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MULTIDRUG-RESISTANT (MDR) HIV: AN OVERVIEW
HIV that harbors resistance mutations to multiple
antiretrovirals of different drug classes poses a
significant threat to the control of HIV within the
infected. Drug resistance to multiple agents not only limits
patients’ future treatment options and compromises their
opportunity to achieve complete viral suppression, but
several studies have documented a poorer prognosis for
patients with MDR HIV. For example,
a recent study of individuals who
had a genotype resistance test performed during
antiretroviral failure demonstrated that patients with
resistance to all three conventional HIV drug
classes—nucleoside reverse transcriptase inhibitors (NRTIs),
nonnucleoside reverse transcriptase inhibitors (NNRTIs), and
protease inhibitors (PIs)—were 5.36 times more likely to
develop an AIDS-related event or die than patients with no
resistance to any of the classes[1].
In “resource rich” countries that have long had access to
antiretroviral agents (e.g., the United States, Western
Europe, Australia), the prevalence of MDR HIV is high among
patients who started therapy before the widespread
introduction of highly active antiretroviral therapy (HAART)
in 1996. These patients were typically started on one
antiretroviral and had another added as they began to fail
therapy—a situation that we now know can swiftly lead to
resistance. In contrast, the prevalence of MDR HIV among
patients who started therapy in the HAART era, especially in
later years, tends to be considerably lower. In an analysis
of more than 128,000 clinical isolates tested for drug
resistance between 1998 and 2004, the percentage of samples
with any NRTI mutations, any PI mutations, or mutations to
all three drug classes declined from 79% to 63%, 82% to 74%,
and 42% to 32%, respectively, between 1998 and 2004[2].
Despite these declines, some studies show that HIV-infected
patients currently have a 20% risk of developing MDR HIV
over 6 years of treatment[3].
However, other studies suggest that MDR HIV will be a
decreasing problem in the future. A Danish cohort study
found that the prevalence of triple-class resistance leading
to treatment failure peaked at 7.0% in 2001 and has since
declined and remained stable in recent years[4].
A LONG TIME COMING: A NEW ERA OF SALVAGE THERAPIES
The management of patients with MDR HIV grows increasingly
complex as patients accrue resistance to multiple
therapeutic agents, because they lose options for effective
salvage therapy. The recent availability of new therapeutic
agents that retain activity in individuals with MDR HIV
represents a windfall for patients who previously had few
treatment choices. These agents include tipranavir (Aptivus)
and darunavir (Prezista), two highly potent PIs that are
boosted with ritonavir (Norvir), and enfuvirtide (Fuzeon,
T-20), the first and only approved agent from the HIV entry
inhibitor class. Both tipranavir and darunavir are still
able to produce dramatic viral load reductions in patients
with extensive PI resistance (³2-3
key PI mutations), although the activity of the agents
diminishes with increasing numbers of PI mutations. Because
enfuvirtide operates by a different mechanism of action from
the traditional antiretrovirals, patients who have never
before received this agent generally harbor no HIV
enfuvirtide resistance mutations and hence their virus is
fully susceptible to the drug.
Data from several key clinical trials—namely,
the TORO, RESIST, and POWER studies—demonstrate that it is
possible to achieve an undetectable viral load (< 50 copies/mL)
in a substantial proportion of patients with MDR HIV by
combining these new agents with each other and/or with other
active antiretrovirals.[5-7]
When tipranavir/ritonavir was administered with an
optimized background regimen (OBR) for 48 weeks, 23% of
patients reached a viral load level below 50 copies/mL
compared with only 10% of patients receiving a boosted
comparator PI with an OBR (P< .0001)[6].
An even greater response rate was observed when boosted
darunavir was combined with an OBR:
45% of patients attained a viral load below 50 copies/mL
after 48 weeks of treatment compared with 11% of patients
receiving a boosted comparator PI plus an OBR (P<.0001)[7].
