Important note: Information in this article was accurate in March 2002. The state of the art may have changed since the publication date.
American Foundation for AIDS Research, March 2002
Mark Mascolini
When to start
Growing concern over the long-term side effects of antiretrovirals led the British HIV Association1 (BHIVA) and the U.S. [quote] Department of Health and Human Services2 (HHS) panel to propose further delays in starting therapy. BHIVA takes the more conservative stance, advising deferral of treatment for asymptomatic people with CD4 counts above 350 cells/mm3. Treatment should start when the count falls below 200 cells/mm3 and may begin between 200 and 350 cells/mm3, depending on "the rate of CD4 decline, symptoms, patient's wishes and viral load."1
HHS notes that "some experts would recommend initiating therapy" at CD4 counts above 350 cells/mm3, but only if the viral load exceeds 55,000 copies/mL.2 For people with 200 to 350 cells/mm3, HHS says "treatment should generally be offered" and cites unpublished data documenting progression to AIDS in three years by 11% of Multicenter AIDS Cohort Study members with CD4 counts between 200 and 350 cells/mm3 and viral loads between 10,000 and 20,000 copies/mL. Nobody with 200 to 350 cells/mm3 and a viral load under 10,000 copies/mL had AIDS in three years.
The hit-hard-but-later trend rests partly on cohort studies showing that people who start antiretrovirals with 200 to 350 cells/mm3 match those who start above 350 cells/mm3 in short-term survival3--5 and in viral load and CD4 responses.3--9 Only one recent study10 found a significant clinical advantage to starting treatment above 350 cells/mm3. These cohort studies cannot nail down the equivalence of delayed and early intervention because statisticians are unable to totally eliminate confounding variables and because follow-up extends only to a few years.
Goals of first-line therapy
Most agree that the prime goal of therapy in treatment-naive people is a viral load below 50 copies/mL, because reaching that level of control yields a more durable virologic response.11--13 However, recent work shows that people with higher pretreatment viral loads may take longer than 24 weeks to achieve an undetectable level.14,15
PI versus NNRTI first-line regimens
U.S. and British guidelines disagree on what antiretrovirals to use first. The HHS panel "strongly recommends" only protease inhibitors (PIs) and the NNRTI efavirenz for first-line therapy.2 Nevirapine is rated an "alternative." But BHIVA lists either efavirenz or nevirapine as "recommended" initial therapy, saying PIs may be "considered" for first-line therapy.1 The British base this distinction on the "equivalent or superior" activity of NNRTIs versus PIs in surrogate marker trials and on easier adherence with NNRTIs.1 They add, though, that no randomized clinical endpoint study establishes this equivalence or superiority and that an NNRTI—unlike PIs—can fail after a single resistance mutation emerges.
Also, resistance to nucleoside analogs (NRTIs) may evolve more quickly when an NNRTI fails than when a PI fails. A study of 47 treatment-naive people starting triple therapy with a PI and 17 starting with an NNRTI found that 41% taking an NNRTI versus 6% taking a PI ended up with dual-class resistance if their viral load rebounded to above 1,000 copies/mL.16
A survey of ten recent studies3,17--25 endorses BHIVA's position that nevirapine or efavirenz can match or better the short-term viral load results obtained with single- or dual-PI regimens. In four studies17--20 NRTIs yielded significantly better viral load responses than PIs. In four others21--23 NNRTIs equaled PIs in viral load outcome. But in one study analyzing three big patient databases, PIs usually produced a better virologic response.24 Two of these studies19,25 suggest PIs may hold an edge over NNRTIs in boosting CD4 counts, while three21,22,24 found no substantial CD4 difference between PIs and NNRTIs.
In 2002, results from three randomized trials—ACTG 384, ACTG 388, and INITIO—should offer more definitive data on the relative potency of first-line NNRTIs versus PIs.
No prospective trial has compared nevirapine with efavirenz, but one retrospective analysis gave the edge to efavirenz.18 This study of 888 people starting their first PI or NNRTI found six-month viral loads under 500 copies/mL in significantly more of those starting with efavirenz (92%) than those starting with nevirapine (83%) or a PI (79%). Efavirenz outdid indinavir by several viral load measures in a large open-label trial,20 and it controlled viremia better than a single PI or ritonavir/saquinavir in a 545-person cohort.17 Nevirapine has not bettered a PI in prospective or retrospective studies, but it apparently promotes a better lipid profile than efavirenz (see below).
