Antiretroviral News: Initial Therapy

Hopkins HIV Report 2006 Sep; 18(5):1-5,15

Joel E. Gallant, M.D., M.P.H.
Johns Hopkins

The XVI International AIDS Conference was held in Toronto from August 18, 2006. It was an enormous conference: estimates of the number of attendees ranged from 26,000 to 31,000. And, while it’s often hard to estimate the impact of a meeting while it’s happening, I suspect that this conference will be a pivotal one. At the Vancouver conference in 1996, the world was introduced to the concept of highly active antiretroviral therapy, and HIV infection suddenly became a treatable disease for people living in the developed world. However, the idea of treating patients in resource-limited countries was not on the table; prevention was all we had to offer. By the time of the 2000 conference in Durban, it became impossible to ignore our moral obligation to provide life-saving therapy to people dying of an otherwise fatal illness, no matter where they lived. In the six years since the Durban conference, we’ve seen steady increases in the number of people on therapy in the developing world, but in many cases prevention efforts have been limited to the “ABC” approach (“Abstinence, Be faithful, and use Condoms”) with varying emphasis on the specific components of that approach depending on one’s political persuasion.

The Toronto meeting may be remembered for its emphasis on the synthesis of treatment and prevention. On the one hand, we saw impressive results from the DART trial in Uganda, demonstrating 94% 2-year survival rates and a 17-fold drop in overall mortality due to antiretroviral therapy compared to historical controls in the Entebbe cohort [Munderi P, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. ThLB0208]. On the other hand, Bill Gates, in his speech at the opening session, stated that “treatment without prevention is simply unsustainable.” He noted that for every one person started on treatment between 2003 and 2005, ten new people were infected.

Gates became uncharacteristically political when he pointed out the weaknesses of the ABC approach to prevention, which ignores a number of harsh realities: that in many parts of the world, women and girls, who must often marry young, do not have the choice to be abstinent, they cannot force their male partners to wear condoms, nor do they have control over whether their husbands are faithful. Gates and his wife Melinda both stressed the importance of putting prevention in the hands of women, through development of vaginal microbicides or even oral agents to be used for pre-exposure prophylaxis. “A woman should never need her partner’s permission to save her own life.” These themes were echoed by many other speakers in Toronto, including Peter Piot from UNAIDS, and former President Bill Clinton.

Understandably, science takes a back seat to these larger global issues at such a conference. Nevertheless, there were a number of important clinical presentations in Toronto, most of them concentrated in a marathon, butt-challenging late-breaker session held on the last day. In this article, I will discuss those studies that dealt with initial therapy.

Efavirenz: An Old Drug Just Keeps Getting Better

Numerous studies were presented in Toronto that solidified the role of efavirenz-based regimens as the best available therapy for HIV infection. The most important of these studies was the eagerly awaited ACTG 5142, a randomized comparison of efavirenz (EFV), the preferred non-nucleoside reverse transcriptase inhibitor (NNRTI) according to current DHHS guidelines, with lopinavir/ritonavir (LPV/r), the preferred protease inhibitor (PI), both in combination with lamivudine (3TC) and either zidovudine (AZT), extended-release stavudine (d4T XR), or tenofovir DF (TDF) [Riddler, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. THLB0204]. A third arm involved LPV/r plus EFV without nucleoside analog reverse transcriptase inhibitor (NRTIs). The study enrolled 753 patients, half of whom had viral loads above 100,000 c/mL, with a median CD4 count of 182 cells/mm³.

On most counts, EFV was the winner. Time to virologic failure was significantly shorter for the LPV/r arm than for the EFV arm (p=0.006). There was also a trend toward a shorter time to regimen completion with LPV/r than with EFV (p=0.02, where significance was defined as p < 0.016). At 96 weeks, 89% of subjects on the EFV arm had viral loads <50 c/mL compared to 77% on LPV/r (p=0.003). Interestingly, the difference could not be explained by side effects, since there was no difference among the arms in time to treatment-limiting toxicity.

