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

Initiating Antiretroviral Therapy in Treatment-Naive Patients

(Last updated: May 1, 2014; last reviewed: May 1, 2014)


Panel’s Recommendations

Panel's Recommendations

  • Antiretroviral therapy (ART) is recommended for all HIV-infected individuals to reduce the risk of disease progression.
    • The strength of and evidence for this recommendation vary by pretreatment CD4 T lymphocite (CD4) cell count: CD4 count <350 cells/mm3 (AI); CD4 count 350–500 cells/mm3 (AII); CD4 count >500 cells/mm3 (BIII).
  • ART also is recommended for HIV-infected individuals for the prevention of transmission of HIV.
    • The strength of and evidence for this recommendation vary by transmission risks: perinatal transmission (AI); heterosexual transmission (AI); other transmission risk groups (AIII).
  • Patients starting ART should be willing and able to commit to treatment and 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

Without treatment, most HIV-infected individuals will eventually develop progressive immunosuppression, as evident by CD4 T lymphocyte (CD4) cell depletion, leading to AIDS-defining illnesses and premature death. The primary goal of ART is to prevent HIV-associated morbidity and mortality. This goal is best accomplished by using effective ART to maximally inhibit HIV replication so that plasma HIV RNA (viral load) remains below levels detectable by commercially available assays. Durable viral suppression improves immune function and overall quality of life, lowers the risk of both AIDS-defining and non-AIDS-defining complications, and prolongs life.

Furthermore, high plasma HIV RNA is a major risk factor for HIV transmission, and effective antiretroviral therapy (ART) can reduce viremia and transmission of HIV to sexual partners by more than 96%.1,2 Modelling studies suggest that expanded use of ART may result in lower incidence and, eventually, prevalence of HIV on a community or population level.3 Thus, a secondary goal of ART is to reduce the risk of HIV transmission.

Historically, HIV-infected individuals have had low CD4 counts at presentation to care.4 However, there have been concerted efforts to increase testing of at-risk patients and to link these patients to medical care before they have advanced HIV disease. Deferring ART until CD4 count declines put an individual at risk of AIDS-defining conditions has been associated with higher risk of morbidity and mortality (as discussed below). Furthermore, the magnitude of CD4 recovery is directly correlated with CD4 count at ART initiation. Consequently, many individuals who start treatment with CD4 counts <350 cells/mm3 never achieve counts >500 cells/mm3 after up to 6 years on ART.5

The recommendation to initiate ART in individuals with high CD4 cell counts—whose short-term risk for death and development of AIDS-defining illness is low6,7—is based on growing evidence that untreated HIV infection or uncontrolled viremia is associated with development of non-AIDS-defining diseases, including cardiovascular disease (CVD), kidney disease, liver disease, neurologic complications, and malignancies. Furthermore, newer ART regimens are more effective, more convenient, and better tolerated than regimens used in the past.

Regardless of CD4 count, the decision to initiate ART should always include consideration of a patient’s comorbid conditions, his or her willingness and readiness to initiate therapy, and available resources. In settings where there are insufficient resources to initiate ART in all patients, treatment should be prioritized for patients with the following clinical conditions: pregnancy; CD4 count <200 cells/mm3 or history of an AIDS-defining illness including HIV-associated dementia, HIV-associated nephropathy (HIVAN), or hepatitis B virus (HBV); and acute HIV infection. 

Tempering the enthusiasm to treat all patients regardless of CD4 count is the absence of randomized trial data that demonstrate a definitive clinical benefit of ART in patients with higher CD4 counts (e.g., >350 cells/ mm3) and mixed results from observational cohort studies as to the definitive benefits of early ART (i.e., when CD4 count >500 cells/mm3). For some asymptomatic patients, the potential risks of short- or long-term drug-related complications and non-adherence to long-term therapy may offset possible benefits of earlier initiation of therapy. An ongoing randomized controlled trial evaluating the role of immediate versus delayed ART in patients with CD4 counts >500 cells/mm3 (see Strategic Timing of Antiretroviral Treatment (START); ClinicalTrials.gov identifier NCT00867048) should help to further define the role of ART in this patient population.

