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transformation of ART outcomes in clinical practice for most patients receiving treatment: Dramatic Decline in the HIV-1 RNA Level Over Calendar Time in a Large Urban HIV Practice (Hopkins), Antiretroviral Therapy: Now "It Just Works"
 
 
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from Jules: so why are their geographic pockets in the USA where HIV care is not as successful among African-Americans?

"During the past 15 years, substantial progress in ART has occurred, including a fuller understanding of optimal treatment strategies and the introduction of better tolerated, safer, and more effective antiviral agents........From 1996 (shortly after highly active antiretroviral therapy [HAART] was introduced) to 2010, the median HIV-1 RNA level decreased from 10 400 to <200 copies/mL. The proportion of patients with an HIV-1 RNA level >500 copies/mL decreased from 75% to only 16% during this same period.....there has been an increased understanding of both the benefits of starting HIV treatment substantially before clinical immunosuppresion occurs and the risks of interrupting treatment even at high CD4 cell counts. In recognition of these advances, treatment guidelines now recommend lifelong ART for asymptomatic patients potentially at all CD4 cell counts, especially if the patient is willing to start treatment or has any of several comorbid conditions....earlier therapy is a more compelling treatment strategy to offer asymptomatic patients when the rates of treatment success are high, and this improvement in outcome has had a corresponding effect of decreasing the incidence of antiretroviral drug resistance......The high rate of virologic suppression reported in the article by Moore and Bartlett should have both individual and public health benefits [8]; together, these benefits provide an urgent impetus for diagnosis of HIV infection early in the course of HIV disease, preferably before both clinical symptoms and HIV transmission to others occur.....HIV treatment can reduce the spread of HIV. More recently, the results of HPTN Study 052, which randomized the HIV-infected member of 1763 serodiscordant couples to early or delayed ART, revealed that treatment prevents transmission, with a 96% protective effect......In this issue of Clinical Infectious Diseases, Moore and Bartlett report trends in virologic suppression rates in that same Johns Hopkins HIV clinical cohort, and the results are remarkable [8]. Since 1996, rates of virologic suppression have steadily increased; in 2010, of 1894 patients receiving care, 74% had an HIV RNA level <500 copies/mL, the definition of virologic suppression used by Lucas et al [2]. Of importance, this number includes not only the 85% who were currently receiving ART but also the entire clinical cohort, including the 15% for whom treatment had not been prescribed or recommended. If we assume that essentially all of the patients not receiving ART had detectable viremia, ~87% of the treated patients would have had viral loads <500 copies/mL."

Clinical Infectious Diseases Sept 15 2011

Antiretroviral Therapy: Now "It Just Works"


Paul Sax

Division of Infectious Diseases and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

(See the Major Article by Moore and Bartlett, below)

In developed countries, combination antiretroviral therapy (ART) with at least 3 active agents became standard of care in 1996, with a consequent rapid reduction in HIV-related mortality [1]. Although the clinical benefits of ART for individuals with advanced HIV-related immunosuppression were plainly evident, enthusiasm for treatment of patients with asymptomatic disease was quickly tempered by several factors. These included the short- and long-term toxicity of therapy, the complexity of available regimens, the cost of treatment, and the realization that virologic outcomes in clinical practice were rarely as good as those achieved in clinical trials.

One of the landmark studies highlighting these discrepant outcomes between clinical trials and clinical practice was a retrospective review of 237 patients receiving initial protease inhibitor-based treatment during 1996-1998 at the Johns Hopkins HIV Clinic in Baltimore, Maryland [2]. The cohort consisted predominantly of an inner-city, relatively poor, and largely African American population. In that study, only 37% achieved virologic suppression (defined as a viral load <500 copies/mL) 1 year after initiation of therapy. Of importance, this was approximately half the rate of treatment success achieved in contemporaneous clinical trials [3]. The authors cited several potential explanations for this difference, most prominently poor adherence to clinic visits, a phenomenon strongly linked to demographic factors that were highly prevalent in their clinic. One group in the cohort was an extreme example of the discordance between clinical trials results and what was happening in actual patient care: younger, non-white patients had a 1-year virologic suppression rate of only 25%.

The results of this study were sobering and had a major impact on clinical practice. Providers were understandably leery of prescribing ART to patients who had such a low rate of treatment success, because virologic failure could select for HIV drug resistance mutations that both reduced future treatment options for the individual and, ominously, could be transmitted to others. The increased recognition of severe metabolic abnormalities and disfiguring body shape changes-sometimes correctly and sometimes incorrectly linked to ART-pushed the favored treatment strategy from a "hit early, hit hard" approach [4] to one in which clinicians could feel justified counseling patients to avoid starting therapy for as long as possible [5, 6]. Treatment guidelines from the early 2000s began to endorse deferring therapy in certain patients, stating that treatment should be started in asymptomatic patients when the CD4 cell count was <200 cells/mm3, offered to those with a count of 200-350 cells/mm3, and generally deferred for patients with a count >350 cells/mm3 [7].

