HIV Infections Clinical Trial
Official title:
Proviral DNA as a Target for HIV-1 Resistance Analysis
In summary, in this project the investigators propose to study the proviral DNA genotyping to
implement a lower cost and wider than the commercial systems currently in use, in order to
analyze all HIV genes that are therapeutic targets of antiretroviral drugs. Using HIV
proviral DNA we can obtain information for: HIV-1 Viral Tropism, Mutations associated to
Integrase Inhibitors, Mutations associated to Transcriptase reverse Inhibitors, Mutations
associated to Protease Inhibitors, and Mutations associated to GP41 Inhibitors.
Along with this the investigators propose to validate the proviral DNA as starting material
for genotyping which is independent of the patient's viral load and achieve a greater number
of patients living with HIV have access to this important test that is essential in
monitoring the HIV infection.
3.2 RESEARCH QUESTIONs Is proviral DNA a genetic compartment suitable for carrying out a
genotypic resistance test in patients with low or undetectable viral load? Does proviral DNA
have the same clinical validity that RNA? 3.3.- HYPOTHESIS A resistance genotyping test
carried out by Proviral DNA detects the same mutations associated to resistance that viral
RNA.
3.4.- OBJECTIVES: General/Specific General objective Develop a methodology to assess the
proviral HIV-1 DNA or RNA as the genetic material for genotyping assays in genes that are
targets of pharmacological interest as TR reverse transcriptase and protease (PRO), Integrase
or GP41 Inhibitors and HIV tropism. Specific Objectives
1. Carry out genotyping by proviral DNA and compare it with the same genes genotyping
performed with viral RNA. 2. Once the correlation between proviral DNA and RNA has shown,
standardize a method to use the technique for clinical use in monitoring HIV patients
according to each patient's needs. RNA for patients with viral load above 1,000 copies/mL.
Proviral DNA for patients with low or undetectable viral load.
A prospective longitudinal observational study, the objective is to observe and describe the
prevalence of INRT, INNRT, Protease and INIS mutations detected by proviral DNA in patients
with virologic failure and low level viremia.
Inclusion/Exclusion: Our Study will include only patients with HIV that had been confirmed by
"Instituto de Salud Pública de Chile" (ISP-Chile). Children less than 18 years are excluded.
Number of Patients: A total of 1,200 patients will be included in a period of three years
(Including statistical justification, if appropriate).
1. - Only patients who have signed informed consent will be admitted to our study.
2. - The admitted patients will have a blood sample taken for an HIV genotypic resistance
test.
3. - from the clinical record of each patient admitted, some relevant clinical data will be
taken to interpret the results such as CD4 T lymphocyte count, Viral Load, date of HIV
diagnosis, date of initiation of therapy in addition to number and type of treatments
antiretrovirals
4. - By way of genotype control, a second blood sample will be taken every year.
Detailed Description
Detection of Resistance Mutations in Proviral DNA in HIV-1 Infection
Background The genetic test HIV proviral DNA (HPD) for resistance to antiretroviral drugs is
very useful to detect mutations in patients under antiretroviral therapy who has failed to
achieve undetectable viral loads levels or with low level viremia (LLV).
HPD allows the detection of circulating resistant variants and archived which could not be
detected in the plasma.
HPD is independent of the viral load of patients. This makes it very useful for studies of
primary resistance as it can detect resistance mutations in recently diagnosed patients with
low baseline viral loads (<1,000 copies/mL).
HPD is recommended by the European AIDS Clinical Society EACS for cases where there is not
HIV RNA for analysis (Barcelona, October 2015).
HPD is able to analyze resistance to all antiretroviral drugs currently available in the
market. Therefore, with the HPD innovation we can carry out the following genetic resistance
tests: HIV Tropism (Maraviroc), resistance to Integrase Inhibitors (Dolutegravir) and
resistance to Transcriptase reversa/Proteasa (Abacavir).
Size Sample and Methodology
During a period of two years, we will study a population of 1,200 patients. These include all
patients we have analyzed in our HIV center until December 2012. The methodology includes
nucleic acid extraction, amplification of HIV-1 genes that are targets of therapeutic
interest and sequencing by traditional and new generation sequencing methods.
Patient Recruitment: a Total of 1.200 (400 by year)
Obtaining blood samples: two samples: sample to the start and one sample to the end after one
year
DNA and viral RNA extraction:
RT-PCR amplification:
Electrophoresis visualization in agarose gels
Sending samples to Macrogen for sequencing services
Automatic sequencing by Sanger method in Macrogen USA
Sequencing by deep sequencing (NGS) in Chile or Macrogen USA
Sequence Analysis
Quality Analysis and assemble of raw sequences in software ReCall
Registry of mutations of clinical interest
Report on resistance to antiretroviral drugs
Biostatistical analysis
Results Report and Publications
Preliminary results Preliminary analysis of 100 patients with viral load <1,000 copies/mL,
detected 10% of patients with mutations of resistance to drugs that inhibit reverse
transcriptase and viral protease. This valuable information enabled earlier therapeutic
intervention by changing the drug scheme before they reach higher levels of viral load with
consequent improvement in the clinical management.
Projections Project Due to the success and immediate application of this preliminary study,
we believe it become very important to validate this technique as a daily routine genetic
testing for HIV clinic patients in the public health system. Permanent financing for this
genetic HIV test for HIV proviral DNA should be given by the Ministry of Health, Government
of Chile.
In conclusion, at present HPD is very useful tool to study virologic failure and LLV in order
to an early change of the antiretroviral therapy.
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