Gay Men's Health Crisis: Treatment Issues, Volume 8 no. 9 - October 1994
Gabriel Torres, M.D.

AZT Monotherapy

The debate regarding early treatment with AZT among asymptomatic HIV positive persons was rekindled by the presentation of the final results of the trial known as ACTG 019.[1] ACTG 019 is the largest and longest study comparing AZT to placebo in HIV-positive, symptomless persons with CD4 counts greater than 500. It enrolled more than 3,200 participants from 32 medical centers in the United States. In August of 1989, analysis of participants with baseline CD4 counts below 500 revealed slower disease progression among those taking zidovudine. Investigators then modified the trial so that those with CD4 cells greater than 500 were randomized to three groups: The 1,637 trial participants either deferred taking AZT until their CD4 count dropped below 500 or immediately began therapy with either 500 or 1,500 mg of AZT. Once CD4 counts dropped under 500, all participants were given open-labeled AZT at a dose of 500 mg per day.

The results of the study indicated that the rates of disease progression (as measured by the occurrence of AIDS-defining events or death) were similar for the three groups over the mean follow-up period of 2.6 years. The time to a drop in CD4 cells below 500 was slightly shorter overall in the deferred therapy group (1 year) than in the AZT groups (1.5 years), but the differences in time to a CD4 count under 500 were not significant for those who started with CD4 counts less than 650. The low intrinsic risk of progression at high CD4 counts, the brief time on blinded treatment and the drop-out rate of approximately 25 percent in this trial may have contributed to the inability of detecting much benefit of early AZT use in persons with CD4 counts exceeding 500.

In reporting on ACTG 019, Paul Volberding, M.D., of the University of California San Francisco concluded that the data do not support initiation of AZT while CD4 counts are above 500. Still, Dr. Volberding continued to recommend AZT for those with CD4 counts under 500. Specific patients with high HIV blood levels and CD4 counts below 500 may also benefit from therapy, although this remains to be demonstrated through clinical trials.

Sequential Monotherapy

Sequential monotherapy implies switching from one drug to another, either after a fixed amount of time or after one drug has failed to yield further benefit. Several published U.S. studies have indicated a benefit from switching to ddI after as little as eight to sixteen weeks on AZT. In Yokohama, several more studies supported this idea.

A study reported by Julio Montaner, M.D., of the Canadian HIV Trials Network compared switching to ddI versus continuing on AZT in a group of 245 patients with baseline CD4 counts between 200 and 500.[2] Those switching to ddI had a higher and more sustained elevation in counts at 48 weeks than those remaining on AZT. The time to the first AIDS-defining illness or death was also significantly longer for those switching to ddI than those continuing on AZT after two years of follow- up. Changing to ddI did not slow the development of AZT resistance or the emergence of the more virulent type of HIV known as SI (syncytia-inducing).

Another comparative study of sequential monotherapy versus combination therapy was described in a poster.[3] In this retrospective study, 162 AZT-treated patients (mean baseline CD4 of 121) were switched to either ddI or combination AZT/ddC and followed for new AIDS-defining infections or death. After a mean follow-up of 32 weeks, there was no difference in rates of new infections, hospitalizations and survival, although there was a trend favoring those switching to ddI.

Douglas Mayers, M.D., of the Walter Reed Army Institute of Research presented data on the virologic response to ddI after AZT monotherapy in a small group of 32 patients with CD4 counts over 400 who had enrolled in an observational study.[4] The objective of the study was to observe the impact on HIV load of switching from prolonged AZT monotherapy to ddI. The average time on AZT in the group was two years, and the mean CD4 at the time of switching was 93. Twenty-six percent of the study group had significant increases in viral burden after switching to ddI, 29 percent had decreases and 45 percent were stable. Neither baseline HIV level nor any of the individual virus characteristics (such as resistance to AZT) were predictive of a study member's response.

Patients' experience when switching to second-line medications has never been stellar. This continuing problem was reflected in the retrospective, observational data presented by Marcus Conant, M.D., of 96 patients (mean CD4 count of 100) he treated with d4T after failure or intolerance on both AZT and ddI.[5] He reported an adverse effect rate of 53 percent. Half of his patients developed peripheral neuropathy, a rate much higher than that reported in d4T's phase I and II trials. In addition, 36 percent of his patients experienced psychiatric disturbances, ranging from insomnia to anxiety and panic reactions. Forty-one percent discontinued d4T, though no deaths were attributed to the drug. A third had rises in CD4 cells and 62 percent had declines in this cell population.

Combination Therapy with Nucleoside Analogs

Various conference papers supported the claim that combination therapy is superior to AZT monotherapy or even sequential monotherapy. According to the reports, combining treatments yields greater increases in CD4 counts and lower HIV levels than monotherapy does.

One of these reports was an analysis from the Multicenter AIDS Cohort Study (MACS), which tracked 853 gay men who started AZT prior to AIDS.[6] The MACS investigators found that the men who at some later point added a second anti-HIV medication to their regimen had a 34 percent lower risk of dying at any given time than those who remained solely on AZT or switched to another monotherapy. The occurrence of AIDS also was 23 percent less per year in the combination group, although this difference was not statistically significant.

Melanie Thompson, M.D., presented a poster that also described the differential impact on survival of AZT monotherapy and sequential or combination antiretroviral therapy.[7] In her cohort of 2,044 Georgia patients, she found combination therapy (mainly AZT plus ddC) to be superior to AZT monotherapy in those with CD4 counts below 500 and to sequential AZT-ddI therapy in those with CD4 counts below 100.

