Objective

This study addressed two questions: (1) What fraction of individuals maintain a sustained high HIV-1 RNA load after the acute HIV-1C infection peak? and (2) How long is a high HIV-1 RNA load maintained after acute HIV-1C infection in this subpopulation?

Design/Methods

Plasma HIV-1 RNA dynamics were studied in 77 subjects with primary HIV-1C infection from African cohorts in Gaborone, Botswana, and Durban, South Africa. HIV-infected individuals who maintained mean viral load of ≥ 100,000 (5.0 log10) copies/ml after 100 days post-seroconversion (p/s) were termed Extended High Viremics. Individuals were followed longitudinally for a median (IQR) of 573 (226;986) days p/s.

Results

The proportion of Extended High Viremics was 34% (95% CI: 23%–44%) during the period 100 to 300 days p/s and 19% (95% CI: 9%–29%) over the period of 200 to 400 days p/s. The median (IQR) duration of HIV-1 RNA load ≥ 100,000 copies/ml among Extended High Viremics was 271 (188;340) days p/s. For the subset with average viral load ≥ 100,000 copies/ml during 200–400 days p/s, the median (IQR) duration was 318 (282;459) days. The Extended High Viremics had a significantly shorter time to CD4 decline to 350 cells/μl (median: 88 vs. 691 days p/s for those not designated as Extended High Viremics; p<0.0001, Gehan-Wilcoxon test).

Conclusions

A high proportion of Extended High Viremics – individuals maintaining high plasma HIV-1 RNA load after acute infection – has been identified during primary HIV-1 subtype C infection. These Extended High Viremics likely contribute disproportionately to HIV-1 incidence.

(See the editorial commentary by Tossonian and Conway, on pages 10–12.)

Background. The benefits of antiretroviral therapy during early human immunodeficiency virus type 1 (HIV-1) infection remain unproved.

Methods. A5217 study team randomized patients within 6 months of HIV-1 seroconversion to receive either 36 weeks of antiretrovirals (immediate treatment [IT]) or no treatment (deferred treatment [DT]). Patients were to start or restart antiretroviral therapy if they met predefined criteria. The primary end point was a composite of requiring treatment or retreatment and the log10 HIV-1 RNA level at week 72 (both groups) and 36 (DT group).

Results. At the June 2009 Data Safety Monitoring Board (DSMB) review, 130 of 150 targeted participants had enrolled. Efficacy analysis included 79 individuals randomized ≥72 weeks previously. For the primary end point, the IT group at week 72 had a better outcome than the DT group at week 72 (P = .005) and the DT group at week 36 (P = .002). The differences were primarily due to the higher rate of progression to needing treatment in the DT group (50%) versus the IT (10%) group. The DSMB recommended stopping the study because further follow-up was unlikely to change these findings.

Conclusions. Progression to meeting criteria for antiretroviral initiation in the DT group occurred more frequently than anticipated, limiting the ability to evaluate virologic set point. Antiretrovirals during early HIV-1 infection modestly delayed the need for subsequent treatment.

Clinical Trials Registration. NCT00090779.

Objective

Single voxel proton magnetic resonance spectroscopy (MRS) can be used to monitor changes in brain inflammation and neuronal integrity associated with HIV infection and its treatments. We used MRS to measure brain changes during the first weeks following HIV infection and in response to antiretroviral therapy (ART).

Methods

Brain metabolite levels of N-acetyl aspartate (NAA), choline (tCHO), creatine (CR), myoinositol (MI), and glutamate and glutamine (GLX) were measured in acute HIV subjects (n = 31) and compared to chronic HIV+individuals (n = 26) and HIV negative control subjects (n = 10) from Bangkok, Thailand. Metabolites were measured in frontal gray matter (FGM), frontal white matter (FWM), occipital gray matter (OGM), and basal ganglia (BG). Repeat measures were obtained in 17 acute subjects 1, 3 and 6 months following initiation of ART.

Results

After adjustment for age we identified elevated BG tCHO/CR in acute HIV cases at baseline (median 14 days after HIV infection) compared to control (p = 0.0014), as well as chronic subjects (p = 0.0023). A similar tCHO/CR elevation was noted in OGM; no other metabolite abnormalities were seen between acute and control subjects. Mixed longitudinal models revealed resolution of BG tCHO/CR elevation after ART (p = 0.022) with tCHO/CR similar to control subjects at 6 months.

