September 28, 2006
What is the current state of the art in HIV treatment? A comprehensive talk given by Dr. Sharon Riddler1 from the University of Pittsburgh tried to answer this question focusing on the timing and type of HIV treatment appropriate for treatment-naive and treatment-experienced patients. Dr. Riddler's talk was part of a symposium at the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2006) entitled "Current Issues and Controversies in HIV Infection Management," which was sponsored by the International AIDS Society-USA.
The symposium was presented in an interactive format, with the audience answering posed questions throughout the talks using touch keypads. The basic questions that Dr. Riddler posed for each type of patient -- naive and experienced -- were as follows:
1. When to Start Therapy?
The current U.S. guidelines2 for the management of HIV infection recommend that highly active antiretroviral therapy (HAART) be initiated when CD4+ cell counts fall below 200 cells/mm3 and be considered when CD4+ cell counts are between 200 and 350 cells/mm3. The current consensus is to defer therapy when the CD4+ cell count is above 350 cells/mm3. Despite these recommendations, Dr. Riddler reviewed several recent studies that indicate that starting therapy earlier may be beneficial to patients.
Kenneth Lichtenstein from the Colorado Health Sciences Center presented data from the HIV Outpatient Study (HOPS) at the 13th Conference on Retroviruses and Opportunistic Infections (CROI) in 2006 on the risk of HIV progression and complications based on different baseline CD4+ cell count strata.3
Of 2,304 patients seen in HOPS clinics at least twice from 1996 to 2005, the incidence of death and AIDS-defining illnesses decreased when HAART was initiated at a higher CD4+ cell count. In addition, common complications of HIV infection, including renal insufficiency, peripheral neuropathy and lipoatrophy, had a lower probability of development when HAART was initiated at higher CD4+ cell counts (350-499 cells/mm3) versus lower CD4+ cell counts (200-349 cells/mm3).
Data from the Johns Hopkins HIV Clinical Cohort in Baltimore, Maryland, were presented at the 2006 International AIDS Conference (IAC) in Toronto on this same question regarding the most suitable timing of HAART initiation.4 This analysis examined all patients in the cohort who were followed for more than one year while on HAART and who had sustained viral load suppression below 400 copies/mL. Patients meeting these criteria were stratified by their starting CD4+ cell count (below 200, 201-350, more than 350 cells/mm3) and followed for six years to examine annual changes in CD4+ cell counts and the development of new AIDS-defining illnesses that emerged after the initiation of HAART.
By six years, the median CD4+ cell count was lowest in patients who had a baseline CD4+ cell count below 200 cells/mm3 and highest in those with a baseline CD4+ cell count above 350 cells/mm3. Notably, only patients who initiated therapy when their CD4+ cell count was above 350 cells/mm3 achieved a return to "normal" CD4+ cell count ranges. Similarly, the probability of an AIDS-defining illness was highest in those with a baseline CD4+ cell count below 200 cells/mm3 and lowest in those with a baseline CD4+ cell count above 350 cells/mm3. Therefore, starting therapy at CD4+ cell counts above 350 cells/mm3 was associated with a higher probability of returning to normal CD4+ cell count ranges on treatment and a lower probability of developing a subsequent AIDS-defining illness over six years of follow-up.
|Outcome at Six Years||CD4+ Cell Count Stratum|
|< 200 cells/mm3||200-350 cells/mm3||> 350 cells/mm3|
|Median CD4+ cell count (cells/mm3)||411||514||614|
|Probability of AIDS-defining illness (%)||13||12||1.5|
2. Which Therapy to Start?
The issues to consider when selecting the primary HAART regimen are manifold and include regimen potency, tolerability, the genetic barrier to resistance, expense and convenience. Additional patient factors that must be considered include comorbidities, coinfections, childbearing potential in women, adherence and drug-drug interactions with concomitant medications. Dr. Riddler referenced the International AIDS Society-USA guidelines for the treatment of HIV infection in adults, which were recently published in the Journal of the American Medical Association (JAMA) in August 2006,5 as providing a comprehensive discussion on selecting a primary HAART regimen.
Data from the "FIRST Study" (CPCRA 058) were presented recently at IAC 20066 and address the question of which regimen to start in HAART-naive patients. Between 1999 and 2002, the FIRST study examined the long-term clinical and immunologic outcomes in 1,397 HIV-infected, treatment-naive persons randomized to receive a HAART regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either a non-nucleoside reverse transcriptase inhibitor (NNRTI), a PI, or an NNRTI in combination with a PI.
