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You are here: HomeRecommendations for Primary Care PracticePublished RecommendationsRecommendation SummaryOther Supporting Document : Screening for HIV in Adolescents and Adults: Evidence Summary

Screening for HIV in Adolescents and Adults: Evidence Summary

Other Supporting Document for Human Immunodeficiency Virus (HIV) Infection: Screening

Preface

By Roger Chou, MD; Shelley Selph, MD, MPH; Tracy Dana, MLS; Christina Bougatsos, MPH; Bernadette Zakher, MBBS; Ian Blazina, MPH; and P. Todd Korthuis, MD, MPH.


The information in this article is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This article is intended as a reference and not as a substitute for clinical judgment.

This article may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

This article was first published in Annals of Internal Medicine on November 20, 2012 (Ann Intern Med 2012;157:706-718; http://www.annals.org). Select for copyright and source information.

Abstract

Background: A 2005 U.S. Preventive Services Task Force (USPSTF) review found good evidence that HIV screening is accurate and that antiretroviral therapy (ART) for immunologically advanced disease is associated with substantial clinical benefits, but insufficient evidence to determine the effects on transmission or in less immunologically advanced disease.

Purpose: To update the 2005 USPSTF review on benefits and harms of HIV screening in adolescents and adults, focusing on research gaps identified in the prior review.

Data Sources: MEDLINE (2004 to June 2012) and the Cochrane Library (through the second quarter of 2012).

Study Selection: Randomized trials and observational studies that compared HIV screening strategies and reported clinical outcomes, evaluated the effects of starting ART at different CD4 cell count thresholds and long-term harms, or reported the effects of interventions on transmission risk.

Data Extraction: 2 authors abstracted and checked study details and quality using predefined criteria.

Data Synthesis: No study directly evaluated the effects on clinical outcomes of screening versus no screening for HIV infection. A randomized trial and a subgroup analysis from a randomized trial found that ART initiation at CD4 counts less than 0.250 x 109 cells/L was associated with a higher risk for death or AIDS-defining events than initiation at CD4 counts greater than 0.350 x 109 cells/L (hazard ratios, 1.7 [95% CI, 1.1 to 2.5] and 5.3 [CI, 1.3 to 9.6]). Large, fair-quality cohort studies also consistently found that ART initiation at CD4 counts of 0.350 to 0.500 x 109 cells/L was associated with lower risk for death or AIDS-defining events than delayed initiation. New evidence from good-quality cohorts with longer-term follow-up confirms a previously observed small increased risk for cardiovascular events associated with certain antiretrovirals. Strong evidence from 1 good-quality randomized trial and 7 observational studies found that ART was associated with a 10- to 20-fold reduction in risk for sexual transmission of HIV.

Limitations: Only English-language articles were included. Observational studies were included. Studies done in resource-poor or high-prevalence settings were included but might have limited applicability to general screening in the United States.

Conclusion: Previous studies have shown that HIV screening is accurate, targeted screening misses a substantial proportion of cases, and treatments are effective in patients with advanced immunodeficiency. New evidence indicates that ART reduces risk for AIDS-defining events and death in persons with less advanced immunodeficiency and reduces sexual transmission of HIV.

Introduction

In 2008, an estimated 1.2 million persons in the United States were living with HIV, and approximately 1 in 5 were unaware of their status1–3. Incidence of HIV in the United States is approximately 50,000 cases per year1, 4, with an estimated 20,000 such cases believed to be due to transmission from persons who are unaware that they are infected 5, 6. Screening for HIV antibodies can detect infection in asymptomatic patients, who might benefit from interventions to reduce risk for AIDS-related clinical events and transmission.

In 2005, the U.S. Preventive Services Task Force (USPSTF) recommended screening all adolescents and adults at increased risk (defined as persons who reported HIV risk factors or were evaluated in settings with an HIV infection prevalence >1%) 7 on the basis of an earlier evidence review 8–10 that found a high yield from screening these patients, good evidence that HIV screening tests are accurate (sensitivity and specificity each >99%) and good evidence that treating HIV infection at immunologically advanced stages of disease (defined as CD4 counts <0.200 x 109 cells/L) with antiretroviral therapy (ART) markedly reduces risk for AIDS-related clinical events and death. Although the USPSTF found that ART was associated with short-term adverse events and an increased risk for long-term cardiovascular events, it determined that benefits substantially outweighed harms.

The USPSTF made no recommendation for or against screening for HIV in adolescents and adults who were not at increased risk for HIV infection7. Because of the lower prevalence of HIV infection in such persons, it determined that the benefits of screening would be smaller than in higher-risk populations. The USPSTF found insufficient evidence to estimate benefits from screening persons at less immunologically advanced stages of disease (CD4 counts >0.200 x 109 cells/L) or on the effects of screening and subsequent interventions on HIV transmission.

In 2006, the Centers for Disease Control and Prevention (CDC) issued its revised guideline11 recommending routine voluntary HIV screening of all persons aged 13 to 64 years, unless the prevalence of undiagnosed HIV infection was less than 0.1%. A key reason for this recommendation was evidence showing that 20% to 26% of patients with HIV infection report no risk factors12, suggesting that risk-based screening strategies miss an important proportion of infected persons. Other reasons for the differences between recommendations include that the CDC placed greater weight on studies showing reductions in self-reported risky behaviors after HIV diagnosis, accepted modeling studies to estimate effects of HIV diagnosis on transmission risk, and placed greater weight on modeling studies that showed acceptable incremental cost-effectiveness ratios for screening versus no screening in low-prevalence populations7.

This report updates the previous USPSTF review on HIV screening in nonpregnant adolescents and adults. It focuses on key research gaps identified in the earlier review with the potential greatest effect on assessment of benefits and harms associated with screening in persons not known to be at higher risk, including effects of screening, counseling, and ART use on HIV transmission risk; effectiveness of ART for HIV-infected persons with CD4 counts greater than 0.200 x 109 cells/L, and long-term harms of ART. The full report13 provides detailed methods and data for the review, including search strategies and evidence tables with quality ratings of individual studies. Additional key questions about various screening strategies, the effects of knowledge of HIV-positive status and use of ART on risky behaviors, and associations between viremia or risky behaviors and HIV transmission are reviewed in the full report13 but are not presented here.

Methods

We followed a standardized protocol and developed an analytic framework (Figure) that included the following key questions:

What are the benefits of universal or targeted HIV screening versus no screening in asymptomatic, nonpregnant adolescents and adults on disease transmission, morbidity, mortality, and quality of life?

What is the yield (number of new diagnoses) of HIV screening at different intervals in nonpregnant adolescents and adults?

How effective is ART for reducing transmission of HIV in nonpregnant adolescents and adults with chronic HIV infection?

How effective is behavioral counseling for reducing transmission of HIV in nonpregnant adolescents and adults with chronic HIV infection?

In asymptomatic, nonpregnant adolescents and adults with chronic HIV infection, what are the effects of initiating ART at different CD4 cell count or viral load thresholds on morbidity, mortality, and quality of life?

What are the longer-term harms associated with ART for nonpregnant adolescents and adults with chronic HIV infection?

We defined “universal” testing to mean routine testing of all persons aged 13 to 64 years, unless the prevalence of HIV infection has been documented to be less than 0.1%11 and "targeted" screening to mean routine screening of persons who have risk factors or are in high-prevalence (>1%) settings7.

Data Sources

We searched Ovid MEDLINE from 2004 to June 2012 and the Cochrane Library through the second quarter of 2012 and reviewed reference lists to identify relevant articles published in English.

Study Selection

At least 2 reviewers independently evaluated each study to determine inclusion eligibility. Papers were selected for full review if they were about HIV screening or treatments in nonpregnant adolescents and adults, were relevant to a key question, and met the predefined inclusion criteria (Appendix Table 1). For treatment interventions, we focused on ART and counseling to reduce transmission risk. Outcomes were mortality, AIDS-related events, HIV transmission risk, and long-term (defined as ≥2 years after initiation of treatment) cardiovascular harms associated with ART. We included randomized, controlled trials and cohort studies for all key questions. We also included systematic reviews published since 2010 that met all predefined quality criteria14.

Data Extraction and Quality Assessment

One investigator abstracted details about the study design, patient population, setting, screening method, interventions, analysis, follow-up, and results. A second investigator reviewed data abstraction for accuracy. Two investigators independently applied criteria developed by the USPSTF15 to rate the quality of each study as good, fair, or poor. Discrepancies were resolved by consensus.

Data Synthesis and Analysis

We assessed the aggregate internal validity (quality) of the body of evidence for each key question as good, fair, or poor by using methods developed by the USPSTF, on the basis of the number, quality, and size of studies; consistency of results among studies; and directness of evidence15. Meta-analysis was not attempted, although we reported meta-analyses from published systematic reviews that met our quality criteria.

