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Monotherapy With Two Drugs: Is Lopinavir/Ritonavir Enough?
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A report from the XVI International AIDS Conference
Toronto, August 13-18, 2006
Mark Mascolini
Are you bored by antiretroviral research?
Just before the XVI International AIDS Conference in Toronto, two top-tier antiretroviral researchers suggested as much in casual chats with this reporter. Joep Lange (Academic Medical Center, Amsterdam) and Charles Boucher (University Medical Center Utrecht) betrayed no hints of flippancy in making this assertion--independently--at a workshop just before the international extravaganza.
Only 10 years after the last global meeting in Canada, the seminal Vancouver conclave, Lange and Boucher argued research has solved the problem of shutting down HIV--for a lifetime in people without multiclass-resistant virus and scant treatment options. From here on, they said, everything else we learn about antiretrovirals is filigree.
One could claim that the salvage quandary looks monumental in countries with 20 years of antiretroviral experience, that resistant virus can out-dance the best regimen, that side effects erode the resolve of even A+ patients. But when you look at the leading treatment strategy news from Toronto, it does seem that Lange and Boucher have added one more correct call to their long lists of savvy forecasts.
HIV docs everywhere--in rich countries and poor--now know that if they pick a suitable first-line regimen, or often even a suitable second or third, viral load will fade to under 50 copies, CD4s will climb, and even once-wasted people will soon look as stalwart as stevedores.
Is that why most antiretroviral headlines from Toronto came from studies trying to coax out some incremental edge, some nuanced margin, that makes life easier for people with HIV?
That may be a fair way to label research on triple-nuke therapies, triple-class therapies, class-sparing therapies, primary infection therapies, structured treatment interruptions, and maintenance monotherapies. Trouble is, these sometimes (but not always) well-conceived stratagems have a habit of falling flat when facing that dowdy old standard of care--one nonnucleoside (NNRTI) or ritonavir-boosted protease inhibitor (PI) plus two nucleosides (NRTIs).
Triple-nuke starting combos got X-ed off guideline "preferred" lists after a sad roll call of collapse in clinical trials,[1-3] although the DART trial continues to weigh this suspect strategy in sub-Saharan Africa [4]. The prime earmark of triple-class therapies appears to be a higher risk of side effects in return for no more viral control [5-7], a finding confirmed in the US FIRST trial [8] (reviewed later in this series of reports).
The Toronto meeting also offered evidence that class-sparing regimens and treatment for primary infection hold no special promise for people with HIV, and evidence against planned drug holidays mounted as well. These Toronto reports will weigh each of these strategies in turn. But first up is the newest and most controversial tactic, ritonavir-boosted PI monotherapy.
Can first-line monotherapy make a comeback?
Back when clinicians had only one antiretroviral, monotherapy made lots of sense for a rapidly fatal disease. Ten years after the international get-together in Vancouver enshrined triple therapy as the surest way to stymie HIV, clinical researchers asked in Toronto whether lopinavir/ritonavir monotherapy may not be just as good as the canonic three-drug combo.
Most of the randomized monotherapy results unveiled at the conference came from studies that started with a standard triple regimen, then down-shifted all the way to first gear after people reached an undetectable viral load to see if lopinavir/ritonavir alone could keep HIV muffled. But one trial pitted lopinavir/ritonavir alone against those PIs plus two nukes from the first day of treatment.
MONARK (an acronym for MONotherapy AntiRetroviral Kaletra that sounds more ancien regime than ART nouveau) randomized 83 treatment-naive people to the standard twice-daily dose of lopinavir/ritonavir and 53 to lopinavir/ritonavir plus AZT/3TC [9]. An on-treatment analysis combining virologic endpoints from 24 and 48 weeks found a significantly better response in the triple-therapy arm.
Most people who signed up for MONARK had CD4 counts that called for quick treatment, averaging 257 in the monotherapy group and 234 in the control arm. But pretreatment viral loads looked less ominous, averaging about 24,540 copies in the monotherapy group and just a little less in the triple-drug arm. So most of these people did not have to go far to reach an undetectable load.
