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April 1997

  1. Oxandrolone for wasting syndrome
  2. Update: Paromomycin ineffective against cryptosporidiosis
  3. Regression of PML in an aggressively treated patient
  4. C.D.C. reports substantial drop in AIDS deaths
  5. Study finds treatment of pain inadequate in AIDS patients
  6. Smoking increases risk of cryptococcosis
  7. Cidofovir for CMV retinitis

Oxandrolone for wasting syndrome

An oral anabolic steroid increases body weight and cell mass in patients with AIDS cachexia

Wasting is exceedingly common in patients with late-stage HIV disease, and it has a marked impact on survival. Significantly, wasting can occur in the absence of weight loss -- if decreases in lean body mass are offset by increases in body fat. The use of anabolic agents for treatment of the malnutrition associated with advanced HIV infection has recently received considerable attention, and several studies have reported modest weight gains in patients treated with human growth hormone (see "Management of Wasting Syndrome in Late-Stage HIV Infection," Vol. 1, No. 5, pages 91-97). Two studies presented at the 4th Conference on Retroviruses and Opportunistic Infections suggest that oxandrolone, an orally bioavailable anabolic steroid that offsets muscle catabolism, is also effective in reversing the effects of AIDS-related wasting. This synthetic steroid is 97% bioavailable and it has 6.7 times the anabolic activity of methyltestosterone.

When given at a dose of 10 mg b.i.d. for 120 days to AIDS patients who had lost 5% or more of their baseline body weight, oxandrolone led to significant and steady increases in body fat, cell mass, and weight (Figure). Subjects regained roughly equivalent amounts of body cell mass and fat. These positive changes were accompanied by a steady decrease in extracellular water, and there were no adverse effects of therapy.

A similar study combined the same dose of oxandrolone with 20 g of L-glutamine per day. Glutamine is the most abundant amino acid in the body, is stored in skeletal muscle, and is released in response to physiological stress. Because glutamine depletion is a causative factor in AIDS-related wasting, researchers hypothesized that the addition of glutamine to a standard oxandrolone regimen might reverse the catabolic process and result in the preferential restoration of lean body mass. That is precisely what happened in this month-long pilot study. All patients gained body weight (mean: 2.9 kg) and body cell mass (mean: 1.2 kg). Although increase in body fat were seen in 12 of the 16 treated patients, the mean increase was statistically insignificant. Treatment was well tolerated, with no adverse events observed.

These findings indicate that oxandrolone, especially when taken in combination with L-glutamine, can reverse some of the deleterious effects of AIDS wasting, particularly the loss of lean body mass -- a key factor in wasting-related mortality. Poles MA, Meller JA, Lin A, Weiss WR, Gocke M, Dieterich DT. Oxandrolone as a treatment for AIDS-related weight loss and wasting. 4th Conference on Retroviruses and Opportunistic Infections, Washington, D.C., January 22-26, 1997. Abstract 695.

Fisher A, Abbaticola M. Effects of oxandrolone and L-glutamine on body weight, body cell mass, and body fat in patients with HIV infection -- preliminary analysis. 4th Conference on Retroviruses and Opportunistic Infections, Washington, D.C., January 22-26, 1997. Abstract 692.

Update: Paromomycin ineffective against cryptosporidiosis

ACTG 192 finds commonly prescribed drug no more effective than placebo

Paromomycin, a nonabsorbable aminoglycoside marketed as Humatin¨, has been the treatment of choice for patients with cryptosporidiosis since 1994, when White et al. showed an apparent benefit to paromomycin therapy in a small, prospective, double-blind trial (see "Cryptosporidiosis in Patients with HIV Disease," Vol. 2, No. 5, pages 107-111). Newly-released data from a larger, randomized, double-blind placebo-controlled trial of paromomycin in patients with cryptosporidiosis infection (ACTG 192) show no significant differences in response to paromomycin compared to placebo, and the authors of this study conclude that there is no clinical benefit to treating cryptosporidiosis with paromomycin in patients with advanced HIV infection. The variable nature of the disease is such that some patients do improve without intervention, however. This study was too small to determine if paromomycin had a modest benefit in a subgroup of treated patients.

This leaves clinicians with two therapeutic options: azithromycin, which has shown some activity against cryptosporidial enteritis (at a dose of 600 mg daily for 14 to 28 days) but has yet to be evaluated in placebo-controlled clinical trials, and nitazoxanide, an experimental agent that is available from its manufacturer, under a compassionate-access program, to physicians who call 1-800-864-6330, ext. 3032. Maximizing the effectiveness of antiretroviral therapy through the use of drug combinations that include a protease inhibitor may also lead to improvement in patients with cryptosporidiosis.