An interesting study from the National Cancer Institute in the U.S. examined HIV plasma levels and the development of mutations in 26 patients receiving long-term combination or alternating AZT-ddI therapy.[8] This study found that AZT is more potent in activated, dividing cells, whereas ddI is more potent against HIV in resting cells. Study participants had a greater initial suppression of virus if the drugs were given together than if the drugs were alternated. Virus levels remained reduced for at least two years, but by then there was little difference between the alternating and combination regimens. AZT-ddI combination therapy also prevented the emergence of a major mutation related to ddI resistance (at codon 74 on the HIV genome), yet did not prevent a similar AZT-related mutation at codon 215. In this study, no correlation was found between changes in CD4 counts and changes in plasma viremia.

A Dutch study examined the safety and efficacy of adding AZT to lamivudine (3TC) monotherapy.[9] In the laboratory, a mutation at codon 184 confers resistance to 3TC but simultaneously reverses resistance to AZT. This led investigators to believe that adding AZT could result in salutary effects.

In the phase I/II 3TC study, which was open-labeled and non-randomized, 30 patients with greater than one year of previous 3TC (either 200 or 600 mg/day) therapy or clinical failure on 3TC started also taking AZT at a dose of 600 mg/day. Baseline CD4 count was 110. CD4 counts increased and were above baseline for at least a year. Plasma HIV RNA viral load had a rapid decrease after adding AZT (over 90 percent) but had a slow and steady rise towards baseline by week 36. Side effects included nausea, fatigue and neutropenia. The authors concluded that adding AZT to 3TC is effective in patients with 3TC-resistant virus. ddI and ddC would not be expected to combine well with 3TC since 3TC-resistant virus has been shown to be cross-resistant to both ddI and ddC.

Lest one conclude that by adjusting nucleoside analog combinations one can easily stay ahead of HIV and its evolving resistance to therapy, another National Cancer Institute report[10] described how combination therapy using AZT plus ddI or ddC can give rise to a set of novel HIV mutations. The evolving set of changes in the virus's reverse transcriptase make it insensitive to all three drugs (the decrease in sensitivity to the drugs was 125-, 16- and 30- fold to AZT, ddI and ddC, respectively). The mutations appear as a successive group of seven changes in the reverse transcriptase amino acid sequence. In one patient, virus levels increased as the mutations developed over 38 months. NNRTIs

One class of compounds that could supplement nucleoside analog combinations is the so-called non-nucleoside reverse transcriptase inhibitors (NNRTIs). Like the nucleoside analogs, NNRTIs block HIV's infection of new cells. An NNRTI fits into the reverse transcriptase's active site so that the enzyme can no longer transcribe the HIV genome into a DNA form insertable into the cell's normal genetic machinery. (Nucleoside analogs are faulty DNA building blocks that cause DNA transcription to terminate prematurely.)

There have been repeated problems with rapid emergence of HIV resistant to NNRTIs, however, and their usefulness seemed limited in the past. But various reports at Yokohama on these compounds' synergism with nucleoside analogs may prompt a second look at NNRTIs, especially at the new members of this class --delavirdine and loviride.

Bill Freimuth, M.D., from the Upjohn Company presented data on the surrogate marker responses in the completed two trials of delavirdine.[11] These trials were either open-labeled or dose-escalating studies of delavirdine in combination with AZT or AZT plus ddI in persons with prior experience on these drugs. Both trials found that adding nevirapine to the combination gave CD4 counts a boost and decreased HIV levels in the blood. One important observation was that the response to delavirdine was improved if the virus was sensitive to AZT. Resistance to delavirdine was observed over time and was associated with baseline AZT resistance and the virulent SI virus type.

Loviride is an NNRTI manufactured by Janssen Pharmaceuticals. A double-blind placebo-controlled study was reported by a German group.[12] HIV-positive patients with CD4 counts more than 400 were randomized to receive either loviride, placebo or R18893 (a compound similar to loviride). After 24 weeks of follow-up, the loviride group had the best CD4 responses with an average increase of approximately twenty percent over baseline. None of the known mutations conferring resistance to loviride were detected. Further trials are planned for this very promising compound.

Conclusion

For early-stage patients with higher CD4 counts, combination therapy may result in greater reductions in viral load, improved clinical outcome and perhaps a delay in the emergence of resistance. The final word on this issue awaits the results of larger trials currently underway. For more advanced patients with very low CD4 counts, combination therapy still has not proven to be better than monotherapy and may be associated with more toxicity.

The NNRTIs seem to have considerable potential, at least in combination with two nucleoside analogs. Resistance apparently does develop rapidly, but the observed lack of resistance to loviride is encouraging.

Protease inhibitors are new agents that will increase the number of possible combinations immensely. How the addition of one or more such compounds affects the activity of combination or sequential drug regimens remains to be answered, perhaps at the next international conference.

1 Volberding P et al. Tenth international conference on AIDS abstract book. Aug 7-12 1994; II(abstract 355B):16.

2 Ruedy N et al. Tenth international conference. II(abstract 358B):16.

3 Barr M and Torres RA. Tenth international conference. I(abstract PB0266):209.

4 Mayers DL et al. Tenth international conference. II(abstract 359B):17.

5 Conant M et al. Tenth international conference. I(abstract 003B):7.

6 Graham NMH et al. Wellcome satellite symposium at the tenth international conference on AIDS. Aug 7 1994; abstract 5.

7 Thompson M et al. Tenth international conference. I(abstract PB0279):212.

8 Mitsuya H et al. Tenth international conference. I(abstract 056B):21.

9 van Leeuwen R et al. Tenth international conference. I(abstract 057B):21.

10 Shirasaka T et al. Tenth international conference. II(abstract 377A):21.

11 Friemuth B et al. Tenth international conference. II(abstract 512B):59.

12 Staszewski S et al. Tenth international conference. II(abstract 513B):59.

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