.
To help increase compliance, AZT is also given at a dose of 200 mg every 8 hours. However, risk of nausea increases. Also of note, doses as high as 2,000 mg/day have been used for some patients with HIV dementia.
A recently completed study, ACTG 076, demonstrated that the use of AZT by certain HIV-positive women and their infants could reduce by two thirds the risk of perinatal HIV transmission. Recommendations based on this study were published in the Morbidity and Mortality Weekly Report on August 5, 1994.17 These recommendations should be discussed between a woman and her health care provider.
Headache, nausea and malaise are the most common adverse affects to occur during the first several weeks of AZT therapy, especially in persons with early HIV infection. Other early adverse affects include insomnia, vomiting, abdominal distention, diarrhea, myalgia and fever. Generally, symptoms become tolerable as therapy continues. AZT can be given with food to decrease nausea while increasing compliance. Significant anemia (hemoglobin less than 7.5 g/dL or reduction of baseline value by more than 25% of baseline value) and/or granulocytopenia ((granulocyte count less than 750 mm3 or reduction by more than 50% of baseline value) can occur, necessitating treatment modifications.18 Therefore, close monitoring of CBC (Complete Blood Count) (every 2 to 4 weeks depending on HIV disease status and other medications) is warranted. Treatment modifications may include lowering the dose of AZT, discontinuing AZT and initiating ddI or ddC, addition of epoetin-alfa (for anemia if erythropoietin levels are not elevated) or coadministration of granulocyte colony-stimulating factor to help control neutropenia.
Drug interactions with AZT are due primarily to additive bone marrow toxicity. Many of these drugs are used to treat or prevent opportunistic infections; therefore, continuation of either therapy must be based on risk vs. benefit as treatment options are very limited.19 These drugs include amphotericin B, dapsone, trimethoprim-sulfamethoxazole, and ganciclovir. Also of note, AZT can either raise or lower phenytoin levels; therefore, close monitoring of phenytoin concentrations is warranted. As people with HIV generally have low albumin levels, free fraction phenytoin levels may be necessary for appropriate monitoring.
Didanosine (Videx, dideoxyinosine, ddI):
ddI is indicated for the treatment of adults with advanced HIV infection who have received prolonged prior AZT therapy, and for the treatment of adults and children (over six months of age) with advanced HIV infection who have demonstrated intolerance or significant clinical or immunologic deterioration during AZT therapy.20
ddI is rapidly degraded by an acidic pH. Therefore, ddI oral formulations contain a buffering agent designed to increase gastric pH and must be taken on an empty stomach.
ddI is available in three formulations and is dosed according to weight for adults and body surface area for children (Table 2). It is important to emphasize to the person the importance of strict adherence to preparation technique and administration on an empty stomach (30 minutes prior or two hours after a meal). The tablets must be chewed completely, swallowed and then followed by at least one ounce of water (not fruit juice or acid containing juices); alternately you may crush/dissolve tablets in at least one ounce of water, stir until dissolved completely, then drink immediately. Most people over one year old should receive two tablets per dose. These should be administered together so that adequate buffering is provided to prevent gastric acid degradation of ddI.
The buffered powder is to be mixed with four ounces of water. Instruct the client to stir completely until dissolved, then to drink immediately.
The pediatric powder must be prepared by a pharmacist before dispensing. Appropriate directions are on the label. The admixture must be shaken prior to administration and is stable for 30 days if refrigerated. The most common adverse reactions noted soon after initiation of ddI are dry mouth, altered taste, nausea (particularly with the chewable tablets) and diarrhea (particularly with the buffered powder). Once again, if the person is well-versed on the preparation technique and administration of ddI, these problems should be minimized. Also, increasing the volume of cold water in preparation may also help to decrease these problems.21
Pancreatitis and peripheral neuropathy are the most serious complications associated with ddI. Pancreatitis is dose related and occurs annually in approximately 7% to 13% of those treated with ddI.22 Instruct people to notify their health care provider with any complaints of abdominal pain, nausea or vomiting. Amylase and lipase levels should be monitored closely. Concomitant administration of intravenous pentamidine may increase the risk of pancreatitis (as well as a history of alcohol abuse).
Peripheral neuropathy, also dose related, occurs annually in approximately 13% to 14% of those treated with ddI.22 Caution must be taken when coadministering medications with similar adverse reaction profiles, such as dapsone, disulfiram, isoniazid, metronidazole and phenytoin. The combination of ddI and ddC is not recommended due to increased peripheral neuropathy.
Drug interactions with ddI are also related to the buffering agents' ability to alter the absorption of medications that require a gastric pH. These include ketoconazole, dapsone, tetracyclines and quinolones. These medications should be given preferably two hours prior to ddI administration. Additional monitoring of antihypertensive medications and those people on lithium therapy is necessary as each ddI tablet contains 264.5 (two tablet doses at 529 mg) of sodium and each packet contains 1380 mg of sodium.
Zalcitabine (Hivid, dideoxycytidine, ddC):
ddC is approved by the FDA for use in combination with AZT for selected persons with advanced HIV infection (CD4+ counts 300/mm3) and for the treatment of HIV infection in adults with advanced HIV disease who either are intolerant to AZT or who have disease progression while receiving AZT.23
ddC is rapidly absorbed from the GI tract with mean absolute bioavailability above 80%. Food does decrease the rate and extent of absorption. ddC is primarily excreted by the kidneys with a mean elimination half-life of two hours.
For adults weighing 30 kg and over, the appropriate dosage of ddC is 0.75 mg (with AZT 200 mg) every 8 hours. The following adjustments must be made for decreased renal function: Creatine Clearance 10-40 mL/min. = 0.75 mg every 12 hours; Creatine Clearance The common initial self-limiting adverse effects usually occur within the first four weeks of ddC therapy. These include skin rashes, aphthous oral ulceration's (painful open sores in the mouth) and fevers. Coadministration of antihistamines, acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) as well as the use of mouth rinses may be helpful. Nausea, vomiting, diarrhea and abdominal pain are also common.
Peripheral neuropathy is present in approximately 22% to 35% of people receiving normal dosing of ddC.23 As with ddI, caution must be taken when administering other medications with similar adverse reaction profiles. Pancreatitis is a rare adverse effect of ddC. Nonetheless, the same precautions apply as with ddI therapy.
Concomitant use with drugs that may impair renal function such as aminoglycosides, amphotericin B and foscarnet may also increase the risk of ddC-induced adverse effects.
