A conceptual framework to assess the effectiveness of HIV prevention

Aim: The relative effectiveness of different methods of prevention of HIV transmission is a subject of debate that is renewed with the integration of each new method. The relative weight of values and evidence in decision-making is not always clearly defined. Debate is often confused, as the proponents of different approaches address the issue at different levels of implementation. This paper defines and delineates the successive levels of analysis of effectiveness, and proposes a conceptual framework to clarify debate. Method / Issue: Initially inspired from work on contraceptive effectiveness, a first version of the conceptual framework was published in 1993 with definition of the Condom Effectiveness Matrix (Spencer, 1993). The framework has since integrated and further developed thinking around distinctions made between efficacy and effectiveness and has been applied to HIV prevention in general. Three levels are defined: theoretical effectiveness (ThE), use-effectiveness (UseE) and population use-effectiveness (PopUseE). For example, abstinence and faithfulness, as proposed in the ABC strategy, have relatively high theoretical effectiveness but relatively low effectiveness at subsequent levels of implementation. The reverse is true of circumcision. Each level is associated with specific forms of scientific enquiry and associated research questions: basic and clinical sciences with ThE; clinical and social sciences with UseE; epidemiology and social, economic and political sciences with PopUseE. Similarly, the focus of investigation moves from biological organisms, to the individual at the physiological and then psychological, social and ecological level, and finally takes as perspective populations and societies as a whole. The framework may be applied to analyse issues on any approach. Hence, regarding consideration of HIV treatment as a means of prevention, examples of issues at each level would be: ThE: achieving adequate viral suppression and non-transmission to partners; UseE: facility and degree of adherence to treatment and medical follow-up; PopUseE: perceived validity of strategy, feasibility of achieving adequate population coverage. Discussion: Use of the framework clarifies the questions that need to be addressed at all levels in order to improve effectiveness. Furthermore, the interconnectedness and complementary nature of research from the different scientific disciplines and the relative contribution of each become apparent. The proposed framework could bring greater rationality to the prevention effectiveness debate and facilitate communication between stakeholders.

Serological Evidence of HTLV-I and HTLV-II Coinfections in HIV-1 Positive Patients in Belém, State of Pará, Brazil

The occurrence of HTLV-I/II and HIV-1 coinfections have been shown to be frequent, probably in consequence of their similar modes of transmission. This paper presents the prevalence of coinfection of HTLV among HIV-1 infected and AIDS patients in Belém, State of Pará, Brazil. A group of 149 patients attending the AIDS Reference Unit of the State Department of Health was tested for the presence of antibodies to HTLV-I/II using an enzyme immunoassay and the positive reactions were confirmed with a Western blot that discriminates between HTLV-I and HTLV-II infections. Four patients (2.7%) were positive to HTLV-I, seven (4.7%) to HTLV-II and one (0.7%) showed an indeterminate pattern of reaction. The present results show for the first time in Belém not only the occurrence of HTLV-II/HIV-1 coinfections but also a higher prevalence of HTLV-II in relation to HTLV-I. Furthermore, it also enlarges the geographical limits of the endemic area for HTLV-II in the Amazon region of Brazil.

Quantitation of HIV-1 RNA Viral Load Using NASBA Methodology and Comparison with other Surrogate Markers for Disease Progression

In this study, HIV-1 viral load quantitation determined by Nucleic Acid Sequence Based Amplification (NASBA) was compared with other surrogate disease progression markers (antigen p24, CD4/CD8 cell counts and b-2 microglobulin) in 540 patients followed up at São Paulo, SP, Brazil. HIV-1 RNA detection was statistically associated with the presence of antigen p24, but the viral RNA was also detected in 68% of the antigen p24 negative samples, confirming that NASBA is much more sensitive than the determination of antigen p24. Regarding other surrogate markers, no statistically significant association with the detection of viral RNA was found. The reproducibility of this viral load assay was assessed by 14 runs of the same sample, using different reagents batches. Viral load values in this sample ranged from 5.83 to 6.27 log (CV = 36 %), less than the range (0.5 log) established to the determination of significant viral load changes.

HIV type 1 drug resistance among naive patients from Venezuela.

