Monthly Archives - July 2007

The End of Nandrolone ?

The End of Nandrolone

Nelson Vergel, Program for Wellness Restoration

http://www.gmhc.org/health/treatment/ti/ti21_1.html

The current terrain for wasting patients in the era of HAART On March 20, 2007, Watson Laboratories stopped the production of nandrolone decanoate (old brand name: Deca Durabolin), a low-cost injectable anabolic steroid used for HIV wasting, citing the lack of raw-material suppliers for the product. Patients found out when they went to their pharmacies for a prescription a week later.

Although there are other makers of generic nandrolone internationally (easily located on the Internet), this offers little help to U.S. patients. Anabolic steroids and testosterone are designated by the Drug Enforcement Administration (DEA) of the U.S. Department of Justice as Class III drugs, which are illegal to import even for personal and medical uses.

Over the past 20 years, anabolic steroids have suffered from a lot of bad publicity and misconceptions due to their use in sports and bodybuilding. However, that did not stop activists in the 1990s from convincing doctors and researchers to look into these medicines to help those with HIV-related wasting syndrome. Since then, more than eight studies have been performed that showed nandrolone and oxandrolone (brand name Oxandrin, an oral anabolic steroid) to be effective and safe for increasing lean body mass (LBM) and strength in men and women with HIV. Many physicians quickly learned how to prescribe them and monitor their use for helping their HIV-positive patients to survive what used to be one of the main causes of AIDS mortality.

While Watson was abandoning nandrolone, another company was making a decision that would also limit options for HIV wasting patients. Savient Pharmaceuticals informed patients in April 2007 that it had stopped its 10-year-old patient assistance program (PAP) that gave free Oxandrin (oxandrolone) to HIV patients with no insurance or third-party payment sources. Oxandrin has been shown to be mildly effective in men, women, and children with HIV wasting. It can be taken by mouth daily, while nandrolone must be injected in the butt once a week. Whereas Oxandrin has been approved for the treatment of unintentional weight loss, nandrolone’s use for HIV wasting was off-label (it was approved for the treatment of anemia in individuals with kidney problems). However, Oxandrin costs $1,300 a month for a 20 mg/day regimen, compared to around $200 a month for 200 mg/week for nandrolone.

Savient’s PAP was set up by BTG Pharmaceuticals (bought out by Savient later on) in 1996 after activists pressured the company to provide the drug for free to those with no access or means. As with nandrolone, only 13 states include Oxandrin in their AIDS Drug Assistance Programs (ADAPs). The termination of Savient’s PAP means many patients will have no way to afford this drug. The company informed patients that Watson would sell generic Oxandrin, thus eliminating the need for its PAP. Unfortunately, the generic price for Oxandrin sold by Watson is no different than that for the brand-name product, which will continue to be sold by Savient. Watson will not provide free Oxandrin via a PAP either. This is the first time in AIDS history that a company has stopped a PAP while still selling the drug.

Cost is not the only consideration. Unlike nandrolone, Oxadrin can increase liver enzymes and could be problematic for people with liver disease, or for people taking medications that heavily affect the liver, such as the HIV medication Reyataz, and drugs for those with hepatitis B and C. “The decisions of these two companies have a huge impact on many of my patients’ health,” says Dr. Richard Loftus, a San Francisco physician with a large HIV practice. “We use nandrolone extensively in patients who have problems gaining weight and who feel fatigued, even with undetectable viral loads. Many of my patients feel better and have experienced no side effects at the doses we use.”

In the 1980s researcher Dr. Donald Kotler found that the loss of lean body mass can dramatically decrease survival in HIV-positive people.1 Even though the incidence of wasting syndrome has declined dramatically since protease inhibitors were introduced 10 years ago, many people still need extra help to hang on to their muscle to sustain health and productivity. A study performed at Tufts University School of Medicine reported that as many as 29% of people with HIV in the era of HAART are still losing weight or lean body mass, despite undetectable viral loads.2

Dr. Nathan Sherlock knows first hand about the importance of nandrolone for his health and that of his partner:

“My partner has had a significant problem with wasting due to AIDS and the only way he has been able to stop the dangerous weight loss is to use anabolic steroids. He is also hepatitis B positive. His doctor first prescribed Oxandrin in 1998. Within a couple of weeks he had chemical induced hepatitis with the symptoms of nausea, vomiting, loss of appetite and jaundice. His liver enzymes were all elevated. He stopped Oxandrin and the symptoms promptly resolved. His doctor then prescribed nandrolone 200mg/week and he regained weight back to his norm with no side effects. When he stops taking it the wasting returns so he has been on nandrolone for close to 9 years now…I have been taking nandrolone for wasting due to AIDS for over 10 years. Every time I have stopped taking nandrolone I experience rapid weight loss that can only be reversed by resuming the use of nandrolone.”

