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Retention in care under universal antiretroviral therapy for HIV-infected pregnant and breastfeeding women ('Option B+') in Malawi.

Tenthani L et al. AIDS 2014;28:589–98.

• This study investigated the levels and determinants of loss to follow-up with universal lifelong ART for pregnant and breastfeeding women ('Option B+') in Malawi. • Of 21,939 women who started ART under Option B+, 17% appeared to be lost to follow-up 6 months after initiation of ART. Most losses occurred within the first 3 months. • Patients who started ART during pregnancy were five times more likely to never return after their initial clinic visit [OR: 5.0; 95% CI: 4.2–6.1] than women who started ART at WHO stage 3/4 or with a CD4 cell count ≤350 cells/μL. • Patients who started ART while breastfeeding were twice as likely to miss their first follow-up visit (OR: 2.2; 95% CI: 1.8–2.8). • Loss to follow-up varied considerably between facilities, ranging from 0% to 58%. • Conclusions: The effectiveness of Option B+ will be improved by reducing loss to follow-up. Tailored interventions, e.g. community or family-based models of care, could also help.

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Editorial Option B+ for prevention of mother-to-child transmission of HIV in resource-constrained settings: great promise but some early caution.

Shaffer N et al. AIDS 2014;28:599–601.

• This study investigated the levels and determinants of loss to follow-up with universal lifelong ART for pregnant and breastfeeding women ('Option B+') in Malawi. • Of 21,939 women who started ART under Option B+, 17% appeared to be lost to follow-up 6 months after initiation of ART. Most losses occurred within the first 3 months. • Patients who started ART during pregnancy were five times more likely to never return after their initial clinic visit [OR: 5.0; 95% CI: 4.2–6.1] than women who started ART at WHO stage 3/4 or with a CD4 cell count ≤350 cells/μL. • Patients who started ART while breastfeeding were twice as likely to miss their first follow-up visit (OR: 2.2; 95% CI: 1.8–2.8). • Loss to follow-up varied considerably between facilities, ranging from 0% to 58%. • Conclusions: The effectiveness of Option B+ will be improved by reducing loss to follow-up. Tailored interventions, e.g. community or family-based models of care, could also help.

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Sexual behaviour of heterosexual men and women receiving antiretroviral pre-exposure prophylaxis for HIV prevention: a longitudinal analysis.

Mugwanya KK et al. Lancet Infect Dis 2013;13:1021–8.

• This longitudinal analysis of data from the Partners PrEP Study investigated whether the use of PrEP in HIV– men and women in HIV-serodiscordant couples (n=3,163, aged ≥18 years) was associated with increased sexual risk behaviour. • The average frequency of unprotected sex with the HIV+ study partner was 59 per 100 person-months before unmasking versus 53 after unmasking. • Conclusion: as part of a comprehensive prevention package, PrEP might not result in substantial changes in sexual risk behaviour by heterosexual couples.

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Are they really lost? "True" status and reasons for treatment discontinuation among HIV infected patients on antiretroviral therapy considered lost to follow up in urban Malawi.

Tweya H et al. PLoS One 2013;8(9):e75761.

• This study investigated the extent to which patients considered lost to follow-up (LTFU) are misclassified as true disengagement from care when they are still taking ART. • Adult patients receiving ART who missed a clinic appointment by >3 weeks between January 2006 and December 2010 were identified. Patients considered LTFU were traced and true ART status documented. • Of 3,176 traced patients, 952 (30%) were dead and 2,224 (70%) were alive, of who 2,183 (99.5%) had started ART. • Of the patients who had started ART, 957 (44%) had stopped and 1,226 (56%) were continuing treatment by sourcing drugs from another clinic, using alternative ART sources or taking ART interruptions. • Among 940 cases with documented reasons for discontinuing ART, failure to remember (17%), too weak/sick (12%), travel (46%) and lack of transport (16%) were the most frequent cited. • Conclusions: The LTFU category includes a large proportion of patients still taking ART that may potentially bias retention estimates and misdirect resources at the clinic and national levels if not properly accounted for. • Clinics should consider further decentralisation efforts, increase drug allocations for frequent travellers and improve communication on patient transfers between clinics to increase retention and adherence.

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When to Start ART in Africa - An Urgent Research Priority.

De Cock KM, El-Sadr WM. N Engl J Med. 2013 Feb 20. [Epub ahead of print]

• This ‘Perspective’ article discusses the issues surrounding ART initiation in Africa. • At least two thirds of people living with HIV infection are in sub-Saharan Africa. • Debates about how best to use ART for both prevention and individual health are most relevant to the generalised HIV epidemics in this poorest geographic region. • TB rates have increased by a factor of 5–10 in sub-Saharan Africa since the HIV–AIDS epidemic began. • Mathematical modelling and a meta-analysis of treatment experience in resource-poor settings suggest that early ART could reduce the incidence of TB among patients with a wide range of CD4 counts but conclusive data are lacking. • Early initiation of ART in Africa might also prevent HIV transmission. • Mathematical models predict a large-scale effect from immediate ART use by all infected persons. • Conclusion: A randomised, controlled trial should be undertaken immediately to determine when to initiate ART in Africa for maximal individual health benefit.

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Increases in adult life expectancy in rural South Africa: valuing the scale-up of HIV treatment.

Bor J et al. Science 2013;339:961–5

• This study measured changes in adult life expectancy from 2000–2011, using data from a population cohort of >101,000 individuals in rural KwaZulu-Natal, South Africa. • In 2003, the year before ART became available in the public-sector health system, adult life expectancy was 49.2 years. By 2011, this had increased to 60.5 years, an 11.3-year gain. • Based on a standard monetary valuation of life, the survival benefits of ART far outweigh the costs of providing treatment in this community. • Conclusions: The gains in adult life expectancy show the social value of ART and have implications for the investment decisions of individuals, governments and donors.

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High coverage of ART associated with decline in risk of HIV acquisition in rural KwaZulu-Natal, South Africa.

Tanser F et al. Science 2013;339:966–71.

• This study investigated HIV seroconversion from 2004–2011 among 16,667 individuals HIV– at baseline, using data from one of Africa's largest population-based prospective cohort studies (in rural KwaZulu-Natal, South Africa). • Individual HIV acquisition risk declined significantly with increasing ART coverage in the surrounding local community. • An HIV– individual living in a community with high ART coverage (30–40% of HIV+ individuals on ART) was 38% less likely to acquire HIV than someone living in a community with low ART coverage (<10% HIV+ individuals on ART). • Conclusion: The risk of acquiring HIV declined significantly with increasing ART coverage in the local community.

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Editorial commentary: turning the tide on HIV in women and children: preventing breast-milk HIV transmission while increasing maternal life expectancy.

Becquet R, Dabis F. Clin Infect Dis 2013;56:140–2.

