Important note: Information in this article was accurate in August 2000. The state of the art may have changed since the publication date. 
"Rigor is not the issue of the day, reality is." So spoke Oxford researcher Roy Anderson at a plenary session on "Living with HIV" at this summer's International AIDS Conference. More often than not, neither rigor nor reality won out at the Durban, South Africa gathering. Instead, the two exerted an opposed, almost magnetic pull on a parade of speakers struggling to find solutions to glaring global inequities in access to anti-HIV drugs. Hovering somewhere above the plane determined by these two poles was a third principle: reducing prices of anti-HIV drugs through any means necessary so that poor countries facing catastrophic losses from the epidemic could have access to effective antiretroviral therapy.
Parallel importing, compulsory licensing, generic production, tiered pricing, bulk buying were the most commonly mentioned means to reach goal. Yet another tantalizing, albeit elusive possibility is novel treatment strategies to simplify, improve and decrease the cost of the existing standard of care. Simplification is vitally needed in industrialized countries, too, as healthcare systems strain to support the cost of lifelong HAART (highly active antiretroviral therapy), and their HIV-positive inhabitants strain to support lifelong antiretroviral drug side effects.
At the end of the International Conference, researchers were still frustrated in their attempts to navigate between these conflicting poles of attraction. They could not chart a definitive course, but perhaps they had begun to trace out an emerging global effort to treat persons with HIV.
When it comes to using HAART in Africa, there's good news and bad. The good news: Data from small pilot programs in the Ivory Coast and Senegal suggest that combination therapy will be no less effective in Africa than it is in the United States. In the Ivory Coast study, for example, 51% of those on antiretroviral therapy had undetectable viral loads after 10 months.
This Ivory Coast UNAIDS Initiative enrolled 2,144 individuals and provided anti-HIV therapy to those who could pay or qualify for subsidies. Even with subsidies and UNAIDS involvement, most Africans still not afford antiretroviral drugs. Only 422 of the 2144 participants received treatment. Of these, almost two-thirds took AZT/ddI dual therapy A mere 36% had a protease inhibitor (indinavir) in their regimen.
In an overlooked presentation, Ivory Coast researcher A. Juillet analyzed the extent to which UNAIDS had improved drug access and concluded that, "the Initiative had a small impact on the prices of ARV [antiretroviral therapy] in the short-term." In contrast, generic availability of such drugs as AZT and d4T brought a 16% price reduction.
Dual therapy is undeniably a poor substitute for HAART. But when a UNAIDS-funded program treats two-thirds of patients with two nucleoside analogs, the question looms: Is some treatment better than none at all? This debate played out in various sessions and was officially tackled by Julio Montaner of the British Columbia Centre for Excellence in HIV/AIDS and Praphan Phanuphak, director of the Thai Red Cross AIDS Research Centre in Bangkok. Phanuphak, an outspoken advocate of maximizing limited resources, posed the question this way: Is dual nucleoside therapy worth providing if it can in the short run reduce disease progression, increase CD4 counts and possibly drop viral load enough to significantly reduce chances of transmission? His answer was an emphatic yes.
Little research has been done on how best to use limited therapeutic resources. Phanuphak cited HIV NAT 002, a trial of d4T plus ddI in which 58% of patients on the two-drug regimen for two years had undetectable viral loads. (This trial used the bDNA assay, which measures viral load down to what the more standard PCR test would consider 1,500 copies/mL.) Phanuphak argued that even if two nucleoside analogs do not fully suppress viral load, they may buy patients valuable time. Delaying treatment until CD4 cell counts approach 200 is a cost-saving measure, but other considerations can prevail. If a patient wants to secure a window of time to earn money, attend a wedding, or await the birth of a child, it may be better to intervene earlier.
One of the NAT 002 co-investigators, well known Australian AIDS researcher David Cooper, agreed. He commented, "We are encouraged by the persistent good responses. I think that on balance dual nukes are OK in the developing world as a hold measure for persons who can't afford triple [combination therapy]."
The Thai trial participants may also have benefited from improved treatment of concurrent infections after they began receiving special attention from the trial staff. Treating such infections is much easier than treating HIV and may significantly diminish HIV replication. In Durban, Zvi Bentwich of Hebrew University of Rehovot, Israel related such an experience when treating HIV-positive Ethiopians for intestinal worms. Bentwich observed that eliminating these helminthic worms reduced chronic immune system activation. Activated CD4 cells are particularly prone to invasion by HIV infection and are the main site for viral replication.
The next question Phanuphak tackled was, "Will double nukes engender resistance and complicate future treatment options?" His answer: not necessarily. HIV NAT 001 was a Thai study of AZT plus ddC in which 95 participants were able to switch after 66 weeks on dual therapy to a three-drug regimen that contained AZT/3TC or d4T/ddI plus the protease inhibitor Fortovase (soft-gel saquinavir). After 84 weeks of the new regimen, 78% of the volunteers had HIV levels below 50 copies/mL.
For his part, Montaner argued that it is both medically and morally unfeasible to settle for anything less than HAART. "HAART is defined by full [HIV] suppression; not by the number of drugs," Montaner noted. He pointed out that mortality rates are significantly lower among those on triple combination therapy, and that individuals on double nucleoside analog regimens switch drugs more frequently than those on HAART regimens.
As with last winter's 7th Conference on Retroviruses and Opportunistic Infections in San Francisco, much attention was paid at the International Conference to structured treatment interruptions (STIs). STIs promise to cut the costs of therapy first because patients need not continually take drugs and second because they may permit patients eventually to stop therapy altogether.
