HIV This Week

Evolutionary Dynamics of Complex Networks of HIV Drug-Resistant Strains: The Case of San Francisco.

Smith R, Okano J, Kahn J, Bodine E, Blower S. Science. 2010. Jan. [Epub ahead of print]

Over the past two decades, HIV resistance to antiretrovirals has risen to high levels in the wealthier countries of the world able to afford widespread treatment. The authors have gained insights into the evolution and transmission dynamics of ARV resistance by designing a biologically complex multistrain network model. Using this model, they traced the evolutionary history of antiretroviral resistance in San Francisco and predict the future dynamics. Using classification and regression trees, Smith and colleagues have identified the key immunologic, virologic, and treatment factors that increase antiretroviral resistance. Their modelling shows that 60% of the currently circulating antiretroviral-resistant strains in San Francisco are capable of causing self-sustaining epidemics, as each individual infected with one of these strains can cause on average more than one new resistant infection. It is possible that a new wave of antiretroviral-resistant strains that pose a significant threat to global public health is emerging.

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Editors’ note: These modellers predict that a wave of NNRTI- (non-nucleoside reverse transcriptase inhibitor) resistant strains will emerge over the next 5 years in San Francisco due to HIV transmission from untreated individuals. They also claim that if the reproduction number (the number of infections that one person transmits) of wild-type strains is reduced below one in resource-constrained settings (which would normally see an epidemic decline), self-sustaining epidemics of NNRTI-resistant strains could arise. Whether their model’s predictions are accurate or not remains to be seen but clearly increased investment in resistance monitoring around the world is warranted as we scale up to universal access to antiretroviral treatment for all.

Improved Virological Outcomes in British Columbia Concomitant with Decreasing Incidence of HIV Type 1 Drug Resistance Detection.

Gill V, Lima V, Wen Zhang, Wynhoven B, Yip B, Hogg R, Montaner J, and Harrigan R . Clinical Infectious Diseases. 2010. 50:98–105.

There have been limited studies evaluating temporal changes in the incidence of detection of drug resistance among human immunodeficiency virus type 1 (HIV-1) isolates and concomitant changes in plasma HIV load for treated individuals in a population-wide setting. Longitudinal plasma viral load and genotypic resistance data were obtained from patients receiving antiretroviral therapy from the British Columbia Drug Treatment Program from July 1996 through December 2008. A total of 24,652 resistance tests were available from 5422 individuals. The incidence of successful plasma viral load suppression and of resistance to each of 3 antiretroviral categories (nucleoside/nucleotide reversetranscriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors) was calculated for the population receiving therapy. There has been a drastic decrease in the incidence of new cases of HIV-1 drug resistance in individuals followed during 1996–2008. In 1997, the incidence rate of any newly detected resistance was 1.73 cases per 100 person-months of therapy, and by 2008, the incidence rate had decreased 112-fold, to 0.13 cases per 100 person-months of therapy. This decrease in the incidence of resistance has occurred at an exponential rate, with halftimes on the order of 2–3 years. Concomitantly, the proportion of individuals with plasma viral load suppression has increased linearly over time (from 64.7% with HIV RNA levels !50 copies/mL in 2000 to 87.0% in 2008; R2p0.97; P ! .001). The authors’ results suggest an increasing effectiveness of antiretroviral therapy at the populational level. The vast majority of treated patients in British Columbia now have either suppressed plasma viral load or drug-susceptible HIV-1, according to their most recent test results.

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Editors’ note: Rather than investigating the prevalence of transmitted drug resistance in the population or the prevalence of acquired drug resistance among people on treatment, these investigators, who were uniquely placed to do so, assessed the incidence of drug resistance over a 12-year period. They found exponential decreases in the incidence rate of drug resistance, including NNRTI (non-nucleoside reverse transcriptase inhibitor) resistance (40-fold decrease), despite increases in annual and cumulative exposure to antiretroviral drugs. These authors conclude that efforts to improve accessibility to antiretroviral treatment have the potential to greatly reduce HIV-1 levels in a population without increasing the risk of drug resistance.

Halting HIV/AIDS with avatars and havatars: a virtual world approach to modelling epidemics.

Gordon R, Björklund NK, Smith RJ, Blyden ER. BMC Public Health. 2009;9 Suppl 1:S13.

A major deficit of all approaches to epidemic modelling to date has been the need to approximate or guess at human behaviour in disease-transmission-related contexts. Avatars are generally human-like figures in virtual computer worlds controlled by human individuals. The authors introduce the concept of a “havatar”, which is a (human, avatar) pairing. Evidence is mounting that this pairing behaves in virtual contexts much like the human in the pairing might behave in analogous real-world contexts. Gordon et al. propose that studies of havatars, in a virtual world, may give a realistic approximation of human behaviour in real-world contexts. If the virtual world approximates the real world in relevant details (geography, transportation, etc.), virtual epidemics in that world could accurately simulate real-world epidemics. Havatar modelling of epidemics therefore offers a complementary tool for tackling how best to halt epidemics, including perhaps HIV, since sexual behaviour is a significant component of some virtual worlds, such as Second Life. Havatars place the control parameters of an epidemic in the hands of each individual. By providing tools that everyone can understand and use, we could democratise epidemiology.

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Editors’ note: Reviewing current modelling approaches (continuous or deterministic, discrete or individual, and stochastic process modelling), these authors point out that all epidemic modelling second-guesses human behaviour. Their proposition that epidemiological modellers monitor the social networks of havatars (“h” stands for human) to obtain a better representation of real-world disease transmission raises several questions. Although the 13 million people who joined the virtual world Second Life signed waivers that would allow tracking of all transactions, there may be ethical issues to consider when modellers intervene in people’s virtual worlds with HIV epidemic simulations to study the behaviour of the avatars under a person’s control and make extrapolations to human behaviour. Unleashing invisible, simulated viruses that infect havatars and can be transmitted could cause problems, even if the viruses themselves have no effects such as simulated weight loss or changes in colour. The possibility of virtual world stigma might become real. As well, the people currently part of this virtual world are unlikely to represent populations at higher risk of HIV exposure around the world so the validity of the extrapolations to the HIV epidemic we face today could well be in question.

Accuracy of serological assays for detection of recent infection with HIV and estimation of population incidence: a systematic review.