• In this pooled data analysis of 5,396 mother-infant pairs (infants HIV– at birth) from five randomised trials, the efficacy of infant NVP prophylaxis to prevent breast-milk transmission was estimated. • Four daily regimens were compared: NVP for 6, 14 or 28 weeks or NVP+AZT for 14 weeks. • The estimated 28-week risk of HIV transmission was 5.8% (95% CI: 4.3–7.9%), 3.7% (95% CI: 2.5–5.4%), 4.8% (95% C: 3.5–6.7%) and 1.8% (95% CI: 1.0–3.1%), respectively (log-rank test for trend, p<0.001). • NVP reduced the rate of HIV infection by 71% (95% CI: 58–80%; p<0.001) and the rate of HIV infection or death by 58% (95% CI: 45–69%; p<0.001). • Conclusions: Extended prophylaxis with NVP or NVP+AZT significantly reduced postnatal HIV infection. A longer duration of prophylaxis resulted in a greater risk reduction.

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Pooled individual data analysis of 5 randomized trials of infant nevirapine prophylaxis to prevent breast-milk HIV-1 transmission.

Hudgens MG et al. Clin Infect Dis 2013;56:131–9.

• In this pooled data analysis of 5,396 mother-infant pairs (infants HIV– at birth) from five randomised trials, the efficacy of infant NVP prophylaxis to prevent breast-milk transmission was estimated.
• Four daily regimens were compared: NVP for 6, 14 or 28 weeks or NVP+AZT for 14 weeks.
• The estimated 28-week risk of HIV transmission was 5.8% (95% CI: 4.3–7.9%), 3.7% (95% CI: 2.5–5.4%), 4.8% (95% C: 3.5–6.7%) and 1.8% (95% CI: 1.0–3.1%), respectively (log-rank test for trend, p<0.001).
• NVP reduced the rate of HIV infection by 71% (95% CI: 58–80%; p<0.001) and the rate of HIV infection or death by 58% (95% CI: 45–69%; p<0.001).
• Conclusions: Extended prophylaxis with NVP or NVP+AZT significantly reduced postnatal HIV infection. A longer duration of prophylaxis resulted in a greater risk reduction.

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Diagnosis, clinical presentation, and in-hospital mortality of severe malaria in HIV-coinfected children and adults in Mozambique.

Hendriksen IC et al. Clin Infect Dis 2012;55:1144–53.

• This study investigated whether HIV affects the clinical presentation and outcome of severe malaria. • HIV status was prospectively assessed in hospitalised parasitaemic adults and children with severe malaria in Beira, Mozambique. Clinical signs, co-morbidity, complications and disease outcome were compared according to HIV status. • HIV-1 seroprevalence was 11% (74/655) in children aged <15 years and 72% (49/68) in adults with severe malaria. • Children with HIV co-infection presented with more severe acidosis, anaemia and respiratory distress plus higher peripheral blood parasitaemia and plasma Plasmodium falciparum histidine-rich protein-2 (PfHRP2). • During hospitalisation, deterioration in coma score, convulsions, respiratory distress and pneumonia were more common in HIV-co-infected than uninfected children, as was mortality (19/74 [26%] vs 53/58 [19%]; p<0.001). • Conclusions: Severe malaria in HIV-co-infected patients has a higher case fatality rate and presents with a higher parasite burden, more complications and greater co-morbidity. Early identification of HIV co-infection is important for the clinical management of severe malaria.

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Editorial: What is the optimal first line antiretroviral therapy in resource-limited settings?

Kenyon C, Colebunders R. PLoS Med 2012;9(8):e1001291.

• This study investigated the efficacy and safety of ARV regimens with qd versus bid dosing in different regions of the world. • 1,571 HIV-1+ persons (47% women) from nine countries in four continents were assigned with equal probability to open-label ART with EFV+3TC-ZDV, ATV+DDI+FTC or EFV+FTC-TDF. • ATV+DDI+FTC and EFV+FTC-TDF were hypothesised to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% CI for the HR was ≤1.35 when 30% of participants had treatment failure. • During a median of 184 weeks’ follow-up, 95/526 EFV+FTC-TDF patients (18%) versus 98/519 EFV+3TC-ZDV patients (19%) were treatment failures (HR: 0.95; 95% CI: 0.72–1.27; p = 0.74). • Safety endpoints occurred in 243 EFV+FTC-TDF patients (46%) versus 313 EFV+3TC-ZDV patients (60%) (HR: 0.64; 95% CI: 0.54–0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR: 0.50; 95% CI: 0.39–0.64 for women; HR: 0.79; 95% CI: 0.62–1.00 for men; p = 0.01). • During a median of 81 weeks’ follow-up, 108/526 ATV+DDI+FTC patients (21%) versus 76/519 EFV+3TC-ZDV patients (15%) were treatment failures (HR: 1.51; 95% CI: 1.12–2.04; p = 0.007). • Conclusions: EFV+FTC-TDF had similar high efficacy to EFV+3TC-ZDV. Superior safety, especially in HIV-1+ women and qd dosing of EFV+FTC-TDF were advantages for initial treatment of HIV-1 in resource-limited countries. • ATV+DDI+FTC had inferior efficacy and is not recommended as an initial ARV regimen.

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Efficacy and safety of three antiretroviral regimens for initial treatment of HIV-1: a randomized clinical trial in diverse multinational settings.

Campbell TB et al. PLoS Med 2012;9(8):e1001290.

• This study investigated the efficacy and safety of ARV regimens with qd versus bid dosing in different regions of the world. • 1,571 HIV-1+ persons (47% women) from nine countries in four continents were assigned with equal probability to open-label ART with EFV+3TC-ZDV, ATV+DDI+FTC or EFV+FTC-TDF. • ATV+DDI+FTC and EFV+FTC-TDF were hypothesised to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% CI for the HR was ≤1.35 when 30% of participants had treatment failure. • During a median of 184 weeks’ follow-up, 95/526 EFV+FTC-TDF patients (18%) versus 98/519 EFV+3TC-ZDV patients (19%) were treatment failures (HR: 0.95; 95% CI: 0.72–1.27; p = 0.74). • Safety endpoints occurred in 243 EFV+FTC-TDF patients (46%) versus 313 EFV+3TC-ZDV patients (60%) (HR: 0.64; 95% CI: 0.54–0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR: 0.50; 95% CI: 0.39–0.64 for women; HR: 0.79; 95% CI: 0.62–1.00 for men; p = 0.01). • During a median of 81 weeks’ follow-up, 108/526 ATV+DDI+FTC patients (21%) versus 76/519 EFV+3TC-ZDV patients (15%) were treatment failures (HR: 1.51; 95% CI: 1.12–2.04; p = 0.007). • Conclusions: EFV+FTC-TDF had similar high efficacy to EFV+3TC-ZDV. Superior safety, especially in HIV-1+ women and qd dosing of EFV+FTC-TDF were advantages for initial treatment of HIV-1 in resource-limited countries. • ATV+DDI+FTC had inferior efficacy and is not recommended as an initial ARV regimen.

