Looking Beyond the Cascade of HIV Care to End the AIDS Epidemic: Estimation of the Time Interval From HIV Infection to Viral Suppression

Abstract

Background: 

Ensuring early universal access to HIV treatment is critical to reach the end of AIDS. The cascade of HIV care has become a critical metric to assess the coverage of treatment and viral suppression, but it does not provide any information on the elapsed times between becoming HIV-infected and reaching viral suppression.

Methods: 

We estimated the cascade of care, the distribution of times between steps of the care continuum, in France, in 2010, at the national level, overall and by HIV exposure groups, using statistical modelling and large datasets: the national HIV surveillance system, the general social insurance scheme, and the French Hospital Database on HIV.

Results: 

We found that the overall rate of viral suppression was high, with an estimated value of 52% (95% confidence interval: 49 to 54). However, the time intervals from HIV infection to viral suppression were long; overall, the median value was 6.1 years (inter quartile range: 3.6–9.2), and it ranged from ∼5.6 years among men who have sex with men and heterosexual women to 9.6 years among injection drug users. Time lost in achieving viral suppression was mainly due to delays in HIV testing (overall median of 3.4 years), except for injection drug users where it was also due to delayed care entry once diagnosed (∼1 year in median versus <1 month for other groups).

Conclusions: 

High viral suppression rate can hide large gaps between time of HIV infection and time of viral suppression. Estimates of the flow-time between steps of the care continuum should become priority indicators to identify these gaps and monitor whether interventions are successful in closing them.

INTRODUCTION

Early effective combination antiretroviral treatment (cART) dramatically improves the prognosis of HIV-infected patients.^1,2 This is usually achieved by suppressing the HIV viral load to below the detection limit, which typically results in the maintenance or restoration of the CD4 cell count and allows for maximal immunologic reconstitution. It was shown that HIV-infected individuals on cART who maintained or had recovery of CD4 cell counts to at least 500 cells per cubic millimeter have life expectancies approaching that of the general population.^3–5 A recent study found that an HIV-infected person's CD4 cell count is more likely to return to over 900 cells per cubic millimeter if treatment is started within a year of seroconversion.⁶ In addition, several studies have shown that, by suppressing the viral load, cART greatly reduces the risk of HIV transmission.^7,8 Extrapolation of this finding at the population level, using mathematical models, has suggested that early and widespread use of cART could turn the tide against the HIV epidemic^9,10; specifically, elimination of the epidemic would require universal cART initiation shortly after the infection.⁹ Thus, early cART is key for both individual health and prevention of HIV transmission.

Because individual health and prevention have converged, attention has focused on how well individuals living with HIV are engaged in care and, particularly, on the cascade of HIV care. The cascade of HIV care, also called the HIV treatment cascade, shows the percentages of HIV-infected individuals in each step of the care continuum, including HIV diagnosis, linkage and retention in care, receipt of cART, and achievement of viral suppression. It has been evaluated in many settings, and has become a critical metric to assess the coverage of cART and viral suppression.^11–13 Viral suppression levels varied from 20% in Georgia to 62% in Australia.¹³ In 2014, UNAIDS launched an ambitious new target to end the AIDS epidemic, known as 90-90-90.¹⁴ It calls for 90% of people living with HIV to know their HIV status, 90% of them to be on cART, and 90% of them to have achieved viral suppression; taken together, the three 90s calls for 73% of HIV-infected individuals being virally suppressed. However, the cascade of HIV care offers an incomplete picture of the care continuum, because it does not provide any information on the elapsed times between steps of the care continuum, and between becoming HIV-infected and reaching viral suppression. Yet, this information is essential to identify the barriers that delay access to cART and viral suppression and, hence, to end the AIDS epidemic.

To illustrate our point, here, we review data on the French HIV epidemic to describe the continuum of HIV care in France. We estimate the cascade of HIV care, and, for the first time, the distribution of times from one step of the HIV care continuum to the next, and from HIV infection to reaching viral suppression.