Stavudine (Zerit, d4T):
d4T, approved by the FDA in August, 1994, is indicated for the treatment of advanced HIV-1 infection in adults: a) who are intolerant to AZT, ddI or ddC; b) have experienced significant clinical or immunologic deterioration while receiving these therapies; or c) for whom such therapies are contraindicated.24 d4T is also used in combination with the other nucleosides.
d4T is stable at gastric pH and is well absorbed (oral bioavailability in excess of 80%). Renal elimination accounts for approximately 40% of overall clearance; therefore, dosage adjustments must be made according to renal function (Table 3).
Dosage of d4T for adults with normal renal function (CrCl >50mL/min) weighing 60 kg or more is 40 mg every 12 hours and for people weighing less than 60 kg, the dose is 30mg every 12 hours.
Common adverse effects of d4T include peripheral neuropathy (dose related), headache, nausea, vomiting, and confusion.
Drug interactions include medications that impair renal function and those with side effect profiles which include peripheral neuropathy. Caution must be taken when coadministering these combinations.
Lamuvidine (Epivir, 3TC):
3TC, approved recently by the FDA, is indicated for use in combination with Retrovir (Zidovudine) for the treatment of HIV when antiretroviral therapy is warranted based on clinical and/or immunological evidence of disease progression.
3TC is rapidly absorbed after oral administration and may be administered with or without food. 3TC is renally eliminated, thus dosage adjustments must be made in accordance to renal function (Table 4). Dosage of 3TC in adults and adolescents (12-16 years) with normal renal function is 150 mg twice daily in combination with Retrovir. For adults with low body weights, (<50 kg or 110 lbs.), dosage should be decreased to 2 mg/kg twice daily in combination with Retrovir. Doasge for children (3 months-12 years) is 4 mg/kg twice daily (up to maximum of 150 mg twice daily) in combination with Retrovir.
Common adverse effects of 3TC combination therapy includes headache, malaise, nausea, vomiting, diarrhea, anorexia, neuropathy, insomnia, myalgia and arthralgia. Pancreatitis was observed in 3 of 656 adult patients studied (<0.5%) who received 3TC in clinical trials. Lab abnormalities included neutropenia, anemia, elevated liver enzymes, and elevated amylase (although not much greater than AZT monotherapy). The combination of 3TC and TMP160 mg/SMX 800 mg (commonly known as Bactrim or Septra) (once daily) appears to decrease the oral and renal clearance of 3TC. Caution and monitoring is warranted when administered together.
Saquinavir is the first protease inhibitor approved by the FDA (Jan., 1996). Protease inhibitors inhibit the activity of HIV protease (an enzyme) preventing the cleavage of viral poly-proteins which are precursors to the generation of functional proteins in HIV-infected cells.
Saquinavir is indicated in combination with nucleoside analogues (AZT or ddC) for the treatment of advanced HIV infection in selected adults (>16 years old).
The oral absorption of Saquinavir is increased if administered within 2 hours after a full meal. If taken without food, concentrations of Saquinavir in the blood may be substantially reduced and may result in no antiviral activity.
Saquinavir dosage in adults is 600 mg three times daily (within 2 hours of a full meal) in combination with either Hivid (ddC) 0.75 mg three times daily or Retrovir (AZT) 200 mg three times daily.
The most frequent adverse reactions (excluding those toxicities know to be associated with ddC or AZT) are: diarrhea, abdominal cramping, and nausea. Saquinavir did not alter the pattern, frequency, or severity of known major toxicities associated with the use of ddC or AZT.
Saquinavir is hepatically metabolized by the cytochrome D-450 system. See Table 5 for related interactions.
Opportunistic infections (OIs) account for as much as 90% of the mortality in persons with AIDS.25 OIs are caused by pathogens that most people are exposed to but generally only cause severe illness in immunocompromised individuals. In fact, AIDS was first defined in this country in 1981 -- the year the CDC started collecting data on AIDS, in response to people presenting with OIs and an uncommon form of cancer associated with profound immunosuppression (Kaposi's Sarcoma).
The earlier detection of HIV along with increasingly effective prophylaxis and treatment of OIs has increased the life span of persons with AIDS. A 1994 Multi-AIDS Cohort Study reported that after 15 years of HIV infection, 33% of the people studied had not progressed to AIDS, 22% had CD4+ counts over 200/mm3 and 6% had CD4+ counts over 500/mm3.26 As CD4+ cell count declines below 500 mm3 (normal = 1,000/mm3), the immune system lacks resources to fight these often lethal OIs.
All OIs pose a serious threat to those with HIV, but they do not affect all people equally. For example, those who acquire HIV sexually are more likely to suffer from outbreaks of herpes simplex than IV drug abusers. People living in the central United States are at highest risk for developing histoplasmosis while coccidiomycosis is endemic to the southwest. This article will briefly address only a few of the most common OIs.
Pneumocystis carinii Pneumonia (PCP):
PCP is the most common severe OI associated with HIV infection. It occurs at some point in approximately 80% of advanced HIV-infected individuals in the absence of preventative measures with a mortality rate of 10% to 25%.27 The risk of PCP increases as CD4+ cell counts decline below 200 mm3.
P. carinii, which was recently reclassified as a fungus, is ubiquitous in the environment. Most children are infected with P. carinii by age four, but normal host defenses prevent disease. PCP in HIV-infected people usually results from reactivation of latent infections. Signs and symptoms include fever, dry nonproductive cough and difficulty breathing.
The U.S. Public Health Service (USPHS) recommends that PCP prophylaxis be provided to any HIV-infected person with a CD4+ cell count less than 200 mm3 and to those with a history of PCP or unexplained fever or thrush greater than two weeks duration.28 TMP/SMX (Bactrim or Septra) is the primary drug of choice for both prophylaxis and treatment. Alternatives for prophylaxis include dapsone and aerosolized pentamidine. Alternatives for treatment include trimethoprim plus dapsone; clindamycin plus primaquine; atovaquone; pentamidine (IV) or trimetrexate (IV) plus folinic acid.29
T. gondii lives in a variety of animals, especially cats. Transmission of the pathogen is through contact with feces from infected cats or ingestion of undercooked meat from infected animals. In the U.S., 20% of adults harbor these organisms.30 T. gondii infects the CNS system as well as other organs. Toxoplasma infections in people with HIV are almost always a reactivation of a chronic latent infection. Toxoplasmosis of the CNS system occurs usually when the CD4+ cell count is less than 200 mm3. The most common signs and symptoms are headache, confusion, visual disturbances, fever and focal neurologic deficits. The current prophylactic strategy is with TMP/SMX. Alternatives include pyrimethamine (plus folinic acid) with or without dapsone or dapsone alone, although these regimens are not yet established as standards of care in the U.S. The primary suggested treatment regimen for acute infection is pyrimethamine (plus folinic acid) plus one of the following: clarithromycin, azithromycin, atovaquone or dapsone.27,29
Mycobacterium avium complex (MAC):
MAC is a term referring to two closely related species, M. avium and M. intracellulare. These organisms are found in soil, air, water, animals and raw dairy products. Mycobacteremia with multiple organ involvement occurs in people with AIDS (CD4+ count below 100 mm3) as a result of primary infection.