Interpretation

We detected cellular inflammation in the absence of measurable neuronal injury within the first month of HIV infection, and normalization of this inflammation following acutely administered ART. Our findings suggest that early ART may be neuroprotective in HIV infection by mitigating processes leading to CNS injury.

Development of human immunodeficiency virus resistance mutations is a major cause of failure of antiretroviral treatment. We develop a recursive partitioning method to correlate high-dimensional viral sequences with repeatedly measured outcomes. The splitting criterion of this procedure is based on a class of U-type score statistics. The proposed method is flexible enough to apply to a broad range of problems involving longitudinal outcomes. Simulation studies are performed to explore the finite-sample properties of the proposed method, which is also illustrated through analysis of data collected in 3 phase II clinical trials testing the antiretroviral drug efavirenz.

For pathogens that must be treated with combinations of antibiotics and acquire resistance through genetic mutation, knowledge of the order in which drug-resistance mutations occur may be important for determining treatment policies. Diagnostic specimens collected from patients are often available; this makes it possible to determine the presence of individual drug-resistance conferring mutations and combinations of these mutations. In most cases, these specimens are only available from a patient at a single point in time; it is very rare to have access to multiple specimens from a single patient collected over time as resistance accumulates to multiple drugs. Statistical methods that use branching trees have been successfully applied to such cross-sectional data to make inference on the ordering of events that occurred prior to sampling. Here we propose a Bayesian approach to fitting branching tree models that has several advantages, including the ability to accommodate prior information regarding measurement error or cross-resistance and the natural way it permits the characterization of uncertainty. Our methods are applied to a data set for drug resistant tuberculosis in Peru; the goal of analysis is to determine the order with which patients develop resistance to the drugs commonly used for treating TB in this setting.

Objective

We determine whether (1) an audiocomputer-delivered tailored feedback intervention increases emergency department (ED) patient uptake of opt-in, nontargeted rapid HIV screening; and (2) uptake is greater among patients who report more HIV risk and among those whose self-perceived HIV risk increases from baseline after completion of an HIV risk assessment.

Methods

ED patients aged 18 to 64 years were randomly assigned to receive either an assessment about reported and self-perceived HIV risk or an identical assessment plus feedback about their risk for having or acquiring an HIV infection, tailored according to their reported risk. All participants were offered a fingerstick rapid HIV test. Two-sample tests of binomial proportions were used to compare screening uptake by study arm. Multivariable logistic regression was used to assess the relationship of reported HIV risk and an increase in self-perceived HIV risk with uptake of HIV screening.

Results

Of the 566 participants, the median age was 29 years, 62.2% were women, and 66.9% previously had been tested for HIV. Uptake of HIV screening was similar in the intervention and no intervention arms (54.1% versus 55.5% [Δ =–0.01%; 95% confidence interval {CI} –0.09% to 0.07%]). An increase in self-perceived HIV risk predicted greater uptake of HIV screening for women (odds ratio 2.15; 95% CI 1.08 to 4.28) but not men (odds ratio 1.61; 95% CI 0.60 to 4.30). Uptake of HIV screening was not related to reported HIV risk.

Conclusion

Uptake of rapid HIV screening in the ED was not improved by this feedback intervention. Other methods need to be investigated to improve uptake of HIV screening by ED patients.

Recently, the RV144 randomized, double-blind, efficacy trial in Thailand reported that a prime-boost human immunodeficiency virus (HIV) vaccine regimen conferred ∼30% protection against HIV acquisition. However, different analyses seemed to give conflicting results, and a heated debate ensued as scientists and the broader public struggled with their interpretation. The lack of accounting for statistical principles helped flame the debate, and we leverage these principles to provide a more scientific interpretation. We first address interpretation of frequentist results, including interpretation of P values, synthesis of results from multiple analyses (ie, intention-to-treat versus per-protocol/fully immunized), and accounting for external efficacy trials. Second, we address how Bayesian statistics, which provide clearly interpretable statements about probabilities that the vaccine efficacy takes certain values, provide more information for weighing the evidence about efficacy than do frequentist statistics alone. Third, we evaluate RV144 for completeness of end point ascertainment and integrity of blinding, necessary tasks for establishing robustly interpretable results.