METHODS

We evaluated the cascade of HIV care (ie, the percentage of HIV-infected individuals in each step of the care continuum) in 2010 and the timing of HIV care (ie, the distributions of times from one step of the continuum to the next) in the few years before 2010. Determining the timing of HIV care for the period preceding the year in which the coverage of cART is evaluated is important to understand how to further improve the cascade of care. Figures were computed at the national level, overall and by HIV exposure group: men who have sex with men (MSM), injecting drug users (IDUs), and French and non-French national heterosexuals. The exposure group is determined based on what individuals declare as the probable mode of HIV acquisition. If more than 1 mode is reported, the case is classified in the exposure category listed first in the following hierarchy: MSM, IDU, heterosexual. French nationals and non-French nationals were analyzed separately, because, in Europe, migrants are considered a key group at risk for HIV infection.^15,16 In this study, we first describe the data sources we used to obtain information on the HIV population in France and then we describe how we combined these data to estimate the cascade and timing of HIV care. We focused on the 4 stages of the continuum of care: diagnosed, in care, on cART, and virally suppressed. We used a quasi-independent methodology to evaluate the cascade and timing of HIV care,¹⁷ in the sense that our approach does not require success at upstream stages before measuring success at later stages, except for viral suppression stage, because we studied viral suppression only among HIV-infected individuals who were on cART.

Data Sources

We used 3 large data sources to characterize the continuum of care in France: (1) the general social insurance scheme,¹⁸ (2) the French Hospital Database on HIV (FHDH-ANRS CO4),¹⁹ and (3) the HIV surveillance system.²⁰

The general social insurance scheme covers 87% of the French population, which includes mostly (private and public) salaried workers; the other 13% of the French population, including farmers, self-employed, and others, are covered under other smaller public social insurance schemes.²¹ The schemes can provide information on the number of HIV-infected individuals in care throughout the “affections de longue durée” (ALD) system. HIV is one of the 30 long-term illnesses, so-called ALD, for which patients are covered for 100% of their health care costs through their health insurance scheme. All HIV-infected individuals enrolling in care are eligible for ALD status. The status is requested by a clinician and has to be renewed every 5 years. The general social insurance scheme publicly releases, every year, aggregated data on the number of HIV-infected individuals with active ALD status, ie, individuals who had HIV-related expenses over the last year.¹⁸

The FHDH is a large, ongoing, prospective, observational, nationwide, hospital-based cohort that has enrolled HIV patients in care aged >15 years in 70 French general or university hospitals, since 1992. The only FHDH inclusion criteria are HIV-1 or HIV-2 infection and written informed consent. Technical research assistants prospectively collect clinical, biological, and therapeutic data from medical records; demographic data and HIV exposure group are recorded on inclusion. Standardized variables are collected at each outpatient visit, or hospital admission for an HIV-related clinical event or a new treatment prescription, or at least every 6 months. FHDH patients are representative of HIV patients in care in France.¹⁹ In 2010, the database included 54,321 patients (Table S1, Supplemental Digital Content, https://links.lww.com/QAI/A857), which represented ∼50% of HIV patients under care in France.

The HIV surveillance system provides information on newly diagnosed HIV cases since 2003,²⁰ when nationwide mandatory HIV case reporting was implemented. Data on new HIV diagnoses include date of diagnosis, demographic information (sex and nationality), HIV exposure group, and clinical status at diagnosis [primary HIV infection (PHI), AIDS, neither PHI nor AIDS]. Reported cases are adjusted for delay in reporting, under-reporting, and missing data.

The Timing of HIV Care

To estimate the distribution of times from infection to diagnosis, we used data from the HIV surveillance system and statistical modelling. The method has been described elsewhere.²² Briefly, we fitted a back-calculation model to the annual number of new HIV diagnoses to estimate both the HIV incidence and the distribution of times from infection to diagnosis.²² In our approach, we used data on the clinical status (ie, PHI, AIDS, neither PHI nor AIDS) at HIV diagnosis to disentangle the contributions to observed new HIV diagnoses made by HIV incidence and time-varying rates of diagnosis. For the purpose of this study, we report here the estimated distribution of times from infection to diagnosis for individuals who were newly infected with HIV in 2007; estimated distributions for individuals infected in previous or subsequent years were similar (results not shown).

