Many public health programs involve a cascade of interventions, with population-wide coverage at each step dependent upon the coverage in the previous steps. Attrition rates at each step are multiplied, like a pipe with multiple leaks along its length, potentially resulting in low overall coverage and impact of critical final intervention steps in the cascade. The cascade of HIV care and treatment includes: HIV testing, linkage to and retention in longitudinal care, initiation of antiretroviral treatment (ART), adherence to antiretroviral medications, and, lastly, viral load suppression, which results directly in improved health status and reduced risk of HIV transmission. As HIV treatment programs have scaled up in the past decade and as HIV treatment has more recently been identified as an important intervention to prevent HIV transmission, attrition in the cascade of care has emerged as a critical concern.
The cascade has been well characterized in the USA, which can serve as an illustrative example (Fig. 1) [1▪]. In the USA there were an estimated 1.2 million people living with HIV (PLHIV) in 2008, 80% of whom were estimated to have been diagnosed. Of them, about 77% were linked to care and only 51% were retained in ongoing care. Among adults in care, 89% had been prescribed ART and, of these, 77% had a suppressed viral load. Whereas each of these steps in the cascade is greater than 50%, when taken together, only an estimated 28% of all PLHIV in the USA were virally suppressed [1▪].
In this study, we review the cascade of HIV care and treatment, from HIV testing and awareness of HIV infection status, to suppression of viral load. To give workers in the field an up-to-date summary, we highlight the most important and interesting recent publications on the status of these steps in the cascade, as well as interventions and recommendations to reduce attrition. We focus primarily on adult and adolescents in sub-Saharan Africa, home to nearly 70% of PLHIV. As the core strategy for identifying relevant articles, we conducted multiple PubMed searches for publications since 1 January 2011, with the terms ‘HIV’ and either ‘testing’, ‘linkage’, retention’, ‘treatment initiation’, or ‘adherence’. This was supplemented by the authors’ knowledge of other relevant resources, such as agency-published reports. Key resources from before 2011 are cited in a few instances.
HIV testing is the critical, cost-effective first step in the cascade of HIV treatment, as well as the gateway to other prevention and care interventions, such as male circumcision, prevention of mother-to-child HIV transmission, and prophylaxis of opportunistic infections [2▪]. With increasing global resources for HIV interventions, HIV testing rates have been increasing in recent years [3▪▪]. For example, proportion of women in Kenya ever having tested and received their results increased from 18% in 2003 to 73% in 2008 [3▪▪]. In Lesotho, the increase was from 17% in 2004 to 71% in 2009 [3▪▪]. It should be noted, however, that apparent high rates of HIV testing do not directly translate into high awareness of infection status among PLHIV, which should also be monitored as a primary program goal. This was recently highlighted in a study in South Africa where almost half (45%) of all HIV-infected persons were unaware of their HIV-positive status despite 71.0% of the population reporting that they had previously had an HIV test, including 37% in the prior 12 months [4▪]. Reported barriers to HIV testing include fear, stigma, perceived lack of confidentiality, and lack of capacity of the health system .
Several approaches are being evaluated and implemented to increase knowledge of HIV infection status. A community-based intervention with mobile testing in three countries was shown to significantly increase HIV testing; case detection increased nearly four-fold compared with standard clinic-based testing . Provider-initiated HIV testing is also being implemented . A recent systematic review, which identified 19 studies, indicted that provider-initiated testing increased HIV testing and also condom use [8▪]. Self-testing is a potentially very useful emerging approach to HIV testing. In a study in Malawi, 92% of participants opted to self-test and accuracy was 99% (with two false-negatives) [9▪], and in July 2012, the United States Food and Drug Administration approved the first over-the-counter home-use rapid HIV test kit . A systematic review of that test found that oral fluid use, as recommended for home use, had a somewhat lower test performance than use of whole blood . One limitation in HIV testing is the lack of detectable antibodies in early HIV infection, when HIV viral load and transmission risk may be high . Addressing this, a fourth-generation HIV antigen/antibody combination assay compared very favorably to a standard third-generation enzyme immunoassay testing with western blot confirmation and RNA testing of pooled seronegative samples with a much shorter turn-around time [13▪].
