Treatment Issues, Vol 11, No 2; February 1997
Dave Gilden, with John Falkenberg and Gabriel Torres, M.D.

The major factor that is shoring up AZT's position these days is Glaxo Wellcome's other HIV treatment, 3TC. 3TC has the most potent antiviral effect of the nucleoside analogs currently on the market and has comparatively few side effects, but HIV rapidly develops resistance to it unless the agent is used in combination with other medications that further suppress HIV replication. Until recently, nearly all research on 3TC has involved the "incestuous" combination AZT/3TC, a combination that has been touted as having a special "magic." One of the main arguments for this "magic" was the in vitro indication that the mutation at codon 184 of the reverse transcription gene, a single point mutation that confers high level resistance to 3TC, counteracts the mutations giving rise to AZT resistance. In short, HIV supposedly cannot be resistant to both drugs at once, and adding 3TC to the regimen of someone failing on AZT might return that drug to effectiveness. This was proven mainly false some time ago, although the appearance of resistance to the dual combination is delayed compared to monotherapy with AZT (see Treatment Issues article, Conference Looks at HIV Drug Resistance; September, 1995, page 6) and Retrovirus Conference abstract 580). Still, AZT/3TC was the most used nucleoside analog component of the protease inhibitor studies cited in this issue.

Substituting d4T/3TC for AZT/3TC

A popular solution for those failing or intolerant to AZT or AZT/3TC has been d4T/3TC. Until now, this combination has been relegated to backup therapy because there has been little trial data to confirm its worth. Now it appears that d4T/3TC is as respectable as AZT/3TC:

The ALTIS 1 and 2 trials were open-label protocols in which everyone received d4T/3TC (abstract LB4). ALTIS 1 participants had had no prior treatment history, whereas ALTIS 2 covered individuals who were treatment experienced (a median of three years), but who had had no previous d4T or 3TC. Table 1 (ALTIS Open Label Trial of d4T/3TC) contains the baseline characteristics and the results of up to six months treatment.

In the treatment-naive group (ALTIS 1), plasma viral load reduction to below 3,000 copies of HIV RNA/ml was strongly correlated with initial viral load. For the treatment-experienced people (ALTIS 2), the only variable associated with greater viral load reduction was previous use of AZT monotherapy. People with a history of using the AZT/ddI or AZT/ddC combinations did not fare as well as those who had taken only AZT.

One of the concerns about substituting d4T for AZT is that AZT is known to penetrate the blood/brain barrier, thus helping to prevent or treat AIDS-related dementia and also depriving the virus of a drug-free sanctuary. A Dutch study (abstract LB5) looked into this question while comparing the results of d4T/3TC and AZT/3TC in a blinded trial covering people without past treatment. The baseline characteristics and 12 week results are shown in Table 2 (AZT/3TC vs. d4T/3TC)

Three other reports described similar findings to ALTIS 2 concerning the antiviral potency of d4T/3TC in people switching from other therapies -- see abstracts 556, 557 and 560. The first of these presentations, a retrospective study of patients' files by AmFAR's Community-Based Clinical Trials Network, notably found that d4T/3TC provided little viral load improvement to people previously on AZT/3TC.

Blood/brain penetration was checked by conducting lumbar punctures at weeks 0 and 12 and assaying the volunteers' cerebral spinal fluid (CSF). It turned out that while all 31 participants initially had detectable HIV in their cerebral spinal fluid, by week 12 HIV levels were undetectable in every case. The Dutch investigators found that although AZT had greater immediate penetration into the CSF (where it achieved 80% of blood plasma levels), both 3TC and d4T actually had more staying power. Over time, total CSF exposure to these two was much greater. The study's conclusion was that AZT/3TC and d4T/3TC were essentially equivalent and that both should be helpful for dementia.