Role of the Funding Source

This research was funded by the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the work of the USPSTF. Investigators worked with USPSTF members and AHRQ staff to develop and refine the scope, analytic framework, and key questions; resolve issues arising during the project; and finalize the report. AHRQ had no role in study selection, quality assessment, synthesis, or development of conclusions. AHRQ provided project oversight; reviewed the draft report; and distributed the draft for peer review, including to representatives of professional societies and federal agencies. AHRQ performed a final review of the manuscript to ensure that the analysis met methodological standards. The investigators are solely responsible for the content and the decision to submit the manuscript for publication.

Results

The Appendix Figure shows the results of the search and study selection process.

Clinical Benefits of Universal or Targeted Screening

No randomized trial or observational study compared clinical outcomes between adults and adolescents screened and not screened for HIV infection.

Yield of HIV Screening at Different Intervals

No randomized trial or observational study evaluated the yield of repeated HIV screening compared with 1-time screening or compared the yield of different strategies for repeated screening (such as risk-based repeated screening vs. a routinely repeated test).

Effectiveness of ART for Reducing HIV Transmission

A good-quality systematic review16 evaluated the association between use of ART and risk for HIV transmission from HIV-positive persons to uninfected sexual partners. It included 1 good-quality randomized, controlled trial17 and 7 observational studies18–24 (Appendix Table 2).

The randomized, controlled trial (HIV Prevention Trials Network study 052) compared early ART initiation (started at enrollment) with delayed therapy (after CD4 count decreased to <0.250 x 109 cells/L or onset of symptoms) in HIV-infected patients with baseline CD4 counts of 0.350 to 0.550 x 109 cells/L and an HIV-negative partner 17. Fifty-four percent of the 1763 couples were from Africa, with the remainder from Brazil, India, Thailand, and the United States. Ninety-seven percent of couples were heterosexual, and 94% were married. All couples received condoms and counseling. The trial was designed to follow patients for 5 years but was terminated early after meeting prespecified criteria for efficacy in interim analyses. At a median follow-up of 1.7 years, risk for seroconversion in HIV-negative partners was much lower in the early-therapy group than in the delayed-therapy group (0.3 vs. 2.2 per 100 person-years; hazard ratio [HR], 0.11 [95% CI, 0.04 to 0.32]). When restricted to cases that were genomically linked to the HIV-infected patient enrolled in the trial, the HR was 0.04 (CI, 0.01 to 0.27).

Results of the 7 observational studies18–24 included in the systematic revie 16 were consistent with the randomized trial17. Sample sizes ranged from 93 to 3408 couples, with typical follow-up between 1 and 3 years (range, 3 months to 9 years). All were cohort studies of HIV-serodiscordant, heterosexual couples from Africa, Italy, Spain, Brazil, or China. Six studies18–22, 24 were rated fair-quality and the seventh23 was a conference abstract. Three studies19, 21, 24 adjusted for possible confounding variables, such as age, sex, condom use, or frequency of sexual intercourse.

Six18–23 of the 7 observational studies reported that persons receiving ART had a lower risk for HIV transmission than untreated persons, for a pooled HR of 0.34 (CI, 0.13 to 0.92; I2 = 73%)16. Exclusion of 1 study with inadequate person-time data24 and 1 older study that included persons treated with monotherapy21 resulted in a pooled HR of 0.16 (CI, 0.07 to 0.35) and eliminated statistical heterogeneity (I2 = 0%). The treatment effect was also more pronounced when the analysis was restricted to couples in which the HIV-infected person had a CD4 count less than 0.200 x 109 cells/L (pooled HR, 0.06 [CI, 0.01 to 0.54])18–20, 22.

Effectiveness of Behavioral Counseling for Reducing Transmission

The previous USPSTF review8–10 found no randomized trials or controlled observational studies on the effects of counseling HIV-positive persons about risky behaviors on HIV transmission risk.

There remains little direct evidence on the effects of testing and counseling about risky behaviors on HIV transmission. Two studies on effects of counseling regarding sexual behaviors in HIV serodiscordant couples25, 26 were not designed to assess effects on transmission rates and were severely underpowered (5 new HIV diagnoses were observed in each study). No study estimated the effects of counseling HIV-positive persons about injection drug use behaviors on transmission rates.

Effectiveness of Initiating ART at Different CD4 Cell Count Thresholds on Clinical Outcomes

The previous USPSTF review included good-quality randomized, controlled trials27–29 and observational studies30–37 that consistently found a lower risk for AIDS events and death with ART than with placebo or less-intensive regimens in patients with CD4 counts less than 0.200 x 109 cells/L. Evidence showing benefits of starting ART at higher CD4 cell counts was limited. Although a Swiss cohort study38 found that starting ART at CD4 counts greater than 0.350 x 109 cells/L was associated with a lower risk for death and progression to AIDS than starting at less than 0.350 x 109 cells/L, 3 U.S. cohort studies35–37 found no difference in risk between starting ART at CD4 counts between 0.350 and 0.500 x 109 cells/L versus delaying until CD4 counts were between 0.200 and 0.350 x 109 cells/L.

Two good-quality randomized trials17, 39 published since the previous USPSTF review and 1 subgroup analysis40 from another randomized trial evaluated the effects of initiating ART at different CD4 cell count thresholds (Table 1). Five observational studies (reported in 7 publications)41–45, 48, 49, each of which combined data from 12 to 23 U.S., European, and Australian cohorts (ranging from 9000 to >60,000 participants and 2- to 5-year follow-up, with substantial overlap in the cohorts included in the studies), also evaluated the effects of starting ART at different CD4 cell count thresholds (Table 1). All of the observational studies were rated fair-quality. None reported blinding of outcome assessors or persons analyzing data, and attrition rates were often not reported or were unclear. Although all studies adjusted for confounders, most provided insufficient information to determine baseline comparability of patients starting or not starting ART at different CD4 cell count strata.

A retrospective subgroup analysis of 477 patients in the SMART (Strategies for Management of Antiretroviral Therapy) randomized trial who were treatment-naive or had stopped therapy for at least 6 months found that ART initiation at CD4 counts less than 0.250 x 109 cells/L was associated with a higher risk for death or AIDS events than initiation at counts greater than 0.350 x 109 cells/L after a mean of 18 months (HR, 5.3 [CI, 1.3 to 9.6]40. The SMART trial was done in 33 primarily non–resource-poor countries. The HIV Prevention Trials Network study 052, conducted in 1763 patients from primarily resource-poor countries, also found initiation at CD4 counts less than 0.250 x 109 cells/L associated with a higher risk for death or AIDS events than initiation at counts greater than 0.350 x 109 cells/L after a median of 1.7 years (HR, 1.7 [CI, 1.1 to 2.5]) 17. Another randomized trial39 with 816 participants found that ART initiation at CD4 counts less than 0.200 x 109 cells/L was associated with higher mortality than initiation at 0.201 to 0.350 x 109 cells/L (HR, 4.0 [CI, 1.6 to 9.8]; P = 0.001), but this trial was conducted in Haiti and evaluated lower CD4 count cutoffs for treatment than those in the United States.

Four observational studies42–45, 48 consistently found that ART initiation at CD4 counts between 0.350 and 0.500 x 109 cells/L was associated with a lower risk for death than deferred or no ART. One other study49 found a reduction in risk that was not statistically significant. The HIV-CAUSAL (HIV Cohorts Analyzed Using Structural Approaches to Longitudinal data) collaboration43, the largest study in our review (62,760 participants from 12 cohorts), found that ART initiation at CD4 counts of 0.350 to 0.500 x 109 cells/L was associated with a lower risk for death than noninitiation at these counts after 3.3 years of follow-up (adjusted HR, 0.55 [CI, 0.41 to 0.74]). Similarly, the NA-ACCORD (North American AIDS Cohort Collaboration on Research and Design),44 with 17,517 participants from 22 cohorts, found that ART initiation at CD4 counts of 0.351 to 0.500 x 109 cells/L was associated with a lower risk for death than deferred treatment at these CD4 cell counts after 3 years of follow-up (adjusted RR, 0.61 [CI, 0.46 to 0.83]). In 2 studies45, 49, ART initiation at CD4 counts greater than 0.350 x 109 cells/L was also associated with a lower risk for the combined outcome of AIDS-defining events and death than deferred or no ART initiation. One other study48 and a reduction in risk that was not statistically significant.

Studies on ART initiation at CD4 counts greater than 0.500 x 109 cells/L were less consistent. The NA-ACCORD cohort study44 found that ART initiation at CD4 counts greater than 0.500 x 109 cells/L was associated with lower mortality than deferred therapy (adjusted RR, 0.54 [CI, 0.35 to 0.83]) and the HIV-CAUSAL collaboration43 found a lower mortality risk that was not statistically significant (adjusted HR, 0.77 [CI, 0.58 to 1.0]). Another analysis from the HIV-CAUSAL Collaboration42 that directly compared ART initiation at CD4 counts greater than 0.500 x 109 cells/L with initiation at greater than 0.350 x 109 cells/L found no difference in mortality (HR, 0.99 [CI, 0.89 to 1.2]). Two other large cohort studies found that ART initiation at CD4 counts greater than 0.500 x 109 cells/L was associated with no difference in risk for death when compared with noninitiation48 or slightly delayed initiation49. In all 4 studies, absolute mortality rates were low (2% to 5%) in patients with CD4 counts greater than 0.500 x 109 cells/L.

