Late HIV Diagnosis: Predictors, Costs, Consequences, and Solutions

Table of Contents


More than a million people in the United States have HIV infection, and fewer than 1 in 5 has an undetectable viral load.1 That eye-popping estimate -- based on a synthesis of recently published data -- explains why HIV incidence stands at a staggering 56,000 yearly in the United States, and has since the turn of the millennium.2

You don't have to look far for the reasons behind these galling tallies: A perdurably high proportion of HIV-positive people remains untested; those who test positive sometimes never see the inside of an HIV clinic; and those who enter care drift away in waves. This triple threat to steady treatment -- late diagnosis, sluggish linkage to care, and fleeting retention -- conspire to keep the collective viral load so high that further HIV transmission is a foregone conclusion.

Researchers in Denver and Atlanta1 started their analysis with the CDC estimate that 1.1 million US residents have HIV infection and that 21% don't know it. From there, these arithmeticians cited published data to estimate that 75% of newly diagnosed people enter care within 6 to 12 months, while 80% to 90% get care within 3 to 5 years. Among people diagnosed with HIV, half do not stay in regular care. While 80% of HIV-positive people in care should start antiretroviral therapy (at the old 350 cells/mm3 threshold), 25% of that group do not begin treatment.

Figure 1: Limited HIV diagnosis, linkage to care, and retention in care in the US.
Figure 1. Of an estimated 1.1 million HIV-positive people in the United States, 79% are diagnosed, 59% enter care, and 40% stay in care, according to analysis of recently published studies.1 Of those retained in care, 80% need antiretroviral therapy (ART) (32% of 1.1 million), 75% begin treatment (24% of 1.1 million), and 60% adhere to treatment and reach an undetectable viral load (19% of 1.1 million).

Figure 1 details the dwindling ratios of HIV-positive people who get diagnosed, enter care, stay in care, get treated, adhere to treatment, and reach an undetectable viral load. The bottom line reads like this: 209,773 HIV-positive people adhere to antiretroviral therapy and have no measurable virus in blood; that number represents 60% of all those who need antiretroviral therapy and 19% of the 1.1 million with HIV.

Next the researchers used a simple model to project how much the proportion of people with an undetectable viral load would climb if 90% of infected people got diagnosed, 90% entered care, 90% started antiretrovirals, and 90% notched a viral load below 50 copies/mL. When the investigators considered these parameters one by one, none did much to improve the undetectable rate. When they combined all four parameters, the proportion of HIV-positive US residents with an undetectable viral load jumped from 19% to 66%.

This review and the one starting on page 37 analyze recent research (most from the past 5 years) addressing three facets of this problem -- late HIV diagnosis, delayed entry to care, and dropping out of care. For each problem, the review considers epidemiology, predictors, clinical consequences, and potential remedies. Interviews with Bernard Branson from the CDC and Michael Mugavero from the University of Alabama at Birmingham offer additional insights on these issues from policy-making and clinical points of view.

CDC Says Test Everyone (Almost)

As recommended CD4-count thresholds for starting therapy climb, definitions of late presentation or late HIV diagnosis also evolve. In 2011 a European consensus group proposed defining late presentation as coming to care with a CD4 count under 350 cells/mm3, while they defined "presentation with advanced HIV disease" as seeking care with a CD4 count under 200 cells/mm3.3 After analyzing 15,774 United Kingdom residents with HIV, the UK Collaborative HIV Cohort (UK CHIC) formulated essentially the same definition.4

To limit delayed HIV diagnosis and entry to care, in 2006 the Centers for Disease Control and Prevention (CDC) proffered a radical shift in HIV testing strategy for adolescents and adults (including pregnant women) in the United States.5 CDC experts advised health professionals to offer routine opt-out testing for everyone from 13 to 64 -- regardless of perceived HIV risk -- whenever they seek care at a medical office or hospital, unless research shows that prevalence of undiagnosed HIV infection in the area lies below 0.1%. Opt-out testing means telling a person an HIV assay will be part of their routine bloodwork unless they specifically decline HIV testing. The CDC suggested pretest counseling and separate consent for HIV testing could be skipped. Repeat HIV testing is left to the provider's discretion, based on perceived HIV risk. The CDC recommended at least annual testing for high-risk groups. The US Preventive Services Task Force outlines the following HIV risk factors:6

  • Men who have had sex with other men since 1975
  • Men and women who have unprotected sex with multiple partners
  • Past or present injection drug users (IDUs)
  • Men and women who exchange sex for money or drugs or have sex partners who do
  • People whose past or present sex partners are HIV positive, bisexual, or IDUs
  • People being treated for sexually transmitted diseases
  • People who had a blood transfusion between 1978 and 1985
  • People who request an HIV test

The CDC adds another high-risk category: anyone -- gay or straight -- "who themselves or whose sex partners have had more than one sex partner since their most recent HIV test."5

Because people who know they have HIV may be more likely to avoid risky sex, the CDC argues, knowledge of HIV status "in unaware persons" might reduce new HIV infections by 30%.7 And of course knowing one's HIV status is the first step to care. Although plenty of people disagree with the CDC strategy (see "Universal opt-out testing: pros and cons" below), no one doubts the pernicious impact of late HIV diagnosis on individual and public health. And as detailed in the next section, CDC data suggest the revised testing guidance has already begun to turn the tide.

Late HIV Diagnosis: Numbing Numbers

HIV infects about 1 million people in the United States.8 For years the CDC reckoned that 40,000 more US residents got infected every year, but in 2008 (using a more precise estimating method) they bumped that number to 56,000 yearly -- dating back to the year 2000.2 An estimated 32% of Americans diagnosed with HIV in 2008 had AIDS within 12 months.8

Using that same definition of late diagnosis, the CDC tallied more dire data from 33 US states and Canada from 1996 through 2005, estimating a 54% late-diagnosis rate in the United States and a 64% rate in Canada.9 In the United States, proportions of people with a late HIV diagnosis were no higher among blacks (53%) or Hispanics (58%) than whites (54%). By 2011, however, in 33 states the CDC discerned a possible dip in late diagnoses that seemed to start in 2005.10 In these 33 states, the late-diagnosis rate held steady at 37% from 2001 to 2004, then slipped to 32.3% in 2007.

