Michael A. Horberg

Effect of Early versus Deferred Antiretroviral Therapy for HIV on Survival

BACKGROUND The optimal time for the initiation of antiretroviral therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection is uncertain. METHODS We conducted two parallel analyses involving a total of 17,517 asymptomatic patients with HIV infection in the United States and Canada who received medical care during the period from 1996 through 2005. None of the patients had undergone previous antiretroviral therapy. In each group, we stratified the patients according to the CD4+ count (351 to 500 cells per cubic millimeter or >500 cells per cubic millimeter) at the initiation of antiretroviral therapy. In each group, we compared the relative risk of death for patients who initiated therapy when the CD4+ count was above each of the two thresholds of interest (early-therapy group) with that of patients who deferred therapy until the CD4+ count fell below these thresholds (deferred-therapy group). RESULTS In the first analysis, which involved 8362 patients, 2084 (25%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimeter, and 6278 (75%) deferred therapy. After adjustment for calendar year, cohort of patients, and demographic and clinical characteristics, among patients in the deferred-therapy group there was an increase in the risk of death of 69%, as compared with that in the early-therapy group (relative risk in the deferred-therapy group, 1.69; 95% confidence interval [CI], 1.26 to 2.26; P<0.001). In the second analysis involving 9155 patients, 2220 (24%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimeter and 6935 (76%) deferred therapy. Among patients in the deferred-therapy group, there was an increase in the risk of death of 94% (relative risk, 1.94; 95% CI, 1.37 to 2.79; P<0.001). CONCLUSIONS The early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds significantly improved survival, as compared with deferred therapy.

Primary Care Guidelines for the Management of Persons Infected With HIV: 2013 Update by the HIV Medicine Association of the Infectious Diseases Society of America

Evidence-based guidelines for the management of persons infected with human immunodeficiency virus (HIV) were prepared by an expert panel of the HIV Medicine Association of the Infectious Diseases Society of America. These updated guidelines replace those published in 2009. The guidelines are intended for use by healthcare providers who care for HIV-infected patients. Since 2009, new antiretroviral drugs and classes have become available, and the prognosis of persons with HIV infection continues to improve. However, with fewer complications and increased survival, HIV-infected persons are increasingly developing common health problems that also affect the general population. Some of these conditions may be related to HIV infection itself or its treatment. HIV-infected persons should be managed and monitored for all relevant age- and sex-specific health problems. New information based on publications from the period 2009-2013 has been incorporated into this document.

HIV INFECTION AND THE RISK OF CANCERS WITH AND WITHOUT A KNOWN INFECTIOUS CAUSE

Objective:To evaluate the risk of cancers with and without a known infectious cause in HIV-infected persons. Design:Retrospective cohort study. Methods:Adult HIV-infected and matched HIV-uninfected members of Kaiser Permanente followed between 1996 and 2007 for incident AIDS-defining cancers (ADCs), infection-related non-AIDS-defining cancers (NADCs; anal squamous cell, vagina/vulva, Hodgkins lymphoma, penis, liver, human papillomavirus-related oral cavity/pharynx, stomach) and infection-unrelated NADC (all other NADCs). Results:We identified 20 277 HIV-infected and 202 313 HIV-uninfected persons. HIV-infected persons experienced 552 ADC, 221 infection-related NADC, and 388 infection-unrelated NADC. HIV-uninfected persons experienced 179 ADC, 284 infection-related NADC, and 3418 infection-unrelated NADC. The rate ratio comparing HIV-infected and HIV-uninfected persons for ADC was 37.7 [95% confidence interval (CI): 31.7–44.8], with decreases in the rate ratio over time (P < 0.001). The rate ratio for infection-related NADC was 9.2 (95% CI: 7.7–11.1), also with decreases in the rate ratio over time (P < 0.001). These results were largely influenced by anal squamous cell cancer and Hodgkins lymphoma. The rate ratio for infection-unrelated NADC was 1.3 (95% CI: 1.2–1.4), with no change in the rate ratio over time (P = 0.44). Among infection-unrelated NADCs, other anal, skin, other head and neck, and lung cancer rates were higher and prostate cancer rates lower in HIV-infected persons. Among all infection-unrelated NADCs, the rate ratio decreased over time only for lung cancer (P = 0.007). Conclusion:In comparison with those without HIV infection, HIV-infected persons are at particular risk for cancers with a known infectious cause, although the higher risk has decreased in the antiretroviral therapy era. Cancers without a known infectious cause are modestly increased in HIV-infected persons compared with HIV-uninfected persons.