In this study, we characterize proviral DNA of 20 HIV-1 asymptomatic antiretroviral-naive patients from Venezuela in env, gag, and pol genes regions. Results from both env/gag HMA subtyping and phylogenetic analysis of pol partial sequences led to the description of clade B in all cases. Nevertheless, the high prevalence of polymorphisms was particularly evident among the protease sequences. A 10% prevalence of major resistance mutations to RTIs was found. Our data also suggested that the protease polymorphisms I62T and V77T could be considered as molecular markers of the subtype B local epidemic. In addition, we show how proviral DNA can be used as a reliable tool to follow trends of resistance mutation transmission.

Parasite Genotypically Related to a Monoxenous Trypanosomatid of Dog's Flea Causing Opportunistic Infection in an HIV Positive Patient

An HIV positive patient presenting a clinical picture of visceral leishmaniasis co-infection was submitted to a bone marrow aspiration after admission to hospital. Amastigotes forms were seen in the bone marrow aspirate and the parasite grew in culture as promastigotes. Molecular analyses showed that the flagellates isolated did not belong to the genera Leishmania, Trypanosoma or Sauroleishmania. It was not possible to establish infection in laboratory animals. In vitro culture of mouse peritoneal macrophages revealed the invasion of the host cells by the flagellates and their killing 48 hr after infection. Opportunistic infection with an insect trypanosomatid was suspected. Further hybridization analyses against a pannel of different monoxenous and heteroxenous trypanosomatids showed kDNA cross-homology with Leptomonas pulexsimulantis a trypanosomatid found in the dog's flea

Rates and determinants of virologic and immunological response to HAART resumption after treatment interruption in HIV-1 clinical practice.

OBJECTIVE: To describe CD4 and HIV RNA changes during treatment resumption (TR) after treatment interruption (TI) compared with response to first highly active antiretroviral therapy (HAART) and to investigate predictors. METHODS: Using Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) data, we identified subjects who interrupted first HAART, not initiated during primary infection. We estimated rate of CD4 change during TR and time from TR to HIV RNA<500 copies per milliliter and subsequent rebound and factors associated with these outcomes. RESULTS: Of 281 persons treated for median 18.4 months before interrupting, 259 resumed HAART. CD4 increases in the first 3 months on HAART were similar pre-TI and post-TI but after 3 months were significantly higher during pre-TI HAART, with median +106 and +172 cells per microliter at 3 and 18 months, respectively, during initial HAART compared with +99 and +142 cells per microliter during post-TI HAART, respectively. Subjects with lower CD4 counts at TI, aged older than 40 years, and those resuming the same HAART as their pre-TI regimen had lower CD4 increases during the first 3 months of TR. The majority (86%) of individuals reinitiating therapy achieved HIV RNA<500 copies per milliliter. CONCLUSIONS: Immune reconstitution after TI is generally poorer than after first HAART, particularly for patients aged older than 40 years at TI and those with poorer immunological responses to pre-TI HAART. Reinitiation of the same HAART regimen as pre-TI also seems to have unfavorable outcomes.

Population pharmacokinetic modelling and evaluation of different dosage regimens for darunavir and ritonavir in HIV-infected individuals.