Results were also mixed for the combined outcome of death plus AIDS-defining events (not reported in the NA-ACCORD study44). The HIV-CAUSAL collaboration42 found that ART initiation at CD4 counts greater than 0.500 x 109 cells/L was associated with a lower risk for AIDS-defining events or death than initiation at greater than 0.350 x 109 cells/L (HR, 0.72 [CI, 0.64 to 0.81]). Two other studies48, 49 found no clear association between starting or not starting ART at CD4 counts greater than 0.500 x 109 cells/L and risk for AIDS-defining events or death.

Longer-Term Harms Associated With ART

The 2005 USPSTF review included results from the large, ongoing DAD (Data Collection on Adverse Events of Anti-HIV Drugs) study (23,468 participants), which found that increased risk for myocardial infarction was associated with longer exposure to ART (adjusted RR, 1.3 per year of exposure [CI, 1.1 to 1.4 per year of exposure]), although absolute event rates were low (3.5 per 1000 person-years)50.

Subsequent analyses from the DAD study51–53 and 3 other cohort studies54–56 reported cardiovascular harms associated with ART through 4 to 6 years of follow-up (Appendix Table 3). Sample sizes ranged from 2952 to more than 30,000 persons. All of the studies were rated good-quality except 1, which was rated fair-quality because of lack of detail about baseline patient characteristics and blinding of study personnel54. All studies adjusted for multiple confounders.

Like the earlier DAD results, the most recent analysis found that longer exposure to indinavir alone (adjusted RR, 1.1 per year of exposure [CI, 1.1 to 1.2 per year of exposure]), ritonavir-boosted indinavir (adjusted RR, 1.2 per year of exposure [CI, 1.1 to 1.3 per year of exposure]), and ritonavir-boosted lopinavir (adjusted RR, 1.1 per year of exposure [CI, 1.0 to 1.2 per year of exposure]) were each associated with a slightly higher risk for myocardial infarction than nonuse (53). No other protease inhibitor was associated with increased myocardial risk.

Evidence on the association between the nucleoside reverse transcriptase inhibitor abacavir and risk for myocardial infarction is mixed. Although 2 studies53, 55 found that abacavir was associated with increased risk (adjusted RRs, 1.7 and 2.0), 2 others54, 56 found no association (adjusted HRs, 0.6 and 1.2).

The DAD study also found that recent didanosine use was associated with increased myocardial infarction risk (adjusted RR, 1.4 [CI, 1.1 to 1.8]), but found no association when analyses were based on cumulative didanosine exposure.53 No association was found between use of other nucleoside reverse transcriptase inhibitors or the nonnucleoside reverse transcriptase inhibitors nevirapine or efavirenz and increased risk for cardiovascular events.53

Discussion

As in the 2005 USPSTF review8–10, we found no direct evidence on the effects of screening for HIV infection versus no screening on clinical outcomes. Table 2 summarizes the other evidence reviewed in this update.

The 2005 review found good evidence that HIV screening tests are accurate and that identifying undiagnosed HIV infection and treating immunologically advanced disease (CD4 count <0.200 x 109 cells/L) are associated with substantial clinical benefits. However, it found insufficient evidence to estimate the effects of diagnosis and subsequent interventions on transmission risks or the clinical benefits of ART in patients with less immunologically advanced disease. New studies included in this update17, 39, 40, 43–45, 48, 49 provide strong evidence for the effectiveness of initiating ART at CD4 counts between 0.350 and 0.500 x 109 cells/L, although evidence showing benefit is less consistent for ART initiation at greater than 0.500 x 109 cells/L43, 44, 48, 49. Recent studies indicate that about 54% of patients present for initial HIV care with CD4 counts less than 0.350 x 109 cells/L57 and about 75% were diagnosed at CD4 counts less than 0.500 x 109 cells/L58, suggesting that many patients identified by screening would benefit from immediate ART initiation. Additional research 51–53, 55 confirms previous findings of a small but statistically significant increase in risk for long-term cardiovascular harms associated with use of certain protease inhibitors. In the DAD study, the absolute increase in risk per year of exposure with certain older protease inhibitors was about 0.3 myocardial infarctions per 1000 person-years53, compared with an absolute decrease in mortality of about 3.2 to 20 per 1000 person-years after initiating ART, depending on the CD4 cell count at baseline43. Whether current first-line protease inhibitors and other antiretrovirals are also associated with increased cardiovascular risk is not yet established. Long-term ART is also associated with other harms, including osteoporotic fractures 59 and lipodystrophy 60, that were not addressed in this review.

Strong evidence from a randomized trial and multiple observational studies16, 17 indicates that ART use is associated with a 10- to 20-fold reduction in risk for sexual transmission. Recent evidence showing that counseling interventions were relatively ineffective in reducing risky behaviors in HIV-infected persons61 suggests that the beneficial effects of screening on transmission are probably driven by use of ART.

Our study has limitations. We excluded non–English-language articles, which could have resulted in language bias, although we identified no non–English-language studies that would have met our inclusion criteria. We did not search for studies published only as abstracts and could not formally assess for publication bias by using graphical or statistical methods because of the few studies for each key question and the differences in study design, populations, and outcomes assessed. We included observational studies, which are more susceptible to bias and confounding than well-conducted randomized trials, although we focused on results from studies that performed statistical adjustment for potential confounding. We also included studies conducted in resource-poor and high-prevalence settings, which could limit the applicability of our findings to U.S. practice.

Additional research may further clarify benefits and harms of screening. Continued follow-up of patients receiving ART is needed to further understand the effects of long-term exposure, because many patients receive treatment for far longer than the 6 years evaluated in the longest studies to date. No clinical study has evaluated the yield of repeated HIV screening, which probably depends on the incidence of new infections in a population61–63. The START (Strategic Timing of Antiretroviral Treatment) randomized trial64, which compares ART initiation at CD4 counts greater than 0.500 x 109 cells/L with deferred treatment until CD4 counts decrease to less than 0.350 x 109 cells/L, is currently recruiting and should help further clarify the effects of very early ART initiation.

The main area of discrepancy between HIV screening guidelines is whether to routinely screen populations not known to be at increased ris 11, 65. Screening tests for HIV are highly accurate, but targeted screening misses a substantial proportion of infected persons because of undisclosed or unknown risk factors. Evidence published since the 2005 USPSTF review shows highly beneficial effects of ART for reducing sexual transmission of HIV and risk for AIDS-defining events and death in persons with less immunologically advanced stages of disease.

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Copyright and Source Information

Source: Agency for Healthcare Research and Quality, Rockville, Maryland.

Acknowledgment: The authors thank Laurie Hoyt Huffman, MS, and Jennifer Croswell, MD, MPH, as well as U.S. Preventive Services Task Force leads Susan Curry, PhD; Virginia Moyer, MD, MPH; Wanda Nicholson, MD, MPH, MBA; Timothy Wilt, MD, MPH; and Douglas Owens, MD, MS.

Grant Support: By contract HHSA 290-2007-10057-I, task order 8, from the Agency for Healthcare Research and Quality.

Potential Conflicts of Interest: Potential Conflicts of Interest: Dr. Chou: Grant: Agency for Healthcare Research and Quality. Dr. Selph: Payment for writing or reviewing the manuscript: Agency for Healthcare Research and Quality. Dr. Dana: Grant (money to institution): Agency for Healthcare Research and Quality; Grants/grants pending: Agency for Healthcare Research and Quality. Dr. Bougatsos: Other: This manuscript was based on a report funded by the Agency for Healthcare Research and Quality. Dr. Zakher: Grant (money to institution): Agency for Healthcare Research and Quality; Support for travel to meetings for the study or other purposes (money to institution): Agency for Healthcare Research and Quality. Dr. Blazina: Grant (money to institution): Agency for Healthcare Research and Quality; Support for travel to meetings for the study or other purposes (money to institution): Agency for Healthcare Research and Quality. Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-1085.

Requests for Single Reprints: Roger Chou, MD, Oregon Health & Science University; 3181 Southwest Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239; e-mail, chour@ohsu.edu.

Current author addresses and author contributions are available at http://www.annals.org.

Figure. Analytic framework and key questions for screening for HIV in nonpregnant adolescents and adults.

Text Description is shown below.

HIV Ab = HIV antibody.
* Selected key questions have been omitted from this article. Details on these key questions are available in the full report13.

