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Treatment is prevention!

Keith Alcorn
Published: 29 July 2011

Treatment is prevention: HPTN 052 study shows 96% reduction in transmission when HIV-positive partner starts treatment early

Results from a trial showing that antiretroviral treatment prevents HIV from being passed onto uninfected partners received a standing ovation today at the Sixth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Rome.

HPTN 052 showed that early treatment – started at a CD4 count between 350 and 550 cells/mm3 – reduced the risk of HIV transmission to an uninfected partner – by at least 96%. Almost all the study participants were heterosexual couples.

The study lends some support to advice given three years ago in the Swiss statement, a document issued by Swiss doctors which stated that, for heterosexual couples where the HIV-positive partner had an undetectable viral load on stable treatment (and no sexually transmitted infections) the risk of HIV transmission through vaginal intercourse was negligible.

But Professor Myron Cohen of the University of North Carolina, who led the study, urged caution in interpreting the results, reminding the audience that the transmission study had followed patients for a median of 1.7 years.

Nevertheless, he said, “these are important results to give to a serodiscordant couple.”

The HPTN 052 study recruited 1763 couples in Malawi, Zimbabwe, Botswana, Kenya, South Africa, Brazil, Thailand, the US and India.  The trial recruited serodiscordant couples – one HIV-positive, one HIV-negative – in which the HIV-positive partner had a CD4 cell count between 350 and 550 cells/mm3, and was thus ineligible for treatment.

The HIV-positive participants were randomised either to start treatment immediately, or to defer treatment until their CD4 counts fell into the range 250 to 200, the threshold for starting treatment in national guidelines at the time the study began recruiting.

The overall gender balance in the trial was even, but the HIV-positive participants were significantly more likely to be women in the Africa region.

Approximately 95% of the couples were married, and 6% reported unprotected intercourse in the previous month at baseline.

Of note, just over one-quarter of HIV-positive individuals reported no sexual activity at baseline, and there is some indication that sexual activity actually declined at some points during the follow-up period in both the immediate- and the deferred-treatment arms.

However, condom use was high, reported by 94% of HIV-positive individuals at baseline, and there was no evidence of a decline in self-reported condom use as the study went on.

Results

A total of 39 individuals became infected during the study, four in the immediate-treatment arm and 36 in the deferred-treatment arm, during a median follow-up period of 1.7 years.

A careful genetic analysis of virus samples from the HIV-positive partner and the subsequently infected partner was conducted to determine how many of the infections could be attributed to the index partners.

Eleven cases of transmission were unlinked, that is, attributable either to sex outside the primary relationship, or else the source could not be confidently determined. There was a strong association between unlinked infection and reporting more than one sexual partner in the three months prior to seroconversion (p<0.0001).

This left 28 infections, of which only one occurred in the immediate-treatment arm. This represented a reduction in the risk of transmission of 96%, and was highly statistically significant (P <0.001).

Sixty-four per cent of transmissions occurred from the female to the male partner, and 82% of transmissions took place at African trial sites.

Surprisingly, the majority of transmission events were estimated to have occurred when the index partner had a CD4 count above 350 cells/mm3, indicating that any potential prevention benefit of treatment might only be maximised by providing treatment above the threshold currently recommended by the World Health Organization. (It recommends that treatment should start once a person’s CD4 cell count has fallen below 350.)

In the delayed arm, the median viral load (as measured at the last clinic visit) at which transmission took place was 4.9 log (approximately 80,000 copies/ml), while the median CD4 count was 391 cells/mm3.

In the immediate treatment arm the only verified transmission took place during the early months of treatment, with HIV antibodies fully detectable 85 days after baseline in the partner who became infected. The transmitting partner had a baseline viral load of 87,202 copies, and after 28 days a viral load below 400 copies/ml.

Professor Cohen said that couples need to be counselled about the possible differences in risk between the first few months of treatment and later periods.

Final multivariate analysis showed that baseline viral load was the strongest predictor of transmission in both groups (hazard ratio 2.84, 95% confidence interval  1.51-5.41). Consistent condom use at baseline was highly protective (HR 0.33, 95% CI 0.12-0.91).

Reactions

The results of the study were announced in late May after the study’s independent data and safety monitoring board decided that the magnitude of benefit made it unethical to continue with a randomised study.

The results have fundamentally changed attitudes towards treatment scale-up and the possibility of halting the epidemic, but the hard work of winning funding and implementing wider treatment is not over.

