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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: November 9, 2015; last reviewed: May 1, 2014)

The HHS Panel on Antiretroviral Guidelines for Adults and Adolescents has issued a statement regarding the results from the START and TEMPRANO trials. With the availability of the START and TEMPRANO trial results, the Panel continues to recommend ART for all HIV-infected patients, regardless of pre-treatment CD4 count. However, the strength of the recommendation has been changed to AI for all patients. An updated section will be available in the future.

Panel's Recommendations for Initiating Antiretroviral Therapy in Treatment-Naive Patients

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


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); 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.


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)
  • 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.


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.



  1. 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. 2000;342(13):921-929. Available at
  2. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365(6):493-505. Available at
  3. 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. 2009;373(9657):48-57. Available at
  4. Althoff KN, Justice AC, Gange SJ, et al. Virologic and immunologic response to HAART, by age and regimen class. AIDS. 2010;24(16):2469-2479. Available at
  5. Moore RD, Keruly JC. CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression. Clin Infect Dis. 2007;44(3):441-446. Available at
  6. Study Group on Death Rates at High CDCiANP, Lodwick RK, Sabin CA, et al. Death rates in HIV-positive antiretroviral-naive patients with CD4 count greater than 350 cells per microL in Europe and North America: a pooled cohort observational study. Lancet. 2010;376(9738):340-345. Available at
  7. Mocroft A, Furrer HJ, Miro JM, et al. The incidence of AIDS-defining illnesses at a current CD4 count >/= 200 cells/muL in the post-combination antiretroviral therapy era. Clin Infect Dis. 2013;57(7):1038-1047. Available at
  8. HIV Trialists' Collaborative Group. Zidovudine, didanosine, and zalcitabine in the treatment of HIV infection: meta-analyses of the randomised evidence. Lancet. 1999;353(9169):2014-2025. Available at
  9. 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. 1997;337(11):725-733. Available at
  10. 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. Available at
  11. Mocroft A, Vella S, Benfield TL, et al. Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet. 1998;352(9142):1725-1730. Available at
  12. 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. 2001;286(20):2568-2577. Available at
  13. 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. 2009;373(9672):1352-1363. Available at
  14. Baker JV, Peng G, Rapkin J, et al. CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS. 2008;22(7):841-848. Available at
  15. 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. 2003;138(8):620-626. Available at
  16. 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. 2011;154(8):509-515. Available at
  17. Severe P, Juste MA, Ambroise A, et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med. 2010;363(3):257-265. Available at
  18. Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med. 2009;360(18):1815-1826. Available at
  19. Writing Committee for the CASCADE Collaboration. Timing of HAART initiation and clinical outcomes in human immunodeficiency virus type 1 seroconverters. Arch Intern Med. 2011;171(17):1560-1569. Available at
  20. 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. 2008;197(8):1133-1144. Available at
  21. Grinsztejn B HM, Swindells S, et al. Effect of early versus delayed initiation of antiretroviral therapy (ART) on clinical outcomes in the HPTN 052 randomized clinical trial. Abstract ThLBB05. Paper presented at: AIDS 2012 Conference; July 2012; Washington, DC. 
