Early Antiretroviral Therapy Reduces HIV-Related Sequelae

WASHINGTON  – Early use of antiretroviral therapy significantly reduced the incidence of clinical events – including tuberculosis and AIDS-defining events – among HIV positive adults in a large multinational trial.

"Overall, our interpretation was that there is a marked clinical benefit in terms of reduced clinical events by starting antiretroviral therapy early," Dr. Mina C. Hosseinipour said in a press briefing held during the meeting.

The data are the latest from the landmark HIV Prevention Trials Network study number 052 (HPTN 052), which previously had shown that use of antiretroviral therapy (ART) early – when CD4 counts were between 350 and 550 cells/mm³ – in the HIV-positive partners of a total of 1,763 serodiscordant couples reduced the rate of HIV transmission to the uninfected partner by 96%. It also showed that early ART is associated with a longer time to HIV disease progression and preservation of the immune system over 2 years in the patients themselves (N. Engl. J. Med. 2011;365:493-505).

"So, we think that combined with the preventive benefit, the clinical benefit that one can see from earlier antiretroviral therapy does support earlier antiretroviral initiation" when CD4 counts are between 350 and 550 cells per cubic millimeter, said Dr. Hosseinipour, clinical director of the University of North Carolina Project in Lilongwe, Malawi.

The new analysis, including an additional 3 months of follow-up from the earlier report, focused on clinical end points among those randomized to early vs. later (CD4 count less than 250/mm³ or the onset of AIDS) antiretroviral treatment. The data were presented at the conference by Dr. Beatriz Grinsztejn of Instituto de Pesquisa Clinica Evandro Chagas, Manguinhos, Brazil.

At baseline, the 886 participants in the immediate ART group were similar to the 875 participants in the delayed ART group with regard to gender (about 50/50); two-thirds between the ages of 26 and 40 years. Just over half (54%) were from Africa, and slightly less than a third (30%) from Asia. The rest were from South America. Baseline CD4 counts were 428 cells/mm³ for the delayed ART group and 442 cells/mm³ for the immediate group, and baseline HIV-1 RNA level was 4.4 log10 copies/mL in both groups.

During an overall median follow-up of 2.1 years, 24% (213) patients in the delayed arm initiated ART, at a median of 3.8 years to initiation. Median duration of exposure to ART was 1 year, vs. 2 years in the immediate treatment group.

The specified primary clinical events were death, World Health Organization stage 4 events, tuberculosis, severe bacterial infection, and targeted non-AIDS events, including serious cardiovascular/vascular disease, serious liver disease, end stage renal disease, non-AIDS malignancy, and diabetes mellitus.

There were no differences in primary event rates between the two groups during the first year, but by the end of the follow-up period, 9% (77) of the delayed group vs. 6% (57) of the immediate group experienced at least one primary event, for a hazard ratio of 1.37. AIDS-related events occurred in 61 of the 77 delayed-therapy group and 40 of the 57 immediate-therapy group patients. Deaths occurred in 15 and 11, respectively. Non-AIDS events occurred in 9 delayed vs.12 immediate-therapy group patients, including diabetes mellitus in 5 and 4, respectively, Dr. Grinsztejn reported.

There were no significant differences in primary event rates by region, gender, or baseline CD4 count above vs. below 450 cells/mm³, she said.

In a multivariate analysis, factors significantly associated with primary events were age 40 years and older vs. 18-24 years (HR, 2.42), having a greater pretreatment HIV-1 log10 RNA count (1.34/1 log higher), a higher hemoglobin (grade 2 or higher vs. 0/1), and hepatitis B coinfection (1.85 for yes vs. no). In addition, regardless of treatment arm, each 50 CD4 cell higher count was associated with a 10% lower risk of primary events, she reported.

Tuberculosis was significantly more frequent in the delayed treatment group, 4% (34) vs. 2% (17), as were WHO stage 4 events (2% vs. 1%), with chronic herpes simplex being the most common of those (in 8 vs. 2 patients, respectively). Serious bacterial infections were more common among the immediate treatment patients, 2% vs. 1%.

Among the secondary events, herpes zoster, oral candidiasis, and seborrheic dermatitis were the most prevalent, all being more common in the delayed-treatment group, she noted.

Combining all primary and secondary events, the incidence was 29/100 person-years for delayed treatment vs. 25/100 person-years for immediate treatment, a significant difference (P = .02). At the time of primary clinical events, the CD4 count was significantly higher in the immediate-treatment group, compared with the delayed group (502 vs. 351). There was a similar distribution with the secondary events (540 vs. 377). Approximately half of the events in the delayed arm occurred at CD4 cell counts higher than 350, Dr. Grinsztejn noted.