One must be cautious in comparing results of the tipranavir
and darunavir trails as the study populations were not
identical. As a consequence of the excellent results, the
widespread introduction of these agents into clinical
practice has caused a dramatic shift in the goals of therapy
for treatment-experienced patients. Previously, the goal of
achieving undetectable viral loads was often not considered
feasible for these individuals. However, given these newly
available agents, current guidelines now stress viral load
suppression to levels below 50 copies/mL, which avoids
further resistance, preserves immune function and prevents
clinical progression[8,9].
The key to achieving complete virologic suppression in
patients with MDR HIV is to create a high genetic barrier to
resistance by using at least two fully active agents. All
three of the TORO, RESIST, and POWER studies demonstrated
that the effectiveness of an active boosted PI dramatically
improved when enfuvirtide was added to the OBR (Figure 2)[10].
Enfuvirtide has a very low genetic barrier to resistance
that can lead to rapid virologic failure when the agent is
used as monotherapy or when it is added to a failing regimen[11].
The use of an active agent in conjunction with enfuvirtide
likely provides protection for the fusion inhibitor by
better staunching viral replication and raising the
genetic-barrier bar to a sufficiently high level to prevent
the emergence of enfuvirtide and other mutations.
Although it has been shown that certain antiretrovirals
continue to exert some beneficial anti-HIV activity despite
the presence of resistance mutations to those agents, the
benefit of continuing enfuvirtide after failure is not well
defined. A recent study performed by Steven Deeks and
colleagues of 25 individuals with incomplete virologic
suppression who stopped the enfuvirtide component of their
regimen but continued to take all other agents revealed that
enfuvirtide discontinuation produced a very small but
immediate and significant increase in viral load (mean HIV-1
RNA increase of 0.22 log10 copies/mL at Week 2;
P=.046), indicating that enfuvirtide appears to
maintain some degree of residual activity despite the
presence of resistance[12].
It was also shown that some of these enfuvirtide resistance
mutations may impair the fitness of HIV and decrease the
ability of the virus to infect CD4 cells.
HOLDING STRATEGIES FOR PATIENTS AWAITING NEW DRUG OPTIONS
As illustrated above, a regimen containing at least two
active agents offers the best hope for completely
suppressing viral load. In cases where patients with MDR HIV
are failing treatment and no, or only one, active agent is
available for use in a new regimen, the best therapeutic
approach to take may be hard to decide and depend on many
patient-related and viral factors. General consensus
supports the idea that it is probably better to continue a
patient on a failing regimen—ideally one that is least
likely to select for clinically-relevant additional
resistance mutations—until new drugs become available,
rather than start them on a regimen with only one active
agent. That way, the benefit of the drug can be maximized
through combination with other active agents when they
become available, rather than squandered by use as
functional monotherapy to which resistance will rapidly
develop. Importantly, clinical judgment will determine when
short-term immunological and clinical benefit may outweigh
the risks of further resistance. Individualized care is
important in this MDR population, especially with advanced
disease.
Maintaining patients on a failing regimen may preserve
immunologic function, slow disease progression, and prolong
survival, but it may also jeopardize future treatment
options by promoting further resistance over time. One
recent study showed that continuing partially-effective
antiretroviral therapy preserved CD4 cell counts in the
short term, but patients developed an average of 1.96 new
resistance mutations over a 6-month period[13].
To help overcome this problem,
many clinicians are employing a strategy in which they drop
all PI components from a patient’s regimen and maintain them
on NRTI-only therapy with close patient monitoring. Deeks
and colleagues have shown that discontinuing all NRTIs in
patients with MDR HIV leads to much greater increases in
viral loads and greater declines in CD4 cell counts than
discontinuing PIs in the short term[14].
This observation may be due to the fact that
HIV containing the M184V mutation,
which confers high-level resistance to lamivudine (Epivir,
3TC), a commonly used NRTI, is less fit than wild-type HIV[15].