To estimate the distribution of times in between steps of the care continuum once diagnosed with HIV, we used data on 6268 HIV-infected individuals who newly engaged in care between 2008 and 2010, and were enrolled onto the FHDH cohort (Table S2, Supplemental Digital Content, https://links.lww.com/QAI/A857). We used the dates of HIV diagnosis, care entry, cART initiation, and viral suppression to estimate the distribution of times from HIV diagnosis to care entry, from care entry to cART initiation, and from cART initiation to reaching undetectable viral load. Individuals who entered care and did not initiate treatment, and individuals who initiated treatment and did not achieve viral suppression were censored at the time of last known contact. From these data, we obtained nonparametric estimates of the cumulative distribution functions accounting for censoring.²³

We then used the 4 estimated distributions and the inversion method to generate 10,000 random values for each time interval.²³ We summed up the simulated time intervals to obtain 10,000 simulations of the time intervals from HIV infection to viral suppression, and of the time intervals from HIV diagnosis to viral suppression. Mean, median, and interquartile range were calculated for each time interval.

The Cascade of HIV Care

To estimate the number of individuals living with undiagnosed HIV, we used estimates of HIV incidence and distribution of times from infection to diagnosis, obtained as aforementioned. The method and results have been described elsewhere.²⁴ Briefly, the estimated number of new HIV infections was projected forward according to the distribution of times from infection to diagnosis, to obtain estimates of the number of individuals with undiagnosed HIV infection in 2010. Two thousand bootstrap estimates were obtained.²⁴

To estimate the number of individuals who are aware of their HIV infection and not engaged in care in 2010, we used estimates of the size of the undiagnosed HIV population in 2010 and of the percentage of individuals aware of their HIV infection for more than 3 months among HIV-infected individuals who newly engaged in care between 2008 and 2010 (noted P); this percentage was estimated using data on the dates of HIV diagnosis and care entry of the 6268 FHDH enrollees (Table S2, Supplemental Digital Content, https://links.lww.com/QAI/A857). Specifically, we know that, every year, HIV-infected individuals present for HIV care. A fraction of these individuals were aware of their HIV infection for several months, whereas others just discovered their HIV status. We then assumed that the percentage of individuals aware of their HIV infection for more than 3 months among those newly engaging in care (P) corresponds to the fraction of individuals aware of their HIV infection who are not engaged in care among all HIV-infected individuals not engaged in care, which also comprises a fraction (1−p) of individuals unaware of their HIV infection. Then, using 2000 randomly generated values of P and 2000 estimates of the number of undiagnosed HIV-infected individuals in 2010 (U), we obtained 2000 estimates of the number of individuals aware of their HIV infection not engaged in care in 2010 using the following formula: Up/(1−p).

To estimate the number of HIV-infected individuals in care in 2010, we used data from the general social insurance scheme. In 2010, the number of individuals affiliated to the general social insurance scheme who had active ALD status for HIV was 96,963. Because this scheme covered 87% of the French population in 2010, we estimated the number of HIV-infected individuals in care, by dividing 96,963 by 87%; we thus assumed that the prevalence of active ALD for HIV among the population covered by schemes other than the general social insurance scheme was similar to that observed among the population covered by the general social insurance scheme.

To determine the number of HIV-infected individuals in care who were on cART and the number of individuals who were virally suppressed among those on cART, we used the cART coverage and the viral suppression rate that was observed among FHDH enrollees. We obtained 2000 characterizations of the HIV population in care in 2010, by generating 2000 random values of the cART coverage and viral suppression rate based on the percentages observed among all FHDH enrollees in 2010 (Table S1, Supplemental Digital Content, https://links.lww.com/QAI/A857).

We then summed up estimates of the numbers of individuals in care and not in care, and obtained 2000 estimates of the total size of the HIV epidemic as well as of the number and percentages of individuals in each step of the care continuum, from which mean and 95% confidence interval were calculated.

Statistical comparisons between HIV exposure groups were carried out with the nonparametric Kruskal–Wallis test. Data analyses were performed using Matlab version R2014b and SAS version 9.4.