The news wasn’t all bad for LPV/r, however. There has been some provocative evidence from prior studies suggesting that the use of LPV/r may lead to better CD4 responses than some other therapies, and this was supported by the results of 5142, in which patients on the LPV/r and EFV + LPV/r arms had significantly better CD4 increases than those on the EFV arm (285, 268, and 241 cells/mm³, respectively, p=0.01 for comparisons between EFV and the two LPV/rcontaining regimens). In addition, while virologic failure was less common with EFV, the resistance consequences for those who did fail were greater: Of those failing therapy in the EFV + NRTI arm 48% had NNRTI resistance, which appeared to be even more common in the EFV + LPV/r arm (69%). In contrast, PI mutations did not occur in the LPV/r arm. Two-class resistance was also more common among those failing EFV.

Dan Kuritzkes presented data from ACTG 5095 specifically focusing on the 765 patients randomized to the two EFV-containing arms: EFV plus AZT/3TC (Combivir) and EFV plus AZT/3TC/abacavir (ABC) (Trizivir) [Ribaudo H, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. THLB0211]. As has been reported previously [Gulick R, et al. JAMA. 2006 Aug 16;296(7):769-81], there was no difference in outcome between the two arms. Time to virologic suppression was different, but this difference did not affect the proportion of participants who achieved and maintained suppression, which was the same. What was striking in the presentation at this meeting was that there was no difference in virologic suppression or time to virologic failure among participants in the various baseline viral load strata, which included the quarter of subjects who entered the trial with viral loads above 300,000 c/mL. CD4 response was also similar, except that those with baseline viral loads above 300,000 c/mL had larger increases, consistent with the greater magnitude of virologic suppression.

Similar results were reported from CPCRA 058, the FIRST Study, in which 1397 treatment-naïve patients were randomized to one of three strategies: a PI-based strategy, an NNRTI-based strategy, and a 3-class strategy, which included a PI, an NNRTI, and 1-2 NRTIs [MacArthur RD, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. TUAB0101]. In contrast to ACTG 5142, however, the choice of drugs was left to the clinicians. Only one-quarter of the participants assigned to the PI arm took a ritonavir (RTV)-boosted PI; 61% took nelfinavir. Of the patients randomized to the NNRTI arm, 63% took EFV. Approximately half used AZT/3TC as their NRTI backbone. Median follow-up was 60 months.

In the FIRST study, there was no difference in progression to AIDS, death, or a CD4 count <200 cells/mm³. However, both of the NNRTI-containing arms outperformed the PI arm with respect to virologic suppression, and time to virologic failure was faster for the PI arm. As with ACTG 5142, failure of the NNRTI arm was associated with more class-specific mutations than the PI arm. The 3-class strategy was not superior to either of the 2-class approaches, because switching drugs was twice as likely as in the 2-class arms, occurring in 80% of those on triple-class therapy.

Finally, an observational cohort study involving over 900 patients at Johns Hopkins and Vanderbilt Universities found that patients who started therapy with an EFV-based regimen had more durable virologic responses than those who started with a boosted PI [Sterling T, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. TUPE0205].

Taken together, these studies provide a ringing endorsement for initial antiretroviral therapy with EFV-based regimens. What was previously a standard of care has now become the standard of care. ACTG 5142 and 5095 may finally put to rest the popular but unsupported myth that patients with advanced disease need PIs. However, these studies also point out some limitations of EFV-based therapy. Aside from the fact that not everyone can take EFV (e.g. women who aren’t preventing pregnancy, people with baseline NNRTI resistance, or those intolerant of the neuropsychiatric side effects), it’s clear that the consequences of virologic failure are greater for NNRTI-based regimens than for those involving boosted PIs. The long half-life of EFV makes it forgiving of an occasional missed or late dose, but patients who are prone to complete treatment interruptions are at higher risk for resistance with EFV than with boosted PIs. The greater CD4 count increase seen with LPV/r in ACTG 5142 also suggests that there may be a role for this agent in patients with low CD4 cell counts. While the baseline count probably shouldn’t affect the choice of therapy–after all, most people had good CD4 count increases in all three arms–there may be a role for LPV/r, or perhaps for other boosted PIs, in those who fail to experience a significant increase in CD4 count on EFV.