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Editorial. Viral load monitoring in resource-limited settings: a medical and public health priority.

Ford N et al. AIDS 2012;26:1719–20. Aug

• This analysis used a Markov model to compare the cost-effectiveness of three different strategies for long-term monitoring of ART failure and regimen switching in sub-Saharan Africa: a symptom-based approach and monitoring of either CD4 cell counts or VL.
• A symptom-based approach produced a life expectancy of 64.0 months at a total cost of US$4,028/person.
• Both laboratory-based strategies, at testing intervals of 6 or 12 months, were cost saving and improved life expectancy versus a symptom-based approach.
• The life-expectancy gain was larger for VL than CD4 count at 6- (2.3 versus 0.9 months) and 12-monthly testing (2.0 versus 0.8 months).
• Cost savings of 6-monthly VL or CD4 count were similar (US$630 versus US$621), whereas 12-monthly CD4 counts were more cost-saving than 12-monthly VL (US$1,132 versus US$880).
• Conclusion: Routine VL monitoring may be preferred as a replacement for CD4 cell counts because of its additional public-health advantages in preventing drug resistance, supporting adherence and reducing HIV transmission.

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Cost-effectiveness of laboratory monitoring for management of HIV treatment in sub-Saharan Africa: a model-based analysis.

Hamers RL et al. AIDS 2012;26:1663–1672. August

• This analysis used a Markov model to compare the cost-effectiveness of three different strategies for long-term monitoring of ART failure and regimen switching in sub-Saharan Africa: a symptom-based approach and monitoring of either CD4 cell counts or VL.
• A symptom-based approach produced a life expectancy of 64.0 months at a total cost of US$4,028/person.
• Both laboratory-based strategies, at testing intervals of 6 or 12 months, were cost saving and improved life expectancy versus a symptom-based approach.
• The life-expectancy gain was larger for VL than CD4 count at 6- (2.3 versus 0.9 months) and 12-monthly testing (2.0 versus 0.8 months).
• Cost savings of 6-monthly VL or CD4 count were similar (US$630 versus US$621), whereas 12-monthly CD4 counts were more cost-saving than 12-monthly VL (US$1,132 versus US$880).
• Conclusion: Routine VL monitoring may be preferred as a replacement for CD4 cell counts because of its additional public-health advantages in preventing drug resistance, supporting adherence and reducing HIV transmission.

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Editorial: Preexposure prophylaxis for HIV - where do we go from here?

Cohen MS, Baden LR. N Engl J Med 2012 Jul 11. [Epub ahead of print].

• This randomised study investigated the use of oral ART pre-exposure prophylaxis among HIV-1-serodiscordant heterosexual couples in Kenya and Uganda.
• The HIV-1-seronegative partner in each couple was randomly assigned to one of three regimens (TDF qd, combination TDF-FTC or placebo) and followed monthly for up to 36 months.
• Of 4,747 couples, 1,584 received TDF, 1,579 TDF-FTC and 1,584 placebo. In 62% of couples, the HIV-1-seronegative partner was male.
• 82 HIV-1 infections occurred in seronegative partners during the study: 17 in the TDF group (incidence, 0.65 per 100 person-years); 13 in the TDF-FTC group (incidence, 0.50 per 100 person-years) and 52 in the placebo group (incidence, 1.99 per 100 person-years).
• The relative reduction in the incidence of HIV-1 was 67% with TDF (95% CI: 44–81; p<0.001) and 75% with TDF-FTC (95% CI: 55–87; p<0.001).
• Conclusions: Oral TDF and TDF-FTC protected against HIV-1 infection in heterosexual men and women.

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Antiretroviral prophylaxis for HIV prevention in heterosexual men and women.

Baeten JM et al. N Engl J Med 2012 Jul 11. [Epub ahead of print].

• This randomised study investigated the use of oral ART pre-exposure prophylaxis among HIV-1-serodiscordant heterosexual couples in Kenya and Uganda. • The HIV-1-seronegative partner in each couple was randomly assigned to one of three regimens (TDF qd, combination TDF-FTC or placebo) and followed monthly for up to 36 months. • Of 4,747 couples, 1,584 received TDF, 1,579 TDF-FTC and 1,584 placebo. In 62% of couples, the HIV-1-seronegative partner was male. • 82 HIV-1 infections occurred in seronegative partners during the study: 17 in the TDF group (incidence, 0.65 per 100 person-years); 13 in the TDF-FTC group (incidence, 0.50 per 100 person-years) and 52 in the placebo group (incidence, 1.99 per 100 person-years). • The relative reduction in the incidence of HIV-1 was 67% with TDF (95% CI: 44–81; p<0.001) and 75% with TDF-FTC (95% CI: 55–87; p<0.001). • Conclusions: Oral TDF and TDF-FTC protected against HIV-1 infection in heterosexual men and women.

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Pregnancy and infant outcomes among HIV-infected women taking long-term ART with and without tenofovir in the DART trial.

Gibb DM et al. PLoS Med 2012 May;9(5):e1001217.

• This study investigated pregnancy outcome and maternal/infant ART in Ugandan/Zimbabwean HIV-infected women initiating ART during the DART trial. • Of 226 live births, seven (3%) infants died <2 weeks from perinatal causes and there were seven (3%) congenital abnormalities, with no effect of in utero TDF exposure (p>0.4). • Of 219 surviving infants, 182 (83%) enrolled in a follow-up study. From mothers' ART, 62/9/111 infants had no/20–89%/≥90% in utero TDF exposure; most were also exposed to AZT/3TC. • All 172 infants tested were HIV–. Overall, 14 infants died at a median age of 9 months (IQR 3–23), giving a 12-month mortality of 5%. • During follow-up, no bone fractures were reported. There was no evidence that in utero TDF affected growth after 2 years (p=0.38). • Conclusions: The 1-year infant mortality (5%) was similar to the 2–4% post-neonatal mortality observed in the region. No increase in congenital, renal or growth abnormalities was observed with in utero TDF exposure.

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Impact of antiretroviral therapy on tuberculosis incidence among HIV-positive patients in high-income countries.

The HIV-CAUSAL Collaboration. Clin Infect Dis 2012;54:1364–72.

