AIDSWEEKLY Plus; Monday, March 30, 1998
Daniel J. DeNoon, Senior Editor

Provocative new findings suggest that the 30-year-old cancer drug may find new life as a component of combination therapy for HIV infection.

One patient, treated with hydroxyurea plus didanosine (ddI, Bristol-Myers) plus a protease inhibitor (indinavir, Merck) very soon after becoming infected with HIV, has had no measurable plasma viremia in the 13 months since ceasing antiretroviral treatment.

"We're still not sure exactly what happened," said Franco Lori of the RIGHT Institute, Pavia, Italy.

Lori presented the findings at a late-breaker session of the 5th Conference on Retroviruses and Opportunistic Infections, held February 1-5, 1998, in Chicago, Illinois.

Lori's interest in hydroxyurea dates back to his days at Robert Gallo's NCI laboratory, when he and colleagues found that HIV can remain in resting T cells only in the presence of ribonucleotide reductase. Because the vast majority of T cells are in the resting state, the finding suggested that an inhibitor of the cellular enzyme ribonucleotide reductase could have a profound effect on the progression of HIV infection.

Hydroxyurea (trade name, Hydrea) inhibits ribonucleotide reductase, thereby decreasing the intracellular pool of deoxynucleoside triphosphates (dNTPs). Nucleoside-based reverse- transcriptase inhibitors (NRTIs) exert their anti-HIV effect after intracellular phosphorylation into their triphosphate form. Not surprisingly, when hydroxyurea causes a decrease in cellular dNTPs, uptake and metabolism of NRTI triphosphates is increased.

Lori and co-workers hypothesized that a highly active antiretroviral therapy (HAART) regimen including hydroxyurea could break the cycle of HIV replication leading to disease. This cycle, they suggested, begins with HIV infection of quiescent T cells. Signals generated by HIV cause these cells to become activated, whereupon they produce even more virus, infecting and activating greater numbers of T cells in a pathogenic spiral.

"We were hoping that hydroxyurea and ddI could target quiescent cells," Lori said.

The researchers enrolled 24 patients, several of whom were treated after HIV infection but before seroconversion. They had a mean viral load of 455,700 copies/mL and a mean CD4 count of 499 cells/(micro)L. The patients received hydroxyurea plus ddI plus indinavir.

After treatment, virus load became undetectable in the plasma of all 24 patients and in the semen of all six patients tested.

In the patients treated during active HIV infection - prior to seroconversion - lymph-node biopsies showed no HIV in seven of eight patients tested by PCR assays able to detect one infected cell in 44 million, and two of six patients were negative in assays able to detect one HIV infected cell in 300 million.

Unlike some other studies of hydroxyurea-containing regimens, patients had a mean CD4(+) T-cell increase of 168 cells/(micro)L that was sustained over time.

One of the patients treated during acute infection briefly stopped treatment on day 39; his plasma viral load shot up. He acquired hepatitis A infection on day 141 and stopped taking the study medications. This time, his viral load did not increase. Thirteen months prior to Lori's presentation the patient quit treatment again.

"There is still no rebound in viremia," Lori said.

Lymph-node samples were sent to Johns Hopkins researcher Robert Siliciano; one of three samples had detectable HIV at a frequency of less than one cell per 10 million.

Lori interpreted these and other findings (see below) to show that hydroxyurea plus ddI has a mechanism of action not previously described. This activity appears to target a cellular factor or factors and involves cytostatic effects.

The former NCI researcher noted that researchers are still trying to learn how best to use hydroxyurea in patients with HIV infection.

"Hydroxyurea dosage is very important and has to be worked out, not only for toxicity but also for antiviral effect," he said.

During a press conference, University of Pittsburgh researcher John Mellors was asked about the possible role of hydroxyurea in the treatment of HIV disease. Mellors sits on the advisory panel that establishes recommendations for standard-of-care antiretroviral treatment.