The HPTN 052 study is ongoing. All HIV infected subjects were offered ART and 93% of the index cases are now on it. Retention is 96% among the index cases and 85% for the discordant couples. Still undetermined are the durability of the prevention benefit and the consequences of delayed ART on clinical outcomes over a longer follow-up, she said.

In addition, giving antiretroviral therapy early to HIV-positive patients is cost effective over a 5-year and lifetime horizon, according to a subanalysis of HPTN 052.

Researchers from the Harvard Medical School, Boston, presented the cost-effectiveness analysis on behalf of the HPTN. They analyzed 5-year and lifetime survival and costs in India and South Africa.

To be deemed "very cost effective," early ART had to be less than one times the per capita gross domestic product of each country. To be "cost effective," it would need to be less than three times the gross domestic product (GDP). In South Africa, the per capita GDP was $8,100, and in India it was $1,400.

The cost of ART – whether early or delayed – was higher in South Africa than in India, largely because the costs of care were higher. Early ART for the initially infected patients cost $4,600 over the 5-year horizon in South Africa and $2,300 in India. The lifetime cost for early ART was $18,400 in South Africa, compared with $11,300 in India.

Early ART cost more than delayed ART. But survival was higher with early ART – 93%, compared with 84% for delayed ART in South Africa, for instance – and there was a marked and immediate decrease in transmission for early ART in both India and South Africa, said Dr. Kenneth A. Freedberg, director of the HIV Research Program in the division of general medicine at Massachusetts General Hospital, Boston.

The early therapy also prevented opportunistic infections in South Africa. It was deemed very cost effective in South Africa, at $700/year of life saved in the 5-year time frame, and $1,200/year of life saved over the lifetime.

In India, early ART increased survival also and reduced transmissions of the virus. It was deemed cost effective in that country, at $2,900/year of life saved over the 5-year time frame. The lifetime horizon nudged it up to very cost effective at $1,300/year of life saved.

Increased survival in both countries was a bit of a double-edged sword. Those who lived longer also tended to have more HIV transmissions, Dr. Freedberg explained. Even so, early ART appears to be a winning strategy, he said.

"The clinical data, the behavioral data, the economic data, are converging on the very clear consensus that early antiretroviral therapy is clinically effective for individuals, prevents transmission, and is very cost effective," he said in presenting the abstract.

Dr. Freedberg added that early ART should definitely be given to serodiscordant couples.

In addition, he said, "We’re moving toward the situation where the data support early antiretroviral therapy for anybody infected."

The HIV Prevention Trials Network is funded by the National Institute of Allergy and Infectious Diseases. Study drugs were donated by Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences; GlaxoSmithKline/ViiV Healthcare, and Merck.

Dr. Grinsztejn stated that she has no additional disclosures.

Alicia Ault, a medical media reporter for IMNG, contributed to this article.

WASHINGTON  – Early use of antiretroviral therapy significantly reduced the incidence of clinical events – including tuberculosis and AIDS-defining events – among HIV positive adults in a large multinational trial.

"Overall, our interpretation was that there is a marked clinical benefit in terms of reduced clinical events by starting antiretroviral therapy early," Dr. Mina C. Hosseinipour said in a press briefing held during the meeting.

The data are the latest from the landmark HIV Prevention Trials Network study number 052 (HPTN 052), which previously had shown that use of antiretroviral therapy (ART) early – when CD4 counts were between 350 and 550 cells/mm³ – in the HIV-positive partners of a total of 1,763 serodiscordant couples reduced the rate of HIV transmission to the uninfected partner by 96%. It also showed that early ART is associated with a longer time to HIV disease progression and preservation of the immune system over 2 years in the patients themselves (N. Engl. J. Med. 2011;365:493-505).

"So, we think that combined with the preventive benefit, the clinical benefit that one can see from earlier antiretroviral therapy does support earlier antiretroviral initiation" when CD4 counts are between 350 and 550 cells per cubic millimeter, said Dr. Hosseinipour, clinical director of the University of North Carolina Project in Lilongwe, Malawi.

The new analysis, including an additional 3 months of follow-up from the earlier report, focused on clinical end points among those randomized to early vs. later (CD4 count less than 250/mm³ or the onset of AIDS) antiretroviral treatment. The data were presented at the conference by Dr. Beatriz Grinsztejn of Instituto de Pesquisa Clinica Evandro Chagas, Manguinhos, Brazil.