• This study estimated the effect of combination ART on TB incidence in HIV+ individuals in high-income countries in the HIV-CAUSAL Collaboration, which consisted of 12 cohorts from the United States and Europe of HIV+, ART-naïve, AIDS-free individuals aged ≥18 years with baseline CD4 cell count and HIV RNA levels followed up from 1996–2007. • Of 65,121 individuals, 712 developed TB over 28 months’ median follow-up (incidence, 3.0 cases per 1,000 person-years). • The HR for TB with ART versus no ART was 0.56 (95% CI: 0.44–0.72) overall, 1.04 (95% CI: 0.64–1.68) for individuals aged >50 years and 1.46 (95% CI: 0.70–3.04) for people with a CD4 cell count <50 cells/mm3. • Compared with people who had not started ART, HRs differed by time since ART initiation: 1.36 (95% CI: 0.98–1.89) for initiation <3 months and 0.44 (95% CI: 0.34–0.58) for initiation ≥3 months ago. • Compared with people who had not initiated ART, HRs <3 months after ART initiation were 0.67 (95% CI: 0.38–1.18), 1.51 (95% CI: 0.98–2.31) and 3.20 (95% CI: 1.34–7.60) for people aged <35, 35–50 and >50 years, respectively, and 2.30 (95% CI: 1.03–5.14) for people with a CD4 cell count <50 cells/mm3. • Conclusions: TB incidence decreased after ART initiation but not among people aged >50 years or with CD4 cell counts <50 cells/mm3. • Despite an overall decrease in TB incidence, the increased rate during 3 months of ART suggests unmasking immune reconstitution inflammatory syndrome.

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The macroeconomic consequences of renouncing to universal access to antiretroviral treatment for HIV in Africa: a micro-simulation model.

Ventelou B et al. PLoS One 2012;7(4):e34101.

• This study used a micro-simulation model based on individuals aged 15–49 years selected from nationally representative surveys (Cameroon, Tanzania and Swaziland) to forecast the consequences of alternative scenarios for a country’s macroeconomic performance. • The two scenarios were freezing ART programmes to current levels of access and universal access (scaling up to 100% coverage by 2015, with two variants defining ART eligibility according to previous or current WHO guidelines). • Increased levels of ART coverage result in decreasing HIV incidence and related mortality. • Universal access implied net cost-savings at the society scale when the full macroeconomic consequences were introduced in the calculations. • Conclusions: Universal access to ART with scaling-up strategies, which are more costly in the short term, remain the best economic choice in the long term.

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The cost-effectiveness of cotrimoxazole in people with advanced HIV infection initiating antiretroviral therapy in sub-Saharan Africa.

Abimbola TO, Marston BJ. J Acquir Immune Defic Syndr 2012;60:e8–14.

• This study evaluated the cost-effectiveness and possible cost savings related to prevention of specific opportunistic infections (OIs) of expanding access to cotrimoxazole (CTX) for HIV+ patients in averting mortality during the first 6 months of ART in sub-Saharan Africa. • A decision-analytic model was developed to estimate the incremental cost, deaths averted and incremental cost-effectiveness ratio. • Full coverage reduced deaths from 94 to 72 per 1000 patients, averting 22 deaths during the first 6 months of ART vs the base case. • The incremental cost of moving from base case to full coverage was estimated at $3.29 per person on ART and $146.91 per death averted over 6 months. • Additional benefits from averted OI cases would likely be realised as well as savings from averted OI treatment costs. • Conclusions: The results suggest that expanding CTX coverage is a cost-effective approach to reducing mortality among patients with advanced HIV initiating ART and may also yield benefits for OIs.

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The cost-effectiveness of preexposure prophylaxis for HIV prevention in the United States in men who have sex with men.

Juusola JL et al. Ann Intern Med 2012;156:541–50.

• Using a dynamic model of HIV transmission and progression combined with a detailed economic analysis, this study estimated the effectiveness and cost-effectiveness of PrEP in men who have sex with men (MSM) in the US. • Initiating PrEP in 20% of MSM would reduce new HIV infections by an estimated 13% and result in a gain of 550,166 QALYs over 20 years at a cost of $172,091 per QALY gained. • Initiating PrEP in a larger proportion of MSM would prevent more infections but at an increasing cost per QALY gained (up to $216,480 if all MSM receive PrEP). • PrEP in the general MSM population would cost <$100,000 per QALY gained if the daily cost of ARV drugs for PrEP was <$15 or if PrEP efficacy was >75%. • Conclusions: PrEP in the general MSM population could prevent a substantial number of HIV infections but is expensive. • PrEP in high-risk MSM compared favourably with other cost-effective interventions but could result in annual expenditures of >$4 billion.

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Adherence to HIV treatment guidelines for comorbid disease assessment and initiation of antiretroviral therapy.

Bloch M et al. J Acquir Immune Defic Syndr 2012;59:478–88.

• This study assessed adherence to US DHHS guidelines with Australian Commentary for 500 adults initiating ART at primary care and hospital clinics in Sydney and Melbourne from 2004–2008. • Independent predictors of adherence to guidelines were calculated by stepwise logistic regression. • ‘When to start’ adherence was 87.6% and was less likely with initiation in a clinical trial (0.25, 95% CI: 0.13–0.49; p<0.0001) and previous, short-term non-therapeutic ARV exposure (0.08, 95% CI: 0.03–0.25; p<0.0001). • ‘What to start’ adherence was 69.0% for preferred regimens and 85.8% for preferred or alternative regimens and more likely with ART initiated in 2008 versus pre-2008 (OR: 2.69, 95% CI: 1.64–4.61; p=0.0001). • Median comorbid disease assessment adherence was 56.8% and was more likely in patients with AIDS and initiating ART in hospital or in a clinical trial. • Conclusions: ‘When to start’ and ‘what to start’ guidelines have been largely adhered to in Australia but pre-ART comorbid disease assessment requires greater attention.

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Retention in HIV care between testing and treatment in sub-Saharan Africa: a systematic review.

Rosen S, Fox MP. PLoS Med 2011;8:e1001056.

• This systematic review examined pre-ART retention in care in Africa, looking at the proportion of adults retained between any two points between testing positive for HIV and initiating ART in HIV/AIDS care programmes in sub-Saharan Africa.
• Results were categorized as Stage 1 (from HIV testing to receipt of CD4 count results or clinical staging), Stage 2 (from staging to ART eligibility) or Stage 3 (from ART eligibility to ART initiation).
• In 28 eligible studies, the median (range) proportion of patients retained in Stage 1, 2 and 3 was 59% (35–88%), 46% (31–95%) and 68% (14–84%), respectively.
• The results suggest that less than one-third of patients testing positive for HIV and not yet eligible for ART when diagnosed are retained continuously in care.
• Conclusions: Retention studies in pre-ART care report a substantial loss of patients at every stage, ranging from patients who do not return for their initial CD4 count results to those who do not initiate ART despite being eligible.

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Economic evaluation of monitoring virologic responses to antiretroviral therapy in HIV-infected children in resource-limited settings.

Schneider K et al. AIDS 2011;25:1143–51.