Key Questions:
1. What are the benefits of universal or targeted HIV screening versus no screening in asymptomatic, nonpregnant adolescents and adults on disease transmission, morbidity, mortality, and quality of life?
2a. What is the yield (number of new diagnoses) of HIV screening at different intervals in nonpregnant adolescents and adults?
*2b. What are the effects of universal versus targeted HIV screening on testing acceptability and uptake in nonpregnant adolescents and adults?
*2c. What is the effect of opt-out versus opt-in testing or different pre- or posttest HIV counseling methods on screening uptake or rates of follow-up and linkage to care in nonpregnant adolescents and adults?
*2d. What are the adverse effects (including false-positive results and anxiety) of rapid versus standard HIV testing in nonpregnant adolescents and adults not known to be at higher risk?
*2e. What are the effects of universal versus targeted HIV screening on CD4 cell counts at the time of diagnosis?
*2f. What are the effects of universal versus targeted HIV screening on rates of follow-up and linkage to care in nonpregnant adolescents and adults who screen positive?
*3a. To what extent does knowledge of HIV-positive status affect behaviors associated with increased risk for HIV transmission in nonpregnant adolescent and adults?
*3b. To what extent does use of antiretroviral therapy affect behaviors associated with increased risk for HIV transmission in nonpregnant adolescents and adults?
4a. How effective is antiretroviral therapy for reducing transmission of HIV in nonpregnant adolescents and adults with chronic HIV infection?
4b. How effective is behavioral counseling for reducing transmission of HIV in nonpregnant adolescents and adults with chronic HIV infection?
4c. In asymptomatic, nonpregnant adolescents and adults with chronic HIV infection, what are the effects of initiating antiretroviral therapy at different CD4 cell count or viral load thresholds on morbidity, mortality, and quality of life?
5. What are the longer-term harms associated with antiretroviral therapy for nonpregnant adolescents and adults with chronic HIV infection?
*6a. To what extent are improvements in viremia associated with reductions in HIV transmission rates in nonpregnant adolescents and adults?
*6b. To what extent are improvements in risky behaviors associated with reductions in HIV transmission rates in nonpregnant adolescents and adults?

Text Description.

This Figure depicts the analytic framework, which outlines the evidence areas covered in the review, including populations, screening strategies, tests, interventions, and outcomes. The population includes nonpregnant adolescents and adults who are asymptomatic for HIV and screened in settings generalizable to primary care. Pregnant women and dialysis and transplant patients are excluded. There is an initial branch in the framework that splits patients into low-risk or high-risk groups after screening (key question 2a and 2b), and after testing (key question 2c) it further splits patients into HIV antibody positive and negative groups. From the corresponding areas of the framework, harms of rapid versus standard HIV testing in nonpregnant adolescents and adults not known to be at higher risk are assessed (key question 2d), as are the effects of universal versus targeted HIV screening on CD4 counts at the time of diagnosis (key question 2e) and on rates of followup and linkage to care (key question 2f). A subsequent branch splits the framework into those with low CD4 counts or high viral loads and those with high CD4 counts and low viral loads. Key questions 3a and 3b then assess whether knowledge of HIV-positive status or use of antiretroviral therapy affects behaviors, respectively. Interventions then include antiretroviral therapy (key questions 4a and 4c) and behavioral counseling (key question 4b), and an arrow assesses resulting longer-term harms of antiretroviral therapy (key question 5). Intermediate outcomes of the interventions include improved CD4 counts, viremia, and risky behaviors. Clinical health outcomes include reduced premature death and disability or spread of disease. An overarching arrow from screening to the clinical health outcomes addresses key question 1. A dotted line between the intermediate and clinical health outcomes boxes represents associations between viremia (key questions 6a) or risky behaviors (key question 6b) and transmission rates.

Table 1. Initiating HAART at Different CD4 Cell Counts or Viral Load Thresholds on Progression to AIDS or Mortality

Study, Year (Reference) Study Name Patients, n Duration of Follow-up Comparison Groups
RCTs
Cohen et al, 201117 HPTN 052 1763 Median,
1.7 y
Delayed treatment (n = 877): Initiation of ART after 2 consecutive CD4 counts <0.250 x 109 cells/L or at onset of AIDS-related illness
Early treatment (n = 886): Initiation of ART at CD4 count of 0.350 to 0.550 x 109 cells/L
Severe et al, 201039 NA 816 21 mo Standard treatment (n = 408): Same intervention as early treatment group, started at CD4 count ≤0.200 x 109 cells/L
Early treatment (n = 408): CD4 count, 0.201 to 0.350 x 109 cells/L; lamivudine, 150 mg, plus zidovudine, 300 mg, twice a day and efavirenz, 600 mg/d
Emery et al, 200840, and El-Sadr et al, 200647 SMART Study Group 477 (249 ART-naive) 18 mo Intermittent ART, drug conservation group: CD4 count <0.250 x 109 cells/L, CD4 percentage <15%, or symptomatic; 131 ART-naive patients
Continuous ART, viral suppression group: CD4 count >0.350 x 109 cells/L; 118 ART-naive patients
Cohort studies
Cain et al, 201142, and Ray et al, 201043 HIV-CAUSAL Collaboration 20,971 (12 cohorts); restricted to patients with CD4 counts >0.500 x 109 cells/L at baseline Mean, 1 y By CD4 count*:
0.200 x 109 cells/L (n = 8066)
0.250 x 109 cells/L (n = 8078)
0.300 x 109 cells/L (n = 8101)
0.350 x 109 cells/L (n = 8144)
0.400 x 109 cells/L (n = 8201)
0.450 x 109 cells/L (n = 8281)
0.500 x 109 cells/L (n = 8392)
Ray et al, 201043 HIV-CAUSAL Collaboration 62,760 (12 cohorts) Mean, 3 y By CD4 count:
<0.100 x 109 cells/L (n = 5319)
0.100 to <0.200 x 109 cells/L (n = 6521)
0.200 to <0.350 x 109 cells/L (n = 14,886)
0.350 to <0.500 x 109 cells/L (n = 15,360)
≤0.500 x 109 cells/L (n = 20,674)
Kitahata et al, 200944 NA-ACCORD 17,517 (22 cohorts) Mean, 3 y CD4 count 0.351 to 0.500 x 109 cells/L: early therapy (n = 2084) and deferred therapy (n = 6278)
CD4 count >0.500 x 109 cells/L: early therapy (n = 2220) and deferred therapy (n = 6936)

