Scottish Scribe Tells of Resistance Testing Success, Superinfection, Flaws in Dual Protease Regimens
In contrast to U.K. Drug Therapy Congresses past, where physician attendance from the U.S. was rife but that of U.S. activists lackluster, this year’s late autumn retreat was graced not only with the presence but the participation of David Barr and Mark Harrington. Where Barr, for the past 3 years head of D.C.-based Forum for Collaborative HIV Research delivered a carefully reasoned and provocative address on the by now fully appreciated difficulties of adherence to HIV medications (see accompanying article), Harrington invoked the lessons of ten years of AIDS activism for the opening night plenary crowd (see December 1998 TAGline). Mark’s quick and dirty summary of the meeting, one most notable for the imposing integration of drug company marketing events and the paucity of new data, appears below.
David Barr and I took the night flight across the Atlantic, landed in Paris at dawn, and flew over dazzling Scottish greenswards into Glasgow on November 7. Our lodgings adjoined the Glasgow Conference Centre, which resembles a miniature version of the Sydney opera house, and a canal. The light was silvery and slant, like the skin of a mackerel, and it was cold but brisk. The next morning, I wrote my speech, which was intended to be a retrospective view of the last ten years of AIDS treatment activism.
After the speech, several European treatment activists, despite being disgruntled at not having one of their own selected for the opening plenary, approached me — Ana Sousa Passos from Lisbon, Rob Camp from Barcelona and, a new one, Nikos Dedes from Athens who told me,
“Your speech was very politically correct.”
“Because you mentioned the EATG [European AIDS Treatment Group] four times.”
“Well, we are in Europe after all.”
I hung out at the post-opening reception for half an hour, talking with activists and sipping wine, then took a bus to the conference VIP dinner at a 19th century shipping magnate’s mansion on Devonshire gardens. I talked with Mark Wainberg, current president of the International AIDS Society, about the global epidemic and the Durban conference; with virologist Doug Richman about resistance; with the CDC’s Kevin de Cock about barebacking and reinfection; and with U.K. statistician Janet Darbyshire about the importance of the when-to-start-therapy trial, which she was eager to jump-start.
Most of the Fourth International Congress on Drug Therapy in HIV Infection appeared to be designed for European clinicians who were unable to make it to the Retrovirus conference or to Geneva, as it was a series of plenary lectures which extensively reprised scientific presentations from early in the year, sometimes with minor updates. Its chief feature seemed to be the pharmaceutical fair and the many drug company-sponsored satellite symposia, which I boycotted. David Barr gave an excellent speech on adherence [see here]. However, there was little new science to report.
A Frustrating Community Forum
Monday, November 9th, I was to participate in a community forum alongside the U.K.’s Edward King, Peter Busse of NAPWA South Africa, and EATG chair Arjen Broekhuisen, who refused to participate on the grounds that the EATG had not been given a slot at the opening plenary. He gave a fifteen-minute explanation of this decision. “Why,” he queried with brimming indignation at the Forum’s opening, “Why, at a European AIDS meeting, were the opening night keynote lectures delivered by people from San Diego, Atlanta and New York? Does Europe offer so little?” According to Mike Barr’s scathing HCG review of the meeting, “the lion’s share of the allotted time was squandered with self-indulgent grandstanding, disingenuous protestations and futile efforts to lead the discussion in a constructive direction.”
Update on the South African Epidemic
However, Peter Busse, director of South Africa’s National Association of People with AIDS (NAPWA), eloquently described the birth and growing pains of an activist group in a developing country with an exploding epidemic. NAPWA South Africa was founded as a volunteer organization in 1994 and has slowly evolved into a community-based, non-governmental organization with a budget of approximately $180,000. There are currently seven provincial coordinators. The main issues for NAPWA South Africa currently are disclosure and visibility, community building and mobilization. Most of NAPWA’s members are women. According to current estimates, up to three million South Africans are HIV-infected and up to 1,500 new infecctions occur daily. Condom use, at 3% of the sexually active population, is dangerously low.
Since the first all-race elections in 1994, most non-governmental organization (NGO) funding to South Africa has gone through the government. Few funders support NGOs directly. NAPWA South Africa receives some funding from InterFund, a Scandinavian charity. According to Busse, despite speeches at international fora such as Davos*, President Nelson Mandela has not made speaking of AIDS a domestic priority, and treatment is not a political priority.
