icon- folder.gif   Conference Reports for NATAP  
 
  4th IAS (Intl AIDS Society) Conference on HIV Pathogenesis, Treatment and Prevention
Sydney, Australia
22-25 July 2007
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Integrase Inhibitor Matches Efavirenz for 48 Weeks in Treatment-Naive
 
 
  4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention
July 22-25, 2007
Sydney, Australia
 
Mark Mascolini
 
Raltegravir, Merck's integrase inhibitor (Isentress, MK-0518), controlled HIV as well as efavirenz for 48 weeks in previously untreated people [1]. In fact, the integrase blocker slashed viral loads faster than efavirenz in the first few weeks of therapy, a result leading investigators to propose that the current model of antiretroviral-induced viral decay needs revamping [2].
 
Study participants took placebo or 100, 200, 400, or 600 mg of raltegravir twice daily for 9 days, then continued raltegravir or substituted efavirenz for placebo. At this point everyone added 3TC and tenofovir to their regimen. The 198 enrollees had a median age of 36 years, two thirds were not white, and one third had AIDS. Pretreatment viral loads averaged from 4.6 to 4.8 log in the five treatment groups (about 40,000 to 63,000 copies). Starting average CD4 counts ranged from 271 to 314 in the five study arms.
 
Two people in the 200-mg raltegravir arm (5%) and no one in the other arms stopped treatment by week 48 because of lack of efficacy. Principal investigator Martin Markowitz (Aaron Diamond AIDS Research Center, New York) attributed these failures to spotty adherence. After 24 and 48 weeks, a noncompleter-equals-failure analysis figured equivalent response rates in the raltegravir and efavirenz groups (Table).
 

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People taking raltegravir pushed their viral loads below 50 copies faster than people taking efavirenz, but by week 24 viral load drops were equivalent in the raltegravir and efavirenz arms, and that equivalence persisted through week 48. Average CD4 gains at week 48 ranged from 144 to 221 cells across the five treatment groups, with no significant differences between groups.
 
Among 5 people with virologic failure while taking raltegravir (1 nonresponder and 4 rebounders), raltegravir-related mutations could be detected in 2 (N155H in one person and V151I, N155H, D232D/N, and G163R/G in the other). The 3TC-induced M184V mutation popped up in 4 of 5 people in whom raltegravir failed, and the tenofovir-related K65R change arose in 1. In 1 person who had a viral load rebound while taking efavirenz, the G190E nonnucleoside mutation evolved along with K65R.
 
People taking raltegravir had fewer neuropsychiatric side effects than those taking efavirenz. Raltegravir had no adverse impact on total or low-density lipoprotein cholesterol or on triglycerides, while all those lipids rose in the efavirenz group. But because "good" high-density lipoprotein (HDL) cholesterol also rose with efavirenz, total-to-HDL ratio did not differ significantly between the efavirenz and raltegravir groups. Rates of other treatment-related side effects and lab abnormalities were moderate and similar between the raltegravir and efavirenz arms.
 
Closer scrutiny of how quickly HIV disappeared from patient samples indicated that raltegravir produced a more extensive first phase of viral decay (a fast phase that happens in the first few days of treatment) and a significantly greater second-phase decay (a slower phase over the following weeks) than did efavirenz [2].
 
Half-life for the first phase of viral decay proved equivalent with all raltegravir doses and averaged 1.2 days, a quicker rate than seen with other antiretrovirals. When study participants started taking 3TC and tenofovir with raltegravir or efavirenz, significantly more people taking raltegravir than efavirenz reached a viral load below 50 copies at day 15 (P = 0.047), day 29 (P = 0.003), and day 57 (P = 0.006).
 
Mathematical modeling and comparison with observed viral load changes suggested two hypotheses for the faster second-phase decay with raltegravir:
 
- Virus from long-lived infected cells propagates further rounds of productive infection. These newly infected cells are the source of second-phase virus. Raltegravir inhibits these new rounds of infection more effectively than other drugs.
 
- Activation of latently infected cells with unintegrated HIV DNA gives rise to second-phase virus. Raltegravir inhibits integration of HIV DNA in latently infected cells. Reverse transcriptase inhibitors and protease inhibitors do not affect this process.
 
These modeling studies turned up no suggestion that raltegravir penetrates sanctuary sites better than efavirenz.
 
Does faster viral decay with raltegravir mean anything clinically? Markowitz suggested it's "far too early to tell." But he added that equivalent 48-week virologic and CD4 results with raltegravir and efavirenz suggest the faster RNA slide with raltegravir does not give people a clinical advantage.
 
The Antiviral Drugs Advisory Committee of the US FDA will consider raltegravir for licensing on September 5.
 
References
1. Markowitz M, Nguyen BY, Gotuzzo E, et al. Rapid onset and durable antiretroviral effect of raltegravir (MK-0518), a novel HIV-1 integrase inhibitor, as part of combination ART in treatment HIV-1 infected patients: 48-week data. 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention. July 22-25, 2007. Sydney. Abstract TUAB104.
 
2. Murray JM, Emery S, Kelleher A, et al. The integrase inhibitor raltegravir alters viral decay kinetics of HIV, significantly reducing the second phase and challenging current hypotheses of viral replication. 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention. July 22-25, 2007. Sydney. TUAB103.