HPTN 052

Published

Cohen MS, et al. "Prevention of HIV-1 Infection with Early Antiretroviral Therapy". The New England Journal of Medicine. 2011. 365(6):493-505.
PubMed • Full text • PDF

Clinical Question

Does early initiation of antiretroviral therapy (ART) reduce HIV transmission among HIV-serodiscordant couples and reduce morbidity among HIV-seropositive partners?

Bottom Line

Early ART in HIV-seropositive partners with CD4 counts between 350-550/mm³ reduced HIV transmission among HIV-serodiscordant couples and reduced morbidity without increasing drug toxicity.

Major Points

Several prospective cohort studies in Africa demonstrated that ART in the HIV-seropositive partner reduced transmission to the HIV-seronegative partner. The HIV Prevention Trials Network (HPTN) 052 trial was the first RCT to determine whether ART of the HIV-seropositive partner (CD4 between 350-550 cells/mm³) decreased transmission to the HIV-seronegative partner. The HPTN 052 trial randomized 1,763 HIV-serodiscordant, almost entirely heterosexual couples to initiation of early ART (CD4 count 350-550) or delayed ART (CD4 count <250 or after AIDS-defining illness). Viral gene sequencing after seroconversion determined whether HIV transmission was linked between couples.

The trial was stopped early after a median follow-up of 1.7 years, when HPTN 052 demonstrated a relative risk reduction of 96% in HIV transmissions after early ART among those with CD4 count between 350-550 cells/mm³ compared with delayed ART. Twenty-seven out of 28 linked HIV transmission events occurred in the delayed ART arm (mostly observed in Africa), and the one linked HIV transmission event in the early ART arm most likely occurred before the HIV-seropositive partner started ART or before full viral suppression was achieved (which can take up to 6 months). A reduced risk of transmission was associated with a low baseline plasma viral load, elevated CD4 count, and a self-report of 100% condom use. These results support the use of early ART as part of a public health strategy to prevent the spread of HIV infection.

Although mortality rates were similar, this trial also demonstrated a relative risk reduction of 41% in HIV-associated morbidity among those who initiated early ART compared with delayed ART. Most of the HIV-associated clinical events were driven by extrapulmonary TB, which was mostly observed in India. Of note, only 4% of participants in either group received isoniazid prophylaxis. Among HIV-seropositive patients living in TB-endemic areas, this trial supports epidemiologic studies that suggest ART reduces the risk of TB, and supports the recommendation by the WHO that these individuals should also receive isoniazid prophylaxis.

Guidelines

NIH ART Panel - OARAC (2014, adapted)

• Initiate ART for HIV-infected patients to reduce the risk of disease progression:
  • CD4 <350 (AI)
  • CD4 350-500 (AII)
  • CD4 >500 (BIII)

WHO ART (2013, adapted)

• Start ART in if one of the following (strong recommendation, moderate-quality evidence):
  • Severe or advanced HIV clinical disease (WHO clinical stage 3 or 4)
  • Individuals with CD4 count <350 cells/mm3
• Start ART if HIV and a CD4 count >350 cells and <500 cells/mm3 regardless of WHO clinical stage (strong recommendation, moderate-quality evidence)
• Start ART if HIV, regardless of stage if one of the following:
  • Active TB (strong recommendation, low-quality evidence)
  • Coinfection of HIV and HBV and severe chronic liver disease (strong recommendation, low-quality evidence)
  • Serodiscordant couples to reduce risk of transmission to seronegative partner (strong recommmendation, high-quality evidence)

Design

• Multicenter, non-blinded, parallel group, randomized, controlled trial
• N=1,763 HIV-serodiscordant couples
  • Early ART (n=886 couples; 886 HIV-seropositive, 893 HIV-seronegative)
  • Delayed ART (n=877 couples; 877 HIV-seropositive, 882 HIV-seronegative)
• Setting: 13 sites in 9 countries (Botswana, Kenya, Malawi, South Africa, Zimbabwe, Brazil, India, Thailand, Boston)
• Enrollment: 2007-2010
• Median follow-up: 1.7 years (stopped early)
• Analysis: Intention-to-treat
• Primary end point: linked HIV transmission; death, WHO stage 4 events, severe bacterial infections, and pulmonary TB for HIV-seropositive partners

Population

Inclusion Criteria

• HIV-1 serodiscordant couples in stable relationships for ≥3 mos with ≥3 episodes of vaginal/anal intercourse during this time
• HIV-seropositive partner with positive HIV serology within 60 days; CD4 between 350-550 cells/mm³; Age ≥18 yrs
• HIV-seronegative partner with negative HIV serology within 14 days; Age ≥18 yrs

Exclusion Criteria

• History of IVDU within 5 yrs
• Participated in HIV vaccine study
• Incarceration or involuntary hospitalization for psychiatric or physical illness
• AIDS-defining illness
• Active tuberculosis
• Previous use of ART except for short-term prevention of mother-to-child transmission
• Hb ≤7.5 g/dL; ANC ≤750 mm³; plt ≤50,000/µL
• AST, ALT, alkaline phosphatase ≥5xULN; total bilirubin ≥2.5xULN
• Cr clearance ≤60 ml/min
• Acute hepatitis within 30 days
• Acute therapy for serious medical illnesses within 14 days
• XRT or chemotherapy within 45 days or anticipated need while on study
• Immunomodulator or investigational therapy within 30 days
• Active drug or alcohol use that would interfere with adherence
• Allergy or sensitivity to study medication

