Drugs in Development: Going, Coming, Gone line Clinical Myopia at NIAID From the Treatment Action Group (TAG): Dátà Vu at Summer IAS Meeting A monthly paper of research and policy TAGline en español Volume 8 Issue 7 September 2001 Shreds of Evidence Down the Pike Investigational New Drugs Currently Shudda, Cudda, Wudda. Being Tested in Humans, by Class Argentina IAS Reevaluating the Nucleoside RTI 3 Snoozer Prompts Non-nucleoside RTI 7 Treatment Revolution Protease inhibitor 4 Systematic Review of After the Fall Fusion/binding inhibitor 5 Drug Pipeline Cellular factors inhibitor 4 Other 2 ‘Six years of lost data’ Total 25 ‘Underwhelmingly innovative’ David Barr revisits the changes to the The International AIDS Society inau- federal when-to-start recommendations Economía de Drogas gurated its new program of summer announced earlier this year and urges research meetings with a sleeper of a us to consider both the roots and the Renegado Antiretroviral gathering in the southern hemisphere ramifications of this extraordinary devel- Lucha Contra La Moda port city of Buenos Aires. Mark opment. While acknowleding the Con Dúo Didanosina, Harrington attended on behalf of TAG predicament of a Monday morning and sifted the new from the old to pre- quarterback, his words are frank and Apuestando Su Futuro pare this report for TAGline. hard-hitting. “How many people have En Barreras Genéticas only suffered from the side effects of t midwinter in Buenos Aires the * * * treatment—and not from HIV infec- Adays are short and the weather is tion?” he asks. And “where is the ‘Monoterapia enforzada’ cool, like summer in San Francisco. research infrastructure to study this * * Here the International AIDS Society chronic, if not quite manageable, dis- (IAS) has decided to initiate its patho- Cuándo se pertenece a la gerencia genesis and treatment conference, ease?” de una infección fatal como el VIH, which will take place every other year. se ha dicho que la auto-experi- here is the outcry from AIDS Thus the IAS is setting up an interna- mentación dirige rara vez al advocates following the recent tional counterpart to the Retrovirus W conocimiento. Los otros en este change in the U.S. government’s adult conference. Cleverly, however, virtu- condición son rápidos a indicar que HIV treatment guidelines? The guide- ally the entire leadership of that meet- eses enfoques del tratamiento corri- lines panel sponsored by the National ing has been invited—so as not to ente son todo apenas un experimen- Institutes of Health (NIH) changed its appear that the two are in competi- to grande, de todos modos. Los recommendation from starting antiretro- tion. fines opuestos de una corresponda viral therapy at T cell counts below 500 autoritaria, aparecerían: “No haga to waiting to start until T cell counts fall In an attempt to demonstrate their nada sin la evidencia clínica sólida below 350. New British guidelines have commitment to conducting meetings para apoyarlo”—y el imprimátur gone even further, recommending in developing countries, the IAS orga- sagrado de algún cuerpo burocrático treatment not start until T cell counts fall nizers chose Argentina for the first omnisciente, van los pensamientos below 200. meeting of its kind. Now Buenos del primer campo. “Rebusca todo Aires is not exactly Durban, and the que hay saber, sigue lo que dicen These changes are based on two cen- next two summer IAS meetings are sus instintos, y haga todo qué pueda - continued on page 6, col. 3 - - sigue en la página 10 - - continued on next page - continued from first page, col. 3 — slated for Barcelona (2002) and Paris the second phase of decay, which although it doesn’t in the least under- (2003). David attributes to virus produced mine the prime lesson from his analy- from macrophages. sis of the prognostic level of viral load Buenos Aires is essentially a first from banked 1985 Multicenter AIDS world city within a third world country. It’s remarkable how little research has Cohort Study (MACS) blood samples. Mired in recession with no turn around been done in this second compart- in sight, the country’s fate appears to ment. Macrophages are terminally dif- The Mellors data showed that viral be in the hands of the load shortly after infection International Monetary Fund, strongly predicts rate of which is to say, U.S. CD4 cell loss and hence Treasury Secretary Paul Short-cycle structured rate of disease progression. O’Neill, U.S. President The Montaner data show George W. Bush and a intermittent therapy appears that in the short term, CD4 handful of big lenders at to preserve antiviral efficacy count, especially at low lev- Citibank, Bank of America els, is more predictive of and J.P. Morgan/Chase. while reducing