Guy R, Gold J, Calleja JM, Kim AA, Parekh B, Busch M, Rehle T, Hargrove J, Remis RS, Kaldor JM; WHO Working Group on HIV Incidence Assays. Lancet Infect Dis. 2009 9:747-59.

The authors systematically reviewed the accuracy of serological tests for recent infections with HIV that have become widely used for measuring population patterns incidence of HIV. Across 13 different assays, sensitivity to detect recent infections ranged from 42-100% (median 89%). Specificity for detecting established infections was between 49.5% and 100% (median 86.8%) and was higher for infections of durations longer than 1 year (median 98%, range 31.5-100.0). For four different assays, comparisons were made between assay-derived population incidence estimates and a reference incidence estimate. The median percentage difference between the assay-derived incidence and reference incidence was 26.0%. Serological assays have reasonable sensitivity for the detection of recent infection with HIV, but are vulnerable to misclassifying established infections as recent-potentially leading to biases in incidence estimates. This conclusion is highly qualified by the apparent absence of a standardised approach to assay evaluation. There is an urgent need for an internationally agreed framework for evaluating and comparing these tests.

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Editors’ note: Determining HIV incidence directly by measuring seroconversion and thereby monitoring HIV transmission is key to both assessing the need for and establishing the effectiveness of HIV prevention programmes. This extensive review confirms that the development of reliable and valid tests to detect recent infection is a public health priority. To date virtually all the assays that have been developed involve subtype B virus (clade C is the most common worldwide) and have been plagued by false positive results due to longstanding infections or an increasing duration of antiretroviral treatment. Given that HIV incidence reduction is a foundation of both national and international HIV commitments, it is urgent that a standardised approach to assay validation be developed and implemented.  

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Estimates of HIV incidence from household-based prevalence surveys.

Hallett TB, Stover J, Mishra V, Ghys PD, Gregson S, Boerma T. AIDS. 2010 ;24:147-52.

This study set out to estimate HIV incidence in the general population in countries where there have been two recent household-based HIV prevalence surveys (the Dominican Republic, Mali, Niger, Tanzania, and Zambia). Hallett et al applied a validated method to estimate HIV incidence using HIV prevalence measurement in two surveys. The authors estimate incidence among men and women aged 15-44 years to be: 0.5/1000 person-years at risk in the Dominican Republic 2002-2007, 1.1/1000 in Mali 2001-2006, 0.6/1000 in Niger 2002-2006, 3.4/1000 in Tanzania 2004-2008, and 11.2/1000 in Zambia 2002-2007. The groups most at risk in these epidemics are typically 15-24-year-old women and 25-39-year-old men. Incidence appears to have declined in recent years in all countries, but only significantly among men in the Dominican Republic and Tanzania and women in Zambia. Using prevalence measurements to estimate incidence reveals the current level and age distribution of new infections and the trajectory of the HIV epidemic. This information is more useful than prevalence data alone and should be used to help determine priorities for interventions.

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Editors’ note: Why have we not been estimating HIV incidence from household surveys? This straightforward method of comparing current age cohorts with their representation in a previous survey includes adjustments for deaths and the numbers of people on treatment by age group. The gold standard, a cohort incidence study, is too expensive and the cohorts in question may not represent the national population anyway. Just as trends in HIV prevalence among pregnant women aged 15 to 24 years have been a proxy for HIV incidence, so too can this approach detect changes in HIV incidence, but at a variety of ages .  

Measuring the Impact of the Global Response to the AIDS Epidemic: Challenges and Future Directions.

Mahy M, Warner-Smith M, Stanecki KA, Ghys PD. J Acquir Immune Defic Syndr. 2009; Nov. 52(S1)

In the Declaration of Commitment of the 2001 United Nations General Assembly Special Session on AIDS, all Member States agreed to a series of actions to address HIV. This article examines the availability of data to measure progress toward reducing HIV incidence and AIDS mortality and discusses the extent to which changes can be attributed to programs. Lacking a method to directly measure HIV incidence, trends in HIV prevalence among 15-year to 24-year olds and groups with high-risk behaviours are used as a proxy measure for incidence trends among adults in generalized and concentrated/low-level epidemics, respectively. Although there is limited empirical data on trends in new infections among children, progress in the treatment area is tracked through indicators for the percentage of people who remain on antiretroviral treatment 12 months after initiation and the coverage of antiretroviral treatment. Successive iterations of epidemiological models using surveillance data from pregnant women and groups with high-risk behaviour and data from national household surveys, demographic data and epidemiological assumptions have produced increasingly robust estimates of HIV prevalence, incidence and mortality. Globally, incidence has decreased among adults (accompanied by evidence of changes in behaviour in several countries) and children over the past decade. The decline in AIDS mortality is more recent. On the basis of the underlying logical framework and mathematical models, it is concluded that programs have contributed to a reduction in HIV incidence and AIDS mortality. More data are needed to reliably inform trends in HIV incidence and AIDS mortality in many countries to allow an assessment of progress against national and global targets. In addition, impact evaluation studies are needed to assess the relationship between changes in incidence and mortality and the HIV response and to determine the extent to which these changes can be attributed to specific programmatic interventions.

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Editors’ note: The decline in new infections (incidence) reported in the 2009 UNAIDS/WHO Epidemic Update is not translating into lower numbers of people living with HIV (prevalence) because antiretroviral treatment roll-out is reducing mortality. Thus, there are fewer new infections and fewer deaths but the size of the HIV epidemic in absolute numbers continues to grow. This article examines the availability and nature of data to track the HIV epidemic, the modelling undertaken to estimate trends, and the importance of robust evaluations of programmes and policies to explain what has contributed, and what has not, to the changes in incidence that we are observing. Although generally we are on track to be able to know in 2015 whether the HIV epidemic has been ‘halted and reversed’ (Millennium Development Goal 6), this analysis of UNGASS reporting shows that many countries need to improve their epidemiological data collection and most countries need to conduct carefully designed evaluation studies to know whether specific programmes have contributed to any observed changes.

Evaluation of a dried blood spot HIV-1 RNA program for early infant diagnosis and viral load monitoring at rural and remote healthcare facilities.

Lofgren SM, Morrissey AB, Chevallier CC, Malabeja AI, Edmonds S, Amos B, Sifuna DJ, von Seidlein L, Schimana W, Stevens WS, Bartlett JA, Crump JA. AIDS. 2009 23(18):2459-66.