At baseline, the 886 participants in the immediate ART group were similar to the 875 participants in the delayed ART group with regard to gender (about 50/50); two-thirds between the ages of 26 and 40 years. Just over half (54%) were from Africa, and slightly less than a third (30%) from Asia. The rest were from South America. Baseline CD4 counts were 428 cells/mm³ for the delayed ART group and 442 cells/mm³ for the immediate group, and baseline HIV-1 RNA level was 4.4 log10 copies/mL in both groups.

During an overall median follow-up of 2.1 years, 24% (213) patients in the delayed arm initiated ART, at a median of 3.8 years to initiation. Median duration of exposure to ART was 1 year, vs. 2 years in the immediate treatment group.

The specified primary clinical events were death, World Health Organization stage 4 events, tuberculosis, severe bacterial infection, and targeted non-AIDS events, including serious cardiovascular/vascular disease, serious liver disease, end stage renal disease, non-AIDS malignancy, and diabetes mellitus.

There were no differences in primary event rates between the two groups during the first year, but by the end of the follow-up period, 9% (77) of the delayed group vs. 6% (57) of the immediate group experienced at least one primary event, for a hazard ratio of 1.37. AIDS-related events occurred in 61 of the 77 delayed-therapy group and 40 of the 57 immediate-therapy group patients. Deaths occurred in 15 and 11, respectively. Non-AIDS events occurred in 9 delayed vs.12 immediate-therapy group patients, including diabetes mellitus in 5 and 4, respectively, Dr. Grinsztejn reported.

There were no significant differences in primary event rates by region, gender, or baseline CD4 count above vs. below 450 cells/mm³, she said.

In a multivariate analysis, factors significantly associated with primary events were age 40 years and older vs. 18-24 years (HR, 2.42), having a greater pretreatment HIV-1 log10 RNA count (1.34/1 log higher), a higher hemoglobin (grade 2 or higher vs. 0/1), and hepatitis B coinfection (1.85 for yes vs. no). In addition, regardless of treatment arm, each 50 CD4 cell higher count was associated with a 10% lower risk of primary events, she reported.

Tuberculosis was significantly more frequent in the delayed treatment group, 4% (34) vs. 2% (17), as were WHO stage 4 events (2% vs. 1%), with chronic herpes simplex being the most common of those (in 8 vs. 2 patients, respectively). Serious bacterial infections were more common among the immediate treatment patients, 2% vs. 1%.

Among the secondary events, herpes zoster, oral candidiasis, and seborrheic dermatitis were the most prevalent, all being more common in the delayed-treatment group, she noted.

Combining all primary and secondary events, the incidence was 29/100 person-years for delayed treatment vs. 25/100 person-years for immediate treatment, a significant difference (P = .02). At the time of primary clinical events, the CD4 count was significantly higher in the immediate-treatment group, compared with the delayed group (502 vs. 351). There was a similar distribution with the secondary events (540 vs. 377). Approximately half of the events in the delayed arm occurred at CD4 cell counts higher than 350, Dr. Grinsztejn noted.

The HPTN 052 study is ongoing. All HIV infected subjects were offered ART and 93% of the index cases are now on it. Retention is 96% among the index cases and 85% for the discordant couples. Still undetermined are the durability of the prevention benefit and the consequences of delayed ART on clinical outcomes over a longer follow-up, she said.

In addition, giving antiretroviral therapy early to HIV-positive patients is cost effective over a 5-year and lifetime horizon, according to a subanalysis of HPTN 052.

Researchers from the Harvard Medical School, Boston, presented the cost-effectiveness analysis on behalf of the HPTN. They analyzed 5-year and lifetime survival and costs in India and South Africa.

To be deemed "very cost effective," early ART had to be less than one times the per capita gross domestic product of each country. To be "cost effective," it would need to be less than three times the gross domestic product (GDP). In South Africa, the per capita GDP was $8,100, and in India it was $1,400.

The cost of ART – whether early or delayed – was higher in South Africa than in India, largely because the costs of care were higher. Early ART for the initially infected patients cost $4,600 over the 5-year horizon in South Africa and $2,300 in India. The lifetime cost for early ART was $18,400 in South Africa, compared with $11,300 in India.

