Pensive pilgrims, passing surely
Through our tear-drained city's center
Can your faces, foreign seeming,
Mean your hearts are foreign, too?
Too firm set, your steady pace,
Too far off, your homebound hearts,
To brake, to break, for death?
--Dante, La Vita Nuova¹

Introduction

Africa is a land of vast wealth. Especially south of the Sahara, these riches reach fairy-tale proportions.

Half of the world's gold comes from South Africa, Ghana, and Zimbabwe--half the diamonds from South Africa, Botswana, and Congo.² Uranium, platinum, and petroleum abound. Copper, cobalt, and antimony teem. Almost all the world's chromium rests in the continent's southern end. The Congo River alone has the hydroelectric potential of all US waterways combined.³

Then there are the animals. More species of freshwater fish, 2,000, fin their way through African waters than through any other land's rivers and lakes.² And the continent claims the most ungulate species--impala, kudu, knu, gazelle, kob, and dik-dik, to name just six. Primatologists count 45 species of Old World monkeys, the source of HIV-2, plus two notable great apes, the gorilla and the chimpanzee, source of HIV-1.

When and how these retroviruses (the causes of AIDS) came from forest to village, to town and metropolis, remain the stuff of honest debate and desultory diatribe. Whatever the route, HIV has arrived, has killed millions, and will kill millions more.

Against HIV, Africa's vast wealth counts for little, for reasons well known to political scientists and to anyone with even a passing interest in the past 500 years of history. Much of this unhappy land's inherent wealth left forever by sailing ship and steamer bound for Europe and the Americas. And most of those riches were reaped by unpaid and unwilling native labor. Many of those who did not die hauling the white man's cargo in Africa died elsewhere, planting his cotton.

When Northern countries finally retreated--politically, if not corporately--from Africa, they often left local despots in charge or, as in Zaire, engineered their accession to power.⁴ The debt Europe and the US owe Africa long ago reached proportions that cannot be defrayed by "debt relief."

This continent's native trove of natural bounty renders risible the polite phrase maker who calls southern Africa "resource poor." If sub-Saharan lands are resource poor, England, Belgium, and the Netherlands must grovel at the very nadir of hardscrabble squalor. Yet HIV-infected people in Europe and North America got a fresh lease on longevity a few years back when better and more expensive therapies emerged. In Africa, the epidemic's epicenter, some countries want these therapies and cannot afford them, other countries conjure debates about whether the drugs are worth wanting, and a few others are so war torn that they haven't the time to notice whether gunfire or HIV is winning the mortality race.

For all these reasons, and for many more, pilgrims from North America and Europe to the XIII International AIDS Conference in Durban, South Africa, could only journey with the same penitential remorse borne by Christian pilgrims of an earlier era. It did not help that Durban has become the very vortex of this plague--the most affected city in the most affected province of the most affected country in this most affected continent. And going there to report or record advances in antiretroviral therapy seemed, at first, absurd.

Add to this discomfort the jubilant high spirits of AIDS specialists--medical and nonmedical--who flew to Durban from African countries and struggling nations on other continents. Certainly they had every right to celebrate this first international conference in Africa. The decision of outgoing International AIDS Society President Mark Wainberg to move the meeting there was overdue, courageous, and in every way correct.

Yet it's not hard to imagine that, a few years hence, these elated attendees will see Durban as their Vancouver, their Berlin, and their Atlanta rolled into one--Atlanta because that was the site of the first worldwide AIDS conclave, and this was their first; Vancouver because just being there seemed to solve everything; and Berlin because the news seemed very, very bad.

The sheer statistical burden of this epidemic in Africa made words like cataclysm, apocalypse, and holocaust sound hypobolic. The notion that 80 percent of 15-year-old boys in Botswana may die someday of AIDS⁵ apparently has no correlate in human history. One can only assume the fate of girls will be as bad, or worse. If the Cuban missile crisis of 1962 had evolved to nuclear war, one wonders if the US and the USSR could have pummeled each other thoroughly enough to match that mortality estimate.

Meanwhile, studies that focused on immediate stop-gap measures, like giving women an effective microbicide and slowing rates of mother-to-child transmission, gave little grounds for near-term optimism. A placebo-controlled UNAIDS trial of nonoxynol-9 found that women using this spermicide became infected with HIV more than women using a simple moisturizer [abstract ThOrC660]. The placebo-controlled PETRA study showed that breastfeeding wipes out the transmission-preventing effect of short-course zidovudine/lamivudine (AZT/3TC) given to infected mothers before, during, and briefly after delivery [abstract LbOr5]. Other work confirmed the emergence of nonnucleoside-resistant virus after single-dose nevirapine to prevent mother-to-child transmission [abstract LbOr13] and charted high rates of resistance among Ugandans treated with highly active antiretroviral therapy (HAART) [abstracts TuPeB3293 and WePeA4079].

But only a tiny, temerarious minority frets that antiretrovirals are too dangerous for Africans. No one pretends that antiretrovirals are wholly effective or wholly harmless. Medicine has always been a matter of balancing the wanted effects of drugs against the unwanted. The rest of this report will consider that balancing act from the perspective of Western scientists and clinicians who made the trip to Durban without complaint, indeed, with enthusiasm. That work addresses a single disease called HIV infection, whose similarities from one country to the next vastly outweigh its variations. For that simple reason, their work will directly and indirectly affect the epidemic wherever it festers.

Africa is a land of vast wealth. And the least of it derives from its copper, cobalt, and antimony. Any land best measures its wealth in the bravery and vision of its people. AIDS pilgrims heard two of them, one at the start of the conference and one at the end; one white, one black; one seropositive, one seronegative; one gay, one straight; both insistent that Africa needs AIDS drugs now. South African Justice Edwin Cameron and former president Nelson Mandela arrived at that immutable conclusion from perspectives a world apart, even if engendered in the same country. (Editor's note: See "History Will Judge Us Harshly" for more about Cameron and Mandela.)

Another exemplar of Africa's human wealth lived when Europeans first arrived there. Nzinga Mbemba Affonso assumed the throne in a land called Kongo in 1506 and held it for 40 years, as the Portuguese launched the slave trade.⁶ Affonso I more than held his own, mastering Portuguese and writing learned, if unavailing letters to his European counterpart, João III. And Affonso knew just what he wanted: He wanted the Portuguese to stop stealing his people. He wanted his people to learn the woodworking and masonry skills of the Portuguese. And he wanted their medicine.

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STIs stumble in big Swiss-Spanish study

The Durban meeting offered only a handful of studies on the hottest topic in HIV therapy--structured treatment interruptions (STIs). But, oh, what studies they were. Two in particular stood out. One, the biggest STI trial so far, showed the smallest advantage for this strategy. And during one treatment hiatus in this study, rebounding virus included resistance mutations to two drugs in the study regimen, an apparent first in STI research. Another series of far smaller studies sought to test an entirely new rationale for well-planned drug holidays.

Bernard Hirschel (Cantonal Hospital, Geneva) spelled out some results of the Swiss-Spanish Intermittent Trial (SSITT) [abstract ThOrB747]. The study plan calls for eight weeks of treatment followed by two-week breathers for 40 weeks. Then patients stay off therapy indefinitely, or until their viral load bounces back above 5,000 copies/mL. The 122 persons enrolled so far began with a median CD4⁺ count of 718 cells/mm³; 106 had viral loads below 20 copies/mL, while the other 16 had readings between 20 and 49 copies/mL. Most study participants had never taken antiretrovirals before SSITT, and those with treatment experience had never endured a virologic failure.

Among 56 people who completed four STIs, eight (14 percent) had no rebounds during the two-week breaks, 16 (28 percent) had rebounds to approximately the same level at each interruption, 15 (27 percent) had higher rebounds at each break, and 11 (20 percent) had lower rebounds at each break. The remaining six people (11 percent) didn't roost in any of these pigeon holes. All told, Hirschel could detect no trend toward decreasing viral rebounds from week 2 through week 38.

Nineteen study participants contradicted one consistent STI trend: They all failed to get their viral loads under 50 copies/mL after treatment resumed. Hirschel said clinicians suspected poor adherence in most of these people. (On the issue of adherence and STIs, see the study by Albert Tuldrà [abstract WePeB4207] in the next section.)

The person in whom resistant virus emerged during an STI was taking AZT, 3TC, and nelfinavir. When therapy resumed after the third interruption, this person's viral load dropped only to 2,730 copies/mL. Genotyping sniffed out the 3TC-linked 184V mutation and several common protease mutations. Perhaps, Hirschel suggested, this person was reinfected with resistant virus, but no evidence supported that long-shot possibility.

Among 12 people who completed the STI course and stopped treatment at week 40, four saw their viral load stabilize above the pre-HAART level. In six others the viral load came to rest near the pre-HAART mark. So these 10 people apparently gained nothing, virologically, from their four two-week holidays. In two people, though, post-40-week viral loads stabilized below the pre-HAART baseline. The SSITT team found that one assay verified HIV-specific CD4⁺ T-cell responses in these two people, but another assay did not.

What explains the mixed results in this big study? One possibility, of course, is that treatment breaks simply don't buck up immune function in most people with chronic HIV infection. But another possibility is poor study design. One early and ardent proponent of STIs, Franco Lori (Project RIGHT, Pavia, Italy), suggested that SSITT's two-week drug holiday isn't long enough to rouse slumbering immune sentries into action.

But Hirschel is not so sure. "Brigitte Autran [Pitié-Salpêtrière Hospital, Paris] reported an increase in p24-induced CD4-specific lymphoproliferation after a one-week treatment interruption,"⁷ he wrote to IAPAC Monthly. "She since claims that this response weakens when treatment interruption is more prolonged," he continued, "so the argument can be made either way." Also, because most people have detectable viremia after just a two-week interruption in SSITT, he maintained that "successive interruptions . . . should provide maximal antigenic stimulation, if indeed the concept is of value."

Still, Hirschel hardly hears the death knell for STIs in SSITT's underwhelming results so far. In Durban he characterized the trial as the first of several studies that may someday lead to control of replication without antiretrovirals. One key to more uniform benefits, he proposed, may be to crank up the immune response with agents like GM-CSF or immunostimulatory oligonucleotides.

Two small prospective studies confirmed SSITT's finding that viral loads don't always retreat into undetectable territory when therapy resumes after a break. Hans Jaeger (KIS-Curatorium for Immunodeficiency, Munich, Germany) reported that seven of 12 people with a viral load below 50 copies/mL before a treatment break failed to regain a sub-50 reading when they started their drugs again [abstract WePeB4207]. Study participants had stopped treatment for a median of 1.4 months, but these breaks were not "structured." Jaeger and colleagues tracked anyone who stopped HIV meds for any reason.

A randomized STI study by M. Wellons (Duke University, Durham, N.C., USA) included 11 people with CD4⁺ counts above 400 cells/mm³ and viral loads under 400 copies/mL [abstract WePeB4208]. Four of them never stopped treatment, while seven took two four-week breaks over the course of 16 weeks, then stopped treatment for 12 weeks. Among four holiday takers who had completed the three scheduled breaks, two had no rebound at the first break but did rebound during the next two STIs. The other two individuals had rebounds during all three STIs. Viral loads always dropped when treatment resumed but did not always fall back below 400 copies/mL.

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Do STIs really make people feel better?

Together, the three studies just reviewed show that drug holidays are not always carefree. Resuming treatment is no sure passport to resuppressing viremia. Munich clinician Hans Jaeger also noted that, although most people felt better during their drug breaks, a few suffered symptoms suggesting acute viral infection [abstract WePeB4207]. Indeed, the common assumption that people consistently relish their drug holidays may prove unfounded, according to a 12-person study by Albert Tuldrà (Centra de Canyet, Badalona, Spain) [abstract ThOrB748]. He also found that adherence may turn wobbly after treatment breaks.

The nine women and three men in Tuldrà's study all had viral loads below 20 copies/mL for at least 24 months when they stopped their antiretrovirals for 30 days or until viremia ricocheted above 3,000 copies/mL. After another 12 weeks of treatment, they took another holiday. Throughout this period, Tuldrà gauged their psychological and physical responses to stopping and restarting therapy.

During the first STI, a quality-of-life score improved significantly (P < 0.001), as did perceived health status (P = 0.028). One week after treatment resumed, both scores had sunk (P = 0.002 and P = 0.014). But during the second STI these study participants did not feel their quality of life or health status improved again. The "expected psychological benefits" of STIs "seem not to be substantial," Tuldrà concluded, and early improvements don't persist.

Perhaps even more telling was Tuldrà's finding that adherence sometimes waffled when treatment resumed after an STI. Whereas only one person had less than 100 percent adherence when the study began, three (25 percent) had imperfect pill-taking scores during the first and second treatment resumptions. Tuldrà urged other investigators to monitor adherence closely after holiday-takers return to the antiretroviral grind because some people "seem more interested in stopping therapy than in HIV control."

A careful study of 26 people who stopped treatment for a median of seven week showed that drug breaks can have a substantial impact on some--but not all--metabolic parameters [abstract WePeB4221]. Hirayu Hatano and colleagues (National Institutes of Health [NIH], Bethesda, Md., USA) tracked lipid, insulin, and body fat measures in 26 men who had taken a PI regimen for at least 12 months, had two sub-50 viral loads, and had T-cell counts above 350 cells/mm³. Before the STI, total cholesterol had climbed into the danger zone in nine study participants, and 14 had worrisome triglyceride tallies. Eleven men had evidence of insulin resistance, 13 had lost fat from the face or extremities, and nine had a widening waistline or a buffalo hump.

Average levels of total cholesterol (P < 0.0001), LDL ("bad") cholesterol (P = 0.0013), and triglycerides (P = 0.008) dropped significantly during the treatment break, while 24-hour urinary free cortisol rose (P = 0.016). But insulin profiles did not improve, and fat abnormalities persisted.

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HAART on the installment plan: just as good as full-time therapy?

As the once-limpid stream of STI data widens into a turbid river, it's easy to lose sight of this strategy's source and to forget why it sounded like such a bright idea. For people with well-controlled acute or chronic infection, Bruce Walker (Harvard Medical School, Boston) and Franco Lori proposed that periodic, controlled reexposure to one's own barely simmering viral stew would do something no vaccine has yet done: Train the immune system to recognize HIV and, eventually, to lower its replicative heat permanently, without the help of drugs. Some use the term autoinoculation.

For those lucky few whose HIV infection comes to light before or during seroconversion, Marcus Altfeld in Bruce Walker's group reported that treatment breaks broaden cytotoxic T lymphocyte (CTL) responses [abstract ThOrB750]. That souped-up cellular immunity apparently explains some good early results with five people treated from the earliest days of infection. During the first treatment break, four of the five had steep viral rebounds. But during the second break, all the rebounds were blunted. Three of the five have resumed treatment, while the other two have kept a damper on replication for six and nine months, respectively.

Pointing to results like these, most STI researchers studying people with undetectable viremia during chronic infection still cite the goal of autoinoculation. But in Durban, Anthony Fauci (NIH, Bethesda, Md., USA) proposed an important retrenchment. Fauci has doubted for some time that STIs will help much during chronic infection, and he thinks only a select few with primary infection may benefit.

"It is doubtful that a significant percentage of patients who had originally progressed prior to therapy will be able to have HAART discontinued for prolonged periods of time following repeated interruptions of HAART," Fauci reiterated during a plenary lecture [presentation TuOr36]. But others may enjoy "significant periods of time off therapy," and those breaks could deal a double boon to holiday takers--regular, maybe prolonged breaks from antiretroviral side effects and big-time savings on pharmacy bills. Indeed, as the NIH study reviewed above [abstract WePeB4221] showed, even in the short term holidays can right some metabolic upsets associated with antiretrovirals. This strategy always assumes a return to treatment, however, and Fauci urged clinicians and people with HIV to avoid trying STIs for any reason until large prospective studies can verify their purported merits.

Still, Fauci tantalized attendees with some early results from studies that shuttle people through varying cycles of treatment relieved by strictly timed holidays. But Fauci let his protégé Mark Dybul sketch in the details during a late-breaker session [abstracts LbOr11 and LbOr12]. And Dybul promptly upped the ante on his boss's talk, asking whether 70, 50, or even 30 percent of standard drug doses over a given period can do as well as 100 percent.

To find out, Fauci's team is recruiting people with chronic infection and with a CD4⁺ count above 300 cells/mm³, a viral load below 500 copies/mL for at least six months, and a viral load under 50 copies/mL when they enter the study. Dybul is testing three tactics: cycles of two months on and one off, seven days on and seven off, and even two days on and five off.

That dare-devil third tactic failed to hold viral loads under 50 copies/mL in two of three people so far. But after 14 weeks of follow-up, all five of the people trying the seven-days-on-seven-off strategy got their viral loads below 50 copies/mL every time they started swallowing antiretrovirals again. When one study participant forgot to pack his meds for a one-month cruise, his viral load steamed back to 70,000 copies/mL. That extemporaneous experiment, Dybul said, indicates that the week-by-week plan is doing little to boost immune function, at least not so far. Levels of CD4⁺, CD8⁺, and activated CD8⁺ cells have not changed in this study, which will last six months.

The longest trial to date looks at the two-month-one-month tradeoff. Nine of 70 people have made it through two or three cycles. These study participants were pretty healthy for people with HIV infection. The average CD4⁺ nadir before anyone started antiretrovirals measured 366 cells/mm³, and that had climbed to 740 cells/mm³ (often with the help of interleukin 2) by the time this study started.

The first nine people in this trial have faced viral rebounds every time they stopped treatment, but they all suppressed HIV after they started again. Three people had smaller rebounds during the second treatment interruption, while one had a higher rebound. The average CD4⁺ count swooned by 19 percent during the first drug holiday. But, after that, T-cell counts hardly budged during the one-month treatment breaks.

Like Fauci, Dybul characterized the studies as pilot trials meant to shape strategies for bigger studies. "No one is suggesting that we do anything clinically with this," he stressed. Still, some edgy attendees criticized release of these early results, precisely because they may encourage copycat holidays in the community. But Dybul reminded colleagues that many HIV-infected people are already taking unchaperoned drug holidays. He argued that different strategies must be tested, eventually in controlled trials, to see if the on-off idea works and, if it does, to pinpoint the best timetable. Another questioner noted that intermittent therapy breaks may work only in people who can keep their viral loads under 50 copies/mL with full-time HAART, speculation that Dybul did not dispute.

The strategy certainly has risks, and Dybul ticked off three of them: loss of any HIV-specific T cells that may be stockpiled during HAART, a more general loss of immune response, and the threat that drug-resistant mutants may emerge during drug breaks. Indeed, Joseph Eron (University of North Carolina, Chapel Hill, USA) noted that different drugs have different half-lives. As a result, some may linger longer in the body than coadministered agents and so elicit mutations. "We may be playing with fire," Eron warned, "if we think we know when to stop each drug."

In Africa, where antiretrovirals are absent, adherence is zero." That comment from an audience member after a Durban presentation on pill-taking habits reminded attendees that this international conference, unlike its 12 predecessors, moved simultaneously on two planes. While clinicians from developed countries honestly debated issues of great portent for their patients, clinicians from African nations and other struggling countries would occasionally administer a polite dose of counterpoint from the wide world below the Tropic of Cancer.

Even so, the XIII International AIDS Conference offered more hints of HIV drugs' impact beyond the Americas and Western Europe. Two studies, for example, chronicled the advent of resistance in Uganda. Paul Weidle (US Centers for Disease Control and Prevention [CDC], Atlanta) and colleagues in Kampala, Uganda, reported decreased susceptibility to 3TC in 78 percent of isolates from 51 people taking two nucleosides or HAART for at least 90 days [abstract TuPeB3293]. One of two people exposed to a nonnucleoside had the class-killing 103N mutation. In a group of 20 Ugandans taking antiretrovirals, M. Juntilla (Case Western Reserve University, Cleveland) and Kampala coworkers found that genotypic and phenotypic evidence of resistance "was common and may be associated with suboptimal treatment or poor adherence" [abstract WePeA4079]. Clearly, wherever antiretrovirals go, poor adherence and rampant resistance will follow.

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Is good adherence a matter of life and death?

Paula Braitson (BC Centre for Excellence in HIV/AIDS, Vancouver) studied adherence in 950 persons taking antiretrovirals for a median of 13 months [abstract TuOrB419]. They had a median baseline CD4⁺ count of 280 cells/mm³ and a median starting viral load of 130,000 copies/mL. Braitson estimated adherence based on the number of monthly prescriptions written and dispensed, probably not the most precise yardstick. Still, since antiretroviral prescriptions for everyone in British Columbia are recorded in the Vancouver database, the survey is comprehensive. And since antiretrovirals are free in Canada, cost could not be a factor in filling prescriptions.

Among 817 persons without AIDS at baseline, 59 died from AIDS during the 2.5-year study period. A multivariate analysis looking for predictors of death found three: AIDS (relative risk [RR] 1.8, P = 0.045), every 100-cell decrement in CD4⁺ count (RR 1.49, P < 0.001), and poor adherence (RR 1.24, P < 0.001). Those numbers mean that AIDS increased the risk of death by 80 percent, lower CD4⁺ counts did so by 49 percent, and poor adherence by 24 percent.

Some attendees criticized the analysis for including adherence and CD4⁺ counts in the same model. The findings may be muddied, according to this logic, because good adherence should boost CD4⁺ counts, and poor adherence could lower them. Braitson, not a statistician, could not defend the study methods. But two other studies with different methods reached similar conclusions.

A. Carmona (Hospital del Mar, Barcelona, Spain) tracked 736 people taking HAART, 45 percent of whom injected illegal drugs and 30 percent of whom had AIDS [abstract TuOrB417]. Defining good adherence as taking 90 percent or more of prescribed doses, Carmona determined that 68 percent had good pill-taking habits through an average follow-up of 93.5 weeks. Pharmacists rated patients for good adherence by interviews and pill counts.

In a multivariate analysis considering age, sex, CD4⁺ count, viral load, AIDS status, and adherence, only two factors predicted death during the study period: AIDS and bad adherence. Among 499 good adherers, nine (1.8 percent) died, compared with 20 of 237 poor adherers (8.4 percent, P < 0.0001). That translated into a 67 percent greater chance of death among poor adherers.

AIDS proved a similarly powerful predictor. Among 217 people with AIDS, 21 (9.7 percent) died during the study period. That compared with eight deaths among 519 seropositive people (1.5 percent) without AIDS (P < 0.001). People with AIDS had a 64 percent higher risk of death.

Among 130 people with AIDS and good adherence, six (4.6 percent) died, compared with 15 deaths among 87 people (17.2 percent) with AIDS and poor adherence (P < 0.001). Carmona calculated that poor adherence plus AIDS upped the odds of death 68 percent in this cohort.

Some attendees believed the study's results could be confounded by the overlap of AIDS and adherence as predictors of death. People with AIDS are sicker and often more depressed than those without AIDS, argued Richard Haubrich (University of California, San Diego), so the motivation to take their pills may wane. In fact, Carmona couldn't document whether the poor adherence preceded or followed an AIDS diagnosis in these individuals. On the other hand, another Vancouver study found that an AIDS diagnosis increased the chance of adherence (see abstract MoPpD1056 in the next section). And Carmona's correlation between survival and good adherence with AIDS--versus a higher death rate among poor adherers with AIDS--should prove a powerful motivator for people with advanced disease to take their meds faithfully.

The third study involved 330 San Franciscans living in single-room occupancy hotels or homeless shelters or taking advantage of free meal programs [abstract ThPeB5185]. Through 535 person-years of follow-up, investigators lost track of only seven people (2.1 percent). During this time, 25 people (7.6 percent) died. A team headed by David Bangsberg (University of California, San Francisco) determined adherence in this study by making unannounced visits to study participants' residences and counting their pills. Unlike other adherence methods, such pill counts don't interfere with use of pill box organizers and are less susceptible to pill dumping by people eager to please health professionals.

Bangsberg singled out predictors of AIDS-free survival in a multivariate analysis that accounted for time-fixed covariates (age and CD4⁺ count at baseline; gender; race or ethnicity; injecting drug use; and sex between men) and time-dependent factors (taking three or more antiretrovirals and mean pill count adherence). Only three of these variables correlated significantly with AIDS-free survival: Caucasian race increased the chance of AIDS-free survival by 80 percent (P = 0.035). Every 100-cell increment in baseline CD4⁺ count doubled the chance of AIDS-free survival (P < 0.001). And every 50 percent decrease in average adherence slashed the chance of AIDS-free survival 49 percent (P = 0.03).

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What explains--and what encourages--good adherence?

