Clinical Guidelines Portal

Home > Guidelines > Adult and Adolescent Treatment Guidelines > Initiating Antiretroviral Therapy in Treatment-Naive Patients
Text Size
Search

Guideline Search

Type your search term(s) in the text box. Users can only search one guideline at a time. To search for an exact phrase, use quotation marks (i.e. "what to start"). To narrow your search, add additional relevant terms. If you are not finding what you need, try searching similar terms (i.e. perinatal OR pregnancy) to broaden your search.

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents

Initiating Antiretroviral Therapy in Treatment-Naive Patients

(Last updated:3/29/2012; last reviewed:3/27/2012)

Printer-Friendly Files

Panel’s Recommendations

  • Antiretroviral therapy (ART) is recommended for all HIV-infected individuals. The strength of this recommendation varies on the basis of pretreatment CD4 cell count:
    • CD4 count <350 cells/mm3 (AI)
    • CD4 count 350 to 500 cells/mm3 (AII)
    • CD4 count >500 cells/mm3 (BIII)
  • Regardless of CD4 count, initiation of ART is strongly recommended for individuals with the following conditions:
    • Pregnancy (AI) (see perinatal guidelines for more detailed discussion)
    • History of an AIDS-defining illness (AI)
    • HIV-associated nephropathy (HIVAN) (AII)
    • HIV/hepatitis B virus (HBV) coinfection (AII)
  • Effective ART also has been shown to prevent transmission of HIV from an infected individual to a sexual partner; therefore, ART should be offered to patients who are at risk of transmitting HIV to sexual partners (AI [heterosexuals] or AIII [other transmission risk groups]; see text for discussion).
  • Patients starting ART should be willing and able to commit to treatment and should understand the benefits and risks of therapy and the importance of adherence (AIII). Patients may choose to postpone therapy, and providers, on a case-by-case basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors.

Rating of Recommendations:  A = Strong; B = Moderate; C = Optional
Rating of Evidence:  I = data from randomized controlled trials; II = data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = expert opinion


Introduction

The primary goal of antiretroviral therapy (ART) is to reduce HIV-associated morbidity and mortality. This goal is best accomplished by using effective ART to maximally inhibit HIV replication, as defined by achieving and maintaining plasma HIV RNA (viral load) below levels detectable by commercially available assays. Durable viral suppression improves immune function and quality of life, lowers the risk of both AIDS-defining and non-AIDS-defining complications, and prolongs life. Based on emerging evidence, additional benefits of ART include a reduction in HIV-associated inflammation and possibly its associated complications.

The results of a randomized controlled trial and several observational cohort studies demonstrated that ART can reduce transmission of HIV. Therefore, a secondary goal of ART is to reduce an HIV-infected individual’s risk of transmitting the virus to others. Although the Panel concurs that this public health benefit of ART is significant, Panel recommendations on when to initiate ART are based primarily on the benefit of treatment to the HIV-infected individual.

The strength of Panel recommendations depends on disease stage. Randomized controlled trials provide definitive evidence supporting the benefit of ART in patients with CD4 counts <350 cells/mm3. Results from multiple observational cohort studies demonstrate benefits of ART in reducing AIDS- and non-AIDS-associated morbidity and mortality in patients with CD4 counts ranging from 350 to 500 cells/mm3. The Panel therefore recommends ART for patients with CD4 counts ≤500 cells/mm3 (AI for CD4 count <350 cells/mm3 and AII for CD4 count 350 to 500 cells/mm3).
 
The recommendation to initiate therapy at CD4 count >500 cells/mm3 (BIII) is based on growing awareness that untreated HIV infection or uncontrolled viremia may be associated with development of many non-AIDS-defining diseases, including cardiovascular disease (CVD), kidney disease, liver disease, neurologic complications, and malignancy; availability of ART regimens that are more effective, more convenient, and better tolerated than earlier ART combinations no longer widely used; and evidence from one observational cohort study that showed survival benefit in patients who started ART when their CD4 counts were >500 cells/mm3.

Tempering the enthusiasm to treat all patients regardless of CD4 count is the absence of randomized data that definitively demonstrate a clear benefit of ART in patients with CD4 count >500 cells/mm3 and mixed results on the benefits of early ART from observational cohort studies. In addition, potential risks of short- or long-term drug-related complications and nonadherence to long-term therapy in asymptomatic patients may offset possible benefits of earlier initiation of therapy. When resources are not available to initiate ART in all patients, treatment should be prioritized for patients with the lowest CD4 counts and those with the following clinical conditions: pregnancy, history of an AIDS-defining illness, HIV-associated nephropathy (HIVAN), or HIV/hepatitis B virus (HBV) coinfection.

The decision to initiate ART should always include consideration of other conditions and considerations listed in the Panel’s boxed recommendations, the willingness and readiness of the patient to initiate therapy, and the availability of resources. The known benefits and limitations of ART are discussed below.

Benefits of Antiretroviral Therapy

Reduction in Mortality and/or AIDS-Related Morbidity According to Pretreatment CD4 Cell Count

Patients with a history of an AIDS-defining illness or CD4 count <350 cells/mm3
HIV-infected patients with CD4 counts <200 cells/mm3 are at higher risk of opportunistic diseases, non-AIDS morbidity, and death than HIV-infected patients with higher CD4 counts. Randomized controlled trials in patients with CD4 counts <200 cells/mm3 and/or a history of an AIDS-defining condition provide strong evidence that ART improves survival and delays disease progression in these patients [1-3]. Long-term data from multiple observational cohort studies comparing earlier ART (initiated at CD4 count >200 cells/mm3) with later treatment (initiated at CD4 count <200 cells/mm3) also have provided strong support for these findings [4-9].

Few large, randomized controlled trials address when to start therapy in patients with CD4 counts >200 cells/mm3. CIPRA HT-001, a randomized clinical trial conducted in Haiti, enrolled 816 participants without AIDS. Participants were randomized to start ART at CD4 counts of 200 to 350 cells/mm3 or to defer treatment until their CD4 counts dropped to <200 cells/mm3 or they developed an AIDS-defining condition. An interim analysis of the study showed that, compared with participants who began ART with CD4 counts of 200 to 350 cells/mm3, patients who deferred therapy had a higher mortality rate (23 vs. 6 deaths, hazard ratio [HR] = 4.0, 95% confidence interval [CI]: 1.6–9.8) and greater incident tuberculosis (TB) (HR = 2.0, 95% CI: 1.2–3.6) [10].

Collectively, these studies support the Panel’s recommendation that ART should be initiated in patients with a history of an AIDS-defining illness or with a CD4 count <350 cells/mm3 (AI).

Patients with CD4 counts between 350 and 500 cells/mm3
Data supporting initiation of ART in patients with CD4 counts ranging from 350 to 500 cells/mm3 are derived from large observational studies and secondary analysis of randomized controlled trials. Analysis of the findings from the observational studies involved use of advanced statistical methods that minimize the bias and confounding that arise when observational data are used to address the question of when to start ART. However, unmeasured confounders for which adjustment was not possible may have influenced the analysis.

The ART Cohort Collaboration (ART-CC) included 45,691 patients from 18 cohort studies conducted primarily in North America and Europe. Data from ART-CC showed that the rate of progression to AIDS and/or death was higher when therapy was deferred until CD4 count fell to the 251 to 350 cells/mm3 range than when ART was initiated at the 351 to 450 cells/mm3 range (risk ratio: 1.28, 95% CI: 1.04–1.57) [6]. When analysis of the data was restricted to mortality alone, the difference between the 2 strategies was weaker and not statistically significant (risk ratio: 1.13, 95% CI: 0.80–1.60).

In a collaboration of North American cohort studies (NA-ACCORD) that evaluated patients regardless of whether they had started therapy, the 6,278 patients who deferred therapy until their CD4 counts were <350 cells/mm3 had greater risk of death than the 2,084 patients who initiated therapy with CD4 counts between 351 and 500 cells/mm3 (risk ratio: 1.69, 95% CI: 1.26–2.26) after adjustment for other factors that differed between these 2 groups [11].

Another collaboration of cohort studies from Europe and the United States (the HIV-CAUSAL Collaboration) included 8,392 ART-naive patients with initial CD4 counts >500 cells/mm3 who experienced declines in CD4 count to <500 cells/mm3 [9]. The study estimated that delaying initiation of ART until a patient had a CD4 count <350 cells/mm3 was associated with a greater risk of AIDS-defining illness or death than initating ART with a CD4 count between 350 and 500 cells/mm3 (HR: 1.38, 95% CI: 1.23–1.56). There was, however, no evidence of a difference in mortality (HR: 1.01, 95% CI: 0.84–1.22).