Table 1—Continued

Mortality Progression to AIDS/
AIDS-Related Events
Mortality or Progression to AIDS/AIDS-Related Events
Delayed vs. early treatment: 13/877 (1.5%) vs. 10/886 (1.2%); HR, 1.3 (95% CI, 0.6 to 3.0) Extrapulmonary tuberculosis, delayed vs. early treatment: 17/877 (2%) vs. 3/886 (0.3%); RR, 5.6 (95% CI, 1.7 to 20.0)
Pulmonary tuberculosis, delayed vs. early treatment: 15/877 (1.7%) vs. 13/886 (1.5%); RR, 1.2 (95% CI, 0.6 to 2.4)
Delayed vs. early treatment: 65/877 (7.4%) vs. 40/886 (4.5%); HR, 1.7 (95% CI, 1.1 to 2.5)
Standard vs. early treatment: 23/408 (6%) vs. 6/408 (2%); unadjusted HR, 4.0 (95% CI, 1.6 to 9.8) Tuberculosis, standard vs. early treatment: 36/408 (9%) vs. 18/408 (4%); unadjusted HR, 2.0 (95% CI, 1.2 to 3.6) Not reported
Not reported Drug conservation vs. continuous ART (fatal and nonfatal AIDS events): 3/131 (2/100 PYs) vs. 1/118 (0.5/100 PYs); HR, 4.1; P = 0.22 Drug conservation vs. continuous ART: 4/131 (2.7/100 PYs) vs. 1/118 (0.5/100 PYs); HR, 5.3 (95% CI, 1.3 to 9.6)
ART initiation at CD4 count 0.500 x 109 cells/L (n = 65/8392) vs. initiation at:
0.200 x 109 cells/L (n = 99/8066): HR, 0.83 (95% CI, 0.68 to 1.03)
0.250 x 109 cells/L (n = 95/8078): HR, 0.92 (95% CI, 0.78 to 1.09)
0.300 x 109 cells/L (n = 97/8101): HR, 0.99 (95% CI, 0.84 to 1.18)
0.350 x 109 cells/L (n = 94/8144): HR, 0.99 (95% CI, 0.82 to 1.19)
0.400 x 109 cells/L (n = 89/8201): HR, 0.95 (95% CI, 0.79 to 1.16)
0.450 x 109 cells/L (n = 81/8281): HR, 0.97 (95% CI, 0.88 to 1.09)
ART initiation at CD4 count 0.350 x 109 cells/L (n = 94/8144) vs. initiation at:
0.200 x 109 cells/L (n = 99/8066): HR, 0.85 (95% CI, 0.68 to 1.05)
0.250 x 109 cells/L (n = 95/8078): HR, 0.93 (95% CI, 0.75 to 1.16)
0.300 x 109 cells/L (n = 97/8101): HR, 1.01 (95% CI, 0.79 to 1.28)
0.400 x 109 cells/L (n = 89/8201): HR, 0.97 (95% CI, 0.85 to 1.10)
0.450 x 109 cells/L (n = 81/8281): HR, 0.99 (95% CI, 0.79 to 1.22)
0.500 x 109 cells/L (n = 65/8392): HR, 1.01 (95% CI, 0.74 to 1.41)
Not reported ART initiation at CD4 count 0.500 x 109 cells/L (n = 158/8392) vs. initiation at:
0.200 x 109 cells/L (n = 330/8066): HR, 0.53 (95% CI, 0.47 to 0.60)
0.250 x 109 cells/L (n = 329/8078): HR, 0.60 (95% CI, 0.54 to 0.67)
0.300 x 109 cells/L (n = 317/8101): HR, 0.68 (95% CI, 0.61 to 0.75)
0.350 x 109 cells/L (n = 296/8144): HR, 0.72 (95% CI, 0.64 to 0.81)
0.400 x 109 cells/L (n = 256/8201): HR, 0.78 (95% CI, 0.68 to 0.87)
0.450 x 109 cells/L (n = 209/8281): HR, 0.88 (95% CI, 0.82 to 0.93)
ART initiation at CD4 count 0.350 x 109 cells/L (n = 296/8144) vs. initiation at:
0.200 x109 cells/L (n = 330/8066): HR, 0.73 (95% CI, 0.64 to 0.83)
0.250 x 109 cells/L (n = 329/8078): HR, 0.83 (95% CI, 0.72 to 0.95)
0.300 x 109 cells/L (n = 317/8101): HR, 0.93 (95% CI, 0.81 to 1.09)
0.400 x 109 cells/L (n = 256/8201): HR, 1.06 (95% CI, 0.99 to 1.16)
0.450 x 109 cells/L (n = 209/8281): HR, 1.20 (95% CI, 1.05 to 1.39)
0.500 x 109 cells/L (n = 158/8392): HR, 1.39 (95% CI, 1.14 to 1.69)
Initiation vs. no initiation of ART, by CD4 count:
<0.100 x 109 cells/L: HR, 0.29 (95% CI, 0.22 to 0.37)
0.100 to <0.200 x 109 cells/L: HR, 0.33 (95% CI, 0.25 to 0.44)
0.200 to <0.350 x 109 cells/L: HR, 0.38 (95% CI, 0.28 to 0.52)
0.350 to <0.500 x 109 cells/L: HR, 0.55 (95% CI, 0.41 to 0.74)
≤0.500 x 109 cells/L: HR, 0.77 (95% CI, 0.58 to 1.01)
Not reported Not reported
ART initiation at CD4 count 0.351 to 0.500 vs. ≤0.350 x 109 cells/L: adjusted RR, 0.61 (95% CI, 0.46 to 0.83)
ART initiation at CD4 count >0.500 vs. ≤0.500 x 109 cells/L: adjusted RR, 0.54 (95% CI, 0.35 to 0.83)
Not reported Not reported

Table 1—Continued

Study, Year (Reference) Study Name Patients, n Duration of Follow-up Comparison Groups
May et al, 200745; Lanoy et al, 200941; and Moore et al, 200946 ART Cohort Collaboration 120,379 (12 cohorts) Mean, 3 y By CD4 count:
<0.025 x 109 cells/L (n = 2034)
0.025 to 0.049 x 109 cells/L (n = 1295)
0.050 to 0.099 x 109 cells/L (n = 2059)
0.100 to 0.199 x 109 cells/L (n = 3782)
0.200 to 0.349 x 109 cells/L (n = 5550)
≤0.350 x 109 cells/L (n = 5659)
Sterne et al, 200949 When to Start Consortium 45,691 (18 cohorts);
24,444 received HAART
Mean, 3 y By CD4 count:
<0.051 x 109 cells/L (n = 2594)
0.051 to 0.150 x 109 cells/L (n = 4638)
0.151 to 0.250 x 109 cells/L (n = 6406)
0.251 to 0.350 x 109 cells/L (n = 5753)
0.351 to 0.400 x 109 cells/L (n = 3260)
0.451 to 0.500 x 109 cells/L (n = 1793)
Writing Committee for the CASCADE Collaboration, 201148 NA 9455 (23 cohorts) Median, 5 y Unique individuals (numbers overlap):
0 to 0.049 x 109 cells/L (n = 183)
0.050 to 0.199 x 109 cells/L (n = 1521)
0.200 to 0.349 x 109 cells/L (n = 4459)
0.350 to 0.499 x 109 cells/L (n = 5527)
0.500 to 0.799 x 109 cells/L (n = 5162)

Table 1—Continued

Mortality Progression to AIDS/
AIDS-Related Events
Mortality or Progression to AIDS/AIDS-Related Events
ART initiation at varying CD4 cell counts vs. initiation at <0.025 x 109 cells/L:
0.025 to 0.049 x 109 cells/L: 111/1295 vs. 222/2034; HR, 0.82 (95% CI, 0.66 to 1.04)
0.050 to 0.099 x 109 cells/L: 162/2059 vs. 222/2034; HR, 0.77 (95% CI, 0.63 to 0.95)
0.100 to 0.199 x 109 cells/L: 202/3782 vs. 222/2034; HR, 0.67 (95% CI, 0.55 to 0.82)
0.200 to 0.349 x 109 cells/L: 178/5550 vs. 222/2034; HR, 0.48 (95% CI, 0.39 to 0.60)
≤0.350 x 109 cells/L: 130/5659 vs. 222/2034; HR, 0.34 (95% CI, 0.27 to 0.44)
Not reported ART initiation at varying CD4 cell counts vs. initiation at <0.025 x 109 cells/L:
0.025 to 0.049 x 109 cells/L: 277/1295 vs. 519/2034; HR, 0.85 (95% CI, 0.73 to 0.98)
0.050 to 0.099 x 109 cells/L: 408/2059 vs. 519/2034; HR, 0.76 (95% CI, 0.66 to 0.87)
0.100 to 0.199 x 109 cells/L: 445/3782 vs. 519/2034; HR, 0.49 (95% CI, 0.43 to 0.56)
0.200 to 0.349 x 109 cells/L: 361/5550 vs. 519/2034; HR, 0.29 (95% CI, 0.25 to 0.33)
≤0.350 x 109 cells/L: 298/5659 vs. 519/2034; HR, 0.23 (95% CI, 0.19 to 0.27)
ART initiation at varying CD4 cell counts vs. initiation at 0.351 to 0.400 x 109 cells/L:
0.451 to 0.550 x 109 cells/L: HR, 0.93 (95% CI, 0.6 to 1.4)
0.251 to 0.350 x 109 cells/L: HR, 0.83 (95% CI, 0.59 to 1.25)
0.151 to 0.250 x 109 cells/L: HR, 0.67 (95% CI, 0.51 to 0.99)
0.051 to 0.150 x 109 cells/L: HR, 0.47 (95% CI, 0.34 to 0.58)
Not reported ART initiation at varying CD4 cell counts vs. initiation at 0.351 to 0.450 x 109 cells/L:
0.251 to 0.350 x 109 cells/L: HR, 0.74 (95% CI, 0.59 to 0.95)
0.151 to 0.250 x 109 cells/L: HR, 0.45 (95% CI, 0.37 to 0.53)
0.051 to 0.150 x 109 cells/L: HR, 0.18 (95% CI, 0.15 to 0.21)
Initiation vs. no initiation of ART during the index month, by CD4 count:
0 to 0.049 x 109 cells/L: HR, 0.37 (95% CI, 0.14 to 0.95); RD, −18.2 (95% CI, −32 to −4.4)
0.050 to 0.199 x 109 cells/L: HR, 0.55 (95% CI, 0.28 to 1.07); RD, −7.2 (95% CI, −10.1 to −4.4)
0.200 to 0.349 x 109 cells/L: HR, 0.71 (95% CI, 0.44 to 1.15); RD, −1.4 (95% CI, −3.0 to 0.3)
0.350 to 0.499 x 109 cells/L: HR, 0.51 (95% CI, 0.33 to 0.80); RD, −1.4 (95% CI, −2.2 to −0.6)
0.500 to 0.799 x 109 cells/L: HR, 1.02 (95% CI, 0.49 to 2.12); RD, −0.4 (95% CI, −2 to 1.2)
Not reported Initiation vs. no initiation of ART during index month, by CD4 count:
0 to 0.049 x 109 cells/L: HR, 0.32 (95% CI, 0.17 to 0.59); RD, −30 (95% CI, −45.1 to −15)
0.050 to 0.199 x 109 cells/L: HR, 0.48 (95% CI, 0.31 to 0.74); RD, −15 (95% CI, −19.7 to −10.3)
0.200 to 0.349 x 109 cells/L: HR, 0.59 (95% CI, 0.43 to 0.81); RD, −4.8 (95% CI, −7 to −2.6)
0.350 to 0.499 x 109 cells/L: HR, 0.75 (95% CI, 0.49 to 1.14); RD, −2.9 (95% CI, −5 to −0.9)
0.500 to 0.799 x 109 cells/L: HR, 1.10 (95% CI, 0.67 to 1.79); RD, 0.3 (95% CI, −3.7 to 4.2)

ART = antiretroviral therapy; CASCADE = Concerted Action on Seroconversion to AIDS and Death in Europe; HAART = highly active antiretroviral therapy; HIV-CAUSAL = HIV Cohorts Analyzed Using Structural Approaches to Longitudinal data; HPTN = HIV Prevention Trials Network; HR = hazard ratio; NA = not applicable; NA-ACCORD = North American AIDS Cohort Collaboration on Research and Design; PY = person-year; RCT = randomized, controlled trial; RD = risk difference; RR = relative risk; SMART = Strategies for Management of Antiretroviral Therapy.
* Patient-level data may cross CD4 cell count thresholds.