A study of poor inner-city residents in Hartford, Conn., USA, used MEMS caps, pill counts, and self-reports to track adherence among 40 HIV-positive people over three months [abstract TuOrB416]. JoCarol McNabb (now at the University of Nebraska, Omaha, USA) reported that pill counts greatly overestimated adherence in this analysis, indicating 79.8 percent adherence compared with 53.5 percent with MEMS caps (P < 0.01). Or, as Bangsberg might argue, perhaps MEMS caps underestimated adherence somewhat in this study. So interpretation of any adherence study is always open to question.

Keeping such caveats in mind, one can still discern meaningful trends by comparing results of studies that use different techniques, for example, the correlation between bad adherence and death noted by three teams in the studies reported above. McNabb and the Hartford group used their MEMS cap results to confirm an oft-reported finding--that first-rate adherence usually translates into good virologic suppression. Six of six people with better than 90 percent adherence had viral loads below 400 copies/mL, compared with 11 of 15 (73 percent) whose adherence measured 80 to 90 percent, 12 of 25 (48 percent) with 70 to 80 percent adherence, and 15 of 64 (23 percent) with less than 70 percent adherence (P < 0.01). That surprisingly uniform steplike descent from the highest adherence rung to the lowest was first reported by David Patterson (University of Pittsburgh), Susan Swindells (University of Nebraska, Omaha, USA), and colleagues, who published their findings around the time of the Durban meeting.⁹

At the same time, though, McNabb added a new wrinkle to the adherence tapestry by showing that an undetectable viral load does not necessarily signal good adherence. Eleven of 40 people in this cohort (27.5 percent) had undetectable viremia despite adherence below the 80 percent bracket. That finding is not so surprising when one learns that all 11 had viral loads below 5,000 copies/mL at study entry. But it should warn clinicians not to equate a sub-400 viral load with good adherence.

The Hartford study also confirmed a finding reported by several groups at the 1998 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): Taking fewer antiretroviral doses daily does not automatically improve adherence. McNabb reported no adherence difference between people taking drugs twice a day and those on thrice-daily combinations. Only one person in the group was taking a once-daily regimen, so that result couldn't be factored against the two-times and three-times schedules. However, a covey of clinicians from three US cities found that adherence to a twice-daily nelfinavir regimen was no worse than adherence to twice- or once-daily nonnucleoside regimens [A. Luber et al. Abstract ThPe4991].

Although dosing frequency may not be decisive in determining adherence, pill counts do appear to matter. Analyzing the effect of number of pills swallowed daily in 19 different regimens tested in 22 clinical trials, John Bartlett (Duke University, Durham, N.C., USA) found a statistically significant link between higher pill burdens and viral loads above 50 copies/mL after 48 weeks of treatment (P < 0.01) [abstract ThPeB4998]. That association held true in a multivariate analysis that accounted for disease stage at baseline and antiretroviral drug class. Bartlett proposed that "higher pill burden is a potential barrier to optimum drug adherence, which in turn supports the need for simplified dosing regimens."

Of course Bartlett's study took a back-door approach to the adherence issue because it didn't directly measure how faithfully people stuck with their schedules. By focusing on the relation between number of pills and virologic results toted by intent-to-treat analyses, Bartlett's reckoning favors some regimens with low pill counts that recently yielded good virologic results compared with higher-pill count combos that didn't do as well. For example, the analysis includes the open-label comparison of efavirenz (three pills once daily) and indinavir (six pills daily in three doses) in which efavirenz did better in the intent-to-treat outcome, partly because so many people dropped out of the indinavir arm.¹⁰

Still, it stands to reason that people will adhere better to a regimen with fewer pills. So why doesn't the equally intuitive advantage of fewer daily doses hold true? Perhaps because so many other factors mesh more closely with good adherence. Vancouver investigators drove home that point in a study of 866 people who began antiretroviral therapy between August 1996 and October 1998 [abstract MoPpD1056]. Sophie Low Beer (BC Centre for Excellence in HIV/AIDS) reported that five variables correlated significantly with 95 to 100 percent adherence in a multivariate analysis (Table 2).

Two findings here stand out because they haven't been reported often. An AIDS diagnosis more than doubled the chance of good adherence, and more HIV experience by the treating physician increased the odds favoring adherence by 45 percent. Although one can argue that people with AIDS are sicker and more depressed than asymptomatic seropositive people, and so less likely to adhere well, this study suggests a counter-rationale: An AIDS diagnosis can convince a person that now, indeed, the time has come to get serious about pill-taking. And for someone with AIDS and sturdy support from an experienced physician, taking twice-a-day dual PIs, for example, may not compare so onerously with once-a-day efavirenz.

One other adherence finding reported in Durban bears mentioning, even though it's not new. Two teams confirmed earlier reports that good adherence today doesn't always mean good adherence tomorrow. In a cohort of 637 people who enrolled in two CPCRA¹¹ studies and completed an adherence questionnaire, Gerald Friedland (Yale University, New Haven, Conn., USA) found that 72 percent claimed full adherence one month after enrollment, compared with 64 percent after four months and 60 percent after eight months [abstract TuOrB421]. Questionnaires completed by 224 people in the Dutch ATHENA study charted complete adherence among 66 percent still in their first 24 weeks of antiretroviral therapy and among 47 percent with more than 24 weeks of experience (P = 0.01) [P. Nieuwkerk et al. Abstract ThPeB4987]. In Friedland's words, both studies show that "adherence is a long-term dynamic behavior that needs constant reinforcement."

Getting people to agree that bad adherence has bad consequences is not so tough. But it is tough to figure out ways to prevent bad adherence. K. Rawlings (Southeast Dallas Health Center) and colleagues at five other sites tried to encourage good adherence among people starting treatment with abacavir and Combivir (AZT plus 3TC) by pacing them through an 11-segment basic training program on HIV, antiretrovirals, and adherence [abstract TuPeB3223]. The study randomized 96 people to the training program plus routine counseling and 99 others to only routine counseling.

After 24 weeks of treatment and MEMS cap monitoring, the two groups did not differ significantly in adherence, decrease in viral load, or change in CD4⁺ count. Overall adherence in the study measured only 72 percent, but even at that rate about 80 percent in both groups had 24-week viral loads below 400 copies/mL. Another interesting finding is that 96 percent of those randomized to the 11-module course attended the sessions. But only 27 percent of their "informal caregivers" did. Perhaps individuals in traditionally underserved US populations (only 6 percent in this study were white) need not only careful instruction, but also regular support from someone at home.

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Pipeline PIs and NNRTIs, T-20, and lopinavir (ABT-378)

• DuPont's pipeline protease drugs. Susan Erickson-Viitanen (DuPont) reviewed preclinical work with DPC 681 and DPC 684, protease inhibitors the company hopes will make their mark against virus resistant to current PIs [abstract WeOrA532]. Both agents bind selectively to HIV protease, and with a tighter embrace than indinavir or amprenavir. Against a panel of 30 viral isolates, including samples from group M subfamilies A through H and group O, DPC 681 and 684 have 50 percent inhibitory concentrations (IC₅₀s) that generally range between 2 and 4 nM.

  Virus with the 30N mutation (conferring resistance to nelfinavir) or with the 48V and 90M mutations (conferring resistance to saquinavir) appear to be hypersusceptible to both DuPont PIs. Mutants with strings of other familiar substitutions--including as many as five--had only 2.1- to 5.2-fold drops in susceptibility to DPC 681 and 684. The protein-binding-corrected IC₉₀s for these agents were as much as 150-fold lower than the corrected IC₉₀s for indinavir, nelfinavir, or amprenavir when tested against virus resistant to those three PIs.

  DPC 681 and 684 are perched on the verge of phase I studies, Erickson-Viitanen reported. So it will be some time before these drugs get to prove their mettle in people with virus resistant to today's PIs.

• New nonnukes with tougher resistance profiles. In two slide presentations and one poster, DuPont's Erickson-Viitanen and Lee Bacheler rehearsed early findings (including some phase I results) on the company's second-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs). The phase I dosing studies in healthy volunteers suggest, according to Bacheler, that DPC 961 and DPC 083 will have trough levels high enough to handle efavirenz-resistant virus [abstract WeOrA536]. Pharmacokinetic analyses indicate that the new drugs could share an attractive feature of efavirenz, once-daily dosing. But the second-generation compounds stick to human plasma proteins less than efavirenz, so there's more free drug to fight HIV.

  Bacheler also held forth at a heavily attended poster session describing the activity of DPC 961 and DPC 083 against NNRTI-resistant virus [abstract TuPpA1145]. Susceptibility assays showed that both drugs hardly blinked when confronted with virus marred by single point mutations that typically overwhelm efavirenz and other marketed nonnucleosides. DPC 961 generally did better than DPC 083 in susceptibility studies pitting these new NNRTIs against multiply mutant virus resulting from failure of efavirenz, nevirapine, or delavirdine.

  Erickson-Viitanen unveiled results of in vitro passage studies that aimed to select virus resistant to DPC 961 and DPC 083 and two other investigational NNRTIs, DPC 963 and DPC 082 [abstract TuOrA347]. High-level (greater than 100-fold) resistance required multiple passages with all of these agents. Resistance that Erickson-Viitanen labeled "modest" (10- to 20-fold) usually required only a single amino acid change, but, she added, these nonnucleosides attain blood levels high enough to suppress replication of 10- to 20-fold resistant virus. Unlike current NNRTIs, high-level resistance to the new DuPont drugs required two or three mutations. Although that finding suggests these new NNRTIs will hoist a higher in vivo barrier to resistance than current NNRTIs, Erickson-Viitanen reminded attendees that in vitro passage studies have been notoriously inaccurate in predicting which mutations will hobble nonnucleosides in humans.

• Megasalvage including T-20. As Trimeris gears up for phase III studies of the fusion inhibitor T-20 later this year, Calvin Cohen (Community Research Initiative, Brookline, Mass., USA) presented 48-week data on the drug in a Durban late-breaker poster [abstract LbPp116]. With colleagues from two other US sites, Cohen studied T-20 combined with a median of five other antiretrovirals in 71 people with voluminous treatment histories. Nearly all had tried at least one protease inhibitor, and four of five had taken drugs from all three current antiretroviral classes. Everyone had also taken short-course T-20 in earlier trials. Their median baseline viral load stood at about 63,000 copies/mL, and their median CD4⁺ count was 133 cells/mm³.

  As one might expect in any group like this, a high proportion, 42 percent, did not continue taking the twice-daily 50-mg subcutaneous shots of T-20 for 48 weeks. Side effects that could be attributed to T-20 caused none of these dropouts, but 14 people (20 percent) stopped taking the drug because their viral load fell by less than a half-log. Among the 41 people who made it to the 48-week mark, the average viral load fell by 1.5 logs, and 16 of those 41 (39 percent) had a viral load below 400 copies/mL.

  Most people complained of injection site pain, and subcutaneous nodules arose in many. Trimeris continues to tinker with the formulation of this agent in hopes of avoiding these skin reactions. Serious side effects possibly caused by T-20 included elevated liver or pancreatic enzymes, anemia, and neutropenia. When people are taking five other drugs, it's hard to say exactly which ones are causing the side effects, and exactly which ones are helping to lower the viral load. (Clinicians picked the other drugs with guidance from genotypic testing.) But since T-20 works by a mechanism not exploited by current antiretrovirals, and since it did well in short-course monotherapy studies, it seems likely that this fusion inhibitor played some part in controlling replication among people who responded.

• First look at the next PI in kids. The protease inhibitor farthest through the approval pipeline, lopinavir, plus low-dose ritonavir, showed good antiviral activity in treatment-naive and -experienced children. Avyi Violari (Chris Hani Baragwanath Hospital, Johannesburg, South Africa) reported 24-week data from an open-label study of 100 six-month- to 12-year-old children, 44 of them without treatment experience [abstract MoOrB177]. After a three-week comparison of two doses, investigators settled on 300 mg/m2 of lopinavir every 12 hours, given with 75 mg/m² of ritonavir.

  An intent-to-treat analysis after six months of therapy found that 36 of 44 treatment-naive children (82 percent) had viral loads below 400 copies/mL, as did 37 of 56 kids (66 percent) who had taken antiretrovirals before. Among children who had only nucleoside experience when they started lopinavir, 72 percent slipped under the 400-copy mark, whereas only 58 percent with nucleoside and PI experience did so. CD4⁺ counts surged in both groups, by an average 355 cells/mm³ in the experienced children and an average 328 cells/mm³ in the naive children.