A collaboration of cohort studies from Europe, Australia, and Canada (the CASCADE Collaboration) included 5,527 ART-naive patients with CD4 counts in the 350 to 499 cells/mm3 range. Compared with patients who deferred therapy until their CD4 counts fell to <350 cells/mm3, patients who started ART immediately had a marginally lower risk of AIDS-defining illness or death (HR: 0.75, 95% CI: 0.49–1.14) and a lower risk of death (HR: 0.51, 95% CI: 0.33–0.80) [12].

Randomized data showing clinical evidence favoring ART in patients with higher CD4 cell counts comes from a small subgroup analysis of the SMART trial, undertaken primarily in North and South America, Europe, and Australia, which randomized participants with CD4 counts >350 cells/mm3 to continuous ART or to treatment interruption until CD4 count dropped to <250 cells/mm3. In the subgroup of 249 participants who were ART naive at enrollment (median CD4 count: 437 cells/mm3), participants who deferred therapy until CD4 count dropped to <250 cells/mm3 had a greater risk of serious AIDS- and non-AIDS-related events than those who initiated therapy immediately (7 vs. 2 events, HR: 4.6, 95% CI: 1.0–22.2) [13].

HPTN 052 was a large multinational, multicontinental (Africa, Asia, South America, and North America) randomized trial that examined whether treatment of HIV-infected individuals reduces transmission to their uninfected sexual partners [14]. An additional objective of the study was to determine whether ART reduces clinical events in the HIV-infected participants. This trial enrolled 1,763 HIV-infected participants with CD4 counts between 350 and 550 cells/mm3 and their HIV-uninfected partners. The infected participants were randomized to initiate ART immediately or to delay initiation until they had 2 consecutive CD4 counts less than 250 cells/mm3. At a median follow-up of 1.7 years, there were 40 events/deaths in the immediate therapy arm versus 65 events/deaths in the delayed arm (HR: 0.59, 95% CI: 0.40–0.88). The observed difference was driven mainly by the incidence of extrapulmonary TB (3 events in the immediate therapy arm vs. 17 events in the delayed therapy arm). The difference in mortality rates observed between the immediate and deferred therapy arms (10 vs. 13 deaths, respectively; HR: 0.77, 95% CI: 0.34–1.76) was not significant.

Collectively, these studies suggest that initiating ART in patients with CD4 counts between 350 and 500 cells/mm3 reduces HIV-related disease progression; whether there is a corresponding reduction in mortality is unclear. This benefit supports the Panel’s recommendation that ART should be initiated in patients with CD4 counts of 350 to 500 cells/mm3 (AII). Recent evidence demonstrating the public health benefit of earlier intervention further supports the strength of this recommendation (see Prevention of Sexual Transmission).

Patients with CD4 counts >500 cells/mm3
The NA-ACCORD study also observed patients who started ART at CD4 counts >500 cells/mm3 or after CD4 counts dropped below this threshold. The adjusted mortality rates were significantly higher in the 6,935 patients who deferred therapy until their CD4 counts fell to <500 cells/mm3 than in the 2,200 patients who started therapy at CD4 count >500 cells/mm3 (risk ratio: 1.94, 95% CI: 1.37–2.79) [11]. Although large and generally representative of the HIV-infected patients in care in the United States, the study has several limitations, including the small number of deaths and the potential for unmeasured confounders that might have influenced outcomes independent of ART.

In contrast, results from 2 cohort studies did not identify a benefit of earlier initiation of therapy in reducing AIDS progression or death. In an analysis of the ART-CC cohort [6], the rate of progression to AIDS/death associated with deferral of therapy until CD4 count in the the 351 to 450 cells/mm3 range was similar to the rate with initiation of therapy with CD4 count in the 451 to 550 cells/mm3 range (HR: 0.99, 95% CI: 0.76–1.29). There was no significant difference in rate of death identified (HR: 0.93, 95% CI: 0.60–1.44). This study also found that the proportion of patients with CD4 counts between 451 and 550 cells/mm3 who would progress to AIDS or death before having a CD4 count <450 cells/mm3 was low (1.6%; 95% CI: 1.1%–2.1%). In the CASCADE Collaboration [12], among the 5,162 patients with CD4 counts in the 500 to 799 cells/mm3 range, compared with patients who deferred therapy, those who started ART immediately did not experience a significant reduction in the composite outcome of progression to AIDS/death (HR: 1.10, 95% CI: 0.67–1.79) or death (HR: 1.02, 95% CI: 0.49–2.12).

With a better understanding of the pathogenesis of HIV infection, the growing awareness that untreated HIV infection increases the risk of many non-AIDS-defining diseases (as discussed below), and the benefit of ART in reducing transmission of HIV, the Panel also recommends initiation of ART in patients with CD4 counts >500 cells/mm3 (BIII). However, in making this recommendation the Panel notes that the amount of data supporting earlier initiation of therapy decreases as the CD4 count increases to >500 cells/mm3 and that concerns remain over the unknown overall benefit, long-term risks, and cumulative additional costs associated with earlier treatment.

When discussing starting ART at high CD4 cell counts (>500 cells/mm3), clinicians should inform patients that data on the clinical benefit of starting treatment at such levels are not conclusive, especially for patients with very high CD4 counts. The same is true for individuals with low viral load set points at presentation and for “elite controllers”. Further ongoing research (both randomized clinical trials and cohort studies) to assess the short- and long-term clinical and public health benefits and cost effectiveness of starting therapy at higher CD4 counts is needed. Findings from such research will provide the Panel with guidance to make future recommendations.

Effects of Viral Replication on HIV-Related Morbidity

Since the mid-1990s, measures of viral replication have been known to predict HIV disease progression. Among untreated HIV-infected individuals, time to clinical progression and mortality is fastest in those with greater viral loads [15]. This finding is confirmed across the wide spectrum of HIV-infected patient populations such as injection drug users (IDUs) [16], women [17], and individuals with hemophilia [18]. Several studies have shown the prognostic value of pretherapy viral load for predicting post-therapy response [19-20]. Once therapy has been initiated, failure to achieve viral suppression [21-23] and viral load at the time of treatment failure [24] are predictive of clinical disease progression.

More recent studies have examined the impact of ongoing viral replication for both longer durations and at higher CD4 cell counts. Using viremia copy-years, a novel metric for summarizing viral load over time, the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort found that total cumulative exposure to replicating virus over time is independently associated with mortality. Using viremia copy-years, the HR for mortality was 1.81 per log10 copy-year/mL (95% CI: 1.51–2.18), which was the only viral load-related variable that retained statistical significance in the multivariable model (HR 1.44 per log10 copy-year/mL; 95% CI: 1.07–1.94). These findings support the concept that unchecked viral replication, which occurs in the absence of effective ART, is a factor in disease progression and death, but the precise mechanism remains ill defined [25].  

The EuroSIDA collaboration evaluated HIV-infected individuals with CD4 counts >350 cells/ mm3 segregated by three viral load strata (<500 copies/mL, 500–9,999 copies/mL, and ≥10,000 copies/mL) to determine the impact of viral load on fatal and nonfatal AIDS-related and non-AIDS-related events. The lower viral load stratum included more subjects on ART (92%) than the middle (62%) and high (31%) viral load strata. After adjustment for age, region, and ART, the rates of non-AIDS events were 61% (P = 0.001) and 66% (P = 0.004) higher in participants with viral loads 500 to 9,999 copies/mL and ≥10,000 copies/mL, respectively, than in individuals with viral loads <500 copies/mL. These data further confirm that unchecked viral replication is associated with adverse clinical outcomes in individuals with CD4 counts >350 cells/mm3 [26].

Collectively, these data show that the harm of ongoing viral replication affects both untreated patients and those who are on ART but continue to be viremic. The harm of ongoing viral replication in patients on ART is compounded by the risk of emergence of drug-resistant virus. Therefore, all patients on ART should be carefully monitored and counseled on the importance of adherence to therapy.

Effects of ART on HIV-Related Morbidity

HIV-associated immune deficiency, the direct effects of HIV on end organs, and the indirect effects of HIV-associated inflammation on these organs all contribute to HIV-related morbidity and mortality. In general, the available data demonstrate that:

  • Untreated HIV infection may have detrimental effects at all stages of infection.
  • Earlier treatment may prevent the damage associated with HIV replication during early stages of infection.
  • ART is beneficial even when initiated later in infection; however, later therapy may not repair damage associated with viral replication during early stages of infection.
  • Sustaining viral suppression and maintaining higher CD4 count, mostly as a result of effective combination ART, may delay, prevent, or reverse some non-AIDS-defining complications, such as HIV-associated kidney disease, liver disease, CVD, neurologic complications, and malignancies, as discussed below.
HIV-associated nephropathy
HIVAN is the most common cause of chronic kidney disease in HIV-infected individuals that may lead to end-stage kidney disease [27]. HIVAN is almost exclusively seen in black patients and can occur at any CD4 count. Ongoing viral replication appears to be directly involved in renal injury [28] and HIVAN is extremely uncommon in virologically suppressed patients [29]. ART in patients with HIVAN has been associated with both preserved renal function and prolonged survival [30-32]. Therefore, ART should be started in patients with HIVAN, regardless of CD4 count, at the earliest sign of renal dysfunction (AII).