In a US-Canadian cohort of 44,491 people with HIV, CD4 count at diagnosis edged up by an average 6 cells/mm3 yearly from 1997 through 2007.11 But median initial CD4 count reached only 317 cells/mm3 in 2007, well below the 350-cell antiretroviral start signal at the time. Among people older than 50, median initial CD4 count rose from 203 to only 266 cells/mm3 by 2007.12 Table 1 summarizes these and other studies of CD4 count trends at HIV diagnosis.11-17

Reports from Europe tell similar stories. In an 11-country European survey in 2009, about half of people with newly diagnosed HIV had a CD4 count under 350 cells/mm3.16 The rate was 50% or more in Denmark, France, Slovenia, Spain, and the United Kingdom. A study in England, Wales, and Northern Ireland found higher rates of late HIV presentation for care (under 350 cells/mm3 within 91 days of diagnosis) in people 50 and older (48% versus 33% in younger adults), and older late presenters had a 2.4 times higher risk of dying than younger late presenters within a year of diagnosis.17

The US-Canadian, Swiss, and British Isles studies underline the high risk of late presentation in older adults.12,15,17 These findings probably partly reflect low suspicion of HIV risk in older people and thus delayed testing. The North American study also found that the proportion of people 50 or older when first seeking HIV care rose from 1997 to 2007.12 These results are particularly troubling because older people have a blunted CD4 response to antiretroviral therapy compared with younger people, even though older people tend to be better virologic responders. These investigators called for "targeted renewed prevention and testing strategies ... in all age groups, including those 50-years-old and older."12

Table 1-A. Recent Trends in CD4 Count at HIV Diagnosis or Presentation to Care
#### Table 1-A. Recent Trends in CD4 Count at HIV Diagnosis or Presentation to Care
Table 1-B. Recent Trends in CD4 Count at HIV Diagnosis or Presentation to Care
#### Table 1-B. Recent Trends in CD4 Count at HIV Diagnosis or Presentation to Care

Harbingers of Belated Diagnosis or Presentation

Several studies published after 2005 in the United States, France, and Spain weighed factors that account for late HIV diagnosis or delayed entry to care (Table 2).18-26 Older age proved the most consistent predictor of late diagnosis, although work in San Francisco found that people younger than 30 ran a higher risk of late HIV diagnosis than older people.18 This study involved 2139 people at least 13 years old diagnosed with AIDS from 2001 through 2005 and reported to the San Francisco Department of Public Health; 830 of them (39%) got their AIDS diagnosis within 1 year of their positive HIV test.

Compared with 30-to-39-year-olds, people younger than 30 had a doubled risk of late diagnosis (adjusted odds ratio [AOR] 1.99, 95% confidence interval [CI] 1.4 to 2.8).18 Late diagnosis risk did not differ between the 30-to-39 group and people 40 to 49 or people 50 and older. The researchers suggested the higher risk in younger people reflects their relative lack of awareness about HIV. They did not report how many of these young people were born outside the United States or infected heterosexually, two factors that also emerged as independent predictors of late diagnosis in this study (see below).

Figure 2: Risk of late HIV diagnosis with older age.
Figure 2. An 18,721-person analysis of the French Hospital Database on HIV determined that age over 30 independently raised the risk of having a CD4 count under 200 cells/mm3 or an AIDS diagnosis upon enrollment in the cohort.23 Adjusted odds ratios (and 95% CI) for each age bracket were 1.89 (1.74 to 2.06), 2.76 (2.53 to 3.07), 3.06 (2.69 to 3.46), and 3.46 (2.91 to 4.12).

In contrast, three large studies in France,23-25 one in Spain,26 and one in North Carolina20 linked older age to delayed HIV diagnosis. The largest of these studies, involving 18,721 adults who enrolled in the French Hospital Database on HIV from 1997 through 2002, determined that age over 30 doubled or tripled the risk of late access to care (depending on age range) compared with age under 30 (Figure 2).23 The 30-to-40-year-old group had almost a doubled risk of delayed care (OR 1.89, 95% CI 1.74 to 2.06), while people 50 to 60 had a tripled risk (OR 3.05, 95% CI 2.69 to 3.46). One third of this big cohort -- 6687 people or 36% -- had delayed access to care, defined as a CD4 count under 200 cells/mm3 or an AIDS diagnosis upon enrollment in the cohort. The French investigators underlined the gravity of late presentation to care among people older than 50, including a higher risk of clinical progression and comorbidities and a slower CD4 response to antiretrovirals.

A six-center French study of 4516 people diagnosed with HIV from 1996 through June 2005 rated 1718 of them (38%) as "late testers," defined as having a CD4 count under 200 cells/mm3 or an AIDS diagnosis in the year of their positive HIV test.24 Again, late testing proved more prevalent in people over 30 than in younger adults. A third French study of 1077 people diagnosed with HIV since 1996 and enrolled in a nationally representative sample defined late testers the same way.25 The investigators identified 384 late testers (36%). Compared with people younger than 25, every 5-year older age group had an independently higher risk of late HIV testing. People 40 and older (the oldest group) ran more than a 5 times higher risk of late testing (AOR 5.59, 95% CI 1.50 to 20.81).