Dr Elly Katabira, President of the International AIDS Society, warned that scientists and activists still have a lot to do to convince policy makers and donors of the importance of the findings and the need for rapid action to translate the findings into treatment expansion in the countries worst hit by HIV.

But Dr Tony Fauci of the US National Institutes of Health told reporters: “You shouldn’t underestimate the power of having a scientifically based argument, rather than waving your arms about.”

References

Cohen M et al. Antiretroviral treatment to prevent the sexual transmission of HIV-1: results from the HPTN 052 multinational randomized controlled ART. Sixth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Rome, abstract MOAX0102, 2011.

Eshleman S et al. Analysis of genetic linkage of HIV from couples enrolled in the HPTN 052 study. Sixth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Rome, abstract MOAX0103, 2011.

HPTN 052: early treatment reduces serious illness by 40%

Early treatment in the HPTN 052 study of treatment as prevention reduced serious illness by around 40%, delegates at the Sixth International AIDS Society conference heard – but the effect was almost entirely accounted for by fewer cases of extrapulmonary tuberculosis.

There was no significant difference in deaths, or in the rate of serious bacterial infections or of pulmonary tuberculosis.

The HPTN 052 study was designed to determine whether early treatment for an HIV-infected person would reduce the risk of HIV transmission to his or her regular partner.

The study showed that early antiretroviral treatment – started at a CD4 count between 350 and 550 cells/mm3 – reduced the risk of HIV transmission to uninfected partners by at least 96%.

However, the study also collected information on a number of other endpoints: death, illness , virological and immunological responses to treatment. These data will provide important information on the potential benefits of early treatment in settings where bacterial infections and tuberculosis are more prevalent than in North America and Europe.

The study will also provide information on any differences in rates of clinical or immunological disease progression between different regions of the world, or between men and women. Some studies, but not all, have suggested faster rates of disease progression in sub-Saharan Africa.

The study enrolled 1763 HIV-infected individuals with CD4 counts between 350 and 550 cells/mm3. Participants were randomised either to receive immediate antiretroviral treatment or to defer treatment until their CD4 cell count fell below 250 cells/mm3 on two separate tests. This was the level at which treatment was recommended to begin in national guidelines during the study recruitment period. The study recruited participants in Malawi, India, Zimbabwe, Botswana, South Africa, Kenya, Thailand, the US and Brazil.

The median CD4 count at enrolment was 446 cells/mm3 and the median viral load 4.4 log10 copies/ml (25,000 copies/ml).

Differences between Africa and other regions

Although the proportion of HIV-positive men and women recruited to the study was equal across the study population as a whole, sites in Africa recruited a larger proportion of women than men (58 vs 40%, p< 0.0001), reflecting the higher rates of engagement in care by women in sub-Saharan Africa as a consequence of earlier HIV diagnosis through antenatal programmes.

African sites also recruited a larger proportion of participants in the 18 to 24 age group (20 vs 15%, p=0.003). African participants had slightly lower viral loads (4.4 vs 4.5 log10 HIVRNA, p=0.006).

Although there was no significant difference in baseline CD4 count between regions, Africans in the deferred treatment arm were less likely to reach the CD4 threshold that indicated they needed to start treatment. Participants in the deferred arm outside the Africa region were 40% more likely to start treatment, but when the hazard ratio was adjusted for confounding factors this difference ceased to be statistically significant (aHR 1.30, 95% CI 0.9-1.8, p= 0.06).

The median time to starting treatment in the deferred arm was 3.25 years outside Africa, compared to 4.1 years in Africa.

Overall, 21% of participants in the deferred arm needed to start treatment during the follow-up period (n=184), an incidence rate of 12 per 100 person-years of follow-up. However, among Africans the rate of treatment initiation was 9 per 100 person-years, compared to 15 per 100 person-years of follow-up in participants at non-African sites. 

Unsurprisingly, the factors significantly associated with the need to start treatment in the deferred treatment arm were lower CD4 count or higher viral load at enrolment (adjusted hazard ratio per increase of 100 CD4 0.6; 95% CI,0.5-0.7) and higher log10 HIV RNA (adjusted hazard ratio per log increase 1.5; 95% CI, 1.2-1.8).

Overall, 75% of patients in the deferred arm who initiated treatment did so because of a decline in CD4 cell count.

