Published in the Bulletin of Experimental Treatments for AIDS July 1998 issue, by the San Francisco AIDS Foundation.

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July 1998 Table of Contents

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Research Notes

By Harvey S. Bartnof, MD

HIV Treatment

Changes to Federal Guidelines for the Use of Antiretroviral Agents

Draft Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents were published in the June 1997 BETA. Since then, public comment has been considered and the final guidelines were published on April 24, 1998, in Morbidity and Mortality Weekly Report. The final version contains specific modifications, listed below. Many changes reflect additional research that has been presented at medical conferences during the past 12 months. The guidelines can be found on the web at www.hivatis.org/trtgdlns.html.

1. Recommended antiretroviral agents for treatment of established HIV infection (draft version: BETA June 1997, Table VI). The protease inhibitor column A now includes soft-gel saquinavir (Fortovase) and the combination of ritonavir (Norvir) plus either soft-gel or hard-gel saquinavir (Invirase). Strengths of recommendation are given in parentheses (e.g., A2) and described below. Additions or changes to the original draft chart are in italics:

Preferred: Strong evidence of clinical benefit and/or sustained suppression of plasma viral load. One choice from column A and one from column B. Drugs are listed in random, not priority order:

Alternative: Less likely to provide sustained virus suppression

1 NNRTI (nevirapine)⁴ + 2 NRTI (column B above) (B2)
saquinavir (Invirase) + 2 NRTI (column B above) (B1)

Not generally recommended: Strong evidence of clinical benefit, but initial virus suppression is not sustained in most patients

2 NRTI (column B above) (C1)

Not recommended⁵: Evidence against use, virologically undesirable or overlapping toxicities

All monotherapies (D1)
d4T + AZT (D1)
ddC + ddI ⁶ (D2)
ddC + d4T ⁶ (D2)
ddC + 3TC (D2)

(C1) Optional recommendation. Quality of evidence: at least 1 randomized trial with clinical endpoints.

2. Characteristics of protease inhibitors (draft version: BETA, June 1997, Table IX). The saquinavir column has now been divided into 2 columns, corresponding to the original formulation (Invirase) and the newer formulation (Fortovase). For Fortovase, "refrigerate or store at room temperature (up to 3 months)."

While in the draft version recommendations for ritonavir storage stated "Refrigerate; single dose may be at room temperature for 12 hours," the final version states "Refrigerate capsules; refrigeration for oral solution is preferred but not required if used within 30 days." Note that for ritonavir capsules "storage at room temperature for 12 hours" has been deleted.

Under adverse effects, all 5 protease inhibitors now have hyperglycemia (elevated blood sugar) in the final version.

3. Criteria for changing therapy (draft version: BETA, June 1997). The following has been added to the guidelines for changing an antiretroviral regimen due to suspected drug failure:

In some cases, regimens identified as suboptimal for initial therapy are rational due to limitations imposed by toxicity, intolerance or non-adherence. This especially applies in late-stage disease. For patients with no rational alternative options who have virologic failure with return of viral load to baseline (pretreatment levels) and a declining CD4 T-cell count, discontinuation of antiretroviral therapy should be considered.

4. New regimens for patients who have failed antiretroviral therapy (draft version: BETA, June 1997, Table XIV). The title of this table has been changed to: "Possible regimens for patients who have failed antiretroviral therapy: a work in progress." A footnotes goes on to explain: "These alternative regimens have not been proven to be clinically effective and were arrived at through discussion by the panel of theoretically possible alternative treatments and the elimination of those alternatives with evidence of being ineffective. Clinical trials in this area are urgently needed." Additions or changes to the table are in italics:

2 NRTI +                  2 new NRTI +
nelfinavir                     ritonavir; or indinavir; or saquinavir +
                                 ritonavir; or NNRTI* + ritonavir; or
                                 NNRTI + indinavir**

ritonavir                     saquinavir + ritonavir**; nelfinavir +
                                 NNRTI; or nelfinavir + saquinavir

indinavir                     saquinavir + ritonavir; nelfinavir +
                                 NNRTI; or nelfinavir + saquinavir

saquinavir                 saquinavir + ritonavir; or NNRTI +
                                   indinavir; [deleted as an option:
                                  monotherapy with either nelfinavir                                    or ritonavir]