  22. Grinsztejn B, Hosseinipour MC, Ribaudo HJ, et al. Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial. Lancet Infect Dis. 2014;14(4):281-290. Available at
  23. Lesko CR, Cole SR, Zinski A, Poole C, Mugavero MJ. A systematic review and meta-regression of temporal trends in adult CD4(+) cell count at presentation to HIV care, 1992-2011. Clin Infect Dis. 2013;57(7):1027-1037. Available at
  24. Phillips AN, Gazzard B, Gilson R, et al. Rate of AIDS diseases or death in HIV-infected antiretroviral therapy-naive individuals with high CD4 cell count. AIDS. 2007;21(13):1717-1721. Available at
  25. Grabar S, Selinger-Leneman H, Abgrall S, Pialoux G, Weiss L, Costagliola D. Prevalence and comparative characteristics of long-term nonprogressors and HIV controller patients in the French Hospital Database on HIV. AIDS. 2009;23(9):1163-1169. Available at
  26. Hogan CM, Degruttola V, Sun X, et al. The setpoint study (ACTG A5217): effect of immediate versus deferred antiretroviral therapy on virologic set point in recently HIV-1-infected individuals. J Infect Dis. 2012;205(1):87-96. Available at
  27. Le T, Wright EJ, Smith DM, et al. Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy. N Engl J Med. 2013;368(3):218-230. Available at
  28. 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. 1996;272(5265):1167-1170. Available at
  29. 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. 1998;279(1):35-40. Available at
  30. 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. 1999;13(13):1717-1726. Available at
  31. 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. 1996;276(2):105-110. Available at
  32. 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. 2002;360(9327):119-129. Available at
  33. 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. 2004;140(4):256-264. Available at
  34. 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. 1996;334(7):426-431. Available at
  35. 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. 1997;126(12):929-938. Available at
  36. 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. 2003;362(9385):679-686. Available at
  37. 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. 2009;49(10):1582-1590. Available at
  38. 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. 2011;53(9):927-935. Available at
  39. 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. 2011;25(18):2259-2268. Available at
  40. 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. 2004;66(3):1145-1152. Available at
  41. 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. 2002;8(5):522-526. Available at
  42. 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. 2006;43(3):377-380. Available at
  43. Atta MG, Gallant JE, Rahman MH, et al. Antiretroviral therapy in the treatment of HIV-associated nephropathy. Nephrol Dial Transplant. 2006;21(10):2809-2813. Available at
  44. 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. 2005;16(8):2412-2420. Available at
  45. 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. 2008;22(4):481-487. Available at
  46. 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. 2008;22(15):1979-1991. Available at
  47. 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. 2002;360(9349):1921-1926. Available at
  48. Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med. 2012;156(4):271-278. Available at
  49. 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. 2006;166(15):1632-1641. Available at
  50. Balagopal A, Philp FH, Astemborski J, et al. Human immunodeficiency virus-related microbial translocation and progression of hepatitis C. Gastroenterology. 2008;135(1):226-233. Available at
  51. Blackard JT, Kang M, St Clair JB, et al. Viral factors associated with cytokine expression during HCV/HIV co-infection. J Interferon Cytokine Res. 2007;27(4):263-269. Available at
  52. 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. 2009;49(6):2055-2067. Available at
  53. 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. 2009;50(4):1056-1063. Available at
  54. 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. Available at
  55. Ragni MV, Nalesnik MA, Schillo R, Dang Q. Highly active antiretroviral therapy improves ESLD-free survival in HIV-HCV co-infection. Haemophilia. 2009;15(2):552-558. Available at
  56. 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. 2008;48(4):1062-1069. Available at
  57. 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. 2006;44(5):1110-1116. Available at
  58. 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. 2009;52(4):452-458. Available at
  59. Limketkai BN, Mehta SH, Sutcliffe CG, et al. Relationship of liver disease stage and antiviral therapy with liver-related events and death in adults coinfected with HIV/HCV. JAMA. 2012;308(4):370-378. Available at
  60. 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. 2007;369(9568):1169-1178. Available at
  61. Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med. 2008;359(4):339-354. Available at
  62. 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. 2010;53(3):323-332. Available at
  63. Loko MA, Bani-Sadr F, Valantin MA, et al. Antiretroviral therapy and sustained virological response to HCV therapy are associated with slower liver fibrosis progression in HIV-HCV-coinfected patients: study from the ANRS CO 13 HEPAVIH cohort. Antivir Ther. 2012;17(7):1335-1343. Available at
  64. Brau N, Salvatore M, Rios-Bedoya CF, et al. Slower fibrosis progression in HIV/HCV-coinfected patients with successful HIV suppression using antiretroviral therapy. J Hepatol. 2006;44(1):47-55. Available at
  65. Thorpe J, Saeed S, Moodie EE, Klein MB, Canadian Co-infection Cohort S. Antiretroviral treatment interruption leads to progression of liver fibrosis in HIV-hepatitis C virus co-infection. AIDS. 2011;25(7):967-975. Available at
  66. Smith C. Factors associated with specific causes of death amongst HIV-positive individuals in the D:A:D Study. AIDS. 2010;24(10):1537-1548. Available at
  67. Mocroft A, Reiss P, Gasiorowski J, et al. Serious fatal and nonfatal non-AIDS-defining illnesses in Europe. J Acquir Immune Defic Syndr. 2010;55(2):262-270. Available at
  68. Weber R SC, D:D:D Study Group. Trends over time in underlying causes of death in the D:A:D study from 1999 to 2011. Abstract THAB0304. Presented at: XIX International AIDS Conference; July 22–27, 2012; Washington, DC. 