Effects of depression and selective serotonin reuptake inhibitor use on adherence to highly active antiretroviral therapy and on clinical outcomes in HIV-infected patients.

Objectives:To determine the impact of depression on highly active antiretroviral therapy (HAART) adherence and clinical measures and investigate if selective serotonin reuptake inhibitors (SSRIs) improve these measures. Design:Retrospective cohort study. Methods:In 2 large health maintenance organizations, we measured the effects of depression (with and without SSRI use) on adherence and changes in viral and immunologic control among HIV-infected patients starting a new HAART regimen. HAART adherence, HIV RNA levels, and changes in CD4 T-cell counts through 12 months were measured. Results:A total of 3359 patients were evaluated; 42% had a depression diagnosis, and 15% used SSRIs during HAART. Depression without SSRI use was associated with significantly decreased odds of achieving ≥90% adherence to HAART (odds ratio [OR] = 0.81, 95% confidence interval [CI]: 0.70 to 0.98; P = 0.03). Depression was associated with significantly lower odds of an HIV RNA level <500 copies/mL (OR = 0.77, 95% CI: 0.62 to 0.95; P = 0.02). Depressed patients compliant with SSRI medication (>80% adherence to SSRI) had HAART adherence and viral control statistically similar to nondepressed HIV-infected patients taking HAART. Comparing depressed with nondepressed HIV-infected patients, CD4 T-cell responses were statistically similar; among depressed patients, those compliant with SSRI had statistically greater increases in CD4 cell responses. Conclusions:Depression significantly worsens HAART adherence and HIV viral control. Compliant SSRI use is associated with improved HIV adherence and laboratory parameters.

Late Presentation for Human Immunodeficiency Virus Care in the United States and Canada

BACKGROUND. Initiatives to improve early detection and access to human immunodeficiency virus (HIV) services have increased over time. We assessed the immune status of patients at initial presentation for HIV care from 1997 to 2007 in 13 US and Canadian clinical cohorts. METHODS. We analyzed data from 44,491 HIV-infected patients enrolled in the North American-AIDS Cohort Collaboration on Research and Design. We identified first presentation for HIV care as the time of first CD4(+) T lymphocyte (CD4) count and excluded patients who prior to this date had HIV RNA measurements, evidence of antiretroviral exposure, or a history of AIDS-defining illness. Trends in mean CD4 count (measured as cells/mm(3)) and 95% confidence intervals were determined using linear regression adjusted for age, sex, race/ethnicity, HIV transmission risk, and cohort. RESULTS. Median age at first presentation for HIV care increased over time (range, 40-43 years; P < .01), whereas the percentage of patients with injection drug use HIV transmission risk decreased (from 26% to 14%; P < .01) and heterosexual transmission risk increased (from 16% to 23%; P < .01). Median CD4 count at presentation increased from 256 cells/mm(3) (interquartile range, 96-455 cells/mm(3)) to 317 cells/mm(3) (interquartile range, 135-517 cells/mm(3)) from 1997 to 2007 (P < .01). The percentage of patients with a CD4 count > or = 350 cells/mm(3) at first presentation also increased from 1997 to 2007 (from 38% to 46%; P < .01). The estimated adjusted mean CD4 count increased at a rate of 6 cells/mm(3) per year (95% confidence interval, 5-7 cells/mm(3) per year). CONCLUSION. CD4 count at first presentation for HIV care has increased annually over the past 11 years but has remained <350 cells/mm(3), which suggests the urgent need for earlier HIV diagnosis and treatment.

