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Novel First-Line Tactic: Are They Necessary?
--Tight Viral Control During 1st 18 Months of HAART= fewer deaths
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Written for NATAP: A report from the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Dec 2005
Mark Mascolini
Two nucleosides or tenofovir plus a boosted protease inhibitor (PI) or efavirenz emerged as simple, potent, and durable first-line regimens with the randomized trials of lopinavir/ritonavir and efavirenz. Repeated comparisons of these regimens-in further trials and cohort studies-failed to dislodge them from the "preferred" first-line list in treatment guidelines.
Yet the itch to find something simpler or stronger or longer lasting persists among trial planners. Another ICAAC review written for NATAP charted decidedly mixed results with an up-front four-drug nucleoside/nucleotide regimen-Trizivir plus tenofovir (see http://www.natap.org/2005/ICAAC/icaac_19.htm). This review looks at two more novel first-line concoctions. A third study described here underlines the importance of getting it right the first time when starting antiretrovirals. It is, Danish clinicians showed, a life-or-death matter.
Double-boosted first-line PIs-with no nukes (Kaletra + Saquinavir)
After 48 weeks in a small, nonblinded trial, people randomized to lopinavir/ritonavir plus saquinavir-and no nucleosides-had RNA and CD4 responses equivalent to those of people randomized to lopinavir/ritonavir plus AZT/3TC [1]. Side effect rates also proved similar in the two treatment arms. The University of Ottawa's William Cameron and US colleagues did not report body fat changes in this 30-person trial, but follow-up was probably too brief to discern any meaningful differences in such measures.
Cameron and colleagues recruited 30 treatment-naive people with a viral load above 1000 copies/mL and randomized 14 to take standard doses of lopinavir/ritonavir and AZT/3TC and 16 to take standard-dose lopinavir/ritonavir plus 800 mg of saquinavir twice daily. The two groups had similar median pretreatment viral loads-5.0 log copies/mL (100,000 copies/mL) in the saquinavir group and 5.3 log copies/mL (about 200,000 copies/mL) in the AZT/3TC group. People assigned to AZT/3TC had significantly lower pretreatment CD4 counts (median 120 cells/mm3, range 9 to 428 cells/mm3) than did people who started saquinavir (median 269 cells/mm3, range 3 to 687 cells/mm3) (P = 0.045). Such unbalances between arms are more likely in very small studies.
After 48 weeks of treatment a noncompleter-equals-failure analysis determined that 63% in the saquinavir group and 50% in the AZT/3TC group had a viral load below 50 copies/mL-a nonsignificant difference. In an on-treatment analysis 78% taking saquinavir and 77% taking AZT/3TC had a 48-week viral load under 50 copies/mL.
People randomized to AZT/3TC gained more CD4 cells, on average, than people randomized to saquinavir (187 versus 141 cells/mm3), but that difference lacked statistical significance, and one would expect a group starting with a lower CD4 count (like the AZT/3TC group) to gain more T cells over 48 weeks.
What about side effects? One person (6%) dropped out of the saquinavir group with gastrointestinal complaints and 3 (24%) quit the AZT/3TC arm, two because of gastrointestinal problems and one with elevated liver enzymes. So by that measure it seems this small study group tolerated lopinavir/ritonavir/saquinavir better than lopinavir/ritonavir/AZT/3TC.
But other toxicity measures were balanced between arms. Similar proportions in each group-about 20%-had diarrhea, nausea, or vomiting. Through 48 weeks, glucose and hematocrit changed hardly at all in either group. Total cholesterol rose an average 60 mg/dL in both treatment arms, while average triglycerides climbed 85 mg/dL with the all-PI combination and 64 mg/dL with lopinavir/ritonavir plus AZT/3TC, a nonsignificant difference.
The bottom line is that lopinavir/ritonavir/saquinavir seems a feasible first-line regimen. But this tiny trial provides no rationale for preferring it over a boosted PI-or efavirenz-plus two nucleosides. One can assume that lipoatrophy will show up in people who keep taking AZT/3TC longer than 48 weeks, but backbones such as tenofovir/3TC and tenofovir/emtricitabine (FTC) cause little or no lipoatrophy-and few other side effects-after 3 years of follow-up [2]. The same may not prove true for double-boosted PIs.
Quintuple up-front therapy with enfuvirtide
Pushing the first-line envelope even farther, José Molto and colleagues at Barcelona's Germans Trias i Pujol Hospital talked 15 previously untreated people into starting either a triple-class first-line regimen or a quadruple-class combo including twice-daily injected enfuvirtide [3].
In this nonblinded study Molto and coworkers randomized 7 people to lopinavir/ritonavir (533/133 mg twice daily) plus once-daily doses of efavirenz, 3TC, and tenofovir-already a zesty regimen. Eight others started the same four antiretrovirals plus twice-daily enfuvirtide, the HIV fusion inhibitor. Average pretreatment viral loads and CD4 counts were equivalent in the enfuvirtide group (4.98 log [about 95,000] copies/mL and 463 cells/mm3) and the no-enfuvirtide group (5.10 log [about 126,000] copies/mL and 362 cells/mm3).
Measuring viral loads every 6 hours on the first 3 days of therapy and once a day on the next 3 days, Molto charted a significantly swifter 6-day drop in the enfuvirtide group (-0.802 log/day) than in the no-enfuvirtide group (-0.624 log/day) (P = 0.048). The average day-6 viral load was lower, but not significantly lower (P = 0.079), among people taking enfuvirtide (3.55 versus 3.92 log [about 3550 versus 8300] copies/mL). These changes meant the four-drug regimen had about 79% the antiviral activity of the five-drug regimen over the first 6 days of therapy.