Toxicity figures importantly in picking a first-line regimen. In healthy volunteers, ritonavir quickly increases lipids26 and indinavir boosts glucose and insulin.27 A large cohort study linked longer PI treatment with an increasing heart attack rate.28 Nevirapine, on the other hand, shaped a healthy lipid profile in treatment-naive people randomized to take this NNRTI with ddI and d4T in the Atlantic study.29 Among 34 people using nevirapine, high-density lipoprotein ("good") cholesterol rose 49% over the 24 weeks, compared with gains of 16% in 41 people taking indinavir and 16% in 39 taking 3TC with ddI/d4T.
Nonetheless, people in the Atlantic study's nevirapine group wound up with as many fat abnormalities as people in the indinavir or 3TC arms.30 This substudy observed almost exactly the same proportions in each treatment group with no lipodystrophy or both fat atrophy and hypertrophy after 96 weeks of treatment. The groups also differed little in rates of atrophy alone or hypertrophy alone.
The most daunting NNRTI side effect may be liver toxicity. A survey of 10,611 case records from 21 adult ACTG trials cataloged significantly more grade three or four liver toxicity in trials of nevirapine, delavirdine, or efavirenz (8.2%) than in trials of indinavir or nelfinavir (5%).31 People dropped out of NNRTI studies more than twice as often as PI trials because of liver toxicity.
A prospective cohort study of 610 people beginning nevirapine tied a rising risk of liver toxicity to a longer time taking the NNRTI.32 New cases of hepatotoxicity rose from 3.5% at three months, to 9.7% at six months, and to 20.1% at 12 months. About half the patients were infected with hepatitis C or B when they started taking nevirapine, yet clinical hepatitis developed in only seven people (1.1%) and resolved when they stopped nevirapine. But a review of 1,643 people with nevirapine-related liver toxicity found clinical hepatitis in 9%.33
Starting with three nucleoside analogs (NRTIs)
The Atlantic study found that antiretroviral-naive people randomized to ddI/d4T/3TC lagged behind those randomized to ddI/d4T/nevirapine or indinavir in virologic response.34 Whereas 49% taking indinavir or nevirapine had a viral load below 50 copies/mL at 48 weeks, 40% taking the triple nucleosides had a sub-50-copy viral load. But those differences were not statistically significant.
More interest has focused on abacavir as the linchpin of triple-NRTI therapy, especially now that Trizivir combines abacavir, AZT, and 3TC in one pill taken twice a day. Questions remain about prescribing this regimen for people with high viral loads. A blinded, randomized trial found that treatment-naive people with viral loads exceeding 100,000 copies/mL had a poorer 48-week virologic response to AZT/3TC/abacavir than to AZT/3TC/indinavir.35
An unblinded trial of the same regimens, however, showed equivalent 48-week viral load responses in abacavir- and indinavir-treated people who started with more than 100,000 copies/mL.36
The latest HHS and BHIVA guidelines maintain a skeptical stance about first-line abacavir. The HHS panel calls it an "alternative" first-line drug,2 while BHIVA counsels that three-NRTI combinations should be considered for people with low viral loads and "adherence concerns."1 Roy Gulick (Cornell University, New York) noted four worries over using three NRTIs first: lack of clinical endpoint data, uncertainty about long-term virologic effects, the threat of heightened mitochondrial toxicity with three NRTIs, and "theoretical drawbacks" about blocking a single step in viral replication.37
In deciding between a triple NRTI or an NNRTI- or PI-containing regimen, ability to adhere to a dosing schedule may be the most decisive factor in treatment success. A recent meta-analysis looked at trials of triple therapies utilizing either PI-, NNRTI-, or triple NRTI-based regimens.38 It found that all of the regimens performed similarly and that simpler regimens with fewer doses or pills generally performed better.