  Children began treatment with moderate to high viral loads--4.9 logs in the naive group and 4.5 logs in the experienced group. Violari and colleagues from Panama, the Bahamas, and the US gave treatment-naive children stavudine (d4T) and 3TC with the PIs; they added the nonnucleoside nevirapine and one or two nucleosides to the PIs for experienced children. As in adult lopinavir trials reported so far, none of the treatment-experienced children had used a nonnuke before, so it's hard to sort out how much of the treatment effect in that group came from lopinavir/ritonavir and how much from taking a nonnucleoside for the first time.

  No study participants dropped out because of lopinavir side effects, and the overall 24-week dropout rate measured a scant 1 percent. Complications in treating Burkitt's lymphoma accounted for the sole discontinuation. Side effects possibly related to lopinavir/ritonavir or the other study drugs included two rashes and one case each of constipation, hepatomegaly, vomiting, allergic reaction, fever, and viral infection. Four children had amylase elevations more than 2.5 times the upper limit of normal, and four had platelet counts below 50 x 10⁹/L. Among the other lab abnormalities were elevated bilirubin or liver enzymes, each in three children, and a total cholesterol greater than 300 mg/dL in two.

• Lopinavir efficacy and safety at 72 weeks. For adults, the new Abbott protease inhibitor will be given at a dose of 400 mg twice daily with a 100-mg ritonavir kicker each time. Representing a squadron of clinicians from 14 US centers, Melanie Thompson (AIDS Research Consortium, Atlanta) reported 72-week virologic data from two phase II trials that enrolled treatment-naive and single-PI-experienced people [abstract TuPeB3197].

  A previously untreated group of 100 people added d4T and 3TC to lopinavir/ritonavir. Their median baseline viral load was about 63,000 copies/mL, and the median CD4⁺ count was 326 cells/mm³. After 72 weeks, 89 study participants had not met the "loss-of-response" definition--two consecutive viral loads above 400 copies/mL after any sub-400 reading. Among the 11 people in whom lopinavir did fail by this criterion, the "failure" proved evanescent in six, who reclaimed their under-400 status by week 72. Of the five other patients with loss of response, investigators documented poor compliance in three.

  The study of 70 people who had already taken one PI, but no nonnucleosides, added nevirapine and at least one new nucleoside to lopinavir/ritonavir. These people began the fresh regimen with a median viral load of 10,000 copies/mL and a median T-cell count of 349 cells/mm³. Viral isolates from 63 percent of those who had baseline phenotyping had at least 4-fold resistance to the PI taken before lopinavir.

  After 17 months of lopinavir, 46 (66 percent) attained and kept the virologic response defined by the 400-copy benchmark used in the naive study analysis. Of the 24 people who did stop responding, five regained a sub-400 viral load before reaching the 72-week milepost. Twelve other nonresponders had documented poor adherence, dropped out early, or interrupted their treatment before they rebounded above 400 copies.

  In an on-treatment analysis, 81 of 84 people (96 percent) in the naive study had fewer than 50 HIV RNA copies/mL at week 72, as did 81 of 100 by a missing-data-equal-failure analysis. On-treatment analysis of the PI-experienced cohort counted 40 sub-50 responders among 58 persons (69 percent) after 72 weeks. The missing-data-equal-failure analysis tallied 40 sub-50 responders among 70 people (57 percent).

  A 72-week safety analysis of these same two cohorts, presented by Harold Kessler (Rush University, Chicago), singled out grade 3/4 diarrhea (more than three loose stools daily) or "abnormal stools" (one to three loose stools daily) as the principal side effect of lopinavir/ritonavir [abstract TuPeB3198]. All told, 30 percent in the treatment-naive group and 27 percent in the experienced group had these problems, and most in both groups had more than three loose stools daily. Fifteen percent in the naive study and 4 percent in the experienced study complained of nausea. Loose stools lasted for a median of 12 days in the treatment-naive cohort and 74 days in the experienced group. Respective median durations for nausea measured seven days and 21 days.

  Grade 3 or 4 jumps in cholesterol or triglycerides affected similar proportions in both cohorts. In the treatment-naive study group, lopinavir/ritonavir contributed to hypercholesterolemia in 14 of 100 and to hypertriglyceridemia in 12. Respective numbers among the 70 PI-experienced people were 19 and 17 (27 and 24 percent). But nobody dropped out of either study because of soaring lipids, which usually responded to statins or fibrates. Investigators counted five cases of abnormal fat distribution among the 100 people in the naive study, and six cases among 70 people in the experienced group.

  Four people, one in the naive cohort and three in the experienced group, did drop out by 72 weeks because of side effects. The one treatment-naive person had elevated liver enzymes. In the treatment-experienced group, dropouts resulted from rash in one and gastrointestinal (GI) complaints (including diarrhea) in two.

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Hydroxyurea data: some consistent, some confusing

Two studies--one of them randomized, placebo-controlled, and 48 weeks long--charted high rates of side effects when hydroxyurea is added to didanosine (ddI) and d4T. And the 48-week study found no significant virologic advantage for hydroxyurea over placebo when given with the two nucleosides plus efavirenz. But, to the surprise of many in the audience, a contest between hydroxyurea and a protease inhibitor, both added to ddI/d4T, crowned hydroxyurea the virologic winner at the 24-week mark (though not later) and counted few side effects among people taking hydroxyurea. A fourth study, which also compared hydroxyurea and a PI, found the PI virologically superior at 40 weeks.

Robert Murphy (Northwestern University, Chicago) laid out 24- and 48-week results of the 3D study, so called because of the ddI, d4T, and hydroxyurea combo [abstract WeOrB603]. US, French, and British collaborators randomized 99 treatment-naive persons and 49 with treatment experience to take 400 mg of ddI once daily and standard doses of d4T and efavirenz plus either 600 mg of hydroxyurea twice daily or hydroxyurea placebo. People didn't start hydroxyurea until they had taken the other drugs for eight weeks.

The experienced study participants had never tried hydroxyurea or an NNRTI and had sampled ddI and d4T for fewer than 12 weeks. Nobody had a history of peripheral neuropathy or pancreatitis. The median baseline numbers for the four treatment arms were similar within the naive and experienced subgroups:

• Naive median RNA (copies/mL): 46,006 hydroxyurea, 46,150 placebo
• Naive median CD4⁺ count (cells/mm³): 377 hydroxyurea, 353 placebo
• Experienced median RNA (copies/mL): 12,202 hydroxyurea, 6327 placebo
• Experienced median CD4⁺ count (cells/mm³): 321 hydroxyurea, 341 placebo

Murphy also offered 48-week virologic results, though the number of people who completed 48 weeks was much smaller. In the naive group, about 85 percent taking either hydroxyurea (n = 26) or placebo (n = 33) had a viral load below 400 copies/mL in an intent-to-treat analysis. In the experienced group, an intent-to-treat analysis showed sub-400 scores for about 65 percent taking hydroxyurea (n = 11) and 75 percent taking placebo (n = 4). Hydroxyurea also blunted absolute CD4⁺ counts in this study, even though people already had eight weeks of ddI, d4T, and efavirenz on board before starting hydroxyurea.

These results show no advantage for adding hydroxyurea to ddI, d4T, and efavirenz for treatment-naive individuals, and perhaps a marginal advantage for adding hydroxyurea when treating people with antiretroviral experience. But there was a big disadvantage to adding hydroxyurea: An independent review board stopped the 3D study because side effects in the hydroxyurea arm outran those in the placebo arm. This is the second time a safety panel shut down a recent hydroxyurea trial because of side effects. At the Conference on Retroviruses and Opportunistic Infections earlier this year, Diane Havlir (University of California, San Diego) reported the unhappy wrap-up of ACTG 5025, in which three people taking hydroxyurea, ddI, d4T, and indinavir died, two because of pancreatitis.¹² Those people were taking the same dose of hydroxyurea used in 3D, 600 mg twice daily.

The problem wasn't pancreatitis in 3D, but peripheral neuropathy. Eleven treatment-naive people starting hydroxyurea quit because of side effects, compared with five in the placebo group. Eight of the 11 hydroxyurea dropouts had neuropathy, compared with two of the five getting placebo. Three treatment-experienced people randomized to placebo left 3D because of side effects, including one case of neuropathy. Two experienced people taking hydroxyurea stopped because of side effects--neuropathy in both cases. Overall, 21 people taking hydroxyurea and nine taking placebo had grade 2 or 3 peripheral neuropathy, and neuropathy's pins and needles began pricking significantly sooner in the hydroxyurea group (P = 0.02).

A randomized Swiss study comparing ddI/d4T/hydroxyurea with ddI/d4T/placebo, published in 1998,¹³ did chart a significantly better three-month virologic response in the hydroxyurea group. At that point, patients in the placebo arm could start hydroxyurea if their viral load languished above 200 copies/mL. Anyone in the study could continue their current regimen or switch to something else. In Durban, Bernard Hirschel (Cantonal Hospital, Geneva) reported that 18 of the 72 study participants (25 percent) originally randomized to hydroxyurea and six of the 30 (20 percent) who added hydroxyurea at month 3 continued taking ddI/d4T/hydroxyurea after two years [abstract TuPpB1239]. Reasons for dropping the regimen were lack of efficacy in 45 percent, side effects in 37 percent, and "patient preference" in 18 percent.

An open-label study presented by Monica Maidana (Hospital Dr. Cosme Argerich, Buenos Aires, Argentina) found that ddI/d4T plus hydroxyurea controls viral replication as well as--and sometimes better than--triple therapy with a PI in treatment-naive people [abstract LbOr7]. On top of that, the hydroxyurea regimen caused fewer side effects and facilitated better compliance than the PI combo.

Maidana and colleagues at two other Argentine centers studied three regimens in 284 people: (1) ddI/d4T plus 500 mg of hydroxyurea daily, (2) d4T/ddI or d4T/3TC plus indinavir or nelfinavir, or (3) ddI, 1,000 mg of hydroxyurea daily, and indinavir. To ease side effects, the 500-mg hydroxyurea dose could be sliced to 200 mg, and the 1,000-mg dose could be trimmed to 500 mg.

After 24 weeks, percentages of participants with viral loads below 50 copies/mL in an intent-to-treat analysis were 89 percent taking ddI/d4T/hydroxyurea, 55 percent taking indinavir or nelfinavir plus two nucleosides (P < 0.0001 versus group 1 and P < 0.0007 versus group 3), and 81 percent taking ddI/hydroxyurea/indinavir. Respective 48-week sub-50 results were 93 percent, 69 percent, and 97 percent.

Just as surprising were the proportions with grade 3 or 4 side effects at 48 weeks: 1.6 percent for ddI/d4T/hyroxyurea, 20.6 percent for the indinavir or nelfinavir combos (P = 0.0026 versus group 1), and 12.5 percent for ddI/hydroxyurea/indinavir (not significantly different from group 1 or 2). Investigators reported no cases of pancreatitis. At the time of Maidana's report, 86 percent originally taking ddI/d4T/hydroxyurea continued with the regimen, compared with 34 percent in the indinavir or nelfinavir group and 61 percent in the ddI/hydroxyurea/indinavir group. At 48 weeks, 1.6 percent in the ddI/d4T/ hydroxyurea arm had taken fewer than 70 percent of doses, compared with 29 percent in the indinavir or nelfinavir arm and 12.5 percent in the ddI/hydroxyurea/indinavir arm.

In questioning after the presentation, Maidana said baseline CD4⁺ counts and viral loads were equivalent in the three groups, but she did not spell out those numbers. Some questioners were frankly dubious of the side effect incidence, noting, for example, the utter absence of pancreatitis in a hydroxyurea study of this size. But Maidana argued that the option to taper doses of hydroxyurea could account for that. Indeed, pancreatitis was rare in the 3D study, even at the high 600-mg twice-daily dose.

But would tapered doses of hydroxyurea yield virologic superiority, which Maidana reported at 24 and 48 weeks, but which the placebo-controlled 3D study did not find in naive people taking 600 mg of hydroxyurea twice daily? The high dropout rate in Maidana's group 2 (the only group not taking hydroxyurea) could have contributed much to the intent-to-treat virologic superiority of the hydroxyurea arms. Poor adherence in the nonhydroxyurea arm would also have dimmed the antiviral luster of those PI regimens.