• This study investigated the cost effectiveness and cost utility of different frequencies of plasma VL monitoring in HIV+ children initiating ART in a resource-limited setting (Thailand) using a stochastic agent-based simulation model.
• The model simulated the expected costs and clinical outcomes over time according to different VL monitoring frequencies and initiation of second-line therapies.
• After screening at 6 months, the optimal VL monitoring frequency was annual. Associated costs of VL monitoring and appropriate ART would approximately triple current treatment costs.
• Compared with current practice, a single screening during the first year of ART led to a 58.4% reduction in the total person-years of VF, with annual monitoring leading to a 76.6% reduction.
• The estimated cost of preventing 1 year of VF was US$3,393 with and US$359 without ART costs.
• Conclusions: VL monitoring is cost-effective in many resource-limited settings.

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The DART Trial: ‘The Doctor's Dilemma’ revisited

Nunes EP et al J Antimicrob Chemother; First published online 15 February 2011 doi:10.1093/jac/dkr020

• This is a Leading Article commenting on the results of the DART trial.
• Although antiretroviral drugs are now more accessible in developing countries, and adherence to therapy is good, there remain questions regarding the need for routine laboratory monitoring given the scarce laboratory resources available. .
• DART was a randomised controlled trial carried out in Uganda and Zimbabwe in 2003–2008, and evaluated differences in efficacy and safety outcomes in patients receiving routine laboratory monitoring vs monitoring driven by clinical events.
• The results of DART suggest that in resource constrained settings, clinically driven monitoring is the more cost-effective solution.

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Dose optimisation: a strategy to improve tolerability and lower antiretroviral drug prices in low and middle income countries

Hill A et al Open Infect Dis J; 2010;4:85–91

• This article reviews dose optimisation as a means of increasing access to antiretrovirals for HIV-infected people in low and middle income countries.
• 5 million people in these countries are eligible for treatment but are not receiving it; furthermore, 27–29 million infected people are currently not receiving treatment butwill eventually require it as their disease progresses. The overall costs of treatment programs needs to be reduced to allow for greater access to treatment.
• Several doses of new antiretrovirals are usually evaluated in dose-ranging studies. With efavirenz, lopinavir/ritonavir and raltegravir, although there was no difference in efficacy between several doses tested in phase 2 studies, it was the higher doses that were evaluated in phase 3 studies and approved for clinical use.
• Reanalysis of the dose-ranging trials shows that the effective doses of these drugs could be lowered significantly, thereby allowing wider first- and second-line use in low- and middle income countries, by reducing the costs of these drugs by around 30–35%.

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Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora study): a randomised controlled trial.

The Kesho Bora Study Group. Lancet Infect Dis 2011 Jan 13 [Epub ahead of print].

• This open-label study investigated the efficacy and safety of triple ART (AZT+3TC+LPV/r) vs AZT plus single-dose NVP prophylaxis in pregnant women infected with HIV at five sites in Burkina Faso, Kenya and South Africa.
• The primary endpoints were HIV-free infant survival at 6 weeks and 12 months, HIV-free survival at 12 months in infants who were ever breastfed, AIDS-free survival in mothers at 18 months and serious adverse events in mothers and babies.
• From June 2005 to August 2008, 882 women were enrolled, 824 of whom were randomised and gave birth to 805 singleton or first, live-born infants.
• The cumulative rate of HIV transmission at 6 weeks and 12 months was 3.3% (95% CI: 1.9–5.6%) and 5.4% (95% CI: 3.6–8.1%) with triple ART vs 5.0% (95% CI: 3.3–7.7%) and 9.5% (95% CI: 7.0–12.9%) with AZT plus single-dose NVP (p=0•029).
• The cumulative rate of HIV transmission or death at 12 months was 10.2% (95% CI: 7.6–13.6%) with triple ART vs 16.0% (95% CI: 12.7–20.0%) with AZT plus single-dose NVP (p=0•017). In infants whose mothers declared they intended to breastfeed, the cumulative rate of HIV transmission at 12 months was 5.6% (95% CI: 3.4–8.9%) vs 10.7% (95% CI: 7.6–14.8%), respectively (p=0•02).
• The incidence of serious adverse events in both mothers and infants was similar in both groups.
• Conclusions: Triple ART prophylaxis during pregnancy and breastfeeding was safe and reduced the risk of HIV transmission.

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Effect on transmission of HIV-1 resistance of timing of implementation of viral load monitoring to determine switches from first to second line antiretroviral regimens in resource-limited settings

Phillips A et al AIDS, 2010 Dec 29. [Epub ahead of print]

• The continued use of clinical (CD4 count) monitoring to determine when to switch from first- to second-line ART may result in high rates of transmission of drug-resistant virus, thus posing a long-term threat to optimal virologic efficacy of drugs currently used in resource-limited settings.
• This article describes a simulation model to predict the proportion of new HIV infections with transmitted drug resistance, according to whether and when viral load monitoring is introduced.
• It was predicted that 12.4% of new infections will have primary antiretroviral resistance in 2020 if clinical monitoring is used, compared with 5.4% and 6.1% if viral load-guided switching were introduced in 2010 or 2015, respectively.
• The death rate for those on ART was lowest when viral load monitoring was used, but the overall death rate in all infected people was higher if viral load monitoring were introduced at the expense of a scale-up in HIV diagnosis and ART initiation beyond their 2010 levels.
• Conclusion: In resource-limited settings, there is a need for cheap, practical viral load monitoring to preserve current first-line drugs for the long term. However, this should not overshadow the current priority to increase HIV testing and diagnosis and provide treatment to those in need.

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Mortality among patients with tuberculosis and associations with HIV status — United States, 1993–2008.

Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep 2010;59:1509–13.

•This study investigated the impact of HIV on the risk of death during TB treatment in the United States from 1993–2006.
•The proportion of all patients with TB who died during TB treatment decreased from 18% (2,445/13,629) in 1993 to 9% (682/7,578) in 2006. Among patients with TB and HIV co-infection, the proportion decreased from 41% (950/2,337) in 1993 to 20% (131/663) in 2006.
•Conclusion: Further reductions in mortality could be achieved by enhanced TB and HIV programme collaboration and service integration.

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Impact of drug stock-outs on death and retention to care among HIV-infected patients on combination antiretroviral therapy in Abidjan, Côte d'Ivoire.

Pasquet A et al PLoS One 2010;50:e13414.

This study evaluated the type and frequency of ARV drug stock-outs and their impact on death and interruption of care among HIV+ patients.
The primary outcome was ART regimen modification, defined as at least one drug substitution or discontinuation for ≥1 month due to ARV drug stock-outs at the clinic pharmacy. The secondary outcome was interruption of care or death in patients receiving ART for ≥6 months.
Of 1,554 adults starting ART and followed for a mean of 13.2 months, 72 patients discontinued treatment and 98 modified their regimen because of ARV drug stock-outs. Stock-outs involved NVP in 27% and fixed-dose combination AZT/3TC in 51% of cases.
Of 975 patients who were on ART for ≥6 months, stock-out-related discontinuations increased the risk of interruption of care or death (adjusted HR: 2.83; 95% CI: 1.25–6.44) but ART modifications did not (adjusted HR: 1.21; 95% CI: 0.46–3.16).
Conclusions: ARV drug stock-outs affected at least 11% of treated patients. Treatment discontinuations due to stock-outs were frequent and doubled the risk of interruption of care or death. As access to ART continues to increase in sub-Saharan Africa, first-line regimens should be standardised to decrease the probability of ARV drug stock-outs

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The need for systematic evaluations of diagnostic tests.

