Authored By: B. V Waghmare

Thursday, October 28, 2010


1. Role for Supporting Initial Activity and Dose-Finding Studies
Primary objectives of initial clinical studies in HIV-infected patients should be to establish that the new investigational agent has anti-HIV activity, to determine the magnitude of that effect, and to determine the most active dose that can be taken forward in larger studies. Often, studies that incorporate short periods of monotherapy (e.g., less than or equal to 2 weeks) or functional monotherapy (when a drug is added to a failing but stable regimen) have been helpful in accomplishing these objectives. Compared to combination studies, such protocols can more clearly delineate the effect of the drug of interest. However, resistant viruses sometimes emerge rapidly for certain drugs, such that periods of monotherapy can jeopardize a patient’s future therapeutic options. Thus, some drugs are not candidates for use in monotherapy trials, including trials of short duration. Drugs for which a single mutation is easily selected and able to confer large reductions in susceptibility to the new drug and other drugs of the same class should not be studied as monotherapy, particularly in treatment-naïve individuals. Data from cell culture resistance studies, along with pharmacokinetic and safety data, should be used to determine whether a new drug could be safely administered as a single agent for limited periods of time.
2. Data Collection from Dose-Finding Trials
Sponsors should collect baseline genotype and phenotype information in HIV-infected patients who participate in pharmacokinetic and dose-finding studies. As stated previously, we encourage sponsors to analyze baseline resistance information and outcome in treatment-experienced patients. Analysis of baseline resistance and virologic outcome data in treatment-naïve patients may not be routinely needed; however, analysis of this information may be helpful to interpret unexpected virologic results. Current evidence indicates virologic response is better when drug levels can be maintained some increment above the serum-adjusted EC50 value (see section III, HIV Resistance Testing — General). Study patients with baseline resistance mutations may require higher drug concentrations of the antiretroviral drug to achieve an antiviral response that is comparable to that in patients with WT virus. Patients with particular genotypes and/or phenotypes of interest should be prospectively identified for inclusion in dose-ranging studies.
3. Use of Resistance Data to Establish an Indication
The amount of evidence sufficient to characterize a drug’s general resistance profile and the amount of data to support a specific efficacy claim against a particular resistant strain of HIV are not always the same. Well-controlled, randomized, prospective trials are preferred when attempting to develop a drug product to obtain a specific indication for use in a select group of patients with a particular resistance profile at baseline or antiretroviral treatment history. The amount of evidence sufficient to establish an efficacy claim in a specific patient population will be substantial, and studies of small numbers of patients are unlikely to accomplish this goal. Sponsors are encouraged to discuss their development plans with the division in advance. In addition, resistance data also can be considered for usage statements in a package insert.
4. Use of Resistance Data for Study Enrollment Criteria, Background Regimen Selection, and Stratification Factors
As mentioned earlier, resistance testing at baseline can be helpful in selecting antiretroviral-experienced study patients with particular resistance profiles. For example, to evaluate the efficacy of a new NNRTI in patients who have failed previous NNRTI regimens, sponsors can elect to enroll patients with confirmed genotypic and/or phenotypic NNRTI resistance. We strongly encourage sponsors to use all available phase 1 and phase 2 and nonclinical data to define which mutation or mutations adversely affect response rate. Early determination of the effect of baseline genotype and phenotype for new investigational agents can be important for patient selection into phase 3 clinical trials, thereby restricting specific mutational patterns or limiting the number of mutations to ensure all patients, regardless of randomized treatment, have a reasonable chance of virologic response.
Some studies evaluate a new drug combined with an optimized background, meaning that the concomitantly administered antiretrovirals were chosen based on data from resistance testing. For trials that include an optimized background regimen, genotypic and/or phenotypic resistance testing is used to guide the selection of the background antiretroviral regimen. In addition, some studies have used genotypic and/or phenotypic susceptibility scores to quantify the number of drugs to which a patient may still be susceptible. Sponsors also can consider using an external expert committee to aid in the selection of background regimen, especially for patients with limited therapeutic options.
Baseline resistance testing also can be used to stratify patients. Rationale for specific stratification factors should be discussed with the division in advance.
5. Nonclade B Subtypes
Sponsors are also encouraged to evaluate baseline resistance data and response and the development of resistance in patients with nonclade B viruses versus clade B viruses. Since many sponsors are conducting global development plans and it is unknown if different HIV subtypes develop resistance via different pathways, these data will add to the overall characterization of an investigational drug’s resistance profile (Hirsch et al. 2003).

A. Mechanism of Action
B. Antiviral Activity in Cell Culture
C. Cytotoxicity and Therapeutic Indexes
D. Protein Binding
E. Selection of Drug-Resistant HIV-1 Variants in Cell Culture
1. Genotype
2. Phenotype
F. Cross-Resistance
G. Characterization of Genotypic and Phenotypic Assays
1. Genotypic Assays
2. Phenotypic Assays
A. General Considerations
B. Data Collection
C. Methods and Types of Analyses
1. Baseline Genotype and Virologic Response
2. Development of HIV Mutations
3. Baseline Phenotype and Virologic Response
4. Genotypic and Phenotypic Correlations: Changes in Susceptibility from Baseline
5. Cross-Resistance
6. Additional Analyses
D. Other Considerations
1. Role for Supporting Initial Activity and Dose-Finding Studies
2. Data Collection from Dose-Finding Trials
3. Use of Resistance Data to Establish an Indication
4. Use of Resistance Data for Study Enrollment Criteria, Background Regimen Selection, and Stratification Factors
5. Nonclade B Subtypes
E. Monitoring during Phase 4




Drug Resistance Assay and Antiretroviral drug development guidance--->

There is much more information on HIV virus new findings available on this blog.
Here are given details about symptoms of AIDS , all new symptoms of AIDS and HIV virus infection are updated.

This website provideds complete information about hiv virus , hiv infection , early hiv symptoms , hiv treatment,hiv test and hiv testing centers, aids symptoms, symptoms of hiv immideately after infection.------------------------------------------------------------------------------------------------------------

Following are the most read topic on this website you should find them on blog archive of this website
Stem cell treatment for AIDS
AIDS symptoms
HIV infection symptoms
Latest treatment for AIDS
How anti retroviral medicines are developed
How Chemotherapeutic drugs are developed to treat HIV virus infection
New drug developments against HIV Virus AIDS
Vaccines research for HIV AIDS Why it is difficult to develop a vaccine against HIV
Mother to child prevention of HIV virus infection.
hiv virus infection prevention and education bloggers

Information about HIV Virus AIDS symptoms

Last updated : 28-Oct-2010

No comments: