BETA June 1997.
by Harvey S. Bartnof, MD
Treatments for HIV: Postexposure Prophylaxis
Should HIV negative persons take anti-HIV drugs after an episode of unsafe sex or needle use to help prevent becoming HIV positive? Two situations exist today in which taking anti-HIV therapy to prevent infection is the standard of care:
Many physicians who treat HIV positive patients and those at higher risk for contracting HIV have received telephone calls at 9:00 a.m. Sunday from gay HIV negative men who say, "I had unsafe sex last night -- will you prescribe AZT for me?"
Physician researchers from the San Francisco Department of Public Health and the University of California at San Francisco/San Francisco General Hospital (UCSF/SFGH) have now declared that a rational policy is needed concerning postexposure prophylaxis (PEP) after unsafe sexual contact or unsafe injection drug use. An editorial on the subject by Mitchell Katz, MD, and Julie Gerberding, MD, was published in the April 10 issue of The New England Journal of Medicine.
What are the risks of becoming infected with HIV after unsafe sex or needle use?
Katz and Gerberding reviewed the medical literature and reported the average risk of becoming HIV infected after a single episode of various unprotected sexual and needle use activities (see table). The risk of HIV transmission to a healthcare worker after an accidental needlestick is approximately 1 in 300. Various unsafe sexual and needle-sharing practices are associated with transmission risks that are somewhat similar. Note that several factors can increase or decrease the average risk.
AVERAGE RISK OF BECOMING HIV INFECTED AFTER A SINGLE EPISODE OF VARIOUS TYPES OF HIV EXPOSURE
Unprotected receptive anal intercourse: range of 1 in
32 to 1 in 125
Unprotected receptive vaginal intercourse: range of 1 in
666 to 1 in 2,000
Unprotected insertive vaginal intercourse: range of 1 in
1,100 to 1 in 3,300
Unprotected insertive anal intercourse: no data, but
believed to be similar to unprotected insertive vaginal
intercourse
Unprotected oral-penile or oral-vaginal sex (insertive or
receptive, male-male, male-female, female-female or
female-male): no per exposure estimates, but cases of
each are documented in the medical literature
Unprotected receptive oral-anal sex
("rimming"): one documented case exists in the
medical literature
Use of HIV-contaminated drug injection equipment:
approximately 1 in 150
Needlestick exposure by healthcare worker: approximately
1 in 300
NOTE: Risks are increased (or decreased) when certain factors are present (or absent), including viral infectiousness (viral strain, concentration), bleeding, immune status of host or recipient, skin or mucosal ulceration or break and number of episodes of exposure.
What is the efficacy of PEP?
The concept behind PEP is that there is a "window of opportunity" to contain or eradicate HIV before widespread cellular infection occurs. This model successfully describes other viral infections, including hepatitis A, hepatitis B and rabies (in these examples, prophylaxis utilizes immune globulins or antibodies).
After a needlestick injury, immune cells in the skin present HIV to T-lymphocytes and natural killer cells. Sometimes, an accident places HIV directly into a small vein or arteriole. Injection drug use would also place HIV directly into a vein.
In a monkey model of vaginal infection with simian immunodeficiency virus (SIV), the virus is engulfed by immune cells in the vaginal lining. Within 2 days, SIV is found in groin lymph nodes. Within 5 days, SIV-infected T-cells and free SIV can be detected in the bloodstream. Migration of SIV after rectal or urethral (penile tip) exposure is thought to occur over a similar time frame. It is hoped that PEP can stop viral replication during this period before it gains a "foothold" in the body, and can allow the immune system to completely eradicate the virus.
What are the risks of PEP?
With only 1 month of PEP therapy for accidental needlesticks, serious toxicity is uncommon. However, 1 in 3 healthcare workers stop therapy due to undesirable side effects. Information on long-term toxicity of antiretroviral drugs in HIV negative (and most HIV positive) persons is not known.
The authors comment that the availability of PEP may cause some people to stop practicing safer sex or stop safer needle use. Since therapy would be available to help prevent HIV infection, HIV negative persons may wonder, "Why bother with condoms or clean rigs?" While taking PEP therapy, some people may feel free to practice unsafe sex, believing that they will be protected. Katz and Gerberding comment that since no PEP therapy will be 100% effective, HIV transmission could increase if people adopt these attitudes. However, they further suggest that such unsafe practices could be minimized through appropriate media campaigns and counseling. They also acknowledge that not making PEP therapy available due to fear of these adverse possibilities seems unfair. Even under the best of circumstances among experienced users, condoms do occasionally break.
Other risks of PEP include faster development of drug-resistant HIV strains, both in individuals and in the community at large. This would occur if people do not adhere to the timing of drug doses, if they skip doses, or if repeated courses of PEP therapy were necessary.
What are the recommendations for PEP?
For those who have experienced an unsafe sexual or needle-sharing exposure to HIV, Katz and Gerberding recommend the following (based on an accidental needlestick exposure model):
A detailed history of the current and prior HIV exposuresand
If a partner whose HIV status is unknown consents to HIV testing and is determined to be HIV negative, PEP therapy that was initiated immediately can then be stopped.
