The impact of sexually transmitted infections (STI) and genital tract inflammation on HIV-1 acquisition and rate of disease progression in subtype C infected women.
Mlisana, Koleka Patience.
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Introduction: Women carry more than half the burden of HIV disease globally and this burden is even higher in sub-Saharan Africa (SSA). Young women, in particular, are at disproportionate risk of HIV infection in South Africa. Understanding risk behaviours and factors associated with ability to negotiate safe sex and condom use is one of the key elements in curbing the spread of HIV. Sexually transmitted infections (STI) and bacterial vaginosis (BV), which cause female genital tract inflammation, have been identified as key drivers of the HIV epidemic. This inflammation, which is also present in the absence of symptoms, is associated with increased susceptibility to HIV infection. Although syndromic management of symptomatic STIs or BV at the first encounter with a health care provider is an important public health measure, its effectiveness is minimised because a substantial proportion of individuals have either asymptomatic infections or fail to recognise signs and symptoms of STI and are therefore excluded. Most new HIV infections in SSA occur among young people and particularly among young girls. Prompt diagnosis of acute HIV infection (AHI) is critical and benefits the individual as well as providing opportunities for public health intervention. In South Africa, the majority of HIV infections are due to infection with HIV-1 subtype C for which there is limited data compared to subtype-B HIV-1 infections. The overall aim of this study was to assess the impact of BV, STIs, and associated genital tract inflammation on acquisition of HIV-1 subtype C infections; and evaluate the rate of subsequent disease progression in women. The objectives were: i. to investigate STIs and genital tract inflammation as risk factors for HIV infection in high risk women and adequacy of syndromic management; ii. to evaluate the challenges associated with diagnosing recently acquired (acute) HIV infection in a subtype C prevalent population; iii. and to evaluate the relationship between clinical disease progression and genital and or systemic inflammation in high-risk women who became infected with HIV. We assessed the adequacy of syndromic diagnosis of STIs, compared with laboratory diagnosis of STIs, and evaluated the association between STI diagnosis and the risk of HIV acquisition in a cohort of high-risk women. Genital cytokine profiles and the degree of inflammation associated with common STIs and bacterial vaginosis were assessed. The most common signs and symptoms of acute HIV infection (AHI) were described and a clinical algorithm to identify acute HIV cases was developed. We investigated rates of HIV disease progression of subtype C–infected South African women. Methods: The CAPRISA 002 study was a prospective cohort study established to examine the pathogenesis and natural history of HIV-1 subtype C infection and to describe the immunologic, virologic and clinical characteristics of acute and early infection in KwaZulu Natal, South Africa. A total of 775 high-risk women were screened for HIV infection, and 245 HIV-uninfected women were enrolled into the study. At each monthly visit for a total of 24 months behavioural and clinical data were collected. Cervico-vaginal lavage (CVL) samples were collected at enrolment and at each six month follow-up visits and were tested for STI pathogens (including Chlamydia trachomatis, Neisseria gonorrhoeae, herpes simplex virus type 2 (HSV-2) and Trichomonas vaginalis) and bacterial vaginosis. Forty-two cytokines were measured from the CVL and 13 from the plasma samples at enrolment. All women received monthly HIV-1 antibody and RNA testing and were assessed for AHI. Signs and symptoms at the visit with HIV-1 antibody or HIV-1 RNA positive test were compared to HIV negative visits. Logistic regression identified clinical predictors of AHI and a model-based score was assigned to each predictor to create a risk score for every woman. All women who seroconverted were followed up for more than five years and monitored for HIV disease progression. Rapid disease progression was defined as CD4+ T cell count decline to <350 cells/μl within two years post-infection. Serial clinical and laboratory assessments were compared using survival analysis and logistic regression models. CAPRISA had established several cohorts of HIV negative women to determine the feasibility of establishing cohorts and sites for HIV biomedical prevention trials. Women seroconverting in these studies were referred to the CAPRISA 002 study for longitudinal follow-up for HIV post seroconversion. Results: In this study, the HIV-1 prevalence at screening was 59.6% (95% CI: 55.9% to 62.8%). During a total of 390 person-years of follow-up, 28 new infections occurred, yielding a seroincidence rate of 7.2 (95% CI: 4.5 to 9.8) per 100 person-years. A total of 62 participants, including seroconvertors from other CAPRISA cohorts, were enrolled into the acute HIV infection Women from the HIV-1 negative cohort generally demonstrated a high level of knowledge