Signs and symptoms of disseminated MAC infection include fever, fatigue, weight loss, night sweats, weakness and severe anemia.
Multidrug regimens recommended for the treatment of MAC include clarithromycin or azithromycin plus ethambutol with the addition of one or more of the following drugs: clofazimine, rifabutin, ciprofloxacin, rifampin and, in some situations, amikacin. If clinical and microbiologic improvement is observed, treatment should be continued indefinitely. Prophylactic therapy with rifabutin is recommended by the USPHS in HIV persons with CD4+ counts 3. Clinical trials are evaluating clarithromycin and azithromycin.29,31
Mycobacterium tuberculosis (TB):
In the U.S. alone, based on the decline of TB cases between 1983 and 1984, there were 50,000 cases of TB in excess of what was predicted during the years 1985 to 1992.32 HIV is felt to be one of the most important factors responsible for this increase. In fact, pulmonary tuberculosis was added to the 1993 revised AIDS case definition.
The CDC recommends that all HIV+ persons be evaluated for TB (purified protein derivative [PPD] testing) and those with a positive test should receive isoniazid prophylactically for 12 months. Treatment recommendations for adults with TB include four drugs in the initial regimen; isoniazid, rifampin, pyrazinamide and either ethambutol or streptomycin. If susceptibility to isoniazid and rifampin is demonstrated, continue only isoniazid and rifampin for four months after two months of initial regimen. Three drugs, isoniazid, rifampin and pyrazinamide, may be adequate for initial regimen if drug resistance is unlikely. If resistance to isoniazid develops, continue the four-drug regimen for six months (isoniazid may be discontinued if intolerance develops) or treat with rifampin and ethambutol for 12 months. If rifampin resistance is documented, continue the four-drug regimen for up to 18 months. Treatment for multidrug-resistant TB must be individualized and based on the individual's medication history and susceptibility studies.33,34
Pregnant women must always use alternate regimens as pyrazinamide is contraindicated. In most cases, children are treated with the same regimens as adults, with the exclusion of ethambutol.
Oral thrush caused by C. albicans may be the earliest sign of HIV infection. Candidiasis is by far the most common non-life threatening type of infection associated with HIV. The 1987 AIDS case definition included candidiasis of the esophagus, bronchi, trachea and lungs. The 1993 revised edition added oral and vulvovaginal candidiasis. The current recommended maintenance and treatment for oral and esophageal candidiasis is fluconazole. However, fluconazole-resistant strains of C. albicans are emerging. Alternative treatments available include ketoconazole, itraconazole, clotrimazole or nystatin.27, 29 Amphotericin B is used in cases refractory to all other therapy.
Cytomegalovirus (CMV), Herpes simplex (HSV) types 1 and 2 and Varicella-Zoster (VZV) are widespread in the general population. These viruses have periods of latency and reactivation. Reactivation of CMV can cause retinitis leading to blindness and GI complications.
Ganciclovir IV or foscarnet IV are recommended for initial treatment of CMV. Alternatives include either combination therapy or intraocular ganciclovir (for retinitis). Maintenance therapy for CMV retinitis is recommended with the above-mentioned agents given at lower doses or with the new oral formulations of ganciclovir.27,29 This new formulation is currently in clinical trials to establish its prophylactic efficacy. Oral ganciclovir was approved by the FDA in late 1995 for prophylaxis and maintenance of all forms of CMV.
For patients experiencing reactivation of HSV or VZV, the first-line treatment is often acyclovir. Foscarnet is used in cases resistant to acyclovir.29. Many HIV-infected individuals with recurrent HSV are on maintenance therapy with acyclovir.
Although the number of AIDS cases continues to increase world-wide, a greater knowledge of the disease state and advancement in treatments have occurred. The earlier detection of HIV and aggressive pharmacologic therapy have helped increase the life span of a person infected with HIV.
ADVERSE REACTIONS TO TREATMENT
Adapted from Reference 27, 32
TABLE 1: Antiretroviral Therapy Options
Adapted from Reference 14.
CYTOCHROME P-450 ENZYME INDUCERS:
About the author:
Terri L. Ferreira, R.PH. is the Consulting Pharmacist at Bailey-Boushay House, Seattle, WA (through Evergreen Pharmaceutical Services, an Omnicare Company). She is also a member of the Scientific Review Committee for Seattle Treatment Education Project.
Originally published in U.S. Pharmacist, August, 1995 issue, pages H-3 - H-19.
Acupuncture and Traditional Oriental Medicine
Christopher Huson, M.Ac., L.Ac.
Acupuncture, an art of medicine that has a well-documented clinical history of over 3000 years is an "energetic medicine": it deals with the energy of life, called "qi" (chee). Acupuncture is one of the treatment modalities that comes under the rubric of Traditional Oriental Medicine. Other modalities include Tuina (chinese massage), meditation, qi gong, therapeutic exercise, dietary and nutritional work, and herbal medicine. Traditional Oriental Medicine has recently been getting a lot of attention as an "alternative medicine", but as a practitioner I'd prefer to consider it "complimentary". Its essential nature is to treat the energy of the human system. It works with the medical techniques of the West by supporting and enhancing treatment protocols that are often harsh or difficult for the person due to severity of treatment, or the side effects of strong medication. This paper will outline the nature of acupuncture, explain the use of needles and moxibustion, and show how acupuncture and Traditional Oriental Medicine, because of its essentially flexible nature, is an excellent treatment form for people with compromised immune systems.
Acupuncture is a method of balancing qi by intentionally moving it around with the aid of acupuncture needles. When I was small, a trip to the doctor occasionally meant getting a shot: a source of great trepidation and outright terror. Experience had taught me that when the guy with the tie in the long white coat told me "it wasn't going to hurt", it often hurt like heck. That's where many of us learned our experience of needles.
Fortunately, acupuncture needles are not hypodermic needles. Acupuncture needles are very fine, called "filliform", meaning hairlike. They are of solid-bore construction, and made of high-quality stainless steel. They are both strong and flexible. They range in length from about 1/2" to around 6". Shorter needles are used in places where there is not much tissue such as the ears, the longer ones where there is more tissue, such as the place where you sit down. The tip of an acupuncture needle is rounded. It is used to push tissues out of the way rather than cut through them. A skilled acupuncturist can insert an acupuncture needle through the skin without the patient feeling it at all. It is the purpose of the acupuncture needle to access the place in the tissue where the qi is collecting. This place is known as an acupuncture point.
