Before the year 1981 in the U.S., the number of HIV infections reached 92 diagnosed cases and 29 deaths. Those two statistics jumped to 323 and 122, respectively, in 1981 as the AIDS virus spread. Then the morbidity and mortality numbers took off, according to the Centers for Disease Control and Prevention - in 1982, they climbed to 1,170 cases and 454 deaths.

Up to the year 2001, HIV cases diagnosed in the U.S. totaled 807,075 and AIDS deaths at 462,298. Recent years have seen a marked decline in AIDS incidence and deaths. That trend began in 1996 and continued into 2001. The welcome change was thanks to HAART - the triple-drug anti-HIV regimen. HAART stands for "highly active antiretroviral therapy."

The medically correct word for the act of an AIDS patient sticking closely to and enduring a prescribed course of HAART treatment is "adherence." Goofing off is what too many HIV-positive individuals do when they abandon their highly effective triple cocktail because it's so effective that they feel just fine. That's when they make their big - possibly fatal - mistake. Just because their pre-AIDS symptoms are gone doesn't mean that the HIV virus itself has vanished. Like a gang of mobsters that holes up and hunkers down in a hideaway until danger blows over, the AIDS pathogen hides out and only re-emerges when the HAART threat dwindles away.

In its current issue, dated Dec.11, 2003, the New England Journal of Medicine (NEJM) reports in two research articles a pair of multicenter, randomized, partially double-blind clinical trials, comparing triple-drug HAART regimens with quadruple-drug programs. (A patient's medication must be altered whenever the AIDS virus mutates and starts to initiate drug resistance.)

Primary Endpoint Is Time To Drug Failure

"One specific combination of anti-HIV drugs," observed the twin papers' lead author, Gregory Robbins, of the Harvard-affiliated Massachusetts General Hospital in Boston, "appears to be more effective for initiating therapy than other drug combinations tested in our trial. Patients who started therapy with a combination of zidovudine [AZT], lamivudine [3TC] and efavirenz [EFV] were successfully treated for a longer period. The primary endpoint was the interval to the failure of the second three-drug schedule."

Peripheral neuropathy was assessed on the basis of moderately severe symptoms beginning in the distal portion of the legs, including pain, burning sensations, numbness and paresthesias (pricking, tickling, tingling).

These three front-running remedies are the first of the 20 HAART drugs now approved by the FDA. They belong to just four different classes: nucleoside or nucleotide reverse-transcriptase inhibitors (nucleoside analogues), non-nucleoside reverse transcriptase inhibitors, protease inhibitors and fusion inhibitors. "Because cross-resistance is common," the NEJM article pointed out, "the failure of the initial regimen used may compromise the success of future regimens. Indeed, the results of cohort studies suggest that a patient's first treatment schedule has the greatest chance of success."

Other sources offer the physician the likes of didanosine, stavudine, nelfinavir and the other FDA-approved drugs. "In summary," Robbins noted, "our study demonstrated a strong interaction between the choice of a combination of two nucleoside analogues and the choice of efavirenz or nelfinavir. The initiation of therapy with zidovudine, lamivudine and efavirenz was the optimum strategy.

"Although the mechanisms underlying the favorable interactions among zidovudine, lamivudine and efavirenz are still being explored," he commented in a press statement, "this combination provided greater antiretroviral potency than the other formulations tested, and resulted in a lower rate of failure with genotypic resistance to each class of anti-HIV drugs.

"We've been fortunate," Robbins continued, "to have a variety of choices for antiretroviral therapy. But many people had previously expressed their belief that how the drugs were combined did not make much difference. This trial shows that some combinations are more powerful than others, and that how they are sequenced does make a difference."

Preliminary results of the large-scale study were presented at the 2002 International AIDS Conference in Barcelona, Spain, and have been incorporated into current HIV/AIDS treatment guidelines issued by the U.S. Department of Health and Human Services.

82 U.S. Centers Plus 23 In Italy Took Part

One portion of the study, led by Robbins, compared four three-drug regimens to determine whether the order in which they were used affected how long they were successful. At 82 hospital and clinic sites in the U.S. plus 23 in Italy, 620 patients who had not previously been treated were enrolled and followed for more than two years. For nucleoside reverse transcriptase (RT) inhibitors, participants received either ZVD and 3TC or stavudine (d4T) and didanosine (ddl). The alternatives for the third drug were either the non-nucleoside RT inhibitor EFV or the protease inhibitor nelfinavir (NFV).

The second part of the trial, led by Robert Shafer at Stanford University, questioned whether using four drugs in combination would be better than two consecutive three-drug regimens. Shafer pointed out that "although four drugs could potentially heighten effectiveness, the combination might also increase toxicity. In both studies, participants who began treatment with ddl and d4T had more toxicity problems, such as nerve damage and pancreatic inflammation." Shafer and his team recommended that treatment of HIV infection should not begin with those two drugs, a position now incorporated into the federal guidelines.

Subjects were eligible if they had a plasma HIV-1 RNA level of at least 500 copies per milliliter. They were enrolled between October 1998 and November 1999. The study was designed to accept 800 subjects in the six study groups, but actually received 987. There were six deaths, and 20 participants had new AIDS-defining illnesses.

Robbins made a final point: "We are exploring possibilities that may explain the apparent greater potency of one particular combination. We hope to find new ways to minimize toxicity and side effects. As AIDS patients are living longer,we need longer-term trials that can help us determine which regimens are more effective and better tolerated," he concluded.

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