Highlights from Recent Conferences -- Treatment Guidelines and Immune-Based Therapies

Harvey S. Bartnof, MD

DHHS Updates HIV/AIDS Treatment Guidelines

Reflecting new information that has become available in the past six to twelve months, the U.S. Department of Health and Human Services (DHHS) updated its Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents on December 1, 1998.

Several of the new changes reflect the addition of the recently approved nucleoside analog drug efavirenz (Sustiva). The changes to the guidelines are described below.

1. The goal of anti-HIV therapy should be an HIV viral load less than 50 copies/mL, using the most sensitive tests. Third-generation HIV viral load tests have a lower limit of quantitation of 20-50 copies/mL. These lower viral loads provide a stronger genetic barrier to the emergence of drug-resistant HIV. Viral load testing should be done as early as two weeks and up to eight weeks after starting anti-HIV therapy to initially assess treatment efficacy.

2. Triple combination therapy with efavirenz plus two nucleoside analogs is now included as a preferred option for initial therapy. The use of efavirenz in such a regimen has shown at least equivalent (or better) benefits up to 48 weeks, compared to the use of a protease inhibitor plus two nucleoside analogs. These benefits include HIV viral load suppression to less than 50 copies/mL and CD4 count increases. The double combination of efavirenz plus indinavir (Crixivan) is acknowledged to be as potent as a triple combination of a protease inhibitor plus two nucleoside analogs. While recognizing that there are no direct comparisons among the three available non-nucleoside reverse transcriptase inhibitors (NNRTIs), the panel acknowledges that efavirenz would be preferred over the other two drugs in its class at this time.

3. As alternative treatment recommendations, combinations of either nevirapine (Viramune) or delavirdine (Rescriptor) plus two nucleoside analogs are now specifically listed. The panel states that these two combinations are less likely to provide sustained viral suppression, and that there is inadequate data to include them in the preferred list.

4. Information about avoiding efavirenz during pregnancy has been added. Because of a 15% rate of birth defects in the offspring of female monkeys using a concentration of efavirenz equivalent to that used in humans, efavirenz is not recommended for pregnant women.

5. Information regarding drug-related adverse events has been updated to reflect recent changes in drug package inserts, including information that has come to light during the post-marketing period.
   • For nucleoside analogs, lactic acidosis (low blood pH) with hepatomegaly (liver enlargement) and hepatic steatosis (fatty liver) have been reported. Although rare, these adverse effects can be lethal.
   • For protease inhibitors, reports have been received of hyperglycemia (high blood sugar) and diabetes, fat redistribution with or without blood lipid (fat) abnormalities, and increased bleeding in hemophiliacs. The panel acknowledges that these adverse events were identified by case reports and other uncontrolled data. Therefore, their true rates and their relationship with protease inhibitors have not been definitively established. The panel states that controlled and/or population-based studies evaluating these adverse events are warranted.
   • In persons taking efavirenz, a false positive screening test for cannabinoids (marijuana) may occur.

6. Information about HIV drug resistance testing has been expanded.
   • The panel acknowledges that genotypic (genetic structure) and phenotypic (actual growth pattern) resistance tests may prove useful in guiding both initial therapy and changing failing regimens. However, the panel states that the true value of these tests has not been fully established, and that each test and laboratory requires standardization and validation.
   • The presence of viral resistance to a particular drug suggests that that drug and cross-resistant drugs are likely to be unsuccessful in suppressing HIV replication.
   • The absence of viral resistance does not necessarily indicate that a particular drug will be effective in suppressing HIV replication, particularly if that drug or a cross-resistant drug has been used previously. This is the case because minority drug-resistant viral strains may hide in bodily reservoirs. Under the pressure of a new drug combination, such minority strains may quickly become dominant, leading to new HIV replication and drug failure.
   • The most useful information to guide the selection of an alternative combination regimen in the face of viral breakthrough is a detailed drug treatment history. The safest approach remains changing all drugs in a failing regimen, if possible, regardless of the results of resistance testing.
   • If resistance testing is performed in the setting of viral breakthrough, a person should remain on their current drug regimen until blood is drawn for testing.
   • For genotypic resistance tests, a minimum HIV RNA level of 1,000 copies/mL is necessary to properly perform the test.
   • Expert clinical interpretation is necessary to put results of resistance tests in their proper perspective.