KLEAN: Fosamprenavir Battles Lopinavir

Joseph Eron presented the 48-week results of KLEAN, a comparison of boosted fosamprenavir (FPV/r) and LPV/r, combined with ABC/3TC (Epzicom) in treatment-naïve studies [Abstract Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. THLB0205]. This large study (n=888) was remarkable for the fact that it essentially showed no difference between the two agents by any measure examined. Virologic suppression to <400 c/mL was approximately 72% by time to loss of virologic response (TLOVR) analysis and 97% by on treatment analysis in both arms. Over half the patients enrolled had baseline viral loads above 100,000 c/mL, but there were no differences between arms by viral load or CD4 strata, and CD4 response was the same. Five percent discontinued in each arm due to adverse events. PI resistance was uncommon in either arm, and the mutations seen were felt to be minor ones, although it is worth noting that one patient in the FPV arm developed an I54I/L mutation know to decrease susceptibility to amprenavir/fosamprenavir. The tolerability of the two regimens was comparable, as were the lipid profiles [see Todd Brown, this issue, Update on Metabolic Complications].

So is there a winner in this apparent draw? Some might argue that there are two losers: LPV/r, stinging from its defeat at the hands of EFV in ACTG 5142, now has a harder time holding on to its title as the champion among boosted PIs. On the other hand, all we can say about FPV/r is that it’s as good and as tolerable as the older, less tolerable gel cap formulation of LPV/r, which, by extrapolation, might suggest that it’s less tolerable than the new tablet formulation of LPV/r. KLEAN helps us to feel more confident in the efficacy of FPV/r when we use it, but it doesn’t give us a clear reason to choose FPV/r over other boosted PIs.

GS934: More Differences Emerge at 96 Weeks

The 48-week results of GS934 found that the combination of TDF, emtricitabine (FTC), and EFV was superior to AZT/3TC and EFV, primarily because of greater discontinuation due to toxicity in the AZT/3TC arm [Gallant JE, et al. N Engl J Med. 2006 Jan 19;354(3):251-60]. The 96week results (of a planned 144-week comparative study) were presented in Toronto, showing a similar difference in efficacy, as well as some emerging differences with respect to toxicity and resistance [Gallant JE, et al. Abstract Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. TUPE0064]. At 96 weeks, 75% of patients on TDF/FTC had viral loads <400 c/mL by timeto- loss of virologic response analysis (TLOVR) compared to 62% on AZT/3TC (p=0.004). Using a <50 c/mL analysis, the results were 67% vs. 62%, respectively, a difference that is no longer significant (p=0.19). The reason for the loss of significance between year 1 and 2 has to do with the TLOVR analysis and its intolerance of blips. In fact, most of the patients who failed to meet the <50 c/mL TLOVR criteria were not experiencing virologic failure, but had viral loads below 50 c/mL at 120 weeks. Once again, the proportion of patients who discontinued therapy due to adverse events was higher in the AZT/3TC arm than in the TDF/FTC arm (12% vs. 5%, p=0.007), but there was also significantly more virologic rebound in the AZT/3TC arm (5% vs. 1%, p=0.007). Patients on TDF/FTC experienced a greater CD4 increase than those on AZT/3TC at 96 weeks (270 vs. 237 cells/mm³, p=0.036).

At the end of the first year of the study, there was a hint of greater lipoatrophy in the AZT/3TC arm, as 48-week DEXA data found significantly lower limb fat among AZT-treated patients. The 96-week data now demonstrate that patients in the AZT/3TC arm have significantly less limb fat than they did at 48 weeks, and the difference in limb fat between the two arms (2.3 kg) is now greater (p<0.0001). The demonstration of progressive loss in limb fat is consistent with other studies, though it should be noted that these findings differ from those of ACTG 384, in which patients on AZT/3TC/EFV did not appear to lose limb fat [Komarow L, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. WEPE0167].