toxicity. clinical disease than is viral Local newspaper headlines load. Montaner cautioned are filled with ominous warn- that differences may appear ings of imminent collapse, over longer periods of fol- while those Argentines with the oppor- ferentiated and found in tissue, not low-up. These data don’t prove that tunity scramble to spirit their pesos blood, and thus harder to sample than it’s better to start later, but neither do into dollars and their dollars out of the the latently infected CD4 T cells about they support the notion of hitting earli- country, before the nearly inevitable which so much has been made. er than 200 CD4 cells. (That shred- devaluation—and default. Each new Maybe the five drug regimen will also ding sound? That’s five years of mis- refinancing buys only a few more curtail the second and third phases of guided guidelines being ripped to months of hardship and uncertainty. viral decay. If so, perhaps we need pieces.) take HAART (without a single slip up) Still, the IAS meeting opened with for just thirty years, not sixty, in order Hit intermittently great pomp at a conference center to eradicate HIV. What fun. Tony Fauci kicked off the conference conveniently located under a noisy proper with an update on long cycle jetway, where every five minutes Hit even later (60 days on, 30 days off) and short another plane took off with a great Next Julio Montaner, updating us on cycle (7 days on, 7 days off) struc- roar. The introductions were flowery, the British Columbia HIV cohort, tured intermittent therapy (SIT), with extensive and bilingual. The presenta- showed that baseline CD4 cell count data on the latter out to 32 cycles (64 tions contained more than a bit of has an immediate impact on hospital- weeks). data vu. ization, AIDS, and survival, where a baseline CD4 count below 200 is bad The long cycle was less than optimal Hit even harder and one below 50 very bad indeed. since viral load rebounded, did not David Ho treated us to a review of the always decline below detection after highlights of his work on viral dynam- Adjusting for adherence, however, retreatment, and in some cases ics over the five years since shows that people starting with a appeared with signs of reduced sus- Vancouver. In doing so he proved CD4 count below 50 who were high- ceptibility to drug. that, as Prince put it on a song from ly adherent—about two-thirds of 1990’s Graffiti Bridge, there is indeed them, unlike groups at higher levels, The short cycle SIT, out 32 cycles, joy in repetition. At the end of his talk who may have been less motivat- looked pretty good. Ten people who he showed us that a five-drug regi- ed—had survival results virtually had achieved good viral control men consisting of lopinavir/r with 3TC, indistinguishable from those entering enrolled and switched from their prior efavirenz and tenofovir can accelerate with higher CD4 counts. So you can regimens to d4T/3TC/indinavir/riton- the first phase of viral decay from indeed rescue individuals even with avir twice daily. Their median pre- fourteen days (seen with quite low CD4 counts. (This we knew HAART CD4 count was 406 and AZT/3TC/ritonavir back at Vancouver) from the Merck 060 study in 1996, before the short-cycle SIT was 786. to just seven days. It’s too soon to say but it’s nice to have it corroborated.) The median pre-HAART viral load was whether this regimen will accelerate John Mellors just hates this data, 55,000; the median pre-study was -2- <500. Two of the ten went off study ing towards potential approval (“late ed to 3TC. Franck Rousseau of the (one after rebounding), while the other pipeline”). sponsor, Triangle Pharmaceuticals, eight are all still being followed with showed that of 47 individuals who good viral control. (One participant Nucleoside and nucleotide ana- experienced virologic failure in a com- had a viral blip, but he had gone on logue RTIs parison of daily FTC with twice-daily vacation and stayed off therapy ten— Farthest along in the pipeline is 3TC (plus nevirapine and d4T), 31% rather than seven—days. Upon rechal- Gilead Sciences’ tenofovir disoproxil had wild-type virus (indicating possi- lenge, he resuppressed his ble lack of adherence). virus.) Eighty-eight percent had at least one detectable drug Over 60-64 weeks, there mutation in the 3TC group, was no change in absolute Despite prophecies of imminent compared with just 56.7% CD4 count, CD4 percent- in the FTC group. (For the age, CD8 count, activation doom, the IAS conference reflected M184V mutation, 58.8% of markers, plasma HIV RNA, a rather healthy drug pipeline. breakthroughs in the 3TC cellular HIV RNA, proviral group had it versus just HIV RNA, or number of 16.7% of those in the FTC latently infected CD4 cells.