Coinfection with hepatitis B virus and/or hepatitis C virus
HIV infection is associated with more rapid progression of viral hepatitis-related liver disease, including cirrhosis, end-stage liver disease, hepatocellular carcinoma, and fatal hepatic failure [33-34]. The pathogenesis of accelerated liver disease in HIV-infected patients has not been fully elucidated but HIV-related immunodeficiency and a direct interaction between HIV and hepatic stellate and Kupffer cells have been implicated [35-38]. In individuals coinfected with HBV and/or hepatitis C virus (HCV), ART may attenuate liver disease progression by preserving or restoring immune function and reducing HIV-related immune activation and inflammation [39-41]. Antiretroviral (ARV) drugs active against both HIV and HBV (such as tenofovir disoproxil fumarate [TDF], lamivudine [3TC], and emtricitabine [FTC]) also may prevent development of significant liver disease by directly suppressing HBV replication [42-43]. Although ARV drugs do not inhibit HCV replication directly, HCV treatment outcomes typically improve when HIV replication is controlled or CD4 counts are increased [44]. Chronic viral hepatitis increases the risk of ARV-induced liver injury; however, the majority of coinfected persons do not develop clinically significant liver injury [45-47]. Some studies suggest that the rate of hepatotoxicity is greater in persons with more advanced HIV disease. Nevirapine (NVP) toxicity is a notable exception: the hypersensitivity reaction (HSR) and associated hepatotoxicity to this drug are more frequent in patients with higher pretreatment CD4 cell counts [48]. Collectively, these data suggest earlier treatment of HIV infection in persons coinfected with HBV, and likely HCV, may reduce the risk of liver disease progression. Thus, ART is recommended for patients coinfected with HBV (AII). ART for patients coinfected with HBV should include drugs with activity against both HIV and HBV (AII) (also see Hepatitis B Virus/HIV Coinfection). ART also is recommended for most patients coinfected with HCV (BII), including those with high CD4 counts and those with cirrhosis. Combined HIV/HCV treatment can be complicated by large pill burden, drug interactions, and overlapping toxicities. Although ART should be considered for HIV/HCV-coinfected patients regardless of CD4 cell count, for patients infected with HCV genotype 1, some clinicians may choose to defer ART in HIV treatment-naive patients with CD4 counts >500 cells/mm3 until HCV treatment that includes the HCV NS3/4A protease inhibitors (PIs) is completed (also see HIV/Hepatitis C Virus Coinfection).

Cardiovascular disease
Among HIV-infected patients, CVD is a major cause of morbidity and mortality, accounting for a third of serious non-AIDS conditions and at least 10% of deaths [49-50]. Studies link exposure to specific ARV drugs to a higher risk of CVD [51-52]. In one study, compared with HIV-uninfected controls, HIV-infected men on ART had a more atherogenic lipid profile as assessed by lipoprotein particle size analysis [53]. Untreated HIV infection also may be associated with an increased risk of CVD. In several cross-sectional studies, levels of markers of inflammation and endothelial dysfunction were higher in HIV-infected patients than in HIV-uninfected controls [54-56]. In two randomized trials, markers of inflammation and coagulation increased following treatment interruption [57-58]. One study suggests that ART may improve endothelial function [59].

In the SMART study, the risk of cardiovascular events was greater in participants randomized to CD4-guided treatment interruption than in participants who received continuous ART [60]. In other studies, ART resulted in marked improvement in parameters associated with CVD, including markers of inflammation (such as interleukin 6 [IL-6] and high-sensitivity C-reactive protein [hsCRP]) and endothelial dysfunction [55, 59]. A modest association between lower CD4 count while on therapy and short-term risk of CVD also exists [56, 61-62]. However, in at least one of these cohorts (the CASCADE study), the link between CD4 count and fatal cardiovascular events was no longer statistically significant when adjusted for plasma HIV RNA level. Collectively, the data linking viremia and endothelial dysfunction and inflammation, the increased risk of cardiovascular events with treatment interruption, and the association between CVD and CD4 cell depletion suggest that early control of HIV replication with ART can be used as a strategy to reduce  risk of CVD. Therefore, ART should be considered for HIV-infected individuals with a significant risk of CVD, as assessed by medical history and established estimated risk calculations (BII). Consideration of risk of CVD in the selection of specific ART is discussed in What to Start.

Malignancies
Several population-based analyses suggest that the incidence of non-AIDS-associated malignancies is increased in chronic HIV infection. The incidence of non-AIDS-defining malignancies is higher in HIV-infected subjects than in matched HIV-uninfected controls [63]. Large cohort studies enrolling mainly patients receiving ART have reported a consistent link between low CD4 counts (<350–500 cells/mm3) and the risk of AIDS- and/or non-AIDS-defining malignancies [7, 61, 64-67]. The ANRS C04 Study demonstrated a statistically significant relative risk of all cancers evaluated (except for anal carcinoma) in patients with CD4 counts <500 cells/mm3 compared with patients with current CD4 counts >500 cells/mm3, and, regardless of CD4 count, a protective effect of ART for HIV-associated malignancies [64]. This potential effect of HIV-associated immunodeficiency is striking particularly with regard to cancers associated with chronic viral infections such as HBV, HCV, human papilloma virus (HPV), Epstein-Barr virus (EBV), and human herpes virus-8 (HHV-8)[68-69]. Cumulative HIV viremia, independent of other factors, may also be associated with the risk of non-Hodgkin lymphoma and other AIDS-defining malignancies [67, 70]. Since the early 1990s, incidence rates for many cancers, including Kaposi sarcoma, diffuse large B-cell lymphoma, and primary central nervous system (CNS) lymphoma, have declined markedly in HIV-infected individuals in the United States. However, for other cancers, such as Burkitt lymphoma, Hodgkin lymphoma, cervical cancer, and anal cancer, similar reductions in incidence have not been observed [71-72]. Declines in overall mortality and aging of HIV-infected cohorts increase overall cancer incidence, which may confound a clear assessment of the impact of ART on preventing the development of malignancies [73-74]. Taken together this evidence suggests that initiating ART to suppress HIV replication and maintain CD4 counts at levels >350 to 500 cells/mm3 may reduce the overall incidence of both AIDS-defining and non-AIDS-defining malignancies (CIII), although the effect on incidence is most likely to be heterogeneous across various cancer types.

Neurological diseases
Although HIV RNA can be detected in the cerebrospinal fluid (CSF) of most untreated patients [75-76], these patients usually do not present with overt symptoms of HIV-associated neurological disease [77]. In some patients CNS infection progresses to HIV encephalitis and can present as HIV-associated dementia (HAD) [78-80]. This progression is usually in the context of more advanced untreated systemic HIV infection when severe CNS opportunistic infections (OIs) also cause high morbidity and mortality [81].

ART has had a profound impact on the nervous system complications of HIV infection. Effective viral suppression resulting from ART has dramatically reduced the incidence of HAD and severe CNS OIs [82-84]. Suppressive ART usually reduces CSF HIV RNA to undetectable levels [85-86]. Exceptional cases of symptomatic and asymptomatic CNS viral escape, in which HIV RNA is detectable in CSF despite viral suppression in plasma, have been documented [87-88]. This suggests that in some settings monitoring CSF HIV RNA may be useful.

Recent attention has turned to milder forms of CNS dysfunction, defined by impairment on formal neuropsychological testing [80, 89]. It is unclear whether this impairment is a consequence of injury sustained before treatment initiation or whether neurologic damage can continue or develop despite systemically effective ART [90]. The association of cognitive impairment with low nadir CD4 counts supports pretreatment injury and bolsters the argument that earlier initiation of ART may prevent subsequent brain dysfunction [91-92].

The peripheral nervous system (PNS) also is a target in HIV infection, and several types of neuropathies have been identified [93]. Most common is HIV-associated polyneuropathy, a chronic, predominantly sensory and sometimes painful neuropathy. The impact of early treatment on this and other forms of neuropathy is not as clearly defined as on HAD [94-95].

Age and treatment-related immune reconstitution (also see HIV and the Older Patient)
The CD4 cell response to ART is an important predictor of short- and long-term morbidity and mortality. Treatment initiation at an older age is consistently associated with a less robust CD4 count response; starting therapy at a younger age may result in better immunologic and perhaps clinical outcomes [96-99].

