HIV This Week

Examining the promise of HIV elimination by 'test and treat' in hyperendemic settings.

Dodd PJ, Garnett GP, Hallett TB. AIDS. 2010 Feb 11. [Epub ahead of print]

It has been suggested that a new strategy for HIV prevention, 'Universal Test and Treat', whereby everyone is tested for HIV once a year and treated immediately with antiretroviral therapy if they are infected, could 'eliminate' the epidemic and reduce antiretroviral therapy costs in the long term. The authors investigated the impact of test-and-treat interventions under a variety of assumptions about the epidemic using a deterministic mathematical model. Their model shows that such an intervention can substantially reduce HIV transmission, but that impact depends crucially on the epidemiological context; in some situations, less aggressive interventions achieve the same results, whereas in others, the proposed intervention reduces HIV by much less. It follows that testing every year and treating immediately is not necessarily the most cost-efficient strategy. Dodd and colleagues also show that a test-and-treat intervention that does not reach full implementation or coverage could, perversely, increase long-term antiretroviral therapy costs. Interventions that prevent new infections through antiretroviral therapy scale-up may hold substantial promise. However, as plans move forward, careful consideration should be given to the nature of the epidemic and the potential for perverse outcomes.

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Editors’ note: This modelling analysis highlights three important aspects of ‘test and treat’ strategies that require thoughtful consideration. The first is epidemic context and, in particular, the properties of the sex partner network (heterogeneity, concurrency, and mixing) that can influence the impact of a ‘test and treat’ approach. The second is the diminishing returns of yearly testing – this modelling suggests that testing everyone every 3 to 5 years appears most cost-efficient, depending on the epidemic context, life expectancy, and the costs of testing and treatment. The third is the dramatic spiralling in treatment costs that is likely if testing is not frequent enough and treatment coverage is suboptimal. These qualitative insights are helpful and they show that we need more evidence to inform the modelling. There is no doubt that the science underpinning ‘test and treat’ is promising: viral load drops in individuals placed on antiretroviral treatment and reduced transmission in discordant couple studies. Policy makers need the results of clinical trials, such as HPTN 052, and community impact evaluations such as the British Columbia Seek and Treat pilot project and the NIH Test and Treat feasibility assessments in Washington and the Bronx, to inform policy and programming. In the meantime, millions of people in need of treatment now, whether defined by the old under 200 CD4+ count criterion or the new under 350 CD4+ cell count guidelines, will die if we don’t get treatment to them urgently.

Cost-effectiveness of routine rapid human immunodeficiency virus antibody testing before DNA-PCR testing for early diagnosis of infants in resource-limited settings.

Menzies NA, Homsy J, Chang Pitter JY, Pitter C, Mermin J, Downing R, Finkbeiner T, Obonyo J, Kekitiinwa A, Tappero J, Blandford JM. Pediatr Infect Dis J. 2009 28:819-25.

Infants born to HIV-infected women should receive HIV testing to allow early diagnosis and treatment. Recommendations for resource-limited settings stress laboratory-based virologic assays. While effective, these tests are logistically complex and expensive. This study explored the cost-effectiveness of incorporating initial screening with rapid HIV tests into the conventional testing algorithm to screen-out HIV-uninfected infants, thereby reducing the need for costly virologic testing. Data on HIV prevalence, rapid HIV tests sensitivity and specificity, and costs were collected from 820 HIV-exposed children (1.5-18 months) attending 2 postnatal screening programs in Uganda during July 2005 to December 2006. Cost-effectiveness models compared the conventional testing algorithm DNA polymerase chain reaction (DNA-PCR with Roche Amplicor v1.5) with a modified algorithm (initial rapid HIV tests to screen-out HIV-uninfected infants before DNA-PCR). The model estimated that the conventional algorithm would identify 94.3% (91.8%-94.7%) of HIV-infected infants, compared with 87.8% (79.4%-90.5%) for a modified algorithm using rapid HIV tests (HIV 1/2 Determine) and excluding the need for DNA-PCR for HIV antibody-negative infants. Costs per infant were $23.47 ($23.32-$23.76) for the conventional algorithm and between $22.75 ($21.89-$23.31) and $7.58 ($6.41-$10.75) for the modified algorithm, depending on infant age and symptoms. Compared with the conventional algorithm, costs per HIV-infected infant identified using the modified algorithm were higher in 1.5-to 3-month-old infants, but significantly lower in 3-month-old and older infants. Models replicating the whole infant testing program showed the modified algorithm would have marginally lower sensitivity, but would reduce total program costs by 27% to 40%, producing an incremental cost-effectiveness ratio of $1489 ($686-$6781) for the conventional versus modified algorithms. Screening infants with rapid HIV tests before DNA-PCR is cost-effective in infants 3 months old or older. Incorporating rapid HIV tests into early infant testing programs could improve cost-effectiveness and reduce program costs.