Dual versus single PIs
Single PI regimens—aside from ones with nelfinavir—have largely fallen out of favor. Joel Gallant (Johns Hopkins University) blamed "their unreliable pharmacokinetic profiles and complex dosing schedules and/or pill burdens."39 Although HHS guidelines "strongly recommend" indinavir and nelfinavir as first-line options,2 they list more dual than single PI choices in that category: indinavir/ritonavir, lopinavir/ritonavir, and saquinavir/ritonavir. Lopinavir/ritonavir controlled viremia better than solo nelfinavir in a randomized 60-week comparison.40
"Dual-PI therapy" usually means one PI whose blood levels are boosted by the hepatic suppressive effects of low-dose ritonavir. Such dual PI combinations are not inevitably more potent than single PIs. A randomized study comparing indinavir, ritonavir, and ritonavir/saquinavir in treatment-naive people found that equivalent proportions in the three groups had viral loads under 20 copies/mL after 72 weeks.41 In an open-label comparison of indinavir versus indinavir/ritonavir plus AZT/3TC, similar numbers in each arm had viral loads under 50 copies/mL at 48 weeks.42 A study of 545 people with minimal treatment experience found that durable viral suppression (three or more consecutive viral loads below 400 copies/mL beyond six months of treatment) was achieved by 53% of patients receiving efavirenz plus two NRTIs, 26% of those taking a single PI plus NRTIs, and 29% receiving saquinavir plus ritonavir in addition to NRTIs.17
Other evidence suggests it may be too soon to dismiss nelfinavir-based single PI regimens as a reasonable first-line option. At least three studies show that most nelfinavir failures can be rescued by dual PIs.43--45 So beginning treatment with nelfinavir may give a person two attempts at effective PI therapy. The same may be true for sequencing other single and dual PIs, but the data on nelfinavir look stronger for now.
Few clinicians in developed countries would start therapy without knowing a patient's baseline viral load. Once treatment begins, HHS guidelines call for a viral load assay within two to eight weeks to gauge the initial response.2 A stubbornly high viral load will signal poor adherence, infection with drug-resistant virus, or poor drug penetration. If the viral load sinks appropriately, the guidelines recommend a follow-up test every three to four months.
Shaky adherence can be addressed by better counseling. Covert resistance in a chronically infected person will be flushed out by drug pressure and can be documented by resistance testing. But only measuring plasma drug levels—therapeutic drug monitoring (TDM)—will determine if a standard dose is putting enough drug into
circulation.
Therapeutic drug monitoring
TDM studies have focused primarily on PIs, especially indinavir and nelfinavir. The most convincing trial is a 12-month analysis of the ATHENA cohort.46 At last report, 147 people starting indinavir or nelfinavir had been randomized to the TDM arm or to standard-of-care management. Clinicians with patients randomized to TDM had blood levels checked and received advice from pharmacologists (although they did not have to heed that advice). After a year, 17% in the TDM group and 40% in the control group stopped treatment with indinavir or nelfinavir. That difference reflected fewer virologic failures in the nelfinavir TDM group than in nelfinavir controls (2% versus 18%) and fewer dropouts tied to toxicity in the indinavir TDM group than in indinavir controls (9.5% versus 40%). Overall, significantly more TDM patients (78%) than controls (55%) had a viral load below 500 copies/mL after 12 months.
Principal investigator David Burger (University Medical Center, Nijmegen), noted that the results show only that TDM can help avert toxicity with indinavir and virologic failure with nelfinavir, and only in people starting those PIs in their first regimen. But TDM proponents, Burger included, argue that it makes sense because drug levels vary from person to person, because low levels correlate with failure and high levels with toxicity, and because TDM costs relatively little. Indeed, many European clinicians already consider TDM the standard of care.
Access to TDM and reimbursement issues slow its adoption in the U.S. There are other reasons too, recently spelled out by Johns Hopkins University's Charles Flexner.47 First, no one has pinned down therapeutic concentration ranges for any antiretroviral. Second, drug levels are only one factor that affects treatment outcome. Third, boosting apparently suboptimal drug concentrations may cause side effects. Even if these problems can be solved, Flexner adds, TDM may prove unnecessary if drug levels can be boosted safely in other ways—for example, with low-dose ritonavir.
Flexner does suggest some situations in which TDM "might be considered": to confirm adequate drug levels in children and in people with kidney or liver problems; to appraise interactions between antiretrovirals and herbal remedies; to investigate an unexplained treatment failure; and to evaluate "exaggerated" toxicity.
BHIVA decided not to endorse TDM while awaiting more data.1 The British experts agree with several of Flexner's suggestions on using TDM now and add that it may prove useful when prescribing something other than a standard dose.
When any patient has a viral rebound, the next step is clear: measure the viral load again to see if the viral load uptick is a sustained rebound or a blip—a transient viremic episode. If the breakthrough is a blip, some recent work suggests sitting tight and staying vigilant. But persisting low-level viremia signals danger.
Do viral blips presage failure?