T-cell activation and inflammation
Early untreated HIV infection is associated with sustained high-level inflammation and T-cell activation [100-102]. The degree of T-cell activation during untreated HIV disease is associated with risk of subsequent disease progression, independent of other factors such as plasma HIV RNA levels and peripheral CD4 T-cell count [103-104]. ART results in a rapid, but often incomplete, decrease in most markers of HIV-associated immune activation [105-109]. Persistent T-cell activation and/or T-cell dysfunction is particularly evident in patients who delay therapy until later stage disease (CD4 count <350 cells/mm3) [106, 109-110]. The degree of persistent inflammation during treatment, as represented by the levels of IL-6, may be independently associated with risk of death [58]. Collectively, these observations support earlier use of ART for at least two reasons. First, treatment decreases the level of inflammation and T-cell activation, which may be associated with reduced short-term risk of AIDS- and non-AIDS-related morbidity and mortality [58, 111-112]. Second, because the degree of residual inflammation and/or T-cell dysfunction during ART appears to be higher in patients with lower CD4 cell nadirs [106, 109-110], earlier treatment may result in less residual immunological perturbations on therapy and, hence, less risk for AIDS- and non-AIDS-related complications (CIII).

Antiretroviral Therapy for Prevention of HIV Transmission

Prevention of perinatal transmission
Effective ART reduces transmission of HIV. The most dramatic and well-established example of this effect is the use of ART in pregnant women to prevent perinatal transmission of HIV. Effective suppression of HIV replication, as reflected in plasma HIV RNA, is a key determinant in reducing perinatal transmission. In the setting of ART initiation prior to 28 weeks’ gestation and an HIV RNA level <50 copies/mL near delivery, use of combination ART during pregnancy has reduced the rate of perinatal transmission of HIV from approximately 20% to 30% to <0.5% [113]. Thus, use of combination ART drug regimens is recommended for all HIV-infected pregnant women (AI). Following delivery, in the absence of breastfeeding, considerations regarding continuation of the ARV regimen for maternal therapeutic indications are the same as those regarding ART for other non-pregnant individuals. For detailed recommendations, see the perinatal guidelines [114].

Prevention of sexual transmission
Recent study results provide strong support for the premise that treatment of the HIV-infected individual can significantly reduce sexual transmission of HIV. Lower plasma HIV RNA levels are associated with decreases in the concentration of the virus in genital secretions [115-116]. Studies of HIV-serodiscordant heterosexual couples have demonstrated a relationship between level of plasma viremia and risk of transmission of HIV: when plasma HIV RNA levels are lower, transmission events are less common [117-121].

HPTN 052 was a multicontinental trial that enrolled 1,763 HIV-serodiscordant couples, in which the HIV-infected partner was ART naive and had a CD4 count of 350 to 550 cells/mm3 at enrollment. The study compared immediate ART with delayed therapy (not started until CD4 count <250 cells/mm3) for the HIV-infected partner [14]. At study entry, 98% of the participants were in heterosexual monogamous relationships. All study participants were counseled on behavioral modification and condom use. Twenty-eight linked HIV transmission events were identified during the study period but only 1 event occurred in the early therapy arm. This 96% reduction in transmission associated with early ART was statistically significant (HR 0.04, 95% CI: 0.01–0.27, P <0.001). These results show that early ART is more effective at preventing transmission of HIV than all other behavioral and biomedical prevention interventions studied to date, including condom use, male circumcision, vaginal microbicides, HIV vaccination, and pre-exposure prophylaxis. This study, as well as other observational studies, and modeling analyses showing a decreased rate of HIV transmission among serodiscordant heterosexual couples following the introduction of ART, demonstrate that suppression of viremia in ART-adherent patients with no concomitant sexually transmitted diseases (STDs) substantially reduces the risk of transmission of HIV [120-125]. HPTN 052 was conducted in heterosexual couples and not in populations at risk of transmission via homosexual exposure or needle sharing. However, the prevention benefits of effective ART probably will apply to these populations as well. Therefore, the Panel recommends that ART be offered to patients who are at risk of transmitting HIV to sexual partners. (The strength of this recommendation varies according to mode of sexual transmission: AI for heterosexual transmission and AIII for male-to-male and other modes of sexual transmission.) Clinicians should discuss with patients the potential individual and public health benefits of therapy and the need for adherence to the prescribed regimen and counsel patients that ART is not a substitute for condom use and behavioral modification and that ART does not protect against other STDs (also see Preventing Secondary Transmission of HIV).

Potential Limitations of Earlier Intiation of Therapy
Although there are benefits associated with earlier initiation of ART, there also are some limitations to using this approach in all patients. Concerns about long-term toxicity and development of resistance to ARV drugs have served as a rationale for deferral of HIV therapy. However, evidence thus far indicates that resistance occurs more frequently in individuals who initiate therapy later in the course of infection than in those who initiate ART earlier. Earlier initiation of ART at higher CD4 counts (e.g., >500 cells/mm3) results in greater cumulative time on therapy. Nevertheless, assuming treatment will continue for several decades regardless of when therapy is initiated, the incremental increase in drug exposure associated with starting therapy at higher CD4 counts will represent a small percentage of the total time on ART for most patients.

Newer ARV drugs are generally better tolerated, more convenient, and more effective than drugs used in older regimens but there are fewer longer term safety data for the newer agents. Analyses supporting initiation of ART at CD4 counts >350 cells/mm3 (e.g., NA-ACCORD and ART-CC) were based on observational cohort data where patients were largely treated with regimens less commonly used in current clinical practice. In addition, these studies reported on clinical endpoints of death and/or AIDS disease progression but lacked information on drug toxicities, emergent drug resistance, or adherence. Therefore, in considering earlier initiation of therapy, concerns for some adverse consequences of ART remain.

Antiretroviral Drug Toxicities and Quality of Life

Earlier initiation of ART extends exposure to ARV agents by several years. The D:A:D study found an increased incidence of CVD associated with cumulative exposure to some drugs in the nucleoside reverse transcriptase inhibitor (NRTI) and PI drug classes [52, 126]. In the SMART study, compared with interruption or deferral of therapy, continuous exposure to ART was associated with significantly greater loss of bone density [60]. There may be unknown complications related to cumulative use of ARV drugs for many decades. A list of known ARV-associated toxicities can be found in Adverse Effects of Antiretroviral Agents.

ART frequently improves quality of life for symptomatic patients. However, some side effects of ART may impair the quality of life for some patients, especially those who are asymptomatic at initiation of therapy. For example, efavirenz (EFV) can cause neurocognitive or psychiatric side effects and all the PIs have been associated with gastrointestinal (GI) side effects. Furthermore, some patients may find that the inconvenience of taking medication every day outweighs the overall benefit of early ART and may choose to delay therapy.

Nonadherence to Antiretroviral Therapy

At any CD4 count, adherence to therapy is essential to achieve viral suppression and prevent emergence of drug-resistance mutations. Several behavioral and social factors associated with poor adherence, such as untreated major psychiatric disorders, active substance abuse, unfavorable social circumstances, patient concerns about side effects, and poor adherence to clinic visits, have been identified. Clinicians should identify areas where additional intervention is needed to improve adherence both before and after initiation of therapy. Some strategies to improve adherence are discussed in Adherence to Antiretroviral Therapy.

Cost

In resource-rich countries, the cost of ART exceeds $10,000 per year (see Appendix C). Several modeling studies support the cost effectiveness of HIV therapy initiated soon after diagnosis [127-129]. One study reported that the annual cost of care is 2.5 times higher for patients with CD4 counts <50 cells/mm3 than for patients with CD4 counts >350 cells/mm3 [130]. A large proportion of the health care expenditure in patients with advanced infection is from non-ARV drugs and hospitalization. However, no comparisons of costs for patients starting ART with CD4 count 350 to 500 cells/mm3 and those for patients starting ART at >500 cells/mm3 have been reported.

Historically, concerns about long-term toxicity, reduced quality of life, and the potential for emerging drug resistance served as key reasons to defer HIV therapy in asymptomatic patients for as long as possible. Inherent in this reasoning was the assumption that in asymptomatic patients the harm associated with viral replication was less than the harm associated with the toxicities of ART. There is now more evidence that untreated HIV infection has negative consequences on health at all stages of disease. Also, the currently preferred ART regimens are better tolerated than previous regimens, leading to greater effectiveness, improved adherence [131], and lower frequency of emerging drug resistance. Therefore, the current guidelines emphasize avoiding adverse consequences of untreated HIV infection while managing potential drug toxicity associated with ART.

Conditions Favoring More Rapid Initiation of Therapy

Several conditions increase the urgency for therapy, including:

  • Pregnancy (AI) (Clinicians should refer to the perinatal guidelines for more detailed recommendations on the management of HIV-infected pregnant women [114].) 
  • AIDS-defining conditions (AI)
  • Acute OIs (see discussion below)
  • Lower CD4 counts (e.g., <200 cells/mm3) (AI)
  • HIVAN (AII)
  • HIV/HBV coinfection (AII)
  • Rapidly declining CD4 counts (e.g., >100 cells/mm3 decrease per year) (AIII)
  • Higher viral loads (e.g., >100,000 copies/mL) (BII)
Acute opportunistic infections
In patients with opportunistic conditions for which no effective therapy exists (e.g., cryptosporidiosis, microsporidiosis, progressive multifocal leukoencephalopathy) but in whom ART may improve outcomes by improving immune responses, the benefits of ART outweigh any increased risk; therefore, treatment should be started as soon as possible (AIII).