  69. Friis-Moller N, Reiss P, Sabin CA, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med. 2007;356(17):1723-1735. Available at
  70. 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. 2008;371(9622):1417-1426. Available at
  71. El-Sadr WM, Lundgren JD, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355(22):2283-2296. Available at
  72. 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; 2009; Montreal, Canada.
  73. 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. 2008;52(7):569-576. Available at
  74. Phillips AN, Neaton J, Lundgren JD. The role of HIV in serious diseases other than AIDS. AIDS. 2008;22(18):2409-2418. Available at
  75. Baker JV, Duprez D, Rapkin J, et al. Untreated HIV infection and large and small artery elasticity. J Acquir Immune Defic Syndr. 2009;52(1):25-31. Available at
  76. Marin B, Thiebaut R, Bucher HC, et al. Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy. AIDS. 2009;23(13):1743-1753. Available at
  77. Wright TC, Jr., Ellerbrock TV, Chiasson MA, Van Devanter N, Sun XW. Cervical intraepithelial neoplasia in women infected with human immunodeficiency virus: prevalence, risk factors, and validity of Papanicolaou smears. New York Cervical Disease Study. Obstet Gynecol. 1994;84(4):591-597. Available at
  78. Palefsky JM, Holly EA, Gonzales J, Lamborn K, Hollander H. Natural history of anal cytologic abnormalities and papillomavirus infection among homosexual men with group IV HIV disease. J Acquir Immune Defic Syndr. 1992;5(12):1258-1265. Available at
  79. 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. 2009. Available at
  80. Silverberg MJ, Chao C, Leyden WA, et al. HIV infection, immunodeficiency, viral replication, and the risk of cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2011;20(12):2551-2559. Available at
  81. Silverberg MJ, Leyden W, Warton EM, Quesenberry CP, Jr., Engels EA, Asgari MM. HIV infection status, immunodeficiency, and the incidence of non-melanoma skin cancer. J Natl Cancer Inst. 2013;105(5):350-360. Available at
  82. Shiels MS, Pfeiffer RM, Gail MH, et al. Cancer burden in the HIV-infected population in the United States. J Natl Cancer Inst. 2011;103(9):753-762. Available at
  83. Sigel K, Wisnivesky J, Gordon K, et al. HIV as an independent risk factor for incident lung cancer. AIDS. 2012;26(8):1017-1025. Available at
  84. 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. 2009. Available at
  85. Monforte A, Abrams D, Pradier C, et al. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS. 2008;22(16):2143-2153. Available at
  86. Reekie J, Kosa C, Engsig F, et al. Relationship between current level of immunodeficiency and non-acquired immunodeficiency syndrome-defining malignancies. Cancer. 2010;116(22):5306-5315. Available at
  87. 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. 2009;49(7):1109-1116. Available at
  88. Silverberg MJ, Chao C, Leyden WA, et al. HIV infection and the risk of cancers with and without a known infectious cause. AIDS. 2009;23(17):2337-2345. Available at
  89. 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. 2007;370(9581):59-67. Available at
  90. 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. 2009;200(1):79-87. Available at
  91. Silverberg MJ, Neuhaus J, Bower M, et al. Risk of cancers during interrupted antiretroviral therapy in the SMART study. AIDS. 2007;21(14):1957-1963. Available at
  92. 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. 2011;305(14):1450-1459. Available at
  93. 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. 2008;148(10):728-736. Available at
  94. Simard EP, Pfeiffer RM, Engels EA. Cumulative incidence of cancer among individuals with acquired immunodeficiency syndrome in the United States. Cancer. 2011;117(5):1089-1096. Available at