d4T/ddI: Going Farther Afield

Instead of two Glaxo Wellcome drugs, why not try two from Bristol Myers Squibb? Two French studies (abstracts 553 and 554) found that the combination of full-dose d4T and ddI reduced viral loads by 80 to 90% (0.7 to 1 log), at 24 weeks, accompanied by a CD4 count rise of about 40. One fear about the d4T/ddI combination is the two drugs' overlapping neurotoxicities. Reversible neuropathy or paresthesia (tingling patches on the body) forced six of the 85 participants to discontinue therapy. The current studies managed to produce quite respectable results for nucleoside analog therapy in a group that had advanced disease and was heavily pretreated (though no one had prior exposure to d4T and only three in one trial had previous ddI). Baseline CD4 counts in the two trials were low --116 and 217 on average -- and viral loads high -- an average of 200,000 and 100,000 copies/ml, respectively. The trial's outcomes are not nearly as good, though, as the ones from the American study that peaked interest at 1996's Retrovirus Conference and the International Conference on AIDS last summer (see Treatment Issues article, Back to Nukes; February, 1996, page 7 and Antiviral Roundup; August, 1996, page 7). That 79-person U.S. trial involved less advanced patients than were the case in the French studies. The Americans' entry CD4 counts averaged 343, and their initial viral load was 16,000. All were all treatment-naive. By last summer, the trial as a whole had recorded only one serious case of peripheral neuropathy, but only 20% of participants were receiving full dose d4T and ddI in what was considered a pilot safety test of the combination. One-year results for the first 18 participants also were presented last summer. These 18 exhibited on average a sustained CD4 count rise of 80 to 100 and a viral load drop of 96% (1.4 logs). (See abstract Th.B.293 from the Eleventh International Conference on AIDS).

d4T/ddI/Hydroxyurea

Combining d4T/ddI with protease inhibitors presents problems. Drug drug interactions in the gut and requirements that ddI and indinavir be taken on an empty stomach make for a very complicated dosing schedule when trying to administer d4T, ddI and indinavir concurrently (see Treatment Issues article, ddI and d4T Plus Protease Inhibitors; November, 1996, pages 8/9). And the combined gastrointestinal side effects of ritonavir and ddI might be difficult to endure. A poster at the Retrovirus Conference reported on a Bristol Myers pilot study of d4T/ddI/nelfinavir (abstract 241), which could be the simplest combination. But that study, which included only people naive to all three drugs, was plagued by noncompliance with the regimen: Overall, 16 people had a disappointing viral load drop of 96% (1.4 logs) by week 12, but the six completely compliant participants in that group saw their viral loads shrink 99.4% (2.2.5 logs). Much of the noncompliance was attributed to "inconvenience."

Here is another strategy for triple combination therapy: Adding hydroxyurea to d4T/ddI considerably strengthens this combination's effects, according to one placebo-controlled trial presented at the Conference (abstract 550). This cancer chemotherapy blocks a cellular enzyme that helps produce some of the natural nucleosides used to build DNA. Reducing the natural nucleoside pool makes HIV more susceptible to the nucleoside analogs, especially ddI in this case (see Treatment Issues article, New Data Intensifies Interest in Hydroxyurea; September, 1995, page 1). The Swiss trial enrolled 142 persons, 80% of whom had had no previous treatment. The rest had no more than six months of ddI and no prior exposure to d4T or hydroxyurea. The trial's baseline characteristics and results are summarized in Table 3 (d4T + ddI + Hydroxyurea).

Note that CD4 counts did not rise in the hydroxyurea arm, and total lymphocytes fell considerably. This is probably due to hydroxyurea's inhibitory effect on cell division. Also, 15 of 72 volunteers on hydroxyurea had withdrawn from the study by the twelfth week, compared to only 5 of 70 on placebo. Much of this difference was due to extra nausea and vomiting and other side effects in the hydroxyurea arm.

A 19-person pilot study at the University of Texas in which everyone received d4T/ddI/hydroxyurea (abstract 549) also observed a 99% (2 log) reduction in viral load by week 12 with no change in CD4 count. In this trial, 17 of the volunteers had been on either AZT, ddI or d4T monotherapy. One each were receiving AZT/ddI and d4T/ddI. Baseline CD4 count averaged 226, and average initial viral load was 81,000.

In a third study (abstracts 589 and 591), Franco Lori, M.D., and colleagues from the Research Institute of Genetic and Human Therapy in Maryland presented data on over 40 patients who received ddI and hydroxyurea combination therapy for more than one year with no evidence of viral load rebound. The combination of ddI and hydroxyurea was unable to prevent the emergence of mutations that confer ddI resistance, but the mutants were still sensitive to standard doses of ddI in the presence of hydroxyurea. This continued sensitivity might be due to the deprivation of natural, functional nucleosides induced by hydroxyurea.