The most detailed blip study involved two groups of trial participants taking AZT, 3TC, and indinavir.48 The first group of 13 took that regimen for 4.5 years, during which six had blips above 50 copies/mL and seven did not. No one in either group suffered a virologic failure, defined as two consecutive viral loads above 200 copies/mL. The second group included 96 with blips and 145 who always kept their viral load under 50 copies/mL through a median 84 weeks. Ten with blips (10%) and 20 without them (14%) had two later viral loads above 200 copies/mL. Blips did not predict virologic failure in this group.
Clinicians from a large HIV practice tracked 32 people whose viral load rose from under 50 copies/mL to between 50 and 400 copies/mL.49 Twenty-four (75%) soon regained sub-50-copy control, and they had slightly lower blips than the eight people who did not regain control (96 versus 132 copies/mL). But another factor more clearly distinguished people with blips from permanent rebounders: all with blips were taking their first antiretrovirals, and all rebounders had earlier treatment experience.
Swiss and German investigators studied 1,858 people who had viral loads under 50 copies/mL.50 They divided the group into those who sustained a viral load under 50 copies/mL in four subsequent viral load assays, those with a blip above 50 copies/mL followed by a sub-50 reading, those whose viral load rose and stayed between 50 and 500 copies/mL, and those with a "confirmed virologic failure"—two consecutive viral loads above 500 copies/mL.
After the study's first four viral load assays, confirmed failure rate measured 5.1 per 100 person-years in people without any initial blips, 7.9 per 100 person-years in people with blips observed during the original testing, and 21.7 per 100 person-years in those whose rebounds lingered between 50 and 500 copies/mL during the initial viral load testing. In further analysis, the blip group had only a 6% higher risk of confirmed virologic failure than the best responders, a statistically nonsignificant difference. The people with lingering 50- to 500-copy loads had a 300% higher risk of failure.
How fast, and what, to switch
The results of these studies begin to define a virologic failure cutoff. They show that occasional blips over 50 copies/mL do not necessarily signal a full-fledged rebound—especially in people taking their first regimen. But a rebounding load that stays between 50 and 500 copies/mL almost certainly spells trouble50 and calls for a drug change (after ruling out bad adherence, intercurrent infection, vaccination, or new treatment with an agent that may interact with antiretrovirals being taken). Several studies show that revamping the antiretroviral regimen works best when done at a low viral load.43,44,51 But should all the drugs in the failing regimen be changed?
HHS2 and BHIVA1 guidelines both say yes—"in general." This approach is controversial: changing all drugs precipitously may also lead to a patient quickly developing resistance to multiple members of all classes of drugs. Many clinicians keep their patients on the same regimen as long as viral loads remain modest and immunologic benefit continues. They hope to save potentially effective regimens for use at a later date. By not introducing a more effective regimen too quickly, they avoid the chance that HIV will develop resistance to it prematurely.
A conservative alternative is to change only the particular drugs implicated in the treatment failure. Some studies have found that HIV does not become resistant to every drug in a regimen at the same time. Drugs that can fail after a single mutation fail first.
Two key studies found that the trademark 3TC-resistance mutation arose in virus with no primary protease mutations when a regimen of AZT, 3TC, and indinavir started failing.52,53 Stopping indinavir in such patients and avoiding potentially cross-resistant PIs may be unnecessary, though that tactic has not been well studied.
The only way to tell which drugs in a regimen have failed is resistance testing, and both BHIVA and HHS recommend resistance assays when changing a first-line regimen because of virologic failure. HHS guidelines specify phenotyping, which involves directly evaluating HIV drug resistance in cell culture: "If susceptibility testing indicates resistance to only one agent in a combination regimen, it may be possible to replace only that drug; however, this approach requires clinical validation."2
The problem with quick resistance testing followed by a fast single-drug switch is that today's resistance assays do not work well when someone's viral load lies below 1,000 copies/mL. Because waiting for the viral load to exceed 1,000 copies/mL lets HIV keep evolving, someone with resistance to one drug at a viral load of 500 copies/mL may have resistance to two or three drugs at 1,500 copies/mL. Waiting too long to test for resistance may ruin the chance to substitute only one drug.
Switching before virologic rebound
This strategy gained popularity as a way to avoid or maybe reverse side effects attributed to specific drugs. Switch studies show insulin resistance improves —and thus sometimes visceral fat decreases—when a PI is swapped for an NNRTI or abacavir. Cholesterol and triglycerides fall after switching to nevirapine or abacavir, though not consistently after switching to efavirenz. Improvements in fat atrophy are rare when trading a PI for an NNRTI or abacavir, probably because NRTIs appear to drive atrophy.