RESULTS

In 2010, in France, an estimated 148,900 individuals were living with HIV (Table 1). Among these, 35.7% were MSM, 29.2% French heterosexuals, 23.2% non-French national heterosexuals, and 9.3% were IDUs. The prevalence of HIV in the general population was 0.38%, and varied from 0.12% among French-national heterosexuals to 17% among MSM and IDUs.

TABLE 1.: Estimated Numbers and Prevalence of HIV-Infected Persons Living With HIV (%) in France in 2010 by HIV Exposure Group

The cascade of HIV care in 2010 is displayed on Figure 1 and Table S3, Supplemental Digital Content, https://links.lww.com/QAI/A857. Among the 148,900 individuals living with HIV, 80.6% (95% confidence interval: 78.1 to 83.1) were diagnosed, 74.9% (71.9 to 78.1) were in care, 60.5% (58.0 to 63.1) were receiving cART for >6 months, and 51.7% (49.5 to 53.9) were virally suppressed (<50 copies per milliliter). Among individuals diagnosed with HIV, 75.1% (74.1 to 76.0) were on cART for >6 months, and among individuals on cART for >6 months, 85.4% (85.1 to 85.8) were virally suppressed (Table S4, Supplemental Digital Content, https://links.lww.com/QAI/A857). The cascade of HIV care varied between exposure groups (P < 0.001). IDUs had the highest percentages at every stage of the care continuum, followed by French-national heterosexual women and MSM with intermediate percentages, and then by French-national heterosexual men and non-French national heterosexuals with the lowest percentages. The percentage of HIV-infected individuals who achieved viral suppression was highest among IDUs, 68.3% (61.5 to 73.1), intermediate among MSM and French-national heterosexual women, 54.8% (52.2 to 56.8) and 54.9% (49.8 to 61.8), respectively, and lowest among French-national heterosexual men and non-French national heterosexuals (among women and men), 44.7% (37.7 to 52.6), 43.0% (38.7 to 46.8), and 38.8% (32.1 to 46.9), respectively.

FIGURE 1.: Cascade of HIV care in France in 2010: estimated percentage of HIV-infected persons engaged in selected stages of the continuum of HIV care, overall and by HIV exposure group. Vertical lines within bars represent 95% confidence intervals. VL, viral load.

The timing of care is displayed on Figure 2 and Table S5, Supplemental Digital Content, https://links.lww.com/QAI/A857. The overall median time from infection to reaching viral suppression was 6.1 years. It comprised 4 steps: a median time of 3.4 years from infection to diagnosis, less than a month to engage in care once diagnosed, 0.5 years to initiate cART once in care, and 0.5 years to achieve viral suppression once on cART; overall median time from HIV diagnosis to viral suppression was 1.9 years. MSM and heterosexual women had the shortest median time from infection to viral suppression (∼5.6 years) and IDUs the longest (9.6 years, respectively), P < 0.001. There were considerable and significant timing differences between exposure groups for the first 3 steps of the care continuum (all P < 0.001), and to a much lesser extent for the last step. MSM and heterosexual women had the shortest median time from infection to diagnosis (∼2.9 years) and heterosexual men the longest (∼4.6 years). The median time from diagnosis to care entry was <1 month for all groups except for IDUs for whom it was almost 1 year. The median time from care entry to cART initiation varied from 3 months for non-French national heterosexual men to 10 months for MSM. Once on cART, the median time to reaching viral suppression was around 0.5 years for all groups. Median time from HIV diagnosis to viral suppression ranged from ∼1.5 years for non-French national heterosexuals to 4.1 years for IDUs.

FIGURE 2.: Timing of HIV care in France: estimated times in years (median and interquartile range) between stages of the continuum of HIV care, from infection to viral suppression and from diagnosis to viral suppression, overall and by HIV exposure group. Viral suppression was defined as having less than 50 copies per milliliter.

DISCUSSION

Ensuring early universal access to cART and viral suppression is critical to achieve maximum individual and public health benefits of cART. In this study, we evaluated both the cascade and the timing of HIV care in a specific setting, and we revealed 2 major findings that could likely be extrapolated to other settings. High coverage of cART and viral suppression can coexist with large gap between time of HIV infection and time of viral suppression. Evaluating patient flow-time through the continuum of HIV care is key to identifying what kind of actions is required to accelerate access to cART and viral suppression.

