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Treatment Briefs

April, 1999

CD4 Nadir and Disease Progression

The advent of highly active antiretroviral therapies (HAART) that radically suppress HIV and consequently cause dramatic rises in CD4 cell count in many patients has not settled the decade-long debate over the best time to start treatment. Logically, treatment should begin at an early disease stage and prevent the damage HIV wreaks on the immune system. But current antiviral treatments must be continued for years, if not a lifetime. That may not be possible given their side effects and the ability of HIV to evolve into drug-resistant forms. For this reason, it might be better to delay treatment until it is necessary to prevent opportunistic illnesses from arising. A new observational study (V. Miller et al., Annals of Internal Medicine, April 6, 1999, pages 570-7) seeks to answer the vital question: Does delaying treatment cause irreparable harm to immune defenses?

The investigators followed a cohort of 7,333 Europeans enrolled since 1994 in a multicenter inquiry into disease progression among persons with CD4 counts of 500 or less. Study participants were divided into two cohorts: those with a current CD4 cell count greater than 200 cells/mm3 and a comparison group with a current CD4 count below 50 cells/mm3. The first group was further stratified according its members lowest CD4 count in the past (their "CD4 nadir") -- above 150, 100-149, 50-99 and below 50.

Patients were followed until an AIDS-defining condition or death occurred (or the CD4 count decreased below 200 cells/mm3 in the first cohort or exceeded 50 cells/mm3 in the second). As expected, disease progression was more frequent in those with lower current CD4 counts. This trend applied to the historic CD4 cell nadir, too. In a multivariate analysis that attempted to exclude confounding factors (such as drug regimen, initial CD4 cell count, age and previous diagnosis of AIDS), those with CD4 cell nadirs of less than 150 had a two- to four-fold greater risk of disease progression. Receiving two or more antiviral drugs sharply decreased the risk of disease progression regardless of the present CD4 count. Those with CD4 counts above 200 who were taking three or more drugs had a risk of progression that was only 20% of the risk for those on zero or one drug.

Study participants in the cohort whose CD4 counts remained below 50 cells/mm3 had a frequency of new OIs or death that was 18 times higher than the group whose CD4 count now exceeds 200 cells/mm3. This increase in disease progression fell by two-thirds for those on HAART.

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It looks like starting treatment when CD4 counts are higher improves outcome, but this observational study had some severe limitations: Of the 5,352 persons entering the study with CD4 counts above 200 cells/mm3, 4,230, or 80%, had CD4 cell nadirs above 150 cells/mm3. Only about 30% of the above-150 stratum took more than one antiviral drug, with 46.5% taking none at all. For those with CD4 counts below 50, only 15% were taking three or more antivirals. Further, viral load measurements were not available for most study participants, so the influence of successful combination therapy is impossible to gauge.

The study largely tracked no or lightly treated patients with high or very low initial CD4 counts. It divided the more heavily treated persons, who had CD4 nadirs ranging from 50 to 150 into three small strata. Under these conditions it is hard to tease out the effect of treatment on preserving or restoring immune defenses against AIDS-related conditions. In addition, the observation period only lasted a median of 16 months, making long-term predictions concerning the eventual extent of immune restoration tenuous at best.


Anabolic Steroids, Exercise and Wasting

People with HIV live longer with highly active antiretroviral therapy, but many remain susceptible to losses in lean body mass. Such wasting leads to increased risk of death. Human growth hormone and high-dose testosterone demonstrably reduce wasting. In contrast, trials of synthetic anabolic steroids, which have the muscle-building capacity of testosterone but with fewer masculinizing effects, have shown a benefit only in men with low testosterone. This failure may have been because the doses used were too low, or perhaps because the trials did not include an exercise program with the treatment regimen. Then again, exercise might adequately increase lean body mass all by itself. Two recently published reports describe trials that help to resolve the issues surrounding exercise and anabolics.

In the first (A. Strawford et al., The Journal of the American Medical Association, April 14 1999, pages 1282-90), University of California Berkeley investigators conducted a double-blind study that compared a combination of progressive resistance training plus the oral anabolic steroid oxandrolone (20 mg/day) to exercise plus placebo. They enrolled 24 men who had lost an average 9% of their usual body weight even though their serum testosterone levels were within the normal range. The median CD4 counts for the oxandrolone and placebo arms were 234 cells/mm3 and 337 cells/mm3, respectively. Thirteen of the 24 volunteers were receiving protease inhibitors.