MONARK had a double primary endpoint--proportion of people with a load below 400 copies at week 24 and below 50 copies at week 48. An intent-to-treat analysis that counted dropouts as failures saw no significant difference between study arms in this primary endpoint, though results looked better in the three-drug arm (Table 1). But in an on-treatment analysis a significantly higher proportion of people on triple therapy (98%) than on monotherapy (80%) met this primary endpoint (P = 0.02). The on-treatment analysis also reckoned a significantly better sub-50-copy response at 48 weeks in the three-drug group (98% versus 84%, P = 0.03).
So should you put more stock in the intent-to-treat analysis or the on-treatment analysis? Jean-Francois Delfraissy (Le Kremlin Bicetre Hospital, Paris) recorded a 23% discontinuation rate in the triple-treatment group by week 48, compared with 16% in the solo-PI arm, even though he reported similar tolerance of the two regimens. Perhaps the open-label design of the trial contributed to the higher dropout rate in the triple-drug group. Whatever the reason, that between-arm dropout difference would weigh against triple therapy in an intent-to-treat analysis counting dropouts as failures.
Another way to compare the antiviral punch of the two regimens is to see how many people met study requirements for a resistance test. MONARK researchers ran genotypes on anyone with a viral load above 500 copies after having a sub-400 load, on anyone who quit the trial with more than 500 copies after having fewer than 400 copies, and whenever a study clinician wanted a resistance test for "safety" reasons. By those criteria 21 people (25%) taking monotherapy versus 3 (6%) in the control group got resistance genotypes. In other words the rebound rate was considerably higher in the monotherapy group.
Primary PI mutations emerged in 2 of the 21 people in whom monotherapy failed--a vanishingly rare event when a lopinavir/ritonavir-plus-nucleoside regimen fails. None of the 3 people genotyped in the triple therapy arm ended up with PI mutations. So far MONARK virologists have looked for resistance only with a standard genotyping test. More sensitive assays could detect smaller populations of protease mutations that this standard test overlooks.
The MONARK team did not report how well lopinavir got into the brain or semen (more on this later). Delfraissy did say ongoing analyses of HIV DNA in blood cells, lopinavir level studies, and adherence estimates may sort out people with a higher risk of failure when taking monotherapy. Right now twice-a-day PI monotherapy for treatment-naive people rates as a risky, perhaps needless tactic when tolerable once-daily first-line regimens abound.
Lopinavir/ritonavir monomaintenance in Brazil: KalMo
If the rationale for first-line lopinavir/ritonavir monotherapy looks shaky (see preceding section), how about maintenance monotherapy after a triple regimen squelches viral replication for several months? Three randomized trials appraised this strategy, and two other groups sized up lopinavir/ritonavir monotherapy as a maintenance or switch regimen. Overall results proved more reassuring with maintenance monotherapy than with monotherapy as a first regimen, though mono-maintenance has its risks.
The three trials share several features: They all include only people who kept the lid on HIV for some time with triple therapy, and they all exclude anyone in whom a PI regimen failed. KalMo, the first such study presented in Toronto, recruited 60 people with a load under 80 copies for more than 6 months, no virologic failures of any sort, CD4s over 200, and lowest-ever (nadir) CD4 over 100 [10]. Estevao Nunes (Federal University of Rio de Janeiro) and colleagues from a Rio hospital randomized 30 to stay on their current regimen and 30 to switch to lopinavir/ritonavir alone. The primary endpoint in this open-label trial was a viral load under 80 copies at week 48; virologic failure meant a confirmed load above 1000 copies.
CD4 count averages stood in the 500s in both groups, both groups averaged more than 40 months of antiretroviral therapy, and 63% in each arm were taking an NNRTI when the study began. Two people dropped out of the monotherapy arm, 1 because of grade 3 diarrhea and 1 because of pregnancy. Three people quit the control group, 1 because of virologic failure at week 36, 1 who became pregnant, and 1 who went to jail.