The known and potential benefits and limitations of ART in general, and in different patient populations 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.8-10 Long-term data from multiple observational cohort studies comparing earlier ART (i.e., initiated at CD4 count >200 cells/mm3) with later treatment (i.e., initiated at CD4 count <200 cells/mm3) have also provided strong support for these findings.11-16

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 with CD4 counts in the 200 to 350 cells/mm3 range or to defer treatment until their CD4 counts dropped to <200 cells/mm3 or they developed an AIDS-defining condition. The study was terminated when an interim analysis showed a survival benefit in the early treatment arm. When compared with participants who began ART with CD4 counts in the 200 to 350 cells/mm3 range, patients who deferred therapy had a higher mortality rate (23 versus 6 deaths; hazard ratio [HR] = 4.0; 95% confidence interval [CI], 1.6–9.8) and a higher rate of incident tuberculosis (TB) (HR = 2.0; 95% CI, 1.2–3.6).17

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 cells/mm3 to 500 cells/mm3 are from large observational studies conducted in North America, Europe, and Australia and from secondary analysis of randomized controlled trials. Findings from the observational studies were analyzed using 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.

Among the cohort studies analyzed, 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 in participants who delayed ART initiation until their CD4 counts fell to 251 to 350 cells/mm3 than in those who initiated ART at CD4 count level of 351 to 450 cells/mm3 (risk ratio: 1.28; 95% CI, 1.04–1.57).13 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).

The NA-ACCORD cohort evaluated patients regardless whether they had started therapy. The 6,278 patients who deferred therapy until their CD4 counts fell to <350 cells/mm3 had a greater risk of death than the 2,084 patients who initiated therapy with CD4 counts between 351 cells/mm3 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.18

The HIV-CAUSAL cohort evaluated 8,392 ART-naive patients with initial CD4 counts >500 cells/mm3 that declined to <500 cells/mm3.16 The study estimated that delaying initiation of ART until CD4 count fell to <350 cells/mm3 was associated with a greater risk of AIDS-defining illness or death than initiating ART with CD4 count between 350 cells/mm3 and 500 cells/mm3 (HR: 1.38; 95% CI, 1.23–1.56). However, there was no difference in mortality between the 2 groups (HR: 1.01; 95% CI, 0.84–1.22).

The CASCADE cohort 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,98 0.33–0.80).19

Randomized data showing clinical evidence that supports ART for patients with higher CD4 cell counts came from two studies. In the SMART trial, HIV-infected participants with CD4 counts >350 cells/mm3 were randomized to continuous ART or to treatment interruption until their CD4 counts fell to <250 cells/mm3. In the subgroup of 249 participants who were ART naive at enrollment (median CD4 count: 437 cells/mm3), those who deferred ART until their CD4 counts 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).20 HPTN 052 was a large multi-continent randomized trial that examined whether treatment of HIV-infected individuals reduces transmission to their uninfected sexual partners.2 A secondary 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 <250 cells/mm3. At a median follow-up of 2.1 years, there were 57 primary events in the early therapy arm versus 77 events in the delayed therapy arm (HR: 0.73; 95% CI, 0.52–1.03). The most frequent event was tuberculosis (17 cases in the early therapy arm and 34 cases in the delayed therapy arm); deaths were relatively rare (11 cases in the early therapy arm and 15 cases in the delayed therapy arm).21,22

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 350 to 500 cells/mm3 (AII). Recent evidence demonstrating the public health benefit of earlier initiation of ART in reducing HIV transmission further supports the strength of this recommendation (see Prevention of Sexual Transmission).

Patients with CD4 Counts >500 cells/mm3

An analysis of the risks of HIV-associated disease progression in ART-naive patients with CD4 cell counts >500 cells/mm3 is difficult because only a small proportion of individuals present for clinical care with CD4 cell counts at this level.4,23 However, studies have demonstrated a gradient of increased risk of AIDS and death when ART is initiated at lower CD4 cell count levels and have provided no evidence of a safe CD4 count level.6,24,25

To date, questions regarding the risks and benefits of starting ART in patients with CD4 cell counts >500 cells/mm3 as compared to deferring initiation until CD4 cell counts are lower have not yet been answered in a definitive randomized clinical trial. Evidence supporting early initiation comes from an observational study. The NA-ACCORD study observed patients who started ART with CD4 counts >500 cells/mm3 or after their 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 with CD4 counts >500 cells/mm3 (risk ratio: 1.94; 95% CI, 1.37–2.79).18