After eight weeks of weight-bearing exercise and drug therapy, the men receiving oxandrolone averaged an increase in lean body mass of 6.9 kg, compared to 3.8 kg with placebo. This was accompanied by an average 1.6 kg decrease in fat mass for both groups. Nitrogen retention increased to a greater extent with oxandrolone treatment (5.6 g/day versus 3.8 g/day). Likewise, all men gained strength in their upper and lower body muscle groups, with the oxandrolone arm exhibiting a greater increase.

The use of protease inhibitors, which can interfere with fat and sugar metabolism (see Treatment Issues, March 1999), did not affect the results. Although total fat tissue mass went down in both the oxandrolone and the placebo cohorts, total blood cholesterol rose in the oxandrolone group. At the same time, the proportion of cholesterol complexed with the heart-protective high density lipoprotein (HDL) decreased. There was no change in cholesterol among those receiving the placebo. The significant reduction in the HDL to total cholesterol ratio associated with oxandrolone in this trial could increase the risk of heart disease.

The second trial (F. R. Sattler et al., The Journal of Clinical Endocrinology & Metabolism, April 1999, pages 1268-76) was more definitive about the benefit of adding an exercise program to an anabolic steroid, in this case nandrolone. It compared nandrolone alone to nandrolone plus progressive resistance exercise. The nandrolone dose was escalated over the first two weeks and then held at 600 mg injected once a week during weeks 3 to 12. Twenty-six of the 30 male volunteers were receiving protease inhibitors. Participants had to have normal testosterone levels and stable weight, with less than 5% prior weight loss. Average CD4 count at baseline was 222, and 70% of the trial group had viral loads below 400 copies/ml. After 12 weeks, the slight differences in the two trial groups were statistically significant, though substantial gains occurred in total weight (3.2 kg for nandrolone alone and 4.0 kg for nandrolone plus exercise), lean body mass (3.9 kg and 5.2 kg, respectively) and various strength tests. The nandrolone-only arm experienced a significant decrease in total cholesterol, but the researchers did not separately measure the HDL fraction.

It would appear from these trials that anabolic steroids add to the effect of exercise more than the other way around, at least in the comparatively healthy HIV-positive men and short periods involved in the tests. The outcome over longer periods or in sicker populations (and in women) might be different -- although the use of exercise in patients with health problems might well preclude longer and more general exercise programs.


Hypericin -- The Final Episode

Hypericin, a naturally occurring compound derived from St. John's wort, markedly suppresses HIV replication in lab culture. Its mode of action seems to involve the early stages of viral fusion with uninfected cells. That activity is dependent on exposure to light. A new report confirms previous phase I trial results -- hypericin is toxic and has no anti-HIV activity in the body (R. M. Gulick et al., Annals of Internal Medicine, March 16, 1999, pages 510-4).

The authors assessed 30 adults with CD4 counts less than 350 cells/mm3, who began the open-label trial of hypericin treatment. They were divided into four cohorts (intravenous synthetic hypericin, 0.25 or 0.5 mg/kg of body weight twice weekly or 0.25 mg/kg three times weekly, or oral synthetic hypericin, 0.5 mg/kg per day).

Of the 30 patients receiving hypericin, 16 (53%) failed to complete the initial eight weeks because of moderate-to-severe phototoxicity (abnormal skin sensitivity to light), characterized by skin redness, temperature sensitivity and pain. This toxic response increased with increasing drug dose -- all patients receiving 0.5 mg/kg hypericin orally per day were affected. Only two of the 13 persons who lasted through the eight-week study completed another 16 weeks of therapy.

Hypericin failed to reduce HIV p24 antigen levels for the majority of patients, and the median HIV titer in peripheral blood mononuclear cells after eight weeks decreased only 53% from baseline levels. There was marginal or no change in viral load, and no gains in CD4 counts during this period.


Back to the GMHC Treatment Issues April 1999 contents page.




  
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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
 

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