In the setting of some OIs, such as cryptococcal meningitis or nontuberculous mycobacterial infections, for which immediate therapy may increase the risk of immune reconstitution inflammatory syndrome (IRIS), a short delay before initiating ART may be warranted (CIII).[132-133] In the setting of other OIs, such as Pneumocystis jiroveci pneumonia (PCP), early initiation of ART is associated with increased survival [3]; therefore, therapy should not be delayed (AI).

In patients who have active TB, initiating ART during treatment for TB confers a significant survival advantage [134-138]; therefore, ART should be initiated as recommended in Mycobacterium Tuberculosis Disease with HIV Coinfection.

Clinicians should refer to the Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents [139] for more detailed discussion on when to initiate ART in the setting of a specific OI.

Conditions Where Deferral of Therapy May be Considered

Some patients and their clinicians may decide to defer therapy for a period of time on the basis of clinical or personal circumstances. Deferring therapy for the reasons discussed below may be reasonable in patients with high CD4 counts (e.g., >500 cells/mm3) but deferring therapy in patients with much lower CD4 counts (e.g., <200 cells/mm3) should be considered only in rare situations and should be undertaken with close clinical follow-up. A brief delay in initiating therapy to allow a patient more time to prepare for lifelong treatment may be considered.

When there are significant barriers to adherence (also see Adherence to Antiretroviral Therapy)
In patients with higher CD4 counts who are at risk of poor adherence, it may be prudent to defer treatment while addressing the barriers to adherence. However, in patients with conditions that require urgent initiation of ART (see above), therapy should be started while simultaneously addressing the barriers to adherence.

Several methodologies exist to help providers assess adherence. When the most feasible measure of adherence is self-report, this assessment should be completed at each clinic visit using one of the available reliable and valid instruments [140-141]. If other objective measures (e.g., pharmacy refill data, pill count) are available, these methods should be used to assess adherence at each follow-up visit [142-144]. Continuous assessment and counseling make it possible for the clinician to intervene early to address barriers to adherence occurring at any point during treatment (see Adherence to Antiretroviral Therapy).

Presence of comorbidities that complicate or prohibit antiretroviral therapy
Deferral of ART may be considered when either the treatment or manifestations of other medical conditions could complicate the treatment of HIV infection or vice versa. Examples include:
  • Surgery that may result in an extended interruption of ART.
  • Treatment with medications that have clinically significant drug interactions with ART and for which alternative medications are not available.
In each of these circumstances, the assumption is that the situation is temporary and that ART will be initiated after the conflicting condition has resolved.

Some less common situations exist in which ART may not be indicated at any time while CD4 counts remain high. In particular, such situations include that of patients with a poor prognosis due to a concomitant medical condition who would not be expected to gain survival or quality-of-life benefits from ART. Examples include patients with incurable non-HIV-related malignancies or end-stage liver disease who are not being considered for liver transplantation. The decision to forego ART in such patients may be easier to make in those with higher CD4 counts; they are likely asymptomatic for HIV, and their survival is unlikely to be prolonged by ART. However, it should be noted that ART may improve outcomes, including survival, in patients with some HIV-associated malignancies (e.g., lymphoma or Kaposi sarcoma) and in patients with liver disease due to chronic HBV or HCV.

Long-term nonprogressors and elite HIV controllers
A small subset of ARV-untreated HIV-infected individuals (~3%-5%) can maintain normal CD4 cell counts for many years (long-term nonprogressors), and an even smaller subset (~1%) can maintain suppressed viral loads for years (elite controllers) [145-146]. Although therapy theoretically may be beneficial for patients in either group, clinical data supporting therapy for nonprogressors and elite controllers are lacking.

The Need for Early Diagnosis of HIV

Fundamental to the earlier initiation of ART recommended in these guidelines is the assumption that patients will be diagnosed early in the course of HIV infection, making earlier initiation of therapy an option. Unfortunately, most HIV-infected patients are not diagnosed until they are at much later stages of disease [147-150]. Despite the 2006 Centers for Disease Control and Prevention (CDC) recommendations for routine, opt-out HIV screening in the health care setting regardless of perceptions about a patient’s risk of infection [151], the median CD4 count of newly diagnosed patients remains in the ~200 cells/mm3 range. The exception is pregnant women diagnosed during prenatal care, who have a much higher median initial CD4 count. Compared with other groups, nonwhites, IDUs, and older patients more often receive a delayed diagnosis of HIV infection and a substantial proportion of these individuals develop AIDS-defining illnesses within 1 year of diagnosis [147-150]. Therefore, for the current treatment guidelines to have maximum impact, routine HIV screening per current CDC recommendations is essential. It is also critical that all newly diagnosed patients be educated about HIV disease and linked to care for full evaluation, follow-up, and management. Once patients are in care, focused effort is required to retain them in the health care system if the full benefits of early diagnosis and treatment are to be achieved both for the infected individuals and their sexual partners.

Conclusion
The current recommendations are based on greater evidence supporting earlier initiation of ART than was advocated in previous guidelines. The strength of the recommendations varies according to the quality and availability of existing evidence supporting each recommendation. In addition to the benefit of earlier initiation of therapy for the health of the HIV-infected individual, the reduction in sexual transmission to HIV-uninfected individuals provides further reason for earlier initiation of ART. The Panel will continue to monitor and assess the results of ongoing and planned randomized clinical trials and observational studies, which will provide the Panel with additional guidance to form future recommendations.