Lofgren and colleagues set out to assess technical and operational performance of a dried blood spot-based HIV-1 RNA service for remote healthcare facilities in a low-income country. A method comparison and operational evaluation of dried blood spot RNA against conventional tests for early infant diagnosis of HIV and HIV RNA quantitation under field conditions in Tanzania was conducted. Dried blood spots were prepared and plasma was frozen at -80 degrees C. Dried blood spots were mailed and plasma couriered to a central laboratory for testing using the Abbott m2000 system. Infant diagnosis dried blood spots were also tested for HIV-1 DNA by ROCHE COBAS AmpliPrep/COBAS TaqMan System. Results of dried blood spot RNA were compared with conventional tests; program performance was described. Among 176 infant diagnosis participants, using a threshold of at least 1000 copies/ml, sensitivity and specificity of dried blood spot versus plasma RNA were 1.00 and 0.99, and of dried blood spot RNA versus dried blood spot DNA were 0.97 and 1.00. Among 137 viral load monitoring participants, when plasma and dried blood spot RNA were compared, r value was 0.9709; r value was 0.9675 for at least 5000 copies/ml but was 0.7301 for less than 5000 copies/ml. The highest plasma RNA value at which dried blood spot RNA was not detected was 2084 copies/ml. Median (range) turnaround time from sample collection to result receipt at sites was 23 (4-69) days. The Tanzania mail service successfully transmitted all dried blood spot and results between sites and the central laboratory. Under program conditions in Tanzania, dried blood spot provided HIV-1 RNA results comparable to conventional methods to remote healthcare facilities. The authors propose dried blood spot RNA testing as an alternative to liquid plasma for HIV-1 RNA services in remote areas

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Editors’ note: In this study, the weekly cost of mailing dried blood spot specimens from healthcare facilities to the central laboratory was 6$ compared to a weekly ground transport of frozen plasma samples on dry ice of 515$. The excellent sensitivity and specificity results for paediatric HIV diagnosis reported for dried blood spot specimens here, combined with a reasonable turnaround time for results in the absence of electronic or fax communications, suggests that cost-effectiveness analyses should be quickly undertaken. The earlier that infants with HIV infection are diagnosed, the sooner they can be placed on treatment .

Smith DM, May SJ, Pérez-Santiago J, Strain MC, Ignacio CC, Haubrich RH, Richman DD, Benson CA, Little SJ. AIDS. 2009; 23:2151-8.

To develop less costly methods to virologically monitor patients receiving antiretroviral therapy, the authors evaluated methods that use pooled blood samples and quantitative information available from viral load assays to monitor a cohort of patients on first-line antiretroviral therapy for virologic failure. They evaluated 150 blood samples collected after 6 months of therapy from participants enrolled in a San Diego primary infection program between January 1998 and January 2007. Samples were screened for virologic failure with individual viral load testing, 10 x 10 matrix pools and minipools of five samples. For the pooled platforms (matrix and minipools), the authors used a search and retest algorithm based on the quantitative viral load data to resolve samples that remained ambiguous for virologic failure. Viral load thresholds were more than 500 and more than 1500 copies/ml for the matrix and more than 250 and more than 500 copies/ml for the minipool. Efficiency, accuracy and result turnaround times were evaluated. Twenty-three percent of cohort samples were detectable at more than 50 HIV RNA copies/ml. At an algorithm threshold of more than 500 HIV RNA copies/ml, both minipool and matrix methods used less than half the number of viral load assays to screen the cohort, compared with testing samples individually. Both pooling platforms had negative predictive values of 100% for viral loads of more than 500 HIV RNA copies/ml and at least 94% for viral loads of more than 250 HIV RNA copies/ml. In this cohort, both pooling methods improved the efficiency of virologic monitoring over individual testing with a minimal decrease in accuracy. These methods may allow for the induction and sustainability of the virologic monitoring of patients receiving antiretroviral therapy in resource-limited settings.

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Editors’ note: Pooling strategies mix 5, 10, or more samples together for testing. If the pool is positive then each sample in the pool is tested to see which one(s) is (are) responsible. Viral load monitoring for patients on antiretroviral treatment is not recommended or performed in most resource-limited settings where the focus has been on getting more people in need on treatment. Adaptation of assays in current clinical use for settings with diverse HIV subtypes would allow the kinds of efficiency gains described here. The objective would be improved clinical outcomes and limits on the development of drug resistance.  

A Tale of Two Countries: HIV Among Core Groups in Togo. Sobéla F, Pépin J, Gbéléou S, Banla AK, Pitche VP, Adom W, Sodji D, Frost E, Deslandes S, Labbé AC. J Acquir Immune Defic Syndr 2009 51: 216-23.

Sobéla and colleagues set out to describe the epidemiology of HIV among core groups in Togo. The authors enumerated sex workers and conducted cross-sectional surveys of sex workers and their clients in 2003 in Lomé and in 2005 in the whole country. Sex work was concentrated in Lomé, which comprised 15% of the population, but 52% of the 5397 SWs enumerated in Togo in 2005 and 68% of the estimated 101,376 men who had bought sex in the year before the 2005 survey. HIV prevalence among sex workers was highest in Lomé (45.4% in 2005) and progressively decreased from south to north. A similar geographical pattern was seen for clients (8.3% were HIV infected in Lomé in 2005) and had already been reported for pregnant women. In Lomé, the population attributable fraction of prevalent cases of HIV acquired during transactional sex was estimated at 32%; in the rest of the country, this was only 2%. This is the first study quantifying sex work at a national level in Africa. Variations in HIV prevalence within Togo, with a north-south gradient among sex workers, their clients, and pregnant women, may to a large extent reflect the concentration of the sex trade within Lomé. Prostitution played only a modest a role in HIV dynamics outside Lomé.

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Editors’ note : This unique national study used the anonymous linked method of HIV surveillance by which sex workers and clients who wished to learn their HIV test results returned to the clinic presenting the envelope with their study number they had been given at the time that their fingerprick blood specimen was taken. The authors attribute the relatively low population attributable fraction (the proportion of incidence that is due to sex work-related transmission) in Lomé of 32%, compared to 84% in Accra and 76% in Cotonou, to the sustained NGO-implemented programme (Forces et Action pour le Mieux-Être de la Mère et de l’Enfant) that has ensured condom availability in sex work environments since the early 1990s.