A Spanish study involving 2564 people starting antiretroviral therapy from 2004 through 2006 reckoned that the risk of delayed HIV diagnosis rose linearly with age in men over 30, but an age effect was not seen in women.26

At the Duke University HIV clinic in North Carolina, 55 of 113 people (49%) diagnosed with HIV between October 2002 and August 2004 had a CD4 count below 200 cells/mm3.20 Age averaged 36 years and ranged from 17 to 61. Seventy-one of these people (63%) were black or Hispanic, and 31 (27%) were women. Every 10 years of age raised the risk of a sub-200 CD4 count at diagnosis 72% (AOR 1.72, 95% CI 1.12 to 2.64, P = 0.01). Forty people (35%) got diagnosed with HIV while admitted to the hospital. Every 10 years of age upped the risk of in-hospital diagnosis 79% (AOR 1.79, 95% CI 1.07 to 3.12, P = 0.03). Women had almost a 7 times higher risk of in-hospital diagnosis than men (AOR 6.74, 95% CI 2.08 to 21.81, P = 0.001), but the researchers did not have information on why these women were in the hospital. These clinicians believe "testing based on perceived risk of HIV infection, rather than broader screening approaches, likely contributes to the problem" of late diagnosis. (See the interview with Michael Mugavero in this issue for discussion of these findings.)

Table 2. Predictors of Late HIV Diagnosis or Presentation to Care
#### Table 2. Predictors of Late HIV Diagnosis or Presentation to Care *Compared with nonmigrant women.

Studies in France23,25 and the United States18,19 pinpointed non-native birth as a predictor of late HIV diagnosis. Both US studies come from California, which has a large migrant population from Mexico and Central America. The 2139-person San Francisco Department of Public Health study included 402 people (19%) classified as Latino, 180 of whom (45%) had AIDS within 1 year of their HIV diagnosis.18 There were 301 people (14%) born outside the United States, 168 of whom (56%) had a late diagnosis. Birth outside the United States independently raised the risk of late diagnosis 64% (AOR 1.64, 95% CI 1.2, 2.2).

A study in the northern California country of San Mateo focused on 391 people attending a publicly funded HIV clinic from 2000 through 2002.19 Ninety-four study participants (24%) were born outside the United States. Foreign-born people were significantly more likely to have an opportunistic infection at HIV diagnosis (30% versus 17%, P = 0.009). Birth outside the United States emerged as the only independent predictor of opportunistic infection at HIV diagnosis, tripling the risk (AOR 2.98, 95% CI 1.21 to 7.38). These researchers observed that "migration results in increased sexual mixing of different groups, altered sex ratios of young adults (ratio of men to women) and social disruption that may discourage long term stable partnering patterns."

The third late-diagnosis predictor identified in several studies is infection during heterosexual sex or by injecting drugs rather than during sex between men. Compared with transmission during sex between men, heterosexual transmission independently inflated the risk of late HIV diagnosis in the three French studies,23-25 a Spanish study,26 and the San Francisco study.18 The 18,721-person French analysis determined that injection drug use (versus sex between men) hoisted the risk of delayed HIV care 75%.23 A study of 2564 people attending 19 hospital clinics in Spain from 2004 through 2006 found a doubled risk of delayed diagnosis in injection drug users compared with gay men.26 In the San Francisco study, heterosexual HIV transmission versus male-to-male transmission nearly doubled the risk of late diagnosis (AOR 1.88, 95% CI 1.1 to 3.1).18 These findings clearly reflect heightened awareness of HIV among gay men.

Other independent predictors of late HIV diagnosis in US studies were private insurance or no insurance (versus public insurance),18 "no reported HIV risk,"18 and (in a study focusing on gay men) black race, gay disclosure to fewer than half of family and friends, and having only 1 sex partner in the past 6 months.22

Together these findings bolster the CDC's contention that people without classic HIV risk factors should be screened for infection. People who do not suspect they may pick up HIV during sex (older adults, heterosexuals) and people with limited access to medical care (migrants, rural residents) may be particularly vulnerable to complacency about HIV risk. US clinicians who conducted the North Carolina study recommended "routine rather than risk-based HIV testing ... because high-risk behaviors are frequently not identified in primary care encounters."20

How Much Does Late Diagnosis Cost -- and Who Pays?

Studies analyzing the financial impact of late diagnosis consistently show that HIV care costs more when people come to the clinic (or hospital) with more advanced infection. But recent work also raises two important questions about more aggressive HIV screening in the United States: Does the healthcare system have the capacity to treat a big influx of newly diagnosed people? And where will the money for more testing -- and treating -- come from?

Not all cost analyses concur that universal opt-out testing is a better deal than risk-based testing.

A study of 8348 newly diagnosed people at 10 US clinics in the HIV Research Network found that those diagnosed with a CD4 count under 200 cells/mm3 had higher direct costs for care than people diagnosed with more than 500 cells/mm3 -- and those higher costs persisted throughout the 2000-to-2007 study period.27 Cumulative costs for late presenters versus early presenters were $37,104 versus $9829 in the first year of care, $92,213 versus $30,598 in the fifth year of care, and $135,827 versus $86,721 in the seventh year.

A Canadian study used the same CD4 cutoff for late presenters (below 200 cells/mm3) but a stricter threshold for early presenters (above 200 cells/mm3).28 Of the 241 patients analyzed, 39% came to care with a sub-200 CD4 count. Direct costs in the first year of care totaled $18,448 for late presenters and $8455 for early presenters. Further statistical analysis showed that differences in patient traits did not explain the big cost contrast. Hospital costs accounted for the lion's share of the cost difference. A recent analysis by these same investigators used 350 cells/mm3 as the early-late threshold in people diagnosed from April 1998 through April 2003.29 The disparity in direct costs during the first year of care (Canadian $19,917 versus $7840) remained substantial in the fifth year of care (Canadian $15,663 versus $8883).