References
  1. HIV Trialists' Collaborative Group. Zidovudine, didanosine, and zalcitabine in the treatment of HIV infection: meta-analyses of the randomised evidence. Lancet. Jun 12 1999;353(9169):2014-2025.
  2. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med. Sep 11 1997;337(11):725-733.
  3. Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One. 2009;4(5):e5575.
  4. Mocroft A, Vella S, Benfield TL, et al. Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet. Nov 28 1998;352(9142):1725-1730.
  5. Hogg RS, Yip B, Chan KJ, et al. Rates of disease progression by baseline CD4 cell count and viral load after initiating triple-drug therapy. JAMA. Nov 28 2001;286(20):2568-2577.
  6. Sterne JA, May M, Costagliola D, et al. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet. Apr 18 2009;373(9672):1352-1363.
  7. Baker JV, Peng G, Rapkin J, et al. CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS. Apr 23 2008;22(7):841-848.
  8. Palella FJ, Jr., Deloria-Knoll M, Chmiel JS, et al. Survival benefit of initiating antiretroviral therapy in HIV-infected persons in different CD4+ cell strata. Ann Intern Med. Apr 15 2003;138(8):620-626.
  9. Cain LE, Logan R, Robins JM, et al. When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study. Ann Intern Med. Apr 19 2011;154(8):509-515.
  10. Severe P, Juste MA, Ambroise A, et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med. Jul 15 2010;363(3):257-265.
  11. Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med. Apr 30 2009;360(18):1815-1826.
  12. Writing Committee of the CASCADE Collaboration. Timing of HAART initiation and clinical outcomes in human immunodeficiency virus type 1 seroconverters. Arch Intern Med. Sep 26 2011;171(17):1560-1569.
  13. Emery S, Neuhaus JA, Phillips AN, et al. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. J Infect Dis. Apr 15 2008;197(8):1133-1144.
  14. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. Aug 11 2011;365(6):493-505.
  15. Mellors JW, Rinaldo CR, Jr., Gupta P, White RM, Todd JA, Kingsley LA. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science. May 24 1996;272(5265):1167-1170.
  16. Vlahov D, Graham N, Hoover D, et al. Prognostic indicators for AIDS and infectious disease death in HIV-infected injection drug users: plasma viral load and CD4+ cell count. JAMA. Jan 7 1998;279(1):35-40.
  17. Anastos K, Kalish LA, Hessol N, et al. The relative value of CD4 cell count and quantitative HIV-1 RNA in predicting survival in HIV-1-infected women: results of the women's interagency HIV study. AIDS. Sep 10 1999;13(13):1717-1726.
  18. O'Brien TR, Blattner WA, Waters D, et al. Serum HIV-1 RNA levels and time to development of AIDS in the Multicenter Hemophilia Cohort Study. JAMA. Jul 10 1996;276(2):105-110.
  19. Egger M, May M, Chene G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet. Jul 13 2002;360(9327):119-129.
  20. Anastos K, Barron Y, Cohen MH, et al. The prognostic importance of changes in CD4+ cell count and HIV-1 RNA level in women after initiating highly active antiretroviral therapy. Ann Intern Med. Feb 17 2004;140(4):256-264.
  21. O'Brien WA, Hartigan PM, Martin D, et al. Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. Veterans Affairs Cooperative Study Group on AIDS. N Engl J Med. Feb 15 1996;334(7):426-431.
  22. Hughes MD, Johnson VA, Hirsch MS, et al. Monitoring plasma HIV-1 RNA levels in addition to CD4+ lymphocyte count improves assessment of antiretroviral therapeutic response. ACTG 241 Protocol Virology Substudy Team. Ann Intern Med. Jun 15 1997;126(12):929-938.
  23. Chene G, Sterne JA, May M, et al. Prognostic importance of initial response in HIV-1 infected patients starting potent antiretroviral therapy: analysis of prospective studies. Lancet. Aug 30 2003;362(9385):679-686.
  24. Deeks SG, Gange SJ, Kitahata MM, et al. Trends in multidrug treatment failure and subsequent mortality among antiretroviral therapy-experienced patients with HIV infection in North America. Clin Infect Dis. Nov 15 2009;49(10):1582-1590.
  25. Mugavero MJ, Napravnik S, Cole SR, et al. Viremia copy-years predicts mortality among treatment-naive HIV-infected patients initiating antiretroviral therapy. Clin Infect Dis. Nov 2011;53(9):927-935.
  26. Reekie J, Gatell JM, Yust I, et al. Fatal and nonfatal AIDS and non-AIDS events in HIV-1-positive individuals with high CD4 cell counts according to viral load strata. AIDS. Nov 28 2011;25(18):2259-2268.
  27. Szczech LA, Gupta SK, Habash R, et al. The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection. Kidney Int. Sep 2004;66(3):1145-1152.
  28. Marras D, Bruggeman LA, Gao F, et al. Replication and compartmentalization of HIV-1 in kidney epithelium of patients with HIV-associated nephropathy. Nat Med. May 2002;8(5):522-526.
  29. Estrella M, Fine DM, Gallant JE, et al. HIV type 1 RNA level as a clinical indicator of renal pathology in HIV-infected patients. Clin Infect Dis. Aug 1 2006;43(3):377-380.
  30. Atta MG, Gallant JE, Rahman MH, et al. Antiretroviral therapy in the treatment of HIV-associated nephropathy. Nephrol Dial Transplant. Oct 2006;21(10):2809-2813.
  31. Schwartz EJ, Szczech LA, Ross MJ, Klotman ME, Winston JA, Klotman PE. Highly active antiretroviral therapy and the epidemic of HIV+ end-stage renal disease. J Am Soc Nephrol. Aug 2005;16(8):2412-2420.
  32. Kalayjian RC, Franceschini N, Gupta SK, et al. Suppression of HIV-1 replication by antiretroviral therapy improves renal function in persons with low CD4 cell counts and chronic kidney disease. AIDS. Feb 19 2008;22(4):481-487.
  33. Thein HH, Yi Q, Dore GJ, Krahn MD. Natural history of hepatitis C virus infection in HIV-infected individuals and the impact of HIV in the era of highly active antiretroviral therapy: a meta-analysis. AIDS. Oct 1 2008;22(15):1979-1991.
  34. Thio CL, Seaberg EC, Skolasky R, Jr., et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet. Dec 14 2002;360(9349):1921-1926.
  35. Weber R, Sabin CA, Friis-Moller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med. Aug 14-28 2006;166(15):1632-1641.
  36. Balagopal A, Philp FH, Astemborski J, et al. Human immunodeficiency virus-related microbial translocation and progression of hepatitis C. Gastroenterology. Jul 2008;135(1):226-233.
  37. Blackard JT, Kang M, St Clair JB, et al. Viral factors associated with cytokine expression during HCV/HIV co-infection. J Interferon Cytokine Res. Apr 2007;27(4):263-269.
  38. Hong F, Tuyama A, Lee TF, et al. Hepatic stellate cells express functional CXCR4: role in stromal cell-derived factor-1alpha-mediated stellate cell activation. Hepatology. Jun 2009;49(6):2055-2067.
  39. Macias J, Berenguer J, Japon MA, et al. Fast fibrosis progression between repeated liver biopsies in patients coinfected with human immunodeficiency virus/hepatitis C virus. Hepatology. Oct 2009;50(4):1056-1063.
  40. Verma S, Goldin RD, Main J. Hepatic steatosis in patients with HIV-Hepatitis C Virus coinfection: is it associated with antiretroviral therapy and more advanced hepatic fibrosis? BMC Res Notes. 2008;1:46.
  41. Ragni MV, Nalesnik MA, Schillo R, Dang Q. Highly active antiretroviral therapy improves ESLD-free survival in HIV-HCV co-infection. Haemophilia. Mar 2009;15(2):552-558.
  42. Matthews GV, Avihingsanon A, Lewin SR, et al. A randomized trial of combination hepatitis B therapy in HIV/HBV coinfected antiretroviral naive individuals in Thailand. Hepatology. Oct 2008;48(4):1062-1069.
  43. Peters MG, Andersen J, Lynch P, et al. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology. Nov 2006;44(5):1110-1116.
  44. Avidan NU, Goldstein D, Rozenberg L, et al. Hepatitis C viral kinetics during treatment with peg IFN-alpha-2b in HIV/HCV coinfected patients as a function of baseline CD4+ T-cell counts. J Acquir Immune Defic Syndr. Dec 1 2009;52(4):452-458.
  45. Clotet B, Bellos N, Molina JM, et al. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet. Apr 7 2007;369(9568):1169-1178.
  46. Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med. Jul 24 2008;359(4):339-354.
  47. Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr. Mar 1 2010;53(3):323-332.
  48. van Leth F, Andrews S, Grinsztejn B, et al. The effect of baseline CD4 cell count and HIV-1 viral load on the efficacy and safety of nevirapine or efavirenz-based first-line HAART. AIDS. Mar 25 2005;19(5):463-471.
  49. Smith C. Factors associated with specific causes of death amongst HIV-positive individuals in the D:A:D Study. AIDS. Jun 19 2010;24(10):1537-1548.
  50. Mocroft A, Reiss P, Gasiorowski J, et al. Serious fatal and nonfatal non-AIDS-defining illnesses in Europe. J Acquir Immune Defic Syndr. Oct 1 2010;55(2):262-270.
  51. Sabin CA, Worm SW, Weber R, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. Apr 26 2008;371(9622):1417-1426.
  52. Friis-Moller N, Reiss P, Sabin CA, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med. Apr 26 2007;356(17):1723-1735.