Table 2. Summary of Evidence

Key Question Main Findings From the 2005 USPSTF Review Number and Type of Studies Identified for Update Overall Quality* Limitations Consistency Applicability Summary of Findings for 2012 Update
What are the benefits of universal or targeted HIV screening versus no screening in asymptomatic, nonpregnant adolescents and adults on disease transmission, morbidity, mortality, and quality of life? No evidence No studies - No studies No studies No studies No study directly compared clinical outcomes between adults and adolescents screened and not screened for HIV infection.
What is the yield (number of new diagnoses) of HIV screening at different intervals in nonpregnant adolescents and adults? No evidence No studies - No studies No studies No studies No study evaluated the yield of repeated HIV screening compared with one-time screening.
How effective is ART for reducing transmission of HIV in nonpregnant adolescents and adults with chronic HIV infection? No studies 1 systematic review (1 RCT and 7 observational studies) Good Only 1 RCT Consistent Some studies conducted in resource-poor settings An RCT found that immediate ART in persons with a baseline CD4 count of 0.350 to 0.550 x 109 cells/L was associated with substantially lower risk for transmission than delayed therapy (HR, 0.04 [95% CI, 0.01 to 0.27]). Observational studies were consistent with the RCT (pooled HR, 0.16 [95% CI, 0.07 to 0.35]).
How effective is behavioral counseling for reducing transmission of HIV in nonpregnant adolescents and adults with chronic HIV infection? No RCTs or controlled observational studies 1 RCT and 1 before–after study Poor Underpowered to evaluate effects on transmission Could not determine No major issues Studies identified too few cases of new HIV infection to evaluate effects of counseling interventions on transmission risk.
In asymptomatic, nonpregnant adolescents and adults with chronic HIV infection, what are the effects of initiating ART at different CD4 cell counts or viral load thresholds on morbidity, mortality, and quality of life? 1 cohort study found that initiating ART at CD4 counts >0.350 x 109 cells/L was associated with lower risk for AIDS events and mortality than delayed initiation, but 3 others found no difference in risk 3 RCTs and 5 large collaborative cohort studies Good 1 RCT reported a subgroup analysis, some overlap in patients evaluated in the cohort studies Some inconsistency for CD4 cell counts >0.500 x 109 cells/L 1 RCT evaluated CD4 cell count thresholds not applicable to U.S. practice in a resource-poor setting An RCT and a subgroup analysis from another RCT found that initiating ART at CD4 counts <0.250 x 109 cells/L was associated with higher risk for death or AIDS events than initiation at CD4 counts >0.350 x 109 cells/L. Five large observational studies also found that initiating ART at CD4 counts between 0.350 and 0.500 x 109 cells/L was associated with lower risk for death than deferred or no ART. Four studies on initiation of ART at CD4 counts >0.500 x 109 cells/L did not consistently demonstrate clinical benefits.
What are the longer-term harms associated with ART for nonpregnant adolescents and adults with chronic HIV infection? 1 large cohort study found that longer duration of exposure to some protease inhibitors was associated with increased risk for myocardial infarction (RR, 1.3 per year of exposure [95% CI, 1.1 to 1.4]) 4 cohort studies (reported in 6 publications) Good No major limitations Consistent Duration of follow-up about 6 y Additional follow-up from a large cohort study included in the previous USPSTF review found some protease inhibitors associated with increased risk for MI (RR, 1.1 to 1.2 per year of exposure). Evidence on abacavir from 4 cohort studies was mixed, and no clear association was shown between other antiretrovirals and increased risk for cardiovascular events.

ART = antiretroviral therapy; HR = hazard ratio; MI = myocardial infarction; RCT = randomized, controlled trial; RR = relative risk; USPSTF = U.S. Preventive Services Task Force.
* Based on new evidence identified for this update plus previously reviewed evidence.
Cost-effectiveness modeling studies are not included in this summary table.

Appendix Figure. Summary of evidence search and selection.

Text Description is shown below.

ART = antiretroviral therapy; RCT = randomized, controlled trial.
* Includes the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews.
† Includes reference lists and sources suggested by peer reviewers.
‡ Some articles are included for more than 1 key question.

Text Description.

The Appendix Figure is a flow chart that summarizes the search and selection of articles related to HIV screening in nonpregnant adolescents and adults. Citations were identified through bibliographic databases, including MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews, as well as through other sources, including experts and reference lists. There were 10,297 abstracts of potentially relevant articles reviewed. After excluding 9,421 abstracts and titles of articles from other sources that were not relevant to key questions, 876 full-text articles received further review. A total of 820 full-text articles were excluded for the following reasons: wrong population (111), wrong intervention (69), wrong outcomes (393), wrong study design for key question (149), no original data (69), inadequate duration (25), and sample size too small (4). For key questions 1 and 2a, no studies were included. For key question 2b, one cohort study and two uncontrolled studies were included. For key question 2c, two cohort studies were included. For key question 2d, five uncontrolled studies were included. For key question 2e, two cohort studies were included. For key question 2f, one cohort study and two uncontrolled studies were included. For key question 3a, four uncontrolled studies were included. For key question 3b, seven observational studies were included. For key question 4a, one systematic review (consisting of one randomized, controlled trial and seven observational studies) was included. For key question 4b, one randomized, controlled trial and one observational study was included. For key question 4c, three randomized, controlled trials and five large cohort studies were included. For key question 5, four cohort studies (in six publications) were included. For key question 6a, six observational studies were included. For key question 6b, two cohort studies were included.

Appendix Table 1. Inclusion and Exclusion Criteria, Per Key Question

Key Question Include Exclude
All questions
Settings Primary care or other settings generalizable to primary care (e.g., family planning clinics or school-based health clinics), other health care settings in which screening is commonly performed (e.g., emergency department or urgent care). Focus on studies conducted in the United States and other developed countries, unless studies are not available in those settings. Developing countries, unless fair- or good-quality trials and studies in the United States are lacking
What are the benefits of universal or targeted HIV screening versus no screening in asymptomatic, nonpregnant adolescents and adults on disease transmission, morbidity, mortality, and quality of life?
Populations Asymptomatic adolescents and adults Known HIV infection, receiving dialysis, posttransplant, or occupational exposure
Interventions Rapid or standard HIV testing  
Outcomes Reduction in transmission rates of HIV and morbidity and mortality related to HIV infection and quality of life  
Comparisons Universal or targeted HIV screening vs. no screening or each another  
Study designs Randomized, controlled trials and controlled observational studies Uncontrolled observational studies
What is the yield (number of new diagnoses) of HIV screening at different intervals in nonpregnant adolescents and adults?
Populations Asymptomatic adolescents and adults Known HIV infection, receiving dialysis, posttransplant, or occupational exposure
Interventions Rapid or standard HIV testing  
Outcomes Number of positive test results  
Comparisons Repeated HIV screening vs. 1-time screening or screening at one interval vs. another interval  
Study designs Randomized, controlled trials and controlled observational studies  
How effective is ART for reducing transmission of HIV in nonpregnant adolescents and adults with chronic HIV infection?
Populations HIV-positive adolescents and adults Acute HIV infection
Interventions Use of ART  
Comparisons Use of ART vs. no ART  
Outcomes Transmission rates  
Study designs Randomized, controlled trials and controlled observational studies  
How effective is behavioral counseling for reducing transmission of HIV in nonpregnant adolescents and adults with chronic HIV infection?
Populations HIV-positive adolescents and adults Acute HIV infection
Interventions Behavioral counseling interventions (pre- and posttest) to reduce risky sexual behaviors or enhance protective sexual behaviors for those who were asymptomatic and identified through screening  
Comparisons Counseling vs. usual care  
Outcomes Transmission rates  
Study designs Randomized, controlled trials or controlled observational studies  
In asymptomatic, nonpregnant adolescents and adults with chronic HIV infection, what are the effects of initiating ART at different CD4 cell count or viral load thresholds on morbidity, mortality, and quality of life?
Populations HIV-positive adolescents and adults Acute HIV infection or receiving or previously received HAART
Interventions Antiretroviral regimens  
Comparisons Initiation of ART earlier vs. later  
Outcomes Morbidity and mortality related to HIV infection and quality of life  
Study designs Randomized, controlled trials or controlled observational studies  
What are the longer-term harms associated with ART for nonpregnant adolescents and adults with chronic HIV infection?
Populations HIV-positive adolescents and adults Acute HIV infection or receiving or previously received HAART
Interventions Antiretroviral regimens  
Outcomes Cardiovascular effects  
Study designs Any  
Timing Long-term follow up, defined as >2 y  

ART = antiretroviral therapy; HAART = highly active antiretroviral therapy.