Switching from a first-line PI to abacavir or an NNRTI in people with undetectable viremia typically continues to suppress viral replication. But switching from a PI in people with earlier NRTI experience carries a higher risk of failure, at least for people switching to nevirapine54 or abacavir.55
A second-line regimen can often resuppress breakthrough viremia, but success depends on how much resistance has evolved. "In patients with extensive drug resistance," Joel Gallant writes, "it may be unrealistic to expect full virologic suppression."38 But people with virus resistant only to 3TC, an NNRTI, or one PI stand a better chance of getting their viral load below 50 copies/mL again. However, a big gray area lies between resistance to a single drug and Gallant's "extensive" resistance. That is probably why neither U.S. nor British guidelines specify second-line goals.
NRTI cross-resistance
NRTI cross-resistance, which far exceeds earlier estimates, complicates planning for second-line and later regimens. No longer can one assume that d4T is a backup to AZT, or vice versa. Mutations once labeled "AZT mutations" appear regularly in AZT-naive people taking d4T.56 Although these mutations cause only a small drop in susceptibility to d4T, that drop is enough to hamper the response to this drug.57
The cross-resistance resulting from mutations common to AZT and d4T weakens the effect of NRTIs after first-line therapy. One still-unstudied way around this problem, suggested by Joep Lange (Academic Medical Center, Amsterdam),58 is to avoid both AZT and d4T in first-line regimens. That would mean starting with combinations like ddI/3TC or 3TC/abacavir, or perhaps one of these NRTIs plus tenofovir.
Second-line options
The general options for second-line therapy are obvious (and outlined in Table 11 of BHIVA's latest guideline1). The choice depends on resistance testing and on whether all drugs in a failing initial regimen are changed, or only those that engendered resistance (see "How fast, and what, to switch"). After a single PI failure, the options are double PIs, a ritonavir-boosted PI, or an NNRTI. BHIVA recommends changing both NRTIs at the same time, but notes the potential for NRTI cross-resistance.1 When a first-line NNRTI fails, one or two PIs remain the only option until approval of an NNRTI with a distinct resistance profile. Failure of a first-line NRTI trio leaves three options—one or two PIs or an NNRTI (plus, in each case, two still-potent NRTIs, which may be hard to find).
Prime PI candidates after a first-line PI failure are lopinavir/ritonavir (Kaletra, from Abbott Laboratories) and the investigational drug tipranavir (plus ritonavir). These agents did well in studies involving people with single59 or multiple60,61 PI failures. The results were somewhat clouded because study participants had no NNRTI experience and started nevirapine or efavirenz with lopinavir or tipranavir. Still, reports from the clinic bear out Abbott's contention that people with moderate PI experience often fare well with lopinavir and that the response wanes as protease mutations accrue.62--64
Other agents that will probably find a role in second-line rescue and deeper salvage are tenofovir and the fusion inhibitor T-20, reviewed in the treatment section of this directory.
If a second regimen fails, prospects for success become slimmer still. Joel Gallant notes that, "depending on the starting regimen, it remains challenging or even impossible to design a sequence of three successive drug combinations without using investigational agents."39
Two three-regimen tracks with licensed antiretrovirals seem at least feasible: (1) a single PI regimen, followed by dual PIs, followed by an NNRTI, and (2) triple NRTIs, followed by a PI-based regimen, followed by an NNRTI-based regimen. Both scenarios share the same weakness: they depend on recycling NRTIs (see "NRTI cross-resistance" above.)
The consistent failure of salvage regimens to durably control viral replication forced a reappraisal of salvage goals. BHIVA suggests that lowering viral loads under 50 copies/mL "may not be useful in determining [salvage] success."1 The British experts note that shaving only a half log off the viral load may translate into clinical improvement.65 For people with advanced disease, they add, the goal should be propping up the CD4 count, which correlates more closely with risk of death than viral load does.
Yet researchers have not given up trying to stop replication completely in people with heavy treatment experience. Two strategies with this goal are multiple drug rescue therapy (MDRT) or mega-HAART, and withdrawing all treatment before starting salvage. A third tactic has more modest goals: sustaining the CD4 count and containing HIV as much as possible—while waiting for new drugs.