Refusal bias in HIV prevalence estimates from nationally representative seroprevalence surveys. Reniers G, Eaton J. Aids. 2009; 23 : 621-9.

Reniers and Eaton set out to assess the relationship between prior knowledge of one’s HIV status and the likelihood to refuse HIV testing in population-based surveys and explore its potential for producing bias in HIV prevalence estimates. Using longitudinal survey data from Malawi, the authors estimate the relationship between prior knowledge of HIV-positive status and subsequent refusal of an HIV test. The authors use that parameter to develop a heuristic model of refusal bias that is applied to six Demographic and Health Surveys, in which refusal by HIV status is not observed. The model only adjusts for refusal bias conditional on a completed interview. Ecologically, HIV prevalence, prior testing rates and refusal for HIV testing are highly correlated. Malawian data further suggest that amongst individuals who know their status, HIV-positive individuals are 4.62 (95% confidence interval, 2.60-8.21) times more likely to refuse testing than HIV-negative ones. On the basis of that parameter and other inputs from the Demographic and Health Surveys, the model predicts downward bias in national HIV prevalence estimates ranging from 1.5% (95% confidence interval, 0.7-2.9) for Senegal to 13.3% (95% confidence interval, 7.2-19.6) for Malawi. In absolute terms, bias in HIV prevalence estimates is negligible for Senegal but 1.6 (95% confidence interval, 0.8-2.3) percentage points for Malawi. Downward bias is more severe in urban populations. Because refusal rates are higher in men, seroprevalence surveys also tend to overestimate the female-to-male ratio of infections. Prior knowledge of HIV status informs decisions to participate in seroprevalence surveys. Informed refusals may produce bias in estimates of HIV prevalence and the sex ratio of infections.

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Editors’ note : The results of nationally representative household surveys that include HIV testing are used to adjust for the biases of antenatal care sentinel surveillance estimates to create revised national HIV prevalence estimates in many countries in sub-Saharan Africa. This model suggests that the results of household surveys in some high HIV prevalence urban areas with high HIV testing coverage may underestimate true HIV prevalence. This would be due to the possibility that those refusing to participate, who are more likely to be men, may be more likely to know that they are HIV-positive already. No systematic adjustment for this is warranted at this time but countries should be aware of this potential bias and consider ways to both encourage participation by all those who are sampled and to study the potential for this bias to be influencing estimates in their own settings.

Changing global essential medicines norms to improve access to AIDS treatment: lessons from Brazil. Nunn A, Fonseca ED, Gruskin S. Glob Public Health. 2009;4:131-49.

Brazil ’s large-scale, successful HIV treatment programme is considered by many to be a model for other developing countries aiming to improve access to HIV treatment. Far less is known about Brazil’s important role in changing global norms related to international pharmaceutical policy, particularly international human rights, health and trade policies governing access to essential medicines. Prompted by Brazil’s interest in preserving its national HIV treatment policies during World Trade Organisation trade disputes with the USA, these efforts to change global essential medicines norms have had important implications for other countries, particularly those scaling up HIV treatment. This paper analyses Brazil’s contributions to global essential medicines policy and explains the relevance of Brazil’s contributions to global health policy today.

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Editors’ note: This interesting chronological narrative traces the far-reaching impact of Brazil’s efforts to preserve its domestic HIV treatment policies, which are based on legal commitments to provide universal access to antiretroviral drugs to its people, and yet recognise intellectual property rights. Brazil acted through the United Nations Commission on Human Rights, the United Nations General Assembly, the World Health Assembly, and the World Trade Organisation to improve access to essential medicines. Improved transparency about drug prices, generic drug use to address public health needs, incorporation of antiretroviral drugs into the WHO Essential Medicines List, strengthened TRIPS flexibilities for developing countries, and the defining of access to medicines as part of the human right to health can all be traced to a strong Brazilian influence in shaping global policy.

Brinkhof MW, Boulle A, Weigel R, Messou E, Mathers C, Orrell C, Dabis F, Pascoe M, Egger M. Mortality of HIV-infected patients starting antiretroviral therapy in sub-Saharan Africa: comparison with HIV-unrelated mortality. PLoS Med. 2009 Apr 28;6(4):e1000066.

Mortality in HIV-infected patients who have access to highly active antiretroviral therapy has declined in sub-Saharan Africa, but it is unclear how mortality compares to the non-HIV-infected population. Brinkhof and colleagues compared mortality rates observed in HIV-1-infected patients starting ART with non-HIV-related background mortality in four countries in sub-Saharan Africa.  Patients enrolled in antiretroviral treatment programmes in Côte d’Ivoire, Malawi, South Africa, and Zimbabwe were included. They calculated excess mortality rates and standardised mortality ratios (SMRs) with 95% confidence intervals (CIs). Expected numbers of deaths were obtained using estimates of age-, sex-, and country-specific, HIV-unrelated, mortality rates from the Global Burden of Disease project. Among 13,249 eligible patients 1,177 deaths were recorded during 14,695 person-years of follow-up. The median age was 34 years, 8,831 (67%) patients were female, and 10,811 of 12,720 patients (85%) with information on clinical stage had advanced disease when starting antiretroviral treatment. The excess mortality rate was 17.5 (95% CI 14.5-21.1) per 100 person-years in patients who started antiretroviral treatment with a CD4 cell count of less than 25 cells/microl and World Health Organization (WHO) stage III/IV, compared to 1.00 (0.55-1.81) per 100 person-years in patients who started with 200 cells/microl or above with WHO stage I/II. The corresponding standardised mortality ratios were 47.1 (39.1-56.6) and 3.44 (1.91-6.17).  Among patients who started antiretroviral treatment with 200 cells/microl or above in WHO stage I/II and survived the first year of antiretroviral treatment, the excess mortality rate was 0.27 (0.08-0.94) per 100 person-years and the standardised mortality ratios was 1.14 (0.47-2.77). Mortality of HIV-infected patients treated with combination antiretroviral treatment in sub-Saharan Africa continues to be higher than in the general population, but for some patients excess mortality is moderate and reaches that of the general population in the second year of antiretroviral treatment. Much of the excess mortality might be prevented by timely initiation of antiretroviral treatment.