If a partner's HIV status is unknown and he/she is unwilling to be tested, or if the partner is unavailable, the decision regarding instituting PEP should be based on "both the type of exposure and the likelihood of HIV infection in the partner."
Based on animal models, the success of PEP therapy is maximal when "started within a matter of hours after the exposure. Although any time cutoff is arbitrary, we do not recommend initiating treatment more than 72 hours after the exposure, "state Katz and Gerberding. Although perhaps not as effective as prophylaxis, late PEP (after 72 hours) may still be useful as early treatment.
The authors continue that PEP "is not appropriate for persons who intend to continue their high-risk behavior." They believe that patients who repeatedly ask for PEP treatment are likely to be using successive PEP treatments as a way to avoid practicing safer sex or needle use. The ethics of excluding anyone at risk for infection from prophylaxis are controversial.
If fully informed consent is obtained from the patient, the specific medications recommended for PEP are the same as those recommended for healthcare providers after an accidental needlestick. The regimen consists of 4 weeks of:
if the source has advanced AIDS, has a high HIV viral load, or has been treated with nucleoside analog drugs
Currently, experience during pregnancy with drugs other than AZT is limited. However, this will probably change within the next 1-2 years.
What are the costs of PEP?
The wholesale cost (cost to the pharmacy) of 1 month of AZT plus 3TC is approximately $300. The inclusion of indinavir adds another $300 to the wholesale cost. Laboratory tests and office visits cost approximately $100-200. The authors have not yet analyzed cost-effectiveness. However, assuming that the lifetime cost of HIV/AIDS treatment is $119,000, not including loss of work productivity and diminished quality of life, the estimated $800 (including indinavir) for 1 month of triple therapy would be worth preventing another HIV infection. This must be balanced against the large number of potentially exposed persons who might take PEP.
Another issue is who will pay for PEP? The authors warn that insurers may not pay for a scientifically unproved therapy that is not approved by the Food and Drug Administration (FDA). Furthermore, those with insurance may prefer not to file a claim for reimbursement. As the report reveals, over half of those at risk for HIV do not have health insurance, so the cost may ultimately be borne by MediCal (California's version of Medicaid).
What are the public health policy issues related to PEP?
Katz and Gerberding think that public health messages regarding PEP therapy should ideally be part of an overall program of health promotion and HIV prevention. They feel that because the effectiveness of PEP will be maximal if administered as soon as possible after exposure, public health campaigns are needed that will inform people to seek medical attention within hours of HIV exposure. This must be accomplished without encouraging risky sexual or needle use behaviors.
Katz and Gerberding's report is likely to generate some controversy. It is not surprising that it was published in the "Sounding Board" section of The New England Journal of Medicine. An abundance of letters to the editor will probably follow. It will take some time to measure whether the benefits of PEP after sexual or needle use exposure reach statistical significance. Nonetheless, overwhelming evidence indicates that currently it is appropriate to have PEP therapy available. In San Francisco, a PEP program is scheduled to begin in the coming months. It is to be hoped that the program will include an adequate, ongoing educational campaign, including Friday and Saturday nights at various social venues (see also Advocacy article on page 7).
Katz MH and Gerberding JL. Postexposure treatment of people exposed to the human immunodeficiency virus through sexual contact or injection drug use. New England Journal of Medicine 336(15):1097-1099. April 10, 1997.
Royce RA and others. Sexual transmission of HIV. New England Journal of Medicine 336(15):1072-1078. April 10, 1997.
Other Treatments for HIV
Oral NAC Replenishment Prolongs Survival
Glutathione is one of the body's naturally occurring antioxidants, necessary for normal cell metabolism. Previous studies have shown that those with HIV disease have lower blood levels of the peptide. Researchers from Stanford University have not only further documented a glutathione deficiency in T-lymphocytes from people with HIV/AIDS, but have also shown that oral supplements of N-acetyl cysteine (NAC), a glutathione precursor, normalize the deficiency and prolong survival in people with AIDS. The study was not a long-term prospective trial, and it took place in the pre-HAART (highly active antiretroviral therapy) era. AIDS community advocates have been recommending the "nutritional supplement" for years, and it has been available from HIV/AIDS buyers' clubs. The Stanford study is the first one published to describe a survival benefit from oral supplementation with NAC among people with AIDS. The lead authors are Leonore Herzenberg, MD, and Leonard Herzenberg, MD.
Glutathione is believed to be the body's main defense against oxidative stress, and is involved in the detoxification of many molecules. It is composed of the 3 amino acids (protein building blocks) cysteine, glycine and glutamine. Severe deficiency of glutathione, for example due to acetaminophen (Tylenol) overdose, can result in life-threatening liver and kidney failure. In vitro studies have shown that glutathione deficiency decreases cell survival, increases HIV replication and alters normal T-cell functioning. A 4-month trial of supplemental NAC in people with HIV disease published in 1996 by Akerlund and colleagues demonstrated a significantly slower decline in CD4 counts when compared to people receiving placebo. Baseline CD4 counts were greater than 200 cells/mm3. That trial was too short to measure an effect on survival.