A Rectification in DMP 266 Analysis

The Retrovirus Conference also contained a further "preliminary" report on a trial of DMP 266 (abstract LB2), DuPont Merck's new and powerful non-nucleoside reverse inhibitor (NNRTI). This trial was first described at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) last September. Subsequent to that presentation, Treatment Issues uncovered a hidden flaw in the way the DMP 266 plasma viral load data was analyzed: everyone with a viral load below 100 HIV RNA copies/ml (2 logs) was counted as having a viral load of one (0 logs). Since the PCR assay employed in this trial is commonly considered accurate only down to 400 copies/ml, and most trials have counted any measurement below that figure as "undetectable" and assign it a value of 200 -- or 400 or 500 to be more conservative. Because of its nonstandard analysis, DuPont Merck made DMP 266 appear to reduce viral loads up to 100 times greater than other agents -- reductions which in fact exceeded biologic possibility (see the introduction to the protease inhibitor article, page 5). Happily, DuPont Merck has rethought its approach. The Retrovirus Conference account, delivered by Sharon Riddler, M.D., of the University of Pittsburgh, gave the results obtained when assigning a viral load of 200 to values falling below 400. The two-arm trial compared DMP 266 plus indinavir to indinavir alone for 24 weeks. (Treatment Issues has also complained about this protease inhibitor monotherapy, which represents substandard therapy that imperils volunteers by promoting drug-resistant virus -- see Treatment Issues article, DMP266: Keep the Drug but Dump the Trial; May, 1996, page 8. Several trials reported at the Retrovirus Conference contained similar arms, and others are still enrolling. In particular, the AIDS Clinical Trails Group is now commencing a trial of Glaxo Wellcome's 141W94 monotherapy versus, once again, Glaxo's AZT/3TC combination plus 141W94. DuPont Merck is not planning any more trials with monotherapy comparison groups. Neither should anyone else. )

At the end of the trial period, viral loads were down 2.2 logs (99.4%) in the combination arm and only 1.5 logs (96.8%) in the indinavir arm. (The mean baseline viral load was 99,000.) Eighty-two percent of the 21 volunteers on combination therapy and 38% of the nine on indinavir had viral loads below the 400 copy/ml limit. (If DuPont Merck's old method of calculating viral load had been used, the reductions in the two arms would have been 4.l and 2.4 logs, respectively.) CD4 counts, initially averaging 224, were up about 100 cells in both groups.

The results achieved with DMP 266/indinavir rival those achieved with indinavir plus AZT/3TC or any two nucleoside analogs, even with this more conventional analysis. DMP 266 is an impressive drug. There remains the issue of the proper dose of indinavir to use with this NNRTI, which stimulates indinavir's breakdown in the liver. Midway through the trial, the indinavir thrice daily dose was raised from 800 mg to 1,000 mg, which may still be suboptimum. The toxicity implications in raising the indinavir dose under the influence of DMP 266 (particularly concerning kidney stones) have yet to be fully explored, although a similar dose escalation is recommended when indinavir is used with nevirapine. The main side effects noted during the trial were rashes, headaches, diarrhea and abnormal liver function test results.

DMP 266 not only is potent but is taken only once a day. Along with such agents as ABT-378 and Glaxo Wellcome's experimental nucleoside analog 1592U89, it indicates there is still plenty of room for improving the activity, convenience and possibly the durability of current classes of anti-HIV agents.

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Table 1: ALTIS Open Label Trial of d4T/3TC

ALTIS 1 ALTIS 2

initial group size 42 41

group size, 6 months 42 35

asymptomatic 71% 41%

previously on monotherapy 0% 49%

previously on combination therapy 0% 51%

baseline viral load 76,500 91,255

viral load change, week 4 -2.0 log -1.4 log

(-99.0%) (-96.0%)

viral load change, week 24 -1.66 log -0.66 log

(-97.9%) (-78.1%)

baseline CD4 count 258 172

CD4 change, week 4 +85 +46

CD4 change, week 24 +108 +46

Viral load below 3,000 57% 22%

Viral load below 200 21% 5%

Table 2: AZT/3TC vs. d4T/3TC

AZT/3TC d4T/3TC

group size 15 16

median baseline viral load 44,000 56,000

viral load change, 12 weeks -1.4 log -1.6 log

(-96.0%) (-97.5%)

median baseline CD4 count 300 290

CD4 change, week 4 +85 +46

CD4 change, week 24 +115 +115

Table 3 omitted

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