The original theory behind STIs was that periodically going off therapy allows HIV levels to rebound temporarily, enabling the immune system to learn how to control HIV through repeated controlled exposures to the virus. STIs would function much like a vaccine and eventually permit patients to stop treatment permanently.
Data presented in Durban suggested that this approach was unlikely to be successful. The first long-term results from the 122-person Spanish Swiss Intermittent Therapy Trial, which is the largest STI trial to date, revealed no trend toward decreased viral loads after successive STIs. The SSITT participants begin the study with viral loads below 50 copies/mL while on HAART. They are supposed to stop HAART four times for two-week intervals separated by eight weeks on treatment. At week 40, they go off therapy until their viral loads rise above 5,000 copies/mL. Of the 14 now beyond week 40, only two had viral loads that stabilized below the 5,000-copy threshold.
There were some indications that anti-HIV immune responses improved in SSITT participants, but cell culture tests measuring such responses might not reflect the situation within the human body, warned Andrew McNeil of the National Institute of Allergy and Infectious Diseases (NIAID) in the U.S. In his study of seven persons taking a break in treatment, immune responses to HIV actually decreased, not because the necessary CD4 cells disappeared, but because they lost the ability to proliferate as HIV levels increased. McNeil warned that some as yet undiscovered property of HIV infection suppresses immune activity beyond the virus's cell-killing effects.
If STIs now seem unlikely to lead to drugless control of HIV, at least they still could reduce the burden of drug side effects and costs. They also could make patients' lives easier by reducing the amount of medication they must take. Anthony Fauci, chief of the NIAID, was excited enough about these prospects to conclude his Durban lecture by showcasing his lab's treatment interruption research.
Fauci later commented, "[HIV] remission or eradication – that's not feasible for people in chronic infection. We're trying to create a situation in which people could be off drug for a fixed period and HIV doesn't rebound or impair CD4 count."
Fauci and his NIAID group are now focusing on what they call "SITs" – structured or short-cycle intermittent therapy. They are testing three different schedules: two months on therapy with one month off; seven days on with seven days off; and two days on with five days off. In Durban, Fauci and his associate Mark Dybul presented the preliminary results of two pilot studies testing the SIT technique. The trials enrolled persons whose HIV had subsided on HAART to less than 50 copies/mL.
All nine volunteers following the one-month off schedule did experience a rebound in their HIV, but all returned to undetectable levels when back on therapy. So far, they have gone through two on-and-off cycles. There has not yet been any sign of drug-resistant HIV. This is everyone's main concern when allowing periodic high-level HIV replication. As in the SSITT, there also was no evident tendency for reduced peak viral levels during successive interruptions.
Four volunteers spending seven days on and seven days off drug have maintained viral loads below 50 copies/mL for two months so far. Three volunteers following the two-day on/five-day off schedule have not fared so well. By week eight, two of the three were dubbed failures because their viral loads had rebounded to above 500 copies/mL. CD4 counts remained stable on both schedules.
Of course, such provisional data should not encourage community use of SITs. The long-term success of this approach remains an open question. Patients may not be able to keep their HIV suppressed over long periods because of the emergence of drug resistance. The interval between treatment cycles that best precludes this danger is still not known.
The precise steps required when interrupting therapy are also undetermined: Current knowledge of the speed with which the body eliminates drugs is insufficient to decide exactly when each drug should be stopped. If all drugs in a combination regimen are stopped at once, some will disappear from the body very quickly while low levels of other drugs persist. A patient's HIV will in effect be exposed to suboptimal treatment for up to several days As the virus again begins to replicate under these conditions, mutated drug-resistant HIV may out-compete normal, "wild-type" virus and become widespread in the patient's body. Only further experience will define the extent of that risk of developing drug resistance.
In the NIAID study, patients on efavirenz stopped the drug a day before their other medications because of its particularly long half-life in the blood. Giving the drug a 24-hour head start to clear out of the body appears to have worked – at least so far. A major worry is the nucleoside analogs. Their intracellular half-lives vary immensely, making it nearly impossible to know exactly when to stop each drug.
The number of open questions surrounding SITs led some community advocates to question whether NIAID should have brought its data to the conference. Doubts do remain about SITs' ultimate impact on HIV suppression, drug side effects and patient quality of life, the economic benefit is self-evident.
That economic benefit last year led Bombay AIDS specialist Shashank Joshi on his own to try month-long on-off cycles of AZT or d4T, 3TC and saquinavir. He tested this schedule in 26 newly diagnosed patients with HIV viral loads above 20,000. Joshi reported that after a year, all had undetectable viral loads and remained clinically asymptomatic.
The economic benefit of treatment interruptions may be most compelling in resource-poor regions. It also has great attraction in developed countries as these nations struggle to cope with HAART's pharmaceutical and patient management costs.
Western models of HIV care may in any case be too aggressive. British AIDS specialists in particular take this position, as does Dr. I. S. Gilada, Secretary General of People's Health Organization in India. He said, "I don't even think what the Western world is doing is right. On more than 60 to 70% of occasions, they are over-treating their patients, treating when it is not required, often treating with higher doses than what is optimal, and with more drugs." The argument over "rigor versus reality" may have an unanticipated resolution if it turns out that simplified therapies are preferable even in industrialized lands.
There is a difference between conservative treatment and blindly cutting corners, however. Techniques like treatment interruptions, dual nucleoside analog therapy and delayed therapy have yet to be vetted by extensive, long-term study. For that reason, they are not ready for acceptance as standard practice.
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