HIV Infection, Immunodeficiency, Viral Replication, and the Risk of Cancer

Background: Few studies have compared cancer risk between HIV-infected individuals and a demographically similar HIV-uninfected internal comparison group, adjusting for cancer risk factors. Methods: We followed 20,775 HIV-infected and 215,158 HIV-uninfected individuals enrolled in Kaiser Permanente (KP) California for incident cancer from 1996 to 2008. Rate ratios (RR) were obtained from Poisson models comparing HIV-infected (overall and stratified by recent CD4 count and HIV RNA) with HIV-uninfected individuals, adjusted for age, sex, race/ethnicity, calendar period, KP region, smoking, alcohol/drug abuse, and overweight/obesity. Results: We observed elevated RRs for Kaposi sarcoma (KS; RR = 199; P < 0.001), non-Hodgkin lymphoma (NHL; RR = 15; P < 0.001), anal cancer (RR = 55; P < 0.001), Hodgkin lymphoma (HL; RR = 19; P < 0.001), melanoma (RR = 1.8; P = 0.001), and liver cancer (RR = 1.8; P = 0.013), a reduced RR for prostate cancer (RR = 0.8; P = 0.012), and no increased risk for oral cavity/pharynx (RR = 1.4; P = 0.14), lung (RR = 1.2; P = 0.15), or colorectal (RR = 0.9; P = 0.34) cancers. Lung and oral cavity/pharynx cancers were elevated for HIV-infected subjects in models adjusted only for demographics. KS, NHL, anal cancer, HL, and colorectal cancer had significant (P < 0.05) trends for increasing RRs with decreasing recent CD4. The RRs for lung and oral cavity/pharynx cancer were significantly elevated with CD4 < 200 cells/μL and for melanoma and liver cancer with CD4 < 500 cells/μL. Only KS and NHL were associated with HIV RNA. Conclusion: Immunodeficiency was positively associated with all cancers examined except prostate cancer among HIV-infected compared with HIV-uninfected individuals, after adjustment for several cancer risk factors. Impact: Earlier antiretroviral therapy initiation to maintain high CD4 levels might reduce the burden of cancer in this population. Cancer Epidemiol Biomarkers Prev; 20(12); 2551–9. ©2011 AACR.

Impact of tenofovir on renal function in HIV-infected, antiretroviral-naive patients.

Objective:To better characterize the long-term effects of tenofovir on renal function in a large managed care organization. Methods:We performed a retrospective cohort analysis in Kaiser Permanente for years 2002 to 2005 comparing renal function among antiretroviral naïve patients initiating a tenofovir-containing regimen (964 patients) or tenofovir-sparing regimens (683 patients). We evaluated glomerular filtration rate (GFR, [Modification of Diet in Renal Disease equation]), serum creatinine, and the development of renal proximal tubular dysfunction. We report multivariable hazard ratios (HR, Cox modeling) and linear outcomes (repeated measures) with predictors retained if P < 0.10 (backward selection). Potential predictor variables included in multivariate models were age, sex, Black race, baseline laboratories (including CD4 count), history of diabetes mellitus, hypertension, malignancy, hepatitis, and concurrent medications. Results:Overall, tenofovir-exposed patients had a larger relative decline in GFR through 104 weeks (−7.6 mL/min/1.73 m2 relative to tenofovir-sparing, P < 0.001); the degree of the difference varied by baseline GFR, with the greatest effect seen in those patients with GFR greater than 80 mL/min/1.73 m2. Tenofovir-exposed patients had greater development of proximal tubular dysfunction over time (at 52 wk: HRadjusted = 1.95 [P = 0.01] and at 104 wk: HRadjusted = 5.23 [P = 0.0004]) and had greater risk of medication discontinuation (HRadjusted = 1.21, P = 0.02), especially as renal function worsened. Viral control and CD4 count changes were similar between the two groups. Conclusions:Tenofovir is associated with greater effect on decline in renal function and a higher risk of proximal tubular dysfunction in antiretroviral naïve patients initiating antiretroviral therapy.