Baseline Characteristics

Demographic

• Age: 18-25 yrs (18%); 26-40 yrs (61%); ≥40 yrs (21%)
• Female: 49%
• Education level: None (10%), Primary (39%), Secondary (42%); Postsecondary (9%)
• Married or living with partner: 94%; Single or widowed: 6%
• Region: Africa (54%), Asia (30%), America (16%)

Sexual activity

• Unprotected sex in past week: 5%
• No. sexual partners in past 3 mos: ≤1 (96%), ≥2 (4%)
• No. sexual encounters in past week: 0 (27%), 1-2 (49%), 3-4 (18%), >4 (6%)

Clinical data for HIV-seropositive partners

• Median CD4 count: 442 vs. 428 cells/mm³
• Median log₁₀ plasma viral load: 4.4
• Women reporting previous ART during pregnancy: 27%
• Type of serodiscordancy: heterosexual (98%)
  • HIV-positive man, HIV-negative woman: 49%
  • HIV-positive woman, HIV-negative man:49%
  • HIV-positive man, HIV-negative man:2%
  • HIV-positive woman, HIV-negative woman:<1%
• STIs
  • Hepatitis B: 5%
  • Syphilis: 3%
  • Gonorrhea: 1%
  • C. trachomatis: 2%
  • Trichomonas: 4%

Interventions

• HIV-1 serodiscordant couples randomized to early or delayed strategy
  • Early therapy arm: ART initiated with HIV-seropositive partner at CD4 count 350-550/mm³
  • Delayed therapy arm: ART initiated with HIV-seropositive partner after AIDS-defining illness or two consecutive CD4 count ≤250/mm³
• Three monthly visits followed by quarterly visits
  • Counseling regarding safer sex, condom use, treatment of STIs, and medical adherence
  • Testing for HIV seroconversion in HIV- partners; HIV-1 pol gene sequences were analyzed among seroconverters to see if HIV transmission was linked between couples.
• Additional HIV-seronegative partners were enrolled as a result of a new relationship
• Study drugs included: efavirenze, atazanvir, nevirapine, tenofovir, lamivudine, zidovudine, didanosine, stavudine, ritonavir, and combinations (lamivudine and zidovudine, lopinavir and ritonavir, emtricitabine and tenofovir)
• Most frequently used initial primary regimens: See supplementary appendix for regimens by site.
  • (AZT/3TC)/EFV: 72%
  • (AZT/3TC)/ATV: 9%
  • (FTC/TDF)/EFV: 9%
  • (AZT/3TC)/(LPV/RTV): 6%
  • Other: 3%

Outcomes

Comparisons are early ART vs. delayed ART.

Primary Outcomes

Linked HIV transmission

1 vs. 27 events or 0.1 vs. 1.7 events per 100 person-years (HR 0.04; 95% CI 0.01-0.27; P<0.001)

Death, WHO stage 4 events, severe bacterial infections, and pulmonary TB for HIV-seropositive partners

40 vs. 65 events or 2.4 vs. 4.0 events per 100 person-years (HR 0.59; 95% CI 0.40-0.88; P=0.01)

Secondary Outcomes

Any HIV transmission

4 vs. 35 events or 0.3 vs. 2.2 events per 100 person-years (HR 0.11; 95% CI 0.04-0.32; P<0.001)

Death

10 vs. 13 events

Severe bacterial infections

16 vs. 11 events

Pulmonary tuberculosis

14 vs. 16 events

Extrapulmonary tuberculosis

3 vs. 17 events

Composite of death or WHO stage 4 event for HIV-seropositive partner or HIV transmission to HIV-seronegative partner

23 vs. 79 events or 1.4 vs. 4.8 events per 100 person-years (HR 0.28; 95% CI 0.18-0.45; P<0.001)

Subgroup Analysis

Multivariate analysis of prognostic factors for linked HIV transmission

Baseline viral load (per unit log₁₀ increment)

HR 2.85; 95% CI 1.51-5.41

Baseline CD4 count (per 100 CD4 increment)

HR 1.24; 95% CI 1.00-1.54

Gender of HIV-seropositive partner

HR 0.73; 95% CI 0.33-1.65

Baseline condom use (100% vs. <100%)

HR 0.33; 95% CI 0.12-0.91

Early vs. delayed ART

HR 0.04; 95% CI 0.01-0.28

Adverse Events

Severe or life-threatening adverse events (grade 3 or 4) excluding primary clinical endpoints

14% vs. 15% (P=0.64)

Grade 3 or 4 laboratory events including neutropenia, elevated alkaline phosphatase, and hyperbilirubinemia

27% vs. 18% (P<0.001)

Criticisms

• Given short follow-up period, a mortality benefit was not detected.
• Stable HIV-1 discordant couples in this study may not generalizable to the general population.
• Couples counseling and condom distribution probably contributed to a lower incidence of HIV transmission.
• Majority of couples in this study were heterosexual and may not be generalizable to homosexual couples.

Funding

• National Institute of Allergy and Infectious Diseases of the NIH
• ART donated by pharmaceutical companies not involved in design or management of study