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Editors’ note: In the absence of antiretroviral prophylaxis, between 70 and 85% of infants born to mothers with HIV infection do not acquire HIV during pregnancy, labour, and delivery. However, all infants born to such mothers will have a positive HIV antibody test because their mother’s HIV antibodies cross the placenta before birth and persist in the baby’s blood up to 18 months of age. Because parents want to know whether their baby is infected and because antiretroviral treatment should be started in infants as soon as HIV infection is detected, it is not acceptable to wait until 18 months of age for a negative HIV antibody test to confirm that the baby has no antibodies of its own. Current policy in Uganda recommends testing of all HIV-exposed infants at 10 weeks of age, at their second immunization visit, by DNA-PCR which detects the virus itself, not antibodies. Although cost-effectiveness studies such as this one are context-specific with results varying by HIV prevalence, costs of supplies and personnel, equipment, etc., they are nonetheless of interest for programme planners in similar settings. The idea of using a rapid test to screen out infants that are likely not infected and then use the DNA-PCR test only on those that are rapid test-positive is partly motivated by the cost and complexity of DNA-PCR testing and partly by an appreciation of the visit burden imposed on parents by repeated testing visits should the first DNA-PCR be negative and the baby continues to breastfeed. Given that the algorithm studied here was cost-effective only in infants 3 months or older, there is not much to suggest that Uganda should change its current 10-week DNA-PCR testing policy. Using a rapid test to screen above that age in breastfeeding infants in order to decide whether a DNA-PCR should be done could be considered.

Cost-effectiveness of newborn circumcision in reducing lifetime HIV risk among U.S. males.

Sansom SL, Prabhu VS, Hutchinson AB, An Q, Hall HI, Shrestha RK, Lasry A, Taylor AW. PLoS One. 2010;5:e8723.

HIV incidence was substantially lower among circumcised versus uncircumcised heterosexual African men in three clinical trials. Based on those findings, the authors modelled the potential effect of newborn male circumcision on a U.S. male's lifetime risk of HIV, including associated costs and quality-adjusted life-years saved. Given published estimates of U.S. males' lifetime HIV risk, they calculated the fraction of lifetime risk attributable to heterosexual behaviour from 2005-2006 HIV surveillance data. They assumed 60% efficacy of circumcision in reducing heterosexually-acquired HIV over a lifetime, and varied efficacy in sensitivity analyses. They calculated differences in lifetime HIV risk, expected HIV treatment costs and quality-adjusted life years (QALYs) among circumcised versus uncircumcised males. The main outcome measure was cost per HIV-related QALY saved. Circumcision reduced the lifetime HIV risk among all males by 15.7% in the base case analysis, ranging from 7.9% for white males to 20.9% for black males. Newborn circumcision was a cost-saving HIV prevention intervention for all, black, and Hispanic males. The net cost of newborn circumcision per QALY saved was $87,792 for white males. Results were most sensitive to the discount rate, and circumcision efficacy and cost. Newborn circumcision resulted in lower expected HIV-related treatment costs and a slight increase in QALYs. It reduced the 1.87% lifetime risk of HIV among all males by about 16%. The effect varied substantially by race and ethnicity. Racial and ethnic groups who could benefit the most from circumcision may have least access to it due to insurance coverage and state Medicaid policies, and these financial barriers should be addressed. More data on the long-term protective effect of circumcision on heterosexual males as well as on its efficacy in preventing HIV among men who have sex with men would be useful.

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Editors’ note: This cost-effectiveness analysis in the USA, which assessed the impact of infant male circumcision programmes on the lifetime HIV risk from heterosexual contact, found that African American and Hispanic males would benefit most from newborn circumcision. They have a higher lifetime risk of HIV, a higher risk of acquiring through heterosexual contact (6.2% for black males versus 0.94% for white males), and lower adult male circumcision prevalence. Although 88% of white males are circumcised, this figure falls to 73% among black males, and 42% among Hispanic males. However, these very populations are often least likely, on financial and insurance coverage grounds, be able to obtain newborn circumcision in the current US health care system should they decide to circumcise their male infants on health grounds. These include reduced risk of some sexually transmitted infections, infant urinary tract infections, penile cancer and cervical cancer in female partners. Cost-effectiveness analysis can inform decision-making when conditions for implementation are in place. In this case, the long road to health care reform in the USA has possibly been a major factor delaying policy change on infant male circumcision in the USA.

