MacArthur RD, Novak RM, Peng G, Chen L, Xiang Y, Hullsiek KH, et al. A comparison of three highly active antiretroviral treatment strategies consisting of nonnucleoside reverse transcriptase inhibitors, protease inhibitors, or both in the presence of nucleoside reverse transcriptase inhibitors as initial therapy (CPCRA 058 FIRST Study): a long-term randomised trial
Long-term data from randomised trials on the consequences of treatment with a protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or both are lacking. Here, we report results from the FIRST trial, which compared initial treatment strategies for clinical, immunological, and virological outcomes.
Between 1999 and 2002, 1397 antiretroviral-treatment-naive patients, presenting at 18 clinical trial units with 80 research sites in the USA, were randomly assigned in a ratio of 1:1:1 to a protease inhibitor (PI) strategy (PI plus nucleoside reverse transcriptase inhibitor [NRTI]; n=470), a non-nucleoside reverse transcriptase inhibitor (NNRTI) strategy (NNRTI plus NRTI; n=463), or a three-class strategy (PI plus NNRTI plus NRTI; n=464). Primary endpoints were a composite of an AIDS-defining event, death, or CD4 cell count decline to less than 200 cells per mm3 for the PI versus NNRTI comparison, and average change in CD4 cell count at or after 32 months for the three-class versus combined two-class comparison. Analyses were by intention-to-treat. This study is registered ClinicalTrials.gov, number NCT00000922.
1397 patients were assessed for the composite endpoint. A total of 388 participants developed the composite endpoint, 302 developed AIDS or died, and 188 died. NNRTI versus PI hazard ratios (HRs) for the composite endpoint, for AIDS or death, for death, and for virological failure were 1.02 (95% CI 0.79-1.31), 1.07 (0.80-1.41), 0.95 (0.66-1.37), and 0.66 (0.56-0.78), respectively. 1196 patients were assessed for the three-class versus combined two-class primary endpoint. Mean change in CD4 cell count at or after 32 months was +234 cells per mm3 and +227 cells per mm3 for the three-class and the combined two-class strategies (p=0.62), respectively. HRs (three-class vs combined two-class) for AIDS or death and virological failure were 1.15 (0.91-1.45) and 0.87 (0.75-1.00), respectively. HRs (three-class vs combined two-class) for AIDS or death were similar for participants with baseline CD4 cell counts of 200 cells per mm3 or less and of more than 200 cells per mm3 (p=0.38 for interaction), and for participants with baseline HIV RNA concentrations less than 100 000 copies per mL and 100,000 copies per mL or more (p=0.26 for interaction). Participants assigned the three-class strategy were significantly more likely to discontinue treatment because of toxic effects than were those assigned to the two-class strategies (HR 1.58; p<0.0001).
Initial treatment with either an NNRTI-based regimen or a PI-based regimen, but not both together, is a good strategy for long-term antiretroviral management in treatment-naive patients with HIV.
"The role of genetics has been emphasized by several authors: the stimulation of C-C chemokine receptor type 5 (CCR5) on CD4+ T-cell surface has been associated with T-cell activation ; in subjects carrying a CCR5 polymorphism, determining CD4+ T-cell activation, the polymorphism has been found to be predictive of immunologic response . Multiple studies reported that patients receiving PI-based regimens had a better T-cell recovery [59–62], possibly because PIs may restore T-cell proliferative responses  and activate antiapoptotic pathways . The administration of other antiretroviral drugs has been reported to have a deleterious effect on CD4+ T-cell gain: AZT, for instance, has been shown to be toxic for hematopoietic progenitors , didanosine to block T-cell proliferation and differentiation . "
[Show abstract][Hide abstract] ABSTRACT: HAART has significantly changed the natural history of HIV infection: patients receiving antiretrovirals are usually able to control viremia, even though not all virological responders adequately recover their CD4+ count. The reasons for poor immune restoration are only partially known and they include genetic, demographic and immunologic factors. A crucial element affecting immune recovery is immune activation, related to residual viremia; indeed, a suboptimal virological control (i.e., low levels of plasma HIV RNA) has been related with higher levels of chronic inflammation and all-cause mortality. The sources of residual viremia are not yet completely known, even though the most important one is represented by latently infected cells. Several methods, including 2-LTR HIV DNA and unspliced HIV RNA measurement, have been developed to estimate residual viremia and predict the outcome of antiretroviral therapy. Considering that poor immunologic responders are exposed to a higher risk of both AIDS-related and non-AIDS-related diseases, there is a need of new therapeutic strategies, including immunomodulators and drugs targeting the latent viral reservoirs, in order to face residual viremia but also to "drive" the host immunologic responses.
"As highly active antiretroviral therapy (HAART) has been developed from 1996, many studies have found that the increase in life expectancy and the decrease in mortality were directly associated with the use of ART (Borrell et al. 2006; MacArthur et al. 2006; Lima et al. 2007). In most developing countries, HAART began in the early 2000s and was scaled up by public health approach since 2003 when WHO launched the '3 · 5' project. "
[Show abstract][Hide abstract] ABSTRACT: To evaluate HIV drug resistance (HIVDR) among Chinese patients with HIV receiving first-line highly active antiretroviral therapy (HAART).
Based on the WHO HIVDR surveys, a prospective cohort study with 12-month follow-up was conducted to estimate the prevalence of HIV RNA<1000 copies/ml and HIVDR.
A total of 341 study subjects naïve to prior antiretroviral therapy (ART) were followed up for a median of 12.1 months. The overall mortality rate was 9.9 per 100 person-years. The median of CD4 counts increased from 182 cells/mm(3) at baseline to 268 cells/mm(3) at 12 months (P<0.0001). Of patients with plasma HIV-1 RNA concentrations ≥1000 copies/ml at 12 months, the proportions of resistance to non-nucleoside reverse transcriptase drugs, nucleoside/nucleotide reverse transcriptase inhibitors, and protease inhibitor drugs were 34.2%, 23.7% and 0%, respectively. The overall proportion of HIV RNA<1000 copies/ml was 85.7% at 12 months. Occupation of farmer (AOR=0.3, 95% CI: 0.08, 0.94; P=0.0393) and HAART counselling and instruction through telephone (AOR=2.8, 95% CI: 1.4, 5.6; P=0.0047) were significantly associated with HIV RNA<1000 copies/ml.
Our study demonstrated that the community-based ART had significant effects on viral suppression and immune recovery. HIVDR should be monitored in the long term to guide informed decisions on preventing HIVDR and choices of first- and second-line regimens.
Tropical Medicine & International Health 11/2010; 15(11):1357-63. DOI:10.1111/j.1365-3156.2010.02621.x · 2.33 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.