New Booklet for Salvage Patients by Dr Paul Bellman- NYC

Paul Bellman is one of the most concerned doctors in the US on the subject of how to rescue HIV patients who have ran out of options. Here is a manuscript he wrote for patients and medical students on the subject that I highly recommend for all to read:

http://salvagetherapies.org/articals/salvageTreatment_ManualDrBellmanAug07.pdf

Are we losing mental capacity in HIV?

This study really worries me. Median CD4 cells were in the 400, and half were naive. So these are not sick patients. I wish they had defined what mild cognitive impairment is. I forget faces, names, things to do, sometimes important personal data, etc. At 48 years old, I have the feeling that this is not normal. Studies like this one just feed that concern....
They say that may be most of the HIV meds we are taking may not be penetrating the central nervous system as well as they should, and thus we may be losing mental capacity with time.
I wonder if anyone is doing studies with the use of Alzheimer drugs for HIV related cognitive impairment....

Link:The prevalence and incidence of neurocognitive impairment in the HAART era (08/30/07)

The study conclusions:

"....By the most conservative estimate, an assessment of neurocognitive function revealed that 26% of subjects selected from the ALLRT study were cognitively impaired at their baseline Neuroscreen....226 (58%) had a follow-up visit at which their test scores indicated they were neurologically unimpaired. This may be related to the favorable effects of HAART on neurological function
There was a relationship between immunological status and prevalent neurocognitive impairment, but we did not find substantial evidence to suggest that virological factors were associated with prevalent neurocognitive impairment....

the observed decline in neurocognitive functioning despite ART is consistent with the hypothesis that viral replication in the CNS may not be well controlled in some patients treated with HAART, perhaps because antiretroviral drugs may not penetrate adequately into the CNS..."

Be Aware of TMC 125 (Etravirine, Tibotec new non nucleoside) limitations

If you are thinking about obtaining TMC 125 (Etravirine, a new non nucleoside yet to be approved) via Tibotec's expanded access program (EAP) and you have developed resistance to non nucleosides in the past (Sustiva, Viramune, Rescriptor), be aware that it is very difficult to know if TMC 125 will work for your virus since the mutations that predict its efficacy may not be present in your genotype. Non nucleoside old mutations are "archived" and may not show up in your current genotype or phenotype tests. In fact, many people with past non nucleoside resistance show complete sensitivity to non-nucleosides years after developing resistance and not using that drug class. Doctors sometimes try to search old charts to see if they can pull out old genotype test results from a time when the patient was on non-nucleosides and failing. In many instances, that information is not found. We are also learning that TMC 125 specific mutations were not included in genotype tests years ago, so looking for old patient charts may be a moot subject.

We know from studies so far that TMC 125 is not effective in people with previously accumulated and extensive NNRTI resistance, but it can still work in those with more limited mutations.

My suggestion is that if you are going to start TMC 125, make sure that you are not gambling about assuming drug sensitivity, so NEVER start it with only one fully active agent but TWO. This will ensure that you have enough of an active background for viral suppression and sustained response in case that you may not have sensitivity to TMC 125.

Possible combinations :

No resistance to Prezista but resistance to Fuzeon: Darunavir (Prezista) + TMC 125 + Raltegravir (Merck integrase available via expanded access as of Aug 2007) + nukes (approved agents + two EAPs)

If you have resistance to Prezista and Fuzeon and have an R5 tropic virus: Maraviroc+ TMC 125+ Raltegravir + nukes (approved agents + two EAPs)

If you do not have resistance to Fuzeon or Prezista: Fuzeon + TMC 125 + Prezista + nukes ( all approved agents + one EAP)

If you have resistance to Prezista but not Fuzeon: Fuzeon + TMC 125 + raltegravir (approved agents plus two EAPs)

If you do not have a R5 only tropic virus and have resistance to Fuzeon and Prezista: TMC 125 + raltegravir + ???...you may want to wait

If you have resistance to Prezista, Fuzeon, and have a R5 tropic virus: TMC 125 + Maraviroc +raltegravir

A lot of these combinations have not been fully researched. So far, we have some knowledge of interaction data between these agents and the only contraindication that I have seen is TMC 125 + Tipranavir (Aptivus)

Message: a new agent may not be an active agent, so be cautious and combine agents in such a way that you do not take too many chances. Make sure that you have a doctor who knows the data on these agents, potential interactions, and how to deal with lacking resistance information.

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.

Call for Improving System of Patient Access to Investigational Drugs

I was part of this meeting and was very happy with the outcome. I hope the FDA and pharma listen to us. Representatives from the FDA, industry (Merck, Pfizer, Tibotec, Panacos and BI) , physician groups, Kaiser Permanente, researchers, and others were part of the discussion.


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HIV Research Group Calls for Improving System of Patient Access to Investigational Drugs


With the first agents from 2 new classes of antiretroviral drugs poised to receive regulatory approval this year, the Forum for Collaborative HIV Research, an independent advocacy group, has called for reassessment of the way investigational new drugs are made available to patients in need.

Below is the text of the group's June 14 press release:

HIV Research Group Calls for Improving System of Patient Access to Cutting-Edge Investigational HIV Drugs

With New Treatments in the Pipeline, Scientists, Industry, Patient Groups Say Change is Needed if All are to Benefit

WASHINGTON, DC (June 14, 2007) -- With at least three promising new HIV drugs in development, radical reform is needed of "expanded access programs" that allow patients to take new drugs before final federal approval.

Such programs can be critically important to HIV patients who no longer respond to current treatments. However, the system for providing access to experimental drugs is fragmented and under-funded, and discourages academic health centers and private physicians from participating, according to a report released today by the Forum for Collaborative HIV Research, an independent public-private partnership comprised of academic researchers, patient advocates, government officials and industry representatives.

