Undiagnosed infections and poor retention in care mean that few US patients fully benefit from HIV treatment

Only a small minority of HIV-positive patients in the United States are gaining the full benefit of antiretroviral therapy, a study published in the November 29th edition of Morbidity and Mortality Weekly Report shows.  Investigators calculated that only a half of all patients are retained in care and that only 28% of people infected with HIV in the US have an undetectable viral load.

“More effort is needed to ensure that…patients remain in care and to eliminate disparities between subgroups who are prescribed ART [antiretroviral therapy] and subsequently achieve viral suppression,” comment the authors.

They warn that the goals of the 2010 US National HIV/AIDS Strategy to increases access to care, improve outcomes and reduce health inequalities can only be met by “achieving high levels of engagement at every stage in the continuum of care.”

The current low proportion of patients with viral suppression would also suggest that the use of HIV treatment as prevention will have only a minimal impact on the continuing epidemic in the US until these issues can be addressed.

An estimated 1.2 million individuals were living with HIV in the US at the end of 2008. With appropriate treatment and care the prognosis of HIV-infected patients can be excellent. Moreover, therapy that suppresses viral load to below the limit of detection significantly reduces the risk of onward transmission of the virus.

To take advantages of the benefits offered by modern HIV medicine it is essential that infected patients are diagnosed, linked and retained in care, prescribed antiretroviral therapy when appropriate, and that this treatment achieves virological suppression.

Using recent surveillance data, the investigators calculated the proportion of patients in the US receiving services at various points in this care continuum.    

They calculated that a fifth of HIV infections in the country were undiagnosed. An analysis of published studies suggested that 77% of diagnosed patients were initially linked with care. However, retention rates were poor and only 51% of individuals continued to regularly access care.

Use of antiretroviral therapy among the patients remaining in care was high, with 89% of individuals taking this treatment. Moreover, 77% of these patients achieved an suppression of the virus (defined as a viral load below 200 copies/ml).

Overall, the high rate of undiagnosed infections and the large proportion of patients dropping out of care meant that only 28% of all HIV-positive patients in the US had an undetectable viral load.

Racial disparities were apparent in the use of HIV therapy and in treatment outcomes.

Of the 92% of whites who were treated with anti-HIV drugs, 84% achieved virological suppression. Use of treatment was less prevalent among Hispanic patients (89%), and the proportion with suppression of the virus was somewhat poorer than those seen in whites (79%). Lower still were rates of treatment utilisation in black patients (86%) and only 70% of these patients experienced a fall in their viral load to below 200 copies/ml.

The study also suggested that HIV prevention efforts needed to be intensified. Only 45% of patients in care had received HIV prevention counselling. There were disparities according to age, with 73% of patients aged 18 to 24 receiving such counselling, compared to 36% of those aged over 55. Over half of black (54%) and Hispanic (52%) of patients were provided with prevention counselling compared to only 29% of whites. The proportion of patients receiving counselling also differed by HIV risk group, and was higher for gay men and other men who have sex with men (MSM) compared to men reporting sex with a woman (50% vs. 39%).

“These low percentages, especially among MSM, who account for most new HIV infections in the United States, indicate a need for health-care providers to deliver HIV prevention more consistently,” suggest the authors.

“Only an estimated 28% of all HIV-infected persons in the United States are virally suppressed, largely because even among those with diagnosed infections, only 51% are receiving regular HIV care,” emphasise the investigators.

They warn: “Without substantial improvement in these percentages, 1.2 million new HIV infections would be expected to occur over the next 20 years.” This could result in $450 billion in health-related expenditure. “Only with success at each step of the continuum of HIV care…can the ultimate goals of improving health, extending lives, and preventing further HIV transmission be achieved.”

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Treatment switches after CD4 count decline reduce risk of death by 75% in Zambia, Malawi

Mortality was reduced by about 75% among adults experiencing immunological failure according to the World Health Organization (WHO) criteria who switched to a second-line regimen compared to those who remained on a failing regimen in two public sector ART programmes without access to routine viral load monitoring in Zambia and Malawi, researchers report in the advance online edition of AIDS.