Editors’ note: This study, the first to compare mortality among people starting antiretroviral treatment in sub-Saharan Africa to non-HIV-related mortality in the general population, cannot determine the CD4 count at which antiretroviral treatment should be started in order to minimise mortality. What is clear though is that much of the excess mortality during the first two years of antiretroviral treatment – 18 times higher than the general population not infected with HIV – could be reduced by more timely initiation of treatment. Patients with very low CD4 counts and advanced clinical disease had mortality 300 times higher in the first 3 months of treatment than the general population. These results are likely applicable to many other patients receiving antiretroviral treatment in diverse settings in Africa south of the Sahara.

Baral S, Trapence G, Motimedi F, Umar E, Iipinge S, Dausab F, Beyrer C. HIV prevalence, risks for HIV infection, and human rights among men who have sex with men (MSM) in Malawi, Namibia, and Botswana. PLoS ONE. 2009;4(3):e4997.

In the generalized epidemics of HIV in southern sub-Saharan Africa, men who have sex with men have been largely excluded from HIV surveillance and research. Epidemiologic data for men who have sex with men in southern Africa are among the sparsest globally, and HIV risk among these men has yet to be characterized in the majority of countries. A cross-sectional anonymous probe of 537 men recruited with non-probability sampling among men who reported ever having had sex with another man was conducted in Malawi, Namibia, and Botswana using a structured survey instrument and HIV screening with the OraQuick© rapid test kit. The HIV prevalence among those between the ages of 18 and 23 was 8.3% (20/241); 20.0% (42/210) among those 24-29; and 35.7% (30/84) among those older than 30 for an overall prevalence of 17.4% (95% CI 14.4-20.8). In multivariate logistic regressions, being older than 25 (aOR 4.0, 95% CI 2.0-8.0), and not always wearing condoms during sex (aOR 2.6, 95% CI 1.3-4.9) were significantly associated with being HIV-positive. Sexual concurrency was common with 16.6% having ongoing concurrent stable relationships with a man and a woman and 53.7% had both male and female sexual partners in proceeding 6 months. Unprotected anal intercourse was common and the use of petroleum-based lubricants was also common when using condoms. Human rights abuses, including blackmail and denial of housing and health care was prevalent with 42.1% (222/527) reporting at least one human rights abuse. Men who have sex with men are at higher risk of HIV exposure for HIV infection and human rights abuses in Malawi, Namibia, and Botswana. Concurrency of sexual partnerships with partners of both genders may play important roles in HIV spread in these populations. Further epidemiologic and evaluative research is needed to assess the contribution of men who have sex with men to southern Africa’s HIV epidemics and how best to mitigate this. These countries should initiate and adequately fund evidence-based and targeted HIV prevention programs for men who have sex with men.

Editors’ note: This simple epidemiology and human rights study, the first to link individual level rights abrogation to HIV biological outcomes in the African context, was implemented through collaboration with local community groups and can be replicated in similar settings. The overall findings of a high risk of exposure to both HIV and human rights abuses, in these three high HIV prevalence countries that criminalize same sex behaviour among consenting adults, are striking. Effective HIV prevention programming for men who have sex with men, particularly younger men, in Botswana, Malawi, and Namibia requires urgent governmental attention with dedicated funding and creative innovations, including use of the internet to reach this hidden population, training of health care providers, and strategies to address and minimise human rights abuses.

Human papillomavirus is a common sexually transmitted agent that causes anogenital cancer and pre-cancer lesions that have an inflammatory infiltrate, may be friable, and bleed. Chin-Hong and colleagues aimed to determine the association between anal HPV infection and HIV acquisition using a prospective cohort study design. They recruited 1409 HIV-negative men who have sex with men from a community-based setting in Boston, Denver, New York, and San Francisco. The authors used Cox proportional hazards regression modeling and assessed the independent association of HPV infection with the rate of acquisition of HIV infection. Of 1409 participants contributing 4375 person-years of follow-up, 51 HIV-seroconverted. The median number of HPV types in HPV-infected HIV-seroconverters was 2 (interquartile range 1-3) at the time of HIV seroconversion. After adjustment for sexual activity, substance use, occurrence of other sexually transmitted infections, and demographic variables, there was evidence (P = 0.002) for the effect of infection with at least two HPV types (hazard ratio 3.5, 95% confidence interval 1.2-10.6) in HIV seroconversion. The authors conclude that anal HPV infection is independently associated with HIV acquisition. Studies that incorporate high-resolution anoscopy to more accurately identify HPV-associated disease are needed to determine the relationship between HPV-associated disease and HIV seroconversion.

Editors’ note: HPV disease has long been considered to be opportunistic, taking advantage of HIV-induced immunosuppression but not increasing the risk of HIV acquisition. If, as this first study to do so suggests, anal HPV infection is independently associated with HIV acquisition, immunizing HPV-unexposed people to prevent invasive cancer and anogenital warts may have the potential to reduce the risk of HIV acquisition through anal sex.

New HIV infections are being observed among men who have sex with men (MSM). Understanding the fusion of risky sexual behaviours, stimulant drug use, and erectile dysfunction drug use with HIV seroconversion may provide direction for focused intervention. During the follow-up period (1998-2008), Ostrow and colleagues identified 57 HIV seroconverters among 1667 initially HIV-seronegative men. Time to seroconversion was modelled using Cox proportional hazards regression analysis for 7 combinations of sex drugs (inhaled nitrites or “poppers”, stimulants, and erectile dysfunction drugs) used at the current or previous semi-annual visit, adjusting for other risk factors including sexual behaviour, alcohol and other drugs used, and depression. Model-based adjusted attributable risks were then calculated. The risk of seroconversion increased linearly with the number of unprotected receptive anal sex partners, with hazard ratios ranging from 1.73 [95% confidence interval (CI): 0.75 to 4.01] for 1 partner, to 4.23 (95% CI: 1.76 to 10.17) for 2-4 partners, and to 14.21 (95% CI: 6.27 to 32.20) for 5+ partners, independent of other risk factors. After adjustment, risks for seroconversion increased from 2.99 (95% CI: 1.02 to 8.76) for men who reported using stimulants only (1 drug) to 8.45 (95% CI: 2.67 to 26.71) for men who reported using all 3 sex drugs. The use of any of the 7 possible sex drug combinations accounted for 63% of the 9-year HIV seroincidence in the Multicenter AIDS Cohort Study. When contributions of increased unprotected receptive anal sex partners and combination drug use were analyzed together, the total attributable risk for HIV seroconversion was 74%, with 41% attributable to unprotected receptive anal sex partners alone and a residual of 33% due to other direct or indirect effects of sex drug use. Use of poppers, stimulants, and erectile dysfunction drugs increased risk for HIV seroconversion significantly in this cohort. These data reinforce the importance of implementing interventions that target drug reduction as part of comprehensive and efficacious HIV prevention strategies.