Cost-effectiveness studies -- though hard to interpret for people unversed in modeling mazes -- build the case for routine general-population HIV screening, at least on a one-time basis. A 2006 study by US researchers linked simulation models of various screening approaches to published reports of HIV transmission risk, with and without antiretroviral therapy.30 The study population consisted of people with low to moderate HIV prevalence (0.05% to 1.0%) and annual HIV incidence (0.0084% to 0.12%). When the investigators figured that antiretroviral therapy has a moderately favorable impact on HIV transmission, cost-effectiveness ratios remained below $50,000 per quality-adjusted life year for one-time screening with HIV prevalence as low as 0.20% and for screening every 5 years with prevalence as low as 0.45%.

A more recent US modeling probe weighed the impact of expanded HIV screening with or without antiretroviral therapy on new infections and cost per quality-adjusted life year in both a high-risk population (injection drug users and gay men) and a low-risk 15-to-64-year-old population.31 If people reduce sexual activity 20% after screening (a big if, suggest some studies discussed in the next section), one-time HIV screening of low-risk people plus annual screening of high-risk people could prevent 6.7% of a projected 1.23 million new infections and cost only $22,382 per quality-adjusted life-year gained. Starting antiretrovirals when the CD4 count lies above 350 cells/mm3 would prevent 20% to 28% of projected new infections.

French modelers compared current risk-based HIV screening with universal routine screening in both the general adult population and high-risk subpopulations.32 Assuming undiagnosed HIV prevalence at 0.10% and annual HIV incidence at 0.01%, the model calculated one-time screening of the general population (versus current practice) increased quality-adjusted life months by only 0.01 (about 7 hours) while boosting costs by €50 ($70) per person for a cost-effectiveness ratio of €57,400 ($80,995). More frequent screening increased quality-adjusted life months, costs, and cost-effectiveness ratio. Still, the investigators believe one-time HIV screening of the general population compares favorably in cost-effectiveness when sized up against other screening interventions recommended in Western Europe.

Not all cost analyses concur that universal opt-out testing is a better deal than risk-based testing. Taking a payer's perspective and limiting the analysis to a single year, David Holtgrave of the Johns Hopkins Bloomberg School of Public Health figured that targeted testing would diagnose more HIV cases than opt-out testing (188,170 versus 56,940) if HIV prevalence stands at 1%.33 Targeted testing would also prevent more HIV infections (14,553 versus 3644) at a lower gross cost per infection averted ($56,383 versus $237,149). Even when HIV prevalence stands as low as 0.3%, Holtgrave calculated that targeted testing performs better than opt-out testing in several outcome variables.

Responding to Holtgrave's analysis, CDC experts argued that "the scenarios upon which the analysis is based are implausible" (click on the Comments tab after opening the Holtgrave article in the link provided in the references.33) The CDC also observed that Holtgrave's analysis does not consider whether the alternatives to wide opt-out testing "are equally feasible or equally acceptable to patients and providers." (For details, see the interview with the CDC's Bernard Branson in this issue of RITA!)

Regardless of who's right about the cost-effectiveness of opt-out screening, it's worth remembering what cost-effectiveness means. It does not mean a strategy is necessarily cheap, affordable, money-saving, or likely to fit into the healthcare economics of a given country. Cost-effective means only that a strategy is "a good value" relative to other accepted strategies or the strategy it may replace, according to the American College of Physicians (ACP).34 Results of cost-effectiveness analyses depend on the quality of the input data, the strength of assumptions the analysts make, and the validity of their formulas. Also, the ACP notes, "the very notion of cost-effective requires a value judgment -- what you think is a good price for an additional outcome, someone else may not."34

But even if everyone agrees that universal adult HIV screening is "a good value," a critical question remains: Where will we get the money to pay for it? An impressive set of US HIV modelers tackled that question in 2010, asking how more frequent HIV testing will affect government discretionary programs (like the Ryan White CARE Act and its AIDS Drug Assistance Program, ADAP) and entitlement programs (like Medicaid and Medicare).35

This analysis relied on data from multiple sources and made sundry assumptions to project the impact of shifting from current adult US testing rates (set at once every 10 years) to expanded testing (set at once every 5 years). The investigators did not consider people with private insurance or those eligible for Veterans Affairs care. They distinguished between entitlement and discretionary programs because entitlement program budgets expand in response to ballooning case loads, while discretionary programs have set annual allocations, which make them "more vulnerable to unexpected increases in the number eligible for care."35 Indeed, anyone familiar with recent ADAP outlays knows that program's beneficiaries are already squeezed by budgetary belt tightening.

Figure 3: Impact of current versus expanded HIV screening 2009-2013.
Figure 3. A cost projection by academic researchers determined that expanded (Exp) HIV screening (testing every 5 years) would result in 46,000 new HIV diagnoses compared with current (Cur) screening (testing every 10 years) from 2009 through 2013. Expanded screening would cost an extra $2.7 billion over those 5 years, adding $10.9 billion to spending by discretionary (DIS) programs (like ADAP) while saving $2.8 billion in spending by entitlement (ENT) programs (like Medicaid and Medicare).35

These researchers calculated that 50.1 million HIV-negative adults without private insurance or VA benefits were eligible for discretionary or entitlement programs in 2009, along with 711,000 HIV-positive adults aware of their infection, 189,000 people with undiagnosed HIV infection, and 46,000 with incident (newly diagnosed) HIV infection.35 If HIV screening continues at the current average of once every 10 years, testing would detect an additional 177,000 cases through 5 years, whereas doubling the screening rate to once every 5 years would detect another 46,000 infections on top of that (Figure 3). The current testing scheme would cost $83.7 billion over the next 5 years, and more frequent testing would add another $2.7 billion.

Compared with testing for HIV every 10 years, according to this model, testing every 5 years would add $10.9 billion to the cost of discretionary programs through 2013 while saving entitlement programs $2.8 billion. Thus entitlement program savings would not offset the higher discretionary program tally. Most of the increased cost would come in spending on drugs, as thousands more people become eligible for antiretroviral therapy. The investigators calculated that the drug price tag would quadruple from $0.2 billion under current screening practice to $0.8 billion with expanded screening.