Among those who initiated treatment immediately (886 patients), at a median CD4 count of 442 cells/mm3, 90% had an undetectable viral load (below 400 copies/ml) after one year of treatment. They experienced a mean CD4 cell increase of 158 cells/mm3, to 603 cells/mm3.

In the delayed-treatment group, the median CD4 count at treatment initiation was 225 cells/mm3, and the median time to treatment initiation in the deferred arm was 3.5 years. After one year, 93% had an undetectable viral load (below 400 copies/ml) and CD4 cell counts had risen by a mean of 191 cells/mm3, to 418 cells/mm3.

Virologic failure was rare; only 5% in the immediate-treatment arm and 2.7% in the deferred-treatment arm experienced virologic failure. Of these, 67% in the immediate arm and 60% in the deferred arm switched to second-line therapy.

Clinical outcomes

The effect of early treatment on clinical outcomes was very clear.

Early treatment significantly reduced the risk of clinical illness, but there was no difference in the risk of death between the two study arms.

Primary endpoint clinical events were defined as:

  • A WHO stage IV event.

  • Pulmonary tuberculosis.

  • Severe bacterial infection.

  • Death.

Around 7% of participants received cotrimoxazole prophylaxis against bacterial infections, and around 4% received isoniazid preventive therapy to prevent the development of active TB.

A total of 105 participants developed a primary clinical event during 3304 person-years of follow-up. Forty primary events occurred in the immediate arm (2.4 per 100 PY), compared to 65 in the deferred arm (4.0 per 100 PY, hazard ratio 0.59, 95% CI: 0.40 - 0.88, p=0.01.)

Early treatment did not significantly reduce the risk of developing pulmonary tuberculosis. There were 14 cases of pulmonary TB in the immediate-treatment arm (0.8 per 100 PY), compared with 16 in the delayed-treatment arm (0.9 per 100 PY). Pulmonary TB cases were diagnosed at a median CD4 count of 521 in the immediate-treatment arm and 295 in the delayed-treatment arm.

In contrast, early treatment did significantly reduce the risk of extrapulmonary TB. Three cases were diagnosed in the immediate-treatment arm (0.2 per 100 PY), at a median CD4 count of 443, compared to 17 in the delayed-treatment arm (1 per 100 PY), at a median CD4 count of 342.

Bacterial infections occurred somewhat more frequently in the immediate-treatment arm (19 vs 13, 1.1 vs 0.8 per 100 PY). In each arm the most common bacterial infection was pneumonia, and the difference between arms was chiefly driven by four cases of sepsis in the immediate-treatment arm. Three participants in the immediate arm each experienced more than one bacterial infection.

There was no significant difference in the death rate between arms: ten occurred in the immediate arm and 13 in the deferred arm. Deaths were largely attributed to causes other than HIV in the immediate arm: 3 suicides, one stroke, and three unknown causes, with only three deaths due to infection (leptospirosis, TB and sepsis) in the immediate arm. Almost half the deaths in the delayed arm were of unknown cause, with two accidental deaths, one stroke and only two deaths due to infection.

There was no significant difference in severe adverse events between the two arms (14% in each), nor any difference in the distribution of types of adverse event between the two arms.

References

Grinsztejn B et al. Effects of early versus delayed initiation of antiretroviral therapy (ART) on HIV clinical outcomes: results from the HPTN 052 randomised clinical trial. Sixth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Rome, abstract MOAX0105, 2011.

Hosseinipour MC et al. Immunologic and virologic disease progression and responses to ART across geographic regions: outcomes from HPTN 052 study. Sixth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Rome, abstract MOAX0104, 2011.

Treatment as prevention: what are the next steps?

Turning treatment into a prevention tool that can end the HIV pandemic will require not one, but a host of different improvements, in the delivery of health care to achieve its full impact, and will not succeed without full respect for the human rights of people with HIV, the Sixth International AIDS Society conference heard this week in Rome.

Following Monday’s comprehensive presentation of results from HPTN 052, the landmark study which showed that early treatment of HIV-positive people reduced the risk of HIV transmission to their partners by 96%, experts have reviewed some of the challenges in translating these results into action.

Professor Julio Montaner of the University of British Columbia, a long-time champion of treatment as prevention, pointed to the first hurdle: the fact that many people with HIV do not know of their infection, and even if they do, many others are either not in regular care or not on treatment.

Only 19% of HIV-infected people in the United States are estimated to have an undetectable viral load, Prof. Montaner noted.