Hence, continuing exposure to lamivudine to maintain this
mutation may impair the rapidity of viral replication,
although other mechanisms are possible
and multiple NRTI—not just
3TC—may be of value. The
NRTI-only approach is also attractive in that
cross-resistance within the NRTI class is often extensive in
individuals with MDR HIV, so the accrual of additional NRTI
mutations often has little impact. That said, there is a
lack of objective data showing the clinical effect of the
NRTI-only maintenance approach, as well as a lack of
comparative studies that reveal which NRTI regimen is
optimal.
EMERGING AGENTS FOR SALVAGE THERAPY
There remains an unmet need for new agents that can be used
in salvage therapy. Fortunately, several new therapeutics in
the development pipeline show promise in
treatment-experienced patients and may soon
offer additional drug options for patients with MDR HIV.
These agents include raltegravir, an investigational
integrase inhibitor, etravirine, a NNRTI with improved
resistance characteristics—both of which are currently
available to treatment-experienced patients through
expanded-access programs—and CCR5 inhibitors including
maraviroc, also available in expanded access.
Raltegravir
(integrase inhibitor): Formerly known as MK-0518,
raltegravir blocks the integration of HIV into the DNA of
host cells and hence belongs to a novel antiretroviral drug
class. In two parallel, blinded, phase III studies
(BENCHMRK-1 and -2), 699 patients with HIV resistance to all
three conventional antiretroviral classes were randomized to
raltegravir 400 mg twice daily or to placebo, both in
combination with an OBR[16,17].
After 16 weeks of treatment, undetectable viral loads (< 50
copies/mL) were attained by 61-62% of patients assigned to
raltegravir versus 33-36% of those assigned to placebo (all
P values<.001). Increases in CD4 cell counts were
also significantly greater for raltegravir-treated patients
versus placebo-treated patients (83-86 vs 31-40 cells/mm3;
all P values<.001).
Entravirine
(NNRTI): The investigational NNRTI etravirine has been
called a “second generation” NNRTI because it is active
against many HIV-1 isolates with traditional NNRTI
resistance mutations. A randomized trial conducted in
individuals with extensive NNRTI and PI resistance
demonstrated that two doses of etravirine (400 or 800 mg
twice daily) in combination with an OBR produced
significantly greater viral load reductions than the control
group of patients who received at least three antiretroviral
agents (mean HIV-1 RNA change from baseline: -1.04 to -1.18
vs -0.19 log10 copies/mL; P<.05 for both
etravirine groups vs control)[18].
Moreover, a small pilot study indicated that the combination
of etravirine and darunavir/ritonavir was safe and highly
effective in patients with drug resistance to all three drug
classes: 9 of 10 patients achieved a viral load below 50
copies/mL by Week 24, and the tenth was just shy of this
threshold with a viral load of 59 copies/mL at Week 32[19].
Conversely, a large study using etravirine as second line
therapy in NRTI + NNRTI failures with substantial resistance
showed very poor results[20].
CCR5 inhibitors,
another type of entry inhibitor with a different mechanism
of action from enfuvirtide, function by blocking the CCR5
receptor on the surface of CD4 T-cells, which some HIV
strains must use to gain cell entry. As such, these agents
fall in a new drug class. Maraviroc, the CCR5
inhibitor closest to FDA approval, plus an OBR has been
shown to produce complete viral suppression in up to 48.5%
of patients (compared with 24.6% of patients receiving
placebo; P=.0005)[21].
Despite the impressive potency of this agent, approximately
half of long-infected MDR patients are predicted to be
ineligible for the use of CCR5 inhibitors due to infection
with HIV that does not exclusively use the CCR5 receptor for
CD4 entry (i.e., CXCR4-tropic virus or dual/mixed-tropic
virus)[22].
These findings highlight the importance of performing
diagnostic testing to determine HIV tropism in order to
eliminate the risk of placing patients on potentially
ineffective therapy.