2 NRTI + NNRTI      2 new NRTI + a protease inhibitor
2 NRTI                      2 new NRTI + a protease inhibitor
                                  2 new NRTI + ritonavir +
                                    saquinavir
                                  1 new NRTI + 1 NNRTI + a
                                    protease inhibitor
                                  2 protease inhibitors + NNRTI
1 NRTI                      2 new NRTI + a protease inhibitor
                                  2 new NRTI + NNRTI
                                  1 new NRTI + 1 NNRTI + a
                                   protease inhibitor

5. Delavirdine has been added as a new NNRTI therapy in several locations in the final version, since it received FDA approval after publication of the draft. Like nevirapine, the other FDA-approved NNRTI, FDA listed delavirdine in pregnancy category C. Drug safety data during human pregnancy has not been determined; animal studies are either positive for fetal risk or have not been conducted, and the drug should not be used unless the potential benefit outweighs the potential risk to the fetus.

6. The intracellular half-life of ddI has been increased from 12 hours in the draft version to 25-40 hours in the final version. This may, in part, explain why several newer experimental combination antiretroviral regimens include once-daily ddI dosing at 300-400 mg.

7. Many patients remain unaware that grapefruit juice reduces indinavir blood levels by 26%, while hard-gel saquinavir (Invirase) blood levels are increased by grapefruit juice. Fortovase levels are probably also increased by grapefruit juice, although this has not yet been reported.

Guidelines for the use of antiretrovirals agents in HIV-infected adults and adolescents. Morbidity and Mortality Weekly Report 47/No. RR-5. April 24, 1998.

CD4 Cell Count Benefits from HAART Even Though HIV Viral Load Persists

The current paradigm for treating HIV infection holds that reductions in HIV viral load induced by highly active antiretroviral therapy (HAART) are associated with an increase in CD4 and CD8 T-cell counts (including naive T-cell subsets), with a subsequent lowered risk of opportunistic conditions and death. However, approximately half of those treated with HAART do not achieve or maintain undetectable HIV viral loads. Still, many of these individuals remain relatively healthy for months and even years. What is the maximum level of HIV viremia associated with a lack of CD4 cell loss? Researchers of the Swiss HIV Cohort Study have suggested that perhaps this may be the wrong question.

A research letter published in The Lancet analyzed 101 HIV positive people who took HAART for at least 3 months. Prior to HAART, the mean CD4 cell count was 162 cells/mm³. Undetectable HIV viral loads were not achieved in 66% of this cohort. Nonetheless, at 48 weeks, 93% (91 of 98) had CD4 cell count increases. There were 82 people in the cohort who took HAART continuously. Among those with a persistently undetectable viral load (28 of 82), the mean CD4 cell increase was 138 cells/mm³. Among those with transient undetectable viral loads (21 of 82), the mean CD4 increase was 130 cells/mm³. However, among those with persistently detectable viral loads (33 of 82), the mean CD4 cell increase was a surprising 105 cells/mm³. Even more surprising was that among the 16 patients who did not strictly adhere to their regimens, the mean CD4 cell increase was 57 cells/mm³, despite a mean treatment interruption of 55 days. Interruption of HAART was associated with a mean decrease of 49 cells/mm³.

The authors suggested that adherence to HAART, not viremia, was the most significant factor determining the number of CD4 cells after 48 weeks. The authors further observed, "Even without suppression of viremia, HAART may have a prolonged effect on CD4 cell counts with potential clinical benefit."

The researchers remind us that in the pre-treatment era, the mean change in CD4 count was a decrease of 60 cells/mm³ annually. In the pre-HAART era (when double nucleoside analog therapy was the norm), the mean change in the CD4 count was an increase of up to 40 cells/mm³ after 1 year. HAART has allowed for CD4 cell increases of over 100 cells/mm³ in the present study, even with a lack of complete HIV viral suppression.

The authors hypothesize that the reason for the increases may be decreased viral fitness associated with HIV mutations, the cumulative benefit of a small reduction in HIV viral load, or a decrease in cell killing mediated by HIV. They conclude that their findings need to be confirmed in larger cohort studies.