Abstract

The purpose of this study is to evaluate whether the choice of a PI- or an efavirenz (EFV)-based HAART initial regimen impacts on the viral diversity after failure from a second, class-switch salvage regimen. Sequential HAART failures after a class switch were identified for which the genotypes showed evidence of signature mutations at each failure. Each second failure was required to be from a viral burden <400 RNA c/ml. Thirteen cases of sequential failure from an initial EFV-containing to a PI-containing regimen (EP), and 19 sequential failures from an initial PI-containing to an EFV-containing regimen (PE) were identified. The persistence of signature mutations from the first failure were evaluated at second failure and compared between the EP and PE groups. Phylogenetic trees were constructed for a subgroup of cases from existing genetic sequence information and branch length analysis was used to determine evidence of viral diversity between groups. For EP sequential therapy, 10 of 12 cases carried forward a key non-nucleoside reverse transcriptase inhibitor (NNRTI) mutation in the second failure compared to 5 of 13 cases for PE sequential therapy (p = 0.041). Phylogenetic analysis demonstrated that there was more viral diversity in the PE group as compared to the EP group, consistent with the interpretation that mutations at the second failure added to an ancestral virus closer to baseline rather than to the dominant virus at first failure. The development of HIV viral diversity after multiple HAART failures is determined by the sequence in which the regimens are ordered.

Objective

To determine the proportion of emergency department (ED) patients who have been tested for human immunodeficiency virus (HIV) infection and assess if patient history of HIV testing varies according to patient demographic characteristics.

Design

From July 2005–July 2006, a random sample of 18–55-year-old English-speaking patients being treated for sub-critical injury or illness at a northeastern US ED were interviewed on their history of HIV testing. Logistic regression models were created to compare patients by their history of being tested for HIV according to their demography. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated.

Results

Of 2107 patients surveyed who were not known to be HIV-infected, the median age was 32 years; 54% were male, 71% were white, and 45% were single/never married; 49% had private health-care insurance and 45% had never been tested for HIV. Of the 946 never previously tested for HIV, 56.1% did not consider themselves at risk for HIV. In multivariable logistic regression analyses, those less likely to have been HIV tested were male (OR: 1.32 [1.37–2.73]), white (OR: 1.93 [1.37–2.73]), married (OR: 1.53 [1.12–2.08]), and had private health-care insurance (OR: 2.10 [1.69–2.61]). There was a U-shaped relationship between age and history of being tested for HIV; younger and older patients were less likely to have been tested. History of HIV testing and years of formal education were not related.

Conclusion

Almost half of ED patients surveyed had never been tested for HIV. Certain demographic groups are being missed though HIV diagnostic testing and screening programmes in other settings. These groups could potentially be reached through universal screening.

The aim of this investigation was to assess emergency department (ED) patients’ perceptions and preferences about an opt-in, universal, rapid HIV screening program and identify patient groups who expressed stronger beliefs about components of the testing program. From July 2005 to July 2006, ED patients in the opt-in, universal, rapid HIV screening program were interviewed in person. Multivariable regression models were used to compare participants on their beliefs about the program components. Of the 561 participants, 62.0% had previously been tested for HIV. The majority of participants (58.8%) believed the rapid and standard/conventional HIV tests to be equally accurate, 27.7% believed the rapid test to be less or much less accurate, and 8.7% believed the rapid test to be more or much more accurate. Almost two-thirds (65.1%) favored having a rapid instead of a standard/conventional HIV test, 94.6% wanted the test results within one hour, and 61.3% would be likely or very likely to undergo testing in the ED if it prolonged their ED visit. Almost all (92.5%) believed that their medical care was “not at all” delayed because of being tested, 94.1% believed that testing did “not at all” divert attention from the reason for their ED visit, and 80.9% thought that testing in the ED was “not at all” stressful. In multivariable logistic regression models, males and those with more than 12 years of formal education showed greater concerns about the rapid HIV test’s accuracy. Hispanic/Latinos, participants with governmental insurance, and those previously HIV tested were more apt to be screened for HIV even if testing delayed their ED departure. Overall, participants were highly accepting of the components of this opt-in rapid HIV screening program. However, concerns regarding the accuracy of the rapid HIV test might limit test acceptance and should be addressed during pre-test information procedures.

Objectives

Prior research has demonstrated that emergency department (ED) patient acceptance of human immunodeficiency virus (HIV) screening is partially dependent on patients’ self-perceived risk of infection. The primary objective of this study was to determine the effectiveness of audio computer-assisted self-interview (ACASI)-based feedback. The intervention aimed to increase patient’s self-perceived risk of being HIV infected by providing immediate feedback on their risk behaviors.