Jani IV. Clin Infect Dis 2010;51:609–10.

• This study assessed how frequently routine testing detected significant laboratory abnormalities and calculated the cost per disability-adjusted life year (DALY) averted by detection of these events in the asymptomatic stage compared with a strategy of symptom-prompted testing in a cohort study of HIV+ adults in Haiti.
• At baseline testing, 48 patients (3.5%) had severe anaemia so did not receive AZT and 53 AZT-treated patients developed severe anaemia during follow up.
• Monitoring for asymptomatic anaemia with haematocrit testing was cost-saving at baseline and had a cost-effectiveness ratio of US$317/DALY averted during follow up. With a complete blood count, costs increased to US$10,781/DALY averted.
• With glucose monitoring, 11 patients were diagnosed with new-onset hyperglycaemia during follow up, resulting in a cost-effectiveness ratio of US$9845/DALY averted. Monitoring for asymptomatic hepatitis and renal insufficiency was expensive and rarely affected care.
• Conclusions: Resource-poor countries should select which laboratory tests to perform based on their cost effectiveness. Routine monitoring with multi-test haematological and chemistry panels is unlikely to be cost effective.

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Clinical impact and cost of monitoring for asymptomatic laboratory abnormalities among patients receiving antiretroviral therapy in a resource-poor setting.

Koenig SP et al. Clin Infect Dis 2010;51:600–8.

• This study assessed how frequently routine testing detected significant laboratory abnormalities and calculated the cost per disability-adjusted life year (DALY) averted by detection of these events in the asymptomatic stage compared with a strategy of symptom-prompted testing in a cohort study of HIV+ adults in Haiti.
• At baseline testing, 48 patients (3.5%) had severe anaemia so did not receive AZT and 53 AZT-treated patients developed severe anaemia during follow up.
• Monitoring for asymptomatic anaemia with haematocrit testing was cost-saving at baseline and had a cost-effectiveness ratio of US$317/DALY averted during follow up. With a complete blood count, costs increased to US$10,781/DALY averted.
• With glucose monitoring, 11 patients were diagnosed with new-onset hyperglycaemia during follow up, resulting in a cost-effectiveness ratio of US$9845/DALY averted. Monitoring for asymptomatic hepatitis and renal insufficiency was expensive and rarely affected care.
• Conclusions: Resource-poor countries should select which laboratory tests to perform based on their cost effectiveness. Routine monitoring with multi-test haematological and chemistry panels is unlikely to be cost effective.

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Prognosis of patients with HIV-1 infection starting antiretroviral therapy in sub-Saharan Africa: a collaborative analysis of scale-up programmes.

May M et al. Lancet 2010;376:449–57.

• This study provides two prognostic models to estimate the probability of death in patients starting ART in sub-Saharan Africa.
• Weibull survival models were used to construct two prognostic models: one with CD4 cell count, clinical stage, bodyweight, age and sex (CD4 count model) and one that replaced CD4 cell count with total lymphocyte count and severity of anaemia (total lymphocyte and haemoglobin model) as CD4 cell count is not routinely measured in many African ART programmes. The primary outcome was all-cause mortality in the first year of ART.
• Mortality was strongly associated with high baseline CD4 cell count (≥200 versus <25 cells/mm3; adjusted HR: 0.21; 95% CI: 0.17–0.27), WHO clinical stage (stages III/IV versus I/II; adjusted HR 3.45; 95% CI: 2.43–4.90), bodyweight (≥60 versus <45 kg; adjusted HR 0.23; 95% CI: 0.18–0.30) and anaemia status (none versus severe: HR: 0.27; 95% CI: 0.20–0.36). Other independent mortality risk factors were low total lymphocyte count, advanced age and male sex.
• The probability of death at 1 year ranged from 0.9% (95% CI: 0.6–1.4) to 52.5% (43.8–61.7) with the CD4 count model and from 0.9% (0.5–1.4) to 59.6% (48.2–71.4) with the total lymphocyte and haemoglobin model. Both models accurately predicted early mortality.
• Conclusions: Prognostic models should be used to counsel patients, plan health services and predict outcomes for patients with HIV-1 infection in sub-Saharan Africa.

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Comparative effectiveness of HIV testing and treatment in highly endemic regions.

Bendavid E et al. Arch Intern Med 2010;170:1347–54.

• This study simulated the HIV epidemic and disease progression in South Africa to compare the outcomes of the current HIV treatment campaign with four test and treat strategies to increase ART access: 1 universal test and treat without changes in linkage to care and loss to follow up; 2 universal test and treat with improved linkage to care; 3 universal test and treat with reduced loss to follow up and 4 comprehensive care with universal test and treat, improved linkage to care, and reduced loss to follow up.
• The main outcome measures were survival benefits, new HIV infections and HIV prevalence.
• Compared with the present strategy, 1 was associated with a mean (95% uncertainty bounds) life expectancy gain of 12.0 months (11.3–12.2 months), and 35.3% (32.7–37.5%) fewer HIV infections over 10 years. Substantial additional benefits were provided by 2, 3 and 4: life expectancy gains versus the current strategy were 16.1, 18.6, and 22.2 months and new infections were 55.5%, 51.4% and 73.2% lower, respectively.
• Conclusions: A universal test and treat strategy with the current levels of linkage to care and loss to follow up could substantially reduce HIV mortality and new infections. Increasing linkage to care and preventing loss to follow up provides nearly twice the benefits of universal test and treat alone.

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Use of generic antiretroviral agents and cost savings in PEPFAR treatment programs.

Holmes CB et al. JAMA 2010;304:313–20.

• This study evaluated the uptake of generic ARVs and changes over time in ARV use and costs among PEPFAR (US President's Emergency Plan for AIDS Relief) -supported programmes in Guyana, Haiti, Vietnam and 13 countries in Africa.
• ARV expenditures increased from $116.8 million (2005) to $202.2 million (2008) and procurement increased from 6.2 million to 22.1 million monthly packs.
• The proportion spent on generic ARVs increased from 9.17% (95% CI: 9.17–9.18%) in 2005 to 76.41% (95% CI: 76.41–76.42%) in 2008 (p<0.001) and the proportion of generic packs procured increased from 14.8% (95% CI: 14.79–1.84%) in 2005 to 89.33% (95% CI: 89.32–89.34%) in 2008 (p<0.001).
• Conclusions: Among PEPFAR-supported programmes in 16 countries, the availability of generic ARVs was associated with increased ARV procurement and substantial estimated cost savings.