A similar theme was voiced in a letter to the editor in The New England Journal of Medicine. Two patients (1 man and 1 woman) at Boston Medical Center were described who had marked HAART-induced increases in their CD4 cell counts despite moderately high HIV viral loads. The lowest CD4 cell counts for the 2 were 30-40 cells/mm³. After responding to HAART regimens (d4T/3TC/ddI/nelfinavir and d4T/ddI/ritonavir/saquinavir), their CD4 cell counts increased to 528 and 375 cells/mm³, respectively. Nonetheless, they had only modest HIV viral load decreases of less than 1 log copies/mL, to 46,110 and 92,580 copies/mL, respectively. Adherence to medication schedules was "excellent," according to pharmacy records.

These 2 letters suggest that a significant subset of HIV positive patients derive substantial clinical benefit from HAART-induced CD4 cell count increases with only moderate, minor or possibly no change in HIV viral load. Analysis of larger cohorts should provide more specific answers.

Kaufmann D and others. CD4-cell count in HIV-1-infected individuals remaining viremic with highly active antiretroviral therapy (HAART). Lancet 351:723-724. March 7, 1998.

Acute HIV Symptoms Recur after Stopping HIV Drug Cocktail

• Case report of a man who started triple HIV therapy before his HIV antibody test turned positive. He remained on combination HIV therapy for 6 months, then stopped
• 1 month later, acute HIV symptoms returned

An interesting case of acute recurrent HIV symptoms was reported by researchers at the Cedars-Sinai Burns and Allen Research Institute at the University of California, Los Angeles. A 38-year-old gay man was diagnosed with acute HIV retroviral syndrome 13 days after unprotected, receptive oral-genital sex. At the time of sexual exposure, he had a sore on the roof of his mouth. When he saw his physician, his HIV symptoms had been present for 5 days and included fever, swollen lymph glands, headache, sore throat, muscle aches and a rash. His blood plasma HIV RNA viral load was 1,800,000 copies/mL. Two days later, his viral load increased to 5,600,000 copies/mL. Blood tests for 6 other viruses and an HIV antibody test were negative (it was too early for the antibody test to be positive). The man started an anti-HIV regimen of AZT/3TC/ritonavir. His viral load became undetectable (limit of detection 500 copes/mL) and his HIV symptoms resolved. Because of toxic side effects, his medications were changed. The specific drugs were not mentioned in the report.

Against medical advice, the man stopped his anti-HIV therapy 6 months later. Exactly 35 days after stopping his anti-HIV drug "cocktail," the identical acute HIV symptoms returned and his HIV viral load rebounded. The man chose not to restart anti-HIV therapy and his acute HIV symptoms resolved after 10-14 days. His HIV antibody test then became positive.

The man did not develop a CD8 T-cell lymphocyte response or memory cytotoxic T-cell activity until the recurrent HIV symptoms occurred. The authors believe that this finding may be relevant to the development of an effective HIV vaccine.

This is the first documented case of acute HIV symptoms recurring after stopping combination anti-HIV therapy. HIV viral load rebound is common when therapy is stopped, but this is the first reported case in which therapy was started before the antibody test turned positive.

Daar ES and others. Acute HIV syndrome after discontinuation of antiretroviral therapy in a patient treated before seroconversion. Annals of Internal Medicine 128(10):827-829. May 15, 1998.

Johns Hopkins University Declared a "Grapefruit-Free Zone"

Charles Flexner, MD, a faculty member at Johns Hopkins University, announced at the recent International AIDS Society-USA meeting in San Francisco that the Johns Hopkins School of Medicine is now "grapefruit-free" for patients. Increasing evidence suggests that a component of grapefruit adversely affects the metabolism of many different drugs (including indinavir and saquinavir) by altering P450 liver enzyme metabolism.

The responsible grapefruit component is a flavonoid called naringenin. The study of citrus fruits’ effects on the metabolism of different drugs is rapidly expanding. Many different foods may alter the metabolism of various therapeutic agents. A complete understanding of such effects may help to explain both why some drugs are "ineffective" in some patients (due to food-induced more rapid drug metabolism leading to low drug levels) and why other drugs become toxic in some patients (due to food-induced slower drug metabolism leading to high drug levels).

Page last updated 14 July 1998

July 1998 Research Notes -- Part 2

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