Traditional Oriental Medicine operates on the simple idea that qi not only permeates all living tissues, but that it moves throughout the organism. Illness and disease are the end products of the imbalances of qi. Qi has often been compared to water in its properties of movement and nourishment of the terrain. Qi flows in pathways known as "meridians". It is thought that these pathways are lines through the fascia of connective tissue where electromagnetic resistance is low. As the qi flows in these pathways, it tends to pool, or eddy, due to changes in anatomical structure, much like water flow in a river changes because of changes in the structure of the river bed. It is these places of flow, or swirling, or collection, which are the locations of the acupuncture points internally. It is into these places that an acupuncturist seeks to go with the tip of the acupuncture needle.
An adjunct to the use of needles is Moxibustion. The term is derived from the Japanese mogusa and refers to the burning of the pulverized plant material of Mugwort, folium artemisia vulgaris. The frequency of the heat produced seems to be especially complimentary to human tissues. It has a deeply penetrating effect which can be quite soothing locally as well as systemically energizing when correctly applied. Together, acupuncture and moxibustion are the basic tools of this most flexible treatment form. Its flexibility is derived from its essentially simple nature of seeking energetic balance.
As energy, qi exists at a variety of frequencies. An acupuncturist seeks to balance qi at any or all of these various levels. This is why acupuncture is so successful at effectively treating such a broad variety of complaints beyond those of a simple physical nature. As a treatment choice for those people who are immunocompromised, acupuncture and Traditional Oriental medicine is excellent because treatment takes place at the mental, the emotional, and the spiritual, as well as the physical level. Indeed, one of the most enjoyable examples of feedback I've received from a person was the statement: "I feel well; I had fogotten what that was like; I thought I'd never feel well again."
This is the magic of Traditional Oriental Medicine: by teaching a person it is possible to feel well as a result of receiving acupuncture, the person comes to understand that a return to health is an accessible option. Acupuncture provides relief for many problems which are caused by disease pathogens or are side-effects of medications provided by Western medicine. Such symptoms include night sweats, diarrhea, digestive difficulty, nausea and vomiting, depression, insomnia, anxiety, peripheral neuropathy, muscle pains, and sinus congestion -- to name a few. To an acupuncturist, each of these complaints may be seen as elements of a symptom complex, each of which may be different from person to person, for each person is recognized as being ill in his or her own way. The person can expect a thorough subjective interview coupled with objective observation and physical examination. From this information the acupuncturist synthesizes a diagnostic pattern and, attempts to alleviate the imbalances within the pattern. For the first-time acupuncture client some of the questions may seem pretty far removed from the main complaint. However, when all the symptoms are viewed as a whole, a clear yet often complex pattern emerges. The practitioner then treats the pattern of which the main complaint is a part. When the main complaint is resolved, other symptoms in the pattern are also alleviated.
Finally, as a compliment to acupuncture, herbal formulations are often recommended. The Chinese materia medica is large and varied. Formulations are given to people as "patent medicines" which are prepared and bottled in pill or capsule form; or as bags of raw herbs which are taken as decoctions or "soups". Raw herb formulations are used when a practitioner needs to tailor a formula to an individual by adding or subtractiong an herb from a classical formulation, and varying the amounts of the ingredients. Most herbal decoctions are prepared by boiling herbs for about half an hour, straining off the liquid, and drinking it. They are well-known to often smell bad in the cooking and taste worse in the drinking. As most people would prefer to take a pill than go through the effort of making a soup, prepared herbs are more general in their scope and easier to take. Each form has its advantages and difficulties. As patents are more generalized, they can be given to more people, they are easier to take and easier to prescribe. But the true art of the medicine is in the custom formulation of the raw herbs, and it is in this realm that the subtlety and the power of the medicine is truly evident.
Acupuncture and Traditional Oriental Medicine have almost as many variations of application as there are practioners. There are many schools of thought about knotty problems that are "hard to treat". One would expect this from a medicine that is over 3000 years old. The more questions one answers, the more questions one has. I've tried in this article to give a cursory overview of the medicine and why it is so effective for people living with HIV and AIDS. I enjoy my work and always welcome questions. By simply balancing energy, it is possible to enhance the quality of a person's life, to encourage longevity and wellness, and to help people take control of their well-being.
In Seattle there are several opportunities for people living with HIV and AIDS to receive the benefits of acupuncture and Traditional Oriental Medicine. I am a practitioner at the Kang Wen Acupuncture Clinic at 1111 Harvard Ave (206) 322-6945). We are a non-profit clinic serving the HIV+ population. We work on a donation basis, but no one is turned away for lack of funds. We are open Tuesdays from 9 am to 1:30 pm and on Thursdays from 3:30 pm to 6:30 pm. We accept clients on a walk-in basis as well as by appointment. Other clinics in town are the Bastyr University Immune Clinic on Thursday evenings Ph (206) 632-0354, and most recently the Madison Clinic / NIAOM satellite Clinic from 12.00 to 4.30 on Thursday afternoons (633-2419).
Gut Drama: MalabsorptionJennifer Jensen, MS, RD
Knowledge is Power! The HIV/AIDS-affected gut is not lacking for things to do! The more we learn about how body systems work, the better able we will be to work around tight situations, and manipulate the way we function -- all this, made possible just by knowing why!
"HIV/AIDS represents a primary disorder of the Gastrointestinal Tract," says Jennifer Jensen, an HIV/AIDS nutrition expert. (This organ is often called the gut, an easier word to work with.) As it turns out, a good case can be made to validate the above quotation of myself. Then, maybe we'll start to see HIV/AIDS differently -- as the primary nutritional challenge it truly is.
The news must get out, very out, that nutritional adequacy is critical when it comes to the specialized needs -- which do exist -- in dealing with comprehensive HIV/AIDS healthcare.
Nutrition Vocabulary 101
Chewing is an often-neglected and under-appreciated part of the digestive process, and must be emphasized. My bottom line: What the teeth do not do, the intestines will have to. Note that we need to pay especially close attention to this if gas (flatulence/farting) is a problem.
A handy trick, to re-train chewing behavior for intestinal relief, is to count your chews; if you're not to thirty, you're not done! Just how are your intestines? We'll get there -- stay tuned.
Digestion is when the gut breaks down food into its smallest possible size, often into simple molecules (very very tiny). This process is mostly done in first 10 inches (the duodenum), of the small intestine; not the stomach! (Betcha didn't know that!) The duodenum makes its own digestive enzymes and also uses enzymes made in and delivered from the pancreas, liver, and other GI-tract members.