MDRT or mega-HAART
MDRT essentially calls for as many antiretrovirals as a person can tolerate. Julio Montaner's Vancouver team has championed this approach. But the group's most recent published report raises questions about MDRT's clinical value.66
This nonrandomized study involved 106 people who had taken a median of seven antiretrovirals; 59% had virus with decreased susceptibility to seven or more drugs. Montaner's team gave them five to nine drugs and defined success as two consecutive viral loads under 400 copies/mL. After 47 to 57 weeks of follow-up, 40% reached that goal and 33% had at least two viral loads under 50 copies/mL. But 62% of the cohort had never used an NNRTI before starting an MDRT. Many still had a potent backup antiretroviral and would not strictly rate as "salvage candidates." NNRTI-naive individuals had nearly a three-time higher chance of responding to MDRT than did people with NNRTI experience.
By another measure, CD4-cell gains, MDRT failed in this cohort. Even people whose viral load went under 50 copies/mL twice in a row gained a median of only 2 CD4 cells/mm3. Reviewing this study, Steven Deeks and Jeffrey Martin (University of California, San Francisco) observed, "the failure of multiple-drug rescue therapy to increase CD4 T cell counts…suggests that a clinical benefit may not have been achieved."67 Indeed, two people had new AIDS diagnoses during the study, and seven died. Because the regimens combined so many drugs, some with uncharted interactions, almost everyone endured some clinical side effect or lab abnormality.
Presalvage resistance testing and treatment breaks
Deeks and Martin reject MDRT for salvage, arguing that resistance testing can help pick more focused regimens and "may have rendered [MDRT] obsolete."67 The BHIVA1 guidelines "strongly recommend" resistance testing before starting salvage.
So far, randomized studies of phenotyping have failed to confirm the value of these assays for people with heavy treatment experience. European68 and U.S.69 studies involving such patients found that phenotyping did not help pick new regimens that improved 12-, 16-, or 24-week virologic responses when compared with switching based on drug history. In people with less antiretroviral experience, phenotyping improved the 16-week response in one study70 but not the 6- or 12-month response in another.71
Two published randomized trials of successful genotyping largely enrolled people without deep treatment experience.72,73 (Genotyping is a genetic assay that is simpler than phenotyping. Rather than culturing virus and cells, genotyping uses polymerase chain reaction—PCR—to detect genetic mutations in HIV that reputedly confer drug resistance.) The European trial with a more experienced population68 also evaluated genotyping. Although genotyping yielded no better results than phenotyping or no resistance testing at 12 weeks, it did better than no resistance testing when investigators combined week 12 and 24 viral load results. But genotyping has its limits in people with long treatment histories, because resistance mutations aroused by earlier regimens may remain in small, residual HIV subpopulations.
As studies of people taking drug holidays show, conventional assays can miss low-level drug-resistant virus.74,75 These "archived" mutations have undermined the strategy of suspending treatment before starting salvage. In 45 Frankfurt cohort members who took presalvage treatment breaks, genotyping and phenotyping showed an apparent reversion to wild-type, drug-sensitive virus in 28.76
Reversion to wild type might occur as a result of an outgrowth of the small surviving population of drug-sensitive HIV that had been suppressed by therapy or by a reverse evolution of drug-resistant HIV to wild-type genetic makeup once drug pressure is removed. Either way, the assumption is that wild-type HIV is more "fit", ie, it replicates more quickly. The technology to evaluate viral fitness is still limited, however, and data confirming the role of viral fitness as a significant variable in disease progression is still lacking.
The Frankfurt reverters had a significantly better virologic response to their salvage therapy than the patients whose virus stayed resistant during the break. But that virologic benefit proved short-lived. In a later report that included a few more "wild-type reverters,"77 viral load rebounded from below 500 copies/mL in 75% within a median 78 days.
Preliminary results of a randomized trial of megadrug salvage with or without a preliminary eight-week treatment break suggest at least a temporary advantage for the presalvage holiday.78 Twelve weeks after the rescue regimen began, 59% in the break group and 26% in the no-break group had at least a 1 log (90%) drop in viral load. Disappearance of HIV with drug-resistance mutations had little to do with this statistically significant difference, because 55% of the break-takers had no mutation loss and another 14% had loss of mutations to only one antiretroviral class. Adequate versus low drug concentrations did appear to correlate with a better virologic response. CD4 results were not presented.78
CD4 counts typically plummet when drug pressure is lifted. In the Frankfurt study, the average CD4 count plunged from 192 to 58 cells/mm3 in people with apparent reversions to wild-type virus.76 Observation of the expanded Frankfurt cohort, which included 163 break-takers, found that 15 cohort members suffered 17 new AIDS diagnoses as their CD4 counts declined.77 Four smaller studies showed that CD4 cell drops during treatment breaks can be both steep and unpredictable.79--82 One of these studies80 and two others83,84 confirmed that presalvage breaks confer little virologic benefit compared with continued treatment before salvage.
