Risk if ART is deferred is taken from [328]. The predicted 6-month risk if ART is initiated is based on the assumption that the rate with immediate therapy initiation is one-third the rate without therapy initiation. This (probably conservative) value is based on considering evidence from multiple sources, including references [32,[329][330][331][332][333].BHIVA treatment guidelines 569 r 2008 British HIV Association HIV Medicine (2008) 9, 563-608 but high CD4 percentages, but also may support a decision to start therapy earlier in patients with absolute CD4 counts 4350 cells/mL but with low CD4 percentages {e.g. o14%, where Pneumocystis carinii pneumonia (PCP) prophylaxis is indicated [35]; some studies have indicated increased risk of disease progression in patients with CD4 percentages o15-17% [36]}. Patients with a CD4 count 4350 cells/mLAs detailed above, at CD4 counts 4350 cells/mL, multiple cohort studies have suggested that there might be benefits to ART. This is supported by data from the substudy of patients not on therapy at entry to the SMART study [32]. Some of the previous concerns about earlier initiation of therapy have been reduced because of the availability of simpler, less toxic and better tolerated antiretroviral regimens, improved pharmacokinetic profiles and increasing options after virological failure. For the majority of patients, the absolute risk of deferring therapy until the CD4 count is o350 cells/mL is likely to be low, but in a subgroup at particularly high risk of clinical events that may be preventable by ART, this is not the case. For all these reasons, in a small number of patients, treatment may be started or considered before the CD4 count is below 350 cells/mL, including the following: AIDS diagnosis (e.g. Kaposi's sarcoma); any HIV-related comorbidity; hepatitis B infection, where treatment of hepatitis B is indicated (see hepatitis guidelines); hepatitis C infection in some cases, where treatment for hepatitis is deferred; low CD4 percentage (e.g. o14%, where PCP prophylaxis would be indicated); established CVD or a very high risk of cardiovascular events (e.g. Framingham risk of CVD 420% over 10 years).Additionally, it is likely that successful antiretroviral treatment, by reducing viral load, reduces infectivity irrespective of the current CD4 cell count, and this may be taken into account in deciding on the timing of starting treatment, particularly in discordant couples where the infected partner has a high viral load. This is likely to be an issue in a very small number of patients, and it must be stressed that antiretroviral treatment in this context would be an adjunct rather than an alternative to safer sex.In patients who do not have an AIDS diagnosis or coinfection with hepatitis B or C virus, and whose CD4 counts are above 500 cells/mL, the benefits of starting therapy remain unclear, the risk of deferring therapy is low, and we recommend that they consider enrolment in the START study, where this is an option. ComorbiditiesWhilst it has been clearly shown that...

This trial assessed the rate of virological failure at 48 weeks in adult human immunodeficiency virus (HIV) type 1-infected patients assigned indinavir/ritonavir (Idv/Rtv; 800/100 mg 2 times daily) or saquinavir/ritonavir (Sqv/Rtv; 1000/100 mg 2 times daily) in an open-label, randomized (1:1), multicenter, phase 4 design. Three hundred six patients began the assigned treatment. At 48 weeks, virological failure was seen in 43 (27%) of 158 and 37 (25%) of 148 patients in the Idv/Rtv and Sqv/Rtv arms, respectively. The time to virological failure did not differ between study arms (P=.76). When switching from randomized treatment was counted as failure, this was seen in 78 of 158 patients in the Idv/Rtv arm, versus 51 of 148 patients in the Sqv/Rtv arm (P=.009). A switch from the randomized treatment occurred in 64 (41%) of 158 patients in the Idv/Rtv arm, versus 40 (27%) of 148 patients in the Sqv/Rtv arm (P=.013). Sixty-four percent of the switches occurred because of adverse events. A greater number of treatment-limiting adverse events were observed in the Idv/Rtv arm, relative to the Sqv/Rtv arm. In conclusion, Rtv-boosed Sqv and Idv were found to have comparable antiretroviral effects in the doses studied.

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Patients with IV > 400 copies/ml are three times more likely to experience sustained viral rebound and to have an impaired CD4 cell rise relative to those who maintain undetectable VL. This supports the adoption of a more pro-active approach to treatment intensification and the need for caution with structured treatment interruptions.