OBJECTIVES: Darunavir is a protease inhibitor that is administered with low-dose ritonavir to enhance its bioavailability. It is prescribed at standard dosage regimens of 600/100 mg twice daily in treatment-experienced patients and 800/100 mg once daily in naive patients. A population pharmacokinetic approach was used to characterize the pharmacokinetics of both drugs and their interaction in a cohort of unselected patients and to compare darunavir exposure expected under alternative dosage regimens. METHODS: The study population included 105 HIV-infected individuals who provided darunavir and ritonavir plasma concentrations. Firstly, a population pharmacokinetic analysis for darunavir and ritonavir was conducted, with inclusion of patients' demographic, clinical and genetic characteristics as potential covariates (NONMEM(®)). Then, the interaction between darunavir and ritonavir was studied while incorporating levels of both drugs into different inhibitory models. Finally, model-based simulations were performed to compare trough concentrations (Cmin) between the recommended dosage regimen and alternative combinations of darunavir and ritonavir. RESULTS: A one-compartment model with first-order absorption adequately characterized darunavir and ritonavir pharmacokinetics. The between-subject variability in both compounds was important [coefficient of variation (CV%) 34% and 47% for darunavir and ritonavir clearance, respectively]. Lopinavir and ritonavir exposure (AUC) affected darunavir clearance, while body weight and darunavir AUC influenced ritonavir elimination. None of the tested genetic variants showed any influence on darunavir or ritonavir pharmacokinetics. The simulations predicted darunavir Cmin much higher than the IC50 thresholds for wild-type and protease inhibitor-resistant HIV-1 strains (55 and 550 ng/mL, respectively) under standard dosing in >98% of experienced and naive patients. Alternative regimens of darunavir/ritonavir 1200/100 or 1200/200 mg once daily also had predicted adequate Cmin (>550 ng/mL) in 84% and 93% of patients, respectively. Reduction of darunavir/ritonavir dosage to 600/50 mg twice daily led to a 23% reduction in average Cmin, still with only 3.8% of patients having concentrations below the IC50 for resistant strains. CONCLUSIONS: The important variability in darunavir and ritonavir pharmacokinetics is poorly explained by clinical covariates and genetic influences. In experienced patients, treatment simplification strategies guided by drug level measurements and adherence monitoring could be proposed.

Prolonged antiretroviral therapy initiated at seroconversion is associated with a polyfunctional HIV-1-specific T-cell profile comparable to that of long-term non-progressors (LTNPs)

Background: Early initiation of antiretroviral therapy (ART) may dramatically curtail cumulative immunological damage allowing maximal levels of immune preservation/reconstitution and induce an immunovirological status similar to that of HIV-1 LTNPs with low viral reservoirs and polyfunctional HIV-1 specific T cell responses.Methods: We performed a cross-sectional study of an HIV-1 seroconverter cohort on long-term ART (LTTS) and compared it to one of LTNPs. Inclusion criteria for 20 LTTS were: (a) ?4 years ART; (b) long-term aviremia and (c) absence of treatment failure and for 15 LTNPs: (a) ?7 years of documented HIV-1 infection; (b) <1000 HIV-1 RNA copies/mL and ?500 CD4+ T-cells/mm3 in >90% of measurements; (d) absence of AIDS-defining conditions; (e) ART-naı¨ve except for temporary ART for prevention of MTCT. In both cohorts, we analysed residual viral replication and reservoirs in peripheral blood, as measured by cellassociated HIV-1 RNA and DNA in PBMCs, respectively and used polychromatic flow cytometry to analyse HIV-1-specific CD4+ and CD8+ T-cell functional profile in terms of cytokine production using IFN-c, IL-2, TNF-a production.Results: Cell-associated DNA [47.7 (4.8-583.2) in LTTS and 19.7 (0.5-295.5) in LTNPS, p=0.10], and RNA [3.9 (0-36) and 5.8 (0-10.3), respectively] were shown to be similarly low in both cohorts. We identified 103 CD8 T cell epitope-specific responses, all subjects responding to ?1 epitope. Mean responding number of responding epitopes per patient was 2 and 4 in LTTS and LTNPS, respectively. Mean% of cytokine-secreting CD8 T cells was 0.37% and 0.50% (p=0.06), of these 43% and 39% (p=0.12) were secreting simultaneously IFN-c, IL-2 and TNF-a. Respective values for CD4 T cells were 0.28% and 0.33% (p=0.28) of which 33% and 30% (0.32) were secreting these 3 cytokines simultaneously.Conclusions: Long-term aviremia after very early ART initiation is associated with low levels of reservoirs saturation ad residual replication. Although less broad CD8 T cell responses were found in LTTS, HIV-1 specific CD4 and CD8 T cell responses showed similar magnitude and functional profile in the 2 cohorts. Our results indicate that prolonged ART initiated at the time of HIV-1 seroconversion is associated with immuno-virological features which resemble those of LTNPs. (BHIVA Research Award Winner 2008: Anna Garcia-Diaz.)

A comparison of initial antiretroviral therapy in the Swiss HIV Cohort Study and the recommendations of the International AIDS Society-USA.