Absorption is the process of getting nutrients into the bloodstream from the small intestine, and this "should" occur throughout its entire 21-foot (average) length. Nutrients must pass through the intestinal wall into nearby blood vessels for delivery to the circulation. Food that is not absorbed is delivered to the toilet. Metabolism is the process through which we use foods, nutrients, and medications. It's measured in units of energy. (Sorry, that's as far as my math capacity allows.) Ultimately, it becomes a matter of high-level use required by the priority of fighting HIV to create this energy. Then high-kinetic energy is spent, like in finance where what we spend qualify as reductions -- in finances. With HIV/AIDS, our needs are greatly enhanced so we have to do more processing than "normal." Lots more. That requires more energy, thus more calories, especially protein.
A host of problems can get in the way from word "go." Just to name a few, and to start with a particular personal annoyance, dry mouth. This problem can arise from many things, and HIV itself is one of them. Depressed hydration status is common and it could contribute to low saliva flow. Meanwhile, Opportunistic Infections (OIs) can involve the mouth in many ways, by their own actions eg, thrush, herpes, and KS, and by drugs and medical treatments -- many of which do tend to cause "dry mouth syndrome."
There's a bit of a "myth" about digestive enzymes in saliva. It's a kind-of yes/no situation. True, enzymes may be there, but they make a rather insignificant contribution to efficiency in the digestive enzyme power pool. The enzyme-making specialists are the intestines, pancreas, liver, and supportive digestive system spare parts. Bottom Line: If you should suddenly cease to produce salivary enzymes, different, higher-capacity digestive system counterparts are ready to take on the whole job!
Mouth sores may require a soft and/or bland diet. This can be Boring! But, as uninterested in eating as we may become, the last thing we need is to force-feed ourselves with food we don't taste or enjoy. Life should be more fun!
If you're forcing yourself to eat -- really going at it well, but are having trouble with the task of eating, it's OK (and a good suggestion) to get nutrients from liquid meal-replace supplements, i.e., supplemental nutritionals. My advice (and a personal favorite): "All You Have To Do Is Drink!" But, you may need to drink a lot!!
Try starting with a liquid meal-type drink supplement such as instant breakfast and/or nutraceuticals. You can make wonderful, good-tasting high-power nutrition shakes. Try making two or more at a time and save the extra for later. If you wake up overnight, it will then be there, ready to drink. Don't miss any "calorie opportunities" like the overnighters you could be sipping. Your nutritionist can be really helpful with shake suggestions! Use his or her vast knowledge -- after all: This is what we do!
Clever use of a straw and some amusing flavoring agents can have you drinking your way through nearly any bout of mouth/throat sores. Here's an easy blender clean-up trick -- pour in about a cup of very hot water and some dishwashing detergent -- then "buzz" it clean. A hefty swipe with a soapy brush, followed by a major hot rinse, a fast-dry, and the blender's ready for another "shake-it" event. I believe in practicalities, and if cleaning your blender has been holding you up, try buzzing.
The tube leading from the mouth (candida risk), past the throat (candida risk) to the stomach, is the esophagus (candida risk). These digestive parts, as it turns out, are all at high risk of candida! Candida in the esophagus could cause a blockage -- preventing food from getting to the stomach. This would mean Trouble!
Often, too, we can sometimes get painful, acid-sensitive ulcers in the esophagus -- back to the bland diet, again. Cold foods help; popsicles and ice cream can be useful. If diarrhea's not a problem, try freezing grapes -- great for grape gorging!
The stomach is supposed to be highly acidic, with a low pH of 1- 2.5 (7 is neutral). This is one way in which the normal gut is supposed to act as an immune-related organ: stomach acids kill off bugs and risky stuff we may unconsciously eat, from time to time. There's usually less acid in the HIV stomach so weakening this important immune barrier.
What does the stomach actually do: It acidifies food as noted, especially protein; it mechanically manipulates its contents, kind of like a blender on low speed; and then the stomach holds the food for sequential delivery to the small intestine (duodenum) where the major part of digestion occurs. Again, normally the stomach doesn't really do much digesting, but HIV screws everything up, so why not just assume it'll hit on the stomach too? HIV/AIDS - specific nutrition concerns stomach irregularities: loss of vitamin B12 absorption, the loss of our acidic immune-barrier, and decreased digestive capacity, especially with protein.
In preparation for reading further, imagine the intestinal system as a long hose -- with tiny "pin-prick holes" like those used for soaking gardens. What an incredible bit of anatomical architecture we have in our intestines! We really need to understand that there's serious additional action going on in the gut -- more so than ever before. It demands tender loving care, and Nutrition Power says we can all do this!
All Opportunistic Infections can affect the gut. Actually, OIs can go anywhere they darn well want to -- salmonella can infect the brain, tuberculosis can infect the intestines, and Kaposi's Sarcoma (KS), a skin cancer can develop in all organs and tissue types throughout our bodies. Intestinal blockages can occur from KS tumors as well!
Medications: all but a very few go into the gut -- they are processed and metabolized there just like anything else we consume. Are you eating? Taking any medications? Using vitamin/mineral/antioxidant supplements? Using any herbs?
Food also goes through the gut, and interacts with anything else that's in there with it. The more we dump into ourselves, the more gut-level activities needed for metabolic processing.
In the duodenum, just past the stomach, major digestion begins. Here, food deliveries from the stomach are enzymatically broken down into very small -- microscopic -- particulates which pass through the little tiny 'soaking holes' (from the "hose") and on into the bloodstream. This should continue through the jejunum and ileum (i.e., the next 20 feet of intestine) on to the colon (one of our riskier body-parts). Here food and fiber residues are held, bulked, and hydrated until (relief!) contents are dumped into the plumbing -- normally, that is. And -- don't forget that a medical diagnosis is the real priority here for treatment of digestive disturbances. Nutrition Power is definitely a secondary (and absolute requisite) co-therapy for use with primary medical and dental healthcare services. Then, it's really time to call your nutritionist -- we can't help if you don't ask! The last thing I want to do is add more confusion, but the small intestine is also an impressive immune-cell making machine -- representing another "arm" of intestinal function. The type of immune cells made here (immunoglobulins, especially IgA) are not the same ones as the CD-4s (T-cells) that get depleted from HIV/AIDS.
We may be getting into "ouch" time here. By-products of digestion, roughage for example, are collected, and fluid-balanced, into this 5-feet long disposal unit. In HIV/AIDS this is almost never the case.
To fully explain how the colon gets so messed-up, let's consider diarrhea. All food becomes non-nutrient food with diarrhea -- it's not processed so its health merits are lost. Few nutrients actually get to where they could be of benefit when diarrhea acts up -- Nutrition Power down the drain!