Additionally in this collaborative analysis Thomas Gsponer and colleagues on behalf of the Southern African region of the International epidemiological databases to evaluate AIDS (IeDEA-SA) showed the less time spent on a failing regimen the lower the risk of death, HR:0.70 (95%  credible intervals (CI): 0.44-1.09), p=0.11 for each six months of shorter exposure.

An estimated 6.6 million people are now getting ART in resource-poor settings. As access to treatment increases so does the number of people experiencing treatment failure with a corresponding increase in the use of second-line treatment regimens.

Cost and the absence of the necessary laboratory infrastructure preclude the regular use of viral load monitoring in resource-poor settings, especially in rural areas.

Without viral load monitoring immunological (CD4 cell counts) and clinical criteria are used to determine treatment failure. However, the accuracy of such criteria to detect virological failure is poor. This may lead to unnecessary switching with many health care providers reluctant to switch using these criteria. So people are switched later and at lower CD4 cell counts compared to programmes where viral load monitoring is available, note the authors.

The authors chose to examine further the effect of switching to second-line ART on mortality in settings without viral load monitoring.

All adult patients experiencing treatment failure according to WHO immunological criteria from two public sector ART programmes in Lusaka, Zambia and Lilongwe, Malawi were included in the analysis. Clinical and immunological monitoring was done every three to six months. In both sites viral load testing is limited because of cost and operational difficulties.

Criteria for inclusion: all patients 16 years of age and over with immunological failure after January 1, 2004 based on any of the three WHO criteria: 1) CD4 cell counts staying persistently under 100 cells/mm3 2) a fall of CD4 cell counts below the baseline count and 3) a fall greater than 50% from the peak value.

Marginal structural models and inverse probability weighting of switching to compare mortality between patients who switched and those who did not and between those who switched immediately and those who switched later were used. The authors believe this to be the first study of its kind using this model in a resource-poor setting.

From 2004 to 2009 of the 80,937 patients who started ART, 2411 met the eligibility criteria and experienced failure; 96.1% (2317) from Zambia and 3.9% (94) from Zambia.

Of these 324 (13.4%) were switched to second-line ART during a median of 1.7 years of follow-up.

Median CD4 cell count in those who switched was lower at the start of ART and failure compared to those who did not: 80 cells/mm3 compared to 155 cells/mm3, p<0.001 and 77 cells/mm3 compared to 146 cells/mm3, p<0.001, respectively.

In addition to lower mortality, loss to-follow-up was also lower among people who switched compared to those who did not: 14.2 (6.8-25.9) compared to 50.5 (43.2-58.5) per 1000 person years, p<0.001, respectively.

After adjusting for baseline and time-dependent confounders the risk of death among those who switched to a second-line regimen immediately after failure was significantly lower than those who remained on a failing regimen (HR 0.25, 95% CI: 0.09-0.72, p=0.01).

27.2% (655) patients had at least one viral load measured between six months after starting ART and immunological failure. Viral load measurement was more common among those who switched compared to those who did not, but was not statistically significant.

The authors note that ideally a randomised clinical trial should be used to determine the causal effect of switching to second-line treatment among immunologically failing patients. But they caution this is highly improbable since it raises ethical concerns.

So observational data as provided in this study offer the best available evidence to guide and inform clinical practice and public health decisions on when and if to switch, they add.

The authors note that prognostic factors can distort results from observational studies. Inverse probability of treatment weighting was used to adjust for confounding by time-updated CD4 cell counts.

The authors note that while the reduction in death was significant it may have unknowingly included patients who met the immunological failure criteria but had an undetectable viral load.

While two public sector programmes were involved, the authors question how generalisable their findings are. These programmes are equipped with electronic medical records systems, have access to regular CD4 cell counts and are involved in an international collaboration of HIV cohorts. Yet, they nonetheless follow national guidelines for the public health approach common to many programmes in the region.

The authors conclude, “in ART programmes [in sub-Saharan Africa] switching patients to second-line regimens based on WHO immunological failure criteria appears to reduce mortality, with the greatest benefit in patients switching immediately after failure is diagnosed.”  