Methods

This 1-year, randomized, controlled trial at a U.S. ED enrolled a random sample of 18- to 64-year-old subcritically ill or injured adult patients who were not known to be HIV infected. All participants completed an anonymous, ACASI-based questionnaire about their HIV risk behaviors related to injection drug use and sex, as well as their self-perceived risk for being HIV infected. Participants were randomly assigned to one of two study groups: an intervention group in which participants received immediate ACASI-based feedback in response to each of their reported risk behaviors or a no-intervention group without feedback. Participants were asked to indicate their level of HIV risk on a five-point scale before and after they answered the questions. Change in level of self-perceived HIV risk was calculated and compared by study group using Pearson’s chi-square test. An HIV risk behavior score that summarized reported HIV risk behavior was devised. Because HIV risk behaviors differ by sex, scores were calculated separately for each sex. Linear regression models that adjusted for study group and same subject covariance were employed to determine if higher HIV risk behavior scores were associated with an increase in self-perceived HIV risk.

Results

Of the 566 trial participants, the median age was 29 years (interquartile range [IQR] = 22–43 years), 62.2% were females, and 66.9% had been tested previously for HIV. After answering the reported HIV risk behavior questions, 12.6% of participants had an increase, 79.9% had no change, and 7.5% had a decrease in self-perceived HIV risk. Of the 46.6% of participants who initially indicated that they were not at risk for HIV, 11.4% had an increase in self-perceived HIV risk after answering the reported HIV risk behavior questions. Change in self-perceived HIV risk did not differ by study group (p = 0.77). There were no differences in reported HIV risk scores between the intervention and no-intervention groups for females (p = 0.78) or males (p = 0.86). In the linear regression models, a greater increase in self-perceived HIV risk was associated with higher reported HIV risk behavior scores for females (β = 0.59, 95% confidence interval [CI] = 0.15, 1.04) but not for males (β = 1.00, 95% CI = −0.13 to 2.14).

Conclusions

Some ED patients can be moved, although modestly, to recognize their risk for being HIV infected by asking about their HIV risk behaviors. However, ACASI-based feedback messages about HIV risk behaviors do not increase subjects’ self-perceived HIV risk. Female ED patients appear to increase their self-perceived HIV risk more than males when queried about their HIV risk behaviors.

Objective

Among a random sample of emergency department (ED) patients, determine the extent to which reported risk for HIV is related to ever having been tested for HIV.

Methods

A random sample of 18–64-year-old patients at an urban, academic, adult ED were surveyed about their history of ever having been tested for HIV and their reported HIV risk behaviors. A reported HIV risk score was calculated from the survey responses and divided into four levels, based upon quartiles of the risk scores. Pearson’s X2 testing was used to compare HIV testing history and level of reported HIV risk. Logistic regression models were created to investigate the association between level of reported HIV risk and the outcome of ever having been tested for HIV.

Results

Of the 557 participants, 62.1% were female. A larger proportion of females than males (71.4% versus 60.6%; p<0.01) reported they ever had been tested for HIV. Among the 211 males, 11.4% reported no HIV risk, and among the 346 females, 10.7% reported no HIV risk. The proportion of those who had been tested for HIV was greater among those reporting any risk, compared to those reporting no risk, for females (75.4% vs. 37.8%; p<0.001), but not for males (59.9% vs. 66.7%; p<0.52). However, certain high-risk behaviors, such as a history of injection-drug use, were associated with prior HIV testing for both genders. In the logistic regression analyses, there was no relationship between increasing level of reported HIV risk and a history of ever having been tested for HIV for males. For females, a history of ever having been tested was related to increasing level of reported risk, but not in a linear fashion.

Conclusions

The relationship between reported HIV risk and history of testing among these ED patients was complex and differed by gender. Among these patients, having greater risk did not necessarily mean a higher likelihood of having ever been tested for HIV.

As described elsewhere in this supplement, development of effective methods for prevention of human immunodeficiency virus (HIV) infection has proven to be more challenging than development of effective treatment for the disease. New strategies to control the HIV epidemic are urgently needed; this urgency creates interest in investigation of the possibility of using antiretroviral treatment in combination with other modalities to control the epidemic. This article summarizes current knowledge concerning prevention modalities in the context of the drivers of the HIV epidemic in specific communities, describes challenges in investigating test-and-treat strategies, and proposes research directions for addressing these challenges to investigate the impact of prevention strategies on mitigation of epidemics.