Entitlement programs like Medicaid and Medicare would save money with expanded screening, the researchers explained, because diagnosing HIV earlier in the disease course would shave costs for hospital care and treating opportunistic diseases. Most people diagnosed with expanded screening would be younger and have less advanced disease, so they would more likely get covered through discretionary programs.

These researchers reckoned that expanded HIV screening would cost government-financed testing programs an additional $503 million over 5 years, almost 10 times more than the $53 million budget boost proposed for all CDC HIV prevention and surveillance work in the current fiscal year. "If expanded screenings were implemented consistent with the CDC guidelines," the authors concluded, "the policy may not be feasible without additional funds from state and local governments."35 Expanded HIV screening will not have the intended beneficial impact, they argued, "unless government programs have sufficient budgets to expand testing and provide care for newly identified cases."35

A research review by Kaiser Family Foundation investigators bolsters the contention that people diagnosed in a wider US HIV screening program will probably have to lean heavily on discretionary programs.36 "They are likely to have a disproportionately lower income, to be uninsured and/or reliant on public-sector health care coverage, and to be people of color, particularly black individuals," the Kaiser researchers wrote. And because of these demographics, their care costs will probably be compounded by comorbidities like hepatitis, mental illness, and drug dependence.

Clinical Consequences of Late HIV Diagnosis

The clinical impact of delayed diagnosis is easier to calculate than cost because the numbers are there for the parsing in well-designed cohort studies. For example, analysis of 16,375 heterosexuals diagnosed with HIV in England and Wales from 2000 through 2004 had CD4 data on 10,503 people, 4425 (42%) of whom did not get diagnosed until their CD4 count sagged below 200 cells/mm3.37 In this late-diagnosis group, 6.1% died within a year of their positive HIV test, compared with 0.7% of people diagnosed with more than 200 cells/mm3 (P < 0.01). These investigators calculated that earlier diagnosis would have cut 1-year mortality by 56% and overall mortality by 32% between 2000 and 2004. The 2564-person Spanish study discussed earlier determined that delayed HIV diagnosis multiplied the death risk by 5.2 (95% CI 1.9 to 14.5).26

A 5494-person analysis of the Netherlands ATHENA cohort linked more frequent HIV testing to lower mortality and to higher pretreatment CD4 count.38 Focusing on people infected during sex, ATHENA investigators divided cohort members into three groups: group 1: no negative test before a first positive test; group 2: 1 to 2 years between last negative and first positive test; group 3: less than 1 year between last negative and first positive test. Mortality in the 4067 people in group 1 was 1.33 per 100 person-years. Compared with them, the 1561 people in group 2 had a 50% lower risk of death (relative risk 0.50, P = 0.04), while the 866 people in group 3 had a 51% lower risk (relative risk 0.49, P = 0.04). Almost half of group 1 (48%) had a CD4 count below 200 cells/mm3 when starting antiretroviral therapy. Risk of a sub-200 CD4 count was 57% lower in group 2 and 63% lower in group 2 (P < 0.0001 for both comparisons).

UK Collaborative HIV Cohort (CHIC) Study investigators published a novel analysis comparing 2741 "late presenters" (CD4 count below 200 cells/mm3 at diagnosis and when starting therapy), 947 "late starters" (CD4 count above 350 cells/mm3 at diagnosis and below 200 cells/mm3 when starting therapy), and 1290 "ideal starters" (CD4 count above 350 cells/mm3 at diagnosis and between 200 and 350 cells/mm3 when starting therapy).39 Median CD4 gains after 48 and 96 weeks of treatment were significantly lower in late presenters than in late starters, and late presenters had a doubled risk of clinical progression in the first year of therapy compared with late starters (OR 2.04, 95% CI 1.19 to 3.51, P = 0.01).

In 2006 the CDC estimated a 3.5 times higher HIV transmission rate from US residents unaware of their infection than from people who knew that had HIV.40 Many studies show a higher risk of HIV transmission from people with higher viral loads. Thus, reason suggests, diagnosing and treating HIV during acute infection (when viral loads are highest) or earlier in the course of chronic infection (when viral loads are lower than in late infection) should slice the risk of HIV transmission. The recently ended HPTN 052 trial offered hard evidence supporting that hypothesis.41 This international randomized trial calculated a 96% lower risk of HIV transmission when the infected partner in an HIV-discordant couple began antiretrovirals immediately rather than waiting until the CD4 count dropped below 250 cells/mm3.

A province-wide study in British Columbia yielded data showing more HIV testing, more people taking antiretrovirals, more people with undetectable viral loads, and fewer new HIV infections from 1996 through 2009.42 Over the study period the number and rate of HIV tests rose from 137,585 per year in 1996-1999 (3.5% of the population), to 139,464 per year in 2000-2003 (3.4% of the population), and to 168,924 in 2004-2008 (4.0% of the population). From 1996 through 2009, the number of people taking combination antiretrovirals soared from 837 to 5413 per year (P = 0.002) while the number of new HIV diagnoses waned from 702 to 338 per year (P = 0.001). The investigators calculated a strong negative correlation between number of treated people and number of new HIV diagnoses (–0.89, P < 0.0001). Among people who ever had a viral load test, the proportion with a load below 500 copies/mL jumped from under 10% in 1996 to over 50% in 2009 (P < 0.0001). A drop in unprotected sex did not explain the falling HIV diagnosis rate since newly reported cases of syphilis, gonorrhea, and chlamydia rose.

A study in San Francisco also saw a link between falling "community viral load" and fewer new HIV diagnoses.43 San Francisco Department of Public Health investigators calculated mean community viral load (average of most recent viral loads for all HIV-positive people) and total community viral load (sum of most recent viral loads in all HIV-positive people). Both sank significantly from 2004 through 2008 (P = 0.037 and P = 0.021). In tandem, new HIV diagnoses fell from 798 in 2004 to 434 in 2008. Both mean and total community viral load were significantly associated with new HIV diagnoses over the study period (P = 0.003 and P = 0.002).