"In acute infection, there may be a role for hydroxyurea," Mellors said. "In initial early infection if you provide nucleotide chain disrupters and deprive the virus of nucleotides, you have a better chance of preventing establishment of infection. All this, of course, is highly speculative."

But Mellors warned doctors against premature prescription of the drug.

"The hydroxyurea information is insufficient to make a statement at this time," he said. "Several clinical trials are ongoing. The most important issue is that CD4 cell counts have not responded despite viral load reduction in some studies. There seems to be a disconnect in hydroxyurea. This means hydroxyurea is having an effect on the outgrowth of CD4 cells. I'm concerned about this. Reduction in viral load in regimens containing hydroxyurea may not have the same effect as reductions in viral load with other regimens. ... Hydroxyurea is a new kid on the block. The relation between virus load and CD4 responses make me a little concerned."

There were several other reports on hydroxyurea clinical trials at the 1998 Retrovirus conference.

R. Rossero and colleagues of the University of Texas, Galveston, treated 31 NRTI-experienced patients with hydroxyurea (1 gram one time per day), stavudine (d4T, Bristol-Myers) and ddI.

After 12 weeks of treatment, eight of 14 patients had viral load decreases at or below the level of detection (500 copies/mL, bDNA assay). The mean CD4 count increased by 84 cells/(micro)L in the 12 patients who completed 16 weeks of treatment. Neutropenia occurred in four patients who entered the study with absolute neutrophil counts (ANC) of less than 1700/(micro)L; this symptom resolved when hydroxyurea was withdrawn.

Jeffrey E. Galpin of Shared Medical Research, Tarzana, California, and colleagues enrolled 42 patients in a 52 week study comparing hydroxyurea monotherapy to hydroxyurea plus ddI to hydroxyurea plus ddI plus d4T.

"Treatment with hydroxyurea, particularly in combination with d4T and ddI, appears to stabilize and improve CD4 percentage and viral load levels over a 28-week period," Galpin et al. wrote in their presentation abstract. "Hydroxyurea may well offer protection to other antiretrovirals as to resistance emergence and to be synergistic with these drugs in preventing reactivation or activation of virus in T cells and macrophages while enhancing the action of these agents."

Galpin et al. also reported that patients receiving hydroxyurea showed a reversal in the progressive loss of naive, programmed, and long-term memory cells characteristic of HIV disease. Patients had a mean 30 percent increase in total naive lymphocytes (CD45RA(+)), a mean 140 percent increase in naive CD4 associated memory cells (CD4(+)CD45RA(+)), and a 222 percent increase in long-term memory cells (CD45RA(+)CD62L(+)).

"This suggests the possibility of the reconstitution of a more normal immune complement of cells with this innovative combination therapy," Galpin et al. wrote.

O.T. Rutschmann and colleagues of the Swiss HIV Cohort study randomized 144 patients - 75 percent of whom had never received antiretroviral medications - to receive ddI plus d4T in addition to hydroxyurea (500 mg bid) or placebo.

Twenty of the 72 (28 percent) patients receiving ddI/d4T/placebo and 39 of the 72 (54 percent) receiving ddI/d4T/hydroxyurea had their viral load drop to below 200 copies/mL. Using an assay able to detect 20 HIV RNA copies/mL, 19 percent of the patients receiving hydroxyurea remained undetectable versus 8 percent of those receiving placebo.

However, this study did show a disassociation between virus response and CD4 count: patients receiving the hydroxyurea-containing regimen had a mean CD4 increase of 28 cells/(micro)L, while those not receiving hydroxyurea had an increase of 107 cells/(micro)L.

"Hydroxyurea combined to ddI + d4T is associated with a more profound decrease in HIV RNA and a greater proportion of patients with undetectable viremia," Rutschmann et al. wrote in their presentation abstract. "This combination could be a cost-effective alternative to standard triple therapy in moderately immunosuppressed patients."

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