Update from the International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication
AIDS INFORMATION NEWSLETTER
AIDS Information Center
VA Medical Center, San Francisco
Protease Inhibitors and Long-Term Viral Suppression
Continued evolution of HIV-1 during combination therapy despite
levels of HIV-1 < 500 copies/ml
A group from the NIH performed intensive virological studies
on four patients who attained long-term viral suppression on
indinavir and IL-2. All four patients achieved undetectable levels
of HIV-1 RNA, and remained there for at least two years. The
investigators looked at viral genotype, both at baseline and 1.5
years into therapy. Surprisingly, in all 4 patients, the protease
gene appeared to evolve over time. This observation, limited by
technical difficulties in obtaining sufficient PCR products from
patients with low levels of plasma HIV-1 RNA, indicates that viral
evolution can occur in the presence of effective protease inhibitor
therapy. If true, viral replication must be ongoing [Imanici et al,
Comment: This provocative study may not be generalizable, since
patients also received IL-2. However, it does raise concerns about
the ability of current regimens to suppress viral replication
indefinitely. Other studies presented at the meeting suggest that
HIV does not evolve in the presence of potent therapies [Emini et
al, abstract 128; Gunthard et al, abstract 66].
Emergence of drug resistance in different tissue compartments
after 1 year of potent antiretroviral therapy
Evidence for prevention of new HIV-1 infection cycles in patients treated with
indinavir plus zidovudine plus lamivudine
Merck 035 is an important study of 90 patients treated with
AZT + 3TC
monotherapy or AZT
+ 3TC + indinavir.
Approximately 86% of patients receiving the three-drug combination
had viral loads of < 500 copies/mL through 68 weeks of therapy.
This impressive data set has established AZT + 3TC + indinavir as
the standard of care in most clinical studies.
Two groups performed intensive studies on these patients in
an attempt to determine if viral replication is completely
suppressed. Gunthard and colleagues in San Diego studied the
emergence of genotypic resistance to 3TC in 10 patients. Since the
M184V mutation typically occurs rapidly in the presence of 3TC,
this group assumed that the lack of M184V after prolonged therapy
indicates complete, or near complete, viral suppression.
Viral sequences were analyzed using automated
dideoxynucleotide (ABI) and high-density oligonucleotide
(Affymetrix) sequencing techniques. Plasma HIV-1 RNA and peripheral
blood mononuclear cells (RNA, DNA) were obtainedat baseline and
after one year of treatment. Samples were also obtained from lymph
node biopsies. In subjects with undetectable levels of HIV-1 RNA
after one year of therapy, M184V did not evolve in each of the
compartments evaluated [Gunthard et al, abstract 66].
The clinical scientists at Merck performed a similar analysis.
During the course of Merck 035, several patients receiving AZT, 3TC
and indinavir had transient elevations in viral RNA (to > 500
copies/mL) or persistent low levels of viral RNA (using
ultrasensitive viral load assays). Genetic analysis from eight such
patients revealed no new mutations in the reverse transcriptase or
protease genes. One patient did have a new M184V, suggesting loss
of viral control [Emini, abstract 128].
Comment: These studies provide evidence that potent combination
therapy can fully suppress viral replication. If true, resistance
mutations theoretically can not evolve. Long term viralsuppression,
and possibly viral eradication, is therefore feasible.
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