The report reviews these problems and recommends guidelines for fixing the system, including a recommendation that drug companies consider reimbursing health care providers for Expanded Access Program (EAP) costs.

"The goal of expanded access programs is to make promising drugs in the late stages of clinical trials available to patients who urgently need treatment and have exhausted all currently approved therapies," said Ben Cheng, Deputy Director of the Forum. "Unfortunately, the current mechanism for early access to these promising drugs serves neither patients, companies, nor regulators."

The United States lacks data regarding the extent to which patients have run out of treatment options, but one estimate in the report suggests that as many as 13 percent of HIV patients have run out of treatment options. EAPs have provided critical medical options for such patients since the early years of HIV treatment, when HIV activists first pressed the Food and Drug Administration [FDA] for such options. But today EAPs are riddled with problems, according to the report, "Rethinking the Approach to Expanded Access Programs."

Among the main problems, EAPs are:

• Expensive to administer, limiting the ability of many healthcare sites to participate, as they must cover such costs themselves. The costs of administration are currently not reimbursed by drug companies, though they are when drugs are provided to patients in clinical trials.• Poorly advertised;• Usually dependent on only one novel drug in treating patients. Though policies may recommend using at least two active therapies, many patients are resistant to the other drugs that are available. This can lead to virtual monotherapy, and to the risk of developing resistance to the new treatment.• Relatively inaccessible to minorities, women and rural residents;

• Failing to take advantage on a valuable opportunity to gather useful safety data on emerging drugs.

The associated expenses and administrative obstacles can be particularly onerous at academic medical centers, where financial and bureaucratic hurdles are greater than in private practices or community-based clinics.

As a result, many academic centers have opted out of participation in EAPs. But treatment opportunities offered by the emergence of simultaneous EAPs for three new drugs (raltegravir [Isentress, formerly MK-0518], etravirine [TMC125], and maraviroc [Celsentri]) are leading some of these institutions to reconsider their decisions so they can offer the new drugs to patients who need them.

But, according to the report, administrators warn that the programs will remain in jeopardy until reliable sources of funding are found to cover high expenses related to data collection requirements and approval processes from internal review boards.

The report is being released at a pivotal moment in the history of HIV drug development, according to its authors. There are a number of drugs in the development pipeline that offer novel approaches to treating HIV. Among these are: a new protease inhibitor, new entry inhibitor drugs that block the CCR5 receptor on immune cells, and new integrase inhibitors.
"Patients groups are particularly excited that so many new options are becoming available," said Veronica Miller, Director of the Forum. "But it is clear that changes must be implemented to make sure that we can expand access to these new therapies as they are proven basically safe and effective."

The report's recommendations are based on the outcome of a recent Forum workshop, which brought together representatives of academic health centers, advocacy groups, pharmaceutical companies, and the Food and Drug Administration. It is particularly timely, given that the United States Food and Drug Administration is in the midst of revising its rules for the regulation of EAPs for other diseases.

Report Recommendations

The HIV Forum report identifies several key directions for improving the EAP system, suggesting that:

• Policymakers explore a two-tiered approach to EAPs. One would be an actual research protocol designed to answer specific questions leading to drug approval. The other would be a simplified system, with fewer data requirements. Both would be would eligible for reimbursement from drug companies, as are traditional clinical trials;

• Pharmaceutical companies work together and with regulatory agencies to design EAPs that simultaneously use several different new drugs in order to limit the use of "virtual monotherapy" and lessen the chance of developing drug-resistant strains of HIV;

• Changes be implemented to decrease the burden of paperwork, among them, standardization of EAP data collection requirements and safety reporting;• Pharmaceutical companies collaborate to standardize their case report forms and adverse events reporting for their EAPs;

• Develop a centralized electronic database, and other technological tools, to provide real-time access to analyse results, including adverse events for the EAP.

"Every time there is an adverse event, physicians have to report it," Cheng said. "But there is no way to find out whether this is happening in five or 50 percent of patients. None of the information is being analyzed until the program is finished."

Since EAPs were first initiated for HIV drugs in the 1980s, they have saved or prolonged the lives of thousands of HIV patients. Since 1998, however, the use of EAPs for HIV drugs has decreased, and that the size of the patient population that currently needs access to investigational antiretroviral drugs is difficult to estimate. Refining this estimate will be an important aspect of reforming EAPs, according to the study.

The Forum for Collaborative HIV Research is an independent public-private partnership whose mission is to facilitate discussion on emerging issues in HIV clinical research and the transfer of research results into care. It is comprised of international experts from government agencies, pharmaceutical companies, academia, advocacy and community organizations, and private foundations. The Forum is housed in the Department of Prevention and Community Health at The George Washington University School of Public Health and Health Services. For further information, visit: http://www.hivforum.org/ and click on "Rethinking the Approach to Expanded Access Programs"

06/29/07

SourceForum for Collaborative HIV Research. HIV Research Group Calls for Improving System of Patient Access to Cutting-Edge Investigational HIV Drugs. Press release. June 14, 2007.

Anal Cancer- Can it be prevented? Lecture in Houston this Thurs June 21

Rates of anal cancer among gay and bisexual men are 35 times greater than the general population

HIV+ men and women are 80 times more likely to have anal cancer.

THE GOOD NEWS IS THAT ANAL CANCER IS POTENTIALLY PREVENTABLE AND HIGHLY CURABLE.


Come to hear Houston's Dr. Eric Haas speak about ways to detect and treat it early.
Location: United Way at 50 Waugh Drive, Houston
Map: Map of 50 Waugh Dr Houston, TX by MapQuest

When: This Thursday, June 21, 6:30 p.m. Light dinner provided. Limited seating. RSVP to 713-520-5288

This is the first seminar of its kind on this topic in Houston which is not talked about in the community

Sponsored by: Program for Wellness Restoration(www.powerusa.org ) and the Houston Buyers Club (http://www.houstonbuyersclub.com) )


ABOUT THE SPEAKER:


Dr. Eric Haas earned his medical degree from the University of Texas Medical School at Houston, did his General Surgery Internship at the M.D. Anderson Cancer Center and completed his General Surgery Residency at St Joseph Hospital. He is board certified by both the American Board of Surgery and by the American Board of Colon and Rectal Surgery. He is the Director of Aparoscopic Colon and Rectal Surgery and has received the 2005 Chief Resident Award for most outstanding Academic Faculty for the Methodist/St. Joseph Hospital General Surgery Residency Program. In addition, Dr. Haas serves as faculty surgeon at The Methodist Hospital, St Luke's Hospital , and Memorial Hermann Hospital. More info on (http://www.houstoncolon.com)

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More on the subject:

Bay Area doctors promote Pap tests for gay men to combat cancer

(04-21) 13:18 PDT San Francisco (AP) --
Some Bay Area doctors are promoting Pap tests for gay men to reduce rising rates of anal cancer.
U.S. cases of anal cancer have risen 37 percent in the last 10 years, compared to a 1 percent increase in overall cancer cases. Part of the increase is believed to be because of better reporting.
Anal Pap smears would help doctors detect precancerous lesions before they turn malignant, said Dr. Joel Palefsky, director of the Anal Neoplasia Clinic at the University of California, San Francisco.
"We haven't proven it yet, but we believe that we are likely to be preventing anal cancer," said Palefsky, who is preparing a report on anal cancer prevention.
Other doctors say there is disagreement over whether the tests are necessary or effective. The test should be left to the doctor's and patient's discretion, said Dr. Michael Horberg, director of HIV-AIDS for Kaiser Permanente and an HIV specialist at Kaiser Santa Clara Medical Center.
The American Cancer Society said there were about 4,660 cases of anal cancer in the United States last year, resulting in 660 deaths. Anal cancer accounts for less than 1 percent of cancer cases and is readily treatable if detected.
Overall, more women than man get anal cancer. But the disease is disproportionately high among gay men and people who are HIV-positive or have other immune-suppressive conditions.
Studies have found rates of anal cancer as high as 35 cases for every 100,000 gay men, similar to rates for cervical cancer before women began routinely getting Pap tests 60 years ago. Cervical cancer rates have dropped 70 percent since then. Both cancers are caused by the same sexually transmitted virus.
"Anal cancer is a silent issue that's been building for at least 10 years," said Jason Riggs, a spokesman for the Stop AIDS Project. "And it's sad because it's incredibly preventable."
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Information from: San Francisco Chronicle,
www.sfgate.com/chronicle

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Cancer Rates in HIV Positive People in the HAART Era

By Liz Highleyman
Past research has yielded conflicting data on rates of cancer in HIV positive individuals since the advent of HAART. While effective therapy has reduced in incidence of some opportunistic malignancies, other types of cancer may be more common now that people with HIV are living longer.
Review of Cancer in People with HIVIn the May 2007 issue of Oncology Reports, G. Barbaro and G. Barbarini of University La Sapienza in Rome presented a review of cancer studies in the HAART era.The authors noted that the majority of cancers affecting HIV positive individuals are AIDS-defining malignancies including Kaposi's sarcoma (KS), non-Hodgkin's lymphoma (NHL), and invasive cervical cancer (ICC). However, they added, other types of cancer -- such as Hodgkin's disease, anal cancer, lung cancer, and testicular tumors -- appear to be more common among HIV positive people compared with the general population. While not classified as AIDS-defining, these cancers have been referred to as AIDS-associated malignancies. Some experts believe invasive anal cancer, like ICC, should be considered AIDS-defining.The mechanisms by which immune suppression could increase the risk for cancer are unclear, the authors wrote, except for KS and most subtypes of NHL, which are strictly associated with low CD4 counts. Although it remains unclear whether HIV acts directly as an oncogenic (cancer-causing) agent, the virus may contribute to the development of malignancies through several mechanisms, including impaired immune surveillance and/or an imbalance between cell proliferation and differentiation. While a significant decrease in the incidence of KS has been observed with the widespread use of combination antiretroviral therapy, they continued, HAART has not had a significant impact on the incidence of NHL (particularly systemic NHL), Hodgkin's disease, ICC, anal cancer, or other non-AIDS-defining malignancies. Barbaro and Barbarini concluded that regardless of whether these cancers are directly related to HIV-induced immunodeficiency, "treating cancer in HIV-infected patients remains a challenge because of drug interactions, compounded side effects, and the potential effect of chemotherapy on CD4 count and HIV-1 viral load.""A better knowledge of viral mechanisms of immune evasion and manipulation will provide the basis for a better management and treatment of the malignancies associated with chronic viral infections," they added.Cancer Rates in CaliforniaCalifornia researchers presented results from a study of cancer rates among HIV positive people in the May 15th American Journal of Epidemiology. The investigators analyzed data from adults in the San Francisco AIDS surveillance registry and patients in the California Cancer Registry matched for age, sex, and race. Adjusted standardized incidence ratios (SIRs) were computed, and proportional hazards models evaluated the effect of HAART use on cancer incidence and survival time. Results
• Among 14,210 adults with AIDS diagnosed in 1990-2000, 482 non-AIDS-defining cancers were diagnosed. • Overall, the risk of developing non-AIDS-related cancers was somewhat higher among all HIV positive individuals during the HAART era (a 43% increased risk), but slightly lower for those who actually used HAART (21% reduced risk).• Compared with rates for the general population, significantly higher incidence rates were observed for:- anal cancer (SIR 13.4);- Hodgkin's lymphoma (SIR 11.5);- liver cancer (SIR 3.6);- cancers of the mouth and throat (SIR 2.6);- respiratory tract cancers (SIR 2.6);- leukemia (SIR 2.4);- melanoma of the skin (SIR 2.4);- prostate cancer (SIR 1.7). • The risk of liver cancer was lower with HAART use (relative hazard [RH] 0.32). • The risk of anal cancer increased after 1995 (RH 2.9). • Respiratory tract cancers (RH 0.40) and Hodgkin's lymphoma (RH 0.17) showed increased cancer survival times with HAART use.• Survival with anal cancer may have decreased slightly (RH 1.4).
ConclusionIn conclusion, the authors wrote, "The impact of HAART on non-AIDS-defining cancer incidence rates and survival is not uniform, and the mechanism(s) responsible for these differences should be investigated further.""We found that HAART use does not appear to substantially reduce the risk of non-AIDS cancers, and the impact of HAART on specific non-AIDS-defining cancer incidence rates and survival time is not uniform," lead author Nancy Hessol told Reuters Health. "The underlying etiology for each cancer type contributes to this observed variation, along with changes in HIV and cancer treatments."
Hessol recommended better cancer screening and prevention for people with HIV. For example, she said, "given the high rate of anal cancers in HIV-infected men who have sex with men, anal Pap testing should be encouraged for early detection and treatment of pre-cancerous and cancerous lesions."
Department of Medicine, University of California, San Francisco, CA; AIDS Office, San Francisco Department of Public Health, San Francisco, CA; California Cancer Registry, Public Health Institute, Sacramento, CA; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA.
06/19/07
ReferencesG Barbaro and G Barbini. HIV infection and cancer in the era of highly active antiretroviral therapy (Review). Oncology Reports 17(5): 1121-1126. May 2007.NA Hessol, S Pipkin, S Schwarcz, and others. The Impact of Highly Active Antiretroviral Therapy on Non-AIDS-Defining Cancers among Adults with AIDS. American Journal of Epidemiology 165(10): 1143-1153. May 15, 2007.

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NATAP http://natap.org/
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Anal pre-cancer test for HIV-positive men

LOS ANGELES, March 22 (UPI) -- A type of anal-canal Pap smear has been found to detect precancerous changes in the anal canals of HIV-positive men, a U.S. study found.The University of California at Los Angeles study found abnormal anal cytology -- anal-canal Pap smear -- was highly predictive of anal cell abnormalities that were subsequently confirmed by anal biopsy.The study, published in the International Journal of STD & AIDS, was based on data from 244 patients at the UCLA CARE clinic who had anal cytology screenings between February 2002 and December 2004.HIV-positive men who have sex with men are up to 90 times more likely than the general population to develop anal cancer, according to UCLA CARE clinic.The UCLA CARE Center is one of a few U.S. clinics offering anal dysplasia screening, a procedure that has not yet entered standard practice.“The prevalence, and predictive value, of abnormal anal cytology to diagnose anal dysplasia in a population of HIV-positive men who have sex with men”R D Cranston*, S D Hart- J A Gornbein , S L Hirschowitz-, G Cortina- and A A Moe§*Department of General Internal Medicine; -Department of Pathology; Department of Biomathematics;§ Department of Infectious Disease,University of California, Los Angeles, CA, USATo date, most of the information available on anal dysplasia is derived from a limited number of natural history studies. This current study reflects clinical practice in a HIV primary care setting and aims to (1) estimate the prevalence of anal cytologic abnormalities, (2) estimate the positive predictive value of anal cytology for any degree of dysplasia and for high-grade dysplasia.“…….screening for anal cytological abnormality, defining the abnormality pathologically by anal biopsy, and subsequently treating potentially premalignant lesion(s) has been proposed as a management strategy for the anal canal to prevent the progression of high-grade dysplasia to anal cancer….… detection of abnormal anal cytology is useful clinically in HIV-positive MSM to predict the presence of anal dysplasia. In this study, 96% of the samples were adequate for cytological interpretation. The majority of abnormal cytology samples showed lower grades of dysplasia while more than half of these abnormal cytology specimens had high-grade dysplasia on biopsy. Thus, any abnormality on anal cytology testing should prompt HRA follow-up to determine grade of dysplasia and allow consideration of treatment for high-grade disease.….anal cytology underestimated the degree of anal dysplasia… While only 6% of the cytology results indicated high-grade lesions or possible high0grade lesions, the researchers found, 52% of biopsy specimens were either grades 2 or 3 anal intraepithelial neoplasia...…Despite the poor correlation of anal cytology with biopsy, empirically abnormal anal cytology identified subjects that were then referred for HRA and biopsy with over half of these subjects subsequently diagnosed with high-grade disease and referred for treatment….….Anal cytology grade showed poor correlation with the grade of dysplasia detected by paired HRA-directed anal biopsy. Ninety-two percent of the abnormal anal cytology was ASC-US or LSIL, however anal pathology reports showed high-grade dysplasia (anal intraepithelial neoplasia] [AIN] 2 or 3) in 52% of specimens, indicating that anal cytology underestimated the degree of anal dysplasia….Previous modalities used to treat high-grade dysplasia have included cold scalpel excision with electrofulguration that showed lower rates of treatment efficacy in an HIV-positive population.25 More recently, the use of infrared coagulation (IRC) to treat high-grade dysplasia has been associated with higher efficacy rates with reduced post procedure pain…”Summary: Due to the increasing incidence of anal cancer in HIV-positive men who have sex with men, and the potential to detect and treat high-grade anal dysplasia - the putative anal cancer precursor - we have introduced an anal cytology screening service. Patients with abnormal anal cytology have follow-up high-resolution anoscopy (HRA) with biopsy of lesions clinically suspicious for high-grade dysplasia. In total, 244 men were screened and 235 (96%) of the samples were adequate for cytological interpretation using the Bethesda 2001 system. One hundred and sixty-four (67%) men had abnormal anal cytology, and 93 of them had follow-up HRA and anal biopsy. The positive predictive value for any anal cytological abnormality to predict any degree of anal dysplasia was 95.772.1%, and for any anal cytological abnormality to predict high-grade anal dysplasia was 55.975.1%. Abnormal anal cytology was highly predicative of anal dysplasia on biopsy.INTRODUCTIONAnal cancer is a rare malignancy accounting for only 1.5% of all gastrointestinal tumours.1 However, in certain groups, the incidence of anal cancer is increased in comparison to the general population. Prior to the HIV pandemic, the incidence of anal cancer in men who have sex with men (MSM) who practice receptive analintercourse (RAI) was approximately 35 per 100,000,2 equivalent to the incidence rate of cervical cancer prior to the introduction of cervical cytology screening in developed countries. Currently, the incidence of anal cancer in HIV-positive MSM is estimated to be between 70 and 80 per 100,000 based on studies in both Europe and the USA.3,4The anal and cervical canal share a common embryological origin, are classified cytologically using the same 2001 Bethesda system, and both develop dysplasia in association with anogenital human papillomavirus (HPV) infection.5 HPV can be grouped phenotypically into high-risk and low-risk HPV related to its association with cervical cancer.6 High-risk HPV, most commonly HPV 16 or 18, is present in almost 100% of anal and cervical cancers,7,8 and is now considered essential for the development of cervical cancer in association with co-factors such as cigarette smoking.9The presence of either HPV or anal dysplasia, unlike other HIV-related infections or tumours, does not appear to be significantly influenced by the introduction of highly active antiretroviral therapy (HAART).10,11 Moreover, reports from San Diego and San Francisco Counties have shown that the incidence of anal cancer in these regions has increased from the pre- to the post-HAART era.12,13 While it is unlikely that HAART therapy per se increases the risk of anal dysplasia and anal cancer, this finding may be explained by the fact that individuals with HIV infection taking HAART are living longer and allowing the anal canal to have prolonged exposure to oncogenic HPV in the context of relative immunosuppression.14 In addition, there is in vitro evidence that HIV tat protein interacts with the HPV genome to increase oncoproteinexpression that leads to chromosomal dysregulation and the potential of malignant cellulartransformation.15,16Using the cervical paradigm, screening for anal cytological abnormality, defining the abnormality pathologically by anal biopsy, and subsequently treating potentially premalignant lesion(s) has been proposed as a management strategy for the anal canal to prevent the progression of high-grade dysplasia to anal cancer. Anal cytology screening has similar sensitivity to cervical cytology screening in HIV-positive MSM to detect the presence of dysplastic cells.17,18 Liquid-based cytology collection methods are increasingly being used for the cervix, and have the advantage that remnant liquid fixative may be tested for HPV, as occurs in the triage of cervical samples that show atypical squamous cells of undetermined significance (ASC-US). The liquid cytology method may additionally abrogate potential problems associated with hypocelluarity, air drying artefact and faecal contamination in anal samples.17,19 While no national or international guidelines exist for anal cytology screening, investigators from the largest natural history study at the University of California, San Francisco, have suggested the following screening algorithm in MSM:-- Normal anal cytology is repeated in one year in an HIV-positive population and in two to three years in an HIV-negative population. -- All abnormal anal cytology is referred for high-resolution anoscopy (HRA). At HRA a biopsy is taken of any lesion(s) suspicious for dysplasia based on standard colposcopic criteria.20 If no dysplasia is identified, the individual has routine anal cytology screening as above. Using this system, the aim of anal cytology testing is to detect either normal or abnormal results, as previous studies have shown that anal cytology grade is poorly predictive of anal dysplasia grade following HRA and biopsy, and should not be relied upon without histological confirmation.21 -- Low-grade dysplasia on biopsy is followed up at six-monthly intervals with HRA due to the high rate of progression from low-grade to high-grade dysplasia.22 -- High-grade dysplasia on biopsy is treated, or followed-up depending on the size of the lesion.To date, most of the information available on anal dysplasia is derived from a limited number of natural history studies. This current study reflects clinical practice in a HIV primary care setting and aims to (1) estimate the prevalence of anal cytologic abnormalities, (2) estimate the positive predictive value of anal cytology for any degree of dysplasia and for high-grade dysplasia.METHODSSubjectsAll subjects in this clinical study were MSM who attend the University of California Los Angeles (UCLA) Center for AIDS Research and Education (CARE) clinic. Anal cytology specimens were collected sequentially at the discretion of the treating clinician.Anal cytology collectionPrimary care physicians received anal cytology collection training. The cytology specimens were taken using a water-moistened Dacront swab and ThinPrept collection method with the patient in the left lateral position. The Dacront swab was introduced two inches beyond the anal margin, and removed with lateral pressure and a spiral motion over 10 seconds. After removal, the swab was immediately immersed and agitated in ThinPrept solution to disgorge the cells. Anal cytology samples were read by a UCLA cytopathologist and reported as ASC-US, atypical squamous cells cannot rule out high-grade (ASC-H), lowgradesquamous intraepithelial lesions (LSIL), or highgrade squamous intraepithelial lesions (HSIL) using Bethesda 2001 terminology.5High-resolution anoscopyOne practitioner performed all HRA exams. All patients with abnormal anal cytology were referred for further evaluation using HRA. This procedure uses a high-resolution anoscope (colposcope) set at 16 magnification to examine the peri-anal area and anal canal after the application of 3% acetic acid.23 The acetic acid causes acetowhitening of dysplastic anal epithelium similar to the effect on cervical squamous epithelium. Cervical colposcopic features of high-grade dysplasia such as coarse punctuation and mosiacism have been shown to similarly indicate high-grade disease in the anal canal.20 Abnormal acetowhite epithelium was biopsied using disposable Trilobites (ESCO medical Instruments, Stony Brook, NY, USA) endoscopic forceps with a 2.3mm non-serrated cup. The biopsy specimens were immediately fixed in 10% formalin. Haemostasis was achieved with Monsell's solution prior to the end of the procedure.Biopsies were processed using standard paraffin processing and read following staining with haematoxylin and eosin.Statistical analysisBiopsy results are used as the gold standard in the statistical analysis. Since biopsies were performed only for patients with non-negative cytology, estimates of sensitivity, specificity or likelihood ratios based on sensitivity and specificity using this data are biased and uninformative. Negative predictive values (NPV) also cannot be computed since no negative patients were biopsied. The positive predictive value (PPV) is computed using those with AIN 1, 2 or 3 biopsy results as true positives and is also computed using only AIN 2 or 3 as true positive. The weighted kappa statistic is computed as a measure of agreement beyond chance between the ordered cytology versus biopsy results and the Spearman rank correlation (rs) is computed as a measure of association between the ordinal cytology versus biopsy results. Computations were carried out using StatXact version 5.0 (Cytel Software Inc., Cambridge, MA, USA). Results are reported as estimate7standard error.RESULTSA total of 244 patients had anal cytology screening between February 2002 and December 2004. The average age of patients was 44.1 years (range of 22-71 years), and ethnic breakdown was African American 8% (19), Asian 4% (9), Caucasian 72% (176), and Latino 16% (39) and Others 0% (1) - consistent with the general clinic population. The mean CD4 count at screening cytology was 457 cells per mm3 (range 1-1408 cells/mm3).Twenty-nine percent (71) of patients had normal anal cytology, 67% (164) had abnormal anal cytology and 4% (9) of samples were unsatisfactory for interpretation due to hypocellularity (5), bacterial excess (2) and a predominance of anucleated squames (2). Abnormal cytology was reported as -- ASC-US in 48% (78) (atypical squamous cells of undetermined significance)-- ASC-H in 3% (5) (atypical squamous cells-high grade)-- LSIL in 46% (76) ( low-grade squamous intraepithelial lesions)-- HSIL in 3% (5) (high-grade squamous intraepithelial lesions)Of the 166 patients with abnormal anal cytology, 93 had follow-up HRA and anal biopsy (Table 2). Patients who did not have HRA had either elected not to have the procedure or have yet to make an appointment.Anal cytology grade showed poor correlation with the grade of dysplasia detected by paired HRA-directed anal biopsy. Ninety-two percent of the abnormal anal cytology was ASC-US or LSIL, however anal pathology reports showed high-grade dysplasia (anal intraepithelial neoplasia] [AIN] 2 or 3) in 52% of specimens, indicating that anal cytology underestimated the degree of anal dysplasia. The weighted kappa statistic is 0.0370.06 (P1/40.6337) and the Spearman correlation is rs1/40.05670.106 (P1/40.5956),confirming poor agreement and correlation within the group of positive tests.The PPV for any grade of anal cytological abnormality to predict any grade of anal dysplasia (AIN 1, 2 or 3) on biopsy was 95.772.1%. The PPV for any grade of anal dysplasia to predict high-grade anal dysplasia (AIN 2 or 3) on biopsy was 55.975.1%.No significant adverse events such as infection, haemorrhage or pain uncontrolled with simple analgesia were reported in the study.DISCUSSIONThe clinicians in this study received one short training session on how to take an adequate anal cytology specimen and were able to collect adequate anal cytology samples in the majority of cases similar to a previous study.24 However, compared with previous studies, the grade of cytology was predominantly ASC-US and LSIL with fewer samples showing HSIL.21 This may have been due to the technique employed by the sampling clinicians or may reflect cytopathological reporting. Assuming this result is more likely to reflect anal cytological sampling technique, repeating sampling technique instruction may have resulted in specimens that more closely reflect the anal cellular environment.This study corroborates the poor correlation between the cytological grade of anal dysplasia and the histopathological examination of matched anal biopsy collected during HRA.21 As no patients with normal anal cytology were referred for HRA, sensitivity, specificity or NPV could not be reported for this population. However, given the high- PPVs of abnormal anal cytology to detect any grade of anal dysplasia, clinicians may be confident that an abnormal cytology result is likely to indicate the presence of some grade of anal dysplasia.Despite the poor correlation of anal cytology with biopsy, empirically abnormal anal cytology identified subjects that were then referred for HRA and biopsy with over half of these subjects subsequently diagnosed with high-grade disease and referred for treatment. Previous modalities used to treat high-grade dysplasia have included cold scalpel excision with electrofulguration that showed lower rates of treatment efficacy in an HIV-positive population.25 More recently, the use of infrared coagulation (IRC) to treat high-grade dysplasia has been associated with higher efficacy rates with reduced post procedure pain.26 This device is used in an outpatient setting and delivers infra red light in aliquots of 0.5-3 second intervals (1.5 seconds for anal dysplasia) to previously anesthetized anal epithelium producing a focal shallow burn that reflects the time setting in mm, i.e. setting the IRC at 1.5 seconds will deliver a burn depth of 1.5mm26,27 Early clinical reports indicate efficacy (with follow-up biopsies showing normal or low-grade dysplasia) of 72% at six months.27If referral for HRA is not available, patients with abnormal anal cytology should be informed about the risk of progression to anal cancer particularly with high-grade cytology results. Additionally, they should be made aware of common presenting symptoms of anal cancer such as pain, bleeding and the presence of a mass that would allow early investigation and referral for treatment.The result of this study is likely to be reflective of other HIV primary care settings in the USA that have a predominance of Caucasian MSM over the age of 40 years. Thus, these clinics may also have a high burden of undiagnosed anal dysplasia.In conclusion, detection of abnormal anal cytology is useful clinically in HIV-positive MSM to predict the presence of anal dysplasia. In this study, 96% of the samples were adequate for cytological interpretation. The majority of abnormal cytology samples showed lower grades of dysplasia while more than half of these abnormal cytology specimens had high-grade dysplasia on biopsy. Thus, any abnormality on anal cytology testing should prompt HRA follow-up to determine grade of dysplasia and allow consideration of treatment for high-grade disease.

NEW HIV DRUGS AND THEIR STUDIES- COMMENTS FROM RESPECTED DOCTORS

THIS GREAT INFORMATION WAS PROVIDED BY CLINICAL CARE OPTIONS. THESE ARE COMMENTS ABOUT CLINICAL STUDY DESIGN ISSUES THAT I FOLLOW VERY CLOSELY AS AN ACTIVIST. IT IS VERY INTERESTING TO ME HOW SOME COMPANIES CHOSE TO SHOW THEIR DATA AND HURRY THEIR STUDY ENROLLMENT AT THE EXPENSE OF PATIENT VOLUNTEERS.


THE NEXT HIV DRUG TO BE APPROVED : MARAVIROC - COMMENTS FROM Daniel R. Kuritzkes, MD ABOUT MOTIVATE 1/2 STUDIES AND PFIZER'S EXCLUSION OF FUZEON DATA IN ITS ANALYSIS...

One interesting aspect of this study was that there was no discernable increase in the rate of virologic suppression among maraviroc patients who also received enfuvirtide. This contrasts with data from the A4001029 study, which evaluated the use of maraviroc in patients with dual/mixed-tropic virus; in this study, a similar reduction in HIV-1 RNA was observed with maraviroc vs placebo, but there was a slightly greater reduction in HIV-1 RNA when enfuvirtide was coadministered with maraviroc

One possible interpretation of why enfuvirtide had no discernable benefit in the MOTIVATE studies is that the background regimen may already have been so potent that the use of enfuvirtide did not result in any additional HIV-1 RNA reduction. Moreover, the virologic response data did not differentiate between enfuvirtide recipients who were using enfuvirtide for the first time from those with previous enfuvirtide experience. Overall, approximately 60% of the study population was enfuvirtide naive at baseline, and 40% was enfuvirtide experienced. This suggests that perhaps one fourth to one third of the patients initiated enfuvirtide for the first time with maraviroc; this may be too small a proportion to have a discernable impact in the subgroup analysis.

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THE NEXT DRUG TO BE APPROVED AFTER MARAVIROC: MK 518 (RALTEGRAVIR, MERCK'S INTEGRASE INHIBITOR) - COMMENTS FROM Daniel R. Kuritzkes, MD ABOUT THE BENCHMRK STUDY AND ITS OBR (OPTIMIZED BACKGROUND THERAPY)


Baseline resistance scores showed that approximately two thirds of patients had a genotypic susceptibility score of either 0 or 1 for the background regimen. It is worth noting that patients were considered to be resistant to a drug if the fold-change in susceptibility to that drug exceeded the lower cutoff in the phenotypic assay. The lower cutoff marks the transition between full activity and reduced activity, rather than no activity, so drugs that had partial activity could have been assigned a score of 0; in other words, the phenotypic susceptibility scores could have slightly underestimated the activity of the OBR. Approximately 20% of patients were naive to enfuvirtide at study entry; in the case that enfuvirtide was used in a previously enfuvirtide-naive patient, a score of 1 was assigned to the phenotypic susceptibility score. Phenotypic susceptibility testing for darunavir was not available at the study outset, so darunavir was also assigned an activity score of 1 when administered to a patient who had previously been darunavir naive; this approach may have overestimated the activity of darunavir in some patients. Approximately 25% of patients in BENCHMRK‑1 and nearly 50% in BENCHMRK‑2 were darunavir naive and received darunavir as part of their OBR; this is probably the major difference between the trials.

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COMMENTS ABOUT GILEAD'S INTEGRASE INHIBITOR (ELVITEGRAVIR) STUDY AND ITS HURRIED IMPLEMENTATION THAT EXPOSED PATIENTS TO VIRTUAL MONOTHERAPY


Daniel R. Kuritzkes, MD:I agree that the failure kinetics of elvitegravir appear to resemble that of lamivudine or an NNRTI, with which a single-point mutation confers resistance and is associated with rapid viral rebound, whereas failure with raltegravir appears similar to failure with a PI, that is, resistance requires mutations at multiple loci and rebound is more gradual. Whether similar failure kinetics would have been observed with raltegravir if PIs had been excluded from the BENCHMRK studies is a matter of speculation.

Development of elvitegravir has been complicated somewhat by the fact that it has many drug-drug interactions. The manufacturer had to decide whether to elucidate all those interactions first, so that studies could allow the concomitant use of as many other drugs as possible, or to proceed with studies more rapidly but restrict the drugs that could be combined with elvitegravir. The consequences of choosing the latter approach was that in this treatment-experienced patient population, there were insufficient drugs available to provide an effective background regimen to support the integrase inhibitor. Most patients received NRTIs only, and approximately one half of them contributed no activity, meaning that those patients received de facto monotherapy with elvitegravir.

Joseph J. Eron, Jr, MD:Although I agree about the limitations of the current study, the goal of a phase IIb study is to identify the best dose to take forward into phase III development, and it does seems likely that the right dose of elvitegravir was identified.