Background

National initiatives offering NNRTI-based combination antiretroviral therapy (cART) have expanded in sub-Saharan Africa (SSA). The Tshepo study is the first clinical trial evaluating the long-term efficacy and tolerability of EFV- vs. NVP-based cART among adults in Botswana.

Methods

Three year randomized study (n = 650) using a 3×2×2 factorial design comparing efficacy and tolerability among: A: ZDV/3TC vs. ZDV/ddI vs. d4T/3TC; B: EFV vs. NVP, and C: Com-DOT vs. standard adherence strategies. This manuscript focuses on comparison B.

Results

There was no significant difference by assigned NNRTI in time to virologic failure with resistance (log-rank p = 0.14), NVP vs. EFV risk ratio (RR) = 1.54 [0.86-2.70]. Rates of virologic failure with resistance were 9.6% NVP-treated [6.8-13.5] vs. 6.6% EFV-treated [4.2-10.0] at 3 years. Women receiving NVP-based cART trended towards higher virological failure rates when compared to EFV-treated women, Holm-corrected log-rank p = 0.072, NVP vs. EFV RR = 2.22 [0.94-5.00]. 139 patients had 176 treatment modifying toxicities, with shorter time to event in NVP-treated vs. EFV-treated, RR = 1.85 [1.20-2.86], log-rank p = 0.0002.

Conclusions

Tshepo-treated patients had excellent overall immunologic and virologic outcomes, and no significant differences were observed by randomized NNRTI comparison. NVP-treated women trended towards higher virologic failure with resistance compared to EFV-treated women. NVP-treated adults had higher treatment modifying toxicity rates when compared to those receiving EFV. NVP-based cART can continue to be offered to women in SSA if routine safety monitoring chemistries are done and the potential risk of EFV-related teratogenicity is considered.

Background

Numerous national antiretroviral (ARV) treatment initiatives offering protease-inhibitor (PI)-sparing combination antiretroviral therapy (cART) have recently commenced in southern Africa, the first of which began in Botswana in January 2002. Evaluation of the efficacy and tolerability of various PI-sparing cART regimens requires intensive study in the region, as does investigation of the development of drug resistance and the optimal means of sustaining adherence. The Tshepo Study is the first large-scale randomized clinical trial which addresses these important issues among HIV-1 subtype C infected, ARV-treatment naïve adults in southern Africa.

Methods

The Tshepo Study is a completed open-labeled randomized study that enrolled 650 ARV-naïve adults between December 2002 and December 2004. The study is a 3 × 2 × 2 factorial design comparing the efficacy and tolerability among factors: (i) three combinations of nucleoside reverse transcriptase inhibitors (NRTIs): zidovudine (ZDV) + lamivudine (3TC); ZDV + didanosine (ddI); and stavudine (d4T) + 3TC; (ii) two different Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): nevirapine (NVP) and efavirenz (EFV); and (iii) two different adherence strategies: the current national “Standard of Care (SOC)” versus an “intensified adherence strategy”, incorporating “community-based Directly Observed Therapy (Com-DOT)”. Study patients were stratified into two balanced CD4+ T cell count groups: less than 201 cells/mm3 versus 201-350 cells/mm3 with viral load greater than 55,000 copies/mL. Following DSMB recommendations in April 2006, ZDV/ddI-containing arms were discontinued due to inferiority in primary endpoint, namely, virologic failure with resistance. We report both overall data and pooled data from patients receiving ZDV/ddI- versus ZDV/3TC- and d4T/3TC-containing cART through 1 April 2006.

Results

Four hundred fifty-one (69.4%) females and 199 males with a median age of 33.3 years were enrolled into the study. The median follow-up as of 1 April 2006 was 104 weeks, and loss to follow-up rate at two years was 4.1%. The median baseline CD4+ T cell count was 199 cells/mm3 [IQR 136-252] and the median plasma HIV-1 RNA level was 193,500 copies/mL [IQR 69-250, 472-500]. The proportion of participants with virologic failure and genotypic resistance mutations was 11% in those receiving ZDV/ddI-based cART versus 2% in those receiving either ZDV/3TC- or d4T/3TC-based cART (p=0.002). The median CD4+ T cell count increase at one year was 137cells/mm3 [IQR 74-223] and 199 cells/mm3 [IQR 112-322] at two years with significantly lower gain in the ZDV/ddI arm. At one and two years, respectively, 92.0% and 88.8% of patients had an undetectable plasma HIV-1 RNA level (≤400 copies/mL). Kaplan-Meier survival estimates at one and two years were 96.6% and 95.4%. One hundred twenty (18.2%) patients had treatment modifying toxicities, of which the most common were lipodystrophy, anemia, neutropenia, and Stevens-Johnson syndrome. There was a trend towards difference in time to treatment modifying toxicity by pooled dual NRTI combination, and no difference in death rates.