In contrast, in an analysis of the ART-CC cohort,13 the rate of progression to AIDS/death associated with deferral of therapy until CD4 counts fell to the 351 to 450 cells/mm3 range was similar to the rate with initiation of therapy with CD4 counts in the 451 to 550 cells/mm3 range (HR: 0.99; 95% CI, 0.76–1.29). The analysis showed no significant difference in rate of death in the immediate and deferred therapy groups (HR: 0.93; 95% CI, 0.60–1.44). In the CASCADE Collaboration,19 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).

Although not a clinical endpoint study, a recent clinical trial (Setpoint Study) randomized patients within 6 months of HIV seroconversion to receive either immediate ART for 36 weeks or deferred treatment. More than 57% of the study participants had CD4 counts >500 cells/mm3. The deferred treatment group had a statistically higher risk of meeting study defined ART initiation criteria than the immediate treatment group. The study was halted early, showing that the time from diagnosis of early infection and the need for initiation of ART was shorter than anticipated in the deferral therapy group. Fully half of the participants in the deferral group met the criteria for treatment initiation by week 72.26

Another recent study provides evidence that early treatment enhances recovery of CD4 counts to levels >900 cells/mm3.27 Among individuals who were identified during primary infection, those who initiated ART within 4 months after the estimated date of infection were more likely to have CD4 cell recovery and had a faster rate of recovery than those initiating ART at 4 to 12 months or >12 months after the estimated date of infection. However, even among participants who started ART earlier, those who initiated ART with lower CD4 counts were less likely to have CD4 cell recovery and had a lower rate of recovery than those who initiated ART with higher CD4 counts.

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 recommends initiation of ART in patients with CD4 counts >500 cells/mm3 (BIII). 

When discussing initiation of 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. Clinicians should also inform patients that viral suppression from effective ART can reduce the risk of sexual transmission. Lastly, patients should be informed that untreated HIV infection will eventually lead to immunological deterioration and increased risk of clinical disease and death. Therefore, if therapy is not initiated, continued monitoring and close follow-up are necessary. 

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 further evidence to help the Panel make future recommendations.

Effects of Viral Replication on HIV-Related Morbidity

Since the mid-1990s, it has been known that measures of viral replication predict HIV disease progression. Among untreated HIV-infected individuals, time to clinical progression and mortality is fastest in those with higher viral loads.28 This finding is confirmed across the spectrum of HIV-infected patient populations, such as injection drug users (IDUs),29 women,30 and individuals with hemophilia.31 Several studies have shown the prognostic value of pre-treatment viral load for predicting post-therapy response.32,33 Once therapy has been initiated, failure to achieve viral suppression34-36 and viral load at the time of treatment failure37 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 quantifying viral load over time, the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort found that cumulative exposure to replicating virus 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 independent of CD4 count.38 

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 rates of fatal and nonfatal AIDS-related and non-AIDS-related events. The lower viral load stratum included more participants 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/mm3.39

Collectively, these data show that the harm of ongoing viral replication affects both untreated patients and those who are on ART but remain 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 Antiretroviral Therapy 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 likely contribute to HIV-related morbidity and mortality. In general, the available data demonstrate the following:

  • Untreated HIV infection (ongoing viral replication) may have negative 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 levels, 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.40 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;41 HIVAN is extremely uncommon in virologically suppressed patients.42 ART in patients with HIVAN has been associated with both preserved renal function and prolonged survival.43-45 Therefore, regardless of CD4 count, ART should be started in all patients with HIVAN 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.46,48 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.49-52 In individuals co-infected 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.53-55 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.56,57 Although ARV drugs do not inhibit HCV replication directly, HCV treatment outcomes typically improve when HIV replication is controlled or CD4 counts increase.58 In one prospective cohort, after controlling for liver and HIV disease stage, HCV co-infected patients receiving ART were approximately 66% less likely to experience end-stage liver disease, hepatocellular carcinoma, and fatal hepatic failure than patients not receiving ART.59 While some studies have shown that chronic viral hepatitis increases the risk of ART-induced liver injury, the majority of coinfected persons do not develop clinically significant liver injury60-62 and the rate of hepatotoxicity may be greater in persons with more advanced HIV disease. Collectively, these data suggest that earlier treatment of HIV infection in persons coinfected with HBV (and likely HCV) may reduce the risk of liver disease progression. ART is recommended for patients coinfected with HBV, and the ART regimen should include drugs with activity against both HIV and HBV (AII) (also see Hepatitis B Virus/HIV Coinfection). ART is also recommended for most patients coinfected with HCV (BII), including those with high CD4 counts and those with cirrhosis. This recommendation is based on findings from retrospective and prospective cohort studies that indicated that the receipt of ART is associated with slower progression of hepatic fibrosis and reduced risk of liver disease outcomes.59,63-65 Combined treatment of HIV and HCV can be complicated by large pill burden, drug interactions, and overlapping toxicities; however, the complexity of treatment depends on the HCV regimen selected. ART should be considered for HIV/HCV-coinfected patients regardless of CD4 cell count. However, for patients with CD4 counts >500 cells/mm3 and also infected with HCV genotype 1, if treatment is to include an HCV protease inhibitor, some clinicians may choose to defer ART until HCV treatment is completed (also see HIV/Hepatitis C Virus Co-Infection).

Cardiovascular Disease 

In HIV-infected patients, CVD is a major cause of morbidity and mortality, accounting for one-third of serious non-AIDS conditions and at least 10% of deaths.66-68 A number of studies have found that, over time, HIV-infected persons are at greater risk for CVD events than age-matched uninfected individuals. 

Persons living with HIV infection have higher rates of established CVD risk factors, particularly smoking and dyslipidemia, than HIV-uninfected individuals. In the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) cohort study such factors, including age, male gender, obesity, smoking, family history of CVD, diabetes, and dyslipidemia, were each independently associated with risk of myocardial infarction (MI).69 This study also found that the risk of CVD was greater with exposure to some ARV drugs, including certain PIs (ritonavir-boosted lopinavir and ritonavir-boosted fosamprenavir) and abacavir, than with exposure to other ARV drugs.69,70 

In terms of preventing the progression to CVD events, it has not been determined whether delaying ART initiation is preferable to immediate treatment. In the meta-analysis mentioned above, the risk of CVD in HIV-infected individuals was 1.5 times higher in those treated with ART than in those not treated with ART.63

These analyses were limited by concern that the treated individuals may have been infected for longer periods of time and had prior episodes of untreated HIV disease, as well as the fact that the untreated people were at higher risk for competing events, including death. Furthermore, there is evidence that untreated HIV infection may also be associated with an increased risk of CVD. 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.71 In other studies, ART resulted in marked improvement in parameters associated with CVD, including markers of inflammation (such as interleukin 6 [IL-6]), immune dysfunction (e.g., T cell activation, T cell senescence), monocyte activation (e.g., IL-6, soluble CD14 and CD163), hyper-coagulation (e.g., D-dimers) and, most importantly, endothelial dysfunction.72,73 Low nadir and/or proximal on-therapy CD4 cell count has been linked to CVD (MI and/or stroke),74-76 suggesting that low CD4 count might result in increased risk of CVD. 

Collectively, the increased risk of cardiovascular events with treatment interruption, the effects of ART on markers of inflammation and endothelial dysfunction, 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, particularly if drugs with potential cardiovascular toxicity are avoided. However, no study has demonstrated that initiation of ART prevents CVD. Therefore, a role for early ART in preventing CVD remains to be established. For HIV-infected individuals with a significant risk of CVD, as assessed by medical history and estimated risk calculations, risk of CVD should be considered when selecting a specific ART regimen.