Other studies have yielded similar results. Lower community viral load among Vancouver injection drug users predicted HIV incidence independently of unsafe sex and needle sharing.44 Researchers in Taiwan charted a 53% drop in HIV transmission after the country started providing free antiretrovirals.45 Because syphilis incidence did not change in the same period, a dip in unsafe sex did not appear to explain the dwindling HIV transmission rate.

Of course the associations documented in these studies do not mean that more frequent testing or lower group viral loads are the only reasons, or even the major reasons, for drops in new HIV diagnoses. These studies offered some evidence that safer sex during the study period did not account for lower HIV incidence. But a list of confounding variables is not hard to imagine: Stronger antiretroviral regimens with a higher barrier to resistance, more serosorting, better needle exchange programs, better care for marginalized groups, and other factors could also contribute to falling rates of new HIV infection. Still, results like these buttress the rationale for more frequent HIV testing, followed by prompt treatment. And conclusive early results of the randomized HPTN 052 trial (described above), although largely dependent on data from Africa, Brazil, India, and Thailand, argue strongly for the impact of earlier treatment on preventing transmission.41

Proponents of more frequent HIV testing argue that people who know they carry the retrovirus are less likely to have risky sex, at least with partners they believe to be HIV-negative. But some peer-reviewed evidence indicates that HIV-positive people taking antiretrovirals may forsake condoms since they assume they will not pass the virus to sex partners because they have a low or undetectable viral load.46-49 French researchers documented a doubling of HIV risk behaviors among HIV-positive heterosexual men since 2006.49 Because antiretroviral treatment for at least 6 months or a viral load below 400 copies/mL also predicted risky sex in this group, the investigators speculated that the doubled rate of unsafe sex "may be related to increasing awareness of the 'treatment-as-prevention' concept."

A CDC meta-analysis tried to gauge how knowing one's HIV status affects chances of unprotected anal or vaginal intercourse.50 This study is now 6 years old, but it did yield data showing that people who knew they carried HIV had unprotected sex less often than people who did not know their HIV status. The CDC team weighed data from eight studies presented from January 1987 through January 2004. In an analysis considering unprotected intercourse with HIV-negative partners, knowing one's HIV status lowered the chance of risky sex 68%.

Reconciling differences in these types of studies is impossible because of the differing populations analyzed and methods used. Few would disagree that sexual behavior by people who know their HIV status varies from person to person and from one sexual foray to the next. Chance and vicissitude may have more to do with donning a condom than moral precepts about transmission risk.

Why Physicians Don't Test for HIV Infection

The HIV literature is rife with studies examining why US physicians don't test people for the retrovirus. Most reasons fall into three broad groups: physicians don't have the time,51 they won't get paid,51 or they don't perceive a risk.52-55

Lack of perceived risk is the stumbling block the CDC hopes to remove with its advice to screen all teens through 64-year-olds who cross paths with a healthcare professional. Yet a 10-year retrospective study at a Boston center figured that all of 221 people who eventually tested positive had one or more "triggers" (such as patient traits, symptoms, and physical findings) that should have prompted physicians to recommend HIV testing earlier.55 But these people made a median of five medical visits before their first positive HIV test. These findings suggest that if healthcare professionals aren't going to follow CDC screening guidelines, they should print out this trigger list (see link at reference 55) and pin it someplace prominent.

Table 3. Physician Barriers to HIV Testing in Three Clinical Settings
#### Table 3. Physician Barriers to HIV Testing in Three Clinical Settings51

A 2007 study of physicians' excuses for not testing relied on a review of recent literature, meeting abstracts, and other sources.51 The investigators excluded non-US studies and those that sized up only patients' reasons for eschewing HIV tests. They grouped physician-related barriers to care into three settings: prenatal clinics, emergency departments, and all other medical settings, including internal medicine, sexually transmitted infection (STI) clinics, and adolescent clinics. This survey disclosed 41 reasons for not testing: 24 in prenatal clinics, 20 in the emergency department, and 23 in other settings. Feeble imagination seems to be the only factor limiting perceived or fancied reasons for not testing. All three settings shared eight barriers (Table 3). The authors proposed that "some or all of these barriers must be addressed before the CDC recommendation for routine HIV testing can be realized in all US medical settings."

Strategies for Earlier HIV Testing

A half-decade ago, opt-out HIV testing for all adults and adolescents regardless of perceived risk became the CDC-sanctioned strategy to diagnose positive people earlier.5 But even if physicians and other potential testers adopt this approach, they should take other steps to make sure it works. Reviewing tactics to promote earlier diagnosis of HIV, David Hardy, a seasoned HIV clinician in Los Angeles, advised colleagues to do two things before taking a more aggressive testing stance.56 First, they must understand regional and state HIV testing laws. Second, they must develop a testing strategy that relies on a particular HIV test with a set policy for confirmatory testing. When telling patients they will be tested for HIV as part of routine care, healthcare professionals should explain that any sexually active person may be at risk for HIV and assure patients that results will remain confidential. In the interview in this issue, the CDC's Bernard Branson outlines steps institutions should take when implementing opt-out HIV testing.