Conclusions

The preliminary study results show overall excellent efficacy and tolerability of NNRTI-based cART among HIV-1 subtype C infected adults. ZDV/ddI-containing cART, however, is inferior to the dual NRTIs d4T/3TC or ZDV/3TC when used with an NNRTI for first-line cART.

Abstract

Six randomized clinical trials have been implemented to examine the efficacy of tenofovir disoproxil fumarate (TDF) and/or TDF/emtricitabine (TDF/FTC) as preexposure prophylaxis for HIV-1 infection (PrEP). Although largely complementary, the six trials have many similar features. As the earliest results become available, an urgent question may arise regarding whether changes should be made in the conduct of the other trials. To consider this in advance, a Consultation on the Implications of HIV Pre-Exposure Prophylaxis (PrEP) Trials Results sponsored by the Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), and the Bill and Melinda Gates Foundation (BMGF) was held on January 29, 2010, at the Natcher Conference Center, NIH, Bethesda, MD. Participants included basic scientists, clinical researchers (including investigators performing the current PrEP trials), and representatives from the U.S. Food and Drug Administration (FDA) and the agencies sponsoring the trials: the U.S. Centers for Disease Control and Prevention (CDC), the U.S. Agency for International Development (USAID), the BMGF, and the U.S. NIH. We report here a summary of the presentations and highlights of salient discussion topics from this workshop.

Motivation: Modern HIV-1, hepatitis B virus and hepatitis C virus antiviral therapies have been successful at keeping viruses suppressed for prolonged periods of time, but therapy failures attributable to the emergence of drug resistant mutations continue to be a distressing reminder that no therapy can fully eradicate these viruses from their host organisms. To better understand the emergence of drug resistance, we combined phylogenetic and statistical models of viral evolution in a 2-phase computational approach that reconstructs mutational pathways of drug resistance.

Results: The first phase of the algorithm involved the modeling of the evolution of the virus within the human host environment. The inclusion of longitudinal clonal sequence data was a key aspect of the model due to the progressive fashion in which multiple mutations become linked in the same genome creating drug resistant genotypes. The second phase involved the development of a Markov model to calculate the transition probabilities between the different genotypes. The proposed method was applied to data from an HIV-1 Efavirenz clinical trial study. The obtained model revealed the direction of evolution over time with greater detail than previous models. Our results show that the mutational pathways facilitate the identification of fast versus slow evolutionary pathways to drug resistance.

Availability: Source code for the algorithm is publicly available at http://biorg.cis.fiu.edu/vPhyloMM/

Contact: pbuendia@miami.edu

Background

Antiretroviral treatment (ART) initiatives have now been established in many sub-Saharan African countries showing early benefits. To date, few results are available concerning long-term clinical outcomes in these treatment programs.

Methods

Response to ART is described in the first HIV–1C infected adults enrolled in the Botswana ART program in 2002. Data analysis was conducted on available longitudinal data up to April 1st, 2007.

Results

633 severely immunodeficient patients with a median CD4+ cell count of 67 cells/mm3 were initiated on NNRTI-based combination ART and followed for a median of 41.9 months. The median CD4+ increases were 169 cells/mm3, 302 cells/mm3, and 337 cells/mm3 at 1, 3, and 5 years, respectively. The percentages of patients with a viral load of less than 400 copies/mL at 1, 3, and 5 years were 91.3%, 90.1%, and 98.3%, respectively. 75% of patients did not miss a single, or missed only one, monthly ART pick-up per year with a mean pick-up rate of 92.5%. The Kaplan-Meier survival estimates (95% CI) at 1, 3, and 5 years were 82.7% (81.2%, 84.3%), 79.3% (77.6%, 81.0%), and 79.0% (77.3%, 80.7%), respectively. At six months, the risk of treatment modification for anemia was 6.94% (5.9%, 8.0%) for cutaneous hypersensitivity reactions, 1.3% (0.8%, 1.7%), and 1.1% (0.7%, 1.6%) for hepatotoxicity.