  95. Gopal S, Patel MR, Yanik EL, et al. Temporal trends in presentation and survival for HIV-associated lymphoma in the antiretroviral therapy era. J Natl Cancer Inst. 2013;105(16):1221-1229. Available at
  96. Worm SW, Bower M, Reiss P, et al. Non-AIDS defining cancers in the D:A:D Study–time trends and predictors of survival: a cohort study. BMC Infect Dis. 2013;13:471. Available at
  97. Riedel DJ, Mwangi EI, Fantry LE, et al. High cancer-related mortality in an urban, predominantly African-American, HIV-infected population. AIDS. 2013;27(7):1109-1117. Available at
  98. 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. 1997;42(5):689-698. Available at
  99. Spudich SS, Nilsson AC, Lollo ND, et al. Cerebrospinal fluid HIV infection and pleocytosis: relation to systemic infection and antiretroviral treatment. BMC Infect Dis. 2005;5:98. Available at
  100. Ellis RJ, Badiee J, Vaida F, et al. CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS. 2011;25(14):1747-1751. Available at
  101. Valcour V, Chalermchai T, Sailasuta N, et al. Central nervous system viral invasion and inflammation during acute HIV infection. J Infect Dis. 2012;206(2):275-282. Available at
  102. Navia BA, Jordan BD, Price RW. The AIDS dementia complex: I. Clinical features. Ann Neurol. 1986;19(6):517-524. Available at
  103. Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69(18):1789-1799. Available at
  104. Heaton RK, Clifford DB, Franklin DR, Jr., et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology. 2010;75(23):2087-2096. Available at
  105. Schnell G, Price RW, Swanstrom R, Spudich S. Compartmentalization and clonal amplification of HIV-1 variants in the cerebrospinal fluid during primary infection. J Virol. 2010;84(5):2395-2407. Available at
  106. Schnell G, Joseph S, Spudich S, Price RW, Swanstrom R. HIV-1 replication in the central nervous system occurs in two distinct cell types. PLoS Pathog. 2011;7(10):e1002286. Available at
  107. 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. Available at
  108. d'Arminio Monforte A, Cinque P, Mocroft A, et al. Changing incidence of central nervous system diseases in the EuroSIDA cohort. Ann Neurol. 2004;55(3):320-328. Available at
  109. 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. 2008;63(2):213-221. Available at
  110. Lescure FX, Omland LH, Engsig FN, et al. Incidence and impact on mortality of severe neurocognitive disorders in persons with and without HIV infection: a Danish nationwide cohort study. Clin Infect Dis. 2011;52(2):235-243. Available at
  111. Abdulle S, Mellgren A, Brew BJ, et al. CSF neurofilament protein (NFL) -- a marker of active HIV-related neurodegeneration. J Neurol. 2007;254(8):1026-1032. Available at
  112. Simioni S, Cavassini M, Annoni JM, et al. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS. 2010;24(9):1243-1250. Available at
  113. Munoz-Moreno JA, Fumaz CR, Ferrer MJ, et al. Nadir CD4 cell count predicts neurocognitive impairment in HIV-infected patients. AIDS Res Hum Retroviruses. 2008;24(10):1301-1307. Available at
  114. Heaton RK, Franklin DR, Ellis RJ, et al. HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol. 2011;17(1):3-16. Available at
  115. Garvey L, Surendrakumar V, Winston A. Low rates of neurocognitive impairment are observed in neuro-asymptomatic HIV-infected subjects on effective antiretroviral therapy. HIV Clin Trials. 2011;12(6):333-338. Available at
  116. Robinson-Papp J, Simpson DM. Neuromuscular diseases associated with HIV-1 infection. Muscle Nerve. 2009;40(6):1043-1053. Available at
  117. Evans SR, Ellis RJ, Chen H, et al. Peripheral neuropathy in HIV: prevalence and risk factors. AIDS. 2011;25(7):919-928. Available at
  118. 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. 2010;67(5):552-558. Available at