The current study was randomized, double-blind and placebo-controlled. Participants included 97 patients with a CD4 lymphocyte count of less than 200 cells/mm3 and 107 with a count between 200 and 500 cells/mm3. Unfortunately, HIV viral load measurements were not available for most participants. None had active opportunistic infections or malignancies. No participants had taken anti-HIV therapy during the previous 4 months; none had ever taken protease inhibitors. No participants consumed "excessive amounts" (not defined) of products that could alter levels of glutathione, including acetaminophen, alcohol, NAC, or vitamins C or E. Survival was measured over a 2-3 year period.
A subset of 37 participants was selected for the NAC replenishment study. They had low baseline levels of glutathione, defined as at least 1 standard deviation below the median for uninfected control subjects. This subset consumed 3,200-8,000 (average 4,400) mg of NAC daily in the form of effervescent 800 mg oral tablets. The blinded portion of the study compared NAC to placebo for 8 weeks, followed by open label access to NAC for an additional 6 months.
The results showed that HIV negative control participants had a mean baseline glutathione level of 1.24 mM (millimolar concentration), while HIV positive participants had a lower mean baseline level of 0.97 mM. When the HIV positive individuals were subdivided by CD4 count, those with 200 cells/mm3 or more had a mean NAC level of 1.05 mM, while those with a CD4 count less than 200 cells/mm3 had a lower mean level of 0.88 mM. Survival analysis after 2-3 years revealed that among HIV positive participants, lower baseline glutathione levels statistically correlated with shorter survival times, even when other factors such as CD4 counts were taken into account (again, HIV viral load was not measured). Conversely, survival over 2-3 years statistically improved as baseline glutathione levels increased, independent of CD4 cell count.
Among those with a CD4 count less than 200 cells/mm3, over 85% survived 2.5 years if their baseline glutathione level was greater than 1.05 mM. However, only 15% of those with a CD4 count less than 200 cells/mm3 and a glutathione level less that 1.05 mM survived the same 2.5 year period.
In the NAC replenishement substudy, taking NAC statistically improved survival almost 2-fold. The 2-year survival rate for those who took NAC was over 65% compared to 40% in the placebo group. Moreover, increased survival in those who took NAC was approximately equal to the period of time they ingested NAC. Not surprisingly, the researchers determined that 8 weeks of NAC replenishmenst normalized those subjects' levels of glutathione.
Nine patients given NAC stopped therapy within 1 week because of nausea and rash. Similar symptoms were reported by participatnts who did not stop NAC therapy.
Given the small number of patients in the NAC substudy, the authors view their findings as preliminary evidence that:
The researchers recommend a prospective long-term trial using NAC, given the compound's relatively low expense and low toxicity. In the new era of HAART with potent protease inhibitor-based cocktails, such a trial is unlikely to occur. However, for the approximately 15% of HIV positive persons who do not respond to HAART, NAC replenishment may be beneficial for those with a relative NAC deficiency. Also, NAC replenishment may have a therapeutic role for HIV positive individuals in less developed countries. Lower doses than the average ones used in the present study may still provide the same benefits without the side effects of nausea and rash.
One significant limitation of the research is lack of HIV viral load measurements. Glutathione levels may correlate with HIV viral load, and the glutathione survival advantage may disappear after viral load data are included in the analysis. Antiretroviral therapy that leads to lower HIV viral loads may also increase glutathione levels. Similarly, higher viral loads may cause glutathione deficiency in HIV positive persons. This question could easily be answered by analyzing stored blood specimens from persons in HAART trials. Another study limitation was the failure to control for confounding factors between the time NAC was stopped and the time of evaluation 2-3 years later. If this was done, the authors did not so state in the article.
The authors stress how important it is for HIV positive persons to avoid factors known to decrease glutathione levels. Such factors include unnecessary or excessive consumption of alcohol or acetaminophen (a component of many over-the-counter medications) and exposure to ultraviolet light (sunlight and tanning booths).
Culliton BJ. The microbial plague continues. Nature Medicine 3(1):1. January 1997.
Herzenberg LA and others. Glutathione deficiency is associated with impaired survival in HIV disease. Proceedings of the National Academy of Sciences 94:1967-1972. March 1997.
Indinavir Kidney Stones may be More Common when Excessive Sweating Occurs
Currently, the most commonly used protease inhibitor is indinavir. Approximately 4% of patients taking the drug will develop painful kidney stones, usually accompanied by back or groin pain and bloody urine. This occurs due to crystallization of the drug in the urine. The risk of kidney stones is decreased when adequate fluid is consumed. Patients are advised to drink 1.5 liters, or approximately 1.5 quarts, of fluid daily.