Our study shows that more than 60% of individuals living with HIV in France were on cART for more than 6 months and more than 50% had undetectable viral load. Nevertheless, in parallel, we found that it takes more than 6 years to reach viral suppression once HIV-infected, for 50% of individuals. Findings at the group level show that there is no straightforward relationship between the rates of viral suppression and the time to reach viral suppression. IDUs and MSM had the highest rates of viral suppression, 68% and 55%, respectively, but very different time intervals from HIV infection to viral suppression. IDUs had the longest median time intervals (9.6 years) and MSM one of the shortest (5.7 years). Heterosexual women, whether French or non-French nationals, had similar median time interval from infection to viral suppression (∼5.6 years), but different rates of viral suppression: 55% for French-national women versus 43% for non-French national women.

These paradoxical results at first sight can be easily reconciled by considering the different nature of the 2 metrics used to describe access to cART and viral suppression. Indeed, the time from HIV infection to viral suppression measures the pace of access to HIV care and treatment in the recent past, whereas the coverage of cART and viral suppression is an aggregate measure of what happened in terms of HIV transmission, access to care and treatment, retention in care, and survival rates since the beginning of the HIV epidemic. To give an example, in France, the coverage of cART and viral suppression is high among IDUs for the following reasons. In this group, HIV transmission has substantially decreased over time due to needle program exchange, from several thousand new infections per year in the 1980s to around 100 per year in the mid-2000s.²² Some of the many IDUs infected many years ago survived until now, because they had access and had been adherent to treatment since then. The “few hundred” IDUs infected with HIV in more recent years, who are the most likely to be unaware of their status and/or not engaged in care, then can only account for a small fraction of all HIV-infected IDUs. Hence, the coverage of cART and viral suppression among IDUs is high, mostly, because the number of HIV-infected IDUs entering the care cascade, ie, the number of new HIV infections is low compared with the number of IDUs already in care (a “few hundred” versus 12,600, see Table S4, Supplemental Digital Content, https://links.lww.com/QAI/A857). Nevertheless, IDUs infected in recent years have long time intervals between infection and viral suppression according to our estimates of the timing of care. This cannot be reflected in the cascade of care, because IDUs infected in recent years only represent a small proportion of all HIV-infected IDUs. All these show that the coverage of cART and viral suppression is determined by many factors, including changes in the intensity of the HIV epidemic over time, and thus does not necessarily reflect gaps in recent access to care and treatment. Hence the cascade of care, while useful to assess the percentage of HIV-infected individuals at risk of HIV transmission, might not be the right tool to determine what kind of actions are required to accelerate access to cART and viral suppression, and thus to decrease the percentage of individuals at risk of HIV transmission.

As for estimates of the timing of HIV care, it provides information to identify recent gaps in the care continuum which delays access to cART and viral suppression. In France, we found that the time lost in achieving viral suppression was mainly due to delays in HIV testing (overall median of 3.4 years), except for IDUs where it was also due to delayed care entry once diagnosed (∼1 year in median versus <1 month for other groups). The median time from infection to HIV diagnosis was the shortest for MSM and heterosexual women (∼2.9 years) and especially long for heterosexual men (∼4.6 years). Once in care, times to move from one stage to the next remained short (less than 5 months in median), except for MSM and French-national heterosexual women for which the median time from care entry to cART initiation was 10 and 7 months, respectively. Time to initiate cART was longer among MSM and French-national heterosexual women, because a higher fraction of them (compared with other exposure groups) presented for HIV care before being eligible for cART (ie, with CD4 count >350 cells per cubic millimeter) and thus had to wait to initiate treatment; according to FHDH data, median CD4 counts at presentation for care was 453 cells per cubic millimeter for MSM and 400 cells per cubic millimeter for French-national heterosexual women, whereas it was less than 367 cells per cubic millimeter for all the other exposure groups. Time to initiate cART is however expected to have decreased after 2010, because the cART eligibility threshold was lowered to 500 cells per cubic millimeter in October 2010 and to universal treatment in 2013.²⁸