To help with diarrhea, avoid high fiber foods like vegetables, wholegrains (use white bread), most fruits and fiber-containing cereal and/or crackers. No popcorn, berries (seeds!), corn or beans. Flatulence (gas) can be so embarrassing!
Oats, rice and barley, however, are in a league of their own; do use them. Picture in your mind, oatmeal on a spoon. There it stays. And stays. Sort of sluggish -- to say the least! This is how oats (also barley and rice) can help fix diarrhea -- create sluggishness!
Also, Infalyte, with rice syrup solids, is still sent to diarrhea clients at Project Angel Food -- because it (still) works. HIV-specialty pharmacies carry it and it's not a bad idea to have some on hand for unexpected diarrhea emergencies. It doesn't taste bad and it will help. Call (800) 345-0248 if you have trouble finding Infalyte.
Reverse the above advice for constipation. Fiber management is a really handy trick to learn -- it's about options, and that means control -- that's why I call it Nutrition Power!
The Ultimate Cost: Malabsorption
Now, with this enhanced vocabulary and a new way to visualize and understand the gut, we can define and beat malabsorption. Remember that food will either end up in our bloodstream carrying oxygen and nutrients to all parts of the body, or it will be delivered, often with pain, into the toilet.
If the intestinal tract malfunctions (and we've just seen all kinds of ways for this to happen), nutrition is compromised and health status becomes more precarious.
As a reminder, absorption is when particulate food is delivered through the intestinal wall into the circulation. The "soaking hose" type of delivery system is used. If and when the holes in the soaking hose are plugged up, or if food and nutrients pass them by too quickly for absorptive action -- to occur; they will be efficiently excreted. That's malabsorption!
For this malabsorption problem, we need to eat more, maybe twice as much as before -- just to stay "even." Again, nutraceutical drinks can be inexpensive and very handy for adding extra calories and protein to contribute to "double-eating" behavior that I often recommend.
How to detect if you're malabsorbing? Carefully look into the toilet before flushing. If food seems to be intact, it may be from inadequate chewing, and/or because the intestines are moving too fast for adequate absorption. One client reported observing an intact french fry! Chew very well! (This is why we have teeth!) Avidly eating and drinking more calories, protein and nutrients really is the best way to overcome malabsorption. As to what you should eat? It depends. What do you like? What agrees with your digestive tract? What do you need to avoid? Work with a good nutritionist -- we can help you combat malabsorption -- if you call, that is.
Did I make my point? To summarize: OIs can damage the gut, food, nutrients and medications go thru the gut. The individual digestive tract members are all disarranged by HIV/AIDS so specialized nutrition support is necessary. Yes, the gut is definitely a target for HIV-related malabsorption, weight loss, and wasting. Prevent it! Nutrition Power -- awesome!
First do no harm: If this advice is, or seems to be, connected to adverse symptoms, consult your physician, dentist, nutritionist -- or all three!
Jennifer Jensen, MS, RD, CNSD is in private practice. To accommodate financial depressions that still occur with HIV/AIDS, she offers a "sliding scale" for affordable nutrition services. And she always welcomes your calls at: (310) 450-5581. Nutrition Power is a registered trademark of Health and Nutrition Awareness. Permission for use, with appropriate credit, is granted to STEP.
Jeffrey T. Schouten, MD
The FDA approved 2 new protease inhibitors on March 4, 1996. Ritonavir (Norvir®) was approved in a record 72 days following application, and Crixivan® (Indinavir sulfate) was approved pending availability of adequate supplies from the manufacturer. Ritonavir (Norvir®) was approved for combination therapy; the recommended dose is 600 mg twice a day. Crixivan® (Indinavir sulfate) was approved for monotherapy and combination therapy, the recommended dose is 800 mg every 8 hours.
Side effects of both of these new drugs appear to be fairly mild. Ritonavir use was associated with nausea, vomiting, and diarrhea. Up to 20% of the patients in trials had to discontinue ritonavir. Indinavir was most commonly associated with headaches, rash, diarrhea, and nausea. The most concerning side effects were kidney stones (3%) and elevated bilirubin (jaundice) (8-11%). Merck recommends that people taking indinavir stay well-hydrated to minimize the risk of kidney stones.
The rapid approval of these protease inhibitors was based in large part on the very encouraging results from protease inhibitor combination trials reported at the Third Conference on Retroviruses and Opportunistic Infections (January 28-February 1, 1996, Washington, DC). Ritonavir (Norvirr) therapy was found to decrease the death rate from 8.4% to 4.8%, and clinical progression was decreased from 27% to 13% in people with late-stage disease. Nearly 1,100 people were randomized to receive Ritonavir or placebo in addition to their current antiviral treatment. Participants were taking many other combinations of antiviral compounds. None were allowed to take 3TC, and about a quarter took either AZT or d4T. Ritonavir was well-tolerated; only 15% of the people dropped out of the study, mainly due to gastrointestinal problems. CD4 counts rose for about 16 weeks. In this trial though, viral HIV RNA levels rose during the course of the trial after large decreases observed in the first two weeks.
A more encouraging trial reported at the Conference evaluated the triple drug combination of Crixivan® (Indinavir sulfate), AZT and 3TC. After three months of triple therapy, 85% of the participants had no viral HIV RNA detectable, using an assay which detected 500 or more viral copies per ml. As discussed later in this article, the lack of detectable virus does not mean that a person is cured or is not capable of transmitting the virus to another person, only that the level of virus present is below the level detectable by the test, or is present in other cells in the body. However, no other drug combination to date has had such a pronounced, prolonged suppression of HIV replication. The triple drug combination was compared to Crixivan alone, and AZT plus 3TC.
Another study compared Crixivan, AZT plus ddI (Videx®), and the three drugs combined in people who had never taken AZT. Results for this triple combination showed that 59% of the people had levels of HIV below detection after 5 months. Even though resistance is a major problem if protease inhibitors are used as a single therapy, the researchers reported that one person had no detectable virus after two years of Crixivan monotherapy.
The other protease inhibitor already approved by the FDA is Invirase® (saquinavir). This drug currently has low absorption (bioavailability) and a better formulation should be available soon with increased absorption. Studies of the combination of saquinavir and ritonavir have shown that blood levels of saquinavir are significantly increased, and significant toxicity will probably be experienced if a person takes both drugs at the recommended doses. People with HIV/AIDS and their health care providers now have many options for therapy, monotherapy versus combination therapy, choice of several nucleoside analogs (AZT, ddC, ddI, 3TC, or d4T) and now one of the three approved protease inhibitors. Resistance data from clinical trials may help guide this complex decision. While saquinavir does not cause as great a decrease in HIV RNA as the other two protease inhibitors, it has an advantage that resistance to saquinavir does not cause cross-resistance to the other protease inhibitors. Preliminary resistance data shows that ritonavir and indinavir may cause cross-resistance to the other protease inhibitors. An additional consideration is that indinavir has many drug interactions requiring the reduction of doses for many other drugs, including, rifabutin, ketoconazole, seldane, and ddI. Ritonavir also has numerous and significant drug interactions. It should not be administered with rifabutin, and doses of clarithromycin need to be decreased. Ritonavir also decreases levels of AZT, but no dose adjustments are recommended. Saquinavir has fewer drug interactions than the other protease inhibitors.