Physicians from Tampa, FL, have suggested that even more fluid may be needed by patients who reside in warmer climates. Michael Bach, MD, and Eliot Godofsky, MD, reported that 50% of their patients (7 of 14) who took indinavir developed kidney stones. Those 7 stated that they were drinking 1.5 liters of fluid daily. They had no reported extra sources of fluid loss including diarrhea or vomiting. After additional hydration, 6 of 7 were able to resume taking indinavir. Most of the 6 patients engaged in activities in Florida's warm climate that are associated with excessive sweating, including working or exercising outdoors on hot and humid days, visiting a sauna or sunning at the beach.
The physicians state that the rate of kidney stones due to indinavir in warmer climates may be higher than has been previously reported due to activities that lead to increased sweating. They recommend that their patients drink 2-3 liters (approximately 2-3 quarts) of fluid daily, unless the individual will be in an air-conditioned setting throughout the day and night. The recommendations may be reasonable for anyone who takes indinavir who will be engaging in activities associated with prolonged sweating.
Bach MC and Godofsky EW. Indinavir nephrolithiasis in warm climates. 14(3):296-297. March Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology14(3):296-297. March 1997.
New Uncommon Indinavir Side Effects Reported
After newly FDA-approved drugs come into more widespread use, uncommon side effects may be detected that did not occur during the original drug studies. Two reports have appeared in the medical literature that reveal serious, yet uncommon organ toxicities due to indinavir.
In a report published in The Lancet, physicians from New York University and the University of Maryland have found that acute severe hepatitis (liver inflammation) induced by indinavir occurred in 3 different patients (2 men and 1 woman). Inflammation began between 4 and 38 days after initiating the medication. Prior to starting indinavir therapy, all 3 patients were already taking between 5 and 12 other medications commonly prescribed for those with HIV/AIDS. Two of 3 patients were already taking AZT plus 3TC, while the third was taking only AZT. Also, all 3 patients had had prior liver infection with hepatitis B virus. One also had prior hepatitis C virus infection. Before starting indinavir, all 3 had low CD4 counts, ranging from 7 to 56 cells/mm3.
One patient died as a result of the acute liver insult (he also had prior liver cirrhosis). The other 2 survived, and their acute hepatitis resolved after stopping indinavir and some or all other medications. In all 3 patients, other causes of acute hepatitis were ruled out, including viruses, alcohol and other liver toxins. The authors recommend close monitoring of liver function tests before and after starting indinavir therapy, particularly when it is given with other medications or when there is known or suspected underlying liver disease.
In a letter to The New England Journal of Medicine, clinicians reported another new but uncommon side effect from indinavir. Reversible kidney damage occurred in a 30-year-old woman who was taking indinavir monotherapy as a participant in a clinical trial. After 6 months of therapy, she took a 7-day course of the antibiotic amoxicillin for bronchitis. Between the seventh and tenth months of indinavir monotherapy, her kidney function decreased somewhat, as measured by an increasing blood creatinine level. Urine testing revealed the abnormal presence of eosinophils (white blood cells) and protein. The kidney malfunction caused the woman's blood pressure to increase abnormally, requiring medication to treat that condition. She also reported back pain and fatigue. A kidney biopsy revealed the presence of crystals in immune cells. The crystals appeared similar to those in indinavir capsules. Staining tests of the crystals were negative for other known causes of crystalization. One month after discontinuing indinavir, the woman's blood creatinine level had nearly normalized, her urine no longer contained white cells and she no longer needed medication to control her blood pressure.
The reporting physicians doubted that amoxicillin played a role in kidney complications and concluded that indinavir was the probable cause. They also stated that additional hydration may have prevented the complication; the patients' adherence to oral hydration was not described. Another side effect, kidney stones accompanied by back pain and bloody urine, is a well-characterized side effect that occurs in 4% of those taking indinavir. It can be avoided with adequate hydration.
While these 2 reports add to the list of potential complications associated with indinavir, it must be emphasized that side effects occur infrequently. The overall benefit of indinavir in combination with other anti-HIV therapies will outweigh the potential adverse effects for the majority of patients. Relative benefits and risks must be weighed by the physician and patient.
Brau N and others. Severe hepatitis in three AIDS patients treated with indinavir. The Lancet 349:924-925. March 29, 1997.
Tashima KT and others. Indinavir nephropathy. New England Journal of Medicine 336(2):138-139. January 9, 1997.
Protease Inhibitors Can Cause Diabetes
(For more on this topic, see Advocacy, this issue.)
Michael Dube, MD, of the University of Southern California has documented that diabetes mellitus (high blood sugar) can occur as a result of protease inhibitor therapy. He has submitted a summary of 7 cases for publication. Dube stated that FDA has received less that 100 total case reports of diabetes as an adverse effect of protease inhibitors; the condition has been reported in persons taking all 4 currently approved protease inhibitors. FDA is currently tabulating the case reports and will make the information publicly available.