Al Benson, an HIV treatment advocate in Los Angeles concurs. “Nandrolone is truly ‘the Lazarus drug’… it has brought me back from the brink, restored my health and made all the difference in the quality of my life.”

Other HIV Wasting drugsThe Food and Drug Administration (FDA) has approved other drugs for the treatment of HIV wasting or appetite loss. Megace (megestrol acetate), a female sex hormone-based product, tends to produce weight gain by increasing fat rather than lean body mass. Adding fat during AIDS wasting has not been shown to improve survival. Megace has also been associated with side effects such as diabetes, blood clots, impotence, and the development of female sex characteristics.

Serostim, a recombinant human growth hormone, requires daily injections and can cause joint aches, swelling, and diabetes. It can cost as much as $6,000 a month, so most insurance companies do not want to pay for it and many ADAPs can’t. The kickback scandal Serostim’s manufacturer was involved in hasn’t helped matters either. FDA-approved appetite stimulants such as Marinol contain THC, the psychoactive ingredient in marijuana. This can be an issue for many people with HIV who are in recovery. It has also been suggested that Marinol may simply owe its ability to increase appetite and weight to a side effect of the THC high — “the munchies.”

Compounding Pharmacies:a Viable Option at Risk?Many doctors and patients do not know that nandrolone and oxandrolone can also be obtained in smaller quantities legally by prescription and at a lower cost through compounding pharmacies (where drugs are not only dispensed but can be prepared according to a doctor’s specifications). No one knows how much longer this option will remain available. One pharmacy owner reports that the DEA has raided several compounding pharmacies in the past few months, including his own. The Safe Compounding Drug Act of 2007, now under consideration, would place these sites under greater regulation and presumably greater surveillance. In the meantime, compounding pharmacies such as Applied Pharmacy, Kronos, the Compounding Shop, College Pharmacy, and others are still economical sources of nandrolone, oxandrolone, and testosterone gels and injections. However, they do not process insurance claims and are not equipped to supply ADAPs, insurance, Medicaid, or Medicare Part D vendors.

In this era when HIV/AIDS patients are living longer, it is just as critical to fight for safe, effective, and affordable “quality of life” drugs as it to advocate for accessible antiretrovirals. After all we have done as activists to secure antiwasting medications, we must not lose ground now and fall asleep when vital treatments such as nandrolone are dropped without notice and with little regard for patients’ needs.

For more information or to find out how to get involved, please visit.

Kotler DP, Tierney AR, Wang J, Pierson RN Jr., “Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS,” Am J Clin Nutr. 1989 Sep; 50(3):444-7. “The impact of malnutrition on survival in AIDS was evaluated by examining the magnitude of body-cell-mass depletion as a function of time from death. Body cell mass was estimated as total body-potassium content and determined by whole-body counting. There was progressive depletion of body cell mass as patients neared death. The extrapolated and observed values for body cell mass at death were 54% of normal. Body weight had a similar relationship to death, with a projected body weight at death of 66% of ideal. We conclude that death from wasting in AIDS is related to the magnitude of tissue depletion and is independent of the underlying cause of wasting. The degree of wasting seen in this study is similar to historical reports of semistarvation, with or without associated infections. This observation suggests that successful attempts to maintain body mass could prolong survival in patients with AIDS.”

Mangili A, Murman DH, Zampini AM, Wanke CA, “Nutrition and HIV infection: review of weight loss and wasting in the era of highly active antiretroviral therapy from the nutrition for healthy living cohort,” Clin Infect Dis. 2006 Mar 15;42(6):836-42. Epub 2006 Feb 7.

No Lipodystrophy Approval for Serostim (serono)

I was concerned this would happen. The FDA did not think that the benefits in decreasing visceral fat in HIV positive people outweigh the risks of diabetes, joint pains and hyperglycemia. However, I know this drug works very effectively to decrease belly fat. The problem is that the fat returns when you get off the drug. It is expensive and Serono has made horrible mistakes in the past that have probably costed the company any goodwill they needed for this approval.