A small German study comparing ddI/d4T/hydroxyurea with ddI/d4T/nelfinavir contradicted Maidana's virologic findings [abstract ThPeB5060]. This open-label, prospective, nonrandomized observation, presented by Eva Jaegel Guedes (KIS-Curatorium for Immunedeficiency, Munich, Germany) compared hydroxyurea given to 28 people and the PI given to 17 with statistically similar baseline CD4⁺ counts (medians of 289 cells/mm³ for hydroxyurea and 308 cells/mm³ for nelfinavir) and viral loads (medians of 39,100 copies/mL for hydroxyurea and 60,070 copies/mL for nelfinavir). The dose of hydroxyurea was 500 mg twice daily.

A week 40 on-treatment analysis logged a median 2.8-log viral load drop in the PI group versus a 1.7-log fall in the hydroxyurea arm. At that point, 55 percent taking nelfinavir and 14 percent taking hydroxyurea had a viral load below 50 copies/mL (P = 0.04). Median CD4⁺ counts climbed 210 cells/mm³ in the PI group and 55 cells/mm³ in the hydroxyurea group (P < 0.05). High proportions in both treatment arms changed their antiretroviral regimen--65 percent taking nelfinavir and 59 percent taking hydroxyurea--after medians of 20 and 12 months respectively. Overall, side effects triggered the switches in about 40 percent.

Durban's poster tents brimmed with reports on lipodystrophy. Three teams weighed the contribution of nucleoside reverse transcriptase inhibitors (NRTIs) to this syndrome and came up with two different answers. In something of a surprise, two of these groups failed to link NRTIs to fat abnormalities. Other studies cataloged the effects of pravastatin and recombinant human growth hormone (rhGH) on different aspects of the syndrome, and the news was generally favorable. Another positive study involved testosterone with or without resistance training for HIV wasting.

The impact of lipodystrophy on people taking antiretrovirals has been obvious to anyone caring for those infected with HIV. One Durban poster helped to quantify these impressions. While working at the Gay Men's Health Crisis in New York City, Tobias Kasper and Carlos Arboleda surveyed 74 HIV-positive people, nearly all of whom were taking antiretrovirals [abstract WePpB1380]. The sample included small proportions of Hispanics (26 percent), women (20 percent), and blacks (15 percent). More than three quarters of respondents blamed antiretroviral therapy for body shape changes and metabolic meanderings. Almost half reported four or more body shape changes.

These abnormalities had a decided impact on respondents' thinking about their antiretroviral regimens. Among those with symptoms of lipodystrophy, 30 percent changed antiretrovirals and 7 percent stopped them altogether. Among people who had not changed drugs, 57 percent had thought about it, and 46 percent said they'd switch if their fat problems worsened. Most of those who changed their regimens--83 percent--changed only the drug or drugs thought to be causing the problems.

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Two studies absolve NRTIs of guilt in lipodystrophy, but one study doesn't

Achim Schwenk (now at St. George's Hospital, London) detailed a cross-sectional study of 278 consecutive HIV-positive outpatients at the internal medicine clinic of the University of Cologne [abstract WePeB4236]. Everyone had been taking antiretrovirals since 1989. Schwenk defined lipodystrophy as (1) loss of subcutaneous fat in arms, legs, or cheeks, or (2) apparent gain in abdominal fat or localized subcutaneous masses in the neck, or (3) any combination of these signs. By these criteria, clinic physicians diagnosed lipodystrophy in 88 persons (32 percent).

Although cumulative time taking any antiretroviral inflated the risk of lipodystrophy by 9 percent in a multivariate analysis (P < 0.05), cumulative time taking just NRTIs did not. After controlling for total antiretroviral treatment time, this logistic regression model linked only protease inhibitors, as a class, with lipodystrophy (relative risk 4.5 for more than one year of PI treatment, P < 0.001). No specific antiretrovirals in any class correlated with lipodystrophy by this method. For example, the relative risk for d4T was a wash--1.01 (P = 0.96).

In a second multivariate logistic regression model, Schwenk tied three factors to lipodystrophy. A CD4⁺ nadir below 200 cells/mm³ raised the risk of lipodystrophy 84 percent (P < 0.05). Every year of PI treatment upped the odds 61 percent (P < 0.001). And every additional 10 years of age when starting antiretrovirals drove up the risk by 43 percent (P < 0.05).

Meanwhile, a multicenter German study presented by Stefan Mauss (Heinrich Heine University, Düsseldorf) absolved PIs of guilt in lipodystrophy in a multivariate analysis, but indicted d4T [abstract ThPpB1486]. Among 212 people in this analysis, 72 percent had taken at least one PI and 33 percent had taken an NNRTI. The prevalence of lipodystrophy, again by physician diagnosis, measured 37 percent, close to the 32 percent in Schwenk's single-site survey.

Multivariate logistic regression analysis in the multicenter study linked three factors to a higher risk of lipodystrophy. A CD4⁺ nadir below 200 copies/mm³ raised the risk 2.2 times (P < 0.05), somewhat more than the 1.84 times in Schwenk's cohort. Treatment with d4T for more than 12 months also ballooned the risk 2.2 times (P < 0.05). And treatment with an NNRTI for more than 12 months slashed the risk 80 percent (P < 0.05). In the univariate analysis, PI treatment doubled the risk of lipodystrophy, and male gender lowered the risk 60 percent, but those factors did not hold in the multivariate analysis.

The single-center Dutch study took a similar approach to the German studies. Again, investigators defined lipodystrophy by familiar physical signs diagnosed by a clinician, and they used logistic regression analysis to weigh risk factors [abstract WePeB4247]. Milly Hillebrand (Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands) and colleagues tracked 207 people being treated with PI-based HAART for a median of 755 days. The lipodystrophy rate was lower in this cohort than in the German studies, 15.5 percent, perhaps because of the generally shorter duration of HAART.

Three factors figured in lipodystrophy according to the Dutch multivariate analysis: a longer time taking PI-based HAART, older age when beginning HAART, and higher weight when beginning HAART. Higher pre-HAART triglyceride and glucose levels also favored lipodystrophy, but not significantly. Neither being treatment naive before HAART nor duration of NRTI therapy independently predicted lipodystrophy.

Hillebrand concluded that the significant correlation between PI duration and lipodystrophy suggests that "protease inhibitors alone or their combination with NRTIs are responsible" for lipodystrophy. The impact of older age, heavier weight, and higher baseline serum glucose, though not statistically significant, "may point to an antagonizing effect on insulin," Hillebrand speculated.

Schwenk's and Hillebrand's studies buck the trend of several recent an alyses--including Mauss's--that implicate NRTIs individually or as a class in fat distribution changes. Why? Schwenk grappled with that question in his poster and posed four possible confounders that may influence results in reported studies:

1. Different populations: Are study participants from a single site, a site where people are likely to be referred for lipodystrophy, or from a broader sampling of people taking antiretrovirals? Are the treatment histories of individuals in the population likely to be similar or variable?
2. Different case definitions: Is lipodystrophy defined, as in all three of these studies, by physical signs interpreted by a clinician? Or are fat changes quantified, for example, by DEXA or CT scans?
3. Different methods: Although methods clearly vary in many reported studies, the Schwenk and Mauss analyses took the same approach and reached different conclusions.
4. Small sample size: All three studies summarized here involved more than 200 individuals. "But," Schwenk cautioned, "the multiple correlations between potential risk factors indicate that all current studies . . . are much too small to detect interactions between different drugs, or between drugs and other cofactors."

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Pravastatin, metformin, or rhHG for lipodystrophy

What can be done about unwanted body fat changes, high lipids, and insulin resistance? The possibilities are many, and some early studies--including a few presented in Durban--have had favorable results. Pravastatin lowered PI-associated cholesterol, and rhGH (in the form of Serostim) relieved symptoms of lipodystrophy, though usually only while being taken and at the cost of toxicity. Shortly after the Durban meeting, US clinicians published a pilot placebo-controlled study showing that metformin reduces insulin levels, weight, and visceral abdominal fat in people with lipodystrophy. In a Durban study of eugonadal men with wasting, testosterone plus resistance training increased muscle mass and strength.

• Pravastatin and dietary advice. Graeme Moyle (Chelsea and Westminster Hospital, London) randomized 31 PI-treated men with high cholesterol to treatment with pravastatin plus dietary advice or to dietary advice alone [abstract ThPpB1438]. All had viral loads below 500 copies/mL and cholesterol numbers above 6.5 mmol/L (250 mg/dL). People in the pravastatin group began with 20 mg daily for the first two weeks, then scaled up to 40 mg daily. Moyle and colleagues measured everyone's fasting cholesterol at day 0, week 12, and week 24. Baseline values in the two groups, including weight and body mass index, matched well.

  Cholesterol dropped significantly (P < 0.05) in the pravastatin group at weeks 12 (-1.25 mmol/L) and 24 (-1.15 mmol/L). But respective decreases in the dietary-advice-only arm (-0.49 and -0.34 mmol/L) were not significantly different from baseline values. In both groups, LDL cholesterol accounted entirely for the fall in total cholesterol, and HDL cholesterol rose marginally in both treatment arms. Weight, fasting glucose, and triglycerides didn't change much in either group, and no one's viral load bounced above 500 copies/mL. Four people in the advice-only arm dropped out before 24 weeks, as did two in the pravastatin group. But side effects caused none of these dropouts.

• Recombinant human growth hormone. Several posters sized up the effects of rhGH on hallmarks of lipodystrophy. Two seemed particularly noteworthy.

  The first was a one- to 41-month follow-up of 27 men and nine women by Ramon Torres (Bentley-Salick Medical Practice, New York) and colleagues at other New York clinics [abstract WePeB4234]. The average follow-up measured 16 weeks. Before treatment everyone had truncal adiposity, 30 (83 percent) had peripheral wasting, and 18 (50 percent) had facial fat atrophy. Other fat abnormalities were buffalo hump in eight, breast enlargement in seven, and lipomata in four. Triglycerides stood above 150 mg/dL in 31 (86 percent), and half had total cholesterol levels above 200 mg/dL.

  Torres distinguished between people with early versus late HIV-associated adipose redistribution syndrome (HARS) on the basis of clinical signs: "Early" meant truncal adiposity and/or facial fat atrophy without peripheral lipodystrophy, whereas "late" meant truncal adiposity (with or without facial fat atrophy) and peripheral lipodystrophy (with or without buffalo hump, lipomata, and/or breast enlargement). To simplify--no one with early HARS had peripheral lipodystrophy, but everyone with late HARS did.

  Men began treatment with 6 mg of rhGH daily, and women with 5 mg daily. Doses could be shaved, or stopped altogether, to control side effects. Torres and colleagues aimed to continue treatment for 12 weeks. They defined a response as reduced truncal adiposity by waist measurement, decreased bra cup size, and/or increased fat-free mass by bioelectic impedance analysis--plus overall improved body shape documented by serial photos.

  By these benchmarks, 32 of 36 people (89 percent) chalked up a response after four to 12 weeks of treatment. But only two of those 32 (6 percent) maintained the response after stopping rhGH--one of them (a man who exercises regularly) for 16 months. Fasting glucose rose in five people and required antidiabetic therapy. Four people stopped rhGH before week 12 because of side effects, which included joint pain (in 64 percent overall), hand or foot swelling (in 27 percent), and carpal tunnel syndrome or myalgias (both in 11 percent).

  Torres noted a distinct response difference between people with early versus late HARS. Everyone with early HARS responded, compared with two thirds with advanced HARS. Nobody with advanced HARS enjoyed improvements in peripheral lipodystrophy, facial fat atrophy, or lipomata. And nobody with early HARS went on to endure peripheral lipodystrophy or other stigmata of advanced HARS. Those findings led Torres to suggest that "early intervention [with rhGH] in patients with early HARS may prevent the development of peripheral lipodystrophy." He also linked early treatment with "faster and more durable responses and improved tolerance."

  If those impressions can be confirmed, earlier rhGH would surely make sense. Still, the bottom line of this study must be that nearly all responders relapse and require further rounds of this expensive agent. Photos in the poster showed that one woman's truncal girth and enlarged breasts responded dramatically to 12 weeks of treatment, but she couldn't continue taking rhGH because her insurer stopped paying.

  Hansjakob Furrer (University Hospital, Berne, Switzerland) presented a small, double-blind, placebo-controlled crossover trial involving five men and three women with PI-associated "fat accumulation disease" [abstract LbPp114]. One person quit after four weeks of rhGH (6 mg daily) because of foot numbness and swelling. The others all completed three months of rhGH injections and three months of placebo.

