Gay Men's Health Crisis "Treatment Issues", Vol 8, No. 10, November, 1994
David Gold and Gabriel Torres, M.D.

Viral Load Dynamics

David Ho, M.D., of the Aaron Diamond AIDS Research Center presented a model that describes the dynamics of HIV replication.1 Dr. Ho noted that patients given Abbott Laboratories' ABT-538 protease inhibitor experienced a dramatic decrease in HIV RNA levels within a matter of days. Based on this observation, he infers that nearly half the viral population in the plasma is renewed every day. There is also a constant destruction of CD4 cells in infected persons -- Dr. Ho estimated that approximately 22 million CD4 cells are destroyed each day in the blood and 50 times more in the lymphoid tissue.

According to Dr. Ho, the greatest amount of virus is produced in the first two to four weeks after a person becomes infected by HIV. HIV production in that period equals the total amount of virus produced over the next four to five years. This suggests to Dr. Ho that intervention with antiretroviral therapy should be instituted as soon as possible after infection to reduce viral burden and delay disease.

In a subsequent presentation, Michael Saag, M.D., of the University of Alabama emphasized the need for the earliest intervention possible with as many active drugs as can be tolerated.2 He stressed his view that monotherapy with one drug will soon become a thing of the past, with combinations of protease inhibitors and nucleoside and non-nucleoside reverse transcriptase inhibitors becoming the state-of-the- art in managing HIV infection.

Maternal Viral Load Predicts Transmission

A landmark study by a group of New York investigators measured HIV levels in a small group of pregnant women with a technique known as QC-PCR.3 The 27 mothers in the study had HIV measurements at the time of delivery, and their infants were followed prospectively. Eight of the 27 (29.6 percent) mothers transmitted HIV to their infants. The eight were among the eleven study volunteers with very high HIV levels in their blood (more than 175,000 copies of HIV RNA per milliliter of plasma). None of the sixteen mothers with lower viral loads transmitted the virus.

The authors concluded that QC-PCR measurements are a far more powerful predictor of transmission than CD4 counts or viral cultures using peripheral blood mononuclear cells. This study provides further evidence for the need to use viral load measurements in clinical practice, since the decision to institute antiretroviral therapy may be guided by the viral load of the mother during pregnancy.

Increased Transmission of AZT-Resistant HIV

A study presented by researchers from the Walter Reed Research Institute indicated that AZT-resistant strains of HIV are increasingly found in newly infected individuals.4 Three cohorts of patients from the U.S., Australia and Switzerland were evaluated for transmission of AZT-resistant virus. HIV isolates were obtained at the time of seroconversion to assess whether the viral strain was resistant to AZT. From 1988 through 1991, only three percent of the isolates demonstrated AZT-resistance, compared to nineteen percent in the Swiss group and eighteen percent in the U.S. cohort during 1993 and 1994. This rise in the transmission of AZT-resistant strains will significantly limit the ability to treat seroconverters with AZT during acute infection and impair the usefulness of AZT as an early intervention strategy.

Blood Transfusions May Increase HIV

A small study by researchers from two medical centers, Case Western Reserve in Cleveland and the VA Medical Center in Los Angeles, suggested that blood transfusions may modestly increase HIV replication in HIV-positive patients.5 Of five HIV-positive patients who received blood transfusions, all five had an increase in HIV levels (measured by p24 antigen) one to two weeks after transfusion.

CD4 Benefits From d4T

AZT-Naive Patients: Researchers from Bristol-Myers Squibb, presented data on d4T (stavudine) in 108 patients, 41 of whom had never taken AZT or any other anti-retroviral drug.6 Not surprisingly, AZT-naive patients had a better response in terms of CD4 improvement. After 24 weeks, these patients had a median increase of 74 CD4 cells. The researchers then compared this CD4 response to that seen in ACTG 116A, where AZT-naive patients were given either AZT or ddI. The cross- study comparison revealed that in AZT-naive persons with similar CD4 counts, d4T produced a CD4 response equal or perhaps superior to AZT. (Comparisons between studies are always difficult to interpret, however.)