Diabetes was reportedly detected within several days to a few months after starting protease inhibitor therapy. While some of the patients reported to FDA required hospitalization for complications, including life-threatening diabetic ketoacidosis, there were no reported deaths. Most of the cases resembled type 2 diabetes, or adult-onset diabetes that can be controlled with oral diabetes medication. However, a few patients required insulin injections to keep their blood sugar levels under control. Approximately half of the cases reported to FDA stopped protease inhibitor therapy as a result of diabetes; the condition reportedly resolved for those who discontinued the drugs.
The condition has been seen in positive patients who never had diabetes, and among those who have and do not have a family history of diabetes. Diabetes occurred even when other drugs that can cause high blood sugar, including pentamidine and steroids (e.g., Megace), were not taken.
Other specific information will become available from FDA, in the medical literature and at future HIV/AIDS meetings. No data were immediately available regarding any trends in terms of gender, race/ethnicity or age. Discovering the complication at this point reveals one downside of accelerated approval of drugs by FDA. Such approval is granted even when there is limited experience with a drug in terms of total number of patients who have used it.
Dube M. Personal communication. May 26, 1997.
Opportunistic Infections
Updated Guidelines for Opportunistic Infection Prophylaxis
The U.S. Public Health Service will publish updated guidelines for opportunistic infection prophylaxis later this summer. Highlights include the following:
Kaplan J. Prevention of opportunistic infections. National Conference on Women and HIV. May 4-7, 1997. Pasadena, CA. Oral presentation and abstract #210.2. HIV-Related Wasting
Increased Resting Energy Expenditure Correlates with Increased HIV Viral Load
Researchers from the UCSF/SFGH have documented that the increase in resting energy expenditure among HIV positive persons statistically correlates with increasing HIV viral loads. The increase in resting energy expenditure among HIV positive persons is thought to be a factor that contributes to HIV-related wasting.
While clinically stable, 36 HIV positive patients were studied after an overnight fast and abstaining from nicotine or caffeine on the morning of testing. Those with the highest HIV viral loads had the highest resting energy expenditures, as measured by calories burned per lean body weight. Similarly, those with the lowest HIV viral loads had the lowest resting energy expenditures. The results were statistically significant.
In a separate analysis, resting energy expenditure was measured in response to influenza vaccination among HIV positive and HIV negative persons. HIV positive persons had an exaggeratedly higher energy expenditure up to 4 weeks after vaccination compared to HIV negative control participants. The authors concluded that either "(1) resting energy expenditure increases as a result of the [immune] response to increases in HIV, or (2) the increase [in energy expenditure] reflects the exaggerated host immune response in HIV positive persons."
Mulligan K and others. Energy expenditure in human immunodeficiency virus infection. New England Journal of Medicine 336(1):70-71. January 2, 1997.
Kaposi's Sarcoma
KSHV Cleared from White Blood Cells after Potent Combination Anti-HIV Therapy
Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus type 8 (HHV-8), has been closely linked with all forms of Kaposi's sarcoma, the most common malignancy in AIDS (for a review of KSHV, see BETA, March 1996, page 14; December 1996, pages 31-32 and 40; March 1997, pages 45-6). The finding of KSHV in blood mononuclear cells or seroconversion to KSHV antibody positive status is associated with an increased risk of developing Kaposi's sarcoma (KS). Highly ac-tive antiretroviral therapy (HAART) including a protease inhibitor has been shown to be effective for KS lesions in several case reports (see BETA, March 1997; September 1996). Researchers from Duke University have now shown that HAART cleared KSHV from an HIV positive man's peripheral white blood cells. He never had nor did he develop KS disease.
The man was found to be HIV positive in 1990; his CD4 count was 400 cells/mm3. He had been placed on 3 sequential nucleoside analog regimens: AZT plus ddC (Hivid), followed by d4T (Zerit), then followed by AZT plus 3TC. After 2 months of AZT plus 3TC, his CD4 count was 229 cells/mm3. At that time, KSHV was detected in his blood mononuclear cells by polymerase chain reaction (PCR). Indinavir was then added to his therapy. Six weeks later there was no detectable KSHV in his blood mononuclear cells. His HIV viral load was also undetectable at that time (earlier measurements were not stated).
The mechanisms for this apparent anti-KSHV effect are not yet known. Possibly certain protease inhibitors have a direct effect on KSHV protease genes. Alternatively, anti-HIV effects due to HAART may lead to beneficial immune improvements that allow for clearance of KSHV. This research adds to our knowledge of Kaposi's sarcoma and the benefits of HAART.
Rizzieri DA and others. Clearance of HHV-8 from peripheral blood mononuclear cells with a protease inhibitor. The Lancet 349:775-776. March 15, 1997.
KSHV is Grown In Vitro
In what researchers are describing as the next step in understanding how KSHV contributes to the development of KS, the new virus has been propagated in vitro.
Kimberly Foreman, PhD, and colleagues from the University of Michigan Medical Center, described their research in the January 16 issue of The New England Journal of Medicine. They obtained virus from the skin of AIDS-KS patients. Isolating the spindle cells of KS, the researchers co-cultured them with a kidney cell line. They were able to grow a filterable virus agent with DNA identical to that of KSHV. They removed the new virus particles from the tissue culture fluid (i.e., cell-free virus) and were able to grow the virus again using new kidney cells in a separate dish. They were able to repeat the experiment a total of 20 times for 20 "serial infections" (also called propagations). Each culture grew virus to a concentration of 1 million particles per milliliter.