Nunes reported 1 virologic failure at week 48 in the monotherapy arm, but that person stayed in the study after recontrolling HIV by adding tenofovir and 3TC; standard genotyping saw no mutations in virus from that person. Another person in each arm had low-level viremia during the trial (220 to 850 copies in the monotherapy group and 98 copies in the control arm).
A noncompleter-equals-failure analysis figured equivalent sub-80-copy response rates at 48 weeks--86% with monotherapy and 83% with standard therapy. Results with an on-treatment analysis did not differ between the two groups. Triglycerides rose more with solo lopinavir/ritonavir (to 261 mg/dL) than with standard therapy (to 207 mg/dL), but that difference lacked statistical significance (P = 0.229). Gut problems troubled 66.7% of those trying lopinavir/ritonavir monotherapy versus 16.7% of those who stayed with their initial regimen. That difference appears to be the only major disadvantage of mono-maintenance in this small trial.
(note from Jules Levin: KalMo was not as rigorously conducted as the other 3 monotherapy studies.)
Mono-maintenance looks OK in Spain
In the OK04 trial Jose Arribas (Hospital La Paz, Madrid) and colleagues at other Spanish clinics started with 200 people who kept their viral load under 50 copies for more than 6 months, who had no record of virologic failure with a PI combo, and who had taken lopinavir/ritonavir plus two NRTIs for more than 1 month [11]. They randomized 100 people to the only-Kaletra (OK) arm and 100 to continue Kaletra with two nukes. Two people in the control group never took a dose during the study. Baseline sub-50-copy rates averaged more than 1 year in both arms. Though CD4 counts looked good at randomization (474 monotherapy versus 473 triple therapy), CD4 nadirs were low (107 versus 103).
The primary endpoint in OK04 was therapeutic failure at 48 weeks, which could mean one of four things:
- Two viral loads above 500 copies 2 weeks apart, except in people on monotherapy who regained a sub-50-copy load after adding two NRTIs back to the regimen
- A drug switch for any reason other than adding back two NRTIs in the monotherapy arm
- Treatment discontinuation
- Loss to follow-up (not coming back for checkups)
By week 48 Arribas counted six virologic breakthroughs in the monotherapy arm (6%) versus 3 in the triple-drug arm (3%). One of the 6 people with a monotherapy breakthrough resumed NRTI treatment, 3 stopped coming back for visits, and 1 switched to a completely new regimen. Five other people in the monotherapy group also restarted two nucleosides. So by week 48 Arribas had 89 people who stayed with monotherapy the whole time. Besides the three breakthroughs in the control arm, 3 people dropped out because of side effects and 4 stopped returning for checkups, so this arm had 88 people taking lopinavir/ritonavir plus two NRTIs at week 48.
In the primary endpoint analysis Arribas figured an 89% response rate in the monotherapy arm versus 88% with triple therapy. Even when he counted resuming two NRTIs as failure in the monotherapy arm, the 48-week sub-50 response rate hardly differed in the two groups (85% monotherapy versus 90% triple therapy).
OK04 clinicians ordered resistance genotypes whenever a viral load topped 500 copies, which happened to 11 people (11%) in the monotherapy group and 4 people (4%) in the triple-therapy group. Two of 11 people taking monotherapy ended up with primary PI mutations versus 1 of 4 in the three-drug group.
Based on these findings, Arribas proposed that about 85% of people like those who qualified for this trial do not need nucleosides to maintain viral suppression with boosted lopinavir, about 10% lose viral control because of episodic poor adherence, and about 5% have persistent low-level viremia without clear evidence of poor adherence. Predicting shaky adherence is not easy; predicting low-level viremia with good adherence is probably impossible.
Mono-maintenance comes up short in Canada
The lopinavir/ritonavir maintenance trial reported by William Cameron (University of Ottowa) is the only one of the three without a snappy name (Study M03-613), the only one that tested monotherapy against efavirenz plus AZT/3TC, the only one with follow-up to 96 weeks, and the only one with a worse failure rate for monomaintenance--at least by one metric [12].