On the treatment front, just about 200 people can afford the cost of highly active antiretroviral therapy [HAART], and a few hundred others are currently receiving HAART in clinical trials, although there is no guarantee that they will continue to have access when the studies conclude. The South African health minister, who is engaged in a struggle with the pharmaceutical industry over pricing, has declined to provide AZT to HIV-infected pregnant women, in spite of the fact that Glaxo-Wellcome was offering the drug free. Busse stated that NAPWA South Africa could benefit from formal skills building training on advocacy, lobbying and coalition-building with other groups such as gay and lesbian civil rights groups.
Planning a New International Treatment Activist Network
On Tuesday, November 10, an international group of activists met to start planning a new international treatment information network utilizing existing websites and adding new material for activists in three languages — English, French and Spanish — to improve information exchange around the world. We will continue planning this at the Sixth Retrovirus Conference in Chicago during February 1999.
Some scientific tidbits:
Two Groups Find No Third Compartment Decay
Neither Brigitte Autran’s chronically infected cohort in France (N=317) nor Luc Perrin’s acutely infected cohort in Switzerland (N=3) demonstrated any reduction in cell-associated HIV DNA provirus in resting CD4 cells over two years of follow-up (Autran, abstract PL2.2; Perrin, abstract PL1.1). Robert Siliciano’s updated estimate of the half life of the reservoir of latently infected resting memory CD4+ T cells stands at 16 months. Even at an estimated pool of fewer than 1,000,000, this means it would take 22.9 years to turn over and die given normal rates of turnover of these cells.
Once-Daily Salvage Regimen
A German team switched 24 people with viral load beneath the limit of detection (<500 copies/mL) from a protease-containing triple therapy regimen to a once-daily regimen of ddI, 3TC and nevirapine. (They previously showed the efficacy of this regimen in 70 injecting drug users.) At 16 weeks, 18/24 (75%) continued to have a viral load below 500 copies/mL. Of the six treatment failures, five were NNRTI-experienced (Rottmann, abstract OP2.1).
Four Drugs Rescue Amprenavir Failures
Rob Murphy showed by-now familiar data on the 70% efficacy (viral load beneath limit of quantitation, henceforth BLQ) of d4T, 3TC, indinavir and nevirapine in patients who failed amprenavir monotherapy or amprenavir plus AZT and 3TC. Monotherapy failures fared better than those who failed triple therapy (Murphy, abstract OP2.4).
Dual Protease Regimens May Not Reach the CSF or Genital Fluids
Gisolf and colleagues from the Dutch Prometheus group reported that a majority (4/7, 57%) of patients on ritonavir/saquinavir dual therapy maintained measurable HIV RNA in their cerebrospinal fluid (CSF) at week 12, versus a small minority (1/11, 9%) of those on ritonavir/saquinavir/d4T (p<0.05). Drug sampling was performed on serum and CSF from thirteen patients. While all three drugs were detectable in serum, ritonavir and saquinavir levels were beneath the limit of quantification in the majority of patients’ CSF (Gisolf, abstract OP1.2). A second paper found that ritonavir and saquinavir levels in seminal fluid were just 2-4% of those in plasma (Taylor, abstract P40).
Baby-Dose Ritonavir Enables BID Indinavir Dosing, without Food Restrictions
Co-administration of 100 mg BID of ritonavir plus 800 mg BID of indinavir increases indinavir trough levels and allows indinavir to be taken twice daily — with food. More pharmacokinetics on this combination, also reported in Geneva, were presented in Glasgow (Burger, abstract P38; Van Heeswilk, abstract P55). Roche also demonstrated similar 32-week activity between soft-gel saquinavir (a.k.a. Fortovase) twice (1,600 mg BID) or thrice (1,200 mg TID) daily in a randomized study with 829 subjects (Carey, abstract P68).
Randomized French Salvage Study Suggests Genotypic Resistance Testing Improves Likelihood of Successful Switching
In an exciting late-breaker, Durant and colleagues presented results from the French VIRADAPT study. They randomized 108 patients who failed virologically (viral load over 10,000 copies/mL and at least six months’ prior nucleosides and at least three months’ prior protease inhibitors) to switch regimens based on a) physician judgement, taking into consideration U.S. treatment guidelines; or b) treatment modified by results of genotypic resistance testing (test unspecified).