Editors’ note: Whether or not and how vasoactive sex drug use could increase the likelihood of HIV infection through unprotected sex, over and above the disinhibiting effects of drug use, is unclear. Nonetheless, the magnitude of the risk posed by the use of stimulant, poppers, and erectile dysfunction drugs is clear – among men who used all three drugs the relative hazard for HIV seroconversion was 8 times that of men who reported no use of these sex drugs. With noninjection substance use seemingly on the increase among men who have sex with men, particularly the use of erectile dysfunction drugs as men age, attention addressed to the linked epidemics of substance use and high-risk sex should inform tailored harm reduction and safer sex strategies.

Bärnighausen T, Tanser F, Newell ML. Lack of a Decline in HIV Incidence in a Rural Community with High HIV Prevalence in South Africa, 2003-2007. AIDS Res Hum Retroviruses. 2009 Apr;25(4):405-9.

To understand the dynamics of the HIV epidemic and to plan HIV treatment and prevention programs, it is critical to know how HIV incidence in a population evolves over time. Bärnighausen and colleagues used data from a large population-based longitudinal HIV surveillance in a rural community in South Africa to test whether HIV incidence in this population has changed in the period from 2003 through 2007. They observed 563 seroconversions in 8095 individuals over 16,256 person-years at risk, yielding an overall HIV incidence of 3.4 per 100 person-years (95% confidence interval 3.1-3.7). The authors included time-dependent period dummy variables (in half-yearly increments) in age-stratified Cox regressions in order to test for trends in HIV incidence. They first did regression analyses separately for women and men. In both regressions, the coefficients of all period dummy variables were individually insignificant (all p >/= 0.338) and jointly insignificant (p = 0.764 and p = 0.111, respectively). They then did regression analysis using the pooled data on women and men, controlling for sex and interactions between sex and age. Again, the coefficients of the eight period dummy variables were individually insignificant (all p >/= 0.387) and jointly insignificant (p = 0.701). They show for the first time that high levels of HIV incidence have been maintained without any sign of decline over the past 5 years in both women and men in a rural South African community with high HIV prevalence. It is unlikely that the HIV epidemic in rural South Africa can be reversed without new or intensified efforts to prevent HIV infection.

Editors’ note: Changes in HIV prevalence figures are difficult to interpret as they reflect both the incidence of new infections and mortality in people living with HIV. What we really need to know is the trend in HIV incidence as this reflects the effectiveness of prevention programming and predicts eventual treatment demand. The findings from this prospective, longitudinal study are highly disturbing: with a constant, unrelenting incidence of 3.4 per 100 person-years, 15 out of every 100 people who were HIV-negative at the start of the study in 2003 had seroconverted by its end 5 years later. The prevention programmes that have been operating clearly do not reach enough people with effective prevention messages, skills building, and support for changed sexual behaviour norms. Safe male circumcision services, positive prevention programmes, and community mobilisation to address the structural factors underlying risk in this rural KwaZulu-Natal community are additional approaches that deserve immediate attention.

HIV programs in generalized epidemics have traditionally relied on antenatal clinic sentinel surveillance data to guide prevention and to model epidemic trends. Antenatal clinic data, however, come from a subset of the population, and their representativeness of the population has been debated. Musinguzi and colleagues compared data from a national population-based Uganda HIV Sero-Behavioral Survey with those from antenatal clinic sentinel surveillance. Using geographic information system, Uganda HIV Sero-Behavioral Survey clusters within a 30 km radius of the antenatal clinic sites were mapped. Estimates of HIV prevalence from antenatal clinic surveillance were compared with those from Uganda HIV Sero-Behavioral Survey. They found that the antenatal clinic-based HIV prevalence, 6.0% [confidence interval (CI) 5.5% to 6.5%], was similar to that from Uganda HIV Sero-Behavioral Survey, 5.9% (CI 5.4% to 6.4%). The antenatal clinic-based estimate correlated with that of Uganda HIV Sero-Behavioral Survey catchment area women who were pregnant and those who had given birth in the 2 years preceding the survey. Antenatal clinic data overestimated prevalence in the 15-year to 19-year age group, were similar to Uganda HIV Sero-Behavioral Survey for ages 20-29 years, and underestimated prevalence in older respondents. Antenatal clinic data underestimated HIV prevalence among women (6.0% vs. 7.4%; CI 6.6% to 8.2%) and urban women (7.6% vs. 12.7%) but was similar for rural women (5.3% vs. 4.9%). Antenatal clinic -based surveillance remains an important tool for monitoring HIV programs. Antenatal clinic and Uganda HIV Sero-Behavioral Survey data were similar overall and for 15-year to 29-year olds, women who were pregnant, and women who had a birth in the 2 years before the survey. Antenatal clinic estimates were lower in those >/=30 years and in urban areas. Periodic serosurveys to adjust antenatal clinic -based estimates are needed.

Editors’ note: In a mature epidemic such as Uganda’s, antenatal surveillance is likely to underestimate HIV prevalence in older women because older women can be at significant risk of acquiring HIV after the reproductive age and women with HIV who are of reproductive age tend to have lower fertility. Antenatal surveillance does generally reflect the general population prevalence among 15 to 29 year olds and in the age group 15 to 19 years it can be used as a general proxy measure of HIV incidence. Thus, antenatal clinic surveillance, supplemented by periodic population-based sero-behavioural surveys to provide an adjusted picture of national HIV epidemics, remains a valid surveillance tool.