In this issue of Clinical Infectious Diseases, Moore and Bartlett report trends in virologic suppression rates in that same Johns Hopkins HIV clinical cohort, and the results are remarkable [8]. Since 1996, rates of virologic suppression have steadily increased; in 2010, of 1894 patients receiving care, 74% had an HIV RNA level <500 copies/mL, the definition of virologic suppression used by Lucas et al [2]. Of importance, this number includes not only the 85% who were currently receiving ART but also the entire clinical cohort, including the 15% for whom treatment had not been prescribed or recommended. If we assume that essentially all of the patients not receiving ART had detectable viremia, ~87% of the treated patients would have had viral loads <500 copies/mL.

The improvement in treatment outcomes has been accomplished with substantial barriers to care. Although there has been a slight shift in the demographic characteristics of the cohort over time (patients are older and include a higher proportion of women and a lower proportion of injection drug users), many aspects of the patient demographic characteristics remain similar (73% of the cohort is black, and more than one-third report injection drug use as the source of HIV infection). In addition, there has been no change in the zip codes of the patients receiving care, with 80% reporting residence in the city of Baltimore. In short, the cohort is still largely the same difficult-to-treat urban poor population described in the original article by Lucas et al [2].

One potential explanation for these extraordinary results is that Johns Hopkins has been a longstanding leader in HIV care and research, with a well-established multidisciplinary HIV program that, in the present study, had a 94% patient retention rate. Although the care given is undoubtedly excellent, as evidenced by the hospital's annual number one ranking in a well-publicized national survey [9], it is important to emphasize that this improvement in outcomes is also occurring at other sites [10, 11]; the authors fully acknowledge that they cannot take full credit. Furthermore, multicenter clinical trial results have kept pace, with a recent study of frequently used initial therapies revealing that >80% of study participants remained free of virologic failure during receipt of their first regimen after a minimum of 96 weeks of treatment [12].

What are the factors contributing to this dramatic improvement in HIV treatment? During the past 15 years, substantial progress in ART has occurred, including a fuller understanding of optimal treatment strategies and the introduction of better tolerated, safer, and more effective antiviral agents. Several of the more important advances are outlined in Table 1, in addition to the approximate dates of widespread implementation. The aggregate result of these improvements has been a transformation of ART outcomes in clinical practice for most patients receiving treatment.

In addition to these improvements, there has been an increased understanding of both the benefits of starting HIV treatment substantially before clinical immunosuppresion occurs [29, 30] and the risks of interrupting treatment even at high CD4 cell counts [31]. In recognition of these advances, treatment guidelines now recommend lifelong ART for asymptomatic patients potentially at all CD4 cell counts, especially if the patient is willing to start treatment or has any of several comorbid conditions [32, 33]. Furthermore, earlier therapy is a more compelling treatment strategy to offer asymptomatic patients when the rates of treatment success are high, and this improvement in outcome has had a corresponding effect of decreasing the incidence of antiretroviral drug resistance [10].

The high rate of virologic suppression reported in the article by Moore and Bartlett should have both individual and public health benefits [8]; together, these benefits provide an urgent impetus for diagnosis of HIV infection early in the course of HIV disease, preferably before both clinical symptoms and HIV transmission to others occur. It has long been known that a person's individual HIV RNA level provides the best indication of risk of viral transmission [34], and observational studies strongly suggest that HIV treatment can reduce the spread of HIV [35]. More recently, the results of HPTN Study 052, which randomized the HIV-infected member of 1763 serodiscordant couples to early or delayed ART, revealed that treatment prevents transmission, with a 96% protective effect [36]. There are already early findings from urban regions with high rates of HIV treatment that show an association between HIV therapy uptake and reduced incidence of HIV infection [37, 38], and it would not be surprising to see this reflected on a national scale soon.

The results of the study by Moore and Bartlett [8] are highly relevant for clinicians, because they show extremely high treatment success rates, even in the context of challenging sociodemographic circumstances. Providers faced with potentially difficult cases can be reassured that most of these cases are in patients who will achieve virologic suppression with the effective and well-tolerated regimens currently available. If these excellent outcomes are common, perhaps it is time to retire the term highly active antiretroviral therapy, because this implies the existence of a less active form. At present, in both developed and developing countries, there is only one acceptable form of HIV treatment-the kind that, like the slogan of a famous computer company, "just works."