Early ART cost more than delayed ART. But survival was higher with early ART – 93%, compared with 84% for delayed ART in South Africa, for instance – and there was a marked and immediate decrease in transmission for early ART in both India and South Africa, said Dr. Kenneth A. Freedberg, director of the HIV Research Program in the division of general medicine at Massachusetts General Hospital, Boston.

The early therapy also prevented opportunistic infections in South Africa. It was deemed very cost effective in South Africa, at $700/year of life saved in the 5-year time frame, and $1,200/year of life saved over the lifetime.

In India, early ART increased survival also and reduced transmissions of the virus. It was deemed cost effective in that country, at $2,900/year of life saved over the 5-year time frame. The lifetime horizon nudged it up to very cost effective at $1,300/year of life saved.

Increased survival in both countries was a bit of a double-edged sword. Those who lived longer also tended to have more HIV transmissions, Dr. Freedberg explained. Even so, early ART appears to be a winning strategy, he said.

"The clinical data, the behavioral data, the economic data, are converging on the very clear consensus that early antiretroviral therapy is clinically effective for individuals, prevents transmission, and is very cost effective," he said in presenting the abstract.

Dr. Freedberg added that early ART should definitely be given to serodiscordant couples.

In addition, he said, "We’re moving toward the situation where the data support early antiretroviral therapy for anybody infected."

The HIV Prevention Trials Network is funded by the National Institute of Allergy and Infectious Diseases. Study drugs were donated by Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences; GlaxoSmithKline/ViiV Healthcare, and Merck.

Dr. Grinsztejn stated that she has no additional disclosures.

Alicia Ault, a medical media reporter for IMNG, contributed to this article.

WASHINGTON  – Early use of antiretroviral therapy significantly reduced the incidence of clinical events – including tuberculosis and AIDS-defining events – among HIV positive adults in a large multinational trial.

"Overall, our interpretation was that there is a marked clinical benefit in terms of reduced clinical events by starting antiretroviral therapy early," Dr. Mina C. Hosseinipour said in a press briefing held during the meeting.

The data are the latest from the landmark HIV Prevention Trials Network study number 052 (HPTN 052), which previously had shown that use of antiretroviral therapy (ART) early – when CD4 counts were between 350 and 550 cells/mm³ – in the HIV-positive partners of a total of 1,763 serodiscordant couples reduced the rate of HIV transmission to the uninfected partner by 96%. It also showed that early ART is associated with a longer time to HIV disease progression and preservation of the immune system over 2 years in the patients themselves (N. Engl. J. Med. 2011;365:493-505).

"So, we think that combined with the preventive benefit, the clinical benefit that one can see from earlier antiretroviral therapy does support earlier antiretroviral initiation" when CD4 counts are between 350 and 550 cells per cubic millimeter, said Dr. Hosseinipour, clinical director of the University of North Carolina Project in Lilongwe, Malawi.

The new analysis, including an additional 3 months of follow-up from the earlier report, focused on clinical end points among those randomized to early vs. later (CD4 count less than 250/mm³ or the onset of AIDS) antiretroviral treatment. The data were presented at the conference by Dr. Beatriz Grinsztejn of Instituto de Pesquisa Clinica Evandro Chagas, Manguinhos, Brazil.

At baseline, the 886 participants in the immediate ART group were similar to the 875 participants in the delayed ART group with regard to gender (about 50/50); two-thirds between the ages of 26 and 40 years. Just over half (54%) were from Africa, and slightly less than a third (30%) from Asia. The rest were from South America. Baseline CD4 counts were 428 cells/mm³ for the delayed ART group and 442 cells/mm³ for the immediate group, and baseline HIV-1 RNA level was 4.4 log10 copies/mL in both groups.

During an overall median follow-up of 2.1 years, 24% (213) patients in the delayed arm initiated ART, at a median of 3.8 years to initiation. Median duration of exposure to ART was 1 year, vs. 2 years in the immediate treatment group.

The specified primary clinical events were death, World Health Organization stage 4 events, tuberculosis, severe bacterial infection, and targeted non-AIDS events, including serious cardiovascular/vascular disease, serious liver disease, end stage renal disease, non-AIDS malignancy, and diabetes mellitus.

There were no differences in primary event rates between the two groups during the first year, but by the end of the follow-up period, 9% (77) of the delayed group vs. 6% (57) of the immediate group experienced at least one primary event, for a hazard ratio of 1.37. AIDS-related events occurred in 61 of the 77 delayed-therapy group and 40 of the 57 immediate-therapy group patients. Deaths occurred in 15 and 11, respectively. Non-AIDS events occurred in 9 delayed vs.12 immediate-therapy group patients, including diabetes mellitus in 5 and 4, respectively, Dr. Grinsztejn reported.

