Vina Churdboonchart

Genotypic resistance profiles in antiretroviral-naive HIV-1 infections before and after initiation of first-line HAART: impact of polymorphism on resistance to therapy

Genotypic testing using TRUGENE was performed for treatment-naive, human immunodeficiency virus type 1 (HIV-1)-infected patients at baseline and after initiation of protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) regimens. The genetic diversity of HIV-1 pol sequences from 92 CRF01_AE and 21 B strains was compared. Subsequently, the impact of polymorphism on resistance to therapy was studied in CRF01_AE-infected (n=29) and subtype B-infected (n=14) patients. At baseline, the differences between CRF01_AE and B strain were mainly observed in the minor mutations L10I/V, M36I and L63P/I/H (P<0.001, chi(2)). In the reverse transcriptase sequence, M41L and T215Y/S were more common in patients infected with subtype B virus (P<0.05, chi(2)). Although all patients treated with PI-based HAART had pre-existing minor mutations, a low prevalence of resistance to PIs was observed (5/43; 11.6%). Moreover, major mutations (D30N and N88D) conferring resistance to PIs were found in patients infected with subtype B strain. In conclusion, polymorphisms at the protease region may not reduce PI susceptibility during treatment. However, this study also revealed the difference in natural mutations among subtypes, which may affect the manifestation of drug resistance.

Surveillance of Genotypic Resistance Mutations in Chronic HIV-1 Treated Individuals After Completion of the National Access to Antiretroviral Program in Thailand

Background:Due to the establishment of the National Access to Antiretroviral Program for People who have AIDS (NAPHA), approximately 80,000 Thai HIV-1 infected patients received antiretroviral drugs through the NAPHA program, which was completed at the end of 2005. The development of drug resistance is required for access to ARV drugs. The objective of this study was to determine the prevalence of antiretroviral drug resistance in Thai HIV-1 treated individuals after completing the NAPHA program.Patients and Methods:Viral genotypic resistance testing was carried out for 1,880 HIV-infected patients experiencing treatment failure, who enrolled during 2000–2005. All patients were in a follow-up treatment with ARV drugs available in clinical practice. The genotype was performed with the TRUGENE HIV-1 kit to assess resistant mutations to reverse transcriptase inhibitors and to protease inhibitors.Results:The frequency of ARV drug resistance has significantly increased after the National Access To Antiretroviral Program was implemented. The reverse transcriptase genes M184V/I (919/1,880; 48.9%) and K103S/H (416/1,880; 22.1%) were the most frequent in nucleoside reverse transcriptase and non-nucleoside reverse transcriptase, respectively. In the protease genes, minor mutations or polymorphisms were found in the majority. Thymidine analogue mutations were presented and increased over time. This study showed a sharp increase in the prevalence of mutations associated with the GPO-VIR combination; nevirapine (948/1,880; 50.4%), lamivudine (889/1,880; 47.3%), and stavudine (703/1,880; 37.4%) after the program was completed.Conclusion:With the increased availability of antiretroviral therapy in a resource-constrained country, antiretroviral drug resistance should be closely monitored. HIV-1 drug resistance testing to enable the salvage therapy will remain a priority in Thailand. Furthermore, resistance testing should also become routine before prescribing treatment, and the consequences of continuing to provide a failing regimen must be considered.

A Double-Blind, Adjuvant-Controlled Trial of Human Immunodeficiency Virus Type 1 (HIV-1) Immunogen (Remune) Monotherapy in Asymptomatic, HIV-1-Infected Thai Subjects with CD4-Cell Counts of >300

ABSTRACT We examined the effect of a human immunodeficiency virus (HIV)-specific immune-based therapy in Thailand, where access to antiviral drug therapy is limited. A 40-week trial was conducted with 297 asymptomatic, HIV-infected Thai subjects with CD4-cell counts greater than 300 μl/mm3. Subjects were randomized to receive either HIV type 1 (HIV-1) immunogen (Remune; inactivated HIV-1 from which gp120 is depleted in incomplete Freunds adjuvant or adjuvant control at 0, 12, 24, and 36 weeks at five different clinical sites in Thailand. Neither group received antiviral drug therapy. The a priori primary endpoint for the trial was changes in CD4-cell counts with secondary parameters of percent changes in CD8-cell counts (percent CD4, CD8, and CD4/CD8) and body weight. Subsets of subjects were also examined for changes in plasma HIV-1 RNA levels, Western blot immunoreactivity, and HIV-1 delayed-type hypersensitivity (DTH) skin test reactivity. There was a significant difference in changes in CD4-cell counts that favored the HIV-1 immunogen-treated group compared to those for the adjuvant-treated control group (P < 0.05). On average, for HIV-1 immunogen-treated subjects CD4-cell counts increased by 84 cells by week 40, whereas the increase for the control group was 38 cells by week 40. This increase in CD4-cell count was associated with increased HIV-specific immunogenicity, as shown by Western blotting and enhanced HIV-1 DTH skin reactivity. No significant differences in adverse events were observed between the groups. The results of this trial suggest that HIV-1 immunogen is safe and significantly increases CD4-cell counts and HIV-specific immunity compared to those achieved with the adjuvant control in asymptomatic HIV-1-infected subjects not taking antiviral drugs.

Long-term follow-up of HIV-1-infected Thai patients immunized with Remune monotherapy.

Abstract Purpose: The purpose of this 2-year follow-up study was to investigate the long-term effect of Remune as monotherapy for HIV-1 infection. BACKGROUND: Participants previously enrolled in the phase II double-blind, randomized, adjuvant-controlled study of the HIV-1 Immunogen (Remune) were followed for 2 years. Open-label immunization with Remune monotherapy was given to each participant every 12 weeks. Remune, a gp 120-depleted HIV-1 that was inactivated in beta-propiolactone and irradiation, was emulsified with mineral oil (incomplete Freund’s adjuvant). Method: In Study 2101B, the effect of four doses of Remune given every 12 weeks over 40 weeks was compared to placebo in 297 asymptomatic type E HIV-infected patients [Churdboonchart et al., 2000]. A group of 17 volunteers were separated into a subset study and another 57 were excluded from analysis due to discontinuation or addition of other treatments. This 2-year follow-up study continued with open-label dosing of HIV-1 Immunogen every 12 weeks for the remaining 223 patients. Changes in CD4+ cells, CD8+ cells, and body weight were monitored at each patient visit. Results: Overall, immunizations were safe; common adverse events were tolerable injection site reactions. CD4+ T-cell counts remained stable over the 132-week observation period for this cohort with a slight increase of 36.01 cells/μL. CD8+ T-cell counts showed an increase from baseline uring the follow-up period (415.21 cells/μL). Furthermore, we also observed an increase in body weight from baseline (1.08 kg) at week 132. In addition, baseline CD4 count appeared to predict CD4 count at week 132 (slope = 0.31, p < .0001). Conclusion: These results suggest that long-term treatment of HIV-1 infection with Remune monotherapy is safe and results in a stabilization of CD4+ counts. Furthermore, it is likely that HIV-1 therapeutic immunization may show its greatest clinical benefit in participants with higher CD4+ cell counts. Such an approach may have important ramifications in developing countries where access to antiviral drugs is limited and also in early chronic HIV-1 infection when CD4+ cells are still over 300 cells/μL in order to limit the cost and toxicity.