Intracellular accumulation of the protease inhibitors (PIs) saquinavir (SQV), ritonavir (RTV), and indinavir (IDV) was determined in 50 human immunodeficiency virus-positive patients. Following extraction, PIs were quantified by mass spectrometry. Paired plasma and intracellular samples were collected over a full dosing interval from patients (13 on SQV, 6 on RTV, 8 on IDV, 16 on SQV plus RTV, 7 on IDV plus RTV) with a plasma viral load of <400 copies/ml. Data were expressed as intracellular/plasma drug concentration ratios. A hierarchy of intracellular accumulation was demonstrated by the following medians: 9.45 for SQV > 1.00 for RTV > 0.51 for IDV. Coadministration of RTV did not boost ratios of SQV or IDV within the cell or in plasma, although absolute plasma and intracellular SQV concentrations were increased by RTV. Seven individuals receiving SQV in hard-gel capsule form (median, 32 months) had higher intracellular/plasma drug ratios than all other patients receiving SQV (median, 17.62 versus 4.83; P ‫؍‬ 0.04), despite consistently low plasma SQV concentrations. How this occurs may provide insight into the mechanisms that limit adequate drug penetration into sanctuary sites.The failure to achieve and maintain suppression of human immunodeficiency virus (HIV) replication is emerging as a major problem in antiretroviral therapy (ART). One large cohort study has recently reported a mean time before virological failure on first-ART-regimen drugs of 12 months but with markedly decreasing durability for each successive regimen (F. Palella, J. Chmiel, M. Deloria-Knoll, A. Moorman, S. Holmberg, and the HIV Outpatient Investigators, 8th Conf. Retrovir. Opportunistic Infect., abstr. 268B, 2001). Treatment failure is multifactorial and includes viral resistance, poor adherence, and pharmacological and host factors. Much interest has been generated by potential pharmacological mechanisms of failure. HIV replicates within cells; therefore, drugs must penetrate intracellularly at concentrations sufficient to inhibit viral replication. Failure to do so results in the establishment of a sanctuary site where virus may evolve in the absence of selection pressure from the drug (22) or where subtherapeutic levels generate drug-resistant virus with subsequent "seeding" into plasma. Virus from sanctuary sites, such as the central nervous system and seminal fluid, can exhibit genotypic resistance profiles, which differ from peripheral blood isolates (6, 21). Pharmacological studies that examine the cellular and tissue penetration of HIV drugs are crucial to the understanding of sanctuary sites and the subsequent evolution of drug resistance and the failure of ART. This understanding may inform the design of strategies to maximize drug potency. In particular, the roles of cellular efflux transporters such as the P-glycoprotein (P-gp) in limiting the intracellular penetration of drugs and the potential for ritonavir (RTV) to boost intracellular drug accumulation within sanctuary sites deserve further investigation.We have previou...

SummaryBackground Present combination antiretroviral therapy (cART) alone does not cure HIV infection and requires lifelong drug treatment. The potential role of HIV therapeutic vaccines as part of an HIV cure is under consideration. Our aim was to assess the effi cacy, safety, and immunogenicity of Vacc-4x, a peptide-based HIV-1 therapeutic vaccine targeting conserved domains on p24Gag , in adults infected with HIV-1.

Low levels of vitamin D are reported in HIV-infected individuals. In HIV-negative people, low vitamin D levels have been associated with an increased risk of cardiovascular disease and cancer and with worse survival. The MONET trial recruited 256 European patients with HIV RNA <50 copies/ml at screening, while taking either NNRTI- or PI-based HAART. Patients were switched to DRV/r 800/100 mg once daily, either as monotherapy or with two NRTIs. In all, 221 patients were measured for 25-hydroxyvitamin D at a central laboratory before randomized treatment started and at week 96. Multiple regression was used to correlate vitamin D levels with gender, season, ethnic group, treatment group, and use of antiretrovirals. Overall, 80% of patients were male and 91% were white, with a mean age of 44 years. At screening, 170/221 (77%) patients had vitamin D deficiency (<50 nmol/liter). At the screening visit, lower vitamin D levels were significantly associated with calendar month (p = 0.0067), black ethnicity (p = 0.013), use of efavirenz (p = 0.0062), and use of zidovudine (p = 0.015). Mean vitamin D levels were lowest from January to April (mean = 35.8 nmol/liter) and highest in September (mean = 45.4 nmol/liter). Increases in vitamin D between screening and week 96 were significantly greater for patients who discontinued efavirenz or zidovudine before the MONET trial versus those who stopped other antiretrovirals. At screening, lower vitamin D levels were associated with season, race, and use of efavirenz and/or zidovudine. Switching from efavirenz and/or zidovudine to darunavir/ritonavir during the trial led to increases in vitamin D levels. Routine screening of HIV-positive patients for vitamin D should be considered and the optimal management further defined.

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