Though others demonstrated that a quintuple first-line combo clears circulating HIV faster than a standard triple regimen in the first weeks of treatment [4], no one has proved that faster early clearance pays off clinically over the first few years of therapy. At least five 48-week randomized trials found no benefit in starting with four antiretrovirals rather than three [5-9], including a comparison of efavirenz/Combivir with efavirenz/Trizivir presented at the same ICAAC where Molto described his results [5]. And Molto's trial must be seen as highly theoretical, since few people seem likely to opt for an injected drug as a first-line antiretroviral.
But one three-drug regimen that stymies HIV faster and longer than another three-drug regimen will certainly win favor among antiretroviral prescribers, and for good reason, as the study reviewed below shows.
Tight control for first 18 months means fewer deaths
Tight viral control during the first 18 months of antiretroviral therapy means lower mortality 90 months after treatment begins [10]. And a drug break for any reason during the first 18 months of therapy-by people with a sometimes-detectable viral load-raises the risk of death down the road.
Those findings emerged from the Danish HIV Cohort Study, which includes everyone in the country who began a potent antiretroviral regimen since January 1995. Not only is this a comprehensive database, it is also one that loses few members. Nicolai Lohse from Odense University Hospital reported that only 67 people in his multiyear analysis (3.2%) stopped coming back for follow-up visits.
Lohse's study involved 2046 people who started potent therapy between January 1995 and January 2002 and did not die for at least 18 months after beginning treatment. He divided them into three groups, depending on how often during treatment months 6 through 18 they had a viral load above 400 copies/mL:
- Group 1: Never had a load above 400 copies/mL
- Group 2: Above 400 copies/mL 1% to 99% of the time
- Group 3: Always above 400 copies/mL
People in group 1 tended to start potent therapy in a later year than those in the other groups, and they started a strong combination much more often as their first regimen (Table). Group 1 members also tended to start before their CD4 sank below 200 cells/mm3, although the three groups began treatment with similar viral loads. Whereas 1% in group 1 interrupted treatment for 2 weeks or more during the first 18 months of therapy, 17% in groups 2 and 3 took a drug holiday in that time.
Significantly more people in group 1 than in the other groups had a viral load below 400 copies/mL 90 months after starting potent therapy (Table). Group 1 also gained significantly more CD4 cells from month 18 through month 90. These advantages translated into 92.7% survival 90 months after group 1 began a strong combination, compared with 85.6% and 76.1% survival in groups 2 and 3. Compared with group 1, group 2 had a 2.63 times higher risk of death and group 3 a 4.53 higher risk in an analysis adjusted for relevant risk factors.
Perhaps most notably, a treatment break of at least 2 weeks during the first 18 months of treatment proved a strong predictor of death in group 2, the people with intermittent viral control. The 92 people who took drug breaks in that period had a death rate of 6.87 per 100 person-years. These people usually interrupted therapy because of poor adherence (30%), drug intolerance (27%), or "patient's wish" (27%), and rarely because their physician proposed a holiday (6%).
Lohse and coworkers noted that treatment interruptions may reflect other mortality risk factors, such as end-stage AIDS, antiretroviral toxicity, or non-HIV conditions that may affect antiretroviral adherence. But the higher death rate in people who took drug breaks remained high throughout follow-up. That consistency, the Danish group argues, makes it unlikely that end-stage AIDS or toxicity explains the high death rate in this group. Also, fewer people who interrupted therapy died of non-HIV causes than did people who never suspended therapy. That suggests non-HIV mortality does not account for the high death rate among treatment interrupters.
Danish clinicians have always regarded planned treatment breaks with a skeptical eye, and findings like these bolster that belief. Lohse and colleagues conclude that "physicians should focus on improving adherence through intensive patient coaching, individualizing drug regimens, and treatment of underlying comorbidity in order to avoid virological failure and these [treatment] interruptions."
Mark Mascolini writes about HIV infection.
References
1. Cameron DW, Eron J, Farthing C, et al. Comparative safety and anti-HIV activity of a dual protease inhibitor regimen (lopinavir/ritonavir + saquinavir) versus a nucleoside-containing regimen. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-523.
2. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004;292:191-201.
3. Molto J, Ruiz L, Valle M, et al. Increased antiretroviral (ARV) potency by the addition of enfuvirtide to a four drug regimen in ARV naive HIV-infected patients. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-528.
4. Weverling GJ, Lange JM, Jurriaans S, et al. Alternative multidrug regimen provides improved suppression of HIV-1 replication over triple therapy. AIDS 1998;12:F117-F122.
5. Gulick RM, Ribaudo HJ, Shikuma CM, et al. ACTG 5095: zidovudine/lamivudine/abacavir vs. zidovudine/lamivudine + efavirenz vs. zidovudine/lamivudine/abacavir + efavirenz for initial HIV therapy. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H.-416a.
6. Moyle G, Pozniak A, Opravil M, et al. The SPICE study: 48-week activity of combinations of saquinavir soft gelatin and nelfinavir with and without nucleoside analogues: Study of Protease Inhibitor Combinations in Europe. JAIDS 2000;23:128-137.
7. Katzenstein TL, Kirk O, Pedersen C, et al. The Danish protease inhibitor study: a randomized study comparing the virological efficacy of 3 protease inhibitor-containing regimens for the treatment of human immunodeficiency virus type 1 infection. J Infect Dis 2000;182:744-450.
8. Shafer RW, Smeaton LM, Robbins GK, et al. Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003;349:2304-2315.
9. van Leth F, Phanuphak P, Ruxrungtham K, et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN study. Lancet 2004;363:1253-1263.
10. Lohse N, Kronborg G, Gerstoft J, et al. Virological control during the first 6-18 months after initiation HAART as a predictor for mortality, CD4+ cell increase, and viral suppression. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-515.
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