The primary endpoint of the study was a composite of AIDS events, death and CD4+ cell count changes; other endpoints were examined as well. There was no difference in the clinical composite endpoint for the group of patients on PI-based regimens versus NNRTI-based regimens after a median follow-up period of five years, although the virologic failure endpoint (HIV-1 RNA >1000 copies/mL after four months) differed by treatment class. For patients assigned to receive an NNRTI versus a PI, the hazard ratios for the composite endpoint, the AIDS or death endpoint and the virologic failure endpoint were 1.02 (95% confidence interval [CI]: 0.79-1.31), 1.07 (95% CI: 0.80-1.41) and 0.66 (95% CI: 0.56-0.78), respectively. Therefore, the NNRTI-based strategy was virologically superior to the PI-based strategy, despite similarity in the clinical outcomes over time. The three-class strategy was not superior to either two-class strategy in terms of immunologic or clinical outcomes and was associated with greater drug toxicity.
On a similar topic, Dr. Riddler summarized the findings of her late-breaker abstract, also presented at IAC in Toronto, that described findings from the AIDS Clinical Trials Group (ACTG) 5142 study.7 This prospective phase III trial enrolled 753 treatment-naive participants at 55 centers and randomized them to receive a regimen containing lopinavir/ritonavir (LPV/r, Kaletra) + efavirenz (EFV, Sustiva, Stocrin) versus two NRTIs + efavirenz versus two NRTIs + lopinavir/ritonavir as an initial regimen for HIV infection.
This study showed that the combination containing two NRTIs + efavirenz suppressed HIV to undetectable levels in a greater percentage of participants than the lopinavir/ritonavir-based regimen (76% versus 67%; P = .0006). The efavirenz + lopinavir/ritonavir regimen (nucleoside-sparing) performed nearly as well as the efavirenz-based regimen, suggesting that initial therapy need not include NRTIs in treatment-naive patients. As expected, the patients on the efavirenz-based regimen with virologic failure had a higher prevalence of two-class resistance (i.e., resistance to the NNRTI and NRTI classes) than patients who failed on the lopinavir/ritonavir-based regimen.
Finally, Dr. Riddler reviewed data from IAC on MK-0518, the new integrase inhibitor from Merck & Co., Inc. (protocol 004), since this new drug class may eventually be suitable for initial therapy for HIV infection. In this analysis, MK-0518 resulted in a rapid and significant reduction in viral load in treatment-naive patients at all four doses studied and sustained this level of suppression out to 24 weeks8 The reduction in viral load was achieved slightly more rapidly in the four MK-0518 arms than in the efavirenz control arm, as shown in the graph below.
3. What Is the Role of Simplified Maintenance Therapies?
Although simplifying HAART to a single agent after achieving complete virologic suppression with combination therapy is a concept still under active investigation, about 15% of the audience indicated that they would use single-PI therapy in a clinical setting at this point in time. Dr. Riddler reviewed two recent studies on the topic of simplified maintenance therapies, both summarized below.
The 48-week results of the OK04 trial, a randomized, controlled clinical trial comparing continuation of triple-drug therapy versus switching to lopinavir/ritonavir monotherapy in patients who initially suppressed HIV replication on combination therapy with LPV/r + two NRTIs, were recently presented at IAC.9 This study allowed the two NRTIs to be re-introduced in the monotherapy arm if virological rebound occurred without the emergence of major PI mutations. This noninferiority trial was performed in 198 patients: 100 were randomized to the monotherapy arm and 98 to the triple-drug arm. After 48 weeks, the percentage of patients without therapeutic failure was similar in both arms: 94% in the monotherapy arm versus 90% in the triple-drug arm.
The percentage of patients with HIV-1 RNA below 50 copies/mL at 48 weeks was also similar in the two arms. Six percent of patients in the monotherapy arm and 10% of patients in the triple-drug arm were deemed to be therapeutic failures during the 48 weeks, defined as an increase in HIV-1 RNA above 500 copies/mL. Four patients with confirmed virologic rebound after monotherapy had their NRTIs re-introduced and again achieved an HIV-1 RNA load below 50 copies/mL by 48 weeks. Therefore, in patients with prior stable suppression, monotherapy with lopinavir/ritonavir was deemed noninferior to continuing on triple-drug therapy for maintaining virologic suppression.