Adding that targeted viral load may further reduce unnecessary switching and recommend that future studies “investigate at what CD4 cell count levels patients should ideally be switched and should examine long-term outcomes including after second-line failure.”

Reference

Gsponer T et al. The causal effect of switching to second-line ART in programmes without access to routine viral load monitoring. AIDS, advance online edition, doi: 10.1097/QAD.0b013e32834e1b5f, 2011.

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Electrocautery ablation: safe and effective treatment of high-grade pre-cancerous anal lesions in gay men

A clinic-based intervention offers safe and effective treatment for high-grade pre-cancerous anal lesions, US investigators report in the online edition of the Journal of Acquired Immune Deficiency Syndromes.

Doctors at the Mount Sinai School of Medicine, New York, used a technique called electrocautery ablation to treat pre-cancerous anal lesions in 232 gay men, 132 of whom were HIV-positive.

Eighteen months after treatment, 83% of HIV-negative men and 69% of those with HIV were free of high-grade pre-cancerous anal lesions.

“Electrocautery ablation of high-grade anal squamous intraepithelial lesions is a safe and effective office-based procedure comparable to other available treatments,” comment the investigators.

Incidence of anal cancer has increased dramatically among gay men in recent years. HIV-positive gay men appear to be especially vulnerable to the disease, and its incidence is five-times higher in these patients compared to HIV-negative men.

Infection with high certain high-risk strains of human papillomavirus can cause cell changes in the anus, resulting in the formation of lesions. The severity of these changes is graded, and between 9% and 13% of high-grade lesions progress to anal cancer.

There are a number of treatments for these pre-cancerous lesions including infrared coagulation and topical creams such as imiquimod.

Another therapy is electrocautery ablation. The investigators described the procedure thus: “Using a gentle brushing technique the lesion was ablated [worn down] by moving [a] blade lightly across the surface like a paint-brush.” The therapy has a number of advantages and can be performed in clinics without the need for anaesthetic or sedation.

Investigators wished to assess the safety and effectiveness of this procedure. They therefore retrospectively analysed the notes of gay men who had the treatment between 2006 and 2010. The patients received an initial treatment and were then followed at intervals of three to six months and were provided with additional treatment if necessary.

At the first treatment session, a total of 375 lesions were treated in HIV-infected men compared to 226 lesions in the HIV-negative patients, a significant difference (p = 0.006).

Lesions recurred in 53% of HIV-negative men (mean number of lesions, 1.6) and in 61% of HIV-positive men (mean number of lesions, 1.9).

The number of lesions present at the time of the initial treatment session was associated with the risk of recurrence. Patients with only one lesion at this time were 55% and 73% less likely to experience a recurrence than individuals with two or three lesions (p = 0.008 and p < 0.001 respectively).

The persistence of individual lesions after the initial session of treatment was also examined by the researchers. They found a cure rate of 85% in HIV-negative individuals and 75% in HIV-positive patients.

The first treatment session appeared to offer the best chance of eradicating lesions. In HIV-negative patients the persistence rate after a second ablation treatment was 3.03 times greater than that observed after the first session.

Further analysis showed that lesions were a significant 2.34 times more likely to recur in HIV-positive men compared to HIV-negative men after a second treatment (p = 0.008).

“Extensive dysplastic tissue may indicate either infection with more oncogenic virus or a more immune compromised host,” suggest the investigators.

Nevertheless, at the last follow-up visit, 83% of HIV-negative individuals and 69% of men with HIV were free of high-grade anal lesions.

Such a level of efficacy is comparable to that achieved with alternative therapies.

“Given that infrared coagulation and electrocautery ablation have similar outcomes when treating high-grade anal squamous intraepithelial lesions, the choice of modality should be based on clinician comfort and preference,” comment the authors. “In our hands the overall impression was that electrocautery ablation seemed faster, more hemostatic and allowed more extensive disease to be treated in office.”

Pain after treatment was the most commonly reported side-effect. However, this was adequately controlled with mild painkillers. One HIV-positive patient progressed to anal cancer, despite multiple ablation treatments.

“While we documented a single progression (0.4%), rates were far lower tan series advocating a ‘watch and wait’ approach,” conclude the authors.

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