  As one might expect, active treatment outdid placebo by many measures, including change in DEXA-measured truncal fat (-2.4 kg versus +1.79 kg, P = 0.004), reduced total fat mass (P = 0.01), increased truncal lean body mass (P = 0.01), increased total lean body mass (P = 0.06), and increased bone mineral density (P = 0.003). As in Torres's cohort, extremity fat did not change significantly during the study.

  Six of the seven people who completed the study joined the early dropout in suffering side effects, usually pain, swelling, or numbness in the hands and feet. Diabetes mellitus (fasting glucose 17 mmol/L) and hypertriglyceridemia (62 mmol/L) developed in one person after three months of rhGH, and both resolved when treatment stopped. Fasting lipids and glucose, CD4⁺ counts, and viral load changed significantly in no one.

• Metformin for lipodystrophy. The first randomized, double-blind, placebo-controlled trial of metformin, an insulin-sensitizing agent, in people with antiretroviral-related lipodystrophy demonstrated significant reductions in mean insulin area under the curve (P = 0.01), weight (P = 0.005), and diastolic blood pressure (P = 0.009) with metformin versus placebo.¹⁴ People taking metformin also had decreased visceral abdominal fat (P = 0.08), a common feature of HIV lipodystrophy that forebodes coronary artery disease in HIV- negative individuals. Levels of lipids and glucose did not change significantly during the three months of treatment.

  This small study, published a week after the Durban meeting, had 14 people in the metformin arm and 12 taking placebo. All study participants were nondiabetic and had abnormal oral glucose tolerance test results, hyperinsulinemia, or both. The low dose, 500 mg twice daily, may explain the low rate of side effects (mostly moderate diarrhea). Lactate levels did not rise significantly in the metformin group, and that's good news because metformin has led to lactic acidosis in people without HIV infection. Colleen Hadigan (Massachusetts General Hospital, Boston) and coauthors note, though, that they excluded people with liver or kidney disease from the study. "Our results cannot be extrapolated to the general population of HIV-infected patients with lipodystrophy syndrome," they warn, "in whom more severe liver disease may be seen."

• Testosterone and resistance exercise for wasting. The testosterone study involved 100 eugonadal men with wasting (less than 90 percent ideal weight and/or more than 10 percent weight loss) randomized in a 12-week factorial design to receive 200 mg of testosterone enanthate weekly or placebo injections, and to undergo progressive resistance training three times a week or no training [abstract WePpB1383]. Study participants could begin no new antiretrovirals in the eight weeks before the trial started. Colleen Corcoran (Massachusetts General Hospital, Boston) and coworkers measured lean body mass with DEXA, cross-sectional muscle area with CT scans, and muscle strength by isometric testing.

  Lean body mass rose 2.3 kg with training alone, 4.2 kg with testosterone, and 4.6 kg with both. Arm and leg muscle area burgeoned 7.5 percent with training, 9 percent with testosterone, and 15 percent with both. All increases were statistically significant compared with testosterone placebo or no training. Testosterone improved muscle strength (elbow flexion, shoulder extension, and upper extremity strength) significantly compared with placebo (P < 0.04). HDL cholesterol fell substantially with testosterone versus placebo (P = 0.011) and with training versus no training (P = 0.052).

  Corcoran concluded that progressive resistance training alone yields significant gains in lean body mass and muscle area. And testosterone alone significantly increases lean body mass, muscle area, and muscle strength. The results also "suggest [that] further increases in muscle mass and strength occur in response to combined testosterone and training," but the study wasn't big enough to compare the combined intervention with testosterone or training alone.

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Rebounds above 50 copies: not so threatening after all?

As the epidemic rages unabated in Africa, it has taken some curious, if more genteel, turns in lands of plenty. The heady promise of PI therapy seemed fulfilled in 1996, when the first big randomized trials of indinavir and ritonavir made news. And plummeting death rates in North America and Europe confirmed that promise. Only the ornery questioned the dictum that viral load should be suppressed as much as possible, for as long as possible. And then, when dual PI therapy debuted, only the obdurate asked if the rewards outweighed the risks.

Two years of traumatic side effect discoveries changed all that. Piggy-backed PIs seemed a more dangerous option. And more than one erstwhile treatment hawk could be heard cooing about purported boons of treatment holidays. "As much as possible" and "as long as possible" suddenly seemed less the twin pillars of prescribing than the pilloried theory of yesteryear.

Two clusters of Durban reports will encourage further reappraisal of the "as much/as long" logic and the double PI paradigm. Although no one came out and touted the virtues of viremia (excepting STI proponents for the moment), three studies suggested that less than complete control of replication is less than a five-alarm virologic fire. And although no one called for a moratorium on pairing PIs, two studies showed that just any two PIs at just any doses won't always beat a solitary protease inhibitor. But to keep everyone honest, another trial showed two PIs easily whipping one after 180 days of treatment.

Peter Sklar and Douglas Ward, clinicians at a large HIV practice in Washington, D.C., discovered that a viral rebound from below 50 copies/mL to between 50 and 400 copies/mL "is not necessarily an indication of failure of an antiretroviral regimen" [abstract MoPpB1019]. Most rebounders re-entered the land of undetectability without changing their regimens, and everyone taking their first regimen got back under 50 copies.

Sklar and Ward's analysis involved 32 people who endured rebounds from sub-50 territory. Most of them, 22 (69 percent) were back below 50 copies on their next viral load measure, and another two joined them soon. Eight people never controlled their viremia as well with that regimen. The viral blips were slightly lower among those who regained a sub-50 status (96 versus 132 copies/mL), and successful resuppressers had higher CD4⁺ counts at the time of the brief breakthroughs than did permanent rebounders. But neither of these differences proved statistically significant. One factor distinguished the eight people whose rebounds kept rising: None were taking their first antiretroviral regimen.

Sklar and Ward noted two limitations of this study--its small size and their inability to determine whether bad adherence contributed to any of the rebounds. But these clinicians believe their results "suggest that repeat testing and caution are warranted before changing therapeutic regimens."

Diane Havlir (University of California, San Diego) reached similar conclusions in a study involving many more people--241 participants in ACTG 343,¹⁵ a trial everyone started with AZT, 3TC, and indinavir [abstract TuPeB3195]. Havlir figured how many people with viremic blips from below 50 copies/mL ultimately suffered virologic failure. She defined a blip as a foray above 50 copies/mL and subsequent resuppression below that mark. Virologic failure meant two consecutive viral loads above 200 copies/mL. Everyone in the analysis had reached a sub-50 viral load within 24 weeks of starting the indinavir regimen.

During a median follow-up of 84 weeks, Havlir counted 97 people with intermittent viremia. Among 29 individuals who later met the virologic failure criterion, nine (31 percent) had blips. But among 212 people who did not fail virologically during this follow-up, 88 (42 percent) had blips. The blip rate difference between the two groups was not statistically significant (P = 0.31). The overall rate of intermittent viremia proved high in this cohort--97 of 241 people, or 40 percent--yet blips did not betoken loss of virologic control.

These studies do not necessarily mean blips are clinically innocuous. Bharat Ramratnam (Aaron Diamond AIDS Research Center, New York) showed last year that viral peregrinations beyond the 50-copy milepost slow the emptying of latent T-cell reservoirs¹⁶--that much-sought but still-elusive grail. So maybe, over the course of years, rather than the 84 weeks in Havlir's inquest, spurts of virus into T-cell reservoirs, spinal fluid, gut tissue--wherever--will take their toll on immune control or reconstitution.

But a smaller analysis Havlir presented earlier this year suggests that blips become less frequent over time, and this follow-up lasted 4.5 years.¹⁷ She tracked trends among 13 people enrolled in the Merck 035 study of AZT, 3TC, and indinavir. None of seven people without blips had a permanent viral rebound. But neither did six people with blips during those 4.5 years.

These two Durban reports say nothing about the importance of pushing the viral load under 50 copies/mL to begin with. Everyone studied by Sklar and Havlir attained that golden goal. And work by Janet Raboud (Canadian HIV Trials Network, Vancouver) indicates that a durable virologic response depends on slicing the viral load to fewer than 20 copies/mL.¹⁸ But even that tenet took a hit in Durban.

Jeffrey Greene (New York University) and colleagues from other New York practices found no difference in progression between people who kept their viral loads below 50 copies/mL and those who had loads under 400 but above 50 copies/mL [abstract MoPeB2171]. These clinicians decided to address the 50-versus-400 question when they started using ultrasensitive assays. Not surprisingly, they soon learned that many people with "undetectable" virus according to the 400-copy assay had plenty of measurable HIV in blood according to the more discerning test. So, they wondered, should they revamp the regimens of people in the 50-to-400 gray zone to notch a sub-50 reading? Or should they leave them alone?

To help them decide, Greene and colleagues looked more closely at 95 people with viral loads below 400 copies/mL. Fifty-four had viral loads invisible to the more exacting assays, while 41 had sub-400 loads that the newer assays could still count. The groups differed little in years since HIV diagnosis (8.7 versus 9.1), rates of AIDS symptoms (67 versus 66 percent), mean CD4⁺ count after beginning a HAART regimen (342 versus 320 cells/mm³), or number of antiretroviral regimens taken. The median duration of HAART in one group nearly mirrored that in the other: 1,060 days for the sub-50 responders and 1,157 days for the 50-to-400 group. Overall, then, both groups had been taking HAART for a median of almost three years.

How did the two groups compare after their latest check-ups? Greene reported virtually indistinguishable numbers. Respective readings for the sub-50 cohort and the 50-to-400 group were an average annual gain of 73 and 77 CD4⁺ cells/mm³, most recent T-cell counts of 535 and 582 cells/mm³, and most recent Karnofsky scores of 90 and 90. One person in the sub-50 group died (from valvular heart disease), while none in the other group died. Rates of new opportunistic infections and neoplasms did not differ between the groups.

"While subtle or delayed differences may emerge with further study," Greene concluded, "it seems unlikely that additional time on HAART, beyond the almost three-year average experience of these subjects, will reveal major differences in the two cohorts." Ultrasensitive viral load assays, he suggested, "may not provide clinical information that leads to better patient outcomes." The newest assays can certainly spot smaller jumps in viral load. But, as Sklar and Havlir found, those little blips don't always blossom into full-blown rebounds.

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Are some 2-PI combos "more equal" than others?

If one certainty emerges from the deluge of double-PI studies, it is that some combinations are less equal than others. But two studies contested an even more fundamental question: Are two PIs necessarily better than one?

David Butcher (Chase Brexton Health Services, Baltimore) and colleagues at Abbott Laboratories and an HIV database company called Clinical Partners compared 301 treatment-naive people starting a single-PI regimen with 41 starting dual PIs between October 1, 1994 and March 31, 1999 [abstract WePeB4147]. Baseline values for the single and dual groups were equivalent--4.2 and 4.46 log copies/mL, and 293 and 281 CD4⁺ cells/mm³, respectively.

Butcher and coworkers then checked the Clinical Partners database to see how these people made out 90 and 180 days after treatment began. Those who sacrificed their antiretroviral virginity on the dual PI altar did better at both checkpoints, both virologically and immunologically, than the single-PI initiates. Respective viral load drops in the dual and single groups measured -1.6 logs and -0.8 logs at 90 days (P < 0.0001) and -1.77 and -1.12 logs at 180 days (P = 0.0046). CD4⁺ counts climbed an average 99 cells/mm³ in the dual group versus 48 cells/mm³ in the single group at 90 days (P = 0.048), and 148 cell/mm³ for two PIs versus 86 cells/mm³ for one PI at 180 days (P = 0.053).

Those differences look pretty clear-cut. But what do they say about longer-term durability? Maybe not too much, according to some results from the Dutch ATHENA study, a wide-ranging investigation addressing many treatment questions [abstract WePeB4143]. As in the Butcher study, this analysis compared single versus double PIs in treatment-naive people, but ATHENA study participants began treatment in a narrower period, between July 1997 and July 1999. Another, possibly telling, difference between the studies is that ATHENA investigators looked at the 48-week response, almost twice as long as the other study's maximum 180-day follow-up.

When they started treatment, the 231 people in ATHENA's one-PI group had more advanced HIV disease, on the average, than the 118 people in the two-PI group. Median baseline viral loads measured 5.1 logs for the solo group and 4.9 logs for the duo group (P = 0.02). Respective baseline CD4⁺ counts clocked in at 190 and 260 cells/mm³ (P = 0.05). But both groups started their antiretrovirals around the same time, at median start dates of April 10, 1998 in the one-PI group and April 24, 1998 in the two-PI group.