Regression of PML in an aggressively treated patient

Splenectomy and triple-drug therapy induce remission

Spontaneous remissions may occur in patients with HIV-related progressive multifocal leukoencephalopathy, but they have not been reported in the literature. There is, at present, no treatment for PML. As a result, deterioration is rapid and death usually occurs within a few months of diagnosis (see "How to Distinguish HIV Dementia from Progressive Multifocal Leukoencephalopathy," Vol. 1, No. 1, pages 11-15).

Given this grim situation, any progress in treating PML is welcome news. A group of Canadian physicians report that they have seen a marked reduction of the cranial lesion -- and resolution of ataxia and other symptoms -- in a 30-year-old hemophiliac with AIDS and PML following splenectomy and triple-drug antiretroviral therapy. The patient was on d4T monotherapy at the time his PML was diagnosed (by MRI and brain biopsy), and his viral load was 960,000 particles/mL.

Because studies have shown that CD4 counts rise and viral burden drops in HIV-infected subjects when their spleens are removed, a splenectomy was performed. Following surgery the patient was switched to a combination regimen of saquinavir, ZDV, and 3TC. After seven months of follow-up, the patient continues to do well. His viral load has dropped to 6,000 particles/mL and MRI imaging shows a greatly reduced left cerebellar lesion (Figure). His physicians conclude that aggressive antiretroviral therapy, combined with splenectomy, may be beneficial in AIDS patients with PML. However, it is not clear from this report whether splenectomy contributed to the therapeutic benefit that was seen.

Power C, Nath A, Aoki FY, Del Bigio M. Remission of progressive multifocal leukoencephalopathy following splenectomy and antiretroviral therapy in a patient with HIV infection (letter). N Engl J Med 1997; 336: 661-2.

Dr. William G. Powderly, a member of the editorial advisory board of HIV Newsline, comments:

As I indicated in an editorial that I contributed to Vol. 2, No. 3, of HIV Newsline, the striking clinical improvements seen in patients treated with antiretroviral therapies that include a protease inhibitor raise a simple but fundamental question: Are the improvements in immune function seen with protease inhibitor therapy, as measured by CD4 counts and HIV RNA assays, sufficient to offer protection against opportunistic infections in the absence of prophylaxis?

The scientific evidence -- which now includes several elegant and persuasive studies presented earlier this year at the 4th Conference on Retroviruses -- is that the rebound in immune function seen in many patients treated with protease inhibitors does not confer a comparable degree of immunity -- not initially, at any rate. In these subjects, the total population of CD4 cells is dominated by naive cells rather than so-called memory cells, those programmed to remember specific pathogens and mount a defense against them.

However, there is accumulating anecdotal evidence to suggest that there are ancillary benefits to aggressive multidrug therapy (also known as highly active antiretroviral therapy, or HAART). We have previously reported an instance in which the addition of saquinavir to a nucleoside regimen led to complete resolution of candidiasis in a patient with azole-refractory infection (Vol. 2, No. 5, page 112). This case, like the one recently reported by Power et al., lends support to the notion that HAART strengthens the body's capacity to resist OIs.

At the 4th Conference on Retroviruses my colleagues and I presented additional evidence of the ancillary benefits of combination therapy: several cases of intractable cryptosporidiosis that responded to aggressive antiretroviral therapy, Taken together, these reports suggest that, in patients treated with HAART, the real rebound in immune function may not be as great as the increases in CD4 counts would suggest, but it is not inconsequential.

C.D.C. reports substantial drop in AIDS deaths

First decline in annual mortality rate since 1981

For the first time since the Centers for Disease Control began to tally deaths from AIDS-related causes, the death toll has begun to fall. The decline in overall mortality for the first six months of 1996, compared to the first six months of 1995, was 13%. The death rate fell in all regions of the country and in all risk categories except persons exposed to HIV through heterosexual contact.

Race, region, and risk factors all influenced the size of the reductions in mortality: The largest reductions were seen among non-Hispanic whites (21%) and native Americans (32%); the smallest, among non-Hispanic blacks (2%). Mortality declined 15% in the Northeast and 16% in the West, but only 8% in the South. Among men who have sex with men, deaths dropped 18%, versus 6% among injection-drug users.