LINKAGE TO AND RETENTION IN CARE
Linkage to and retention in longitudinal HIV care is the next key step in the cascade of HIV treatment, affording access to ART, as well as other ongoing prevention and care interventions. As ART programs have scaled up in recent years, suboptimal rates of linkage and retention in care have emerged as critical concerns. A recent systematic review of 28 eligible studies in sub-Saharan Africa identified proportions retained at three stages from HIV diagnosis to initiation of ART [14▪▪]. A median of 59% of patients were retained in stage 1, from the time of HIV testing to receipt of CD4 cell count results or clinical staging (range 35–88%). In stage 2, from the time of laboratory or clinical staging to determination of ART eligibility, a median of 46% of patients were retained (range 31–95%). Finally, in stage 3, from determination of ART eligibility to ART initiation, median retention was 68% (range 14–84%). None of the studies followed a cohort of patients from diagnosis to ART initiation, but the authors estimated that less than one-third of HIV-positive patients not yet eligible for ART when diagnosed are retained continuously in care from HIV diagnosis through ART initiation. A previous systematic review by these authors, which included 39 cohorts in sub-Saharan Africa, found that retention in care from initiation on first-line ART was 70% at 24 months and 65% at 36 months . In that review, 59% of attrition was due to loss to follow-up and 41% was due to death. Similarly, in a recent study in three countries in southern Africa, after 3 years, cumulative incidence of loss to follow-up was 25% and of death was 12% .
Recent studies have also added to our knowledge of risk factors for attrition from HIV care. A study in Malawi showed that mortality was higher when ART was fee-based . Other studies have shown that population mobility also contributes to attrition  and that CD4 cell count and viral load at 6 months have been shown to be important prognostic markers for longer-term clinical outcomes . Rapid point-of-care CD4 testing is being used to facilitate laboratory staging and improve to linkage to care . A study in Kenya demonstrated that a ‘High-Risk Express Care’ model that provided frequent rapid contacts with nurses for individuals initiating ART reduced mortality by 41% and reduced loss to follow-up by 38% . Other interventions to improve linkage and retention are included with interventions to improve adherence described below.
ANTIRETROVIRAL THERAPY COVERAGE
Rates of ART coverage of PLHIV are driven by recommendations, availability of resources, and adherence to recommendations by patients and clinicians. Offer of ART use at any CD4 cell count is now recommended in the USA, whereas many other countries have recommended ART initiation at CD4 cell count levels ranging from 200 to 500 cells/μl or less [22▪]. Since 2010, WHO has recommended initiation of ART at a CD4 cell count 350 or less or at any CD4 cell count in PLHIV with tuberculosis or requiring treatment of hepatitis B virus , and, since 2012, recommends consideration of treatment at any CD4 cell count for HIV-infected pregnant women  and HIV serodiscordant couples [25▪▪].
With increasing availability of resources, ART coverage has been rapidly increasing in recent years, from 1.3 million in 2005 to 8 million in 2011 [26▪▪], and is even higher today. In Zimbabwe, for example, some 8000 PLHIV are initiating ART each month (Mutasa-Apollo T, unpublished program data). ART coverage in PLHIV with CD4 cell counts 350 cells/μl or less in low- and middle-income countries in 2011 had reached 54%, including 44% in Asia, 56% in sub-Saharan Africa, and 70% in Latin America [26▪▪]. However, PLHIV with CD4 cell counts 350 or less are estimated to represent about half of PLHIV [3▪▪], so overall ART coverage in these countries was about one in four.
Patient and delivery-level factors relate to ART uptake. Factors associated negatively with ART uptake in a recent study in Malawi included not being offered ART, high CD4 cell count, drug stock outs, and fear of drug toxicities and drug interactions .
Adherence to prescribed ART is a critical late step in the cascade of HIV treatment. A recent meta-analysis of 84 studies in 20 countries underscored the challenge of adherence; an average of only 62% of patients reported at least 90% adherence [28▪▪]. Of note, better adherence was reported in resource-poor countries. In a separate publication, the authors also examined sex differences in adherence and found marginally higher reported adherence in men, with important differences by region and by sex in variables associated with adherence . Recent studies have highlighted depression and alcohol misuse as key factors in nonadherence . Other recent studies have better defined the relationship between adherence and viral load suppression, indicating that longer interruptions may have greater impact than average covered time [31▪] and that somewhat lower levels of adherence may be sufficient with newer antiretroviral medications .
Several studies have highlighted the role of community-based support in improving both retention in care and adherence [33,34]. In one South African study, attrition was 32% lower and viral load suppression was 22% higher in patients with community-based adherence support . Adverse drug effects have been identified as an important factor in adherence , and a focus on managing side effects was shown to be a successful adherence intervention [36▪]. Technology-based interventions have also been shown to be effective in recent systematic reviews [37▪▪,38] and clinical trials . A study in Cameroon found that poor adherence was associated with increased sexual transmission risk behavior [40▪], underscoring the importance of integrated interventions . Other studies have confirmed the effectiveness of support and outreach services , and questioned the utility of multiple pretherapy counseling sessions . Other important recent contributions to the field include a recent systematic review of interventions to increase antiretroviral adherence in sub-Saharan Africa [44▪▪], a CDC compendium of eight evidence-based individual and group-level behavioral adherence interventions [45▪], and comprehensive guidelines for improving linkage, retention, and adherence from the International Association of Physicians in AIDS Care .