Appendix Table 2. Evidence Table of Studies of Counseling or ART Use on HIV Transmission

Study, Year
(Reference)
Study Design
Details
Location Duration of
Follow-up
Treatment and
Comparison Groups
Demographic
Characteristics/Baseline
Disease
Participants Virologic Response CD4 Cell Count Response Outcomes Quality Rating
RCT
Cohen et al, 201117 RCT Botswana, Kenya, Malawi, South Africa, Zimbabwe, India, Brazil, Thailand, and United States Median, 42 mo Treatment: Immediate ART
Comparison: Delayed ART initiated after CD4 count decreased to ≤0.250 x 109 cells/L or onset of AIDS-related illness
61% of participants between ages 26 and 40 y; median CD4 count, 0.442 x 109 cells/L forearly-therapy group and 0.428 x 109 cells/L for delayed-therapy group 10,838 screened, 1763 couples enrolled Virologic failure, immediate vs. delayed treatment: 5% (45/886) vs. 3% (5/184); P = 0.23 Treatment: 0.442 x 109 cells/L at enrollment to 0.603 x 109 cells/L at 12 mo
Comparison: 0.428 x 109 cells/L at enrollment to 0.399 x 109 cells/L at 12 mo
Immediate vs. delayed treatment: Transmission events: 4 events (IR, 0.3/100 PYs [95% CI, 0.1 to 0.6/100 PYs]) vs. 35 events (IR, 2.2/100 PYs [95% CI, 1.6 to 3.1/100 PYs]; HR, 0.11 [95% CI, 0.04 to 0.32]); P < 0.001)
Total clinical events: HR, 0.59 (95% CI, 0.40 to 0.88) Linked transmission: HR, 0.04 (95% CI, 0.01 to 0.28)
Good
Observational studies
Del Romero et al, 201018 Prospective cohort Spain 1355 couple-years ART vs. no ART Men, 83% (index cases); median age, 29 y (women) and 32 y (men); median CD4 count, 0.500 x 109 cells/L (IQR, 0.295 to 0.700 x 109 cells/L); median plasma HIV RNA, 200 copies/mL (IQR, ND to 8876 copies/mL); 54% detectable viral load 648 eligible couples; 602 were serodiscordant at first visit and 424 were serodiscordant at follow-up Detectable viral load in 93% (111/120) not receiving ART vs. 21% (30/145) receiving ART; P < 0.001 Not reported No ART vs. ART: Proportion engaging in unprotected sexual intercourse: 57% (73/476) vs. 46% (69/149); P = 0.019
Transmission: 5 instances (0.4/100 couple-years [95% CI, 0.2 to 1.4/100 couple-years]) vs. 0 instances (0/100 couple-years [95% CI, 0 to 1.1/100 couple-years])
Fair
Donnell et al, 201019 Pre–post analysis of prospective cohort data 14 sites in 7 African countries (Botswana, Kenya, Rwanda, South Africa, Tanzania, Uganda, and Zambia Median at ART initiation, 13 mo Pre-ART vs. post-ART transmission HIV-infected partner vs. HIV-susceptible partner: mean age, 32 vs. 33 y; women, 68% vs. 32%; HSV-2–positive, 100% vs. 68% 3408 enrolled, 3381 analyzed
Note: 27 couples' baseline serology did not confirm HIV-1 and HSV-2
Not reported Not reported Pre- vs. post-ART transmission:
Overall: 102/4558 PYs (IR, 2.24 [95% CI, 1.84 to 2.72]) vs. 1/273 PYs (IR, 0.37 [95% CI, 0.09 to 2.04])
Overall adjusted incidence rate ratio: 0
Good
Melo et al, 200820 Retrospective cohort Brazil Median, 25.5 mo (transmitters) vs. 22.3 mo (nontransmitters) Transmitters vs. nontransmitters Women, 72% (index cases); IDUs, 57.7%; unprotected sex, 91%; STD diagnosis, 23.6% 4500 screened retrospectively, 93 enrolled (56 enrolled retrospectively plus 37 enrolled prospectively) Not reported Not reported Transmissions, ART vs. no ART: 0/41 vs. 6/52
Median viral load, transmitters vs. nontransmitters: 24,082 (range, 1479 to 100,539) vs. 4583 (range, 78 to 47,974); P = 0.042
Fair
Musicco et al, 199421 Prospective cohort Italy Mean, 2 y (740 PYs) Zidovudine vs. no zidovudine Mean age, 26 y; women, 100%; median duration of relationship with HIV-positive partner, 3 y; consistent condom use, 56%; regular sexual intercourse, 53%; anal sex, 15%; oral sex, 48% Number screened not reported, 525 eligible, 436 enrolled, number withdrew and percentage analyzed unclear; data from 103 PYs excluded Not reported Not reported Seroconversions, zidovudine vs. no zidovudine: 3.8/100 PYs vs. 4.4/100 PYs; adjusted RR, 0.5 (95% CI, 0.1 to 0.9) Fair
Reynolds et al, 201122 Retrospective cohort Uganda Median, 1.57 y before ART initiation and1.54 y after ART initiation Pre-ART vs. post-ART transmission Male index partner, 58% (142/250); consistent condom use, 4%; polygamous husbands, 20% 15,000 screened, 250 eligible, 250 enrolled 6 months: 71.4% (20/28) below detectable limit and remaining 28.6% (8/28) below 2000 copies/mL
12 months: 85.2% (23/27) below 400 copies/mL, 14.8% (4/27) ranging from 2293 to 672,513 copies/mL
24 months: 100% (28/28) below 400 copies/mL
Not reported Transmission:
Pre-ART: 9.2/100 PYs (95% CI, 6.59 to 12.36/100 PYs)
Post-ART: 0/53.6 PYs (95% CI, −11.91 to 16.38/53.6 PYs); P = 0.010
Fair
Sullivan et al 200923 Retrospective cohort (abstract only) Rwanda and Zambia Median, 512 d (1.4 y) ART vs. no ART Not reported 2993 enrolled Not reported Not reported Transmission, ART vs. no ART:
4/175 (0.7/100 PYs) vs. 171/175 (3.4/100 PYs); RR, 0.21 (95% CI, 0.08 to 0.59); HR, 0.21 (95% CI, 0.09 to 0.52)
Could not assess for quality
Lu et al, 201024 Retrospective cohort China Median, 2.8 y ART vs. no ART Mean age, 44 y; women, 43%; regular sexual intercourse, 84%; condom use, 78%; monogamous, 99% 4348 screened, 4301 eligible, 1927 enrolled, no withdrawals, 100% analyzed Not reported Not reported Seroconversions, ART vs. no ART: 66/1369 (4.8%) vs. 18/558 (3.2%); univariate RR, 0.76 (95% CI, 0.45 to 1.28) Fair

ART = antiretroviral therapy; HR = hazard rate; HSV = herpes simplex virus; IDU = injection drug user; IQR = interquartile range; IR = incidence rate; ND = not detectable; PY = person-year; RCT = randomized, controlled trial; RR = relative risk; STD = sexually transmitted disease.