Furthermore, 21% of the population of HIV-infected are unaware of their HIV status, yet they are estimated to account for 54% of onward infections in the United States.

Similarly, in Mozambique, a study that tracked patients from HIV diagnosis through the medical system found that, of 7005 patients who tested positive, 57% were still in care 30 days later. Of these, 77% had a CD4 cell count to determine if they were eligible for antiretroviral treatment (ART). Half of these patients were eligible for ART, and 471 of these 1506 patients actually started ART within 30 days. Of the original 7005 patients, just 317 made it onto ART and were then adherent for at least six months.

Getting all parts of the process, from the offering of an HIV test through referral to care, starting treatment and ensuring long-term adherence to treatment, will be critical for ensuring that the proportion of people with suppressed viral load is as high as possible.

Couples first

Some voices at the conference are beginning to say that it is unethical not to provide treatment for anyone who is part of a serodiscordant couple.

So should the focus be on population-wide treatment, or should treatment target couples?

Wafaa El-Sadr of Columbia University’s International Center for AIDS Care and Treatment Programs (ICAP), which provides treatment to over one million people in 21 countries, pointed out that individuals with HIV who form part of a serodiscordant couple may form a very small part of the total population of people with HIV in some of the countries she works in.

In Lesotho, for example, 15% of couples contained one HIV-positive partner, according to Demographic and Health surveys (see systematic review by Eyawo et al.), but in Rwanda, only 2.1% of couples tested were serodiscordant. Although high-burden countries are likely to have the biggest proportion of serodiscordant couples, this number is likely to be dwarfed by the number of people who do not know their HIV status.

She argued that any decision made at country level will be highly dependent on population size and on the proportion of diagnosed HIV-positive people in serodiscordant couples. Modelling work by Wafaa El-Sadr and Sally Blower shows that high ART coverage in serodiscordant couples (>70%) could have a substantial impact in Malawi and Lesotho, but a negligible impact in Ghana and Rwanda.

Craig McClure, co-director of Treatment 2.0 activities at the World Health Organization, said: “WHO is very clear that people who are sickest should have first priority for antiretroviral therapy.”

“All my patients are in a serodiscordant couple at some point,” said Professor Montaner. His comment underlines the artificial nature of the distinction being made if serodiscordant couples are chosen as the priority group on the basis of applying strict criteria that do not extrapolate beyond the population studied in randomised trials (these trials are the gold standard on which WHO must base its guidance).

In addition, any strict definition of a couple is likely to ignore the fact that many people with HIV have multiple partners, are unmarried or have several regular partners, pointed out Professor Helen Rees of Wits Reproductive Health and HIV Institute.

The World Health Organization will be convening a high-level panel to review the role of antiretrovirals for treatment and for prevention over the next twelve months, with a view to simplifying and integrating guidance into one document, said Craig McClure.

Human rights

Eric Fleutelot, director of international programmes for Sidaction, a French HIV organisation, warned that thinking about treatment as prevention needs to put people with HIV at the centre of any strategy.

“It is a revolution in prevention, but is it going to be like the French revolution, in which a new elite of experts and public health people become more powerful, or is it going to be a democratic revolution in which people with HIV are freed from the fear of passing the virus to their partners?”

“Treatment as prevention offers a wonderful opportunity to discuss about the sexuality of people living with HIV within the context of positive health, rights and dignity. HIV remains a disease that is highly difficult to disclose to family and friends, and highly prevalent among discriminated and marginalised people.”

He said that community organisations recommend an immediate review of counselling and medical services for serodiscordant couples and pregnant HIV-positive women, and called for more research to look at the impact of treatment as prevention on sexual behaviour, and on the criminalisation of HIV transmission.

He also called for more research to determine the extent to which transmissions that take place despite treatment are due to sexually transmitted infections.

Finally, he noted, “We need to ensure that early treatment has a clear benefit [for the person who is taking it] and the results of the START trial will be very helpful.”

The START trial is a large randomised study which is comparing starting treatment at a CD4 count of 350 – the current WHO recommendation – with starting treatment at a CD4 count above 500, and is expected to report results by 2015.

Waafa El-Sadr commented: “The treatment benefit of HPTN 052 is less compelling than the prevention benefit.”

“Every individual with HIV should decide for themselves when and how to start treatment,” said Fleutelot. “No one should be forced or coerced into treatment primarily for the benefit of the public health rather than the health or the well-being of the individual.”

HATIP #180, July 29th, 2011

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