  119. The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study group. Response to combination antiretroviral therapy: variation by age. AIDS. 2008;22(12):1463-1473. Available at
  120. 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. Available at
  121. 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. 2007;44(3):268-277. Available at
  122. Wright ST, Petoumenos K, Boyd M, et al. Ageing and long-term CD4 cell count trends in HIV-positive patients with 5 years or more combination antiretroviral therapy experience. HIV Med. 2013;14(4):208-216. Available at
  123. 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. 2003;187(10):1534-1543. Available at
  124. 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. 2010;201(12):1788-1795. Available at
  125. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5(10):e203. Available at
  126. Sandler NG, Wand H, Roque A, et al. Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis. 2011;203(6):780-790. Available at
  127. Duprez DA, Neuhaus J, Kuller LH, et al. Inflammation, coagulation and cardiovascular disease in HIV-infected individuals. PLoS One. 2012;7(9):e44454. Available at
  128. Borges AH, Silverberg MJ, Wentworth D, et al. Predicting risk of cancer during HIV infection: the role of inflammatory and coagulation biomarkers. AIDS. 2013;27(9):1433-1441. Available at
  129. Mocroft A, Phillips AN, Gatell J, et al. Normalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study. Lancet. 2007;370(9585):407-413. Available at
  130. Kelley CF, Kitchen CM, Hunt PW, et al. Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis. 2009;48(6):787-794. Available at
  131. Lichtenstein KA, Armon C, Buchacz K, et al. Low CD4+ T cell count is a risk factor for cardiovascular disease events in the HIV outpatient study. Clin Infect Dis. 2010;51(4):435-447. Available at
  132. Freiberg MS, Chang CC, Kuller LH, et al. HIV infection and the risk of acute myocardial infarction. JAMA Internal Medicine. 2013;173(8):614-622. Available at
  133. 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. 2009;200(6):973-983. Available at
  134. 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. 2010;24(11):1657-1665. Available at
  135. 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. 2003;17(14):2015-2023. Available at
  136. 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. 2009;48(3):350-361. Available at
  137. Tubiana R, Le Chenadec J, Rouzioux C, et al. Factors associated with mother-to-child transmission of HIV-1 despite a maternal viral load <500 copies/ml at delivery: a case-control study nested in the French perinatal cohort (EPF-ANRS CO1). Clin Infect Dis. 2010;50(4):585-596. Available at
  138. Townsend CL, Cortina-Borja M, Peckham CS, de Ruiter A, Lyall H, Tookey PA. Low rates of mother-to-child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006. AIDS. 2008;22(8):973-981. Available at
  139. 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. Available at 
  140. 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. 2000;14(2):117-121. Available at
  141. Coombs RW, Reichelderfer PS, Landay AL. Recent observations on HIV type-1 infection in the genital tract of men and women. AIDS. 2003;17(4):455-480. Available at
  142. 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. 2002;29(3):275-283. Available at
  143. Kayitenkore K, Bekan B, Rufagari J, et al. The impact of ART on HIV transmission among HIV serodiscordant couples. Paper presented at: XVI International AIDS Conference; 2009; Toronto, Canada.
  144. Reynolds S, Makumbi F, Kagaayi J, et al. ART reduced the rate of sexual transmission of HIV among HIV-discordant couples in rural Rakai, Uganda. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; 2009; Montreal, Canada.
  145. Sullivan P, Kayitenkore K, Chomba E, et al. 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; 2009; Montreal, Canada.
