The Impact of Combination Antiretroviral Therapy and its Interruption on Anxiety, Stress, Depression and Quality of Life in Thai Patients

OBJECTIVE: Investigation on anxiety, stress, depression, and quality of life (QoL) within STACCATO, a randomised trial of two treatment strategies: CD4 guided scheduled treatment interruption (STI) compared to continuous treatment (CT). PARTICIPANTS: Thai patients with HIV-infection enrolled in the STACCATO trial. METHODS: Anxiety, depression assessed by the questionnaires Hospital Anxiety and Depression Scale (HADS) and DASS, stress assessed by the Depression Anxiety Stress Scale (DASS), and QoL evaluated by the HIV Medical Outcome Study (MOS-HIV) questionnaires. Answers to questionnaires were evaluated at 4 time-points: baseline, 24 weeks, 48 weeks and at the end of STACCATO. RESULTS: A total of 251 patients answered the HADS/DASS and 241 answered the MOS-HIV of the 379 Thai patients enrolled into STACCATO (66.2 and 63.6% respectively). At baseline 16.3% and 7.2% of patients reported anxiety and depression using HADS scale. Using the DASS scale, 35.1% reported mild to moderate and 9.6% reported severe anxiety; 8.8% reported mild to moderate and 2.0% reported severe depression; 42.6% reported mild to moderate and 4.8% reported severe stress. We showed a significant improvement of the MHS across time (p=0.001), but no difference between arms (p=0.17). The summarized physical health status score (PHS) did not change during the trial (p=0.15) nor between arm (p=0.45). There was no change of MHS or PHS in the STI arm, taking into account the number of STI cycle (p=0.30 and 0.57) but MHS significant increased across time-points (p=0.007). CONCLUSION: Antiretroviral therapy improved mental health and QOL, irrespective of the treatment strategy

HIV protease inhibitor resistance

HIV protease is pivotal in the viral replication cycle and directs the formation of mature infectious virus particles. The development of highly specific HIV protease inhibitors (PIs), based on thorough understanding of the structure of HIV protease and its substrate, serves as a prime example of structure-based drug design. The introduction of first-generation PIs marked the start of combination antiretroviral therapy. However, low bioavailability, high pill burden, and toxicity ultimately reduced adherence and limited long-term viral inhibition. Therapy failure was often associated with multiple protease inhibitor resistance mutations, both in the viral protease and its substrate (HIV gag protein), displaying a broad spectrum of resistance mechanisms. Unfortunately, selection of protease inhibitor resistance mutations often resulted in cross-resistance to other PIs. Therefore, second-generation approaches were imperative. Coadministration of a cytochrome P-450 3A4 inhibitor greatly improved the plasma concentration of PIs in the patient. A second advance was the development of PIs that were efficacious against first-generation PI-resistant HIV. Both approaches increased the number of protease mutations required by the virus to develop clinically relevant resistance, thereby raising the genetic barrier towards PI resistance. These improvements greatly contributed to the success of PI-based therapy

HIV protease inhibitor resistance

HIV protease is pivotal in the viral replication cycle and directs the formation of mature infectious virus particles. The development of highly specific HIV protease inhibitors (PIs), based on thorough understanding of the structure of HIV protease and its substrate, serves as a prime example of structure-based drug design. The introduction of first-generation PIs marked the start of combination antiretroviral therapy. However, low bioavailability, high pill burden, and toxicity ultimately reduced adherence and limited long-term viral inhibition. Therapy failure was often associated with multiple protease inhibitor resistance mutations, both in the viral protease and its substrate (HIV gag protein), displaying a broad spectrum of resistance mechanisms. Unfortunately, selection of protease inhibitor resistance mutations often resulted in cross-resistance to other PIs. Therefore, second-generation approaches were imperative. Coadministration of a cytochrome P-450 3A4 inhibitor greatly improved the plasma concentration of PIs in the patient. A second advance was the development of PIs that were efficacious against first-generation PI-resistant HIV. Both approaches increased the number of protease mutations required by the virus to develop clinically relevant resistance, thereby raising the genetic barrier towards PI resistance. These improvements greatly contributed to the success of PI-based therapy