The strengths of our study include the large amount of data source available in France to characterize the continuum of care, including data from the general social insurance scheme which covers 87% of the French population, and the large FHDH cohort that provides information on ∼50% of HIV patients in care. Our study has some limitations. The number of undiagnosed HIV-infected individuals and the distribution of times from infection to diagnosis cannot be directly observed and were estimated using back-calculation modelling,²⁴ similar to recent studies in the US and England.^11,29 Sensitivity analyses, performed in a previous study, showed that our estimates were quite robust to our modelling assumptions.²⁴ In the absence of linked data between HIV diagnosis and the first medical visit, we used data on HIV-infected individuals, who were newly engaged in care, to estimate the time intervals from diagnosis to care entry. This may have introduced biases in the estimation because some individuals might have died, before entering into care, from HIV/AIDS-related causes–during the 2008–2010 period, ∼28% individuals were diagnosed at advance disease stage (AIDS or CD4 <200 cell per cubic millimeter)³⁰; and from non–HIV/AIDS-related causes–overdose remains a frequent cause of death among IDUs. In addition, once in care, HIV-infected individuals may drop in and out of care, go on and off treatment, and undetectable viral loads can bounce back. Our time estimates account for drops in and out of care and treatment discontinuation that occurred before treatment initiation or before viral suppression, but not for those that occurred after. Furthermore, we did account for viral rebound after achieving viral suppression. However, it should be noted that, in France, drops in and out of care, treatment discontinuation, and treatment failures remain limited. Indeed, according to data from the national social security scheme, only 6.4% of individuals who had ALD status in 2010, ie, individuals who engaged in HIV care or renewed their status between 2006 and 2010, did not use their ALD status in 2010, ie, did not have any HIV-related expense during 1 year.¹⁸ According to FHDH data, in 2010, only 5.7% of individuals in care had stopped their HIV treatment (results not shown) and, in 2009–2011, only 9.7% of patients treated for at least 6 months experienced at least 1 virologic failure over the 3-year period.³¹ Lastly, our findings reflect the HIV-infected population in 2010. The coverage of cART and viral suppression and the time to reach viral suppression may have changed since 2010. However, this does not invalidate our 2 major findings.

To the best of our knowledge, no study has reported estimates of times from HIV infection to viral suppression, and how these times were affected by the flow-time in between steps of the care continuum. However, large gaps between time of HIV infection and time of viral suppression are likely to exist in other settings. Indeed, in high-income settings, the mean time from infection to diagnosis was estimated to be 5.6 years overall in the United States³² and 3.2 years among MSM in United Kingdom²⁹; for comparison, these times were respectively estimated to be 3.8 and 3.4 years in France in this study (Table S5, Supplemental Digital Content, https://links.lww.com/QAI/A857). In addition, the mean time from diagnosis to viral suppression in 14 US jurisdictions was between 1.3 and 2.8 years,³³ compared with 3.1 years in our study (Table S5, Supplemental Digital Content, https://links.lww.com/QAI/A857). In low-income settings, we recently estimated the mean time from infection to cART initiation at around 10 years in Cameroon³⁴; this time was estimated to be 6.1 years in France in this study (results not shown).

The French health care system offers one of the best environments for HIV care. There is free access to a variety of screening offers such as free testing in anonymous HIV testing centers³⁵ and community-based HIV testing.³⁶ HIV patients are covered at the rate of 100% and exempt from any co-payments. The coverage of cART and viral suppression is high, according to our estimates. Still, the HIV epidemic remains uncontrolled, especially among MSM where HIV incidence is estimated at 1% per year.^22,37 This may be due to existing long delays between HIV infection and diagnosis, as evidenced in our study. Therefore, innovative interventions to increase uptake of HIV testing, such as self-testing programs,³⁸ are urgently needed to shorten the time interval from infection to viral suppression.

CONCLUSIONS

Our study shows that, in France, high coverage of cART and viral suppression hide large gaps between time of HIV infection and time of viral suppression. Similar gap is likely to exist in other settings and should be investigated. Closing this gap will be key to reach the end of AIDS and control the epidemic. Estimates of the flow-time between steps of the care continuum should help identify the barriers that delay access to cART and viral suppression, and thus should become priority indicators to monitor whether public health interventions are successful in addressing these barriers.