Intriguing differences in resistance are also emerging in this study. After two years, there are still no cases of K65R in either group, in contrast to the results of GS903, in which 8 patients had developed K65R in the TDF/3TC arm by this time point. There are also significantly more M184V mutations among participants failing AZT/3TC in the 934 study (9 vs. 2, p=0.037). These data are consistent with those of other studies, such as Abbott 418 trial, in which there has been no emergence of K65R among 190 patients treated with TDF, FTC, and LPV/r, and less M184V than had been observed in studies using either AZT/3TC or TDF/3TC. The reason for the difference is unclear but may have to do with the longer intracellular half-life of FTC compared to 3TC. The comparison of GS934 with GS903 certainly suggests that at least with TDF, there are good reasons to use FTC as opposed to 3TC beyond the convenience of coformulation.

There has been no evidence of renal toxicity in GS 934. The median calculated creatinine clearance by the Cockcroft-Gault equation remains unchanged in both groups over 96 weeks with no differences between groups. However, the median glomerular filtration rate (GFR) calculated by the MDRD equation is significantly lower on the TDF/FTC arm (100 vs. 108 mL/min/1.73m2, p=0.006). This difference is of doubtful clinical significance, however, since the GFR increased immediately in the AZT/3TC arm and then remained stable, whereas the GFR has remained essentially unchanged from baseline in the TDF/FTC arm.

Taking together the results of GS934, ACTG 5142, ACTG 5095, and the FIRST study, discussed above, one can anticipate that the combination of TDF, FTC, and EFV, now coformulated as Atripla, will become the “default regimen” for initial therapy: the one you use unless you have a reason not to. Reasons not to use EFV have already been discussed. The best reasons to avoid TDF/FTC would be preexisting renal dysfunction, especially when progressive, or baseline resistance affecting either TDF or FTC.

Boosted PI Monotherapy Studies

Multiple studies were presented studying monotherapy with boosted PIs, mostly LPV/r. In MO3-613, treatment-naïve patients were randomized to receive either AZT/3TC and EFV or AZT/3TC and LPV/r [Cameron DW, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. THLB0201]. Those on the LPV/r arm switched to LPV/r monotherapy if their viral load remained <50 c/mL for 3 consecutive months. The time to first viral load >50 c/mL was significantly shorter in patients on LPV/r monotherapy (p<0.001). Most virologic failures were at low levels, between 50 and 400 c/mL. Three of 15 patients tested in the LPV/r arm developed PI mutations.

The MONARK study randomized 138 treatment-naïve patients in a 2:1 fashion to receive either LPV/r monotherapy or LPV/r plus AZT/3TC [Delfraissy JF, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. THLB0202]. At week 48, 75% of those on LPV/r plus NRTIs had a viral load <50 c/mL by ITT analysis compared to 71% on LPV/r monotherapy. As in MO3-613, more patients taking LPV/r monotherapy had viral loads in the 50-400 c/mL range throughout the 48 week study period.

In the Spanish OK04 study, 198 patients whose viral loads had been suppressed to <50 c/mL on LPV/r plus 2 NRTIs for at least 6 months were randomized to continue the current regimen or to drop the NRTIs [Arribas J, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. THLB0203]. Time to virologic failure was not significantly different between the arms, but 4 patients in the monotherapy arm required intensification with NRTIs due to virologic rebound to >500 c/mL. When those 4 patients were classified as failures, the proportion without failure was 89.8% in the LPV/r + NRTIs arm and 85% in the LPV/r monotherapy arm. Three primary PI mutations were observed, 2 in the monotherapy arm and 1 in the control arm, although it is not clear whether these were mutations that truly emerged on treatment.