Other experts and investigators have offered suggestions on early testing strategies that do not specifically involve universal opt-out testing:

  • Take advantage of rapid testing technologies to provide results during the testing visit.57
  • Consider nurse-initiated streamlined counseling and rapid testing.58
  • Be aware of barriers to HIV testing in specific groups to provide testing opportunities suitable for specific communities.57
  • Ensure that HIV testing is offered routinely in settings that routinely care for high-risk individuals, including STI clinics, clinics that care for people with viral hepatitis, and drug addiction services.59
  • Test partners of people diagnosed with HIV.59
  • Devise social network strategies to identify people at high risk of HIV infection and encourage them to get tested for HIV.59
  • Take steps to reduce stigma associated with HIV testing.59

In 2010 the Obama administration announced a National HIV/AIDS strategy for the United States that sets out three steps to lower the new infection rate, along with three targets to hit by 2015 (Table 4).60

Table 4. U.S. National HIV/AIDS Strategy to Reduce HIV Incidence
#### Table 4. U.S. National HIV/AIDS Strategy to Reduce HIV Incidence60

Universal Opt-Out Testing: Pros and Cons

The CDC laid out an exhaustive rationale for universal opt-out HIV screening in the original recommendations5 and in later comments:7 (1) Health professionals may perceive risk assessment and counseling, which are not part of the new guidelines, as too time consuming. (2) Routine screening helps remove the stigma of HIV testing. (3) The demographics of HIV infection have changed, and many groups now at risk (women, heterosexuals, rural residents) may not perceive this risk. (4) Many HIV-positive people access health care but remain untested until they have symptoms. (5) Routine HIV testing is an effective prevention intervention. (6) The 20% to 25% of people unaware of their HIV infection account for about half of new infection transmissions. (7) CDC data from 2002-2003, before the new guidelines, showed that the largest proportion of HIV tests were done in doctors' offices (44%), but testing in doctors' offices yielded only 17% of all positive tests. In contrast, tests in hospitals (including emergency departments) accounted for 22% of all tests and 27% of positive tests, tests in public community clinics accounted for 9% of all tests and 21% of positive tests, and tests in HIV counseling and testing facilities accounted for 5% of all tests and 9% of positive tests.

But not everyone agrees that universal opt-out screening makes sense for the United States or countries with similar epidemics. Although some studies figure opt-out testing would be cost-effective,30-32 at least one cost-benefit analysis reckoned that targeted HIV counseling and testing would cost less, diagnose more new HIV infections, and prevent more infections than untargeted opt-out testing33 (see "How much does late diagnosis cost" above). Another study found that doubling the HIV testing rate in the United States would stick discretionary programs (like Ryan White) with an added $10.9 billion in costs over the next 5 years, without saving entitlement programs (like Medicaid and Medicare) nearly as much.35

Beyond questions of cost and effectiveness lies the boggy terrain of legality. A 2011 review of state HIV screening laws found that 46 jurisdictions, including Washington, DC, were compatible with the 2006 CDC recommendations, while 5 states were incompatible on at least one measure.61 For some states, compatibility varied by health care provider, setting, scenario, or type of law. This review did not include case laws or policies issued by other regulatory agencies, such as health departments.

An expert from the Center for HIV Law and Policy warned in 2007 that "rigid application of the new [CDC] guidelines may trigger legal claims, especially if there is no link to care for persons with a positive test result, no proof of informed consent, or inadequate counseling."62 In an interview in this issue of RITA!, the CDC's Bernard Branson says the agency has had no reports of "people suffering adverse consequences or being tested without their permission" in the 5 years the revised guidelines have been in place.

Are U.S. Patients Opting Out or Staying In?

The ultimate question about the CDC's opt-out screening plan is whether people are opting in or out. Twenty recent surveys reported from diverse clinical venues suggest acceptance rates often lie above 50% -- sometimes well above 50% -- in community health centers, hospital emergency departments, and jails.

Three studies from community health centers found widely different acceptance rates -- 67% in a six-clinic study in North Carolina, South Carolina, and Mississippi,63 58% in a South Carolina clinic serving both urban and rural residents,64 and 35% in a Bronx, New York clinic.65 A key difference in the three studies is that the first two offered a rapid HIV test63,64 while the Bronx study used a standard assay requiring venipuncture. The CDC guidelines do not specifically call for rapid testing, but these studies suggest offering on-the-spot results has a clear advantage. In the Bronx, younger age, Hispanic ethnicity, and having another blood test at the same visit independently raised chances that people would say yes to opt-out testing.65 In the six-center study, the number of people offered testing jumped from 3000 in the year before the clinics adopted the CDC strategy to about 16,000 in the year afterwards.63 But the 16,000 people offered testing still represented only 28% of patients between 13 and 64 years old.

A 60-person randomized trial involving STI clinic patients who had declined HIV testing in Syracuse, New York found that brief behavioral counseling yielded a higher rapid testing rate than an educational video, but acceptance rates were low with both interventions (45% versus 19%).66 Overall uptake of opt-out HIV screening at a London STI clinic stood at 53% (n = 573).67 This acceptance rate marked a hefty improvement from the 18% rate recorded before introduction of opt-out testing, nurse-performed asymptomatic genitourinary screening, mail delivery of HIV results, and the end of routine pre-HIV test counseling.

Among 3467 hospital inpatients offered opt-out rapid HIV testing at a Veterans Affairs hospital in Washington, DC during a 17-month period, only 824 (24%) agreed to testing.68 At a Boston teaching hospital, the debut of routine voluntary HIV testing more than tripled the chance that inpatients would get tested when compared with earlier risk-based testing.69 Routine testing yielded approximately 2 new HIV diagnoses per month, compared with 1 per month during the control period.

A May-June 2004 study at 14 geographically diverse antenatal clinics funded by the Ryan White CARE Act found that 90% of 853 women offered opt-out HIV testing accepted, and 91% reported feeling comfortable with testing.70 Feeling comfortable was linked to greater knowledge about HIV. Antenatal opt-out screening proved even more successful at a public hospital in Denver, where 12,000 of 12,221 women (98.2%) agreed to get tested.71 Median time to delivery was 1 day among women who opted out compared with 176 days among women who agreed to testing (P < 0.001).

