Preventing Sexual Transmission of HIV With Anti-HIV Drugs

• Time from enrollment to death [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Immunologic response of HIV infected partner: CD4 count over time, time from enrollment to immunologic failure, time from initiation of ART to immunologic failure, time from initiation of secondary regimen to immunologic failure [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Viral load in blood, semen, and vaginal secretions [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Time to initiation of secondary regimen [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Safety and toxicity [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• HIV drug resistance: prevalence of drug resistance, proportion of HIV infected partners acquiring a drug resistance [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Time from enrollment to the time of first development and subsequent development of STDs [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Adherence to drug regimen over time [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Sexual behavior over time following initiation of starting regimen and following initiation of a secondary regimen [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Quality of life indicators over time following initiation of starting regimen and following initiation of a secondary regimen [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Determine, characterize, and compare the effect of circumcision on HIV transmission in different geographic setting and by antiretroviral treatment strategies. [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

This study will determine whether anti-HIV drugs can prevent the sexual transmission of HIV among couples in which one partner is HIV infected and the other is not.

Initiation of antiretroviral therapy (ART) in the HIV infected population has been shown to dramatically reduce the morbidity and mortality of HIV infection through sustained reduction in HIV viral replication. However, such therapy does not cure HIV infection or prevent the spread of the virus. ART may, however, make HIV infected people less contagious by lowering plasma HIV-1 RNA levels, compared with people not on ART. This study seeks to determine whether initiating ART in ART-naive, HIV infected people can prevent the sexual transmission of HIV among HIV-discordant couples, as well as to demonstrate whether quality of life changes with the initiation of ART. Both opposite and same sex couples will be recruited at study sites in Brazil, India, Malawi, Thailand, the United States, and Zimbabwe for this study.

Participating couples will be enrolled for approximately 78 months (6.5 years). Couples will be randomly assigned to one of two arms. HIV infected partners in Arm 1 will begin ART in addition to receiving HIV primary care. HIV infected partners in Arm 2 will receive HIV primary care. When the CD4 count in these participants reaches 200 to 250 cells/mm3, drops below 200 cells/mm3, or develops an AIDS-defining illness, they will initiate ART. All couples will receive HIV counseling and have their urine and blood collected at screening and enrollment, and at selected monthly, quarterly, and yearly intervals. They will be asked to periodically report information about their adherence to the ART regimen.

Note: Per LoA#5, on the Data and Safety and Monitoring Board (DSMB) recommendation, as of May 10, 2011, all HIV-infected participants in Arm 2 who have not already initiated ART will be offered ART as soon as possible.

• Drug: Atazanavir
  300 mg taken orally once daily
  Other Name: Reyataz
• Drug: Didanosine
  400 mg taken orally once daily
  Other Name: Videx
• Drug: Efavirenz
  600 mg taken orally once daily
  Other Name: Sustiva
• Drug: Emtricitabine/Tenofovir disoproxil fumarate
  200 mg emtricitabine/ 300 mg tenofovir disoproxil fumarate tablet taken orally once daily
  Other Name: Truvada
• Drug: Lamivudine
  300 mg taken orally once daily
  Other Names:

  • Epivir
  • 3TC
• Drug: Lopinavir/Ritonavir
  200 mg lopinavir/ 50 mg ritonavir tablet taken orally once daily
  Other Name: Kaletra
• Drug: Nevirapine
  200 mg taken orally once daily for 14 days followed by 200 mg taken orally twice daily
  Other Names:

  • Viramune
  • NVP
• Drug: Stavudine
  Dosage depends on weight
  Other Names:

  • Zerit
  • d4T
• Drug: Tenofovir disoproxil fumarate
  300 mg taken orally once daily
  Other Names:

  • Viread
  • TDF
• Drug: Zidovudine/Lamivudine
  150 mg lamivudine/ 300 mg zidovudine tablet taken orally twice daily
  Other Name: Combivir

• Experimental: 1
  Participants will begin ART in addition to receiving HIV primary care
  Interventions:

  • Drug: Atazanavir
  • Drug: Didanosine
  • Drug: Efavirenz
  • Drug: Emtricitabine/Tenofovir disoproxil fumarate
  • Drug: Lamivudine
  • Drug: Lopinavir/Ritonavir
  • Drug: Nevirapine
  • Drug: Stavudine
  • Drug: Tenofovir disoproxil fumarate
  • Drug: Zidovudine/Lamivudine
• Experimental: 2

  Participants will receive HIV primary care. When the CD4 count in these participants reaches 200 to 250 cells/mm3, drops below 200 cells/mm3, or develops an AIDS-defining illness, they will initiate ART.