AZT-Experienced Patients: Lisa Dunkle, M.D., from Bristol- Myers Squibb reported an update on a trial comparing d4T to AZT in people with CD4 counts of 50 to 500 and at least six months of AZT therapy.7 In this trial which is still ongoing, 822 patients were randomized to receive either d4T (40 mg twice daily) or continued AZT (200 mg three times daily). An interim analysis of the first 359 patients showed that the CD4 responses and declines in p24 antigen levels and HIV titers were greater and more sustained in those who switched to d4T than in those who remained on AZT. Furthermore, those who switched to d4T had fewer clinical complaints. Peripheral neuropathy occurred in fifteen percent of those on d4T after one year of treatment, but only six percent required discontinuation of treatment, and there were few cases of pancreatitis. The final analysis of this study will be available after December 1994, when the trial is scheduled to close.

Protease Inhibitor Studies

Data presented at ICAAC emphasized the different anti-viral effects of the most-studied protease inhibitors: Roche's saquinavir and Merck's L-735-524. As measured by PCR techniques, Saquinavir can achieve a two-fold reduction in blood- borne HIV particles (at the dose currently being studied). The Merck drug can achieve a three-fold to 1,000- fold reduction (average of 30-fold). But the key question is: how long can these decreases be sustained? Both companies are studying higher doses of their drugs to see whether they can achieve greater and more sustained reductions in HIV levels. Merck Protease Inhibitor: Merck researchers presented data on sixteen patients who received the L-524 drug for six months at a dose of 400 mg every six hours.8 Over 70 percent of the patients achieved greater than ten-fold reduction in viral titers during the first several weeks. Resistance to L-524 was noted in five of fourteen patients after six months. (At a subsequent meeting at Merck headquarters, researchers reported that within four to twelve weeks after initiation of L-524, HIV levels start to increase, and by week 24 almost all patients return to baseline levels.)

The trial participants entered the study with a median CD4 count of 71 and had increases of 70 to 100 cells after a few weeks. These increases were maintained for up to six months. In addition, most patients had improvements in white blood cell counts, neutrophil counts, platelet counts and hemoglobin levels. Most also gained a median of eighteen to nineteen pounds in body weight. The only side effect seen from the Merck protease was a transient increase in blood levels of bilirubin, which is normally removed by the liver. Abbott Protease Inhibitor: A "late breaker" session included a report on the first pharmacokinetic study of ABT-538, the protease inhibitor under development by Abbott Laboratories.9 Researchers from other companies consider the Abbott compound, along with Merck's L-524, to be among the most active and bioavailable of all protease compounds in clinical trials. ABT-538 exhibited potent activity in the test tube (in vitro) against HIV-1 and HIV-2 and achieved impressive blood concentrations when given orally to rats, dogs and monkeys. Humans in phase I trials absorbed the drug even better than the animals. Resistant virus was eventually isolated. Further preliminary results from the phase I trials will be announced at the Second International Conference on Drug Therapy and HIV Infection in Glasgow, Scotland.

GEM-91 Trials begin

GEM-91 is an antisense oligonucleotide being developed by Hybridon Inc., a Massachusetts-based company. In the first human study of the drug, GEM-91 was administered to six HIV- positive individuals by intravenous infusion. No drug-related side effects were seen.10 GEM-91 locks onto and sparks the destruction of exposed HIV RNA within cells. It reputedly targets a number of steps in the HIV life-cycle, including the integration of HIV genes into the nucleus of newly infected cells and the production of new virus particles in cells' cytoplasm. GEM-91 is now entering Phase I/II trials at a number of sites, including New York Hospital. For information, call 212/746-4393.