Is this a done deal? Can the community do anything about it? Stay tuned and I will report some more soon.

Another company going for the same indication (Theratechnologies) should be concerned. Too bad they have done very little to develop community relations in case of any future advocacy needs.


No Lipodystrophy Approval for Serostim

July 20, 2007
By Kenyon Farrow and Tim Horn, Senior Writer & Editor (AIDSmeds.com)

– The Food and Drug Administration (FDA) declined this week to approve EMD Serono’s Serostim for the treatment of HIV-associated adipose redistribution syndrome (HARS)—the accumulation of fat associated with lipodystrophy. Patients with HARS hoping to gain access to the drug, approved since 1996 for the treatment of AIDS-related wasting syndrome, will likely have a difficult time doing so without an official indication from the agency.

“All of us were pretty surprised by this,” says Martin Delaney, founding director of Project Inform in San Francisco. “There had been every indication that this was going to be approved—partly because the data support it and because there’s really nothing else for this particular indication.”

Instead of approval, the company is being permitted to amend Serostim’s labeling—the drug’s package insert—to include safety and efficacy data from two HARS clinical trials.
“The label change is not an approval of Serostim for the treatment of HARS,” a company spokesperson confirms.

According to Richard Klein of the FDA’s Office of Special Health issues and a frequent point person for the agency regarding drug approvals for HIV/AIDS, the potential benefit of Serostim for HARS does not outweigh its potential risk.

The denial of approval ultimately prevents EMD Serono from marketing or advertising the drug for HARS and will likely mean that patients will have a hard time securing access to it. “Because it’s not getting the full indication and doing this goofy label thing instead,” Delaney says, “one of the effects of that is that the company cannot support it with the patient assistance program.”
Like the patient assistance program (PAP) in place for people with AIDS-related wasting syndrome hoping to use the drug, the HARS program would help patients secure access to the drug through private insurance, public payers (e.g., Medicaid or Medicare), or charitable distribution.

Delaney also suspects that the lack of approval will prevent the manufacturer form negotiating with state AIDS drug assistance programs (ADAPs), further limiting affordable access to a high-cost medication (a 12-week course of Serostim for AIDS-related wasting syndrome costs approximately $21,000).

In two clinical trials conducted to date, Serostim—using a 4 mg daily dose for 12 weeks, followed by 4 mg every other day thereafter—achieved and maintained significantly greater reductions in belly fat compared to placebo in patients with HARS. However, patients in these studies receiving Serostim were also more likely to experience increase in their blood glucose levels in the trial, potentially increasing the risk of diabetes and cardiovascular problems.

“My understanding,” Klein says, “is that there was marginal short-term change in fat. That improvement was offset by cardiovascular and diabetic risk shown by laboratory tests in the analysis of the study.”

Delaney questions the FDA’s logic. The agency, he says, is attempting to answer “a long-term question about whether there is an increased risk of diabetes. It is not based on actual findings of either cardiovascular or diabetes in patients. Unless there’s real hard evidence it’s causing harm, the choice ought to be up to the patient as to just what level of theoretical risk they accept in return for some possible benefits.”

With respect to EMD Serono being allowed to include HARS clinical trial data in the package insert, Delaney says that the agency is “talking out of both sides of its mouth. That really is the strangest thing of all. What’s the point? How is a physician supposed to read that and think ‘OK, but I shouldn’t use it for that purpose.’”

EMD Serono says it will continue working with the FDA to further highlight the overall benefit/risk profile of Serostim and to secure a HARS indication for the drug.
Delaney adds that others are also interested in pushing for dialogue with the FDA. “I’ve talked to a couple of the investigators,” he says, referring to independent experts associated with the Serostim HARS studies. “They don’t agree with this decision. They’re going to sit down and strategize. There may even be further meetings on the community’s part with the FDA.”

TITAN and DUET Studies from Tibotec- Commentaries in the Lancet

TITAN & DUET Studies COMMENTARY

No patient left behind-better treatments for resistant HIV infection

The Lancet July 7, 2007

Bernard Hirschel a and Thomas Perneger ba. Division of Infectious Diseases, Geneva University Hospital, Geneva 1211, Switzerlandb. Clinical Epidemiology Service, Geneva University Hospital, Geneva, Switzerland

Darunavir (TMC114) is a protease inhibitor specifically designed for “resistance to resistance”1 and for effectiveness on HIV resistant to earlier protease inhibitors, such as indinavir or lopinavir. At 600 mg combined with ritonavir 100 mg, both twice daily, darunavir proved more efficacious than an investigator-selected protease inhibitor when added to an optimised background regimen in patients with drug-resistant HIV.2 The drug is now licensed in many countries worldwide.