on HIV/AIDS, and 60.3% reported use of condoms. Reported condom use at last sexual encounter varied slightly by partner type (57.0% with steady versus 64.4% with casual partners; p = 0.36), whilst self-perceived ability to choose to use a condom was significantly lower with steady partners compared to casual partners (20.8% versus 53.9%; p=0.01). An important finding was that vaginal discharge was a poor predictor of laboratory-diagnosed STIs, as only 12.3% of women (25/204) who had a laboratory-confirmed discharge causing pathogen had clinical evidence of a discharge (yielding a sensitivity of 12.3% and a specificity of 93.8%). CVL cytokine concentrations did not differ between women with asymptomatic or symptomatic STIs; and were elevated in women with either asymptomatic or symptomatic STIs compared to women with no STIs or BV. Women with chlamydia or gonorrhoea had the highest genital cytokine concentrations, with 17/42 and 14/42 of the cytokines measured in CVL being up-regulated compared with women with no infections, respectively. While BV was associated with elevated pro-inflammatory cytokine concentrations in CVL, women with BV had lower levels of chemokines and haematopoietic cytokines than women with no infections or BV. HSV-2 reactivation was inflammatory, but yielded a comparatively lower level of inflammation than Chlamydia or gonnorhoea. Trichomoniasis, despite being relatively common in this cohort, did not cause significant changes in genital tract cytokine concentrations compared to women with no infections or BV. Genital infections did not influence plasma cytokine concentrations, suggesting that the compartments were not linked with respect to cytokine responses. Although laboratorydiagnosed STIs were associated with increased risk of HIV infection [hazard ratio, 3.3 (95% confidence interval, 1.5 – 7.2)], clinical symptoms were not. Of the women who became infected, factors predictive of AHI included age, 25 years (OR = 3.2; 1.4 – 7.1), rash (OR = 6.1; 2.4 –15.4), sore throat (OR = 2.7; 1.0 – 7.6), weight loss (OR = 4.4; 1.5 – 13.4), genital ulcers (OR = 8.0; 1.6 – 39.5) and vaginal discharge (OR = 5.4; 1.6 – 18.4). A risk score of 2 correctly predicted AHI in 50.0% of cases. The number of signs and symptoms correlated with higher HIV-1 RNA at diagnosis (r = 0.63; p = 0.001). The 62 acutely infected women were identified at a median of 42 days post-infection (IQR = 34 – 59). Mean CD4 count dropped by 39.6% at 3 months and 46.7% at 6 months post-infection in women with pre-infection measurements. CD4 decline to <350 cells/μL occurred in 31%, 44%, and 55% of women at 1, 2, and 3 years post-infection, respectively, and to <500 cells/μL in 69%, 79%, and 81% at equivalent time-points. Predictors of rapid progression were CD4 count at 3 months post-infection (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.31–3.28; P = .002), setpoint viral load (HR, 3.82; 95% CI, 1.51–9.67; P = .005), and hepatitis B coinfection (HR, 4.54; 95% CI, 1.31–15.69; P = .017). Conversely, presence of any of HLAB*1302, B*27, B*57, B*5801, or B*8101 alleles predicted non–rapid progression (HR, 0.19; 95% CI, .05–.74; P = .016). Discussion/Conclusion: This study showed that syndromic STI diagnosis, which is dependent on clinical signs of vaginal discharge, was poorly predictive of laboratory-diagnosed STIs or BV and missed a significant proportion of women with asymptomatic infections. However, the level of genital inflammation, as measured by cytokine concentrations in CVL, was similar in women with symptomatic and asymptomatic infections and therefore place women at increased risk for HIV infection. While laboratory-diagnosed STIs and the presence of inflammatory cytokines in the genital tract were associated with increased susceptibility to HIV acquisition, vaginal discharge was not. Chlamydial infection was associated with the highest genital cytokine concentrations, followed by gonorrhoea, HSV-2, trichomoniasis, and BV. In regions where HIV is prevalent and STIs are managed syndromically, targeted screening of populations at risk for STIs is critical and urgently needed. Recognition of signs and symptoms of AHI is important for early diagnosis of HIV infection. The proposed algorithm of risk-stratifying individuals for AHI provides a useful clinical tool especially in resource-limited settings where there are limited or no routinely available tests for AHI. However, validation of the algorithm on another cohort is needed to assess its utility further. Point-of-care HIV antigen or viral load testing is needed, to detect asymptomatic, antibody negative cases enabling early interventions and prevention of transmission. This cohort showed high rates of rapid disease progression, with nearly half of these subtype C–infected women progressing to a CD4+ T cell count of below 350 cells/μL within 2 years of infection. Implementing 2013 World Health Organization treatment guidelines (CD4+ T cell counts less than 500cells/μL) would require most individuals to start antiretroviral therapy within 1 year of HIV infection. The economic and health systems planning implicated by these findings need to be explored and addressed to guide policy makers as countries adopt the current WHO guidelines.