Appendix Table 3. Cardiovascular Events and ART Use

Study, Year
(Reference)
Study Name Duration of
Follow-up
Population Characteristics Interventions Adjusted Variables
for Statistical
Analysis
MI Other Cardiovascular
Events/Composite Outcomes
Bedimo et al, 201154 NA Median, 4 y Participants: 19,424
Median age: 46 y
Men: 98%
Smokers: 29%
Diabetes: 13%
Hypertension: 38%
Hypercholesterolemia: 26%
Chronic kidney disease: 8%
HCV infection: 32%
Any ART (n =14,063) Age, diabetes, hypertension, hypercholesterolemia, and smoking Adjusted HR for cumulative MI exposure (95% CI):
Abacavir: 1.18 (0.92 to 1.5)
Other NRTIs: 0.99 (0.87 to 1.11)
Mono- or dual-ART: 1.29 (1.10 to 1.52)
Not reported
Worm et al, 2010 53 DAD Study Median, 6 y Participants: 33,308
Median age: 44 y
Women: 26%
Race: not reported
Framingham risk, total population:
Low: 53%
Moderate: 15%
High: 4%
Framingham risk, patients with MI:
Low: 26%
Moderate: 30%
High: 18%
Framingham risk, patients without MI:
Low: 54%
Moderate: 15%
High: 4%
PIs: nelfinavir (n = 10,370), indinavir (n = 11,985), lopinavir–ritonavir (n = 9995), and saquinavir (n = 8070)
NRTIs: zidovudine
(n = 25,754), idanosine
(n = 13,851), zalcitabine
(n = 4951), stavudine
(n = 16,840), lamivudine
(n = 28,835), abacavir
(n = 12,511), and tenofovir
(n = 13,100)
NNRTIs: nevirapine
(n = 12,194) and efavirenz
(n = 13,522)
Age, sex, HIV transmission group, race, calendar year, cohort, smoking, family history of CVD, previous CV event, BMI, and exposure to other ART Adjusted relative rate (95% CI):
Cumulative PI use:
Nelfinavir: 1.04 (0.98 to 1.11)
Indinavir: 1.12 (1.07 to 1.18)
Lopinavir–ritonavir: 1.13 (1.05 to 1.21)
Saquinavir: 1.04 (0.98 to 1.11)

Per year of PI exposure:
Indinavir: 1.11 (1.05 to 1.18)
Indinavir plus ritonavir: 1.18 (1.07 to 1.30)
Saquinavir: 1.07 (0.97 to 1.20)
Saquinavir plus ritonavir: 1.06 (0.97 to 1.14)

Adjusted relative rate for cumulative NRTI use (95% CI):
Zidovudine: not significant (data not reported)
Didanosine: 1.41 (1.09 to 1.82)
Zalcitabine: not significant (data not reported)
Stavudine: not significant (data not reported)
Lamivudine: not significant (data not reported)
Abacavir: 1.07 (1.00 to 1.14)
Tenofovir: 1.04 (0.91 to 1.18)

Recent NRTI use:
Abacavir: 1.7 (1.17 to 2.47)
Tenofovir: 1.14 (0.85 to 1.53)
Cumulative NNRTI use:
Nevirapine: 0.97 (0.92 to 1.03)
Efavirenz: 1.02 (0.96 to 1.08)

Not reported
Sabin, et al, 200852 DAD Study Median, 5 y Participants: 33,347
Mean age: 43 y
Women: 26%
Framingham risk, patients with MI:
Low: 22% (113/517)
Moderate: 26% (134/517)
High: 23% (120/517)
Unknown: 29% (150/517)
NRTIs (numbers not reported):
zidovudine, didanosine, stavudine, lamivudine, abacavir
Age, sex, risk group, race, cohort, BMI, family history of CVD, smoking, previous CV event, year, and cumulative exposure to other ART Adjusted relative rate (95% CI):
Cumulative exposure:
Zidovudine: 1.04 (0.99 to 1.09)
Didanosine: 1.00 (0.93 to 1.07)
Stavudine: 1.02 (0.95 to 1.09)
Lamivudine: 0.99 (0.93 to 1.06)
Abacavir: 1.00 (0.92 to 1.08)

Recent exposure:
Zidovudine: 1.22 (0.82 to 1.81)
Didanosine: 1.53 (1.10 to 2.13)
Stavudine: 1.22 (0.84 to 1.77)
Lamivudine: 1.69 (1.02 to 2.8)
Abacavir: 1.94 (1.48 to 2.55)

Past exposure:
Zidovudine: 1.29 (0.89 to 1.85)
Didanosine: 1.08 (0.84 to 1.39)
Stavudine: 1.24 (0.93 to 1.66)
Lamivudine: 1.45 (0.88 to 2.4)
Abacavir: 1.29 (0.94 to 1.77)

Adjusted relative rates for MI, CV death, or invasive CV procedure (95% CI):

Cumulative exposure:
Zidovudine: 1.04 (1.00 to 1.08)
Didanosine: 0.99 (0.94 to 1.05)
Stavudine: 1.04 (0.99 to 1.10)
Lamivudine: 1.01 (0.96 to 1.06)
Abacavir: 1.03 (0.96 to 1.10)

Any recent exposure:
Zidovudine: 0.98 (0.79 to 1.21)
Didanosine: 1.40 (1.11 to 1.77)
Stavudine: 0.99 (0.78 to 1.25)
Lamivudine: 1.15 (0.91 to 1.44)
Abacavir: 1.63 (1.3 to 2.04)

Friis-Møller et al, 200751 and 200350 DAD Study Median, 5 y Participants: 23,437
Median age: 39 y
Women: 24%
Current/former smokers: 61%
Hypertension: 14%
Dyslipidemia: 42%
Any ART (n = 21,921), PIs (n = 18,919), and NNRTIs (n = 15,142) Model 1: Age, sex, cohort, HIV transmission group, race, age, BMI, family history of CVD, smoking, previous CV event, and calendar year

Model 2: All from model 1 plus total cholesterol level, HDL cholesterol level, hypertension, and diabetes

ART use:
Incidence: 97 events/16,805 PYs (5.77/1000 PYs)

Adjusted relative rate, model 1 (95% CI): 1.16 (1.09 to 1.23)

Adjusted relative rate for PI use (95% CI):
Model 1: 1.16 (1.10 to 1.23)
Model 2: 1.10 (1.04 to 1.18)
Excluding patients exposed to NRTIs: 1.15 (1.06 to 1.25)

Adjusted relative rate for NRTI use (95% CI):
Model 1: 1.05 (0.98 to 1.13)
Model 2: 1.00 (0.93 to 1.09)
Excluding patients exposed to PIs: 0.94 (0.74 to 1.19)

Not reported
Obel et al, 201055 Danish HIV cohort study Mean, 6 y Participants: 2952
Median age: 39 y
Men: 76%
CV risk factors: not reported
Triple NRTI regimen, including abacavir, and NNRTI or PI regimen, including abacavir

Specific drugs: abacavir
(n = 1761), zidovudine
(n = 2711), lamivudine
(n = 2867), stavudine
(n = 1031), didanosine
(n = 813)

Age, sex, year of diagnosis, year of ART initiation, CD4 cell count, viral load, race, injection drug use, use of other antiretrovirals, and comorbid conditions Abacavir use vs. nonuse:
Any abacavir exposure: Incidence, 2.4/1000 PYs (95% CI, 1.7 to 3.4/1000 PYs) vs. 5.7/1000 PYs (95% CI, 4.1 to 7.9/1000 PYs); adjusted RR, 2.0 (95% CI, 1.1 to 3.6)

RR (95% CI):
Actual abacavir use: 1.95 (1.05 to 3.6)
Early abacavir use: 2.37 (0.88 to 6.36)
Abacavir as part of triple NRTI: 1.91 (0.88 to 4.17)
Abacavir with NNRTI or PI: 2.06 (1.06 to 4.01)
Abacavir initiated ≤2 y of ART: 1.77 (0.82 to 3.82)
Abacavir initiated ≥2 y of ART: 2.66 (1.31 to 5.39)

Not reported
Ribaudo et al, 201156 NA Median, 3 y Participants: 5056 (1122 with 6-y data)
Median age: 37 y
Female: 18%
White: 40%
Black: 36%
Hispanic: 21%
Previous injection drug use: 10%
≥2 CVD risk factors: 15%
CVD 10-y risk score ≤10: 5%
Abacavir (n = 1704) and no abacavir (n = 3352) Age, sex, race, CVD risk factors, smoking, and family history of CVD Adjusted HR, abacavir use vs. nonuse (95% CI):
1 y: 0.7 (0.2 to 2.6)
6 y: 0.6 (0.3 to 1.4)
Adjusted HR for serious CVD events, abacavir use vs. nonuse (95% CI):
1 y: 1.1 (0.5 to 2.1)
6 y: 0.9 (0.5 to 1.3)

ART = antiretroviral therapy; BMI = body mass index; CV = cardiovascular; CVD = cardiovascular disease; DAD = Data Collection on Adverse Events of Anti-HIV Drugs; HCV= hepatitis C virus; HDL = high-density lipoprotein; HR = hazard ratio; MI = myocardial infarction; NA = not applicable; NNRTI = nonnucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor, PY = person-year; RR = relative risk.

Current as of: November 2012

Internet Citation: Screening for HIV in Adolescents and Adults: Evidence Summary: Human Immunodeficiency Virus (HIV) Infection: Screening. U.S. Preventive Services Task Force. November 2012.
https://www.uspreventiveservicestaskforce.org/Page/Document/screening-for-hiv-in-adolescents-and-adults-evidence-summary/human-immunodeficiency-virus-hiv-infection-screening

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