Those randomized to arm B were statistically more likely to have a viral load beneath the limit of quantitation (BLQ) at both month 3 (p=0.038) and month 6 (p=0.047) (Durant, abstract OP7.1). This is the first randomized evidence I am aware of which prospectively demonstrates the clinical benefit associated with use of genotypic resistance testing.
Possible Superinfection in Sweden
Anders Sonnenborg of Stockholm’s Karolinska Institute analyzed 50 HAART failures. One intriguing case suggested the possibility of superinfection by a partner who had previously experienced viral rebound. In this case, viruses from both partners (the one who rebounded first and the one who rebounded later) showed similar mutations in the protease enzyme and the V3 loop, suggesting re-infection (Sonnenborg, abstract PL3.3). A team from Italy found that, in 5/13 subjects (38%), viral mutations differed in plasma and semen (Liuzzi, abstract P232).
Lipodystrophy Found in French Dual Nucleoside Patients
Saint-Marc and colleagues used computerized tomography and bioimpedance analysis to investigate whether lipodystrophy (ratio of body, intra-abdominal and subcutaneous fat versus controls) occurred in patients on dual nucleoside therapy. Surprisingly, they found lipodystrophy in 18/44 (40.9%) dual nucleoside patients — all of whose regimens included d4T (Saint-Marc, abstract P152).
Rifabutin Associated with Increased Mortality
ENTA 10, a European study investigating whether rifabutin might work as prophylaxis for M. tuberculosis (TB) as well as Mycobacterium avium complex (MAC), or whether rifabutin MAC prophylaxis predisposed TB to resistance to the rifamycin drugs, was conducted over the cusp of the HAART era and was not able to answer its primary question due to the advent of HAART and the subsequent lack of clinical endpoints. However, 504 subjects with CD4 counts below 200 cells/mL were enrolled and randomized to rifabutin (300 mg/d) or placebo. Curiously, although mycobacterial endpoints were identical in the two arms (13 on rifabutin, 12 on placebo after about 670 days), mortality was greater in the rifabutin arm (34 on rifabutin, 17 on placebo). No reason was given for this difference (de Wit, abstract P292).
* Klaus Schwab’s World Economic Forum, first organized in 1971, an annual international summit of business leaders and other high net worth individuals in the Swiss Alps; see Lewis Lapham’s engaging outsider’s look at the January 1997 meeting: The Agony of Mammon: The Imperial Global Economy Explains Itself to the Membership in Davos, Switzerland; Verso 1998: “…heads of state, finance ministers, policy intellectuals, Nobel Prize-winning physicists, corporate executives as thick upon the ground as pine needles,” and, “…the lesser nations of the earth become colonies not of governments but of corporations, the law of nations construed as the rule of money, and the world’s parliaments intimidated by the force of capital in much the same way that in the eighteenth and nineteenth centuries they had been intimidated by the force of arms.”
At a Glance: South Africa
Number of people living with HIV: 3,000,000
New infections per day: 1,500
(Est’d.) frequency of condom use: 3%
Access to antiretroviral medications
Private means: 200 triple therapy, 1,000 dual nucleoside or monotherapy
Clinical trials: 1,000-2,000 *
Total: 2,200-3,200 (0.07-0.11%)
AZT for HIV-infected pregnant women: Provision recently denied by health ministry
* No continued access once trial ends
|VIRADAPT: Physician Judgment vs. Genotypic Resistance Results for Treatment Switching Decisions Upon Virologic Rebound *|
|Mean Decrease in Plasma HIV RNA|
|N||Month 3||BLQ †||Month 6||BLQ †|
|Physician Judgement||43||-0.6||16.7%||-0.5||9.6% ‡|
|Genotypic Test Results||65||-1.3||33%||-1.3||39% §|
|* One hundred and eight randomized patients were required to have failed virologically (plasma RNA >10,000 copies/mL) and have 6 months or greater nucleoside analogue exposure and 3 months or greater protease inhibitor exposure.|
|† (Below) limit of quantification = 500 copies/mL.
|(Durant, abstract OP7.1)|