Preventing Fungal Infections

William Powderly, M.D., of Washington University in St. Louis gave an excellent overview of prophylaxis for fungal infections in HIV-positive patients.11 Between 70 and 90 percent of people with AIDS will develop oral candidiasis (thrush), about 20 percent develop esophageal candidiasis, and five to ten percent contract cryptococcal meningitis. The most widely studied anti-fungal agent in HIV-positive patients is fluconazole. Itraconazole is another approved anti-fungal agent. Dr. Powderly described fluconazole as an effective agent in preventing fungal infections, but also noted that fluconazole-resistant candidiasis is a significant problem and itraconazole-resistant histoplasmosis and aspergillus are also emerging. Once resistance develops, patients are forced to rely on amphotericin B, an intravenous therapy with major toxicities.

Dr. Powderly also noted the high cost of fluconazole (approximately $20 per pill) and remarked that fungal prophylaxis probably should be considered only for those who are at highest risk for developing cryptococcal meningitis, such as people with CD4 counts below 50.

In a study that demonstrated how common fluconazole-resistant fungal strains are becoming, Swiss researchers took oral swabs from 401 HIV-positive patients who showed evidence of fungal infections.12 Twenty-eight percent of these samples contained organisms resistant to fluconazole. AIDS researchers from Bowman Gray School of Medicine in Winston-Salem followed six patients with less than 50 CD4 cells who developed fluconazole-resistant thrush while on fluconazole prophylaxis.13 All six failed to respond to a higher dose of fluconazole (800 mg per day). Two of the six were susceptible to itraconazole, but all six ultimately needed amphotericin B therapy.

Sorivudine (BV-ara-U) for Herpes Zoster

A new agent for the treatment of herpes zoster called sorivudine was studied in a randomized, double-blind trial, which compared it to acyclovir given at a dose of 800 mg five times a day.14 Sorivudine has the advantage of requiring only one daily dose (40 mg per day). Trial participants receiving sorivudine healed their zoster lesions quicker, had fewer new lesions and required less use of analgesics than patients receiving acyclovir. Time to resolution of the pain associated with the zoster was similar in both groups. Sorivudine is the second new drug being developed for the treatment of herpes zoster. Famciclovir (Famvir, manufactured by SmithKline Beecham) was recently approved. It is similar to acyclovir, but has the advantage of twice daily administration.

Famciclovir for Herpes in Women

According to a study by University of New Mexico researchers, famciclovir can limit the recurrence of new herpes outbreaks in women with chronic herpes infections.15 In the double blind, placebo controlled study, 375 women of unknown HIV status were randomized to either placebo or six doses of the drug. Women who were given 125 mg or 250 mg twice per day had a significantly prolonged time before new herpes outbreaks. When these doses were taken only once daily, no significant benefit was seen. The median time to recurrence of herpes outbreaks was 2.7 months on placebo, 3.9 months on 125 mg twice a day, and greater than four months on 250 mg twice a day.

Foscarnet

A study by European researchers suggests that five days per week treatment with foscarnet may be preferable to seven days in patients with CMV esophagitis or colitis.16 In the study, 33 patients were randomized to receive foscarnet either five or seven per week. Foscarnet was only slightly more effective when given seven days a week, and the added benefit was not statistically significant.

Two studies in animals suggest that liposomal formulations of foscarnet may increase the drug's therapeutic efficacy while decreasing its renal toxicity.17,18 Clarithromycin for MAC Prophylaxis A long-awaited trial contrasting clarithromycin (500 mg twice daily) with placebo for primary prevention of Mycobacterium avium complex (MAC) was presented by researchers from Abbott Laboratories.19 The international trial was randomized and double-blinded. It enrolled 684 HIV-positive volunteers with CD4 counts of less than 100. The average follow-up was eight to nine months. There were fifteen instances (4.5 percent) of MAC bacteremia in the clarithromycin group compared to 42 cases (12.5 percent) in the placebo group, a highly significant difference. There also were fewer deaths in the treatment group (74) than in the placebo group (98), a 30 percent reduction in death rate.

Patients receiving clarithromycin experienced more gastrointestinal side effects and taste perversion than the control group. Unfortunately, nine (60 percent) of the fifteen MAC isolates in the clarithromycin group were resistant to the drug, whereas none of the isolates in the placebo group exhibited resistance.