Malignancies

HIV-infected individuals are at increased risk for developing several cancers and human papilloma virus (HPV)-related pre-malignant intraepithelial neoplasia.77,78 Increased rates of Kaposi sarcoma and non-Hodgkin lymphoma in patients with advanced HIV infection have been noted since early in the AIDS epidemic, and, together with cervical cancer, both diseases have been defined as AIDS-defining malignancies (ADMs) for public health surveillance purposes. HIV infection and associated immunosuppression increase the risk of several cancers identified as non-AIDS-defining malignancies (NADMs). Importantly, the incidence of lung, anal, oropharyngeal, liver and skin cancers, Hodgkin lymphoma, and melanoma, is higher in HIV-infected individuals than in matched HIV-uninfected controls,79-81 and the burden of these NADMs continued to increase in the United States between 1996 and 2007.82 Incidental cancers that occur in HIV-infected individuals are becoming more common, which is due to the aging of the HIV population rather than to HIV-associated risks of malignancies. These cancers are also sometimes considered NADMs. Most cancers with increased incidence are either virally related (i.e., Hodgkin lymphoma, anal cancer, liver cancer) or smoking related (lung cancer), although HIV remains an independent risk factor for the later.83

Large cohort studies enrolling mainly patients receiving ART have reported a consistent link between low CD4 counts (<350 to 500 cells/mm3) and the risk of ADMs and/or NADMs.14,76,84-87 The ANRS C04 Study demonstrated that, in contrast to patients with CD4 counts >500 cells/mm3, patients with CD4 counts <500 cells/mm3 had a statistically significant relative risk of all cancers evaluated (except for anal carcinoma). The study also showed an increased risk of anal cancer based on extent of time with CD4 counts <200 cells/mm3, and that, regardless of CD4 count, ART has a protective effect for HIV-associated malignancies.84 This potential effect of HIV-associated immunodeficiency is striking particularly with regard to cancers and pre-malignant diseases associated with chronic viral infections such as HBV, HCV, HPV, Epstein-Barr virus, and human herpes virus.8.88,89 For some cancers, risk is related to HIV viremia. Cumulative HIV viremia, independent of other factors, is associated with increased risk of non-Hodgkin lymphoma and other ADM.87,90 In the SMART study,91 patients randomized to the drug conservation arm (ART interruption with re-initiation if CD4 count fell to <250 cells/mm3) had a higher incidence of ADM but not NADM, although increased NADM was noted in non-smokers in the drug-conservation arm.

From the early 1990s through 2000, incidence rates for many cancers occurring with advanced immunosuppression, including Kaposi sarcoma, diffuse large B-cell lymphoma, and primary central nervous system (CNS) lymphoma, declined markedly in HIV-infected individuals in the United States, with more gradual declines noted after 2000.92 However, for other ADMs and NADMs, such as Burkitt lymphoma, Hodgkin lymphoma, cervical cancer, and anal cancer, similar reductions in incidence have not been observed.92,93 Declines in competing causes of mortality (e.g., opportunistic infections [OIs]) and concurrent cancer risk factors such as smoking or aging of HIV-infected cohorts, may confound a full assessment of the relative impact of ART on cancer prevention for NADMs.82,94 

Additionally, data from the era of potent combination ART suggest that overall survival in HIV-infected patients who develop ADMs or NADMs also depends on immune status as measured by CD4 count.85,95,96 For non-Hodgkin lymphoma, data from the Center for AIDS Research Network of Integrated Clinical Systems Cohort shows that across CD4 strata, the level of HIV viremia 6 months after the diagnosis of lymphoma (including Hodgkin lymphoma) is associated with an increased risk of death.95 

Together this evidence suggests that initiating ART to suppress HIV replication, maximize immune reconstitution, and maintain CD4 counts at levels >350 to 500 cells/mm3 reduces the overall incidence of ADMs and may reduce the risk of some NADMs as well. The effect of ART on cancer incidence and mortality in patients with cancer95,97 is likely to be heterogeneous across various cancer types.