There were no significant differences in primary event rates by region, gender, or baseline CD4 count above vs. below 450 cells/mm³, she said.

In a multivariate analysis, factors significantly associated with primary events were age 40 years and older vs. 18-24 years (HR, 2.42), having a greater pretreatment HIV-1 log10 RNA count (1.34/1 log higher), a higher hemoglobin (grade 2 or higher vs. 0/1), and hepatitis B coinfection (1.85 for yes vs. no). In addition, regardless of treatment arm, each 50 CD4 cell higher count was associated with a 10% lower risk of primary events, she reported.

Tuberculosis was significantly more frequent in the delayed treatment group, 4% (34) vs. 2% (17), as were WHO stage 4 events (2% vs. 1%), with chronic herpes simplex being the most common of those (in 8 vs. 2 patients, respectively). Serious bacterial infections were more common among the immediate treatment patients, 2% vs. 1%.

Among the secondary events, herpes zoster, oral candidiasis, and seborrheic dermatitis were the most prevalent, all being more common in the delayed-treatment group, she noted.

Combining all primary and secondary events, the incidence was 29/100 person-years for delayed treatment vs. 25/100 person-years for immediate treatment, a significant difference (P = .02). At the time of primary clinical events, the CD4 count was significantly higher in the immediate-treatment group, compared with the delayed group (502 vs. 351). There was a similar distribution with the secondary events (540 vs. 377). Approximately half of the events in the delayed arm occurred at CD4 cell counts higher than 350, Dr. Grinsztejn noted.

The HPTN 052 study is ongoing. All HIV infected subjects were offered ART and 93% of the index cases are now on it. Retention is 96% among the index cases and 85% for the discordant couples. Still undetermined are the durability of the prevention benefit and the consequences of delayed ART on clinical outcomes over a longer follow-up, she said.

In addition, giving antiretroviral therapy early to HIV-positive patients is cost effective over a 5-year and lifetime horizon, according to a subanalysis of HPTN 052.

Researchers from the Harvard Medical School, Boston, presented the cost-effectiveness analysis on behalf of the HPTN. They analyzed 5-year and lifetime survival and costs in India and South Africa.

To be deemed "very cost effective," early ART had to be less than one times the per capita gross domestic product of each country. To be "cost effective," it would need to be less than three times the gross domestic product (GDP). In South Africa, the per capita GDP was $8,100, and in India it was $1,400.

The cost of ART – whether early or delayed – was higher in South Africa than in India, largely because the costs of care were higher. Early ART for the initially infected patients cost $4,600 over the 5-year horizon in South Africa and $2,300 in India. The lifetime cost for early ART was $18,400 in South Africa, compared with $11,300 in India.

Early ART cost more than delayed ART. But survival was higher with early ART – 93%, compared with 84% for delayed ART in South Africa, for instance – and there was a marked and immediate decrease in transmission for early ART in both India and South Africa, said Dr. Kenneth A. Freedberg, director of the HIV Research Program in the division of general medicine at Massachusetts General Hospital, Boston.

The early therapy also prevented opportunistic infections in South Africa. It was deemed very cost effective in South Africa, at $700/year of life saved in the 5-year time frame, and $1,200/year of life saved over the lifetime.

In India, early ART increased survival also and reduced transmissions of the virus. It was deemed cost effective in that country, at $2,900/year of life saved over the 5-year time frame. The lifetime horizon nudged it up to very cost effective at $1,300/year of life saved.

Increased survival in both countries was a bit of a double-edged sword. Those who lived longer also tended to have more HIV transmissions, Dr. Freedberg explained. Even so, early ART appears to be a winning strategy, he said.

"The clinical data, the behavioral data, the economic data, are converging on the very clear consensus that early antiretroviral therapy is clinically effective for individuals, prevents transmission, and is very cost effective," he said in presenting the abstract.

Dr. Freedberg added that early ART should definitely be given to serodiscordant couples.

In addition, he said, "We’re moving toward the situation where the data support early antiretroviral therapy for anybody infected."

The HIV Prevention Trials Network is funded by the National Institute of Allergy and Infectious Diseases. Study drugs were donated by Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences; GlaxoSmithKline/ViiV Healthcare, and Merck.

Dr. Grinsztejn stated that she has no additional disclosures.

Alicia Ault, a medical media reporter for IMNG, contributed to this article.