VIRAL SUPPRESSION AND MONITORING AND SURVEILLANCE
Viral suppression may be considered the final step in the cascade of HIV treatment as the critical marker of risk both for clinical disease progression and for HIV transmission. A systematic review of 89 studies in sub-Saharan Africa determined that in overall, on-treatment analysis suppression (<1000 HIV RNA copies/ml) was 78, 76, and 67% at 6, 12, and 24 months, respectively .
Efforts to monitor and improve the quality of ART programs are critically important. Use of ‘early warning indicators’ for antiretroviral drug resistance is also useful for monitoring retention and adherence [48▪]. Recent publications from the USA have also reported on novel uses of laboratory data to monitor  and target  program activities.
Accurate population-based estimates of the status of the steps in the cascade of care are not available in most countries. Challenges in developing and comparing estimates include use of different data collection and analysis methods in different settings, which can limit the validity of inter-country comparisons. In addition, published data lag behind intervention successes as testing and treatment programs are being rapidly scaled up. Nonetheless, with significant shortfalls at each step of the cascade, low- and middle-income countries are likely to have substantially lower levels than the reported 28% overall viral load suppression in PLHIV in the USA [1▪]. Specifically, testing and diagnosis of PLHIV, although rapidly expanding, are generally relatively lower [3▪▪]. Also, the percentage of PLHIV diagnosed is usually not monitored and lags significantly behind the percentage of people who have ever been tested [4▪]. Linkage and retention in care are global challenges with substantial attrition between diagnosis, laboratory or clinical staging and ART initiation [14▪▪], and additional substantial attrition while on ART due to loss to follow-up and death . ART coverage in low- and middle-income countries, although rapidly expanding, is relatively low, especially when considered as a percentage of all PLHIV [26▪▪]. Adherence is also suboptimal in low- and middle-income countries, although it is better than in resource-rich settings [28▪▪]. Lastly, virological suppression is incomplete on first-line antiretrovirals  and there is limited availability of laboratory monitoring and second- and third-line drugs in many settings.
In Zimbabwe, for example, in 2010–2011, 57% of women and 36% of men had ever been tested for HIV and had received the result of the last test; and 34% of women and 21% of men had been tested and told the result in the 12 months preceding the survey . In addition, 63% of HIV-infected respondents (71% of infected women and 51% of infected men) had been tested. This was a marked increase from 2005–2006, when only 26% of infected women and 19% of infected men reported that they had been tested. However, as noted above, the proportion of PLHIV that is aware of their infection status is substantially lower than the proportion that has ever been tested [4▪], presumably because many were last tested prior to becoming HIV-infected, so it is likely that less than half of PLHIV in Zimbabwe are aware of their infection status, but this statistic is not monitored. Retention in care is relatively good; in a retrospective cohort study in a nationally representative sample of patients initiating ART between 2007 and 2009, although the country faced significant economic challenges, 69% of patients were continuing ART treatment at 24 months, whereas 7% had died and 24% were lost to follow-up . ART coverage is rapidly expanding in Zimbabwe, and is expected to reach 85% of PLHIV with CD4 cell counts less than 350 cells/μl in 2012 (Mutasa-Apollo T, unpublished program data), but this is well under half of the estimated total number of PLHIV. National data on linkage to care, adherence, and viral suppression are not readily available in Zimbabwe or in most other low- and middle-income countries. Zimbabwe, therefore, exemplifies both the challenges in monitoring key steps in the cascade of care and in attaining the desired very high rates of population-wide coverage for each step of the cascade.
More robust and standardized monitoring at each step of the cascade and from the facility to global levels will enable HIV authorities to ‘know your cascade’ and improve HIV program impact. Given the current substantial attrition, implementation of established and emerging interventions is needed at each step of the cascade to enhance HIV diagnosis, linkage to and retention in care, ART use and adherence, and, ultimately, to reduce viral load, thereby improving clinical outcomes and reducing HIV transmission.
Conflicts of interest
Disclaimer: The views expressed in this article are solely the responsibility of the authors and do not necessarily represent the official views of the CDC.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 80–81).
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In this cohort study, patients adherent to ART were less likely to report inconsistent condom use.
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Using defined criteria, CDC has identified eight good-evidence interventions to improve ART adherence.
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