SUMMARY
These and other study results bolster the current view that
patients with relatively less resistant virus have the most
to lose by staying on failing regimens, and that such
patients should have their treatment modified to include at
least 2 new active agents, if possible, to prevent the
development of additional resistance. Those with highly
resistant viruses may have few relevant NRTI mutations to
acquire, and may do well over the medium term (e.g., 6-12
months) while future strategies are planned and access to
new agents determined. While questions remain about the best
way to incorporate the newest available agents into salvage
therapy, many clinicians are already using these agents and
witnessing a favorable impact in patients with MDR HIV—a
trend that will likely grow in coming months given the
excitement generated by these agents.
As these agents near widespread clinical availability,
clinicians must define how to best integrate these drugs
into current treatment paradigms for optimal patient
management.
REFERENCES
-
Zaccarelli M, Tozzi V, Lorenzini P, et
al.
Multiple drug class-wide resistance
associated with poorer survival after treatment failure
in a cohort of HIV-infected patients.
AIDS. 2005;19:1081-1089.
-
Rinehart A, Lecocq P, Pattery T,
Wasikowski B, Bacheler LT. Evolution in the diversity
of HIV-1 resistance mutation patterns in >128,000
clinical samples received for resistance analysis from
1998 to 2004. Program and abstracts of the 12th
Conference on Retroviruses and Opportunistic Infections;
February 22-25, 2005; Boston, Mass. Abstract 684.
-
Phillips AN, Dunn D, Sabin C,et al.
Long term probability of detection of
HIV-1 drug resistance after starting antiretroviral
therapy in routine clinical practice. AIDS.
2005;19:487-494.
-
Lohse N, Obel N, Kronborg G, et al.
Declining risk of triple-class
antiretroviral drug failure in Danish HIV-infected
individuals.
AIDS. 2005;19:815-822.
-
Nelson M, Arasteh K, Clotet B, et al.
Durable efficacy of enfuvirtide over 48
weeks in heavily treatment-experienced HIV-1-infected
patients in the T-20 versus optimized background regimen
only 1 and 2 clinical trials.
J Acquir Immune Defic Syndr. 2005;40:404-412.
-
Hicks CB, Cahn P, Cooper DA, et al.
Durable efficacy of tipranavir-ritonavir
in combination with an optimised background regimen of
antiretroviral drugs for treatment-experienced
HIV-1-infected patients at 48 weeks in the Randomized
Evaluation of Strategic Intervention in multidrug
reSistant patients with Tipranavir (RESIST) studies: an
analysis of combined data from two randomised open-label
trials.
Lancet. 2006;368:466-475.
-
Clotet B, Bellos N, Molina JM, et al.
Efficacy and safety of
darunavir-ritonavir at week 48 in treatment-experienced
patients with HIV-1 infection in POWER 1 and 2: a pooled
subgroup analysis of data from two randomised trials.
Lancet. 2007;369:1169-1178.
-
Panel on Antiretroviral Guidelines for
Adult and Adolescents. Guidelines for the use of
antiretroviral agents in HIV-infected adults and
adolescents. Department of Health and Human Services.
October 10, 2006; 1-113. Available at
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentsGL.pdf.
Accessed May 3, 2007.
-
Hammer SM, Saag MS, Schechter M, et al.
Treatment for adult HIV infection: 2006
recommendations of the International AIDS Society-USA
panel.
JAMA. 2006;296:827-843.
-
Thommes JA, Demasi R, Haubrich R.
Improved virological response in three-class experienced
patients when an active boosted protease inhibitor is
used with enfuvirtide (ENF). Program and abstracts
of the 43rd Infectious Diseases Society of America;
October 6-9, 2005; San Francisco, Calif. Abstract 785.
-
Lu J, Deeks SG, Hoh R, et al.
Rapid emergence of enfuvirtide resistance
in HIV-1-infected patients: results of a clonal
analysis.
J Acquir Immune Defic Syndr. 2006;43:60-64.