The KSHV growth also led to unexpected cytopathic changes in the kidney cells. The research results were confirmed by PCR and electron microscopy. As described in an accompanying editorial by Edward Mocarski, Jr, MD, the research demonstrates that "KSHV DNA sequences are part of a herpesvirus that is able to replicate."
Foreman KE and others. Propagation of a human herpesvirus from AIDS-associated Kaposi's sarcoma. New England Journal of Medicine 336(3):163-171. January 16, 1997.
Mocarski ES. Propagating Kaposi's sarcoma-associated herpesvirus. New England Journal of Medicine 336(3):214-215. January 16, 1997.
Kaposi's Sarcoma is a True Cancer Originating from One Cell Clone
Multiple KS lesions at different sites and at different stages of growth commonly occur in the same patient. There has been controversy in the past as to whether AIDS-KS was a true cancer, which is defined as having originated from a single clone of cells that may subsequently spread (metastasize) to different body locations (see BETA, March 1996, page 14). Since KS lesions can grow simultaneously at different sites, another theory was that the abnormal growths of KS could originate anew from a cell in each location and be stimulated by growth factors. The issue is important because of strong implications for appropriate therapies.
Researchers from the National Cancer Institute have determined that AIDS-KS does indeed originate from a single clone of cells and potentially spreads throughout the body to form multiple lesions. Eight women with AIDS-KS from Zambia had a total of 32 KS lesions that were sampled. Since 1 of the 2 X chromosomes in women is inactivated early during embryonic life, multiple KS lesions from each woman were sampled for concordance of X chromosomal markers. The results were consistent with KS having originated from a single clone of cells. The researchers believe that the original cell is the KS spindle cell. KS spindle cells have been detected in the blood of AIDS-KS patients even before clinical KS develops (see BETA, March 1995, page 72).
Rabkin CS and others. Monoclonal origin of multicentric Kaposi's sarcoma lesions. New England Journal of Medicine 336(14):988-993. April 3, 1997.
Progressive Multifocal Leukoencephalopathy
PML in Remission 2 Years after Combination Anti-HIV Therapy
Progressive multifocal leukoencephalopathy (PML) is a life-threatening AIDS-related infection caused by the JC virus. A 35-year-old man with PML had right arm weakness and was unable to speak. A detailed report of this case, which was originally described at the 4th Conference on Retroviruses and Opportunistic Infections (see BETA, March 1997), was printed in March 22, 1997 issue of The Lancet. A magnetic resonance imaging (MRI) brain scan revealed changes typical of PML. The man's CD4 count was 30 cells/mm3 and his HIV RNA viral load was 189,900 copies/mL. He was started on AZT and ddI (Videx). After 2-4 weeks, his speech improved. After 10 weeks, he returned to weightlifting and aerobics. After 12 weeks, he returned to work as a fisherman. At the 24-week mark, indinavir was added to his regimen. At week 44, his CD4 count increased to 230 cells/mm3, while his viral load decreased to 240 copies/mL. A repeat MRI scan after a total of 16 months revealed marked improvement in the presumed PML abnormalities. The patient continued to have a 95% resolution of his initial symptoms after a total of 104 weeks (2 years).
The man's cerebrospinal fluid (the fluid around the brain and spinal cord) was not tested for JC virus and a brain biopsy was not done to definitively diagnose PML. Clearly this man had already had a marked improvement in his neurologic abnormalities with double nucleoside analog therapy. It is difficult to say exactly how much the protease inhibitor added to his recovery. However, the impressive CD4 count and viral load improvements would have been improbable with double nucleoside analog therapy alone.
Elliot B and others. 2.5 year remission of AIDS-associated progressive multifocal leukoencephalopathy with combined antiretroviral therapy. The Lancet 349:850. March 22, 1997.
Mileno MD and others. Resolution of AIDS-related opportunistic infections with addition of protease inhibitor treatment. 4th Conference on Retroviruses and Opportunistic Infections. Washington. DC. January 1997.
PML in Remission after Anti-HIV Therapy and Spleen Removal
PML has been shown to respond to HAART (see BETA, March 1997 and September 1996). Prior to the era of HAART, PML was usually lethal within 3-6 months of diagnosis. Researchers have now described a man with PML whose symptoms improved dramatically after his spleen was removed and HAART was instituted. The spleen is an abdominal organ that plays an integral role in normal immune function; survival is common after the spleen is removed in HIV negative patients. The patient's HAART included saquinavir (Invirase), AZT and 3TC.