The Brazilian KALMO study randomized 60 patients whose viral loads were suppressed on HAART for at least 6 months to continue their current HAART regimen or to switch to LPV/r monotherapy [Nunes EP, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. THAB0103]. One virologic failure occurred in each arm, with no emergence of PI mutations. The patient who failed in the monotherapy arm experienced virologic resuppression with the addition of NRTIs.

Finally, there was a report on ATARITMO study, a pilot trial in which 30 patients whose viral loads were suppressed on HAART took monotherapy with boosted atazanavir (ATV/r) [Vernazza P, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. WEPE0073]. Two patients experienced virologic failure at week 24, and five had blips. At week 24, 3 of 20 (15%) patients tested had CSF viral loads >100 c/mL and 2 of 15 (13%) had detectable viral load in semen.

What conclusions can we draw from these studies? It seems clear that most people do well on boosted PI monotherapy, but in most of these studies there are patients who fail to maintain suppression to <50 c/mL, which seems to be more common than with standard therapy in the controlled trials. There is also concern that monotherapy may not allow penetration into all anatomical sites, including the central nervous system and genital secretions. Finally, it’s worth noting that none of these studies is large enough to be definitive. It’s fair to say that we’ve now seen enough small trials of PI monotherapy. Each trial suggests that there’s a reason to study this approach further in a larger trial, but none provides a reason to embrace the strategy in clinical practice.

Some might argue that there’s really no rationale for PI/r monotherapy, even if it’s shown to be successful. They would point out that current standards of care for first-line therapy in the developed world are even simpler and better tolerated than PI monotherapy. However, in resource-limited countries, most patients who receive therapy take a combination of an NNRTI, 3TC, and a thymidine analog without viral load monitoring. In such settings, failure of first-line therapy is likely to be associated with high-level NRTI and NNRTI resistance, leaving no effective second-line NRTIs. It’s important to find out whether boosted PI monotherapy could provide adequate rescue therapy for PI-naïve patients with no options among the reverse transcriptase inhibitors. A large clinical trial looking at boosted PI monotherapy for second- line therapy in resource limited settings would be of great interest.

Initial Therapy Using New Agents

Until the end of the late-breaker session, it was looking like nothing could beat efavirenz for initial therapy…then along came MK-0518. Markowitz presented data from a trial in which 203 treatment-naïve patients were randomized to receive EFV or one of 4 doses of Merck’s new integrase inhibitor in combination with TDF and 3TC [Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. THLB0214]. By 24 weeks, most participants had a viral load below 50 c/mL, but those on MK-0518 reached that target much faster than those on EFV: the majority within 4 weeks. MK-0518 was also better tolerated, primarily because of the lack of neuropsychiatric side effects. It’s unclear whether the long-term outcome will be any different with MK-0518 than with EFV, but the extremely rapid rates of virologic suppression, together with the dramatic declines in viral load observed in earlier 10-day monotherapy studies, speak to the potency of this agent, and its short-term tolerability is highly encouraging.

The clinical data at the Toronto conference confirmed just how good our options are for initial therapy. The treatment guidelines of the International AIDS Society-USA were updated and announced at this conference, and published in the “AIDS issue” of JAMA [Hammer SM, et al. JAMA. 2006 Aug 16;296(7):827-43). The new guidelines recommend a nucleoside backbone of either TDF/FTC, AZT/3TC, or ABC/3TC plus either EFV or one of four boosted PIs: LPV/r, ATV/r, FPV/r, or saquinavir/ritonavir (SQV/r). Nevirapine is listed as an alternative NNRTI for selected patients. In contrast to the DHHS guidelines and previous versions of the IAS-USA guidelines, no alternative regimens are listed, which now seems appropriate, since it’s unlikely that there would ever be a reason to stray from the recommended options in patients infected with wild-type virus.

For the immediate future, the 2 NRTI plus NNRTI or boosted PI approach is unlikely to change, though there are a number of new agents in development, especially the integrase inhibitors, which could eventually challenge our approach to treatment-naïve patients.

2006-09-10
HHR-2006-09-01

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