The TITAN randomised study3 in today’s Lancet explored ritonavir-boosted darunavir compared with the combination of lopinavir and ritonavir (Kaletra). All patients also received nucleotide or nucleoside reverse-transcriptase inhibitors chosen after resistance testing. Their previous treatment experience was moderate in length of time (median 5 years) and exposure to drugs; about two-thirds had received protease inhibitors before the trial, but none had been exposed to lopinavir or darunavir. Darunavir performed impressively: at week 48, significantly more patients on darunavir-ritonavir than on lopinavir-ritonavir achieved HIV RNA to below 50 copies per mL (71% vs 60%; intention-to-treat difference 11%, 95% CI 3-19%, p=0·005).

Side-effects were generally mild in both groups, with an excess of rashes in the darunavir group (16% vs 7%) and an excess of diarrhoea in the lopinavir group (15% vs 8%). Most side-effects were low grade, as shown by the proportion that led to discontinuation of treatment (7% in both groups).The comparator treatment in TITAN was not exactly the current gold standard, because the Kaletra to which darunavir was compared is not the Kaletra stocked today in most hospital or community pharmacies. TITAN patients ingested Kaletra capsules, which have since been replaced by tablets. The introduction of the new formulation is acknowledged by the TITAN investigators, who are endeavouring to switch the participants to tablets as soon as circumstances permitted, but at the time of analysis, only 18% in the lopinavir-ritonavir group had switched to the tablets. Compared with capsules, tablets need not be refrigerated, produce similar (though less variable) plasma concentrations of lopinavir, and less nausea and diarrhoea.4 What would have been TITAN’s results if tablets had been used throughout? We can venture a guess: the difference in efficacy may have been the same, but the difference in gastrointestinal side-effects might be absent or smaller.Do the TITAN results presage a large-scale switch from lopinavir to darunavir? Probably not, for two reasons. First, darunavir’s superior efficacy may be difficult to show in drug-naive patients, in whom pre-existing resistance to lopinavir is not the rule. Second, darunavir-ritonavir is more expensive, particularly in the USA, than lopinavir-ritonavir.

In patients similar to those in TITAN, resistance testing (before treatment with lopinavir-ritonavir in the majority with no resistance mutations) would represent a cost-effective alternative to darunavir-ritonavir, with little risk of failure.

Also in today’s Lancet are the DUET-1 and DUET-2 randomised studies,5,6 which examined the efficacy of etravirine in advanced treatment-resistant HIV infection. Etravirine (TMC125) is a non-nucleoside reverse-transcriptase inhibitor (NNRTI), of the same class as nevirapine and efavirenz. Very small doses are effective in vitro,7 even against strains showing resistance to nevirapine and efavirenz, but it has been a challenge to produce a reliably bioavailable formulation. Currently, the 400 mg daily dose is administered in four pills. In a recent study, etravirine rescue was not efficacious after failure of a first-line NNRTI regimen.8 Resistance to the nucleoside reverse-transcriptase inhibitors given with etravirine, and lack of bioavailability of an etravirine formulation that is no longer in use, may have contributed to this failure. By contrast, etravirine lowered the viral load, compared with a standard-of-care control group, in patients with HIV that was resistant to a NNRTI.9 Interest in the combination of darunavir and etravirine arose when a small-scale study to investigate pharmacokinetic interactions (results were reassuring on that point) also showed surprising antiviral activity.10 These results stimulated recruitment for the DUET trials, which were finished in record time.

The typical DUET patients had already received a dozen antiretroviral drugs with selection of extensively resistant HIV, had had one or more AIDS-defining opportunistic diseases, and started the trials with a CD4 count of only 100/μL. They were randomised to darunavir plus etravirine, or to darunavir plus placebo, in addition to background treatment chosen by investigators on the basis of resistance tests. Etravirine’s effect was measured by the proportion of patients reaching a viral load of less than 50 copies per mL after 24 weeks. That proportion was higher, by 17% in DUET-1 (95% CI 9-25%) and 18% in DUET-2 (11-26%), in patients on etravirine than in those in the group on the placebo combination. The difference was particularly striking when genotypic tests predicted that etravirine would be the only active drug (response rates of 44% with etravirine, 7% with placebo, difference 37%). No side-effects, except generally mild rashes, could plausibly be assigned to etravirine.