Neurological Complications

In the untreated HIV-infected patient, CNS involvement is a nearly universal facet of systemic HIV infection as evident by detection of HIV RNA in cerebrospinal fluid (CSF).98-101 The CNS is an important target of ART, not only to treat neurologically symptomatic infection but also to prevent later development of virus-related brain injury, which can range from severe and debilitating encephalopathy to milder and more insidious cognitive and motor dysfunction.102-104 

Like systemic infection, CNS virus populations and the character of CNS infection can evolve within individual patients. Characteristically during the earliest phases of systemic infection, CSF viral isolates are similar to those found in blood and likely reflect transfer of blood populations across CNS barriers in T lymphocytes.105

Over time CSF isolates may exhibit increasing compartmentalization that reflect divergence from the predominant blood populations, a transformation most notable in patients with frank HIV encephalitis presenting with HIV-associated dementia (HAD).106 Combination ART usually reduces CSF HIV RNA to below the level of detection,99,107 largely preventing this development, and consequently, reducing the incidence of severe HIV-related brain disease in virologically suppressed patients.108-110 Hence, prevention of HAD is among the arguments for early ART, although the CD4 threshold for treatment to prevent this disorder is not established. Additionally, treatment of patients presenting with HAD—usually seen in the context of late HIV presentation—can arrest and variably reverse neurological abnormalities;111 therefore, the diagnosis of HAD is an indication for rapid initiation of ART (AI).

With the successful control of HAD with ART, attention has shifted to milder forms of neurocognitive impairment in HIV infection, largely recognized by reduced neuropsychological test performance.104,112 These milder forms of impairment are categorized in two groups: asymptomatic neurocognitive impairment and mild neurocognitive disorder. Although patients with either form exhibit the same degree of impairment on neuropsychological tests (<1 SD below normative performance in two neurocognitive domains), they differ as to the absence or presence of symptoms or mild functional impairment in everyday activities.103 Even after exclusion of confounding conditions, the prevalence of these milder forms of neurocognitive impairment appears to be substantial, including in treated patients with plasma viral suppression.104,112 Less certain is the extent to which these impairments are the consequence of earlier mild or subclinical brain injury sustained before ART initiation, or alternatively, reflect ongoing injury despite ART and plasma viral suppression. Association of these milder deficits with nadir CD4 count may favor the role of earlier injury,100,113-115 providing further argument for early treatment.

Peripheral neuropathies are a second category of important HIV-associated neurological disease.116 In the early decades of the discovery of HIV infection and the use of some nucleoside analogs, painful distal sensory neuropathy was particularly common and a difficult problem that did not respond to ART.117 Although some reports suggest that the incidence of this HIV-associated neuropathy remains high, clinical experience suggests that the condition mainly affects patients with longer duration of HIV infection who initiated ART late in the course of the disease.118 There appears to be a reduced incidence of neuropathies as more patients begin treatment at earlier stages of HIV infection. 

Overall, effective ART may be beneficial in preventing and treating symptomatic and subclinical CNS HIV infection and the CNS and peripheral nervous system consequences of infection.

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. In most, but not all studies, treatment initiation at an older age has been associated with a less robust CD4 count response; starting therapy at a younger age may result in better immunologic and perhaps clinical outcomes.4,119-122

Persistent Inflammation and Immunodeficiency During Antiretroviral Therapy

Untreated HIV infection is associated with chronic inflammation, as defined by the frequency of activated T cells and monocyte/macrophages and levels of a number of pro-inflammatory cytokines (e.g., IL-6, CRP, soluble CD14). Effective ART decreases levels of most of these inflammatory markers, but the effect is often incomplete, with levels in many of those on ART remaining higher than those observed in age-matched uninfected adults.123,124 Chronic inflammation during both untreated and treated disease is strongly associated with risk of non-AIDS defining morbidity and all-cause mortality.125-128 Because HIV replication contributes to this inflammatory state through both direct and indirect mechanisms, earlier use of ART to blunt this process may be beneficial. However, there are no data showing that ART-mediated changes in any inflammatory biomarker are associated with reduced morbidity and mortality.
 
Immune function as defined by the peripheral CD4 cell count is also an important determinant of health. Although effective ART results in a sustained and beneficial increase in CD4 cell counts, this effect is often incomplete. Patients who delay therapy to the point of advanced immunodeficiency may require several years of ART to normalize their peripheral CD4 cell counts,129 and some patients may never achieve a normal level.130 A lower CD4 count on therapy is associated with higher risk of developing cancer, liver disease, cardiovascular disease and death.14 In some studies a history of low CD4 counts is associated with risk of morbidity and mortality during subsequent effective therapy.131,132