To reconstruct the past HIV incidence and prevalence in Thailand from 1980 to 2008 and predict the country’s AIDS incidence from 2009 to 2011, nonparametric backcalculation was adopted utilizing 100 quarterly observed new AIDS counts excluding paediatric cases. The accuracy of data was enhanced through a series of data adjustments using the weight method to account for several surveillance reporting issues. The mixture of time-dependent distributions allowed the effects of age at seroconversion and antiretroviral therapy to be incorporated simultaneously. Sensitivity analyses were conducted to assess model variations that were subject to major uncertainties. Future AIDS incidence was projected for various predetermined HIV incidence patterns. HIV incidence in Thailand reached its peak in 1992 with approximately 115 000 cases. A steep decline thereafter discontinued in 1997 and was followed by another strike of 42 000 cases in 1999. The second surge, which happened concurrently with the major economic crisis, brought on 60 000 new infections. As of December 2008, more than 1 million individuals had been infected and around 430 000 adults were living with HIV corresponding to a prevalence rate of 1.2%. The incidence rate had become less than 0.1% since 2002. The backcalculated estimates were dominated by postulated median AIDS progression time and adjustments to surveillance data. The authors’ analysis indicated that, thus far, the 1990s was the most severe era of HIV epidemic in Thailand with two HIV incidence peaks. A drop in new infections led to a decrease in recent AIDS incidence, and this tendency is likely to remain unchanged until 2011, if not further.

Editors’ note: Backcalculation reconstructs a past pattern of HIV incidence based on AIDS surveillance data and a plausible incubation period from HIV infection to AIDS diagnosis. The relatively short incubation period of 7 years used in this work may have lowered the estimates of backcalculated total infections. Although it makes logical sense that the large cuts of one-third to one-half in government HIV prevention budgets during the financial crisis of 1998 to 2000 could have led to an intriguing second peak in HIV incidence in Thailand, further study is needed to confirm this.

Rennie S, Turner AN, Mupenda B, Behets F. Conducting unlinked anonymous HIV surveillance in developing countries: ethical, epidemiological, and public health concerns. PLoS Med. 2009 20;6(1):e4.

Data collected from HIV surveillance are crucial to guide public health interventions, planning, and prevention efforts. The practice of unlinked, anonymous HIV testing, an important form of HIV surveillance, raises ethical, epidemiological, and public health challenges in low-income countries. Some ways of conducting unlinked, anonymous HIV testing in the field violate the spirit and/or the letter of international ethical guidelines. Vulnerable populations, such as sex workers, may be subject to unjust treatment by local health authorities during HIV surveillance initiatives. Conducting unlinked, anonymous HIV testing in ethically and epidemiologically sound ways in low-income countries requires a multifaceted approach including local capacity building, community engagement, and increased access to HIV and testing for sexually transmitted infections.

Editors’ note: When Canada began anonymous unlinked HIV studies of leftover dried blood spot specimens in 1988, ethical requirements included public gazetting to raise community awareness and access to free, confidential, voluntary HIV counselling and testing for those who wished to learn their HIV status. The quality of HIV surveillance is not compromised by attention to ‘implementation ethics’ and can be enhanced through strengthened in-country capacity for the conduct of ethical epidemiological surveillance. Reviews of the methodological and ethical justifications for anonymous unlinked surveillance should be undertaken by key local stakeholders and ethics review boards to ensure that there are no breaches of confidentiality, there is access to HIV testing and counselling, unintended consequences are minimised, and there is a clear understanding among professionals, opinion leaders, and the public about the differences between case finding and public health surveillance.

Chokoshvili O, Abutidze A, Tsintsadze M, Gatserelia L, Badridze N. Overview of HIV epidemiological situation in Georgia. Georgian Med News. 2008;(165):87-94.

Georgia still belongs to the low HIV epidemic countries and by December 1 st, 2008 there were 1825 HIV cases registered at the Institute of Drug Addiction (IDACIRC) with an estimated number of 3500-4000 (estimated prevalence 0.09%). Majority of HIV patients are male (75%). Four hundred and sixty one patients were receiving antiretroviral treatment, including 23 children. Despite low HIV prevalence, Georgia is considered to be at risk for imminent epidemic spread of HIV mainly due to widespread drug use with high risk practices (needle-reuse), high levels of sexually transmitted infections, and migration to Russia, Ukraine, and other countries, and vice versa. The major route of HIV transmission is associated with drug injecting. At the moment approximately 60% of all reported HIV cases are due to drug injection. However, the heterosexual route of transmission has been gaining in importance, and increased from 29.1% to 36.1% for last five years. The first significant increases of HIV incidence were observed from 1999 to 2000 (2.24 times) and 2003 to 2004. From 2004 incidence has been relatively stable at 6.5-7/100,000. Most HIV positive patients are diagnosed at the age from 25 to 45. The highest HIV prevalence rates are found in Western Georgia, particularly Black Sea coast regions – Megrelia and Adjara (with prevalence of 131.11 and 132.03 among adult HIV cases per 100 000 adult population). Expanding educational activities and prevention interventions, including harm reduction and access to condoms, better financing of HIV programs, and improvement of capacity building will help the country to keep its HIV epidemic at a low prevalence and give it the possibility of achieving “Universal Access to HIV Prevention, Treatment, Care and Support” for 2010 year.

Editors’ note: Georgia began responding to HIV in 1994 and introduced universal access to antiretroviral treatment and care in 2004. No case of mother-to-child HIV transmission has been detected since the prevention of mother-to-child transmission programme was introduced in 2005. Its big challenge will be to reduce HIV transmission due to contaminated injecting equipment as the numbers of people who inject drugs continues to increase in seaside and border locations. Effective harm reduction programmes will be crucial to Georgia’s success in achieving universal access.

Nagelkerke N, de Vlas SJ, Jha P, Luo M, Plummer FA, Kaul R. Heterogeneity in host HIV susceptibility as a potential contributor to recent HIV prevalence declines in Africa. AIDS. 2009;23(1):125-30.

HIV prevalence has recently declined in several African countries, and prior to this the risk of HIV acquisition per unprotected sex contact also declined in Kenyan sex workers. Nagelkerke and colleagues hypothesized that heterogeneity in HIV host susceptibility might underpin both of these observations. A compartmental mathematical model was used to explore the potential impact of heterogeneity in susceptibility to HIV infection on epidemic behaviour, in the absence of other causative mechanisms. Studies indicated that a substantial heterogeneity in susceptibility to HIV infection may lead to an epidemic that peaks and then declines due to a depletion of the most susceptible individuals, even without changes in sexual behaviour. This effect was most notable in high-risk groups such as female sex workers and was consistent with empirical data. Declines in HIV prevalence may have other causes in addition to behaviour change, including heterogeneity in host HIV susceptibility. There is a need to further study this heterogeneity and its correlates, particularly as it confounds the ability to attribute HIV epidemic shifts to specific interventions, including behaviour change.