Cameron and colleagues randomized 104 treatment-naive people to lopinavir/ritonavir plus AZT/3TC and 51 to efavirenz plus the same NRTIs. People in the lopinavir/ritonavir group who got their viral load under 50 copies and kept it there for 3 straight months could drop the nukes, while everyone in the efavirenz arm continued all three antiretrovirals. When the study started CD4 counts averaged 227 in the PI arm and 250 in the efavirenz group. Pretreatment viral loads averaged 100,000 copies in the PI group and about 63,000 copies in the control arm.
Of the 104 people who started lopinavir/ritonavir, 2 switched to efavirenz and later dropped out, 8 quit before stopping AZT/3TC, 15 quit after stopping AZT/3TC, and 8 finished the study taking NRTIs with their lopinavir/ritonavir. So 71 people (68%) completed the study on monotherapy, which they took for 56 to 72 weeks. Of the 51 people who started efavirenz with AZT/3TC, 34 (72%) finished the study on that regimen.
An intent-to-treat analysis of the primary endpoint--percent with a load under 50 copies at week 96--figured a 61% success rate with efavirenz triple therapy versus 50% with lopinavir/ritonavir monotherapy, though that difference fell short of statistical significance (P = 0.23).
But a Kaplan-Meier analysis of people maintaining a sub-50 load did find a significant difference favoring efavirenz-based triple therapy. This analysis figured time to the first of two viral loads above 50 copies from (1) the switch to lopinavir/ritonavir monotherapy or (2) the third consecutive load under 50 copies in the efavirenz arm. At study week 72 Cameron saw a 90% response rate with efavirenz/AZT/3TC versus a 62% response rate with monotherapy, a highly significant difference (P < 0.001). When using the same yardstick to calculate time to the first of two loads above 500 copies, Cameron figured a 95% response with efavirenz triple therapy versus an 84% response with lopinavir/ritonavir monotherapy, a difference that stopped short of statistical significance (P = 0.18).
Among people with a virologic breakthrough while taking monotherapy, 2 of 7 failed to push their load below 50 copies again (Table 2). Among 16 people with blips between 50 and 500 copies while taking monotherapy, 3 did not get under 50 copies again.
Two of 15 people tested for resistance during a monotherapy rebound had new PI mutations, as did 1 taking 2 NRTIs with the PIs. It was not clear whether the PI mutations during triple therapy emerged before monotherapy began or after someone had a breakthrough on monotherapy and resumed triple therapy. One of 5 people tested for resistance in the efavirenz arm had nonnucleoside-related mutations. The 3TC-evoked M184V mutation emerged in 2 of 15 lopinavir failure samples (13%) and in 1 of 5 efavirenz failure samples (20%).
Breakthroughs with atazanavir/ritonavir maintenance
As 25,000 people clogged Toronto's Front Street waiting to register for the international conference, JAMA published results of an AIDS Clinical Trials Group (ACTG) study of atazanavir/ritonavir monotherapy, a regimen even simpler than twice-daily lopinavir/ritonavir [13]. In this nonrandomized pilot study 36 adults with a sub-50 load for 48 weeks or longer switched to atazanavir/ritonavir. Six weeks later they shelved their two nucleosides.
Two people decided to leave the study before dropping their nukes, and 1 more quit before reaching the 24-week finish line. Three of the remaining 33 (9%) had viral rebounds to 4730, 1285, and 28,397 copies 12, 14, and 20 weeks after switching to monomaintenance. Standard genotyping assays spotted no resistance mutations in rebound samples, but atazanavir levels were low or below detection in 2 people with breakthroughs. HIV RNA remained undetectable in 8 men who gave semen samples during monotherapy.
Two cohort studies of stand-alone lopinavir/ritonavir
Clinicians in Berlin and Munich, and a separate team from London, detailed two case series of people who tried lopinavir/ritonavir monotherapy either as a starting regimen or to simplify their current combination. Eva Wolf and her Berlin-Munich colleagues tracked 63 people with no evidence of resistance to lopinavir/ritonavir who wanted to try monotherapy for one of four reasons. Eight (13%) starting their first antiretrovirals were anxious about facial lipoatrophy; 17 (27%) were taking a failing NRTI/NNRTI combination; 26 (41%) were suffering from NRTI or NNRTI side effects; and 12 (19%) wanted to simplify a successful regimen [14].
The 55 people already taking antiretrovirals averaged 6.1 years of treatment experience (range 1 to 12 years). Viral loads for everyone in the study group averaged 68,000 copies, 20 people (32%) had a sub-400 load, and 17 (27%) had a sub-50 load. After an average 14 months of follow-up, a last-observation-carried-forward analysis determined that 46 people (73%) had a viral load under 400 copies and 42 (67%) were under the 50-copy threshold.
These clinicians did not report how many people taking lopinavir/ritonavir as their first regimen reached an undetectable viral load. They did note that 1 person naive to PIs picked up a string of primary protease mutations during monotherapy. Two other people in whom monotherapy failed violated a key entry requirement: They had resistance to PIs when the study began. One can assume they will not be the only people in the world who talk their way into ritonavir-boosted monotherapy with PI-resistant virus. Triglycerides climbed by a median 41 mg/dL and total cholesterol by a median 27 mg/dL during follow-up. Those findings raise questions about one rationale for monotherapy cited by these clinicians and others--limiting side effects.
Laura Waters and colleagues at London's Chelsea and Westminster Hospital offered a good look at what happens when treatment-experienced people with adherence problems or other concerns scale back to lopinavir/ritonavir monotherapy [15]. This chart review found that 14 of 28 people (50%) had a viral load below 50 copies after an average 9.2 months of follow-up on monotherapy, though 10 of the 14 already had an undetectable load when they started monotherapy, 8 of them while taking a lopinavir/ritonavir regimen.
Nineteen of these 28 people tried lopinavir/ritonavir monotherapy because of adherence problems with their combination regimen, while another 4 opted for monotherapy because of side effects, 1 because of drug interactions, and 1 for an otherwise unexplained "request." Records showed no reason why the other people went the monotherapy route.
Of the 14 people who did not reach sub-50-copy territory with monotherapy, 3 had started monotherapy with an undetectable load, 2 while taking lopinavir/ritonavir. Nine of these 14 continued monotherapy, and 7 of those 9 had a load below 400 copies through an average 10 months of follow-up.
Six people had (1) a detectable viral load during monotherapy, (2) a viral sample that could be amplified for genotyping, and (3) a comparison genotype from before monotherapy. One of them (17%) picked up new primary PI mutations during monotherapy and 2 picked up minor PI mutations or natural polymorphisms.
Among 5 people who started monotherapy with a major PI mutation, 1 maintained a load below 50 copies, 1 with fewer than 50 copies when starting monotherapy stayed below 400 copies, 1 got under 50 from 1484 copies, and 2 had little or no RNA or CD4 response.
Is monotherapy back for good?
The outpouring of conference reports on lopinavir/ritonavir monotherapy suggests the answer to that question is yes, or at least for a good while. As the German and British case series show, clinicians and people with HIV started adopting this tactic before any randomized trials weighed its merits--or demerits. This is hardly the first time a winsome notion caught hold in HIV care before any evidence backed it up. But now that a little mound of randomized data has accrued, what does it say?
Monotherapy proponents cite three reasons for one-drug therapy--a lower risk of side effects, improved adherence through simplicity, and lower cost. On clinical grounds, lower cost is a red herring. When the world learned a decade ago that a PI plus two nukes slowed HIV a whole lot better than two nukes alone, no one argued for double-nuke therapy because it cost less.
If limited side effects and simplicity are the goals of first-line therapy, there are other options that some may consider potentially better in terms of side effects and simplicity for many people, including once-daily efavirenz plus tenofovir/emtricitabine (TDF/FTC)-now combined in a single once-a-day pill-as well as once-daily boosted PIs plus TDF/FTC or once-daily, one-tablet abacavir/3TC. In Toronto 96-week follow-up of 257 previously untreated people taking efavirenz plus TDF/FTC as two once-daily pills found that only 12 (5%) had to stop the drugs because of side effects [16].
