Maintaining
high levels of adherence
to HAART is important for the successful management of HIV infection. Although
it is advisable for patients to adhere to all prescribed medications, it is possible
that some HAART regimens are more forgiving of less than perfect adherence than
others.
The
Medication Event Monitoring System (MEMS) provides an accurate means of quantitating
medication adherence over time by electronically recording bottle openings. MEMS
is also accurate for predicting virologic outcomes in HIV-infected patients receiving HAART.
Early
studies using MEMS caps to evaluate adherence to HAART have shown that adherence
rates of 90% to 98% were necessary to achieve complete
virologic suppression in a majority of patients. Most patients in these studies
received regimens consisting of 2 nucleoside
reverse transcriptase inhibitors (NRTIs) and 1 HIV protease inhibitor
(PI) without ritonavir boosting. Their
findings led to the general acceptance of the 95% rule for HAART adherence (i.e.,
that patients must take ≥95% of prescribed doses to achieve complete
virologic suppression).
However,
with improved pharmacokinetic profiles offered by newer antiretroviral drugs (due
in large measure to ritonavir boosting); the possibility of greater forgiveness
of missed doses has risen. A recent report used pharmacy refill data to show that
boosted PI-based HAART is more forgiving of non adherence than other treatment
strategies [1].
The
improved pharmacokinetic properties of lopinavir/ritonavir
(Kaletra) over unboosted PIs and the low likelihood of viral resistance,
even with suboptimal adherence, suggest that lopinavir/ritonavir-based HAART may
be more forgiving of non adherence than earlier unboosted PI-based regimens.
In
the May 1 issue of The Journal of Acquired
Immune Deficiency Syndromes, researchers report on a study that aims to define
the level of adherence needed to achieve virologic suppression in patients receiving
boosted PI-based HAART with lopinavir/ritonavir [2].
A
total of 84 patients were enrolled; ten patients discontinued lopinavir/ritonavir
during the course of this prospective, observational study. Adherence was measured
using the Medication Event Monitoring System (MEMS). HIV-1 viral load (VL) was
measured at week 24.
Results
·The final
study population contained 64 subjects.
·Eighty percent
had AIDS, 97% received lopinavir/ritonavir before enrollment, and most had more
than 7 years of HAART experience.
·Mean adherence
overall was 73%. Eighty percent and 59% achieved a VL <400 copies/mL and a
VL <75 copies/mL, respectively.
·Mean adherence
was 75% in those achieving a VL <75 copies/mL.
·High rates
of virologic suppression were observed in all adherence quartiles, including the
lowest quartile (range of adherence: 23.5%-53.3%).
Based
on these results, the authors conclude that moderate levels of adherence can lead
to virologic suppression in most patients taking lopinavir/ritonavir-based HAART.
Discussion
Lopinavir/ritonavir's
forgiveness of non adherence is likely attributable to 2 separate factors, according
to the study authors. First is its pharmacokinetic profile. A single 400-mg dose
of lopinavir boosted with 50 mg of ritonavir produced lopinavir levels that exceeded
the 50% effective concentration (EC50) for HIV for >24 hours in
normal volunteers.
“It
is thus likely that patients without resistant virus who miss 1 of 2 daily doses
of lopinavir/ritonavir could maintain therapeutic levels of the drug between doses.”
In contrast, the shorter half-lives of unboosted PIs increase the likelihood of
plasma drug concentrations falling to subtherapeutic levels after each missed
dose.
“The
second factor that may enhance the forgiveness of lopinavir/ritonavir is the low
frequency at which the virus develops resistance to this agent,” write the authors.
This feature of the drug may allow for the durable effectiveness of lopinavir/ritonavir
even after the virus has been exposed to subtherapeutic concentrations of the
drug.
The
authors noted no evidence of a significant increase in the rate of virologic failure
when adherence rates fell to less than the 90- 95% level. “These findings challenge
the belief that near-perfect adherence is necessary to achieve virologic suppression
in persons living with HIV in the current HAART era,” write the authors.
Clearly,
physicians should continue to advise their patients to maintain the highest level
of adherence possible. However, the study authors conclude, “Doubts about the
ability of patients to adhere perfectly to their regimens should not dissuade
providers from prescribing HAART,… especially regimens that have demonstrated
greater forgiveness of missed doses.”
06/01/07
References
1.
R Gross, B Yip, E Wood, and others. Boosted protease inhibitors are more forgiving
of suboptimal adherence than non-boosted protease inhibitors or non-nucleoside
reverse transcriptase inhibitors. 13th Conference on Retroviruses and
Opportunistic Infections. Denver.
2006. Abstract K-210.
2.
J Shuter, J Sarlo, T Kanmaz, and others. HIV-Infected Patients Receiving Lopinavir/Ritonavir-Based
Antiretroviral Therapy Achieve High Rates of Virologic Suppression Despite Adherence
Rates Less Than 95% (Rapid Communication). Journal of Acquired Immune Deficiency Syndromes 45(1): 4-8. May 1, 2007.
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Maintaining
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