The 30-year-old man with AIDS complained of headache, double vision, abnormal arm movements and mild dementia (loss of mental capacity). His CD4 count was 64 cells/mm3. His HIV viral load was 960,000 (5 log) copies/mL. He had been taking d4T monotherapy. An MRI scan and brain biopsy with electron microscopy confirmed the diagnosis of PML. The patient's spleen was removed based on previous reports of increased CD4 counts after AIDS patients' spleens were removed and reduced viral load in SIV-infected monkeys that had their spleens removed.
Three weeks after spleen removal and the initiation of HAART, the patient's neurological symptoms improved markedly and his viral load decreased to 110,000 copies/mL. After 7 months, his viral load was 6,000 (3 log) copies/mL. A repeat MRI scan revealed marked improvement as well. Follow-up CD4 counts were not stated.
The authors concluded that the combination of anti-HIV drugs, spleen removal or both contributed to the remission of the patient's PML. Considering that HAART alone has induced remission of PML, it is possible that major abdominal surgery to remove the spleen could have been avoided.
Power C and others. Remission of progressive multifocal leukoencephalopathy following splenectomy and antiretroviral therapy in a patient with HIV infection. New England Journal of Medicine 336(9):661-662. February 27, 1997.
HIV Disease Progression and Pathogenesis
Co-Infection with HIV and Hepatitis C Virus Type 1 Accelerates Progression to AIDS and Death
In the U.S., hepatitis C virus (HCV) infection occurs mainly among injection drug users and blood product recipients who were transfused before the 1990s. Some HCV transmission occurs sexually and from mother to newborn. HCV commonly causes chronic liver complications and death.
HCV infection is common among people with HIV infection. It has been recognized that dual infection with HCV and HIV causes an accelerated progression of liver disease when compared to infection with HCV alone (see BETA, December 1995, page 32). Past studies had not revealed any effects of HCV on HIV disease progression, although there may have been limitations due to study design. Recently, researchers from London have determined that co-infection with HIV and HCV type 1 significantly accelerates HIV disease progression and death when compared to co-infection with HIV and HCV types other than type 1. The increase was independent of CD4 cell count and patient age, other known co-factors for HIV disease progression.
The researchers reported on 92 hemophiliac men from London who were infected with both HCV and HIV when they received contaminated blood products before 1985. Of the 4 subtypes of HCV, 70% were infected with type 1, while 30% were infected with one of the other 3 types. When evaluated, those infected with type 1 had a significant 3-fold increased risk of AIDS and a 3.5-fold increased risk of death compared with those infected with any of the other types. The figures were relatively unchanged after statistical adjustment for age at initial infection and CD4 cell count. An older age at the time of HIV infection is known to increase the subsequent rate of HIV progression. A lower CD4 count is a well-known surrogate marker for HIV progression.
The authors state that their results need to be confirmed in other cohorts of patients co-infected with HIV and HCV. They also indicate that HCV typing may be important for those who are co-infected, because anti-HIV therapy and prophylaxis for opportunistic infections may need to be started at an earlier stage for those who have HCV type 1.
Lemon SM and Thomas DL. Vaccines to prevent hepatitis. New England Journal of Medicine336(3):196-204. January 16, 1997.
Sabin CA and others. The association between hepatitis C virus genotype and human immunodeficiency virus disease progression in a cohort of hemophiliac men. Journal of Infectious Diseases 175:164-168. January 1997.
Severe Stress and Depression are Associated with Accelerated Immune Decline
Researchers from the University of North Carolina and the University of Florida at Gainesville have reported on immune cell decreases associated with symptoms of severe stress and depression in 66 HIV positive men. The authors state that their prospective, longitudinal 2-year study is among the first to show such an association. CD8 cytotoxic T-lymphocytes (CTL) and natural killer (NK) cells are known to decrease with progressive HIV disease. The 66 asymptomatic participants were evaluated prospectively every 6 months for a 2-year period. Measurements of severe life stressors were tabulated, and included a break-up with a long-term committed partner or the death of a close confidant or parent. Stressors due to HIV itself (drop in CD4 count, retirement due to HIV/AIDS) were not included to avoid confounding. Depression was measured using a version of the Hamilton Depression Rating Scale. Again, depressive symptoms directly associated with HIV progression were deleted in an attempt to avoid potential confounding.
At the 2-year mark, 21% of the men had progressive HIV disease. Those who scored above the median in both severe stress and depression lost a median of 53 NK cells/mm3, compared with a median loss of only 5 NK cells/mm3 for those with mid-level stress and depression, and a median loss of only 8 NK cells/mm3 for those with below average stress and depression; the difference was statistically significant. For CTL, those who scored above average in stress and depression lost a median 164 CTL cells/mm3, while those with average or below average stress and depression gained a median 54 CTL cells/mm3.
The results need to be confirmed in larger prospective studies. In 1993, a study from UCSF authored by Jeffrey Burack, MD, and colleagues reported that depression symptoms are associated with a faster decline in CD4 cells. If these various results are true, it is quite possible that antidepressant therapy might slow HIV progression and the loss of immune cell subsets.
Burack JH and others. Depressive symptoms and CD4 lymphocyte decline among HIV-infected men. Journal of the American Medical Association 270:2568-2573, 1993.