Estimation of antiretroviral therapy coverage: methodology and trends.

Mahy M, Tassie JM, Ghys PD, Stover J, Beusenberg M, Akwara P, Souteyrand Y. Curr Opin HIV AIDS. 2010 5:97-102.

The purpose of this review was to present the methodology used to calculate coverage of antiretroviral therapy and review global and regional trends in antiretroviral therapy coverage. There has been a steady increase in antiretroviral therapy coverage over the last decade with a more rapid increase in recent years. Current estimates of antiretroviral therapy coverage are 43% for adults and 38% for children (ages 0-14 years). Methods for calculating coverage rely on good-quality patient monitoring systems in countries, and well informed models are needed to estimate the number of people in need of treatment. The estimated coverage rates show that antiretroviral therapy programs have improved over the past 8 years; however, approximately 58% (53-60%) of those people in need of antiretroviral therapy are still not on treatment. High quality data are needed to accurately measure changes in antiretroviral therapy coverage.

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Editors’ note:  Antiretroviral treatment coverage is defined as the percentage of people on treatment (the numerator) among those in need of treatment (the denominator). Few countries, notably Brasil and Zambia, have a monitoring system based on individual information. Elsewhere facility-based reporting of aggregated data based on patient and pharmacy monitoring is compiled to produce a national level estimate. In 2008, 91% of 149 low- and middle-income countries reported the number of people on antiretroviral treatment and 64% reported disaggregating data by sex. The estimated 9.5 million (8.6-10 million) people currently in need of antiretroviral treatment will be joined by many million more as countries begin to adopt the new WHO antiretroviral treatment guidelines. Therefore, although the numerator (those on treatment), estimated at over 4 million (3.7-4.4 million) in 2008, is steadily growing, the denominator is set to rise dramatically. Regardless of whether the old or the new denominator or both are used to determine coverage, the focus should be on accelerating the growth of the numerator!

Acyclovir and Transmission of HIV-1 from Persons Infected with HIV-1 and HSV-2.

Celum C, Wald A, Lingappa JR, Magaret AS, Wang RS, Mugo N, Mujugira A, Baeten JM, Mullins JI, Hughes JP, Bukusi EA, Cohen CR, Katabira E, Ronald A, Kiarie J, Farquhar C, Stewart GJ, Makhema J, Essex M, Were E, Fife KH, de Bruyn G, Gray GE, McIntyre JA, Manongi R, Kapiga S, Coetzee D, Allen S, Inambao M, Kayitenkore K, Karita E, Kanweka W, Delany S, Rees H, Vwalika B, Stevens W, Campbell MS, Thomas  KK, Coombs RW, Morrow R, Whittington WL, McElrath MJ, Barnes L, Ridzon R, Corey L; the Partners in Prevention HSV/HIV Transmission Study Team. N Engl J Med. 2010 362(5):427-39.

Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1. Celum et al conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, >/=250 cells per cubic millimetre) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrolment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses. A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimetre. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval [CI], 0.60 to 1.41; P=0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log(10) copies per millilitre (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2-positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed. Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log(10) copies per millilitre and a 73% reduction in the occurrence of genital ulcers due to HSV-2.

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Editors’ note: Given that the majority of people with HIV infection also have herpes simplex-2 (HSV-2) infection, genital shedding of herpes occurs on up to 30% of days in co-infected people living with HIV even when they have no symptoms, and HSV-2 reactivation without symptoms has been associated with increased HIV viral load in the blood plasma and genital tract, there was good reason to conduct a large trial of serodiscordant couples to see if herpes suppression would reduce HIV transmission. After all, five trials had already shown that daily suppressive therapy for HSV-2 reduced plasma HIV viral load. Of 6543 HIV-discordant couples screened, 3408 were enrolled at 14 sites in Botswana, South Africa, Zambia, Kenya, Rwanda, Tanzania, and Uganda. With adherence to acyclovir/placebo high and HIV infections acquired outside the couple excluded from the final analysis through genotyping to link transmitted viruses, this well-powered trial gave an unequivocal answer. Despite reductions in HIV viral load, acyclovir did not reduce HIV transmission. However, this study documented a 16% reduction in disease progression for those in the acyclovir arm, all of whom started the study with CD4+ counts above 250. This suggests that, for their own health, co-infected people who are not yet eligible for antiretroviral treatment may benefit from daily acyclovir – it is off-patent and cheap and has few side effects.