Editors’ note: Although there is compelling evidence that the HIV prevalence declines observed in many parts of Africa were likely caused by changes in risk behaviour, this model predicts that unevenly distributed susceptibility may have played a role. Genetic, immune, and infectious correlates of altered susceptibility mean that early HIV acquisition by more susceptible hosts may leave behind more resistant populations with reduced HIV incidence. Despite these underlying epidemic currents, HIV prevalence levels can remain high and each day the millions of young people who become sexually active join the ranks of the susceptible, underscoring the need for intensified combination prevention.

Dandona L, Dandona R, Kumar GA, Reddy GB, Ameer MA, Ahmed GM, Ramgopal SP, Akbar M, Sudha T, Lakshmi V. Risk factors associated with HIV in a population-based study in Andhra Pradesh state of India. Int J Epidemiol. 2008;37(6):1274-86. Epub 2008.

Population-based data on risk factors associated with HIV are not readily available from India. This understanding, and an estimate of the impact of addressing behavioural factors on reducing HIV, would be useful. Dandona and colleagues interviewed a population-based sample of 12,617 persons 15-49 years old from 66 rural and urban clusters in Guntur district in the south Indian state of Andhra Pradesh and tested their dried blood spots for HIV. They used multiple logistic regression to assess the association of risk factors with HIV, and calculated population impact numbers for HIV reduction if behavioural factors were addressed. Among men, there was significant association between HIV and history of sex with men, blood transfusion, having ever visited sex worker or multiple lifetime women sex partners, consuming alcohol before sex, recreational drug use, male non-circumcision, and tattooing (odds ratios 5.74-1.97, P < 0.03, R(2) = 0.11). Among women, the only identified behavioural factor associated with HIV was multiple lifetime men sex partners (P = 0.001, R(2) = 0.10). Taking into account the relative risk and prevalence of risk factors, the highest impact on reducing the HIV number per unit population was for male circumcision. Among the identified factors, male circumcision was estimated to have the highest relative impact on reducing HIV per unit population, but the feasibility of this intervention in India needs further investigation. The low explanatory power in the regression models of the usually considered risk factors for HIV suggests that better understanding of HIV dynamics at the population level in India is needed.

Editors’ note: In this analysis, behavioural risk variables could explain only a small fraction of the variability of prevalent HIV in the Andhra Pradesh population – 11% for men and 10% for women. This may be because there are associations other than recognized risk factors that were not explored or perhaps there was incomplete reporting by respondents about sensitive risk behaviour (8.8% of women and 43.4% of men reported having had sex with more than one person in their life). That male circumcision in urban men in India would have the biggest impact in reducing HIV prevalence provides food for thought in this country where male circumcision is associated with religious identity. Acceptability studies, community conversations, and situational analyses would be needed to assess the relevance of male circumcision for HIV prevention, along with prevention of human papilloma virus infection and genital ulcer disease in India.

Stover J, Fidzani B, Molomo BC, Moeti T, Musuka G. Estimated HIV trends and program effects in Botswana. PLoS ONE. 2008;3(11):e3729.

This study uses surveillance, survey, and programme data to estimate past trends and current levels of HIV in Botswana and the effects of treatment and prevention programmes. Data from sentinel surveillance at antenatal clinics and a national population survey were used to estimate the trend of adult HIV prevalence from 1980 to 2007. Using the prevalence trend, Stover and colleagues estimated the number of new adult infections, the transmission from mothers to children, the need for treatment and the effects of antiretroviral therapy and adult and child deaths. Prevalence has declined slowly in urban areas since 2000 and has remained stable in rural areas. National prevalence is estimated at 26% (25-27%) in 2007. About 330,000 (318,000-335,000) people are infected with HIV including 20,000 children. The number of new adult infections has been stable for several years at about 20,000 annually (12,000-26,000). The number of new child infections has declined from 4600 in 1999 to about 890 (810-980) today due to nearly complete coverage of an effective programme to prevent mother-to-child transmission (PMTCT). The annual number of adult deaths has declined from a peak of over 15,500 in 2003 to under 7400 (5000-11,000) today due to coverage of antiretroviral therapy that reaches over 80% in need. The need for antiretroviral therapy will increase by 60% by 2016. Botswana’s prevention of mother-to-child transmission and treatment programmes have achieved significant results in preventing new child infections and deaths among adults and children. The number of new adult infections continues at a high level. More effective prevention efforts are urgently needed.

Editors’ note: Botswana’s prevention of mother-to-child transmission programme reaches over 90% of HIV-positive women and coverage of people in need of antiretroviral treatment has increased to over 80%. Although Botswana has succeeded in stabilizing its HIV epidemic, it remains at a very high level. An estimated 24,000 people join the ranks of the treatment–eligible each year because of the high number of infections in the past. HIV prevention strategies need rethinking, particularly with respect to the continuing high level of partner concurrency, given that there is a seemingly stable number of 18,000 people newly infected per year today, all of whom will eventually require treatment.

Gyarmathy and colleagues assessed the prevalence of HIV and selected blood-borne and sexually transmitted infections among a convenience sample of 64 residents of Dzsumbuj, a predominantly Roma (Gypsy) neighbourhood in Budapest, Hungary. No cases of HIV were detected, while the prevalence of hepatitis B infection (anti-HBc) was 27% and syphilis prevalence was 2%. Romas (n = 50) were significantly more likely than non-Romas (n = 14) to have hepatitis A antibodies (80% vs. 43%) and less likely to be hepatitis B immunized (anti-HBs only; 6% vs. 29%). Current drug injectors (n = 13) were more likely than non-injectors (n = 51) to have antibodies against hepatitis A (85% vs. 69%) and hepatitis C (85% vs. 8%). While HIV has not been introduced in this population, risk conditions for a potentially explosive HIV epidemic are present. Health care policies should focus on expanding coverage for hepatitis A and hepatitis B immunizations, and access to HIV preventive services needs to be extended to marginalized, mostly minority populations, such as the Roma in Europe.

Editors’ note: Romas or gypsies, thought to comprise 5 to 10% of the population of Central and Eastern Europe, are a mobile, socially marginalised, hard-to-reach minority. This rapid assessment survey produced data that justify extending hepatitis A and hepatitis B immunization services as well as HIV preventive programmes to them now to improve health and block HIV from gaining a toehold in this disadvantaged population.