The only increase in mortality was recorded among those whose chief risk factor is heterosexual contact, where the death rate rose 3%. Significantly, this was the only risk group that experienced a large increase in the incidence of OIs in 1995, a finding predictive of heightened mortality.

These findings confirm a trend that New York City health officials reported earlier this year at the 4th Conference on Retroviruses in Washington, D.C. Although the overall reduction in mortality announced by the C.D.C. is not as great as the 30% decline noted by Hamburg et al., the national figures effectively eliminate concerns that the improvement in survival seen in New York City was due to incomplete reporting or some sort of statistical anomaly.

The Office of AIDS Surveillance of the New York City Department of Health detected this trend first because the city processes death certificate information itself -- instead of forwarding that data to a state agency, as virtually every other large city does.

Many factors are thought to have contributed to the sudden, sharp decline in AIDS deaths across the nation. Chief among these factors are wider and better prophylaxis against the most common AIDS-related OIs, and the advent of the protease inhibitors, introduced in 1995. Other contributory factors include better access to care, better education of infected populations, and greater availability of more potent antiretroviral combinations. These variables would explain why mortality differs by race, region, and risk factor.

Although the AIDS death rate is declining, the overall case load in increasing (Figure), and HIV infection remains the leading cause of death among Americans between the ages of 25 and 44, accounting for 19% of all the deaths in this age group. If this trend holds, it will become increasingly important to monitor HIV infections, rather than AIDS deaths, as a means of tracking the epidemic, devising prevention strategies, and improving clinical management of the disease.

Chiasson M, Berenson L, Li W, Schwartz S, Mojica B, Hamburg M. Declining AIDS mortality in New York City. 4th Conference on Retroviruses and Opportunistic Infections, Washington, D.C., January 22-26, 1997. Abstract.

Study finds treatment of pain inadequate in AIDS patients

Neuropathies particularly undertreated

Elsewhere in this issue Dr. Howard Rosner calls the management of pain in end-stage HIV disease "an underdiagnosed and undertreated aspect of advanced infection" -- and one that presents a particular challenge to the clinician. Consider, for example, the patient with a history of substance abuse who has requested opioids for pain. Such a patient may simply be "drug seeking," or he may indeed have pain -- or he may have pain and be seeking drugs.

To obtain a clearer picture of pain management in patients with HIV infection, Larue et al. recruited 315 seropositive patients from 34 hospitals and clinics in 13 French cities. This study included hospitalized as well as ambulatory patients. Their clinical condition at entry ranged from asymptomatic illness to full-blown AIDS, with the preponderance of subjects in the latter category. Participants were asked to rate their pain on a numerical scale, and they were asked to assess such quality-of-life factors as fatigue, sadness, and depression. The subjects' primary-care physicians provided the researchers with Karnofsky scores for each participant as well as estimates of the patient's levels of pain, anxiety, and depression.

Significantly, more than half of these physicians provided Larue and his colleagues with pain estimates that were lower than the patients' own estimates. Underestimates were more likely for patients with moderate or severe pain than for those with mild pain. Of 69 patients who reported severe pain, only 10 (15%) received opioids, and almost half were not given any form of analgesic at all. The authors calculate that 85% of patients with pain scores greater than zero were undermedicated according to the WHO guidelines reproduced on page TK. Among 33 patients with severe peripheral neuropathy, for instance, only one subject received antidepressants, which have been found to ablate pain in some patients with this condition.

In patients who had an identifiable source of pain, the most frequent sites were oral (33%), muscular (32%), joint/bone (20%), and the central nervous system (19%), and 13% of the study subjects complained of peripheral neuropathy. Patients with an identifiable pain source were more likely to be treated than those whose pain source could not be identified.

Overall, pain prevalence and severity were found to be high -- and yet the data show that in this cohort of HIV-infected individuals pain was "gravely underestimated and undertreated" by primary-care physicians. The authors postulate that these inadequacies may be rooted in the physicians' training, which may not have adequately prepared them to assess pain, analyze its causes, and assign adequate analgesia. They suggest that alternative methods of diagnosing pain, such as multisystem assessment scales, may be helpful in this regard. And, most importantly, they advise clinicians to recognize the validity of any complaint of pain.

Larue F, Fontaine A, Colleau SM. Underestimation and undertreatment of pain in HIV disease: multicenter study. BMJ 1997;314:23-28.