Marielle Jambroes (NATEC, Amsterdam, Netherlands) defined treatment failure as (1) not reaching an undetectable viral load within 24 weeks, (2) a viral rebound after undetectabililty, or (3) a regimen switch for toxicity, patient request, or other failure. According to those criteria, 90 (39 percent) in the single-PI cohort endured a failure by week 48, compared with 52 (44 percent) among the double-PI takers, a nonsignificant difference (P = 0.36). Average CD4⁺ gains proved similar in the two groups, 150 cells/mm³ with one PI and 185 cells/mm³ with two PIs (P = 0.19). Outcomes did differ in one way: Among people who began treatment with a viral load below 100,000 copies/mL, 2 percent in the single-PI group and 8 percent in the dual-PI group suffered a virologic failure by 48 weeks (P = 0.03).

Since neither of these studies randomized people to compare one versus two protease drugs, neither can establish whether one or two PIs make more sense for treatment-naive people. But the longer-term ATHENA results do give one pause. At the same time, the ATHENA findings don't imply that solo-PI combinations should necessarily get the nod for naive people on grounds of convenience, cost, or safety. Compared with some one-PI regimens, some two-PI combos can be more convenient, less costly, and safer. But this study crosses the t in the truism that certain dictates of HIV medicine are best left to the doctrinaire.

Another unanswered bi-PI question got addressed in Durban--the best doses to use when combining indinavir and ritonavir. The study in question didn't have that answer, but it suggested which doses not to use.

José Gatell (University of Barcelona, Spain) detailed 24-week results of an open-label trial that randomized 167 people to continue indinavir at the familiar every-eight-hour 800-mg dose and 161 to scale back the indinavir to 800 mg twice daily while adding 100 mg of ritonavir twice daily [abstract WeOrB484]. Everyone had reached a viral load below 500 copies/mL with thrice-daily indinavir, and the median starting CD4⁺ count was in the 400s for both groups.

Gatell presented data on 111 people taking indinavir alone and 106 taking indinavir/ritonavir for 24 weeks. Substantially more people abandoned the dual PIs because of side effects--31 (29 percent) versus 12 (11 percent) in the indinavir-only group. Gastrointestinal (GI) problems were the downfall of the indinavir/ritonavir arm, causing 16 dropouts (15 percent) compared with two (2 percent) in the indinavir group. Kidney stones or flank pain bothered 19 (18 percent) taking both PIs and eight (7 percent) who continued standard-dose indinavir, but those problems didn't lead to dropouts.

An intent-to-treat analysis counted 87 percent with viral loads under 500 copies/mL in the standard indinavir arm at 24 weeks, versus 88 percent in the indinavir/ritonavir group. On-treatment results also matched: 97 percent below 500 copies/mL with indinavir alone, and 95 percent with indinavir/ritonavir. Although CD4⁺ gains didn't differ significantly in the two study arms, the indinavir group added about 100 cells/mm³, while T-cell counts stayed essentially flat among those who switched to indinavir/ritonavir.

These six-month findings show no virologic or immunologic advantage for trading the three-times-daily dose of indinavir for the twice-daily indinavir/ritonavir regimen, at least not at doses of 800 mg for indinavir and 100 mg for ritonavir. Indeed, side effects caused more dropouts in the dual PI group than in the group that stuck with 800 mg of indinavir every eight hours.

Pharmacologic data presented by another speaker, Edwin DeJesus (IDC Research Initiative, Altamonte Springs, Fla., USA), may explain why. He described a study that randomized people to continue standard-dose indinavir or to switch to 400 mg of indinavir and 400 mg of ritonavir twice daily [abstract WeOrB482]. DeJesus explained that those doses are based on studies showing that, although 100 mg of ritonavir boosts 800-mg indinavir troughs into more comfortable antiviral territory, it also boosts peak levels of 800-mg indinavir. Those steeper peaks could account for the higher rate of kidney complications in the dual-PI group of Gatell's study. A factor that could explain the greater GI intolerance with indinavir/ritonavir in Gatell's trial may be the study's early use of liquid ritonavir, which kids can be trained to take but many adults can't. (The study presented by DeJesus, with only four weeks of data, indicated better adherence with 400/400 mg of indinavir/ritonavir twice daily than with 800 mg of indinavir three times daily.)

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Abacavir jousts with PIs as first-line therapy

Durban did not lack for studies appraising the antiviral vim of PI-sparing therapy, including three regimens with abacavir at their hearts (Table 3). Two trials comparing abacavir head-to-head with PIs showed good marks for this newest nucleoside. And the quartet of abacavir, Combivir (AZT/3TC), and efavirenz made some sweet antiviral music in an open-label study of treatment-naive people. Other work continues to suggest, though, that protease drugs do one or two things RT inhibitors don't.

Sophie Matheron (Hospital Bichat, Paris) outlined 24-week results of an open-label, randomized comparison of abacavir/Combivir and nelfinavir/Combivir in 195 treatment-naive people [abstract WeOrB605]. The median viral load stood at 4.2 logs (about 15,800 copies/mL) in both groups, but people randomized to the abacavir arm had significantly scarcer baseline T cells (387 versus 449 CD4⁺ cells/mm³, P < 0.004). Only five of 98 people taking abacavir and six of 97 taking nelfinavir began treatment with a viral load that topped 100,000 copies/mL, so this study couldn't rate abacavir's moxie in the upper RNA reaches. All but 11 people in the nelfinavir group were taking the PI three times a day.

During 24 weeks of treatment, 10 people in the abacavir arm and nine in the nelfinavir arm switched a drug. An intent-to-treat analysis in which switches equaled failure tallied 67 percent in the abacavir group and 66 percent in the nelfinavir group with viral loads below 50 copies/mL at 24 weeks. Respective sub-50 ratings for an intent-to-treat analysis that condoned switches were 77 percent and 72 percent. The average viral load slumped 2.4 logs in both groups. People taking abacavir enjoyed better 24-week CD4⁺ gains than those taking nelfinavir, 91 versus 65 cells/mm³, a finding that could reflect the lower starting CD4⁺ counts in the abacavir group.

Abacavir did fall short in one contest: Six people had serious side effects in the abacavir group, compared with one in the nelfinavir group. Four people taking abacavir weathered hypersensitivity reactions, none of them serious. Shortly after the Durban conference, Glaxo revised abacavir's label to alert clinicians that hypersensitivity reactions can begin innocuously as dyspnea, cough, or pharyngitis. A letter to clinicians warned, "If the clinical presentation of an acute illness cannot be clearly differentiated from a hypersensitivity reaction, [abacavir] must be permanently discontinued."¹⁹

Another 24-week, randomized, open-label study pitted abacavir/Combivir against indinavir/Combivir, again as a first-line regimen [abstract WeOrB606]. Median baseline viral loads were higher in this study than in the nelfinavir comparison--4.8 logs (about 63,000 copies/mL) in both arms--and median baseline T-cell counts were lower: 323 cells/mm³ for the abacavir group and 300 cells/mm³ for the indinavir group. About one third of study participants began treatment with a viral load above 100,000 copies/mL. Pedro Cahn (Huesped Foundation, Buenos Aires, Argentina) reported that 164 people started therapy with abacavir and 166 with indinavir.

The intent-to-treat analysis in this study considered missing data as a failure. By that barometer, after 24 weeks of treatment 68 percent assigned to abacavir had a viral load below 400 copies/mL, compared with 57 percent randomized to indinavir. Among people who began abacavir with a viral load above 100,000 copies/mL, 66 percent reached a sub-400 viral load, compared with 54 percent for indinavir.

A missing-data-equal-failure analysis also found that people in the abacavir arm did better in trimming viral loads to below 50 copies/mL: 63 percent for abacavir versus 50 percent for indinavir. Again, this good result included those who began treatment with a high viral load: In the abacavir arm, 55 percent who started with more than 100,000 copies/mL had fewer than 50 copies/mL at 24 weeks, compared with 45 percent in the indinavir arm.

Why did the abacavir regimen consistently (if moderately) outperform indinavir? Apparently because adherence was worse in the indinavir group. Cahn reported that 56 percent in the abacavir arm said (in a questionnaire) that they took all their doses, but only 25 percent in the indinavir arm did so. Respective proportions who claimed to take all doses in the preceding four weeks were 78 percent for abacavir and 48 percent for indinavir. At those rates, it's surprising indinavir stifled HIV as well as it did. Session moderator Michel Kazatchkine (Hospital Broussais, Paris) wondered aloud if the results mean poor adherence to indinavir yields nearly as good virologic results as tighter adherence to abacavir.

Side effects did have not a big impact on the intent-to-treat findings. Although 12 percent in the indinavir arm versus 4 percent in the abacavir arm had grade 3 or 4 side effects, dropout rates attributed to drug toxicity were equivalent: 10 percent for indinavir and 9 percent for abacavir. But the higher serious side effect rate with indinavir could certainly have affected adherence. Hypersensitivity reactions vexed 6 percent taking abacavir.

Clinicians inclined to start treatment with nucleosides plus a nonnuke will be keen to know the results of La Francilienne, an open-label French study of efavirenz, abacavir, and Combivir [abstract TuPeB3208]. This 48-week, 12-center study enrolled 31 treatment-naive people with a median baseline viral load of 4.7 logs (about 50,000 copies/mL) and a median CD4⁺ count of 322 cells/mm³. Thirteen study participants (42 percent) began this four-drug regimen with a viral load above 100,000 copies/mL.

Two people dropped out before 48 weeks, one who became pregnant and one who just stopped coming to clinic. Pierre de Truchis (Hospital Garches, France) reported that six people stopped taking efavirenz before the 48-week mark, four stopped abacavir, and three stopped Combivir. In an intent-to-treat analysis that allows drug switching, 90 percent had a viral load below 50 copies/mL at week 48. With a stricter switch-equals-failure analysis, 77 percent had a 48-week viral load below 50 copies/mL. In an as-treated analysis, all 24 people who completed 48 weeks of treatment made the sub-50 grade. Starting treatment with a viral load above 100,000 copies/mL did not blunt this regimen's effect in any of these analyses. The median CD4⁺ cell gain was 128 cells/mm³.

The steep overall side effect rate, 87 percent, reflects the higher risk of toxicity when a regimen includes four drugs instead of three. But only four people (13 percent) had what investigators rated as serious side effects, including three bouts of depression (twice in one person), one alcoholic binge, and one episode of abdominal pain. Less severe but more common side effects included nausea and vomiting in 13, dizziness or vertigo in 12, malaise and fatigue in eight, rashes in seven, and sleep disorders in six. No one had a hypersensitivity reaction to abacavir.

This four-drug regimen incorporating abacavir and Combivir scored better virologic results at 48 weeks than abacavir/Combivir did alone in the just-described 24-week analyses (Table 3). Of course La Francilienne was much smaller than the abacavir/Combivir studies and did not have a randomized comparison arm. But it certainly stands to reason that efavirenz will add some antiviral sting to a triple-NRTI regimen. Whether that extra bite is worth the extra cost and risk of side effects will depend on each clinician's and patient's treatment philosophy.

None of these reverse transcriptase inhibitor studies addresses some of the finer points of anti-HIV prescribing--to wit, do protease inhibitors have certain nonpareil properties that should help them keep their king-of-the-hill footing? Yes, according to one small study detailed in Durban.

Karen Smith (Rush Presbyterian St. Luke's Medical Center, Chicago) sized up a half-dozen immune markers in 16 people taking a PI regimen and 14 taking triple NRTIs or NRTIs plus an NNRTI [abstract TuOrA287]. Everyone had maintained a viral load below 50 copies/mL for at least six months with the current regimen. Months of treatment (26 for RTIs and 28 for PIs) and change in CD4⁺ count (267 cells/mm³ for RTIs and 328 cells/mm³ for PIs) were statistically indistinguishable. Neither did the groups part ways in percentage of naive CD4⁺ cells or thymic size (determined by noncontrast CT scans).

The groups did differ significantly in one regard, and nearly significantly in another. The PI takers had a much lower percentage of activated (HLA-DR+ 38+) CD8⁺ T cells (25 versus 32 percent, P < 0.01). And they had substantially more T cells that had just sallied forth from the thymus (88,700 cells versus 52,700 cells, P = 0.06), which Smith measured by toting up T-cell receptor excision circles, or TRECs. Because thymuses of PI-treated people were no bigger than those of people taking only RT inhibitors, it seemed that PI therapy had somehow evoked more new T cells from the thymus. There weren't enough people in the NNRTI and triple-NRTI subsets to distinguish TREC differences between those groups.