A study of people entering New York City jails in 2006 found that 6411 of 9305 (69%) agreed to rapid HIV testing.72 Among 33,162 people entering jail in Washington, DC from June 2006 through May 2008, 22,515 (68%) agreed to opt-out HIV testing.73 A randomized study of 323 women sequentially admitted to a Connecticut jail recorded a significantly higher opt-out testing acceptance rate in women offered testing the day after admission (73%) than in women offered testing on the day of admission (55%) or 7 days after admission (50%).74 Younger age and a lower likelihood of early release favored agreeing to HIV testing. Despite these high acceptance rates, researchers say "the vast majority of jails in the United States do not screen routinely for HIV or STIs."75

Hospital-based dental clinics may be an overlooked HIV testing venue. Using a counselor-based (not opt-out) approach to offer rapid HIV testing at New York City's Harlem Hospital Center dental clinic in March 2008, researchers registered an acceptance rate of 97.6% in more than 3500 dental patients approached.76 Self-reported HIV risk behaviors included recent unprotected heterosexual intercourse in 73.5%, recent or past injection drug use in 4.6%, and gay sexual orientation in 2.6%.

Much interest has focused on rapid opt-out testing in hospital emergency departments, partly because poor people with a high HIV risk often use emergency rooms for primary care. At a public safety-net hospital in Denver, researchers compared HIV testing and prevalence rates with opt-out testing versus physician-directed testing during sequential 4-month intervals between April 2007 and April 2009.77 During the opt-out phase, 6933 of 28,043 people (24.7%) completed testing and 0.5% had HIV infection. During the physician-directed phase, 243 of 29,925 people (0.8%) completed testing and 0.01% had HIV infection. Nontargeted opt-out screening more than tripled the chance of a new HIV diagnosis (risk ratio 3.6, 95% CI 1.2 to 10.8).

A study of 1959 people offered routine HIV testing at a Boston hospital emergency department recorded an acceptance rate of 71%.78 Independent correlates of refusing HIV testing included female gender, household income above $50,000, lack of self-perceived HIV risk behavior, having a previous HIV test, and enrollment during morning hours. In the emergency department at the Medical College of Georgia, 5080 of 5585 people from 13 to 64 years old (91%) offered opt-out testing agreed to a rapid test from March 2008 to January 2009.79 White and married people were significantly less likely to accept testing than black or single people, and adults were twice as likely to accept as adolescents. The acceptance rate rose as age increased among adolescents, whereas the rate fell as age increased among adults.

At a university hospital emergency department in Washington, DC, 2476 of 4151 people (60%) offered rapid opt-out screening over 3 months in 2006 agreed.80 Older people, Asians, and nonlocal people were more likely to decline testing, while African Americans were marginally more likely to accept testing. In a later report from this same emergency department, 5232 of 9826 people (53%) accepted rapid opt-out screening.81 Acceptance rates were similar among blacks (55%), whites (52%), and Hispanics (50%), but lower for Asians (42%). The most frequent reasons for declining testing were lack of perceived risk (in 49%) and a recent HIV test (in 18%).

In a Chicago hospital emergency department, 2824 of 4849 people (58%) offered a rapid whole-blood HIV test regardless of risk in 2003-2004 accepted testing.82 Among 35 screened people who had a positive test (1.2%), 18 (51%) reported no traditional HIV risk factors. Fourteen of 31 people (45%) with CD4 counts available had fewer than 200 cells/mm3.

Researchers working with a large pediatric emergency department in Memphis, Tennessee developed an opt-out screening procedure through surveys of 118 health care providers, most of whom (78%) did not know about the CDC's opt-out guidelines (in 2008), and most of whom (58%) predicted that routine screening would fail in adolescents because of parent or guardian refusal.83 However, only 13% of 2002 adolescents from 13 to 18 years old opted out. Adolescents 15 or older were less likely to opt out.

Across the United States, the CDC reports, the proportion of people getting tested for HIV began to climb around 2006, the year the Centers called for opt-out screening.10 The CDC estimated that the percentage of 18- to 64-year-olds ever tested for HIV stayed flat at about 40% from 2001 to 2006, then climbed to 45% through June 2009. That uptick may be the best indicator that health professionals have begun to heed the CDC's call for wider HIV screening -- and that people are not opting out.

Summary Points on Late HIV Diagnosis

  1. Of an estimated 1.1 million HIV-positive people in the United States, 1 in 5 remains undiagnosed.1
  2. In 2006 the CDC revised its HIV testing advice to recommend that everyone between 13 and 64 be offered opt-out testing at any medical encounter, unless prevalence of undiagnosed HIV in the area lies below 0.1%.5
  3. An estimated 32% of Americans diagnosed with HIV in 2008 had AIDS within 12 months.8
  4. In a 2007 US-Canadian cohort study, median CD4 count at HIV diagnosis stood 33 cells/mm3 below the 350-cell antiretroviral-start threshold of that time.11
  5. Factors that predict delayed diagnosis in several studies include older age, nonnative birth, and HIV acquisition during heterosexual sex or by injecting drugs rather than during sex between men.
  6. Several studies found that universal opt-out HIV testing is cost-effective,30-32 but not all studies reached that conclusion,33 and some research indicates that wider HIV testing in the United States would put a much heavier burden on discretionary programs like Ryan White and "may not be feasible without additional funds from state and local governments."35
  7. Studies have linked late HIV diagnosis to slower CD4 gains, more new AIDS diagnoses, or higher mortality.37-39
  8. Lower "community viral load" attributed to wider HIV testing and antiretroviral use has been tied to lower HIV incidence or transmission.42-44
  9. Strategies to promote earlier HIV testing include universal opt-out HIV screening, use of rapid HIV tests, understanding and overcoming patient barriers to HIV testing, partner notification and testing, and reducing test-related stigma.
  10. Patient acceptance of opt-out HIV testing varies from study to study, ranging from 35% to 67% in community health centers.63-65 Studies in hospital emergency departments and jails often report acceptance rates well above 50%.


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