Conclusions

This initial group of adults on ART in Botswana had excellent sustained immunologic, virologic, and clinical outcomes for up to five years of follow-up with low mortality among those surviving into the second year of antiretroviral treatment.

The first aim of the study is to assess the distribution of HIV-1 RNA levels in subtype C infection. Among 4,348 drug-naïve HIV-positive individuals participating in clinical studies in Botswana, the median baseline plasma HIV-1 RNA levels differed between the general population cohorts (4.1–4.2 log10) and cART-initiating cohorts (5.1–5.3 log10) by about one log10. The proportion of individuals with high (≥50,000 (4.7 log10) copies/ml) HIV-1 RNA levels ranged from 24%–28% in the general HIV-positive population cohorts to 65%–83% in cART-initiating cohorts. The second aim is to estimate the proportion of individuals who maintain high HIV-1 RNA levels for an extended time and the duration of this period. For this analysis, we estimate the proportion of individuals who could be identified by repeated 6- vs. 12-month-interval HIV testing, as well as the potential reduction of HIV transmission time that can be achieved by testing and ARV treating. Longitudinal analysis of 42 seroconverters revealed that 33% (95% CI: 20%–50%) of individuals maintain high HIV-1 RNA levels for at least 180 days post seroconversion (p/s) and the median duration of high viral load period was 350 (269; 428) days p/s. We found that it would be possible to identify all HIV-infected individuals with viral load ≥50,000 (4.7 log10) copies/ml using repeated six-month-interval HIV testing. Assuming individuals with high viral load initiate cART after being identified, the period of high transmissibility due to high viral load can potentially be reduced by 77% (95% CI: 71%–82%). Therefore, if HIV-infected individuals maintaining high levels of plasma HIV-1 RNA for extended period of time contribute disproportionally to HIV transmission, a modified “test-and-treat” strategy targeting such individuals by repeated HIV testing (followed by initiation of cART) might be a useful public health strategy for mitigating the HIV epidemic in some communities.

Purpose

To evaluate the association of efavirenz hypersusceptibility (EFV-HS) with clinical outcome in a double-blind, placebo-controlled, randomized trial of EFV plus indinavir (EFV+IDV) vs. EFV+IDV plus abacavir (ABC) in 283 nucleoside-experienced HIV-infected patients.

Methods and Results

Rates of virologic failure were similar in the 2 arms at week 16 (p=0.509). Treatment discontinuations were more common in the ABC arm (p=0.001). Using logistic regression, there was no association between virologic failure and either baseline ABC resistance or regimen sensitivity score. Using 3 different genotypic scoring systems, EFV-HS was significantly associated with reduced virologic failure at week 16, independent of treatment assignment. In some patients on the nucleoside-sparing arm, the nucleoside-resistant mutant L74V was selected for in combination with the uncommonly occurring EFV-resistant mutant K103N+L100I; L74V was not detected as a minority variant, using clonal sequence analysis, when the nucleoside-sparing regimen was initiated.

Conclusions

Premature treatment discontinuations in the ABC arm and the presence of EFV-hypersusceptible HIV variants in this patient population likely made it difficult to detect a benefit of adding ABC to EFV+IDV. In addition, L74V, when combined with K103N+L100I, may confer a selective advantage to the virus that is independent of its effects on nucleoside resistance.

Objectives

Video-based delivery of HIV pre-test information might assist in streamlining HIV screening and testing efforts in the emergency department (ED). The objectives of this study were to determine if the video “Do you know about rapid HIV testing?” is an acceptable alternative to an in-person information session on rapid HIV pre-test information, in regards to comprehension of rapid HIV pre-test fundamentals; and to identify patients who might have difficulties in comprehending pre-test information.

Methods

This was a non-inferiority trial of 574 participants in an ED opt-in rapid HIV screening program who were randomly assigned to receive identical pre-test information from either an animated and live-action 9.5-minute video, or an in-person information session. Pre-test information comprehension was assessed using a questionnaire. The video would be accepted as not inferior to the in-person information session if the 95% confidence interval (CI) of the difference (Δ) in mean scores on the questionnaire between the two information groups was less than a 10% decrease in the in-person information session arm's mean score. Linear regression models were constructed to identify patients with lower mean scores based upon study arm assignment, demographic characteristics, and history of prior HIV testing.

