CAPRISA 004 Tenofovir Microbicide Trial: No Impact of Tenofovir Gel on the HIV Transmission Bottleneck

Valley‐Omar, Ziyaad; Sibeko, Sengeziwe; Anderson, Jeffrey A.; Goodier, Sarah; Werner, Lise.; Arney, Leslie; Naranbhai, Vivek; Treurnicht, Florette K.; Abrahams, Melissa-Rose; Bandawe, Gama; Swanstrom, Ronald; Karim, Quarraisha Abdool; Williamson, Carolyn

doi:10.1093/infdis/jis305

Cited by 17 publications

(18 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In order to unravel whether the difference in VL in this study is a direct effect of PrEP, or due to the selection of two distinct cohorts after tenofovir gel exposure, further studies are underway. We have already established that the diversity, fitness and resistance pattern of the transmitted virus, as well as T cell responses 16–19 were not adversely affected by 1% tenofovir gel exposure, and are currently investigating whether a delay in the antibody response of women who used the tenofovir gel could have been a contributing mechanism to explain the difference in VLs.…”

Section: Discussionmentioning

confidence: 99%

“…In the CAPRISA 004 1% tenofovir gel microbicide trial 5 , women who acquired HIV in the tenofovir and placebo arms were offered enrolment into the CAPRISA 002 Acute Infection cohort study 15 . Research on these women from acute HIV infection has already established that the diversity of the transmitting virus was similar between seroconvertors from the two arms 16 and tenofovir gel did not appear to select for viruses with enhanced fitness 17 . Interestingly, T cell responses were relatively preserved during early infection amongst women who were randomized to receive tenofovir gel but who seroconverted 18 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

HIV Disease Progression in Seroconvertors from the CAPRISA 004 Tenofovir Gel Pre-exposure Prophylaxis Trial

Garrett

Werner

Naicker

et al. 2015

JAIDS Journal of Acquired Immune Deficiency Syndromes

Self Cite

View full text Add to dashboard Cite

Background While antiretroviral pre-exposure prophylaxis (PrEP) prevents HIV acquisition, it is not known if it alters HIV disease progression. This study assesses whether tenofovir gel impacted on disease progression among CAPRISA 004 microbicide trial seroconvertors. Methods Eighty-three seroconvertors from the tenofovir and placebo gel arms of the CAPRISA 004 trial were monitored prospectively for a minimum two years by CD4 count and viral load (VL). Linear mixed models were fitted to HIV VL, and log rank test was used to compare time to reach CD4<350. Results Median 2-week post-infection VL was 4.74 and 4.45 log copies/ml in women assigned to tenofovir gel (n=32) and placebo gel (n=51) (p=0.189). Corresponding 12-month post-infection VLs were 4.24 and 3.70 log copies/ml (p=0.016). After adjusting for clinical and behavioral characteristics and protective HLA alleles, mean VLs within the first two years were 4.51 and 4.02 log copies/ml in women from the tenofovir and placebo arms (p=0.013). Among women with vaginal tenofovir measurements, mean VL were 4.53 and 4.60 log copies/ml in those with detectable versus undetectable levels (p=0.840). Overall mean CD4 counts were 463 and 514 cells/μl in women assigned to tenofovir and placebo (p=0.290). Thirty-two (38.6%) women reached CD4<350 at median 9.4 months post-infection, 13 (40.6%) from the tenofovir and 19 (37.3%) from the placebo arms (p=0.786). Conclusions Tenofovir gel had no impact on post-infection CD4 counts or the rate of CD4 decline. While seroconvertors from the tenofovir arm experienced higher VLs, this did not result in a need for earlier antiretroviral therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HIV Disease Progression in Seroconvertors from the CAPRISA 004 Tenofovir Gel Pre-exposure Prophylaxis Trial

Garrett

Werner

Naicker

et al. 2015

JAIDS Journal of Acquired Immune Deficiency Syndromes

Self Cite

View full text Add to dashboard Cite

show abstract

“…The drugs and delivery systems used must protect in the context of these factors. Indeed, this effect may have contributed to the observation in Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 that immune activation was associated with HIV acquisition, even among women using TFV gel (33). Another clear and related advantage of TDF over TFV is the potential for providing protection against HSV-2 acquisition and outbreaks because TDF is ∼100-fold more potent against HSV-2 (13).…”

Section: Significancementioning

confidence: 99%

Intravaginal ring eluting tenofovir disoproxil fumarate completely protects macaques from multiple vaginal simian-HIV challenges

Smith

Rastogi

Teller

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

119

View full text Add to dashboard Cite

Significance Topical prevention of HIV is designed to pharmacologically interrupt sexual transmission at the genital mucosa. Attempts at preventing transmission in women using vaginal gels have yielded disappointing results in part because of poor rates of adherence. Controlled topical drug delivery using intravaginal ring technology should improve efficacy and adherence by providing sustained mucosal delivery of antiretrovirals. In this paper, we describe a reservoir intravaginal ring that delivers tenofovir disoproxil fumarate (TDF) for 1 month. The ring protected pigtailed macaques from weekly vaginal simian–human immunodeficiency virus challenges for 4 mo. The sterilizing performance of this drug delivery system supports the concept that an intravaginal ring delivering TDF could be an effective tool for prevention of HIV sexual transmission in women.

show abstract

“…We previously reported that TFV use did not alter the number of transmitted/founder variants identified in these women (53), nor did it select for transmitted drug resistance (54). However, higher VLs were observed in women who became infected in the TFV arm, raising concerns that TFV might have selected for the transmission of fitter variants (39), but our results provide no evidence to support this hypothesis, as viral infectivity was 2-fold lower in the TFV arm and the RCs did not differ between the trial arms.…”

Section: Figmentioning

confidence: 76%

“…Sequences were excluded if they contained Ͼ3 double peaks in the chromatogram or deletions Ͼ30 nucleotides long. To include plasma-derived Env V3V5 sequences that were already available for comparison (53), all other sequences were truncated to the V3V5 region. Sequences were aligned in BioEdit to a subtype C acute (Ͻ3-month) consensus sequence, which was generated from available CAPRISA 002 plasma Env sequences (n ϭ 592).…”

Section: Methodsmentioning

confidence: 99%

Replication Capacity of Viruses from Acute Infection Drives HIV-1 Disease Progression

Selhorst

Combrinck

Ndabambi

et al. 2017

J Virol

Self Cite

View full text Add to dashboard Cite

The viral genotype has been shown to play an important role in HIV pathogenesis following transmission. However, the viral phenotypic properties that contribute to disease progression remain unclear. Most studies have been limited to the evaluation of Gag function in the context of a recombinant virus backbone. Using this approach, important biological information may be lost, making the evaluation of viruses obtained during acute infection, representing the transmitted virus, a more biologically relevant model. Here, we evaluate the roles of viral infectivity and the replication capacity of viruses from acute infection in disease progression in women who seroconverted in the CAPRISA 004 tenofovir microbicide trial. We show that viral replication capacity, but not viral infectivity, correlates with the set point viral load (Spearman r ϭ 0.346; P ϭ 0.045) and that replication capacity (hazard ratio [HR] ϭ 4.52; P ϭ 0.01) can predict CD4 decline independently of the viral load (HR ϭ 2.9; P ϭ 0.004) or protective HLA alleles (HR ϭ 0.61; P ϭ 0.36). We further demonstrate that Gag-Pro is not the main driver of this association, suggesting that additional properties of the transmitted virus play a role in disease progression. Finally, we find that although viruses from the tenofovir arm were 2-fold less infectious, they replicated at rates similar to those of viruses from the placebo arm. This indicates that the use of tenofovir gel did not select for viral variants with higher replication capacity. Overall, this study supports a strong influence of the replication capacity in acute infection on disease progression, potentially driven by interaction of multiple genes rather than a dominant role of the major structural gene gag.IMPORTANCE HIV disease progression is known to differ between individuals, and defining which fraction of this variation can be attributed to the virus is important both clinically and epidemiologically. In this study, we show that the replication capacity of viruses isolated during acute infection predicts subsequent disease progression and drives CD4 decline independently of the viral load. This provides further support for the hypothesis that the replication capacity of the transmitted virus determines the initial damage to the immune system, setting the pace for later disease progression. However, we did not find evidence that the major structural gene gag drives this correlation, highlighting the importance of other genes in determining disease progression.

show abstract

CAPRISA 004 Tenofovir Microbicide Trial: No Impact of Tenofovir Gel on the HIV Transmission Bottleneck

Cited by 17 publications

References 15 publications

HIV Disease Progression in Seroconvertors from the CAPRISA 004 Tenofovir Gel Pre-exposure Prophylaxis Trial

HIV Disease Progression in Seroconvertors from the CAPRISA 004 Tenofovir Gel Pre-exposure Prophylaxis Trial

Intravaginal ring eluting tenofovir disoproxil fumarate completely protects macaques from multiple vaginal simian-HIV challenges

Replication Capacity of Viruses from Acute Infection Drives HIV-1 Disease Progression

Contact Info

Product

Resources

About