Why Treating HIV on Diagnosis Is A Must

Better Health, Lower Transmission Risk Among Beneffits

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On September 30, 2015, the World Health Organization (WHO) revised its global HIV treatment guidelines to recommend the immediate initiation of antiretroviral therapy (ART) at the time of diagnosis.

Until recently, there had been on-going debate among policy makers and researchers as to whether ART should be started immediately or delayed until such time as the patient's immune function falls below a certain numeric threshold (as measured by the person's CD4 count).

Supporters of immediate ART pointed to data which showed that early intervention decreased the long-term damage HIV can inflict on a person's immune system—damage that could exponentially increase the risk of long-term illnesses. Detractors warned that there was no evidence as to whether starting ART above the currently recommended threshold (CD4 counts under 500 cells/mL) had any real value on disease impacts or a patient's life span.

The change in WHO policy will more the double the number the number of people requiring ART, from the current 15 million to a worldwide HIV population of 37 million.

START Study Transforms Global HIV Policy

On May 27, 2015, scientists at the National Institute of Allergies and Infectious Disease (NIAID) finally put the long-standing debate to rest by terminating the Strategic Timing of Antiretroviral Treatment (START) study more than a year early due to clear-cut evidence that treatment on diagnosis, irrespective of CD4 count, had profound benefits to patients with HIV.

The study, which had enrolled 4,685 HIV-infected men and women 18 years of age and older, was meant to conclude at the end of 2016 but was ended prematurely when interim results showed a striking 53% reduction in the number of serious illnesses among those who were treated immediately versus those whose with delayed ART.

Findings were consistent across study arms, whether patients were from high-, low- or middle-income countries.

In response, scientists and policy makers issued an official statement on July 19, 2015, deemed the Vancouver Consensus, which called  for the immediate initiation of ART in all patients. In their statement, the group outlined the reasons by which ART on diagnosis conferred to better outcomes in patients with HIV.

Early Treatment Reduces the Impact of Long-Term Inflammation

Previous to the START trial, many researchers were cautious about treating HIV on diagnosis as mortality rates for patients who started ART above CD4 counts of 350 cells/mL had essentially the same life expectancy as the general population. Why, they argued, should we risk unforeseen treatment complications when starting at higher CD4 counts afford no added benefit in terms of life extension?

On the basis of mortality alone, that might seem a fair argument. In terms of actual illness, however, the facts speak differently.

During the course of any infection, the body will undergo an inflammatory response in the presence of an infective agent such as HIV. If left untreated, the on-going, persistent inflammation can often cause irreparable damage to cells and tissues of the body.

Because HIV is a chronic disease, even persistent, low-grade inflammation can cause a premature aging of cells—known as premature senescence or "inflammaging"—which accounts for the higher rates of heart disease and cancers in people with HIV, often 10-15 years earlier than in non-infected counterparts.

Even in people with a genetic resistance to HIV—known as "elite controllers"—the impact of chronic inflammation results in far poorer outcomes and a higher rate of illnesss when compared to individuals on ART with fully suppressed virus.

Simply put, by placing a person on ART at the earliest stages of infection, you save that person the needless impact of inflammation associated with untreated disease. Delaying only allows inflammation to persist, unchecked, for anywhere from between 5-10 years.

Newer Drugs Offer Lower Toxicity, Improved Resistance

Many of the concerns related to long-term drug exposure were founded on experiences seen with earlier generation antiretrovirals, where widespread use often resulted in unforeseen adverse impact on the patient.

Drugs like stavudine, for example, were seen to cause high rates of drug toxicities in patients, ranging from lipodystophy (the unsightly redistribution of body fat) to neuropathy (the painful damage to nerve cells) to lactic acidosis (a potentially life-threatening build-up of lactic acid).

Similarly, many of the earlier antiretrovirals had poor drug resistance profiles. The use of nevirapine in monotherapy, for example—a short-lived practice in 2002 to prevent mother-to-child transmission—resulted in high rates of nevirapine resistance, sometimes after a single dose.

These concerns have largely been mitigated with newer generation drugs, which not only offer lower side effect profiles but far smaller pill burdens and greater "forgiveness" (i.e. the ability to maintain therapeutic drug levels even if doses are missed).

Moreover, fears about transmitted drug resistance—the passing of resistance from one person to the next—have largely been abated, with current data from the World Health Organization suggesting  a transmission resistance rate of around 7% in low- to medium-income countries (approximately half that seen in the U.S. and Europe).

In higher-income countries, transmitted drug resistance is more often related to the earlier generation drugs which were introduced to those populations 10-15 years earlier than in most developing countries.

Similar studies have shown that HIV virulence in low-income countries, where the brunt of infections are known to occur, is far lower due, in large part, to fact that far fewer people had been placed on therapy compared to the U.S. and Europe.

Treatment on Diagnosis Can Reduce the Spread of HIV

Treatment as Prevention (TasP) is a preventive strategy which aims to reduce the so-called "community viral load" by placing a population group on ART. In doing so, the likelihood of HIV transmission is significantly reduced as more people are able to maintain complete suppression of viral activity.

The strategy is largely supported by evidence from San Francisco, a city which had seen a 30-33% drop in HIV infections from 2006-2008 due to the widespread coverage of antiretrovirals. Based on these results, city officials introduced a policy of ART on diagnosis in early 2010.

Similarly, a 2015 study from the Henan province of China showed that the risk of transmission in serodiscordant couples (i.e., one HIV-positive partner and one HIV-negative partner) was reduced by 67% from 2006-2009 as nearly 80% of the HIV-infected partners were placed on ART.

In implementing a global policy of ART on diagnosis, most health officials believe that similar gains could be made even in high-prevalence populations like South Africa, where new infections rates continue to rise despite increasing ART enrollments.

Whether global authorities can achieve these goals given stagnating financial contributions from wealthier G8 nations is another matter altogether. With over 35 million people infected with HIV today—and around 13 million on ART—the bigger challenge may be expanding treatment in countries where healthcare infrastructures are often uncertain, at best.

Sources

National Institutes of Health (NIH). "Starting antiretroviral therapy early improves outcomes for HIV-infected individuals." Bethesda, Maryland; issued May 27, 2015.

Hasse, B,; Ledergerber, B.; Egger, M., et al. "Aging and (Non-HIV-associated) Co-morbidity in HIV-positive Persons: The Swiss Cohort Study (SHCS)." 18th Conference on Retroviruses and Opportunistic Infections (CROI). Boston, Massachusetts; February 27-March 2, 2011; abstract 792.

Pantazis, N.; Porter, K.; Costagliola, D.; et al. "Temporal trends in prognostic markers of HIV-1 virulence and transmissibility: an observational cohort study." The Lancet HIV. December 2015; 1(3):e119-126.

Smith, K.; Westreich, D.; Liu, H.; et al. "Treatment to Prevent HIV Transmission in Serodiscordant Couples in Henan, China, 2006 to 2012." Clinical Infectious Diseases. March 13, 2015; pii: civ200. [Epub ahead of print].

Human Sciences Resource Council (HSRC). "South African National HIV Prevalence, Incidence and Behaviour Survey, 2012." Pretoria, South Africa; issued December 1, 2012.

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