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Effectiveness of non-nucleoside reverse-transcriptase inhibitor-based antiretroviral therapy in women previously exposed to a single intrapartum dose of nevirapine: a multi-country, prospective cohort study.

Stringer JSA et al. PLoS Med 2010 Feb 16;7(2):e1000233.

• This study investigated whether women with prior exposure to single-dose NVP would have a higher prevalence of failure with an NNRTI-containing regimen during the first 48 weeks of treatment than women without prior exposure.
• Women who died, discontinued NNRTI-containing ART or had a confirmed plasma VL ≥400 copies/mL were designated treatment failures.
• Overall, 114/355 NVP-exposed (32.1%) and 132/523 NVP-unexposed women (25.2%) were treatment failures (6.9% difference in failure rate; 95% CI: 0.8–13.0%).
• Locally weighted regression analysis indicated a clear inverse relationship between VF and exposure interval.
• Conclusions: Prior exposure to single-dose NVP was associated with an increased risk of treatment failure but this was largely confined to women with more recent exposure. Women needing ART within 12 months of NVP treatment should not be prescribed an NNRTI-containing regimen as first-line therapy.

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Early versus standard antiretroviral therapy for HIV-infected adults in Haiti.

Severe P et al. N Engl J Med 2010;363:257–65.

• This randomized, open-label study compared early with standard initiation of ART in HIV+ adults in Haiti who had a confirmed CD4 cell count 200–350 cells/mm3 at baseline and no history of an AIDS illness.
• Early treatment consisted of AZT, 3TC and EFV therapy within 2 weeks of enrollment. Standard treatment used the same regimen when the CD4 cell count fell to ≤200 cells/mm3 or when clinical AIDS developed. The primary endpoint was survival.
• A total of 408 patients were enrolled in each group. There were 23 deaths in the standard- versus six in the early-treatment group (HR: 4.0; 95% CI: 1.6–9.8; p=0.001).
• Conclusions: Early initiation of ART decreased the rates of death and incident TB. Access to ART should be expanded to include all HIV+ adults with a CD4 cell count <350 cells/mm3, including those in resource-limited regions.

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Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel.

Thompson MA, JAMA 2010;304:321–33.

• Updated recommendations of the International AIDS Society-USA guidelines for the management of HIV-infected adults, using ARVs and laboratory monitoring tools available in the developed world.
• Conclusions: Patient readiness for treatment should be confirmed before initiation of ART. Treatment is recommended for asymptomatic patients with a CD4 cell count ≤500 cells/mm3, for all symptomatic patients and those with specific conditions and comorbidities.
• Treatment should be considered for asymptomatic patients with a CD4 cell count >500 cells/mm3.
• Components of the initial and subsequent regimens must be individualized, particularly in the context of concurrent conditions.
• Patients receiving ART should be regularly monitored.
• Treatment failure should be detected and managed early, with the goal of therapy, even in heavily pre-treated patients, being HIV-1 RNA suppression below commercially available assay quantification limits.

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Effect of treating co-infections on HIV-1 viral load: a systematic review

Modjarrad K, Vermund SH. Lancet Infect Dis, 2010;10:455–63

• This systematic review assessed the effect of treating key co-infections on plasma HIV-1-RNA levels in resource-constrained countries.
• Standardised mean plasma VL decreased after the treatment of co-infecting pathogens in all 18 studies.
• Twelve of 14 studies with variance data reported significant differences in HIV VL before and after treatment.
• Conclusions: Although many of the VL reductions were ≤1.0 log10 copies/mL, even small changes in plasma HIV-RNA concentrations can slow HIV progression and could translate into population-level benefits in lowering the risk of HIV transmission.

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Nevirapine-associated early hepatotoxicity: incidence, risk factors, and associated mortality in a primary care ART programme in South Africa.

Chu KM et al. PLoS One 2010;5:e9183.

• This study investigated NVP-associated hepatotoxicity among 1,809 HIV+ ARV-naïve adults starting NVP-based therapy.
• The cumulative proportion of early hepatotoxicity was 1–2%, giving an incidence rate at 102 days of 3.6–7.6 per 100 person-years. The median time to hepatotoxicity was 32 days (IQR 28–58 days).
• No association was found between age, gender, baseline CD4 count, concurrent TB infection, prior participation in a programme to prevent mother-to-child-transmission, or baseline weight and early hepatotoxicity.
• Hepatotoxicity was not associated with mortality.
• Conclusions: The cumulative proportion of early hepatotoxicity with NVP-based ART was low in this resource-constrained setting.

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Maternal or infant antiretroviral drugs to reduce HIV-1 transmission.

Chasela CS et al. N Engl J Med 2010;362:2271–81.

• This study investigated the efficacy of a maternal triple-drug ARV regimen or infant NVP prophylaxis for 28 weeks during breast-feeding to reduce post-natal transmission of HIV-1 in Malawi.
• All mothers and infants received perinatal prophylaxis with single-dose NVP and 1 week of AZT plus 3TC.
• Among mother-infant pairs, 5.0% of infants were HIV+ at 2 weeks.
• The estimated risk of HIV-1 transmission at 2–28 weeks was higher in the control group (5.7%) than in either the maternal- (2.9%, p=0.009) or the infant-regimen group (1.7%, p<0.001).
• The estimated risk of infant HIV-1 infection or death at 2–28 weeks was 7.0% in the control group, 4.1% in the maternal- (p=0.02), and 2.6% in the infant-regimen group (p<0.001).
• Conclusions: The use of either a maternal ARV regimen or infant NVP for 28 weeks was effective in reducing HIV-1 transmission during breast feeding.

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Antiretroviral regimens in pregnancy and breast-feeding in Botswana.

Shapiro RL et al. N Engl J Med 2010;362:2282–94.

• This randomised study investigated the efficacy HAART regimens to prevent mother-to-child transmission of HIV-1.
• Women received ABC/3TC/AZT (NRTI group), LPV/r + AZT/3TC (PI group) or NVP/3TC/AZT (observational group). Infants received single-dose NVP and 4 weeks of AZT.
• The rate of virological suppression to <400 copies/mL was high and did not differ significantly between the three groups at delivery (NRTI 96%, PI 93% and observational 94%) or during breast feeding (NRTI 92%, PI 93% and observational 95%).
• By 6 months of age, 8/709 live-born infants (1.1%) were infected (95% CI: 0.5–2.2): six were infected in utero (four in the NRTI, one in the PI and one in the observational group) and two were infected during breast feeding (in the NRTI group).
• Treatment-limiting adverse events occurred in 2% of women in the NRTI and PI groups and 11% of women in the observational group.
• Conclusions: All regimens resulted in high rates of virological suppression, with an overall mother-to-child transmission rate of 1.1%.