With so many drug combinations now possible, individualized therapy will be much more common. Changes in viral HIV RNA levels an individual experiences, will likely become much more predictive of the best therapy for that person than the results of drug trials. Reports from drug trials represent average results, some people did better, and some did worse than the reported average. Therefore, the best combination in a trial might not be as good for an individual person as a combination which did not do as well in a similar drug trial. HIV RNA tests should be approved later this year by the FDA and are already available from most laboratories, although insurance may not pay for the test which can cost from $120-$140. One of the major limitations of any of the triple drug combinations reported above will be cost. It is estimated that the annual cost will range from $12,000 to $70,000 per year.
The results of these early trials provide real hope that a triple drug combination may surpress HIV replication to such low levels that resistance may not develop for a long period of time. Resistance develops due to active HIV replication allowing for random mutations, some of which confer drug resistance. Thus any treatment which keeps HIV replication very low will potentially be beneficial over a long treatment period. It should also be emphasized that when the HIV RNA assay reports no detectable virus, this does not mean that the person is "cured" or free of HIV. It only means that the number of HIV particles is so low that the test cannot detect them. People with HIV/AIDS will have a large number of triple combinations to chose from. Certainly people with high HIV RNA values (>100,000) who have not experienced significant decreases in the HIV RNA level with single drug treatment should consider combination therapy. State Medicaid agencies and hospital and HMO (health maintenance organizations) formulary (drug) committees should be aggressively encouraged to make these drugs available to all people with HIV/AIDS immediately.
Jeffrey Schouten is a general surgeon and co-chair of STEP's Scientific Review Committee.
Primary InfectionDr. Tim Schacker, MD
Despite a decade of research into Human Immunodeficiency Virus (HIV) infection, little is known about the earliest stages of infection and what determines the rate of progression to AIDS. Recent data suggests that rates of progression are dependent on several different factors, including duration and severity of illness at the time of seroconversion, stage of HIV disease in the source partner, the genetic profile of the host, "virulence factors" of the infecting virus, and the quality of the host immune response. Thus far it has been difficult to measure the precise contribution these factors contribute to rates of progression, as few studies have identified and followed persons from the time of seroconversion. Two years ago, the University of Washington established a research clinic to identify and enroll such patients into a series of longitudinal studies. Thus far, we have enrolled 85 patients: representing one of the largest cohorts of people identified at the time of seroconversion. The result of this effort is a more complete understanding of the natural history of primary HIV infection (PHIV), a critical first step for the design and implementation of treatment trials for primary HIV infection.
Clinical Manifestations of PHIV
Seroconversion to HIV usually occurs 10-14 days after exposure. Most patients with primary HIV experience a retroviral syndrome consisting of fever, pharyngitis, adenopathy (swollen lymph nodes), fatigue, and weight loss. Often the client and provider mistake the symptoms for mononucleosis, caused by epstein barr virus (EBV). Less common symptoms include muscle and joint pain , nausea, vomiting, diarrhea, and headache. Of interest, the macular "measles-like" rash that is often described in HIV seroconversion is seen in only 30% of patients. Oral, genital, and rectal ulcerations are common as well as oral and esophageal thrush. The range of symptoms experienced during HIV seroconversion is quite wide, with between 50 and 90% of those people experiencing a symptomatic seroconversion syndrome. In 15% of cases, the illness may be severe enough to require hospitalization.
CD4 Cell Changes After Seroconversion
The CD4 cell count should be interpreted with caution during the acute retroviral syndrome and for the first 6 months after HIV infection. During this period, the CD4 count can be quite low, sometimes below 200 cells/mm3, putting the person at risk for pneumocystis pneumonia (PCP). In contrast, some people maintain a normal CD4 cell count throughout the acute phase of the illness. There is data to suggest that some people experience a rebound of CD4 cells to low-normal values after seroconversion, however, our experience suggests the pattern of CD4 cell changes after PHIV may be quite diverse. The median CD4 cell count in our group at 6 months after acquisiton is 501 cells/mm3. This is different form the Multicenter AIDS Cohort Study (MACS) where there is a much more gradual decline of CD4 cell count to 500 cells/mm3 by 48 months after acquisition.
HIV Viral Load After Seroconversion
Plasma HIV RNA values can exceed 60 million copies/ml during the acute retroviral syndrome and persist at those levels for several days, falling rapidly to near undetectable levels as the initial immune response develops. Recently published data from the MACS cohort suggested that HIV RNA measured relatively early after seroconversion may be predictive of time to AIDS, as persons with higher viral loads progressed to AIDS more rapidly than those with lower viral loads. The conclusions were based on only a few measurements of HIV RNA for each person in the first 8 months after seroconversion. Our experience, with frequent HIV RNA measurements during the first 12 months of infection suggests the relationship between viral load and progression is complex. We have seen some people with very low viral loads progress rapidly and some with high viral loads maintain relatively high CD4 cell counts. Longer follow-up, with a more detailed analysis of factors governing progression, is needed to answer these questions with more precision.
Therapy of PHIV
The decision to treat someone with PHIV is complicated. There exists little, if any, prospective data to support the position that everyone would benefit from administration of antiretrovirals (despite a recent editorial in the New England Journal of Medicine). There are no data to suggest what drug, or combination of drugs, should be used, and for how long. There are no defined goals by which to gauge the success or failure of therapy (change in CD4 cell count, change in viral load, delay in time to onset of AIDS, etc.). These studies have simply not been done, and the current standard of care for someone undergoing primary HIV seroconversion remains no antiretroviral therapy. If there existed a safe and well-tolerated therapy that was highly effective at eradicating the infection, the issue would be less complicated. However, all of the antiretroviral agents available today have significant side effects, systemic toxicity, and a time-limited period of efficacy (before the emergence of resistant virus). Under these circumstances, careful thought should be given when placing a client on therapy.