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Dramatic Decline in the HIV-1 RNA Level Over Calendar Time in a Large Urban HIV Practice - pdf attached

Richard D. Moore and John G. Bartlett

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

Abstract

Background.
We have previously showed that as antiretroviral therapy has improved over time since 1995-1996, the likelihood of achieving virologic suppression has also improved. Antiretroviral therapy and antiretroviral therapy guidelines have continued to evolve, and we wished to determine the trend in human immunodeficiency virus (HIV-1) RNA levels over time in HIV-infected persons receiving care in our large urban HIV clinical practice in Baltimore, Maryland.

Methods. The HIV-1 RNA level was assessed each year from 1996 through 2010 at the date closest to 1 July for all patients in care and followed up in the Johns Hopkins HIV Clinical Cohort. The clinic population's median HIV-1 RNA level and stratified threshold levels were plotted. The demographic characteristics of the population were also assessed over time.

Results. From 1996 (shortly after highly active antiretroviral therapy [HAART] was introduced) to 2010, the median HIV-1 RNA level decreased from 10 400 to <200 copies/mL. The proportion of patients with an HIV-1 RNA level >500 copies/mL decreased from 75% to only 16% during this same period. The population itself became older, had a higher proportion of women, and a lower proportion of patients with injection drug use as a transmission risk, but it was geographically stable. There was an increase in HAART use over time.

Discussion. Our results demonstrate the remarkable impact of increased use of and improved management with HAART in this urban HIV-infected population.

Highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV) infection became available in 1995-1996, but the therapy was predominantly anchored by an unboosted protease inhibitor, was used frequently in persons who had previously received nonnucleoside reverse-transcriptase-inhibiting drugs, and was associated with significant side effects. Guidelines for when to start HAART have changed, beginning with use at higher CD4 T-cell counts, later recommending that patients not be treated until their CD4 T-cell count was <200 cells/mm3, and later <350 cells/mm3. Only in recent years have the guidelines recommended earlier initiation of HAART [1]. Over time, HAART has improved, becoming less toxic, and more efficacious. HIV-infected individuals are also less likely to have had previous antiretroviral drug exposure, and if they have prior exposure, the choices for subsequent therapy are broader and allow for selection of drugs for which they are likely to be naive. This should have a salutary effect on the HIV RNA level in a clinical population of HIV-infected individuals. In addition, if the HIV RNA level is decreased within the population, there may also be a decline in the risk of transmitting HIV to others, particularly by sexual contact [2-4].



In 1999, we published the results of a study from our institution showing that 44% of patients who received HAART in 1996-1998 achieved virologic suppression [5]. By early in the past decade, ritonavir-boosted protease inhibitors and efavirenz were in common use, and the prevalence of virologic suppression had improved. Data from our institution showed that 79% of those patients who received HAART in 2001-2002 achieved virologic suppression [6].



The Johns Hopkins HIV Service has provided HIV care to the majority of HIV-infected individuals who have sought care in Baltimore, Maryland, since the service opened in 1984. Its patients are principally from the Baltimore metropolitan region, an East Coast urban region with the fifth-highest incidence of HIV of US urban centers and in a state with the third-highest incidence of HIV infection in the United States [7]. The population has a high proportion of individuals who were infected through drug injection. We conducted an analysis of clinic-wide HIV-RNA levels over calendar time since HAART became generally available in 1996 in Baltimore.



RESULTS

A total of 5290 patients were in care in the Johns Hopkins HIV Clinic during ≥1 calendar year between 1996 and 2010. Table 1 shows the demographic and clinical characteristics of the population by calendar time. The Johns Hopkins HIV Clinic population became older, with an increased proportion of women and associated heterosexual HIV transmission, these characteristics reflecting the changing demography of HIV infection in Maryland during this time. The ZIP code in which the patients resided did not change significantly over time, indicating that the clinic continued to care for the same population geographically. The CD4 T-cell count showed an increasing trend during this time period, consistent with the increase in suppressed HIV RNA levels, associated with the increase in the proportion of patients receiving HAART over time.

The HIV-1 RNA levels (median and upper quartiles) are shown in Figure 1. The number of patients who contributed HIV-1 RNA data is shown in the top row of the table within the figure. Particularly in earlier years, HIV-1 RNA levels were not always obtained on the entire clinic population. It can be seen that the median HIV-1 RNA level decreased from 10 000 copies/mL in 1996 to <200 copies/mL in 2006, and remained <200 copies/mL through 2010. The upper quartile declined from 80 000 copies/mL in 1996 to 500 copies/mL in 2008 and remained at this level through 2010. This demonstrates that only 25% of the patients in care had HIV-1 RNA levels of 500 copies/mL. Figure 2 depicts the HIV-1 RNA thresholds at each calendar year. The table within the figure shows the number of patients who had an HIV-1 RNA level and could contribute to this analysis.