When viewed from this toxicity/simplicity vantage, it's hard to see lopinavir/ritonavir monotherapy as the best first-line choice for just about anyone. Then we come to the question of efficacy. The intent-to-treat analysis of MONARK hints that lopinavir/ritonavir has more antiviral vigor with AZT/3TC than alone, and the on-treatment analysis probably settles the question in favor of triple therapy for most observers (Table 1).
At the same late-breaker session where MONARK monotherapy edged up to abdication, ACTG investigators unfurled 96-week results demonstrating the antiviral superiority of efavirenz (plus two NRTIs) over the older lopinavir/ritonavir soft-gel capsule formulation (plus two NRTIs) [17]. (But this lopinavir/ritonavir formulation outdid efavirenz in other endpoints measured by the ACTG team. An upcoming article in these series of Toronto reports will consider ACTG A5142.)
Whether lopinavir/ritonavir monotherapy makes sense as a simple maintenance regimen is a harder call. Again one must ask whether two pills twice a day (with the new Kaletra tablet) is simpler than one pill once a day with Atripla or four pills once a day with atazanavir/ritonavir plus TDF/FTC or abacavir/3TC. And, more importantly, one must ask whether lopinavir/ritonavir monotherapy is as strong as lopinavir/ritonavir with two NRTIs or alternate standard regimens.
Table 3 conflates results of the four randomized trials involving lopinavir/ritonavir monotherapy from the starting gun (MONARK) or as a maintenance regimen after months of undetectable viremia (KalMo, OK04, and M03-613). No matter how you look at failure rates--combining all four studies or looking only at the maintenance trials; calculating failure rates for all enrollees or only for those who completed the trial on their assigned regimen--the monotherapy arms always had a higher failure rate.
In e-mail to me OK04 researcher Jose Arribas argued that "all current, widely accepted, simplification strategies entail a risk of decreasing efficacy and increased risk of developing resistance. Compared to accepted simplification strategies our [OK04] results are of similar efficacy and with lower risk of resistance." And data Arribas sent comparing OK04 results with simplified regimens based on abacavir, nevirapine, efavirenz, or atazanavir/ritonavir show he's right.
The question for people mulling a lopinavir/ritonavir maintenance regimen is whether that "risk of decreasing efficacy" is worth whatever may be gained in convenience, tolerability, and adherence. The noncompletion rates from monotherapy arms in the four trials outlined in Table 3--16% in MONARK, 6% in KalMo, 11% in OK04, and 32% in M03-613--suggest that even solo lopinavir/ritonavir poses high convenience or tolerability hurdles for some people. And if Arribas is right, as he proposed in Toronto, that about 10% of people with well-controlled viremia will lose control during 48 weeks of monotherapy because of poor adherence, lone-wolf lopinavir/ritonavir may not win any adherence trophies.
Fielding questions on lopinavir and atazanavir monotherapy via e-mail, Daniel Kuritzkes (Harvard Medical School, Boston) wrote that the studies reviewed above "show that this approach does not yield long-term results that are as good as triple therapy, but that the difference is small, and the risk of resistance very low." Although Kuritzkes would not recommend monotherapy for routine practice, he wrote, "I think maintenance therapy with LPV/r is a reasonable option for those settings in which dropping the NRTIs is desirable for one reason or another. I would also say that maintenance therapy is less risky than starting off with LPV/r monotherapy."
Stanford University's Andrew Zolopa, who cochaired the session that featured three of the four monotherapy trials, viewed the results in a similar light. "I don't see a compelling reason to initiate therapy with a boosted PI alone," he wrote, because "most individuals tolerate standard nuc backbones that make up current regimens--at least in the short term." Zolopa thinks the four trials "in total suggest a slightly lower efficacy and slightly more PI resistance at failure" and that "these problems would likely be even larger if this strategy was more widely employed in clinics." Although he agrees that lopinavir/ritonavir monotherapy may be an option for a select few, "the vast majority of patients will tolerate and benefit from a nuc backbone as part of their long-term regimen." But reliance on nucleosides may change, Zolopa adds, when newer antiretroviral classes reach the clinic.