This small study can hardly be called conclusive. Smith proposed that her analysis yielded "some evidence of decreased immune activation and increased thymic output with protease inhibitors" suggesting an immune effect with PI therapy "beyond its antiviral effect." Of course this is only one study of many that are beginning to address the issue of "PI exceptionalism."

Summer is the season for international AIDS conferences. But not this year. Sure, for denizens of the North who flew to Durban for international edition XIII, it was summer when we left home. But it was winter in South Africa, Botswana, and Zimbabwe. And it wasn't only the winter of the solar cycle, but also the winter of solitary AIDS deaths, 6,000 of them daily in sub-Saharan Africa. That was different.

Everyone knew Durban would be different, and, on that score, this meeting didn't disappoint. Durban was certainly the first international AIDS conference whose attendees found a female condom in their meeting bags. It was the first with a Track E on "Rights, Politics, Commitment, and Action," the first to promise a "March of the Traditional Healers," the first kicked off with a lyric as stark and apposite as "I'm lost forever in a future that ain't what it used to be."

After a week of emotional overload, thousands of non-African attendees passed through a South African Airways hangar specially set up to send off foreign delegates. Most had that glazed, postmeeting look that follows any week-long get-together. Most neglected to pocket their name badges.

On sold-out flights to connections in Johannesburg, these attendees mixed with native South Africans, some only dimly aware that the conference had happened and surprised to see their familiar flights crammed with foreigners carrying red conference bags. One South African, who had spent the week on the Natal coast readying his sailboat for a jaunt over to Australia, did know about the meeting. "So," he asked a reporter, "how did it turn out?"

The 50-minute flight did not afford the opportunity to explain. Even a 17,500-word article, like this one, can barely brush the surface of some highly selected topics. Despite premeeting forecasts of slim clinical news, Durban offered much to mull for Western clinicians puzzling over antiretroviral mysteries. But let the record show that this meeting outdid all its predecessors in bringing news from Brazil and Burkina Faso, from Bulgaria, Hungary, and Romania, from Bangladesh, Zimbabwe, and Zambia, from Cameroon and Côte d'Ivoire, from Armenia, Azerbaijan, Trinidad and Tobago.

For the first time at an international AIDS meeting--if only time had allowed--one could come away with a picture of international AIDS. And that picture would have embraced everything from the piquant to the poignant:

• At the clinically sophisticated end of the spectrum, D. Blythe (University of Natal Department of Cardiothoracic Surgery, Durban, South Africa) showed in a study of 29 men and 17 women that thoracic surgery, even open-heart surgery, can be undertaken in HIV-positive people and that those with CD4⁺ counts above 550 cells/mm³ endure the fewest complications [abstract ThPeB5226]. Overall, Blythe reported one death (2 percent), 10 major complications (22 percent), and six minor complications (13 percent) in this cohort.
• From the other side of the Indian Ocean, in a rueful footnote to the international AIDS story, H. Habsyi (Pelita Ilmu   Foundation, Jakarta) addressed the crisis faced in a Muslim country where burial rituals demand that the body be bathed, yet fear of HIV deters funeral workers from that duty [abstract ThPeB5109]. To help overcome this growing problem, Habsyi's group organized teams that include doctors, hospital workers, community members, and Muslim, Christian, and Buddhist leaders to cleanse the bodies of those who die from AIDS.
• Back in South Africa, M. Kruger (Kalafong Hospital, Pretoria) chronicled another chilly episode in the global AIDS winter, describing the founding of a hospice for children with late-stage AIDS [abstract ThPeB5106]. "The hospice enabled us to maintain the dignity of life till death," Kruger reported. "There was a decreased workload in the general wards with the transfer of the children to the hospice. Junior doctors gained experience regarding the management of terminal patients in a training environment. By the end of 1999 70 percent of deaths due to AIDS in our institution occurred in the hospice. We would like to suggest that other hospitals in South Africa create a similar environment for their terminal children."

But no matter how good they felt at meeting's end, attendees from wealthy countries could not--upon the briefest reflection--leave Durban unscathed by a volley of sharp ironies. The issue that claimed the greatest number of individual sessions, 14, was mother-to-child transmission, a problem essentially solved in the North in 1994. While some epidemiologists charted the unchecked epidemic's course through black Africa, others charted its continuing spread among Africans in America.

Treatment in northern climes has become so rarefied that we can now track mental well-being with an "existential loneliness questionnaire," that is, "a 24-item instrument which assesses the deeper emotion of loneliness experienced by individuals faced with death, multiple loss and isolation" [A. Mayers et al. Abstract ThPeD5800]. Some African attendees may not need the 24-item instrument to gauge existential loneliness.

One US speaker, who sought earnestly to reflect the meeting's palpable camaraderie by wearing a native shirt, unknowingly underlined the vast divide between HIV-positive people in San Francisco and Soweto. Arguing against structured treatment interruptions, he conceded that "treatment fatigue" in the developed countries makes treatment breaks tantalizing. Treatment fatigue, surely, is an AIDS problem that will not trouble South Africa soon.

In Africa below the Sahara, HIV prevalence may have hit a ceiling, according to Kevin De Cock (US Centers for Disease Control and Prevention, Kenya), who spoke at a symposium of the International AIDS Society. That's not because exemplary education programs like those in Uganda and Senegal are sweeping the continent. Rather, he explained, "deaths will soon balance incident infection, and I doubt prevalence could rise much above current levels."

De Cock sounded less than dazzled by the North-South bonhomie that began building at the 1998 Geneva meeting and perhaps crested, for now, in Durban. "I'm troubled by our meetings, our conferences, our networking," he confessed, "not because they are not good, but because they occur at a level altogether different from the one at which HIV transmission is occurring [in Africa]. When you go to the local level, the urban slum, the district hospital, the people there have nothing. They have no partnerships. They're waiting."

This view merits attention because De Cock is no stranger to Africa. He helped track down the earliest AIDS cases in Congo; he helped set up a top-notch HIV program in Côte d'Ivoire; now he toils in Kenya. But if the pace of partnership has been slow, it has been persistent. Groups like the International AIDS Vaccine Initiative (IAVI), the International Antiviral Therapy Evaluation Center (IATEC), and the International Association of Physicians in AIDS Care (IAPAC) have poured increasing streams of resources and personnel into Africa and other hard-hit lands. They are on the ground there.

No one pretends such efforts will suffice. More must be done by big philanthropies, flush pharmaceutical companies, rich governments, and--not least--poor governments destined to become poorer as their populations and economies disintegrate.

Today, a few months after the XIII International AIDS Conference, all those who went to Africa for the meeting, all those who stayed there when it ended, everyone with a stake in this global epidemic, must decide what Durban will mean. There are two possibilities, written down by Dante Alighieri in an autobiographical mix of prose and poetry called La Vita Nuova because it takes off from a point in his journal where he noted, "Here begins the new life."

La Vita Nuova enshrines Dante's spiritual infatuation with his lifelong muse, Beatrice, an infatuation never encroached on by the physical needs of love. When Beatrice dies, Dante wanders the streets of Florence, where he encounters a string of foreign pilgrims. He knows they're not Florentine because he can see in their faces that they haven't heard of Beatrice's death.

"If I could speak with them a space," Dante laments, "I am certain that I should make them weep before they went forth from this city; for those things that they would hear from me must needs beget weeping in any."²⁰ But he lets the pilgrims pass without a word. Only later, in the sonnet cited at the top of this article, does Dante pretend to tell the pilgrims of his grief.

The grief-struck cities of Africa mourn not one but millions. Did they tell their story well in Durban? And will their political leaders heed this tale and recite it to any effect? Will those leaders elevate AIDS to a national priority, or squabble about details, or ignore it?

And what about us pilgrims? Many wept, and more than once. But when we confront "treatment fatigue" back home, how much can we remember of lessons learned in that saddest city? And how long must those memories endure before the mourning ends?

In a meeting refulgent with eloquence, one of Dante's cultural scions may have proved the most eloquent in suggesting the answer to that last question. The duty to remember, suggested incoming International AIDS Society President Stefano Vella, belongs not only with the Durban pilgrims, but also with our heirs.

"This is a conference where we should have brought our children," Vella said in the closing session, "because it is necessary to teach the future generations how to fight AIDS."

Mark Mascolini writes about HIV infection (mailmark@ptd.net).

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References and Notes

1. Dante scholars out there may recognize this as a liberal translation of the penultimate sonnet in Dante's La Vita Nuova. Apologies to Dante Gabriel Rossetti and Mark Mussa whose (somewhat stolid) translations inspired this one. Dante. La Vita Nuova. (Rossetti DG, trans.) New York: Viking Press. 1969; 616. Dante. La Vita Nuova. (Musa M, trans.) New Brunswick: Rutgers University Press. 1957:83.

2. "Africa." Britannica CD 98. Multimedia Edition. 1994-1997.

3. Hochschild A. King Leopold's Ghost. New York: Houghton Mifflin Company. Mariner Books edition. 1999;17.

4. Hochschild A. 1999:301. "From the colonial era, the major legacy Europe left to Africa was not democracy as it is practiced today in countries like England, France, and Belgium; it was authoritarian rule and plunder."

5. UNAIDS. Report on the global HIV/AIDS epidemic. June 2000. Geneva: UNAIDS. 2000;15. Online at: http://hivinsite.ucsf.edu/social/un/2098.478b.html.

6. Hochschild A. 1999:12.

7. Carcelain G, Tubiana R, Mollet I, et al. Intermittent interruptions of antiretroviral therapy in chronically HIV-infected patients do not induce immune control of HIV. Presented at: 7th Conference on Retroviruses and Opportunistic Infections. January 30-February 2, 2000; San Francisco. Abstract 356.

8. Hogg RS, Yip B, Chan K, et al.. Nonadherence to triple combination therapy is predictive of AIDS progression and death in HIV-positive men and women. Presented at: 7th Conference on Retroviruses and Opportunistic Infections. January 30-February 2, 2000; San Francisco. Abstract 73.

9. Paterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med 2000 Jul 4;133(1):21-30.

10. Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med 1999 Dec 16;341(25):1865-73.

11. CPCRA stands for Community Programs for Clinical Research on AIDS, a federally funded US trials network of experienced HIV clinicians.

12. Havlir D, Gilbert P, Bennett K, et al. Randomized trial of continued indinavir (IDV)/ZDV/3TC vs switch to IDV/ddI/d4T or IDV/ddI/d4T + hydroxyurea in patients with viral suppression. Presented at: 7th Conference on Retroviruses and Opportunistic Infections. January 30-February 2, 2000; San Francisco. Abstract 456.

13. Rutschmann OT, Opravil M, Iten A, et al. A placebo-controlled trial of didanosine plus stavudine, with and without hydroxyurea, for HIV infection. The Swiss HIV Cohort Study. AIDS 1998 May 28;12(8):F71-7.

14. Hadigan C, Corcoran C, Basgoz N, et al. Metformin in the treatment of HIV lipodystrophy syndrome: a randomized controlled trial. JAMA 2000 Jul 26;284(4):472-7.

15. Havlir DV, Marschner IC, Hirsch MS, et al. Maintenance antiretroviral therapies in HIV-infected subjects with undetectable plasma HIV RNA after triple-drug therapy. N Engl J Med 1998 Oct 29;339(18):1261-8.

16. Ramratnam B, Mittler JE, Zhang L, et al. The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy. Nat Med 2000 Jan;6(1):82-5.

17. Havlir D, Levitan D, Bassett R, et al. Prevalence and predictive value of intermittent viraemia in patients with viral suppression. Antiviral Ther 2000;5(suppl 3):89.

18. Raboud JM, Montaner JS, Conway B, et al. Suppression of plasma viremia below 20 copies/mL is required to achieve a long-term response to therapy. AIDS 1998;12:1619-1624.

19. Kent RS. Fatal hypersensitivity reactions, respiratory symptoms, and Ziagen (abacavir sulfate). Rockville: FDA. Available at: http://www.fda.gov/medwatch/safety/2000/ziagen.htm.

20. Dante. La Vita Nuova. (Rossetti DG, trans.) New York: Viking Press. 1969; 615.

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