Because patients who are less adherent to care and have higher HIV-1 NRA levels could selectively become unavailable for follow-up, we examined retention in care in 1996-2002 and 2003-2009. Retention was defined as a patient in care during one calendar year continuing in care the following calendar year. Retention was 86% in 1996-2002 and 94% in 2003-2009 overall (retention for injection drug users, 85% and 95%, respectively, for 1996-2002 and 2003-2009; for men who have sex with men, 86% and 94%; for heterosexuals, 86% and 93%).

DISCUSSION

Our clinic-wide analysis has shown that the burden of HIV-1 RNA has declined steadily since HAART was introduced in 1996 and that in the most recent year (2010), <17% of the patients had an HIV-1 RNA level of >500 copies/mL. This is a remarkable accomplishment that is probably due to improved antiretroviral drugs and changes in management, including the starting of antiretroviral therapy at less advanced immunosuppression. Proportionally fewer patients in care have HIV-1 RNA levels obtained in the earlier years, probably both because viral load testing was less available for these and because fewer of them were receiving HAART. Therefore, the HIV-1 NRA levels in the clinic may have even been higher than indicated by our data. Selective loss of patients who were less adherent to HIV care is unlikely to have affected our results differentially, because retention improved over time. We believe that our results emphasize that even in an inner urban HIV-infected population with a relatively high proportion of patients who were infected as a consequence of injection drug use, HAART can be highly successful. We note that our previous publications from our clinic focused only on those patients who received HAART [5, 6]. This current study analyzed data from the entire clinic population, irrespective of HAART use, further emphasizing both the utilization of HAART and its effectiveness in our clinical population. A recent study from British Columbia also showed an improvement in virologic suppression from 65% in 2000 to 87% in 2008 [9]. These results therefore reflect the increasing use of HAART and are a testament to the remarkable effectiveness of HAART in our patient population.

We posit that these data may also have implications for the transmission of HIV in the urban community from which the Johns Hopkins HIV Clinic draws its patients. Based on estimates of HIV infection in the United States from the Centers for Disease Control and Prevention, this may be as many as half of the patients who reside in this region [10, 11]. Studies have shown that low HIV RNA levels are associated with a decreased risk of sexual transmission of HIV [2-4]. HAART is effective in reducing HIV transmission by 92% in heterosexual HIV-discordant couples [12]. In more than half of our clinic population, HIV had been transmitted sexually, with transmission through injection drug use in the remainder. Although the association of lower HIV RNA levels with bloodborne HIV transmission is not well described, it is plausible that the risk of transmission by any mode would be reduced in the setting of a suppressed HIV RNA level. In support of this, a recent presentation suggests an ecologic association between a decline in HIV-RNA levels over time and the incidence of HIV in injection drug users [13]. Maryland and the city of Baltimore have had a particularly high prevalence and incidence of HIV infection during the past decade, although the most recently available data suggest that the incidence of new HIV cases may have stabilized or even declined slightly [2]. Whether a decline in prevalent community HIV RNA levels has contributed to the apparent decrease in the rate of new cases is unknown, but it is possible since other efforts to reduce transmission, such as condom use and clean needle exchange, have decreased in recent years owing to budget cuts.

We believe that our results emphasize the importance of early detection and early and successful referral for HIV care. Current guidelines recommend the use of HAART at higher CD4 T-cell counts, so that the earlier a person can receive HIV care, the more likely he or she is to be started on HAART [1]. Of course, many HIV-infected persons do not receive HIV care until more advanced immunosuppression [14, 15], so the challenge of detecting HIV infection and engaging the infected individual in HIV care remains. Efforts to promote universal HIV testing have been underway since 2006 [16], and it is not yet known how effective these have been in identifying HIV infection at earlier stages in the United States. Our findings do not minimize the continuing importance of other prevention interventions, such as condom use, use of clean needles, and diagnosis and treatment of genital ulcers and other sexually transmitted diseases. However it is known that these behavioral interventions can be of limited effectiveness because of poor adherence, and the treatment of HIV with antiretroviral therapy to suppress HIV-1 RNA is likely to be an important contributor to prevention of HIV transmission [17].

In summary, we have shown a dramatic decrease in the HIV-1 RNA level in a community of patients who receive care in a large urban region in the United States. Although these results to not reflect the entire community of HIV-infected individuals from our region, they are likely to represent a substantial proportion of those who are infected, and certainly a group of individuals that can be targeted with among whom an important intervention that may reduce HIV transmission.

 
 
 
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