7. Regarding treatment during primary HIV infection, the panel has deleted the possibility of re-evaluating therapy after one year. This is due to the recognition that viral load rebound may still occur when combination anti-HIV therapy is discontinued after two to three years of treatment.

8. A newly added potential benefit of early initiation of anti-HIV therapy in a patient without symptoms is the possibility of decreased risk of HIV transmission through sex, breast-feeding, or sharing needles. A newly added potential risk is the transmission of drug-resistant HIV by the same routes.

9. The drugs currently available on expanded access are adefovir dipivoxil (Preveon) and amprenavir (Agenerase); abacavir (Ziagen) was approved after the update was issued.

U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents.December 1, 1998.

IMMUNE-BASED THERAPIES

IL-2 plus HAART Helps Flush Out Hidden HIV

• Studies have combined HAART and cytokine(s), including interleukin-2 (IL-2); one such study used five-drug HAART plus two cytokines.
• After HAART plus IL-2, HIV blood cultures were negative, but HIV DNA was still detected.
• Two to four antiretroviral drugs alone are unlikely to eradicate HIV.
• HIV eradication will likely involve HAART plus an immune modulator or a therapeutic vaccine.
• IL-2 therapy is associated with a 10% rate of hypothyroidism.

One of the setbacks in the understanding of highly active antiretroviral therapy (HAART) was the recognition of a small, yet persistent pool of resting lymphocytes that were latently infected with HIV. Even two to three years of HAART-induced CD4 T-cell count increases and undetectable HIV viral load does not eradicate these resting embers of HIV infection. When HAART was discontinued in a few people, that resting pool easily reactivated to yield increasing HIV viral loads.

Now, Anthony Fauci, MD, of the National Institute of Allergy and Infectious Diseases (NIAID) has reported that HAART plus IL-2 appears to flush out a significant portion of that resting pool of lymphocytes from the blood of a small group of people. IL-2 is a cytokine, a chemical messenger that facilitates communication among immune system cells. These results further support the growing belief that combination antiretroviral therapy alone will not cure HIV; some type of immune modulating therapy or therapeutic vaccine will likely also be required. Potential additions include IL-2, interferon-gamma, the Remune vaccine, and OKT3 antibodies. This report underscores the realization that two to four antiretroviral drugs are merely virustatic (stopping viral replication), not virucidal (virus-killing).

Fauci described the results of a study of 26 people with HIV. Twelve received HAART including a protease inhibitor, while fourteen received HAART plus IL-2, either intravenously or subcutaneously (injected under the skin). IL-2 was given in the standard fashion, daily for five days every two months. Daily doses were 3-18 million units. After a median of 39 months of IL-2 and 21 months of HAART, blood samples were taken from all 26 patients. All had an undetectable blood plasma HIV viral load (limit of quantitation 50 copies/mL) at that time. No HIV replication was detected in cultures of 10-20 million resting peripheral blood CD4 lymphocytes from six of the 14 persons in the HAART plus IL-2 arm. Furthermore, no HIV replication was seen in three persons when up to 330 million cells were cultured. In contrast, HIV replication was seen in cultures of 10-20 million resting blood cells from each of the 12 persons taking HAART without IL-2.

In one person taking HAART plus IL-2, a lymph node biopsy revealed no HIV replication. Fauci later reported that all persons were positive for HIV DNA in resting lymphocytes, as was the one biopsy sample. Such proviral (integrated into the human chromosome) DNA may not have been replication-competent (able to reproduce), since the culture tests were negative. Other hidden reservoirs of HIV exist outside of the blood and lymph organ compartments, including in the brain, testes, gut, and macrophages throughout the body.

A second report on attempting to flush out latently infected cells was described by Alain Lafeuillade, MD, and colleagues from Toulon General Hospital in France at the Glasgow meeting. Five anti-HIV drugs plus two cytokines were used by ten antiretroviral-naive persons for a mean of nine months. The anti-HIV regimen included saquinavir (600 mg), ritonavir (400 mg), ddI (200 mg), AZT (300 mg), and 3TC (150 mg), each twice daily. The two cytokines used were IL-2 and interferon-gamma, administered between months three and twelve. Three courses of IL-2 were subcutaneously self-administered, 15 million units daily for five days every eight weeks. Two courses of interferon-gamma were administered (100 micrograms three times weekly), with each course lasting two weeks.