-
Deeks SG, Lu J, Hoh R, et al.
Interruption of enfuvirtide in HIV-1
infected adults with incomplete viral suppression on an
enfuvirtide-based regimen.
J Infect Dis. 2007;195(3):387-391.
-
Cozzi-Lepri A, Phillips AN, Ruiz L, et
al. Evolution of drug resistance in HIV-infected
patients remaining on a virologically failing
combination antiretroviral therapy regimen. AIDS.
2007;21(6):721-732.
-
Deeks SG, Hoh R, Neilands TB, et al.
Interruption of treatment with individual
therapeutic drug classes in adults with multidrug-resistant
HIV-1 infection.
J Infect Dis. 2005;192(9):1537-1544.
-
Feng JY,
Anderson KS. Mechanistic studies examining the
efficiency and fidelity of DNA synthesis by the
3TC-resistant mutant (184V) of HIV-1 reverse
transcriptase. Biochemistry. 1999;38:9440-9448.
-
Cooper
D, Gatell J, Rockstroh J, et al. Results of
BENCHMRK-1, a phase III study evaluating the efficacy
and safety of MK-0518, a novel HIV-1 integrase
inhibitor, in patients with triple-class resistant
virus. Program and abstracts of the 14th Conference
on Retroviruses and Opportunistic Infections; February
25-28, 2007; Los Angeles, California. Abstracts 105aLB.
-
Steigbigel R, Kumar P, Eron J, et al.
Results of BENCHMRK-2, a phase III study
evaluating the efficacy and safety of MK-0518, a novel
HIV-1 integrase inhibitor, in patients with triple-class
resistant virus.
Program and abstracts of the 14th
Conference on Retroviruses and Opportunistic Infections;
February 25-28, 2007; Los Angeles, California. Abstracts
105bLB.
-
Steigbigel R, Kumar P, Eron J, et al.
Results of BENCHMRK-2, a phase III study
evaluating the efficacy and safety of MK-0518, a novel
HIV-1 integrase inhibitor, in patients with triple-class
resistant virus.
Program and abstracts of the 14th
Conference on Retroviruses and Opportunistic Infections;
February 25-28, 2007; Los Angeles, California. Abstracts
105bLB.
-
TMC125-C223 Writing Group; Nadler JP,
Berger DS, Blick G, et al. Efficacy and safety of
etravirine (TMC125) in patients with highly resistant
HIV-1: primary 24-week analysis. AIDS.
2007;21(6):F1-F10.
-
Boffito M, Winston A, Jackson A, et al.
Week 24 results and baseline phenotypic
susceptibility in treatment experienced patients
initiating the combination of TMC114/r and TMC 125.
Program and abstracts of the 46th Interscience
Conference on Antimicrobial Agents and Chemotherapy;
September 27-30, 2006; San Francisco, California.
Abstract H-1000.
-
Woodfall B, Vingerhoets J, Peeters M, et
al. Impact of NNRTI and NRTI resistance on the response
to the regimen of TMC125 plus two NRTIs in Study
TMC125-C227. Program and abstracts of the 8th
International Congress on Drug Therapy in HIV infection;
November 12-16, 2006; Glasgow, Scotland. Abstracts
PL5.6.
-
Lalezari J, Goodrich J, DeJesus E, et al.
Efficacy and safety of maraviroc plus
optimized background therapy in viremic, ART-experienced
patients infected with CCR5-tropic HIV-1: 24-week
results of a phase 2b/3 study in the US and Canada.
Program and abstracts of the 14th
Conference on Retroviruses and Opportunistic Infections;
February 25-28, 2007; Los Angeles, California. Abstract
104bLB.
-
Wilkin TJ, Su Z, Kuritzkes DR, et al.
HIV type 1 chemokine coreceptor use among
antiretroviral-experienced patients screened for a
clinical trial of a CCR5 inhibitor: AIDS Clinical Trial
Group A5211. Clin Infect Dis.
2007;44:591-595.
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