The two DUET papers leave important questions open. These questions include quality-of-life measurements, and detailed correlations between resistance genotype and treatment success which may help to gauge etravirine’s prospects in individual patients. Instead of answers, which have been presented at a scientific meeting,11 we get two identical trials published as two papers, a type of duplicate publication in our view. We object to space and readers’ time and attention thus being wasted, especially because combined analysis yields additional results.For instance, consider the issue of etravirine’s effect on the occurrence of opportunistic infection and death. DUET-1 and DUET-2 describe the difference between the etravirine and control groups as not statistically significant. However, a pooled analysis of clinical events, with 22 of 599 patients on etravirine (3·7%) and 41 of 604 patients in the control group (6·8%) shows a statistically significant difference (by our calculation, Fisher’s exact test, p=0·02; effect difference 3·1%, 95% CI 0·3-6·8%), and establishes that etravirine reduces by half the risk of clinical progression over 24 weeks (pooled odds ratio 0·52, 95% CI 0·30-0·89).

People care whether they get sick and die, and rather less whether their laboratory results are normal. Therefore it matters whether a new drug improves outcomes of clinical importance, in addition to surrogate measures, such as viral HIV RNA concentrations and CD4 counts. Antiviral therapies prevent clinical events, making it more difficult to show that new treatments reduce morbidity and mortality. A combined analysis of the DUET studies would have allowed the investigators to claim as of today a clinically important benefit for etravirine. It is a shame to see this opportunity delayed.Furthermore, a pooled analysis would have more clearly established that the efficacy of etravirine, in terms of viral load, differs by enfuvirtide status. Results of both studies suggested that etravirine benefited only patients who did not use or reused enfuvirtide. In new users of enfuvirtide, etravirine failed to confer any added benefit. The difference between new users of enfuvirtide and others, was of borderline statistical significance in DUET-1 (test of interaction in the paper: asymptotic p=0·046, exact p=0·055) and not significant in DUET-2 (by our calculation, asymptotic p=0·08, exact p=0·10). Again, a pooled analysis would have established that etravirine is significantly more effective in the absence of new treatment with enfuvirtide (odds ratio of viral load >50 copies per mL, 0·39, 95% CI 0·30-0·51) than in its presence (0·81, 0·51-1·30; test for the difference between these two odds ratios, p=0·008).

Purists may insist that separate studies always need to be reported separately, but that is not true when the only difference between them is the place of recruitment. Otherwise, results of different centres in multicentre studies could not be combined either. Some may fall prey to the erroneous perception that the regulatory requirement for “at least two adequate and well-controlled studies, each convincing on its own, to establish effectiveness”12 require two separate publications. Separate publication offers two spots instead of one for the prestigious position of first author and may allow the sponsor to honour a commitment made when the study started. Journals may play along because they compete for high-profile drug trials. Additionally, when prestigious duplicate studies are quoted together, journals get two citations instead of one, and doubled revenue from reprint sales. None of these reasons are compelling, and The Lancet and similar journals owe it to their readers to stop the practice. The high-ranking journals ought to publish the combined analysis of studies with similar protocols.But let us accentuate the positive. Occasionally one hears that the days of innovation in HIV therapy are over and that there is neither the scientific nor economic incentive for further progress. The TITAN and DUET studies, and those with the CCR5 entry inhibitor maraviroc,13,14 the non-nucleoside reverse-transcriptase inhibitor rilpivirine (TMC278), and the integrase inhibitor raltegravir,15,16 show that such pessimism is not justified. Not only are the new drugs effective, but they are also well tolerated. Raltegravir has hardly any drug interactions, which is welcome news when concomitant opportunistic infections, such as tuberculosis, must be treated at the same time.

The day will come when suppression of viral load to undetectable levels can be attained by all. We look forward to reading about it in The Lancet-three times over if need be.

In 2005-06, BH was a member of the data safety and monitoring committee (DMSB) of another study of etravirine, now completed; he is also a member of the DSMB of an ongoing study with darunavir. He has accepted travel grants and speakers’ honoraria from Tibotec, Merck, Roche, GlaxoSmithKline, and Pfizer, and has participated in advisory boards for Tibotec, Pfizer, and Merck. TP declares that he has no conflict of interest.