  146. Tanser F, Barnighausen T, Grapsa E, Zaidi J, Newell ML. High coverage of ART associated with decline in risk of HIV acquisition in rural KwaZulu-Natal, South Africa. Science. 2013;339(6122):966-971. Available at
  147. 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. 2006;20(1):85-92. Available at
  148. 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. 2005;40(1):96-101. Available at
  149. Wilson DP, Law MG, Grulich AE, Cooper DA, Kaldor JM. Relation between HIV viral load and infectiousness: a model-based analysis. Lancet. 2008;372(9635):314-320. Available at
  150. 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. 2010;201(3):318-330. Available at
  151. Horberg M, Tang B, Towner W, et al. Impact of tenofovir on renal function in HIV-infected, antiretroviral-naive patients. J Acquir Immune Defic Syndr. 2010;53(1):62-69. Available at
  152. Laprise C, de Pokomandy A, Baril JG, Dufresne S, Trottier H. Virologic failure following persistent low-level viremia in a cohort of HIV-positive patients: results from 12 years of observation. Clin Infect Dis. 2013;57(10):1489-1496. Available at
  153. Scherzer R, Estrella M, Li Y, et al. Association of tenofovir exposure with kidney disease risk in HIV infection. AIDS. 2012;26(7):867-875. Available at
  154. Uy J, Armon C, Buchacz K, Wood K, Brooks JT. Initiation of HAART at higher CD4 cell counts is associated with a lower frequency of antiretroviral drug resistance mutations at virologic failure. J Acquir Immune Defic Syndr. 2009;51(4):450-453. Available at
  155. Abraham AG, Lau B, Deeks S, et al. Missing data on the estimation of the prevalence of accumulated human immunodeficiency virus drug resistance in patients treated with antiretroviral drugs in north america. Am J Epidemiol. 2011;174(6):727-735. Available at
  156. Freedberg KA, Losina E, Weinstein MC, et al. The cost effectiveness of combination antiretroviral therapy for HIV disease. N Engl J Med. 2001;344(11):824-831. Available at
  157. 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. 2001;91(9):1456-1463. Available at
  158. Mauskopf J, Kitahata M, Kauf T, Richter A, Tolson J. HIV antiretroviral treatment: early versus later. J Acquir Immune Defic Syndr. 2005;39(5):562-569. Available at
  159. Chen RY, Accortt NA, Westfall AO, et al. Distribution of health care expenditures for HIV-infected patients. Clin Infect Dis. 2006;42(7):1003-1010. Available at
  160. Walensky RP, Sax PE, Nakamura YM, et al. Economic savings versus health losses: the cost-effectiveness of generic antiretroviral therapy in the United States. Ann Intern Med. 2013;158(2):84-92. Available at
  161. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at Accessed January 6, 2014. 
  162. 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. 2009;51(2):130-134. Available at
  163. 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. 2005;41(10):1483-1497. Available at
  164. Boulware D MD, Muzoora C, et al. ART initiation within the first 2 weeks of cryptococcal meningitis is associated with higher mortality: a multisite randomized trial. Abstract 144. Paper presented at CROI; 2013.
  165. 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. 2009;50(2):148-152. Available at
  166. Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med. 2010;362(8):697-706. Available at
  167. Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med. 2011;365(16):1492-1501. Available at
  168. 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. 2011;365(16):1471-1481. Available at
  169. Havlir DV, Kendall MA, Ive P, et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011;365(16):1482-1491. Available at
  170. Lu M, Safren SA, Skolnik PR, et al. Optimal recall period and response task for self-reported HIV medication adherence. AIDS Behav. 2008;12(1):86-94. Available at
  171. 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. 2006;10(3):227-245. Available at
  172. 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. 2008;5(5):e109. Available at
  173. 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. 2008;9(5):298-308. Available at
  174. 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. 2004;39(8):1190-1198. Available at
  175. 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. 2008;197(1):126-133. Available at
  176. 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. 2007;81(16):8838-8842. Available at
  177. Hatano H, Yukl SA, Ferre AL, et al. Prospective antiretroviral treatment of asymptomatic, HIV-1 infected controllers. PLoS Pathog. 2013;9(10):e1003691. Available at
  178. Egger M. Outcomes of ART in resource-limited and industrialized countries. Paper presented at: 14th Conference on Retroviruses and Opportunistic Infections; 2007; Los Angeles, CA.
  179. 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. 2008;9(6):397-405. Available at
  180. Centers for Disease Control and Prevention (CDC). Late HIV testing—34 states, 1996–2005. MMWR Morb Mortal Wkly Rep. 2009;58(24):661-665. Available at
  181. 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. Available at
  182. 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. 2006;55(RR-14):1-17. Available at

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