Executive Summary: Primary Care Guidelines for the Management of Persons Infected With HIV: 2013 Update by the HIV Medicine Association of the Infectious Diseases Society of America

Evidence-based guidelines for the management of persons infected with human immunodeficiency virus (HIV) were prepared by an expert panel of the HIV Medicine Association of the Infectious Diseases Society of America. These updated guidelines replace those published in 2009. The guidelines are intended for use by healthcare providers who care for HIV-infected patients. Since 2009, new antiretroviral drugs and classes have become available, and the prognosis of persons with HIV infection continues to improve. However, with fewer complications and increased survival, HIV-infected persons are increasingly developing common health problems that also affect the general population. Some of these conditions may be related to HIV infection itself or its treatment. HIV-infected persons should be managed and monitored for all relevant age- and sex-specific health problems. New information based on publications from the period 2009-2013 has been incorporated into this document.

HIV-1 Protease and Reverse-Transcriptase Mutations: Correlations with Antiretroviral Therapy in Subtype B Isolates and Implications for Drug-Resistance Surveillance

Background. It is important, for drug-resistance surveillance, to identify human immunodeficiency virus type 1 (HIV-1) strains that have undergone antiretroviral drug selection.Methods. We compared the prevalence of protease and reverse-transcriptase (RT) mutations in HIV-1 sequences from persons with and without previous treatment with protease inhibitors (PIs), nucleoside RT inhibitors (NRTIs), and nonnucleoside RT inhibitors (NNRTIs). Treatment-associated mutations in protease isolates from 5867 persons and RT isolates from 6247 persons were categorized by whether they were polymorphic (prevalence, >0.5%) in untreated individuals and whether they were established drug-resistance mutations. New methods were introduced to minimize misclassification from transmitted resistance, population stratification, sequencing artifacts, and multiple hypothesis testing.Results. Some 36 established and 24 additional nonpolymorphic protease mutations at 34 positions were related to PI treatment, 21 established and 22 additional nonpolymorphic RT mutations at 24 positions with NRTI treatment, and 15 established and 11 additional nonpolymorphic RT mutations at 15 positions with NNRTI treatment. In addition, 11 PI-associated and 1 NRTI-associated established mutations were polymorphic in viruses from untreated persons.Conclusions. Established drug-resistance mutations encompass only a subset of treatment-associated mutations; some of these are polymorphic in untreated persons. In contrast, nonpolymorphic treatment-associated mutations may be more sensitive and specific markers of transmitted HIV-1 drug resistance.

Predictive accuracy of the veterans aging cohort study index for mortality with HIV infection: A north american cross cohort analysis

Background:By supplementing an index composed of HIV biomarkers and age (restricted index) with measures of organ injury, the Veterans Aging Cohort Study (VACS) index more completely reflects risk of mortality. We compare the accuracy of the VACS and restricted indices (1) among subjects outside the Veterans Affairs Healthcare System, (2) more than 1–5 years of prior exposure to antiretroviral therapy (ART), and (3) within important patient subgroups. Methods:We used data from 13 cohorts in the North American AIDS Cohort Collaboration (n = 10, 835) limiting analyses to HIV-infected subjects with at least 12 months exposure to ART. Variables included demographic, laboratory (CD4 count, HIV-1 RNA, hemoglobin, platelets, aspartate and alanine transaminase, creatinine, and hepatitis C status), and survival. We used C-statistics and net reclassification improvement (NRI) to test discrimination varying prior ART exposure from 1 to 5 years. We then combined Veterans Affairs Healthcare System (n = 5066) and North American AIDS Cohort Collaboration data, fit a parametric survival model, and compared predicted to observed mortality by cohort, gender, age, race, and HIV-1 RNA level. Results:Mean follow-up was 3.3 years (655 deaths). Compared with the restricted index, the VACS index showed greater discrimination (C-statistics: 0.77 vs. 0.74; NRI: 12%; P < 0.0001). NRI was highest among those with HIV-1 RNA <500 copies per milliliter (25%) and age ≥50 years (20%). Predictions were similar to observed mortality among all subgroups. Conclusions:VACS index scores discriminate risk and translate into accurate mortality estimates over 1–5 years of exposure to ART and for diverse patient subgroups from North American.