Collectively, these observations support earlier use of ART. Treatment decreases the level of inflammation, which may be associated with reduced short-term risk of AIDS- and non-AIDS-related morbidity and mortality.125,133,134 ART also prevents progressive loss of CD4 cells, thus reducing risk of immunodeficiency and its related complications. Some studies have shown that a patient’s pre-therapy CD4 cell count nadir is predictive of the degree of residual inflammation and/or T-cell dysfunction during ART.123,135,136 Thus, earlier ART may result in less residual immunological perturbations during treatment, which theoretically may result in reduced risk of disease during the decades that a patient requires ART (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 before 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 0.1% to 0.5%.137,138 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.139

Prevention of Sexual Transmission

A number of investigations, including biological, ecological and epidemiological studies and one randomized clinical trial, 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.140,141 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.1,142-145 A study conducted in KwaZulu-Natal, South Africa, used geospatial techniques to assess the relationship between ART use and HIV incidence in an observational cohort of more than 16,000 study participants living in many different communities.146 After adjustment for sexual behavior and prevalent HIV cases, each percentage point increase in ART coverage of HIV-infected persons lowered the HIV infection risk in a community by 1.7%. 

Most significantly, the multi-continental HPTN 052 trial enrolled 1,763 HIV-serodiscordant couples in which the HIV-infected partner was ART naive with a CD4 count of 350 to 550 cells/mm3 at enrollment to compare the effect of immediate ART versus delayed therapy (not started until CD4 count <250 cells/mm3) on HIV transmission to the HIV-infected partner.2 At study entry, 97% 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. 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.3,144,145,147-149 HPTN 052 was conducted in heterosexual couples and not in populations at risk of transmission via homosexual exposure or needle sharing. In addition, in this clinical trial, adherence to ART was well supported and near complete. However, the prevention benefits of effective ART observed in HPTN 052 can reasonably be presumed to apply broadly. 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 (see Preventing Secondary Transmission  of HIV).

Concerns Regarding Earlier Initiation of Therapy

Despite increasing evidence showing the benefits of earlier initiation of ART, four  areas of concern remain as reasons for deferral of HIV therapy. 

ARV Drug Toxicities Have an Adverse Effect on Quality of Life and Adherence

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 and protease inhibitor (PI) drug classes.69,150 Renal and bone health are also of concern. Aging coupled with long term use of tenofovir may increase risk of significant renal dysfunction.151-153 In the SMART study, compared with interruption or deferral of therapy, continuous exposure to ART was associated with significantly greater loss of bone density.71 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 quality of life for some patients, especially those who are asymptomatic at initiation of therapy and at low risk of AIDS events. For example, efavirenz can cause neurocognitive or psychiatric side effects and PIs have been associated with gastrointestinal side effects. As noted above, some therapies may increase the risk of CVD. Patients who find that the inconvenience of taking medication every day outweighs the overall benefit of early ART may choose to delay therapy. 

ARV Non-Adherence May Have an Impact on Virologic Response.

At any CD4 count, adherence to therapy is essential to achieve viral suppression and prevent emergence of drug-resistance mutations. Several clinical, 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

Earlier Development of Resistance may Reduce Future Therapeutic Options. 

Non-adherence and subsequent virologic failure may promote emergence of drug resistance mutations and limit subsequent treatment options. Despite concerns about the development of resistance to ARV drugs, the 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.154 Furthermore, recent data have indicated a slight increase in the prevalence of 2-drug class resistance from 2000 to 2005.155

Cost may be a Barrier to Early Initiation of Therapy.

In resource-rich countries, the cost of ART exceeds $10,000 per year (see Cost Considerations and Antiretroviral Therapy). Several modeling studies support the cost effectiveness of HIV therapy initiated soon after diagnosis.156-158 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/mm3.159 Much of the health care expenditure in patients with advanced infection is from non-ARV drugs and hospitalization. However, there are no comparisons of the cost of earlier ART initiation (i.e., CD4 count 350–500 cells/mm3) versus later initiation (i.e., CD4 count >500 cells/ mm3). As generic formulations for more ARV drugs become available in the next several years, the cost of ART may decline. However, despite any significant cost savings, decisions regarding which ARVs to select for system-wide HIV programs must be based on rigorous cost-effectiveness assessments (see Cost section ).160