The results showed a marked decrease in plasma HIV RNA from a baseline of over four log copies/mL to undetectable (limit of quantitation 20 copies/mL) after only three months. HIV RNA in the lymph nodes decreased from a baseline of 5.2 log to 2.2 log copies per million lymph node white blood cells after six to twelve months. After one year, HIV proviral DNA decreased by one log from a baseline 3.7 copies per million blood lymphocytes. Note that although it was markedly decreased, HIV proviral DNA in lymphocytes and RNA in lymph node cells was still present after one year of this seven-drug regimen.

In a separate report from NIAID, intravenous IL-2 therapy was found to be associated with a 10% rate of hypothyroidism (low thyroid hormone levels). Such a high rate has not been reported in the past. Some of the HIV positive persons in the NIAID studies required thyroid hormone supplements. Standard dosing of IL-2 was used for one year. An IL-2 plus HAART group was compared to a control group receiving antiretroviral therapy without IL-2. When comparing the two groups, there were no significant differences in the levels of other hormones, including testosterone, follicle-stimulating hormone, or leuteinizing hormone. IL-2 has several other, usually reversible side effects, including flu-like symptoms such as fever and weakness, in addition to rash, depression, and increased liver enzymes.

Other studies of HAART plus IL-2 not only have shown a higher CD4 count increase than with HAART alone, but also greater HIV viral load reductions and fewer clinical events. These results were summarized at the Glasgow meeting by David Cooper, MD, from the University of New South Wales in Australia. The studies described above are ongoing, and large long-term studies are currently enrolling participants who will be given various combinations of HAART plus IL-2 and/or the Remune vaccine.

Cooper, D. Immune-based therapies. 4th ICDTHI. Abstract PL2.1.

Fauci, A. Host factors in the pathogenesis of HIV disease. 36th IDSA. Abstract S94.

Jubalt, V. and others. High rebound of plasma and cellular HIV load after discontinuation of triple combination therapy. 4th ICDTHI. Abstract P219.

Lafeuillade, A. and others. Combining HAART and cytokines to target the residual pool of HIV-1: preliminary results of the Pentakine trial. 4th ICDTHI. Abstract OP1.1.

Lafeuillade, A. and others. Tracking HIV in patients on triple-therapy since acute infection. 4th ICDTHI. Abstract P205.

Losso, M. and others. A phase II study of subcutaneous IL-2 plus antiretrovirals (ARV) vs ARV alone in patients with HIV infection and CD4+ cell count >= 350 cells/mm³. 4th

ICDTHI. Abstract P192.

Folkers, G. Personal communication. December 7,1998.

Sumida, S. and others. Hypothyroidism is associated with IL-2 therapy in a randomized controlled trial of IL-2 for the treatment of HIV infection. 36th IDSA. Abstract 486.

Zanussi, S. and others. Safety and efficacy of HAART + IL-2 vs HAART alone. 38th ICAAC. Abstract I-184.

Other Immune-Based Therapies Show Benefit for HIV/AIDS

• GM-CSF (Leukine) plus antiretroviral therapy shows benefits for up to six months, including increases in CD4 counts and decreases in clinical events.
• G-CSF (Neupogen) increases numbers of naive T-cells.
• Natural interferon-alpha-n3 (Alferon N) injections show benefits in a placebo-controlled trial, including decreases in HIV viral load without anti-HIV therapy.
• Experimental infusions of genetically modified lymphocytes show benefits in 24 persons followed for up to eight weeks.

Aladdin, H. and others. Recombinant human granulocyte colony-stimulating factor (rHuG-CSF) treatment for 12 weeks enhances the CD4+ count in HIV infected individuals. 4th ICDTHI. Abstract P199A.

Brand, D. and others. Natural interferon alpha treatment of HIV patients: a randomized, placebo-controlled, double-blind study. 38th ICAAC. Abstract I-100.

Brites, C. and others. Granulocyte-macrophage-colony-stimulating-factor (GM-CSF) reduces viral load and increases CD4 counts in individuals with AIDS. 38th ICAAC. Abstract I-243.

Deeks, S. and others. Adoptive immunotherapy of HIV infection with autologous CD4-zeta gene-modified CD4 and CD8 T cells. 38th ICAAC. Abstract I-188.

Hartung, T. and others. G-CSF doubled CD4 counts in normal volunteers and restored IL-2 release in HIV patient blood. 4th ICDTHI. Abstract P189.

Nielsen, S.D. and others. Effect of G-CSF in HIV-infected patients: increase in numbers of naive CD4+ cells and CD34+ cells. 4th ICDTHI. Abstract P190.

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