Study of Tests to Evaluate Effectiveness of Anti-HIV Drugs

The efficacy of highly active antiretroviral therapy (HAART) is limited by the emergence of
drug-resistant virus strains. Development of resistance to one or more antiretroviral drugs
in a HAART regimen may result in substantial rebound viremia and require a new drug regimen.
The use of virus genotyping or phenotyping to identify drugs likely to be active in an
anti-retroviral experienced patient is now recommended, but these tests have limitations and
their clinical utility has not yet been established. The goal of this project is to
investigate the correlation between phenotype/genotype to selected antiretroviral agents and
short-term change in viral load upon discontinuation of a single antiretroviral agent from a
failing regimen. For the nucleoside reverse transcriptase inhibitors (NRTIs) and the
protease inhibitors, resistance is poorly understood; thus, we plan to determine whether a
change in viral load occurs after discontinuing these drugs. If so, we plan to correlate
those changes with phenotypic and genotypic characteristics. Study participants must have a
stable viral load of at least 1000 copies/ml by bDNA assay despite HAART and must be
receiving one of the anti-retroviral agents designated for study:. Baseline viral load will
be established by multiple bDNA sampling over a 10-day period. Next, the drug of interest
will be withdrawn and the rest of the regimen maintained for either a two week (NRTIs except
3TC, protease inhibitor) or four week (3TC) discontinuation to assess for change in viral
load. Finally, the withdrawn agent will be re-instituted, and serial sampling for change in
viral load, genotype or phenotype will follow.

- INCLUSION CRITERIA:

In order to enroll, subjects must:

Be HIV infected.

Be currently receiving highly active anti-retroviral therapy. Drugs available through
expanded access or compassionate use protocols are permitted.

Have received at least 6 months of HAART therapy.

Currently be receiving and be willing to temporarily discontinue the selected
antiretroviral for the indicated duration.

Have a viral load between 1,000 and 100,000 copies/ml within 6 weeks prior to screen or at
screening.

If one value is greater than 100,000 copies and one value less, the average of the two
viral loads will be used to determine eligibility. Similarly, if one value is less than
1,000 and one value greater than 1,000, the average viral load will be used to determine
eligibility.

Have two viral load tests by bDNA method in the NIH laboratory that differ by less than
20% (log10bDNA) in the three weeks prior to enrollment. Viral loads performed through
participation in another NIAID study are acceptable. Alternatively, new patients coming to
the clinic are permitted to have two screening visits.

Have a CD4 T cell number greater than 100 cells within 4 weeks of enrollment or greater
than 100 cells within 8 weeks of enrollment if no more recent CD4 cell count is available.

Be adults age 18 or older.

Self-report adequate adherence to antiviral medications (missing at most one dose of drug
weekly) and commit to work towards adherence during study participation.

EXCLUSION CRITERIA:

In order to enroll, subjects must not:

Have a positive pregnancy test.

Have evidence of recent HIV infection, defined as a history of a negative HIV ELISA within
12 months of screening.

Have any acute infection that might alter viral load with the previous 4 weeks.

Have received a vaccine in the previous 4 weeks.

Have symptomatic HIV disease for which rapid institution of a salvage regimen would be
advisable.

Be receiving concomitant medications or have a concomitant illness with malabsorption or
emesis that could be expected to result in inadequate concentrations of antiretroviral
drugs.

Be receiving an anti-retroviral regimen that includes drugs that should not be used
concomitantly (e.g., stavudine and zidovudine) or inadvisable dosages of antiretroviral
agents.

Have any laboratory abnormality for which withdrawal of a drug or drug regimen might be
considered. For the purposes of general guidance, Grade III toxicities would result in
exclusion from study with the exception of stable thrombocytopenia or proteinuria or
elevated bilirubin resulting from Gilbert's syndrome or indinavir treatment. Grade II SGOT
or SGPT might be a reason for study exclusion if not explained by underlying hepatitis or
if in a pattern of recent increase over a stable baseline.

Have genotypic evidence at screening that would suggest that discontinuing the selected
antiretroviral would result in suboptimal therapy that would clearly place the remainder
of the regimen at risk for the development of new resistance mutations during the
discontinuation period. Two prominent possibilities would be patients taking NNRTI
regimens and discontinuing NRTIs or PI component in patients who have genotypes with no
NNRTI mutations. During the discontinuation period, it would be possible that the patient
may acquire new resistance mutations to NNRTIs. Genotype may be performed as part of the
screen or be performed through PMD.

Have had a change in antiretroviral regimen in the past 6 weeks.

Have received cytotoxic chemotherapy including hydroxyurea in the last 6 weeks, or have
anticipated need for chemotherapy during study.

Have evidence of active hepatitis B infection and wish to interrupt either tenofovir or
3TC.

Have any suggestion of a trend to increase or decrease in viral load in the past 6 weeks.

Have significant active substance abuse or psychiatric illness that might interfere with
study assessments or with your ability to return for study visits.