Leserman J and others. Severe stress, depressive symptoms, and changes in lymphocyte subsets in human immunodeficiency virus-infected men. Archives of General Psychiatry 54:279-285. March 1997.
3 Men Found to be HIV Positive Despite Double CCR5 Mutation
As discussed in the last issue of BETA, there has been rapid progress in understanding chemokine receptors and their relationship to both HIV infection and disease progression. A double deletion mutation of the gene for the CCR5 chemokine receptor on macrophages had been reported to confer protection from HIV infection. Given that only 1% of Caucasian males have the double mutation, none of almost 3,000 HIV positive Caucasian males that had been reported to date carried the double mutation. Moreover, 33% of HIV negative Caucasian gay men who have had repeated high risk sexual exposures to HIV do carry the double mutation. There has been a concern that knowing that one carries the double mutation would lead men to stop practicing safer sex. HIV positive people who carry a single mutation have been reported to have a slower progression of HIV disease.
Recently, 3 different research groups have each identified an HIV positive man who carries the identical double CCR5 mutation. The results challenge our present conceptualization of CCR5 receptors and HIV infection.
The first case was a Caucasian man in the Multicenter Hemophilia Cohort Study (MHCS) at the National Cancer Institute. Although he was HIV positive with a double CCR5 mutation, he experienced faster progression to AIDS than those with normal CCR5 receptors; his CD4 count decreased to fewer than 200 cells/mm3 in only 4.4 years. All 12 of the other hemophiliacs in the MHCS who were identified with the double mutation were HIV negative, despite multiple exposures to HIV from blood transfusions before 1985. The authors believe that this man's HIV strain used an alternate co-receptor other than CCR5 to initially infect his macrophages. The man has since died.
The second case was a Caucasian gay man from the SEROCO (seroconversion cohort) study in Paris. He was the only one of 412 HIV positive Caucasians in the study with the double CCR5 mutation. Unfortunately, he also had a rapid decline in his CD4 count, contrary to expectations considering the slower reported rate of HIV progression in HIV positive men with a single CCR5 mutation.
The third case was a gay man from Australia. He is of European (Caucasian) descent and is the only one among 265 HIV positive patients with the double CCR5 mutation in the Sydney cohort. Most HIV positive patients in Australia are infected with the same clade of HIV-1 that predominates in the United States and most of Western Europe. This man acquired HIV through homosexual contact; he had multiple partners with whom he engaged in both receptive and insertive anal and oral intercourse (presumed unprotected). He denied ever using needles. His double CCR5 mutation has not conferred slow HIV disease progression. He had a recent CD4 count decline to 460 cells/mm3 and an HIV viral load of 19,000 (log 4) copies/mL.
The various research groups are only able to speculate about how HIV infection occurred in each of these 3 men with a double CCR5 mutation. It is clear, however, that we still have more to learn about chemokine receptors and HIV. A normal, functioning CCR5 co-receptor appears to be not essential for HIV infection to occur. Those who know that they have the double CCR5 mutation would be well advised to practice safer sex. There probably will be similar case reports in the future.
Biti R and others. HIV-1 infection in an individual homozygous for the CCR5 deletion allele. Nature Medicine 3(3):252-253. March 1997.
O'Brien TR and others. HIV-1 infection in a man homozygous for CCR5-delta-32. The Lancet 349:1219. April 26, 1997.
Theodorou I and others. HIV-1 infection in an individual homozygous for CCR5-delta-32. The Lancet 349:1219-1220. April 26, 1997.
Woman Dies of AIDS Yet Never Develops HIV Antibodies
In the fourth such case reported in the medical literature, Luc Montagnier, MD, and colleagues from the Institut Pasteur in Paris have reported on a 38-year-old woman from the Ivory Coast in Africa who died of AIDS yet never developed an immune response that produced HIV antibodies. The woman had been tested regularly for HIV antibodies because her husband was known to be HIV positive and they had unprotected sexual intercourse. Montagnier found her blood to be persistently negative for HIV antibodies. Both enzyme-linked immunosorbent assay (ELISA) and Western Blot tests were used in an attempt to detect antibodies to both HIV-1 and HIV-2 (the West African isolate). The less commonly used radioimmunoprecipitation assay (RIPA) for HIV antibodies was also negative, as were tests for the O strain of HIV.
The woman did have positive tests for HIV by virus culture. She was positive for HIV RNA (by both bDNA and RT-PCR assays) and DNA (by PCR). She developed rapid CD4 cell depletion and died from toxoplasmosis in the brain. Montagnier stated that while "immunosilent" HIV infection is extremely rare, it is not exceptional.
Montagnier L and others. Human immunodeficiency virus infection and AIDS in a person with negative serology. Journal of Infectious Diseases 175:9550959. April 1997.
Harvey S. Bartnof, MD, has been a member of the Scientific Advisory Committee at the San Francisco AIDS Foundation since 1987.
This information is designed to support, not replace, the relationship that exists between you and your doctor.