Keep treating and hope
Another salvage option is continuing treatment, even in the face of virologic failure. This stratagem also has risks: Troublesome side effects persist or worsen, and HIV continues to evolve, perhaps into a more highly resistant medley of viral species. Yet stopping a regimen that is failing virologically leads to even sharper leaps in viral load and to dwindling CD4 counts.74,77 Those changes mean that the failing therapy, though not optimal, was at least slowing replication. Other work found that continuing a PI regimen even in people with fewer than 50 cells/mm3 lowered the risk of progression 43% compared with people not taking a PI when their CD4 count fell that low.84 Incompletely suppressive regimens may keep a person clinically and immunologically stable by partly controlling replication, by promoting the persistence of less fit resistant virus, or by both mechanisms.38,67
Regimens that have become only partially effective may keep a person clinically and immunologically stable by partly controlling replication, by promoting the persistence of less fit resistant virus, or by both mechanisms.38,67 One explanation for the continued protection is that the persistent, though partial virologic suppression does afford some protection to CD4 cells, patients' viral loads remain lower, and CD4 counts higher than if they were untreated. Even if the drugs can do nothing against the HIV in a patient's body, the drug-resistance mutations they have triggered in that HIV may reduce the virus's overall fitness, again, resulting in lower viral loads and/or less immune damage compared to what would result from wild-type HIV in the absence of treatment.
Whatever the mechanism, the protective effect of continuing a failing regimen may fade as HIV evolves further in the face of the drugs. Staying with a poorly suppressive regimen may make most sense in two situations—when the clinician has fashioned a partially suppressive combination that is tolerable and easy to take, or when a person's virus remains susceptible to at least one potent drug that is held in reserve while awaiting new, potent salvage agents.
Presalvage STIs meant to revive a vulnerable, drug-susceptible viral population may be fading from the treatment landscape (see the preceding section), though at least one trial, CPCRA 064, is actively recruiting participants for a randomized study of this tactic. Beyond those on failing regimens, the rationale for interruptions keeps changing. Bruce Walker (Massachusetts General Hospital, Boston) first proposed that STIs would provoke the sturdiest immune response if tried after controlling primary infection, because quick treatment would preserve CD4 cells that promote the specific immune defense against HIV infection. Other scientists started studying STIs in people with chronic infection suppressed by treatment below the level of quantification. They hoped that temporary, controlled "autoinoculation" with one's own virus during treatment breaks would jog the immune system's faulty memory into recognizing HIV as clearly as it did when first infected.
A vigorous immune response against HIV might put the virus into remission all by itself and allow patients to eventually go off drugs completely. But intense study has yielded only clues to the possible value of planned treatment breaks while suggesting some distinct disadvantages. The latest rationale promotes treatment breaks not as immune boosters, but as breaks from drug side effects.
Unstructured treatment interruptions
Studies of structured and unstructured breaks by people with chronic infection show that CD4 counts usually fall quickly during interruptions, while viral loads climb to, or above, pretreatment baselines. Analyses of 72 people who took unguided breaks79 and 82 who did so under clinical supervision80--82 charted monthly CD4 drops of 16 to 44 cells/mm3. One of these groups79 had well-controlled replication when the breaks began, and three80--82 did not. The steepest plummet—44 cells/mm3 monthly—came in the first six months of a study involving 16 people with CD4 counts averaging 775 cells/mm3when they stopped antiretrovirals.82 After that, the monthly drop slowed to 17 cells/mm3. The 72-person study of unstructured breaks79 and a presalvage study of 35 people81 confirmed a sharper fall in the first several months without therapy. Four people in the unstructured- break group experienced a new AIDS diagnosis during their break.79
Occasionally, CD4 count does not plunge and viral load soar when a person stops suppressive therapy. Canadian researchers analyzed records of 238 people with good viral control who stopped or interrupted their anti-HIV therapy for any reason.86 In 13 volunteers (5.5%) viral loads remained under 400 copies/mL for at least 90 days. Only three of them had started treatment during primary infection, and none was taking HAART. Seven persons had pretreatment viral tests; all these recorded baseline viral loads were below 10,000 copies/mL, with a median of 1,500 copies/mL. These observations serve as a warning. STI studies could count as "successes" some people who may have kept a low viral load even if they had never started therapy.