Results

The questionnaire mean scores were 20.1 (95% CI = 19.7 to 20.5) for the video arm and 20.8 (95% CI = 20.4 to 21.2) for the in-person information session arm. The difference in mean scores compared to the mean score for the in-person information session met the non-inferiority criterion for this investigation (Δ = 0.68; 95% CI = 0.18 to 1.26). In a multivariable linear regression model, Blacks/African Americans, Hispanics, and those with Medicare and Medicaid insurance exhibited slightly lower mean scores, regardless of the pre-test information delivery format. There was a strong relationship between fewer years of formal education and lower mean scores on the questionnaire. Age, gender, type of insurance, partner/marital status, and history of prior HIV testing were not predictive of scores on the questionnaire.

Conclusions

In terms of patient comprehension of rapid HIV pre-test information fundamentals, the video was an acceptable substitute to pre-test information delivered by an HIV test counselor. Both the video and in-person information session were less effective in providing pre-test information for patients with fewer years of formal education.

SYNOPSIS

Objectives.

We assessed emergency department (ED) patient acceptance of opt-in, rapid human immunodeficiency virus (HIV) screening and identified demographic characteristics and HIV testing-history factors associated with acceptance of screening.

Methods.

A random sample of 18- to 55-year-old ED patients was offered rapid HIV screening. Patient acceptance or decline of screening and the reasons for acceptance or decline were analyzed with multivariable regression models. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated for the logistic regression models.

Results.

Of the 2,099 participants, 39.3% accepted HIV screening. In a multinomial regression model, participants who were never married/not partnered, did not have private health insurance, and had 12 or fewer years of education were more likely to be screened due to concern about a possible HIV exposure. In a multivariable logistic regression model, the odds of accepting screening were greater among those who were younger than 40 years old (OR=1.61, 95% CI 1.32, 2.00), nonwhite (OR=1.28, 95% CI 1.04, 1.58), not married (OR=1.82, 95% CI 1.44, 2.28), lacking private health insurance (OR=1.40, 95% CI 1.13, 1.74), and who had 12 or fewer years of education (OR=1.43, 95% CI 1.16, 1.75). Despite use of a standardized protocol, patient acceptance of screening varied by which research assistant asked them to be screened. Patients not previously tested for HIV who were white, married, and 45 years or older and who had private health insurance were more likely to decline HIV screening.

Conclusions.

In an opt-in, universal, ED HIV screening program, patient acceptance of screening varied by demography, which indicates that the impact of such screening programs will not be universal. Future research will need to determine methods of increasing uptake of ED HIV screening that transcend patient demographic characteristics, HIV testing history, and motivation for testing.

Understanding how long-term clinical outcomes relate to short-term response to therapy is an important topic of research with a variety of applications. In HIV, early measures of viral RNA levels are known to be a strong prognostic indicator of future viral load response. However, mutations observed in the high-dimensional viral genotype at an early time point may change this prognosis. Unfortunately, some subjects may not have a viral genetic sequence measured at the early time point, and the sequence may be missing for reasons related to the outcome. Complete-case analyses of missing data are generally biased when the assumption that data are missing completely at random is not met, and methods incorporating multiple imputation may not be well-suited for the analysis of high-dimensional data. We propose a semiparametric multiple testing approach to the problem of identifying associations between potentially missing high-dimensional covariates and response. Following the recent exposition by Tsiatis, unbiased nonparametric summary statistics are constructed by inversely weighting the complete cases according to the conditional probability of being observed, given data that is observed for each subject. Resulting summary statistics will be unbiased under the assumption of missing at random. We illustrate our approach through an application to data from a recent AIDS clinical trial, and demonstrate finite sample properties with simulations.

Medical laboratory data are often censored, due to limitations of the measuring technology. For pharmacokinetics measurements and dilution-based assays, for example, there is a lower quantification limit, which depends on the type of assay used. The concentration of HIV particles in the plasma is subject to both lower and upper quantification limit. Linear and nonlinear mixed effects models, which are often used in these types of medical applications, need to be able to deal with such data issues. In this paper we discuss a hybrid Monte Carlo and numerical integration EM algorithm for computing the maximum likelihood estimates for linear and non-linear mixed models with censored data. Our implementation uses an efficient block-sampling scheme, automated monitoring of convergence, and dimension reduction based on the QR decomposition. For clusters with up to two censored observations numerical integration is used instead of Monte Carlo simulation. These improvements lead to a several-fold reduction in computation time. We illustrate the algorithm using data from an HIV/AIDS trial. The Monte Carlo EM is evaluated and compared with existing methods via a simulation study.