Long-term effects of early versus delayed initiation of antiretroviral therapy in HIV-infected patients in Port-au-Prince, Haiti

MANUSCRIPT I: Oral Examination to Guide the Initiation of Antiretroviral Therapy: Results from the CIPRA HT001 Trial.;BACKGROUND: HIV-associated oral lesions can guide the decision to initiate antiretroviral therapy (ART). The discrepancies in the incidence of oral lesions as a function of the timing of ART initiation has not been well characterized. This information is invaluable in understanding how the oral exam, can be used to predict the need for ART.;METHODS: A randomized controlled clinical trial was conducted at the GHESKIO Center in Port-au-Prince, Haiti between 2004 and 2009. 816 HIV-infected ART-naive participants with CD4 T cell counts between 200 and 350 cells/mm3 were randomized to either immediate ART initiation (early arm; N=408) or initiation when CD4 T cell count was less than or equal 200 cells/mm3 or with development of an AIDS-defining condition (delayed arm; N=408). Every 3 months, participants underwent an oral exam. Oral lesions were documented using Oral HIV/AIDS Research Alliance case definitions.;RESULTS: The incidence of oral lesions was 4.10 in the early group and 17.85 in the delayed group. There was a significantly higher incidence of candidiasis, leukoplakia, and herpes labialis in the delayed group. The incidence of oral warts in delayed group was 0.97 before therapy and 4.27 post-ART initiation. In the delayed group the incidence of oral warts post-ART initiation was significantly higher than that seen in the early group (4.27 versus 1.09).;CONCLUSIONS: Examination of the oral cavity provided valuable information on HIV progression and the need for ART. The incidence of oral warts increased after ART was initiated, and was four-fold higher if ART was initiated after an AIDS diagnosis.;MANUSCRIPT II: Virologic Failure following a Delayed Initiation of Antiretroviral Therapy is Associated with Increased HIV Replication.;BACKGROUND: Suppression of HIV-1 RNA below detectable limits is associated with decreased mortality. HIV suppression is positively correlated with adherence to antiretroviral therapy (ART) and clinic attendance. Early initiation of ART is associated with decreased mortality, but it is unclear if this is due to differences in ART adherence, clinic attendance, and HIV-1 viral suppression.;METHODS: 816 HIV-infected treatment-naive Haitian participants with CD4 counts between 200-350 cells/mm3 were randomized to early (within 2 weeks; N=408) versus delayed ART initiation (CD4 count ≤200 cells/mm3 or development of an AIDS-defining condition; N=408) between 8/1/2005 and 7/31/2008. In the early arm, 335 participants had viral load data available at 2 years. In the delayed arm, 355 participants eventually started therapy and 280 had viral load data available at 2 years. Participants were seen in follow-up at 1, 2, 3, 6, 12, 18 and 24 months. ART adherence was assessed using 3-day recall. To address the zero-inflated, skewed, and clustered HIV-1 RNA data a two-part hierarchical model was used. All analyses were performed using Stata 13 software (StataCorps, TX).;RESULTS: At ART initiation, subjects in the delayed arm (N=355) had more advanced HIV disease and lower CD4 T cell counts. At 2 years the number of participants with detectable HIV-1 RNA was similar in the early and delayed groups. Among participants with detectable HIV-1 RNA, higher HIV-1 viremia was correlated with poor clinic attendance, which in turn was predicted by randomization to the delayed group.;CONCLUSIONS: Delaying ART initiation until CD4 count ?200 cells/mm3 or development of an AIDS defining condition resulted in significant pre-ART attrition and interim progression of HIV disease. Delayed ART initiation was not associated with increased risk of having a detectable HIV-1 RNA level at 2 years. Among participants with a detectable HIV-1 RNA, delayed ART initiation is associated with poor clinic attendance and higher HIV-1 viremia.