  Note: Per LoA#5, on the Data and Safety and Monitoring Board (DSMB) recommendation, as of May 10, 2011, all HIV-infected participants in Arm 2 who have not already initiated ART will be offered ART as soon as possible.

  Interventions:

  • Drug: Atazanavir
  • Drug: Didanosine
  • Drug: Efavirenz
  • Drug: Emtricitabine/Tenofovir disoproxil fumarate
  • Drug: Lamivudine
  • Drug: Lopinavir/Ritonavir
  • Drug: Nevirapine
  • Drug: Stavudine
  • Drug: Tenofovir disoproxil fumarate
  • Drug: Zidovudine/Lamivudine

• Chan DJ. Fatal attraction: sex, sexually transmitted infections and HIV-1. Int J STD AIDS. 2006 Oct;17(10):643-51. Review.
• Chan DJ. Factors affecting sexual transmission of HIV-1: current evidence and implications for prevention. Curr HIV Res. 2005 Jul;3(3):223-41. Review.
• Davis CW, Doms RW. HIV transmission: closing all the doors. J Exp Med. 2004 Apr 19;199(8):1037-40. Epub 2004 Apr 12. Review. No abstract available.
• Gupta K, Klasse PJ. How do viral and host factors modulate the sexual transmission of HIV? Can transmission be blocked? PLoS Med. 2006 Feb;3(2):e79. Epub 2006 Feb 28. Review. No abstract available.
• Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, Hakim JG, Kumwenda J, Grinsztejn B, Pilotto JH, Godbole SV, Mehendale S, Chariyalertsak S, Santos BR, Mayer KH, Hoffman IF, Eshleman SH, Piwowar-Manning E, Wang L, Makhema J, Mills LA, de Bruyn G, Sanne I, Eron J, Gallant J, Havlir D, Swindells S, Ribaudo H, Elharrar V, Burns D, Taha TE, Nielsen-Saines K, Celentano D, Essex M, Fleming TR; HPTN 052 Study Team. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011 Aug 11;365(6):493-505. Epub 2011 Jul 18.

Inclusion Criteria for HIV Infected Partner:

• Positive HIV test within 60 days of study entry
• CD4 count between 350 and 550 cells/mm3 within 30 days of study entry
• If pregnant or breastfeeding, willing to be randomized to either arm of the study

Inclusion Criteria for HIV Uninfected Partner:

• Negative HIV test within 14 days of study entry

Inclusion Criteria for Both Partners:

• Plans to maintain sexual relationship with partner
• Reports having sex (vaginal or anal) with partner at least three times in the last 3 months
• Willing to disclose HIV test results to partner
• Plans to stay in the area and does not have a job or other obligations that may require long absences during the duration of the study

Exclusion Criteria for HIV Infected Partner:

• Current or previous use of any ART. Participants who previously took a short-term course of ART for prevention of mother-to-child transmission of HIV are not excluded.
• Documented or suspected acute hepatitis within 30 days of study entry, if the infected partner's starting regimen in the study contains nevirapine or atazanavir
• Current or previous AIDS-defining illness or opportunistic infection
• Documented or suspected acute hepatitis within 30 days prior to study entry
• Acute therapy of serious medical illnesses within 14 days prior to study entry
• Radiation therapy or systemic chemotherapy within 45 days prior to study entry
• Immunomodulatory or investigational therapy within 30 days prior to study entry
• Active drug or alcohol dependence that, in the opinion of the investigator, would interfere with the study
• Vomiting or inability to swallow medications
• Require certain medications
• Allergy or sensitivity to any of the study drugs

Exclusion Criteria for Both Partners:

• History of injection drug use within 5 years of study entry
• Previous and/or current participation in an HIV vaccine study
• Currently detained in jail or for treatment of a psychiatric or physical illness
• Any condition that, in the opinion of the study staff, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives
• Certain abnormal laboratory values