Smoking increases risk of cryptococcosis

Five-fold increase in incidence seen in AIDS patients who smoke

There are many reasons why smoking should be discouraged in HIV-infected patients. To this list clinicians should now add that this destructive habit greatly increases the likelihood that a patient with advanced disease will develop disseminated Cryptococcus neoformans -- which is the most common invasive fungal disease, and the third most common CNS disorder, seen in AIDS patients.

When physicians at the Naval Medical Center in San Diego, CA, conducted a retrospective review of all AIDS patients seen at the facility between 1988 and 1995, they found that smokers were 4.75 times more likely to have developed cryptococcosis than non-smokers -- despite that fact that all of these patients were receiving fluconazole as primary antifungal prophylaxis. For the purposes of this review, smoking status was defined categorically: any patient who had a smoking habit at the time his cryptococcosis was diagnosed was regarded as a smoker. No attempt was made to stratify smokers by pack-years or prior history.

The investigators suggest that inhalation and deposition of the organism -- in association with combustion-related chemicals or particulates -- may account for the increased incidence of cryptococcosis seen in their patients who smoked.

Olson PE, Earhart KC, Rossetti RJ, Newton JA, Wallace MR. Smoking and risk of cryptococcosis in patients with AIDS (letter). JAMA 1997; 277: 629.

Cidofovir for CMV retinitis

Therapeutic alternative for patients who develop resistance to ganciclovir

Two small studies of the recently approved anti-CMV drug cidofovir provide additional evidence of the drug's efficacy. Unlike acyclovir and ganciclovir, cidofovir does not require virally-encoded enzymes for phosphorylation and intracellular activation, and thus it is a treatment option in patients with some ganciclovir-resistant strains of CMV.

Researchers with the Study of Ocular Complications of AIDS (SOCA) recruited 64 patients with evidence of peripheral CMV retinal lesions. The patients were randomized in two waves to different treatment arms: in stage one, 29 patients were divided between deferred treatment or low-dose cidofovir; in the second stage, 35 patients were assigned to deferred treatment, low-dose, or high-dose cidofovir. Patients who experienced progression were offered treatment with whatever drug the clinician deemed appropriate. Dosages were as follows:

Examination of fundal photographs showed median time to progression of peripheral lesions to be three times longer in patients who received low-dose cidofovir when compared to untreated patients (64 vs. 21 days). By the end of the observation period, fewer than 50% of patients on high-dose cidofovir had evidence of progression, so no data were reported. In addition, patients on treatment were half as likely to have viruria as patients in the deferred arm, although blood cultures showed no significant difference.

Similarly encouraging results were obtained by Lalezari et al. in a study of 48 patients randomized to deferred treatment or the regimen that was considered "high-dose" in the previous study. Among those patients on deferred treatment (n=23), median time to progression was 22 days, while those receiving cidofovir (n=25) remained progression-free for a median of 120 days. As in the previous study, patients on the deferred arm were treated if they progressed. A small but statistically insignificant difference was seen in median survival: 13.5 months for immediate treatment versus 10.5 months for deferred treatment.

Nephrotoxicity is the most common dose-limiting problem associated with cidofovir therapy. To minimize these effects, patients on both studies were given intravenous saline and concomitant probenecid, which competes with cidofovir for uptake by proximal tubule cells in the kidney. Despite these safeguards, significant numbers of patients in both studies experienced nephrotoxicity. Ten patients in the SOCA study developed serum creatinine >133 mmol/L (1.5 mg/dL) compared to zero patients in the deferred arm. In the second study, 12% of cidofovir recipients developed proteinuria, 5% had increased creatinine, and 15% developed neutropenia. These adverse reactions were usually reversible if treatment was halted.

Cidofovir appears to be a therapeutic option for patients with CMV retinitis who do not have compromised kidney function. It offers convenient IV dosing (weekly induction followed by biweekly maintenance) and does not require an indwelling catheter. However, nephrotoxicity is a serious concern and a treatment-limiting adverse event for some patients.

SOCA Research Group in Collaboration with the AIDS Clinical Trials Group. Parenteral cidofovir for cytomegalovirus retinitis in patients with AIDS: the HPMPC peripheral cytomegalovirus retinitis trial. Ann Intern Med 1997;126:264-74.

Lalezari JP, Stagg RJ, Kuppermann BD, Holland GN, Kramer F, Ives DV, et al. Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. Ann Intern Med 1997;126:257-63.

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