STIs after controlling primary infection
Early results from Bruce Walker's cohort of patients treated before full seroconversion remain the best evidence that STIs may nurture native immunity in such individuals. These 14 people all had undetectable viral loads for at least eight months after starting treatment. They interrupted therapy until their viral load climbed past 50,000 copies/mL once or above 5,000 copies/mL for three straight weeks. Walker now counts seven preliminary successes—people whose viral loads stayed below those thresholds without drugs after one or more STIs.87 Another five are just starting a second or third break. The third break appeared to be failing in another person, even though his CTL response broadened considerably. The last study participant had not controlled replication after four breaks.
Three of the seven responders have falling CD4 counts, which may mean STI-bolstered immunity has begun to lose control of HIV. That result would challenge Walker's hypothesis that protecting CD4 cells early in infection invariably preserves an HIV-specific immune response. Another unwelcome finding is the emergence of 3TC resistance in one of these people.88 Although resistance remains rare during STIs, it is a palpable threat in people who take breaks at any stage of HIV infection.
STIs during well-controlled chronic infection
Three studies,89--91 one of them randomized,89 appraised STIs during well-controlled chronic infection. Criteria for restarting therapy during breaks varied from study to study, but nearly all volunteers took a PI-based regimen and all had a viral load under 50 copies/mL when they took their first STI. Their CD4 counts at that point were robust as well.
Despite their sterling CD4 and viral load numbers, fewer than one quarter of these break-takers could keep their viral loads below 5,000 copies/mL without drugs after three or four breaks. In the biggest study, SSITT (Spanish-Swiss Intermittent Therapy Trial), only eight of 56 people on their fourth two-week treatment break held their viral load under 5,000 copies/mL.91 Of 12 who began an indefinite break at the end of the study, only two persons held their viral loads below 5,000 copies/mL. In one ten-person study, viral loads universally rebounded during three treatment interruptions spread over a year. The first two were four weeks long and the last was open-ended. After 12 months on the final treatment interruption, four of nine volunteers had viral loads below 10,000 copies/mL. Four of these five had pretreatment viral loads below 30,000 copies/mL.
STIs to control drug-related toxicity
The clearest advantage of STIs during chronic infection is the break from antiretroviral toxicities, which is the thrust of two studies by Anthony Fauci's group at the National Institute of Allergy and Infectious Diseases.92 Pulsed therapy may also save money and improve adherence. Taking antiretrovirals every other week would halve drug bills, but this strategy requires much closer monitoring and attendant charges for more doctor's visits, CD4 counts, viral load tests, and maybe other monitoring. For some people, switching on and off therapy every week could worsen adherence, because those off weeks will be much more pleasant.
Fauci did produce evidence of decreased toxicity in ten people taking antiretrovirals every other week. Median triglycerides and LDL ("bad") cholesterol dropped significantly after six months in the eight people still in the study. Other researchers corroborated the triglyceride result, reporting that 20 people taking a single STI saw average triglycerides drop from 296 mg/dL to 192 mg/dL.93
Though heartening, these findings do not prove that pulsed therapy is better than continuous therapy. Reviewing Fauci's study, Diane Havlir (University of California, San Diego) noted that even statistically significant lipids swings do not guarantee a clinical benefit.94 One could also note that a steady nevirapine regimen may yield a similarly attractive lipid profile while controlling HIV better than on-and-off PI treatment.
The other trial by Fauci's group randomized people to take continuous therapy or to take every third month off. The problem with that approach, Fauci learned, is a bigger risk of resistance. Although all 26 people in the on-off group regained a sub-50-copy viral load every time they restarted therapy, four of them had to switch from NNRTIs to PIs because non-nucleoside resistance emerged. Fauci also suggested that each month without treatment raises the risk of transmission and irreparable immunologic deficits.
The nonrandomized one-week-on-one-week-off study used only one regimen—d4T, 3TC, indinavir, and ritonavir—in people whose HIV levels were already well controlled. This group's median CD4 count when starting pulsed therapy stood at 786 cells/mm3. So far, no one has met the study's failure criteria: consecutive viral loads above 500 copies/mL or more than a 25% dip in CD4 cells. Fauci's team found no evidence of increased cell-associated HIV RNA or DNA at six months or more replication-competent virus in CD4 cells.
Though these results stirred some enthusiasm when Fauci presented them, much work remains in validating this approach and other STI formulas. The ACTG and others are enrolling people into randomized trials of treatment interruptions (see "Actively Recruiting Clinical Trials" in this directory). The prudent will await results of such trials before hazarding off-and-on tactics in people responding well to therapy.
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