An ACTG trial that examined simplifying an effective triple-drug regimen to atazanavir (ATV, Reyataz)/ritonavir monotherapy was recently published in JAMA.10 ACTG 5201 was a single-group, open-label, multi-center, 24-week pilot study of 34 HIV-infected adults who had achieved virologic suppression for 48 weeks or longer on their first PI-based regimen. Participants switched their current PI for atazanavir/ritonavir upon entry into the study and then discontinued their NRTI backbone after six weeks. The primary endpoint of virologic failure was recorded within 24 weeks of NRTI discontinuation. Of the 36 participants who initially enrolled, two discontinued before simplification to atazanavir/ritonavir alone. Thus, 34 patients were included in the analysis of the primary endpoint at 24 weeks: 1 withdrew voluntarily, and 33 continued the regimen. Virologic success (absence of failure) through 24 weeks of simplified therapy occurred in 91%. Three participants experienced virologic failure at 12, 14, and 20 weeks after simplification. Notably, resistance testing at failure did not identify the emergence of PI resistance mutations in any of these patients, and two of the participants with failure had low plasma atazanavir concentrations thereby suggesting non-adherence. The authors concluded that simplified maintenance therapy with atazanavir/ritonavir monotherapy may be efficacious for maintaining virologic suppression in patients with HIV infection, although they did acknowledge the limitations of drawing conclusions from such a small study.
1. When to Switch and When to Wait?
Dr. Riddler spent the final portion of her talk discussing the management of treatment-experienced patients. She did not discuss salvage therapy at length, but referred the audience to the International AIDS Society-USA guidelines on this topic.5 She did note, however, that the emergence of newer antiretroviral agents has made it possible to attempt complete virologic suppression in even highly treatment-experienced patients, rather than settling for partial virologic control with HIV RNA levels between 500 and 1000 copies/mL. If two or more new active agents can be added or substituted in a patient's regimen, the goal of therapy should be to achieve HIV viral loads below 50 copies/mL, which will produce immunologic benefits and prevent the emergence of resistance. When complete virologic control is not achievable, stable CD4+ cell counts and clinical status can usually be maintained for relatively long periods with partial reductions in HIV-1 RNA to moderately low levels, although the cumulative acquisition of new resistance mutations is a dangerous consequence of this approach.
The new drugs that Dr. Riddler cited as options for achieving complete virologic suppression in highly treatment-experienced patients included the newly released PIs tipranavir (TPV, Aptivus) and darunavir (TMC114, Prezista), both administered with ritonavir boosting, along with enfuvirtide, an injectable HIV fusion inhibitor The virologic response to therapy in treatment-experienced patients is improved by the use of these newer agents, by the use of ritonavir-boosted PIs in general and by a lower viral load at the time of the switch. The TORO, RESIST and POWER studies were designed to study the efficacy of enfuvirtide, tipranavir and darunavir, respectively, in treatment-experienced patients, and all show high rates of virologic suppression, even in highly experienced patients.11-13
If a regimen cannot be found to achieve complete virologic suppression in a highly treatment-experienced patient, another option is to wait on switching therapy until new antiretrovirals currently in the pipeline become more widely available. Two CCR5 receptor antagonists are in development at the present time -- vicriviroc (SCH 417690, SCH-D) and maraviroc (UK-427857) The results of ACTG 5211, the phase II dose-ranging and efficacy study of vicriviroc in treatment-experienced patients, were presented recently at IAC.14 This CCR5 receptor antagonist was added onto a failing background regimen at study entry in 118 participants, and the background regimen was then optimized at 14 days. Three doses of vicriviroc were studied -- 5 mg, 10 mg and 15 mg. Although all three doses showed potent virologic suppression by 14 days, only the two higher doses produced sustained virologic activity over 24 weeks. Five individuals randomized to vicriviroc developed malignancies over the course of the study, which continues to be of concern as phase III trials are underway. As discussed above, another new drug in development is the integrase inhibitor MK-0518.
2. What to Do While Waiting?
When a clinician cannot identify an active regimen for the treatment-experienced patient and is awaiting drugs in development, what should be done in the interim? Should the relatively inactive regimen be continued, or should the patient be placed on lamivudine (3TC, Epivir) monotherapy or another agent?
Steven Deeks, from the University of California, San Francisco, and colleagues have examined the effect of partial treatment interruptions -- that is, stopping one or more components of a failing antiretroviral regimen -- on subsequent viral loads.15
Patients who discontinued the NRTI backbone of their regimen had a swift and significant increase in HIV-1 RNA levels, whereas those who stopped the PI component of their regimen did not experience a significant increase in HIV-1 RNA. Interestingly, discontinuing the NNRTI in a failing regimen actually led to decreases in HIV-1 RNA levels, possibly due to a pharmacokinetic effect on the other agents in the regimen. Finally, discontinuing enfuvirtide in a failing regimen did lead to significant increases in HIV-1 RNA loads (median increase = 0.2 log10 copies/mL), although the range of this effect was wide.
Several studies have examined the use of lamivudine monotherapy in patients with highly resistant virus who are awaiting new therapeutic options. These studies have shown that maintaining the lamivudine component of the failing regimen, either alone16 or in combination with other drugs,17 can keep viral loads moderately suppressed.
Take Home Points
For the treatment-naive patient:
For the treatment-experienced patient:
|Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.|