Would antiretroviral therapy improve the body's own initial immune response? Persons with primary HIV have very high titers of HIV in blood during the first days and weeks of infection, up to 60 million copies/ml. These levels can fall to nearly undetectable levels as the person's immune response matures. The magnitude of the change in viral titer brought about by the primary immune response is much greater than that seen by antiretroviral therapy alone. Perhaps addition of antiretroviral therapy would further reduce viral titers, which may have a benefit in delaying the onset of symptomatic disease. However, at this time there are no data to support this hypothesis. The only published study comparing AZT to placebo during primary HIV infection did not show a benefit in reduction of viral load and only a marginal benefit in raising CD4 cell counts, however longer follow-up of this cohort may demonstrate a survival benefit for the group randomized to AZT.
Are there any risks of therapy? All of these drugs have been associated with significant toxicity and side effects. The ability of AZT to induce nausea, diarrhea, and anemia is well known. d4T, ddI, and ddC are associated with peripheral neuropathy and gastrointestinal symptoms, and the protease inhibitors are associated with significant liver and kidney toxicity. Would therapy with one or more antiretroviral agents at a time when circulating titers of virus are very high promote resistance to any or all of the drugs? If that were to happen, what therapeutic choices would be available to the person when the disease becomes advanced? Some people given AZT during PHIV may have an altered, or immature immune response to HIV infection. In a small, uncontrolled trial, some people treated with AZT during symptomatic PHIV had delayed development of an immune response to HIV. Moreover, in 20% of individuals we have studied thus far, viral load has been very low (< 10,000 copies/ml) during the first 6-12 months after seroconversion: these people may not require therapy.
The only way to answer the question of therapy for primary HIV infection is to perform a large placebo controlled trial, or in a disease as complicated as HIV, a smaller series of controlled trials. One has only to look at the recent cardiac literature to find a dramatic example of the need for this step. There was a large, multicenter study (called C.A.S.T., or cardiac arrhythmia suppression trial) that was designed to study encainaide and flecainide, drugs designed to control heart rhythms. The investigators compared these drugs to placebo. The expected outcome was that the active drugs would be superior to placebo for controlling arrhythmia's. Early on, the trial was stopped because it was found during an interim analysis that of the 59 people who died of an arrhythmia during follow-up, 43 were on flecainide or encainide and 16 were on placebo.
PHIV Studies at the University of Washington
We began investigating treatment of primary HIV over a year ago with a protocol that compared d4T (Stavudine) to placebo. Our goal was to determine if we could lower the viral load during the first 2 years of infection, and delay progression of disease. This study is ongoing and remains blinded. However we recognize that combination therapy is becoming the treatment of choice, and very recent data (available only after our d4T vs. placebo trial was underway) suggests that combination therapy is be superior to monotherapy for reducing viral load and may be helpful in limiting emergence of resistant virus. Therefore, we have decided to modify our treatment protocols. Our first step will be to enroll 10 people into a small open label study of combination therapy with 3 drugs (including Indinavir, the new protease inhibitor from Merck). In addition to our comprehensive investigation of what the clinical and virologic effects of treatment might be, Dr. Anthony Fauci and members of his laboratory at the NIH will be studying these people to determine the impact of therapy on the primary immune response. The results from this trial will be used to design a large, multicenter trial comparing triple therapy to placebo for treatment of PHIV. Such a study will require participation of multiple centers to enroll an adequate number of people. Successful completion of the placebo controlled trial will answer the sentinel questions of 1) who should get therapy for PHIV, 2) what should that therapy be and how long should patients be treated for, 3) what are the risks of therapy (i.e., delayed immune response, emergence of resistance, etc.) and 4) what are the appropriate markers to follow to gauge efficacy or need to switch or discontinue therapy.
Therapy for primary HIV is only one of the many studies we have available at the Primary Infection Clinic. We remain very interested in following people with evidence of current or recent primary HIV- infection to learn more about the natural history of the disease. Many questions related to transmission and progression remain to be answered. If a person meets the entry criteria, and doesn't want to be on a drug study, we are still very interested in meeting him or her and talking with them. We have begun a new program to try and identify the source partner of the person with primary HIV infection (the person who infected the person with primary HIV). Identification and intense virologic study of such people is critical to our understanding issues surrounding transmission and progression.
All those who qualify and are enrolled into these studies receive all laboratory studies (including multiple CD4 cell counts and viral load measurements) at no cost to them. We will make this information available to the person and his or her primary health care provider. All laboratory testing is done using an identification number for the client, so laboratory results are, in effect, anonymous. If people don't have a primary care provider, we can make an appropriate referral, or provide primary care (if they wish us to). If patients don't have insurance or other resources to obtain appropriate care, we can make the appropriate referrals or provide primary care (if they wish us to).
Criteria for entry into studies at the University of Washington Primary Infection Clinic include:
For further information about these studies, please contact Theresa Shea, P.A.C. at 720-4299 or Timothy Schacker, MD at 720-4340.
New Drug Recommended
J. Mark Bray, RN, BSN, Editor
On Friday, March 15, 1996, the FDA Advisory Panel unanimously voted that Vistide (Cidofovir) be recomended for approval. Vistide is manufactured by Gilead Pharmaceuticals located in Foster City, CA. Cidofovir is a nucleotide analog with potent activity against a broad spectrum of herpesvirus including human cytomegalovirus, herpes simplex virus types 1 and 2, varicella zoster virus, and Epstein-Barr virus. Vistide has been in numerous clinical trials and has an ongoing treatment IND program. Most commonly, Vistide is used after someone has failed BOTH Ganciclovir and/or Foscarnet therapy and continues to have progressing CMV retinitis. Preliminary analysis of the most recent clinical trials has shown that by using Vistide there was a statistically significant delay in median time to CMV-R progression as assessed by retinal photography. Under the treatment IND program clients receive 5mg/kg of intravenous Vistide for two consecutive weekly doses (induction) followed by 5/mg/kg/dose of intravenous Vistide every other week (maintenance). As good as this sounds there are some very strict precautions that MUST be followed when administering Vistide due to the drugs nephrotoxicity (may cause damage to the kidneys due to the drug's potency); these are listed below:
If you or your health care provider would like to find out more information about the Vistide Treatment IND Program, please feel free to give Gilead a call at 1-800-GILEAD 5 (1-800-445-3235)
New HIV Information on the" Web"Jeff Schouten, M.D.
The AMA has introduced a new valuable resource for HIV/AIDS information supported by a grant for GlaxoWellcome on the Internet. The address for this new resource is http://www.ama-assn.org/special/hiv/hivhome.htm.
It provides information in 9 categories: Journal Scan (the most recent significant HIV publications), Newsline, Practice Guidelines, Ethics Update, Expert Advice, Training Center, Treatment Center, Global Link, Information for Patients, Patient Support Groups, and a Glossary. Not all of the links are fully developed, but there is some very useful, readily available information here.