These findings support the use of clarithromycin for MAC prophylaxis and suggest that it is more effective and less toxic than rifabutin. MAC breakthrough rates during rifabutin prophylaxis are approximately eight percent.

TB Prophylaxis

A short course prophylactic regimen may be effective in preventing tuberculosis (TB) in HIV-positive individuals, according to a study by Spanish researchers.20 Twenty-two of 70 HIV-positive individuals (who were either positive on the TB skin test or anergic) received the short course regimen of 300 mg a day isoniazid and 600 mg a day rifampin for three months. None developed TB. Of those not given the short term prophylaxis regimen, five developed TB.

Disappointing Crypto Studies

Two studies of anti-cryptosporidiosis therapies ended disappointingly. In a randomized multicenter study of Bovine Anti-Cryptosporidium Immunoglobulin (BACI), cryptosporidia oocysts (the parasite's fertilized reproductive cell form ) in patients on BACI were reduced, but no difference in either stool volume or frequency was seen.21 BACI is derived from the colostrum of cryptosporidia-immunized cows. Another study of hyperimmune bovine colostrum, infused into two people with AIDS-related cryptosporidiosis, also showed no clinical benefit from the therapy.22

"Off-Label" Drugs for HIV

A survey of 386 physicians in the U.S. found that over 40 percent of all drug therapy administered to people with AIDS involves "off-label" use of medications.23 Drugs prescribed off-label are compounds approved by the Food and Drug Administration (FDA) for some situations, but not for the particular one the physician is treating. According to the survey, over 90 percent of people with AIDS receive at least one off-label drug.

Frequently, off-label use of a drug merely anticipated FDA approval for that use (for example, Bactrim as prophylaxis for pneumocystis pneumonia). Half of the doctors surveyed nonetheless reported having problems obtaining insurance reimbursement for off-label prescriptions. Not surprisingly, patients who had no insurance or were members of health maintenance organizations (HMOs) had less chance of receiving off-label therapies, as did African-Americans.

1 Ho, D. 34th ICAAC. October 4-7, 1994. Orlando, Florida. Symposium 1.

2 Saag, M. Symposium 1.

3 Fang G, et al. Abstract LB-A6.

4 Mayers DL, et al. Abstract LB-A11.

5 Mudido P, et al. Abstract I126.

6 Anderson RE, et al. Abstract I60.

7 Dunkle LM, et al. Abstract LB-3.

8 Deutsch P, et al. Abstract I59.

9 Kempf D, et al. Abstract LB-A4.

10 Zhang R, et al. Abstract LB-A5.

11 Powderly W. Symposium 3-2.

12 Chave JP, et al. Abstract I219.

13 Horn CA, et al. Abstract I221.

14 Dehertogh D, et al. Abstract LB-A7

15 Mertz GJ, et al. Abstract H3.

16 Schrappe M, et al. Abstract H99.

17 Guembel H, et al. Abstract 145.

18 Dusserre N, et al. Abstract H75.

19 Pierce M, et al. Abstract LB-A2.

20 Solera J, et al. Abstract I183.

21 Fries L, et al. Abstract M21.

22 Sluiters JF, et al. Abstract M19.

23 Brosgart C, et al. Abstract I139.

Copyright (c) 1994 - Gay Men's Health Crisis. Noncommercial reproduction encouraged. DISTRIBUTED BY GENA/aegis * 714.248.2836 * 8N1/Full Duplex * v.34.
9411
GM081001

Copyright © 1994 - Treatment Issues. Reproduced with permission. Treatment Issues is published twelve times yearly by GMHC, Inc. All rights reserved. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. GMHC Treatment Issues, The Tisch Building, 119 West 24th Street, New York, NY 10011  fredg@gmhc.org  http://www.gmhc.org

AEGiS is made possible through unrestricted grants from Boehringer Ingelheim, Elton John AIDS Foundation, iMetrikus, Inc., John M. Lloyd Foundation, the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2003. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 2003. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .