The Research Trough — where lack of progress brings more grants
Posted by Henry Bauer on 2008/09/10
Erwin Chargaff wrote wonderfully acerbic essays about the gap between the traditional high ideals of science and the actual practices of scientists, for example, “in our time a successful cancer researcher is not one who ‘solves the riddle,’ but rather one who gets a lot of money to do so. It is all quite similar to the history of alchemy, another truly goal directed, though much less costly, enterprise” (Chargaff, Voices in the Labyrinth, 1977, p. 89).
What might Chargaff have said about the goal-directed missions of trying to invent vaccines and microbicides to prevent infection by HIV?
He would surely have expressed it much more memorably, but the gist would have been, “I told you so”:
“NORFOLK, Va. – Eastern Virginia Medical School is receiving a $100 million grant to develop a product to prevent the transmission of the virus that causes AIDS. . . . Officials say the grant will further two decades of studying microbicides that would block HIV and other sexually transmitted diseases. Microbicides can come in forms such as topical gels, creams, tablets, films or oral pills. The grant will fund the school’s program known as CONRAD. . . . CONRAD researchers have been working on microbicides for 20 years and are focusing on several promising candidates that interfere with the process that allows HIV to replicate” [AP, 8 September 2008; emphases added].
That’s progress for you: after two decades, “some promising candidates”. Note how misleading is the stuff about “topical gels, creams, tablets, films or oral pills”, implying that it’s the vehicle that needs work when the very feasibility is at issue since an effective agent remains to be discovered.
Luddites like myself might suggest that this $100 million throws good money after bad. Naïve observers might ask whether there’s something basically wrong with our view of “HIV”, if twenty years has brought nothing better than some “promise”.
Here’s a short and random recent history of HIV-microbicide research:
“Microbicide Trials On HIV Transmission Prevention Halted — The Chronicle Newspaper (Lilongwe) . . . 7 May 2007 . . . Malawi will continue with phase 3 Trials on the efficacy of a microbicide gel that is being tested for HIV prevention in women despite trials of a similar kind being halted in other participating countries. . . CONRAD, a reproductive health research organization had halted the phase 3 efficacy trials of its Cellulose Sulfate (CS) based microbicides . . . the public [is] asking why the trials . . . being carried out by John Hopkins Foundation in Malawi are still continuing. . . . on the Pro 2000 and Buffer Gel [trials] started in 2005 . . . . CS is a completely different product from Pro 2000 and Buffer Gel . . . preliminary results indicated that Cellulose Sulfate could lead to an increased risk of HIV infection . . . . ‘With these microbicide candidates in large scale efficacy trials and a new generation of microbicides well into safety studies, microbicides could be available in five to seven years’” .
That reminded me that an HIV vaccine, promised in 1984 within a couple of years, has not been delivered after more than a couple of decades.
“FDA Mandates HIV Warning on Contraceptives — Contraceptive gels, foams, films, and inserts sold in the United States will now come with a warning that the products do not protect against HIV and other sexually transmitted diseases. The Food and Drug Administration will require the warning on all over-the-counter products containing nonoxynol-9 . . . . ‘FDA is issuing this final rule to correct the misconceptions that the chemical N-9 in these widely available stand-alone contraceptive products protects against sexually transmitted diseases, Janet Woodcock, FDA’s deputy commissioner for scientific and medical programs, said . . . . The warning was proposed in 2003 after a study in Africa and Thailand found women using the nonoxynol-9-based products were at higher risk of HIV than those on a placebo. The new warning states that because the products can irritate the vagina and rectum they may boost the risk of contracting HIV/AIDS” [emphases added].
Four years between proposing a warning and actually issuing it seems a bit long even for a federal bureaucracy; especially one that’s accustomed to approve new antiretroviral drugs virtually overnight.
“Pfizer Seeks to Prevent HIV” — Wall Street Journal 30 January 2008 — “A new Pfizer Inc. HIV drug will soon be reformulated in an effort to prevent the transmission of the virus, offering a faint ray of hope in an arena littered with disappointments. . . . [Pfizer] will license its new medicine, Selzentry, to a nonprofit that investigates ways to turn HIV medicines for infected patients into vaginal substances to prevent transmission to women during sex. The partnership offers a low-risk way for Pfizer to find out if the medicine could become a frequently taken drug, while potentially offering an empowering concept to women in the developing world. HIV preventives have proven elusive, with researchers and advocates still recovering from last year’s collapse of Merck & Co.’s once-promising vaccine trial. And Pfizer’s new venture with the International Partnership for Microbicides is a long shot that relies on an unproven theory. . . Pfizer’s drug was approved last year for patients who have undergone other HIV treatment. Pfizer is now giving the IPM a license to try to turn the medicine into a vaginal gel, ring or film that might prevent transmission. The Pfizer drug already has a safety portfolio approved by the Food and Drug Administration, potentially making it easier to get through testing in a new form.”
Re “approved safety profile”, note for Selzentry (equivalent generic is maraviroc, MVC) the following “Adverse Events” from the HIV/AIDS Treatment Guidelines, 29 January 2008: “Abdominal pain, cough, dizziness, musculoskeletal symptoms, pyrexia, rash, upper respiratory tract infections, hepatotoxicity, orthostatic hypotension” (Table 14, p. 74).
There’s also a “Pertinent Black Box Warning” (Table 20, p. 86):
“Hepatotoxicity has been reported with maraviroc and may be preceded by evidence of a systemic allergic reaction (e.g., pruritic rash, eosinophilia, or elevated IgE). . . . Immediately evaluate patients with signs or symptoms of hepatitis or allergic reaction.”
The “GOOD” news about MVC (Table 26, p. 101), is that it doesn’t seem to cause cancer in animals.
“The first anti-AIDS vaginal gel to make it through late-stage testing failed to stop HIV infection in a study of 6,000 South African women” — AP, 18 February 2008 — “Scientists . . .plan more tests on a revamped gel containing an AIDS drug that they hope will work better. The gel used in the current study did prove safe, however, and researchers called that a watershed event.”
How Chargaff would have been delighted at this grist for his mill: it’s a watershed event when, finally, an intended medicine at least does no harm.
But the researchers were quite rightly delighted, because “A year ago, scientists stopped two late-stage tests of a different gel after early results suggested it might raise the risk of HIV infection instead of lowering it. . . . The study was paid for by the Bill & Melinda Gates Foundation and the U.S. Agency for International Development . . . . Jeff Spieler, an official at USAID, called the trial ‘groundbreaking work’ in a statement. ‘We have always known that the path to developing a successful microbicide would be a long one.’ The Population Council hopes to start tests this year of a revamped Carraguard containing an experimental AIDS drug, MIV-150. The group also has studies under way of a contraceptive version of the gel, Carraguard plus hormones.”
Sounds very good. Plenty of research needed, so grants will keep coming in for the “long” foreseeable future.
26th February 2008: “CHICAGO (AFP) — The quest to develop a vaginal gel to prevent HIV infection took a step forward Monday when researchers announced that one such gel is safe [cheers!] for women to use on a daily basis. . . . The researchers found no disruption of liver, blood or kidney function . . . . ‘Based on what we have learned we can proceed with greater confidence on a path that will answer whether tenofovir gel and other gels with HIV-specific compounds will be able to prevent sexual transmission of HIV in women when other approaches have failed to do so,’ said lead investigator Sharon Hillier, director of reproductive infectious diseases at the University of Pittsburg School of Medicine.”
“The announcement comes a week after researchers announced that the first prototype to complete advanced clinical trials was ineffective in preventing infection. Microbicides are one of the most eagerly-sought avenues in the war on AIDS, where at present there is neither a cure nor a vaccine . . . . A number of different gels are currently being tested around the world but none have been proven to be effective and some have even increased the risk of contracting HIV.”
As to tenofovir (Viread; also in Atripla and Truvada), the Treatment Guidelines say:
“Renal impairment, manifested by increases in serum creatinine, glycosuria, hypophosphatemia, and acute tubular necrosis, has been reported with tenofovir use . . . . The extent of this toxicity is not completely defined. . . . Renal function, urinalysis, and electrolytes should be monitored in patients while on tenofovir” (p. 23);
Adverse Events (Table 10, p. 69): “Asthenia, headache, diarrhea, nausea, vomiting, and flatulence; renal insufficiency; Lactic acidosis with hepatic steatosis (rare but potentially life-threatening toxicity with use of NRTIs).
Pertinent Black Box Warning (Table 20, p. 86): “Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals. Tenofovir is not indicated for the treatment of chronic hepatitis B (HBV) infection; safety and efficacy in patients with HIV/HBV coinfection have not been established. Severe acute exacerbations of hepatitis B have been reported in patients who discontinued tenofovir — hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months after discontinuation of tenofovir in HIV/HBV-coinfected patients. If appropriate, initiation of anti-HBV therapy may be warranted after discontinuation of tenofovir.”
Tenofovir has also caused liver cancers in mice.
Since microbicides are intended for use by women, yet another comment in the Treatment Guidelines is pertinent:
“Because of lack of data on use in human pregnancy and concern regarding potential fetal bone effects, tenofovir should be used as a component of a maternal combination regimen only after careful consideration of alternatives” (Table 27, p. 102).