The benefit of immediate compared with deferred antiretroviral therapy on CD4+ cell count recovery in early HIV infection.

OBJECTIVE: To assess the impact of immediate vs. deferred antiretroviral therapy (ART) on CD4 recovery among individuals early in HIV infection. DESIGN: Using serologic markers of early infection together with self-reported dates of infection and HIV diagnosis, ART-naive participants who were randomized to immediate vs. deferred ART in the Strategic Timing of Antiretroviral Treatment trial were classified into subgroups of duration of HIV infection at baseline. CD4 cell count recovery over follow-up according to duration of HIV infection was investigated. METHODS: Three subgroups were defined: first, infected 6 months or less (n = 373); second, infected 6-24 months (n = 2634); and third, infected 24 months or longer (n = 1605). Follow-up CD4, CD8, and CD4 : CD8 ratio for the immediate and deferred ART groups were compared by subgroup using linear models. For the deferred ART group, decline to CD4 less than 350 cells/µl or AIDS according to infection duration was compared using time-to-event methods. RESULTS: Follow-up CD4 cell count differences (immediate minus deferred) were greater for those recently infected (+231 cells/µl) compared with the two other subgroups (202 and 171 cells/µl; P < 0.001). CD4 : CD8 ratio treatment differences varied significantly (P < 0.001) according to duration of infection. In the deferred ART group, decline to CD4 less than 350 cells/µl or AIDS was greater among those recently infected (16.1 vs. 13.2 and 10.5 per 100 person years for those infected 6-24 and ≥24 months; P = 0.002). CONCLUSION: In this randomized comparison of immediate vs. deferred ART, the CD4 cell count difference was greatest for those recently infected with HIV, emphasizing the importance of immediate ART initiation.

Comparison of Self-report to Biomarkers of Recent HIV Infection: Findings from the START Trial.

Identifying individuals with recent HIV infection is critical to research related to viral reservoirs, outbreak investigations and intervention applications. A multi-assay algorithm (MAA) for recency of infection was used in conjunction with self-reported date of infection and documented date of diagnosis to estimate the number of participants recently infected in the Strategic Timing of AntiRetroviral Treatment (START) trial. We tested samples for three groups of participants from START using a MAA: (1) 167 individuals who reported being infected ≤ 6 months before randomization; (2) 771 individuals who did not know their date of infection but were diagnosed within 6 months before randomization; and (3) as controls for the MAA, 199 individuals diagnosed with HIV ≥ 2 years before randomization. Participants with low titer and avidity and a baseline viral load > 400 copies/mL were classified as recently infected. A significantly higher percentage of participants who self-reported being infected ≤ 6 months were classified as recently infected compared to participants diagnosed ≥ 2 years (65% [109/167] vs. 2.5% [5/199], p < 0.001). Among the 771 individuals who did not know their duration of infection at randomization, 206 (26.7%) were classified as recently infected. Among those diagnosed with HIV in the 6 months prior to enrollment, the 373 participants who reported recent infection (n = 167) or who had confirmed recent infection by the MAA (n = 206) differed significantly on a number of baseline characteristics from those who had an unknown date of infection and were not confirmed by the MAA (n = 565). Participants recently infected by self-report and/or MAA were younger, more likely to be Asian, less likely to be black, less likely to be heterosexual, more likely to be enrolled at sites in the U.S., Europe or Australia, and have higher HIV RNA levels. There was good agreement between self-report of recency of infection and the MAA. We estimate that 373 participants enrolled in START were infected within 6 months of randomization. Compared to those not recently infected, these participants were younger, had higher HIV RNA levels and were more likely to come from high income countries and from populations such as MSM with more regular HIV testing.

Nucleoside-sparing antiretroviral regimens.

Nucleoside reverse transcriptase inhibitors (NRTIs) were the first drugs approved for use as antiretroviral therapy in patients infected with HIV. Despite the introduction of other classes of antiretroviral drugs, they remain an important component of combination regimens as recommended by many treatment guidelines. They also continue to be used in prevention of disease from mother to child, postexposure prophylaxis, and more recently for preexposure prophylaxis. Unfortunately, the toxicities associated with this class of drugs can limit their use. Although NRTI-sparing regimens are not currently recommended for first-line therapy there is an increasing amount of data supporting their use in both treatment-naive and in treatment-experienced patients.

Micafungin: an evidence-based review of its place in therapy.

Invasive fungal infections have increased throughout the world. Many of these infections occur in patients with multiple comorbidities who are receiving medications with the potential for interactions with antifungal therapy that could lead to renal and hepatic dysfunction. The second marketed echinocandin, micafungin, was approved in 2005 for the treatment of esophageal candidiasis and prophylaxis of invasive Candida infections in patients undergoing hematopoietic stem cell transplantation. The indication for use was later expanded to include candidemia, acute disseminated candidiasis, Candida abscesses, and peritonitis. Like other echinocandins it is fungicidal against Candida species, including those that are polyene- and azole-resistant and fungistatic against Aspergillus species. Its formulation is by the intravenous route only and it is dosed once daily without a loading dose as 85% of the steady state concentration is achieved after three daily doses. It has a favorable tolerability profile with no significant drug interactions and does not need adjustment for renal or hepatic insufficiency.

Anidulafungin: a novel echinocandin for candida infections.

A third echinocandin, anidulafungin, has recently been approved for Candida infections in the non-neutropenic patient. In the EU it is indicated for invasive candidiasis; in 2006 it was approved in the USA for candida esophagitis, candidemia, and two types of invasive infections, peritonitis and intra-abdominal abscesses. It is fungicidal against Candida species and fungistatic against Aspergillus species. In addition to its favorable tolerability in studies to date, it does not need adjustment for renal or hepatic insufficiency and has no known drug interactions. A steady state concentration can be achieved on day 2 following a loading dose of twice the maintenance concentration on day 1, and the drug is administered intravenously once daily. Cross resistance with other classes of antifungals is not a concern as it possesses a unique mechanism of action.

Anidulafungin: a new echinocandin for candidal infections.

Anidulafungin, a new echinocandin, has recently been approved for the treatment of esophageal candidiasis, candidemia and other forms of invasive candidiasis, such as peritonitis and intra-abdominal abscesses in non-neutropenic patients. It is fungicidal against Candida spp. including those that are azole- and polyene-resistant and fungistatic against Aspergillus spp. Owing to its poor oral bioavailability it can only be administered intravenously. Its pharmacokinetics allow for once-daily dosing and a steady state concentration is easily achieved on day 2 following a loading dose of double the maintenance dose on day 1. It does not need adjustment for hepatic or renal insufficiency; there are no known drug interactions and it has a favorable tolerability profile. Its mechanism of action, which differs from other classes of antifungals, should prevent cross-resistance with azoles and polyenes.