BACKGROUND: In order to facilitate and improve the use of antiretroviral therapy (ART), international recommendations are released and updated regularly. We aimed to study if adherence to the recommendations is associated with better treatment outcomes in the Swiss HIV Cohort Study (SHCS). METHODS: Initial ART regimens prescribed to participants between 1998 and 2007 were classified according to IAS-USA recommendations. Baseline characteristics of patients who received regimens in violation with these recommendations (violation ART) were compared to other patients. Multivariable logistic and linear regression analyses were performed to identify associations between violation ART and (i) virological suppression and (ii) CD4 cell count increase, after one year. RESULTS: Between 1998 and 2007, 4189 SHCS participants started 241 different ART regimens. A violation ART was started in 5% of patients. Female patients (adjusted odds ratio aOR 1.83, 95%CI 1.28-2.62), those with a high education level (aOR 1.49, 95%CI 1.07-2.06) or a high CD4 count (aOR 1.53, 95%CI 1.02-2.30) were more likely to receive violation ART. The proportion of patients with an undetectable viral load (<400 copies/mL) after one year was significantly lower with violation ART than with recommended regimens (aOR 0.54, 95% CI 0.37-0.80) whereas CD4 count increase after one year of treatment was similar in both groups. CONCLUSIONS: Although more than 240 different initial regimens were prescribed, violations of the IAS-USA recommendations were uncommon. Patients receiving these regimens were less likely to have an undetectable viral load after one year, which strengthens the validity of these recommendations.

LILRB2 interaction with HLA class I correlates with control of HIV-1 infection.

Natural progression of HIV-1 infection depends on genetic variation in the human major histocompatibility complex (MHC) class I locus, and the CD8+ T cell response is thought to be a primary mechanism of this effect. However, polymorphism within the MHC may also alter innate immune activity against human immunodeficiency virus type 1 (HIV-1) by changing interactions of human leukocyte antigen (HLA) class I molecules with leukocyte immunoglobulin-like receptors (LILR), a group of immunoregulatory receptors mainly expressed on myelomonocytic cells including dendritic cells (DCs). We used previously characterized HLA allotype-specific binding capacities of LILRB1 and LILRB2 as well as data from a large cohort of HIV-1-infected individuals (N = 5126) to test whether LILR-HLA class I interactions influence viral load in HIV-1 infection. Our analyses in persons of European descent, the largest ethnic group examined, show that the effect of HLA-B alleles on HIV-1 control correlates with the binding strength between corresponding HLA-B allotypes and LILRB2 (p = 10(-2)). Moreover, overall binding strength of LILRB2 to classical HLA class I allotypes, defined by the HLA-A/B/C genotypes in each patient, positively associates with viral replication in the absence of therapy in patients of both European (p = 10(-11)-10(-9)) and African (p = 10(-5)-10(-3)) descent. This effect appears to be driven by variations in LILRB2 binding affinities to HLA-B and is independent of individual class I allelic effects that are not related to the LILRB2 function. Correspondingly, in vitro experiments suggest that strong LILRB2-HLA binding negatively affects antigen-presenting properties of DCs. Thus, we propose an impact of LILRB2 on HIV-1 disease outcomes through altered regulation of DCs by LILRB2-HLA engagement.

Tenofovir use is associated with a reduction in calculated glomerular filtration rates in the Swiss HIV Cohort Study.