Daniel R. Kuritzkes, MD:You are correct. However, if the investigators had chosen to perform a 14‑day study of different doses in treatment‑experienced patients, they might have come up with the same result. Unfortunately, the patients who received up to 16 weeks of treatment with the lowest dose (20 mg) before that arm was discontinued—as well as the patients who experienced virologic failure in the other arms because of the lack of an effective OBR—are now likely resistant to this integrase inhibitor and may or may not be cross‑resistant to other drugs in the class. The challenge for all investigational drugs is how to generate the key data that are essential for drug development while minimizing the risk to the patients enrolled in early studies.

Joseph J. Eron, Jr, MD:I agree. Patients in the elvitegravir study had an even higher median CD4+ cell count than those in the maraviroc and raltegravir trials, so most were not in urgent need of a new regimen, yet some of these patients may now have restricted future options because they received elvitegravir combined with NRTIs only.

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COMMENTS ABOUT RELPIVIRINE (TMC 278- A NON NUCLEOSIDE) FROM TIBOTEC:

William G. Powderly, MD:The lipid data from this study were intriguing. Results in the efavirenz arm were as expected: a mean 31 mg/dL (0.80 mmol/L) increase in total cholesterol, a 16 mg/dL (0.41 mmol/L) increase in low density lipoprotein (LDL) cholesterol, and a 12 mg/dL (0.31 mmol/L) increase in high density lipoprotein (HDL) cholesterol. Triglyceride levels also increased in the efavirenz arm by a mean of 18 mg/dL (0.20 mmol/L). By contrast, there were virtually no significant lipid changes in the rilpivirine arms: a 5 mg/dL (0.13 mmol/L) median increase in total cholesterol, no change in LDL cholesterol, a 5 mg/dL (0.13 mmol/L) increase in HDL cholesterol, and a 10 mg/dL (0.11 mmol/L) decrease in triglycerides. This is a potential advantage to rilpivirine over efavirenz, although it is not clear how these changes might translate into differences in cardiovascular risk, since the larger increase in HDL cholesterol in the efavirenz arm might counterbalance the larger increase in LDL cholesterol and triglycerides also seen in that arm.

This is the second time that a study of a novel agent in treatment-naive patients has demonstrated fewer lipid effects than efavirenz. The first was a phase II study in which raltegravir was associated with significantly smaller changes in cholesterol and triglycerides than those observed with efavirenz (P < .05 for 200-mg, 400-mg, and 600-mg doses of raltegravir) . This type of result challenges the notion that a proportion of the lipid changes observed in treatment-naive patients who start antiretroviral therapy represent a “return to normal” in the form of a reversal of the effects of unchecked HIV replication. The results of these studies question that hypothesis and raise the possibility that lipid changes may indeed be a form of drug toxicity in the majority of patients. ******************************************************** COMMENTS ABOUT THE X4 INHIBITOR AMD 11070:

Daniel R. Kuritzkes, MD: There were very few reports on agents in the early stages of development. Two pilot studies of AMD 11070, a CXCR4 inhibitor, were presented at this meeting. The ACTG 5210 trial was an open-label dose-escalating 10-day monotherapy study in patients who had been off therapy for ≥ 14 days and who had X4 or dual/mixed virus detected 18] A total of 6 patients in the first cohort were treated with AMD 11070 200 mg every 12 hours for 10 days (20 doses). Three of the 6 patients had ≥ 1 log10 reduction in the X4 virus population by Day 10 as measured by luciferase assay. Five of the 6 subjects had dual/mixed virus at Day 10, and the sixth had R5 virus. However, none of the patients experienced a ≥ 1 log10 copies/mL reduction in HIV-1 RNA.

The XACT study had similar results. This was a 10-day monotherapy study in treatment-naive and treatment-experienced patients with X4 virus detected (N = 10; 8 received 200 mg twice daily and 2 received 100 mg twice daily). One patient was unevaluable based on discrepancies in tropism assay results. Four of the remaining 9 patients had ≥ 1 log10 reduction in the X4 virus population by luciferase assay by Day 10, and 3 of these 4 had only R5 virus detected at Day 10. However, there were no changes in HIV-1 RNA or CD4+ cell count among the 4 responders.

The fact that reduction in X4 virus was not associated with an overall reduction in HIV-1 RNA would present a huge challenge for subsequent development of an X4 inhibitor because one is unable to demonstrate an impact on what are considered traditional endpoints—decrease in HIV-1 RNA and increase in CD4+ cell count. Development of AMD 11070 is now on hold because of serious toxicity demonstrated in animal models.

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COMMENTS ABOUT RACIVIR

Joseph J. Eron, Jr, MD: Clinical data were also presented on racivir, a racemic mixture of enantiomers of an emtricitabine-like molecule.[20] In this study, patients failing therapy with M184V on a lamivudine-containing regimen were randomized 2 to 1 to substitute racivir for lamivudine (n = 26) or continue lamivudine (n = 16) in a double-blind fashion. Among those receiving racivir, the mean HIV-1 RNA change after 28 days was a decrease of 0.4 log10 copies/mL, whereas those on lamivudine experienced a 0.13 log10 copies/mL increase (P = .0004). In a subgroup analysis of patients with M184V < 3 thymidine analogue mutations with or without NNRTI or PI mutations (n = 14), the HIV-1 RNA decreased 0.7 log10 copies/mL over same period (P = .0002)

The lack of clinical data on drugs at early stages of development highlights an important concern. Within the next year, 3 new drugs may be approved. However, in the next few years beyond that, very few new drugs are likely to become available. Those that do become approved will most likely be second or third in class and therefore more likely to be of incremental benefit, as opposed to the potentially dramatic benefit that may be associated with the first agent in an entirely new class, to which even the most experienced patient is likely to remain fully susceptible. This underscores once again the critical importance of using the current batch of new agents optimally—in combination with other active agents and with the goal of achieving undetectable HIV-1 RNA—in the hope that today’s treatment-experienced patients can achieve durable responses.

Interview for TheBody.com

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