  53. Riddler SA, Li X, Otvos J, et al. Antiretroviral therapy is associated with an atherogenic lipoprotein phenotype among HIV-1-infected men in the Multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr. Jul 1 2008;48(3):281-288.
  54. Ross AC, Armentrout R, O'Riordan MA, et al. Endothelial activation markers are linked to HIV status and are independent of antiretroviral therapy and lipoatrophy. J Acquir Immune Defic Syndr. Dec 15 2008;49(5):499-506.
  55. McComsey G, Smith K, Patel P, et al. Similar reductions in markers of inflammation and endothelial activation after initiation of abacavir/lamivudine or tenofovir/emtricitabine: The HEAT Study. Paper presented at 16th Conference on Retroviruses and Opportunistic Infections (CROI): Feb. 8–11, 2009; Montreal, Canada
  56. Baker JV, Duprez D, Rapkin J, et al. Untreated HIV infection and large and small artery elasticity. J Acquir Immune Defic Syndr. Sep 1 2009;52(1):25-31.
  57. Calmy A, Gayet-Ageron A, Montecucco F, et al. HIV increases markers of cardiovascular risk: results from a randomized, treatment interruption trial. AIDS. May 15 2009;23(8):929-939.
  58. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. Oct 21 2008;5(10):e203.
  59. Torriani FJ, Komarow L, Parker RA, et al. Endothelial function in human immunodeficiency virus-infected antiretroviral-naive subjects before and after starting potent antiretroviral therapy: The ACTG (AIDS Clinical Trials Group) Study 5152s. J Am Coll Cardiol. Aug 12 2008;52(7):569-576.
  60. El-Sadr WM, Lundgren JD, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. Nov 30 2006;355(22):2283-2296.
  61. Marin B, Thiebaut R, Bucher HC, et al. Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy. AIDS. Aug 24 2009;23(13):1743-1753.
  62. Phillips AN, Neaton J, Lundgren JD. The role of HIV in serious diseases other than AIDS. AIDS. Nov 30 2008;22(18):2409-2418.
  63. Bedimo RJ, McGinnis KA, Dunlap M, Rodriguez-Barradas MC, Justice AC. Incidence of non-AIDS-defining malignancies in HIV-infected versus noninfected patients in the HAART era: impact of immunosuppression. J Acquir Immune Defic Syndr. Jul 16 2009;52(2):203-205.
  64. Guiguet M, Boue F, Cadranel J, Lang JM, Rosenthal E, Costagliola D. Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study. Lancet Oncol. Oct 7 2009;10(12):1152-1159.
  65. Monforte A, Abrams D, Pradier C, et al. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS. Oct 18 2008;22(16):2143-2153.
  66. Reekie J, Kosa C, Engsig F, et al. Relationship between current level of immunodeficiency and non-acquired immunodeficiency syndrome-defining malignancies. Cancer. Nov 15 2010;116(22):5306-5315.
  67. Bruyand M, Thiebaut R, Lawson-Ayayi S, et al. Role of uncontrolled HIV RNA level and immunodeficiency in the occurrence of malignancy in HIV-infected patients during the combination antiretroviral therapy era: Agence Nationale de Recherche sur le Sida (ANRS) CO3 Aquitaine Cohort. Clin Infect Dis. Oct 1 2009;49(7):1109-1116.
  68. Silverberg MJ, Chao C, Leyden WA, et al. HIV infection and the risk of cancers with and without a known infectious cause. AIDS. Nov 13 2009;23(17):2337-2345.
  69. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. Jul 7 2007;370(9581):59-67.
  70. Zoufaly A, Stellbrink HJ, Heiden MA, et al. Cumulative HIV viremia during highly active antiretroviral therapy is a strong predictor of AIDS-related lymphoma. J Infect Dis. Jul 1 2009;200(1):79-87.
  71. Shiels MS, Pfeiffer RM, Hall HI, et al. Proportions of Kaposi sarcoma, selected non-Hodgkin lymphomas, and cervical cancer in the United States occurring in persons with AIDS, 1980-2007. JAMA. Apr 13 2011;305(14):1450-1459.
  72. Patel P, Hanson DL, Sullivan PS, et al. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992-2003. Ann Intern Med. May 20 2008;148(10):728-736.
  73. Simard EP, Pfeiffer RM, Engels EA. Cumulative incidence of cancer among individuals with acquired immunodeficiency syndrome in the United States. Cancer. Mar 1 2011;117(5):1089-1096.
  74. Shiels MS, Pfeiffer RM, Gail MH, et al. Cancer burden in the HIV-infected population in the United States. J Natl Cancer Inst. May 4 2011;103(9):753-762.
  75. Ellis RJ, Hsia K, Spector SA, et al. Cerebrospinal fluid human immunodeficiency virus type 1 RNA levels are elevated in neurocognitively impaired individuals with acquired immunodeficiency syndrome. HIV Neurobehavioral Research Center Group. Ann Neurol. Nov 1997;42(5):679-688.
  76. McArthur JC, McClernon DR, Cronin MF, et al. Relationship between human immunodeficiency virus-associated dementia and viral load in cerebrospinal fluid and brain. Ann Neurol. Nov 1997;42(5):689-698.
  77. Spudich SS, Huang W, Nilsson AC, et al. HIV-1 chemokine coreceptor utilization in paired cerebrospinal fluid and plasma samples: a survey of subjects with viremia. J Infect Dis. Mar 15 2005;191(6):890-898.
  78. Navia BA, Jordan BD, Price RW. The AIDS dementia complex: I. Clinical features. Ann Neurol. Jun 1986;19(6):517-524.
  79. Price RW, Brew BJ. The AIDS dementia complex. J Infect Dis. Nov 1988;158(5):1079-1083.
  80. Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. Oct 30 2007;69(18):1789-1799.
  81. Snider WD, Simpson DM, Nielsen S, Gold JW, Metroka CE, Posner JB. Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients. Ann Neurol. Oct 1983;14(4):403-418.
  82. d'Arminio Monforte A, Cinque P, Mocroft A, et al. Changing incidence of central nervous system diseases in the EuroSIDA cohort. Ann Neurol. Mar 2004;55(3):320-328.
  83. Bhaskaran K, Mussini C, Antinori A, et al. Changes in the incidence and predictors of human immunodeficiency virus-associated dementia in the era of highly active antiretroviral therapy. Ann Neurol. Feb 2008;63(2):213-221.
  84. Lescure F-X, Omland LH, Engsig FN, et al. Incidence and impact on mortality of severe neuro-cognitive disorders in persons with and without HIV: a Danish nationwide cohort study. Clinical Infectious Diseases. 2010: Jan. 15 2011;52(2):235-243.
  85. Mellgren A, Antinori A, Cinque P, et al. Cerebrospinal fluid HIV-1 infection usually responds well to antiretroviral treatment. Antivir Ther. 2005;10(6):701-707.
  86. Spudich S, Lollo N, Liegler T, Deeks SG, Price RW. Treatment benefit on cerebrospinal fluid HIV-1 levels in the setting of systemic virological suppression and failure. J Infect Dis. Dec 15 2006;194(12):1686-1696.
  87. Canestri A, Lescure FX, Jaureguiberry S, et al. Discordance between cerebral spinal fluid and plasma HIV replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy. Clin Infect Dis. Jan 25 2010;50(5):773-778.
  88. Eden A, Fuchs D, Hagberg L, et al. HIV-1 viral escape in cerebrospinal fluid of subjects on suppressive antiretroviral treatment. J Infect Dis. Dec 15 2010;202(12):1819-1825.
  89. Simioni S, Cavassini M, Annoni JM, et al. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS. Jun 1 2010;24(9):1243-1250.
  90. Smurzynski M, Wu K, Letendre S, et al. Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort. AIDS. Jan 28 2011;25(3):357-365.
  91. Munoz-Moreno JA, Fumaz CR, Ferrer MJ, et al. Nadir CD4 cell count predicts neurocognitive impairment in HIV-infected patients. AIDS Res Hum Retroviruses. Oct 2008;24(10):1301-1307.
  92. Heaton RK, Clifford DB, Franklin DR, Jr., et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology. Dec 7 2010;75(23):2087-2096.
  93. Cornblath DR, McArthur JC. Predominantly sensory neuropathy in patients with AIDS and AIDS-related complex. Neurology. May 1988;38(5):794-796.
  94. Ellis RJ, Rosario D, Clifford DB, et al. Continued high prevalence and adverse clinical impact of human immunodeficiency virus-associated sensory neuropathy in the era of combination antiretroviral therapy: the CHARTER Study. Arch Neurol. May 2010;67(5):552-558.
  95. Evans SR, Ellis RJ, Chen H, et al. Peripheral neuropathy in HIV: prevalence and risk factors. AIDS. Apr 24 2011;25(7):919-928.
  96. The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study group. Response to combination antiretroviral therapy: variation by age. AIDS. Jul 31 2008;22(12):1463-1473.
  97. Nogueras M, Navarro G, Anton E, et al. Epidemiological and clinical features, response to HAART, and survival in HIV-infected patients diagnosed at the age of 50 or more. BMC Infect Dis. 2006;6:159.
  98. Bosch RJ, Bennett K, Collier AC, Zackin R, Benson CA. Pretreatment factors associated with 3-year (144-week) virologic and immunologic responses to potent antiretroviral therapy. J Acquir Immune Defic Syndr. Mar 1 2007;44(3):268-277.
  99. Althoff KN, Justice AC, Gange SJ, et al. Virologic and immunologic response to HAART, by age and regimen class. AIDS. Oct 23 2010;24(16):2469-2479.
  100. Fahey JL, Taylor JM, Detels R, et al. The prognostic value of cellular and serologic markers in infection with human immunodeficiency virus type 1. N Engl J Med. Jan 18 1990;322(3):166-172.
  101. Giorgi JV, Lyles RH, Matud JL, et al. Predictive value of immunologic and virologic markers after long or short duration of HIV-1 infection. J Acquir Immune Defic Syndr. Apr 1 2002;29(4):346-355.
  102. Deeks SG, Kitchen CM, Liu L, et al. Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood. Aug 15 2004;104(4):942-947.
  103. Giorgi JV, Hultin LE, McKeating JA, et al. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis. Apr 1999;179(4):859-870.
  104. Hazenberg MD, Otto SA, van Benthem BH, et al. Persistent immune activation in HIV-1 infection is associated with progression to AIDS. AIDS. Sep 5 2003;17(13):1881-1888.
  105. Gandhi RT, Spritzler J, Chan E, et al. Effect of baseline- and treatment-related factors on immunologic recovery after initiation of antiretroviral therapy in HIV-1-positive subjects: results from ACTG 384. J Acquir Immune Defic Syndr. Aug 1 2006;42(4):426-434.
  106. Hunt PW, Martin JN, Sinclair E, et al. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis. May 15 2003;187(10):1534-1543.
  107. Neuhaus J, Jacobs DR, Jr., Baker JV, et al. Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis. Jun 15 2010;201(12):1788-1795.
  108. Valdez H, Connick E, Smith KY, et al. Limited immune restoration after 3 years' suppression of HIV-1 replication in patients with moderately advanced disease. AIDS. Sep 27 2002;16(14):1859-1866.
  109. Robbins GK, Spritzler JG, Chan ES, et al. Incomplete reconstitution of T cell subsets on combination antiretroviral therapy in the AIDS Clinical Trials Group protocol 384. Clin Infect Dis. Feb 1 2009;48(3):350-361.
  110. Lange CG, Lederman MM, Medvik K, et al. Nadir CD4+ T-cell count and numbers of CD28+ CD4+ T-cells predict functional responses to immunizations in chronic HIV-1 infection. AIDS. Sep 26 2003;17(14):2015-2023.
  111. Palella FJ, Jr., Gange SJ, Benning L, et al. Inflammatory biomarkers and abacavir use in the Women's Interagency HIV Study and the Multicenter AIDS Cohort Study. AIDS. Jul 17 2010;24(11):1657-1665.
  112. Rodger AJ, Fox Z, Lundgren JD, et al. Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection. J Infect Dis. Sep 15 2009;200(6):973-983.
  113. Centers for Disease Control and Prevention (CDC). Achievements in public health. Reduction in perinatal transmission of HIV infection--United States, 1985-2005. MMWR Morb Mortal Wkly Rep. Jun 2 2006;55(21):592-597.
  114. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States, Sep. 14, 2011; pp 1-207. Available at http://aidsinfo.nih.gov/contentfiles/PerinatalGL.pdf. 2011.
  115. Vernazza PL, Troiani L, Flepp MJ, et al. Potent antiretroviral treatment of HIV-infection results in suppression of the seminal shedding of HIV. The Swiss HIV Cohort Study. AIDS. Jan 28 2000;14(2):117-121.
  116. Coombs RW, Reichelderfer PS, Landay AL. Recent observations on HIV type-1 infection in the genital tract of men and women. AIDS. Mar 7 2003;17(4):455-480.
  117. Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med. Mar 30 2000;342(13):921-929.
  118. Tovanabutra S, Robison V, Wongtrakul J, et al. Male viral load and heterosexual transmission of HIV-1 subtype E in northern Thailand. J Acquir Immune Defic Syndr. Mar 1 2002;29(3):275-283.
  119. Kayitenkore K, Bekan B, Rufagari J, et al. The impact of ART on HIV transmission among HIV serodiscordant couples. 16th International AIDS Conference. Aug. 13-18 2006; Toronto, Canada.
  120. Reynolds S, Makumbi F, Nakigozi G, et al. HIV-1 transmission among HIV-1 discordant couples before and after the introduction of anitiretroviral therapy. AIDS. Feb 20 2011;25(4):437-7.
  121. Sullivan P, Kayitenkore K, Chomba E, al. e. Reduction of HIV transmission risk and high risk sex while prescribed ART: Results from discordant couples in Rwanda and Zambia. Paper presented at 16th Conference on Retroviruses and Opportunistic Infections (CROI): Feb. 8-11 2009; Montreal, Canada.
  122. Granich RM, Gilks CF, Dye C, De Cock KM, Williams BG. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet. Jan 3 2009;373(9657):48-57.
  123. Bunnell R, Ekwaru JP, Solberg P, et al. Changes in sexual behavior and risk of HIV transmission after antiretroviral therapy and prevention interventions in rural Uganda. AIDS. Jan 2 2006;20(1):85-92.
  124. Castilla J, Del Romero J, Hernando V, Marincovich B, Garcia S, Rodriguez C. Effectiveness of highly active antiretroviral therapy in reducing heterosexual transmission of HIV. J Acquir Immune Defic Syndr. Sep 1 2005;40(1):96-101.
  125. Wilson DP, Law MG, Grulich AE, Cooper DA, Kaldor JM. Relation between HIV viral load and infectiousness: a model-based analysis. Lancet. Jul 26 2008;372(9635):314-320.
  126. Worm SW, Sabin C, Weber R, et al. Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study. J Infect Dis. Feb 1 2010;201(3):318-330.
  127. Freedberg KA, Losina E, Weinstein MC, et al. The cost effectiveness of combination antiretroviral therapy for HIV disease. N Engl J Med. Mar 15 2001;344(11):824-831.
  128. Schackman BR, Goldie SJ, Weinstein MC, Losina E, Zhang H, Freedberg KA. Cost-effectiveness of earlier initiation of antiretroviral therapy for uninsured HIV-infected adults. Am J Public Health. Sep 2001;91(9):1456-1463.
  129. Mauskopf J, Kitahata M, Kauf T, Richter A, Tolson J. HIV antiretroviral treatment: early versus later. J Acquir Immune Defic Syndr. Aug 15 2005;39(5):562-569.
  130. Chen RY, Accortt NA, Westfall AO, et al. Distribution of health care expenditures for HIV-infected patients. Clin Infect Dis. Apr 1 2006;42(7):1003-1010.
  131. Willig JH, Abroms S, Westfall AO, et al. Increased regimen durability in the era of once-daily fixed-dose combination antiretroviral therapy. AIDS. Oct 1 2008;22(15):1951-1960.
  132. Bicanic T, Meintjes G, Rebe K, et al. Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study. J Acquir Immune Defic Syndr. Jun 1 2009;51(2):130-134.
  133. Phillips P, Bonner S, Gataric N, et al. Nontuberculous mycobacterial immune reconstitution syndrome in HIV-infected patients: spectrum of disease and long-term follow-up. Clin Infect Dis. Nov 15 2005;41(10):1483-1497.
  134. Velasco M, Castilla V, Sanz J, et al. Effect of simultaneous use of highly active antiretroviral therapy on survival of HIV patients with tuberculosis. J Acquir Immune Defic Syndr. Feb 1 2009;50(2):148-152.
  135. Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med. Feb 25 2010;362(8):697-706.
  136. Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med. Oct 20 2011;365(16):1492-1501.
  137. Blanc FX, Sok T, Laureillard D, et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med. Oct 20 2011;365(16):1471-1481.
  138. Havlir DV, Kendall MA, Ive P, et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. Oct 20 2011;365(16):1482-1491.
  139. Kaplan JE, Benson C, Holmes KH, Brooks JT, Pau A, Masur H. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. Apr 10 2009;58(RR-4):1-207.
  140. Lu M, Safren SA, Skolnik PR, et al. Optimal recall period and response task for self-reported HIV medication adherence. AIDS Behav. Jan 2008;12(1):86-94.
  141. Simoni JM, Kurth AE, Pearson CR, Pantalone DW, Merrill JO, Frick PA. Self-report measures of antiretroviral therapy adherence: A review with recommendations for HIV research and clinical management. AIDS Behav. May 2006;10(3):227-245.
  142. Bisson GP, Gross R, Bellamy S, et al. Pharmacy refill adherence compared with CD4 count changes for monitoring HIV-infected adults on antiretroviral therapy. PLoS Med. May 20 2008;5(5):e109.
  143. Kalichman SC, Amaral CM, Cherry C, et al. Monitoring medication adherence by unannounced pill counts conducted by telephone: reliability and criterion-related validity. HIV Clin Trials. Sep-Oct 2008;9(5):298-308.
  144. Moss AR, Hahn JA, Perry S, et al. Adherence to highly active antiretroviral therapy in the homeless population in San Francisco: a prospective study. Clin Infect Dis. Oct 15 2004;39(8):1190-1198.
  145. Hunt PW, Brenchley J, Sinclair E, et al. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis. Jan 1 2008;197(1):126-133.
  146. Choudhary SK, Vrisekoop N, Jansen CA, et al. Low immune activation despite high levels of pathogenic human immunodeficiency virus type 1 results in long-term asymptomatic disease. J Virol. Aug 2007;81(16):8838-8842.
  147. Egger M. Outcomes of ART in resource-limited and industrialized countries. Paper presented at: 14th Conference on Retroviruses and Opportunistic Infections (CROI): Feb. 25-28 2007; Los Angeles, CA.
  148. Wolbers M, Bucher HC, Furrer H, et al. Delayed diagnosis of HIV infection and late initiation of antiretroviral therapy in the Swiss HIV Cohort Study. HIV Med. Jul 2008;9(6):397-405.
  149. Grigoryan A, Hall HI, Durant T, Wei X. Late HIV diagnosis and determinants of progression to AIDS or death after HIV diagnosis among injection drug users, 33 US States, 1996-2004. PLoS One. 2009;4(2):e4445.
  150. Centers for Disease Control and Prevention (CDC). Late HIV testing - 34 states, 1996-2005. MMWR Morb Mortal Wkly Rep. Jun 26 2009;58(24):661-665.
  151. Branson BM, Handsfield HH, Lampe MA, et al. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep. Sep 22 2006;55(RR-14):1-17.