BACKGROUND: A growing number of case reports have described tenofovir (TDF)-related proximal renal tubulopathy and impaired calculated glomerular filtration rates (cGFR). We assessed TDF-associated changes in cGFR in a large observational HIV cohort. METHODS: We compared treatment-naive patients or patients with treatment interruptions > or = 12 months starting either a TDF-based combination antiretroviral therapy (cART) (n = 363) or a TDF-sparing regime (n = 715). The predefined primary endpoint was the time to a 10 ml/min reduction in cGFR, based on the Cockcroft-Gault equation, confirmed by a follow-up measurement at least 1 month later. In sensitivity analyses, secondary endpoints including calculations based on the modified diet in renal disease (MDRD) formula were considered. Endpoints were modelled using pre-specified covariates in a multiple Cox proportional hazards model. RESULTS: Two-year event-free probabilities were 0.65 (95% confidence interval [CI] 0.58-0.72) and 0.80 (95% CI 0.76-0.83) for patients starting TDF-containing or TDF-sparing cART, respectively. In the multiple Cox model, diabetes mellitus (hazard ratio [HR] = 2.34 [95% CI 1.24-4.42]), higher baseline cGFR (HR = 1.03 [95% CI 1.02-1.04] by 10 ml/min), TDF use (HR = 1.84 [95% CI 1.35-2.51]) and boosted protease inhibitor use (HR = 1.71 [95% CI 1.30-2.24]) significantly increased the risk for reaching the primary endpoint. Sensitivity analyses showed high consistency. CONCLUSION: There is consistent evidence for a significant reduction in cGFR associated with TDF use in HIV-infected patients. Our findings call for a strict monitoring of renal function in long-term TDF users with tests that distinguish between glomerular dysfunction and proximal renal tubulopathy, a known adverse effect of TDF.

Effect of antiretroviral therapy on apoptosis markers and morphology in peripheral lymph nodes of HIV-infected individuals.

BACKGROUND: CD4+ T cell depletion and destruction and the involution of the lymphoid tissue are hallmarks of HIV infection. Although the underlying mechanisms are still unclear, apoptosis appears to play a central role. The objective of this study was to investigate the effect of antiretroviral therapy on the lymph node tissue, particularly with respect to morphology and apoptosis. PATIENTS AND METHODS: Between 1997 and 1999, two inguinal lymph nodes were excised from 31 previously untreated individuals who were in an early stage of HIV infection, the first one prior to treatment and the second after 16 to 20 months of treatment. Paraffin sections were investigated for lymph node architecture, distribution of cellular and viral markers, apoptosis, and expression of apoptotic key molecules which indirectly reflect apoptotic processes. RESULTS: After 16-20 months of antiretroviral therapy, a significant decrease in highly activated HIV-driven immune response was observed in the lymph node tissue as a marked reduction in follicular hyperplasia, a normalization of the follicular dendritic cell network, a significant increase in the number of CD4+ T cells, and a significant decrease in the number of CD8+ T cells. The expression of several proapoptotic (Fas, TRAIL, and active caspase 3) and antiapoptotic (Bcl-2 and IL-7Ralpha) molecules that were reconstituted in the tissues during therapy resembled their expression in lymph nodes of HIV-negative individuals. Limitations of the study are (a) the lack of untreated patients in the late stages, (b) for ethical reasons, the lack of a control group with untreated patients, and (c) for methodological reasons, the restriction of sequential measurements of apotpotic markers to one-third of the patients. CONCLUSION: Antiretroviral therapy initiated in the early stages in HIV infection may halt the irreversible destruction of the lymph node tissue and may partially normalize apoptotic processes.

Predictive value of the acid fast smear for detection of Mycobacterium tuberculosis in respiratory specimens in a Reference Center of HIV/Aids in Rio de Janeiro, Brazil

In order to evaluate the predictive value of acid fast bacilii (AFB) smear for the diagnosis of Mycobacterium tuberculosis in respiratory specimens in a setting with a high prevalence of Aids and an unknown prevalence of nontuberculous mycobacteria (NTM), we retrospectively examined specimens cultured for mycobacteria between 1 September 1993 and 30 September 1994 and medical records of patients with positive culture in a General Hospital, Aids reference in Rio de Janeiro, Brazil. Seventy three per cent (1517/2077) of samples were respiratory specimens and mycobacteria were recovered from 20.6% (313/1517) of these. M. tuberculosis was identified in 94.2% (295/313) and NTM in 5.8% (18/313). The yield of positive AFB smear and of positive culture was 6.1% (93/1517) and 20.6% (313/1517), respectively. The positive predictive value (PPV) of AFB for M. tuberculosis was 98.4% in expectorated sputum and 96.4% in bronchoalveolar lavage. Forty four percent (130/295) of specimens with positive culture for M. tuberculosis and 66.7% (12/18) for NTM were from patients HIV positive. The conclusion was that in our study population, the PPV of AFB for M. tuberculosis in respiratory specimens was high and the prevalence of NTM was low despite the high prevalence of HIV positive.