None of the monotherapy researchers in Toronto had data to show how well, or poorly, lopinavir/ritonavir by itself gets into anatomically secluded lairs like the brain and seminal fluid. Earlier research suggests lopinavir/ritonavir attains reasonable levels in brain [18,19], but several studies found little or no lopinavir in semen [20-23], so lopinavir/ritonavir monotherapy may not be the best bet for sexually active men.
Lots remains to be learned about how often PI-resistant virus emerges during monotherapy. The standard genotyping assays used to trawl for resistant virus in the four monotherapy trials are wide-mesh nets that haul in only big-fish viral variants making up 20% or more of the whole viral population analyzed. More sensitive fine-mesh nets like real-time PCR routinely snare even the smallest minnows of the viral swarm, and those so-called minority variants can quickly expand into brutish majorities if antiretroviral pressure wavers--as it may, for example, if someone misses a dose or two or takes an over-the-counter drug that cuts PI levels.
Besides the few (but worrying) clear-cut virologic breakthroughs during lopinavir/ritonavir monotherapy in these four trials, viral loads often meandered in the dangerous 50- to 400-copy range [see note 24]--replication levels high enough to breed resistant virus [25-27]. Until more sensitive assays check viral samples from monotherapy rebounders and blippers in these and other studies, no one can forecast the real resistance risk with monotherapy.
Mark Mascolini writes about HIV infection
References and Notes
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8. MacArthur RD, Novak RM, Peng G, et al. Long-term clinical and immunologic outcomes are similar in HIV-infected persons randomized to NNRTI vs PI vs NNRTI + PI-based antiretroviral regimens as initial therapy: results of the CPCRA 058 FIRST study. XVI International AIDS Conference. August 13-18, 2006. Toronto. Abstract TUAB0102.
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compared to LPV/r + zidovudine/lamivudine in antiretroviral-naive patients. XVI International AIDS Conference. August 13-18, 2006. Toronto. Abstract THLB0202.
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17. Riddler SA, Haubrich R, DiRienzo G, et al. A prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV infection--ACTG 5142. XVI International AIDS Conference. August 13-18, 2006. Toronto. Abstract THLB0204.
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21. Ghosn J, Chaix ML, Peytavin G, et al. Penetration of enfuvirtide, tenofovir, efavirenz, and protease inhibitors in the genital tract of HIV-1-infected men. AIDS 2004;18:1958-1961.
22. Solas C, Lafeuillade A, Halfon P, et al. Discrepancies between protease inhibitor concentrations and viral load in reservoirs and sanctuary sites in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2003;47:238-243.
23. Sankatsing SU, Droste J, Burger D, et al. Limited penetration of lopinavir into seminal plasma of HIV-1-infected men. AIDS 2002;16:1698-1700.
24. From weeks 4 to 48 in MONARK, about 10% to 20% in the monotherapy group had a load between 50 and 400 copies. Almost no one in MONARK's triple-therapy arm had a detectable load after week 24. One of 30 people in KalMo had a load that wavered between 220 and 850 copies from weeks 24 through 48, compared with 1 person in the control arm who had a single blip to 98 copies at week 48. About 10% in M03-613 had 50 to 400 copies between weeks 24 and 96, whereas blips into that region were rare after week 16 among people taking efavirenz plus AZT/3TC. Only about 5% in OK04 had low-level viremia between weeks 24 and 48, but that was a higher proportion than in the triple-therapy arm.
25. Tobin NH, Learn GH, Holte SE, et al. Evidence that low-level viremias during effective highly active antiretroviral therapy result from two processes: expression of archival virus and replication of virus. J Virol 2005;79:9625-9634.
26. Nettles RE, Kieffer TL, Simmons RP, et al. Genotypic resistance in HIV-1-infected patients with persistently detectable low-level viremia while receiving highly active antiretroviral therapy. Clin Infect Dis 2004;39:1030-1037.
27. Karlsson AC, Younger SR, Martin JN, et al. Immunologic and virologic evolution during periods of intermittent and persistent low-level viremia. AIDS 2004;18:981-989.
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