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Background: There is persistent confusion as to whether abacavir (ABC) increases the risk of myocardial infarction (MI), and whether such risk differs by type 1 (T1MI) or 2 (T2MI) MI in adults with HIV., Methods: Incident MIs in North American Cohort Collaboration on Research and Design participants were identified from 2001 to 2013. Discrete time marginal structural models addressed channeling biases and time-dependent confounding to estimate crude hazard ratio (HR) and adjusted hazard ratio (aHR) and 95% confidence intervals; analyses were performed for T1MI and T2MI separately. A sensitivity analysis evaluated whether Framingham risk score (FRS) modified the effect of ABC on MI occurrence., Results: Eight thousand two hundred sixty-five adults who initiated antiretroviral therapy contributed 29,077 person-years and 123 MI events (65 T1MI and 58 T2MI). Median follow-up time was 2.9 (interquartile range 1.4-5.1) years. ABC initiators were more likely to have a history of injection drug use, hepatitis C virus infection, hypertension, diabetes, impaired kidney function, hyperlipidemia, low (<200 cells/mm) CD4 counts, and a history of AIDS. The risk of the combined MI outcome was greater for persons who used ABC in the previous 6 months [aHR = 1.84 (1.17-2.91)]; and persisted for T1MI (aHR = 1.62 [1.01]) and T2MI [aHR = 2.11 (1.08-4.29)]. FRS did not modify the effect of ABC on MI (P = 0.14) and inclusion of FRS in the MSM did not diminish the effect of recent ABC use on the combined outcome., Conclusions: Recent ABC use was associated with MI after adjustment for known risk factors and for FRS. However, screening for T1MI risks may not identify all or even most persons at risk of ABC use-associated MIs.

Objective: HIV infection and low CD4+ T-cell count are associated with an increased risk of persistent oncogenic human papillomavirus infection-the major risk factor for cervical cancer. Few reported prospective cohort studies have characterized the incidence of invasive cervical cancer (ICC) in HIV-infected women., Methods: Data were obtained from HIV-infected and -uninfected female participants in the North American AIDS Cohort Collaboration on Research and Design with no history of ICC at enrollment. Participants were followed from study entry or January 1996 through ICC, loss to follow-up, or December 2010. The relationship of HIV infection and CD4+ T-cell count with risk of ICC was assessed using age-adjusted Poisson regression models and standardized incidence ratios. All cases were confirmed by cancer registry records and/or pathology reports. Cervical cytology screening history was assessed through medical record abstraction., Results: A total of 13,690 HIV-infected and 12,021 HIV-uninfected women contributed 66,249 and 70,815 person-years of observation, respectively. Incident ICC was diagnosed in 17 HIV-infected and 4 HIV-uninfected women (incidence rate of 26 and 6 per 100,000 person-years, respectively). HIV-infected women with baseline CD4+ T-cells of ≥350, 200-349, and <200 cells per microliter had a 2.3, 3.0, and 7.7 times increase in ICC incidence, respectively, compared with HIV-uninfected women (P(trend) = 0.001). Of the 17 HIV-infected women, medical records for the 5 years before diagnosis showed that 6 had no documented screening, 5 had screening with low-grade or normal results, and 6 had high-grade results., Conclusions: This study found elevated incidence of ICC in HIV-infected compared with -uninfected women, and these rates increased with immunosuppression.

Background: Although combination antiretroviral therapy continues to evolve, with potentially more effective options emerging each year, the ability of therapy to prevent multiple regimen failure and mortality in clinical practice remains poorly defined., Methods: Sixteen cohorts representing over 60 sites contributed data on all individuals who initiated combination antiretroviral therapy. We identified those individuals who experienced virologic failure (defined as a human immunodeficiency virus [HIV] RNA level >1000 copies/mL), received modified therapy, and subsequently had a second episode of virologic failure. Multivariate Cox regression was used to assess factors associated with time to second regimen failure and the time to death after the onset of second regimen failure., Results: Of the 42,790 individuals who received therapy, 7159 experienced a second virologic failure. The risk of second virologic failure decreased from 1996 (56 cases per 100 person-years) through 2005 (16 cases per 100 person-years; P < .001). The cumulative mortality after onset of second virologic failure was 26% at 5 years and decreased over time. A history of AIDS, a lower CD4(+) T cell count, and a higher plasma HIV RNA level were each independently associated with mortality. Similar trends were observed when analysis was limited to the subset of previously treatment-naive patients, Conclusions: Although the rates of multiple regimen failure have decreased dramatically over the past decade, mortality rates for those who have experienced failure of at least 2 regimens have remained high. Plasma HIV RNA levels, CD4(+) T cell counts at time of treatment failure, and a history of AIDS remain independent risk factors for death, which emphasizes that these factors remain important targets for those in need of more-aggressive therapeutic interventions.

Objective: The compound (-)-2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine) is a nucleoside analogue with potent in vitro antiretroviral activity, synergy with zidovudine, activity against zidovudine-resistant isolates and minimal cytotoxicity. In early-phase studies, 3TC had a favourable pharmacokinetic profile, was well tolerated by those with HIV infection, and had a modest effect on HIV-1 p24 antigen levels. Although resistance to 3TC monotherapy develops rapidly, the activity of the drug persists. However, zidovudine-resistant virus, in which the 3TC-resistance mutation is selected for, regains phenotypic sensitivity to zidovudine. Therefore, 3TC and zidovudine are a logical combination to evaluate as initial therapy in treatment-naive HIV-1 infected individuals., Design: Two randomized controlled trials, one in Europe and one in North America, evaluated 3TC in combination with zidovudine and compared this combination to zidovudine monotherapy. In the North American study, 3TC monotherapy was also evaluated. In both studies, subjects entered having received less than 4 weeks of zidovudine therapy and no other previous antiretroviral treatments. In the European study, subjects had CD4 cell counts of 100-400/mm3 and received blinded therapy for 24 weeks; they were then offered open-label 3TC and zidovudine for a further 24-week period. In the North American study, initial patient CD4 cell counts were 200-500/mm3, and blinded treatment continued for 52 weeks. Endpoints measured included CD4 cell counts and HIV-1 RNA in plasma, in addition to clinical and laboratory adverse events., Results: In both studies, the combination of 3TC and zidovudine resulted in rises in CD4 counts of 75-85 cells/mm3 that were sustained at 48-60 cells/mm3 above base-line at 48-52 weeks. Effects on HIV-1 RNA levels in plasma also persisted through 48 and 52 weeks at approximately a 90% reduction (1 log10 decrease) from baseline. In the European study, the combination was superior to zidovudine alone over the first 24 weeks, as measured by CD4 and HIV-1 RNA effects, and the addition of 3TC to zidovudine after 24 weeks resulted in a subsequent increase in the mean CD4 count of 39 cells/mm3. In the North American study, the combination of 3TC and zidovudine was better than zidovudine monotherapy when considering the effect on CD4 cells or HIV-1 RNA through 24 weeks. When these treatment groups were compared, using an average of the mean change from baseline of the CD4 counts and HIV-1 RNA levels over that last three study time points (44, 48 and 52 weeks), the combination treatments remained superior to zidovudine alone. In neither study did the addition of 3TC to zidovudine result in additional toxicity., Summary: In two independent studies in patients with limited antiretroviral treatment experience, remarkably similar results were obtained when 3TC/zidovudine in combination was compared to zidovudine monotherapy, demonstrating sustained antiretroviral and immunological effects of the combination over the 48 and 52 weeks of study.