Conditions Favoring More Urgent 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.139
  • AIDS-defining conditions, including HAD (AI)
  • Acute OIs (see discussion below)
  • Lower CD4 counts (e.g., <200 cells/mm3) (AI)
  • HIVAN (AII)
  • Acute/Early Infection (BII). See more discussion in the Acute/Early Infection section.
  • HIV/HBV coinfection (AII)
  • HIV/HCV coinfection (BII)
  • 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 who have opportunistic diseases for which no effective therapy exists (e.g., cryptosporidiosis, microsporidiosis, progressive multifocal leukoencephalopathy), but in whom ART may improve outcomes by improving immune responses, treatment should be started as soon as possible (AIII). For patients with mild to moderate cutaneous Kaposi’s sarcoma (KS), prompt initiation of ART alone without chemotherapy has been associated with improvement of the KS lesions, even though initial transient progression of KS lesion as a manifestation of immune reconstitution inflammatory syndrome (IRIS) can also occur.161

In the setting of some OIs, such as cryptococcal meningitis, for which immediate therapy may increase the risk of serious immune reconstitution inflammatory syndrome (IRIS), a short delay before initiating ART may be warranted.162-164 In the setting of other OIs, such as Pneumocystis jirovecii pneumonia, early initiation of ART is associated with increased survival;10 therefore, therapy should not be delayed (AI).

In patients who have active TB, initiating ART during treatment for TB confers a significant survival advantage;165-169 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 Adolescents161 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 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. Briefly delaying 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 methods are available to 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.170,171 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.172 174 Continual assessment and counseling allow 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 may 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.

There are some less common situations that preclude ART at any time while CD4 counts remain high. In particular, such situations include that of patients who have a poor prognosis because of a concomitant medical condition and are not 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. In this setting, deciding to forgo ART may be easier in patients with higher CD4 counts who are likely asymptomatic for HIV and in whom ART is unlikely to prolong survival. However, it should be noted that ART may improve outcomes, including survival, in patients with some HIV-associated malignancies (e.g., lymphoma, Kaposi sarcoma) and in patients with liver disease due to chronic HBV or HCV.

Long-term Non-Progressors and Elite HIV Controllers

A small subset of HIV-infected individuals (~3% to 5%) can maintain normal CD4 counts for many years without treatment (long-term non-progressors), and an even smaller subset (~1%) can maintain low to undetectable HIV RNA levels for years (elite controllers).175,176 Although there is significant overlap in these clinical phenotypes, many long-term non-progressors have detectable viremia and some controllers progress immunologically and clinically despite having no detectable viremia. 

There are limited data on how to manage these individuals. Given potential harm associated with uncontrolled HIV replication, many of the preceding arguments for early therapy likely apply to non-progressors who have consistently detectable viremia (i.e., HIV RNA >200 to 1000 copies/mL). Given that ongoing HIV replication occurs even in controllers, ART is also recommended for those rare controllers with evidence of disease progression, as defined by declining CD4 counts or development of HIV-related complications (AII). The Panel has no recommendations on managing controllers with high CD4 counts, although the fact that ART reduces the level of inflammation in this setting suggests that treatment may be beneficial.177

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-infections are diagnosed at later stages of disease,178-181 although in recent years, HIV is increasingly being detected earlier.4 Despite the recommendations for routine, opt-out HIV screening in the health care setting regardless of perceptions about a patient’s risk of infection,182 the median CD4 count of newly diagnosed patients remains below 350 cells/mm3, although this number is increasing.4 Diagnosis  of HIV infection is delayed more often in nonwhites, IDUs, and older patients than in other populations, and many individuals in these groups develop AIDS-defining illnesses within 1 year of diagnosis.178-181

Therefore, to ensure that the current treatment guidelines have maximum impact, routine HIV screening per current CDC recommendations is essential. It is also critical that all newly diagnosed patients are 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 so that both the infected individuals and their sexual partners can fully benefit from early diagnosis and treatment.

Conclusion

The current recommendations are based on growing evidence supporting earlier initiation of ART and the lack of demonstrable harm in starting therapy earlier. The strength of each recommendation varies according to the quality and availability of existing evidence supporting the 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 information to guide future Panel recommendations.

 

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