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Operational research in HIV priority areas: the African way.

Boyd MA, Nwizu CA. Lancet. 2010 Jun 15.

• This study compared outcomes of nurse versus doctor management of ART care for HIV+ patients in two South African primary-care clinics.
• 371 (46%) patients reached an endpoint of treatment failure: 192/404 (48%) in the nurse group and 179/408 (44%) in the doctor group. The HR for composite failure was 1.09 (95% CI: 0.89–1.33), which was within the limits for non-inferiority.
• After a median follow-up of 120 weeks (IQR 60–144), deaths (10 vs 11), virological failures (44 vs 39), toxicity failures (68 vs 66) and programme losses (70 vs 63) were similar in the nurse and doctor groups, respectively.
• Conclusion: Nurse-monitored ART is non-inferior to doctor-monitored therapy. The results support the use of appropriately trained nurses for monitoring ART.

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Nurse versus doctor management of HIV-infected patients receiving antiretroviral therapy (CIPRA-SA): a randomised non-inferiority trial.

Sanne I et al. Lancet 2010 Jun 15

• This study compared outcomes of nurse versus doctor management of ART care for HIV+ patients in two South African primary-care clinics.
• 371 (46%) patients reached an endpoint of treatment failure: 192/404 (48%) in the nurse group and 179/408 (44%) in the doctor group. The HR for composite failure was 1.09 (95% CI: 0.89–1.33), which was within the limits for non-inferiority.
• After a median follow-up of 120 weeks (IQR 60–144), deaths (10 vs 11), virological failures (44 vs 39), toxicity failures (68 vs 66) and programme losses (70 vs 63) were similar in the nurse and doctor groups, respectively.
• Conclusion: Nurse-monitored ART is non-inferior to doctor-monitored therapy. The results support the use of appropriately trained nurses for monitoring ART.

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Body mass index and risk of tuberculosis and death.

Hanrahan CF et al. AIDS 2010;24:1501–8.

• This study investigated the effect of BMI on all-cause mortality and TB incidence among a cohort of HIV+ adults in Soweto, South Africa.
• Mortality rates (per 100 person-years) were 10.4 for baseline BMI of ≤18.5, 3.6 for baseline BMI 18.6–25, 1.7 for baseline BMI 25.1–30 and 1.6 for baseline BMI >30.
• Compared to those with normal BMI, overweight (adjusted HR: 0.59; 95% CI: 0.40–0.87) and obese (adjusted HR: 0.48; 95% CI: 0.29–0.80) individuals had a significantly reduced mortality risk and
• Incidence rates (per 100 person-years) of TB by baseline BMI were 7.3 for underweight, 6.0 for normal, 3.2 / for overweight and 1.9 for obese.
• Compared to those with normal BMI, those with overweight (adjusted HR: 0.56; 95% CI: 0.38–0.83) and obese BMI (adjusted HR: 0.33; 95% CI: 0.19–0.55) were at a significantly reduced risk of developing TB.
• Conclusion: HIV+ individuals with an obese or overweight BMI have a significantly reduced risk of both mortality and TB after adjusting for HAART use and CD4 cell count.

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Decline in early life mortality in a high HIV prevalence rural area of South Africa: evidence of HIV prevention or treatment impact?

Ndirangu J et al. AIDS 2010;24:593–602.

• This retrospective study investigated the temporal and spatial associations between early life mortality rates and a prevention of mother-to-child transmission (PMTCT) programme (single-dose NVP), an HIV treatment programme and maternal HIV in a largely rural population with a high prevalence of antenatal HIV.
• Mortality was independently associated with birth season (adjusted HR: 1.16; 95% CI: 1.02–1.33), maternal education (HR: 1.21; 95% CI: 1.02–1.43), maternal HIV (HR: 4.34; 95% CI: 3.11–6.04) and ART availability (HR: 0.46; 95% CI: 0.33–0.65).
• Children born at home (unlikely to have received PMTCT) had a 35% higher risk of dying than children born in a facility where PMTCT was available (HR: 1.35; 95% CI: 1.04–1.74).
• Conclusions: The results confirm the importance of maternal survival and show the importance of the PMTCT and maternal HIV treatment in improving the survival of their young children.

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HIV drugs for treatment, and for prevention.

Dabis F et al. Lancet 2010 May 27.

• This study investigated the effect of ART use by HIV+ heterosexual African adults on the risk of transmission to their uninfected partners.
• Only one of 103 genetically-linked HIV-1 transmissions was from an infected patient who had started ART, corresponding to a transmission rate of 0•37 (95% CI: 0•09–2•04) per 100 person-years in those who had initiated treatment and 2•24 (95% CI: 1•84–2•72) per 100 person-years in those who had not, a 92% reduction (adjusted incidence rate ratio: 0•08; 95% CI: 0•00–0•57; p=0•004).
• In people not on ART, the highest HIV-1 transmission rate (8•79 per 100 person-years) was in those with a CD4 cell count <200 cells/mm3. In couples in whom the untreated HIV-1 infected partner had a CD4 cell count >200 cells/mm3, 70% (66/94) of transmissions occurred when plasma HIV RNA was >50,000 copies/mL.
• Conclusions: Low CD4 cell counts and high plasma HIV RNA levels may be beneficial in guiding the use of ART to help prevent transmission and achieve population-level reductions in HIV-1 transmission.

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Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: a prospective cohort analysis

Donnell D et al. Lancet 2010 May 27.

• This study investigated the effect of ART use by HIV+ heterosexual African adults on the risk of transmission to their uninfected partners.
• Only one of 103 genetically-linked HIV-1 transmissions was from an infected patient who had started ART, corresponding to a transmission rate of 0•37 (95% CI: 0•09–2•04) per 100 person-years in those who had initiated treatment and 2•24 (95% CI: 1•84–2•72) per 100 person-years in those who had not, a 92% reduction (adjusted incidence rate ratio: 0•08; 95% CI: 0•00–0•57; p=0•004).
• In people not on ART, the highest HIV-1 transmission rate (8•79 per 100 person-years) was in those with a CD4 cell count <200 cells/mm3. In couples in whom the untreated HIV-1 infected partner had a CD4 cell count >200 cells/mm3, 70% (66/94) of transmissions occurred when plasma HIV RNA was >50,000 copies/mL.
• Conclusions: Low CD4 cell counts and high plasma HIV RNA levels may be beneficial in guiding the use of ART to help prevent transmission and achieve population-level reductions in HIV-1 transmission.

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Virological follow-up of adult patients in antiretroviral treatment programmes in sub-Saharan Africa: a systematic review.

Barth RE et al. Lancet Infect Dis 2010;10:155–66.

• This article reviews the virological efficacy and drug-resistance outcomes of 89 ART studies in sub-Saharan Africa.
• In an on-treatment analysis, 10,351 (78%) of 13,288 patients showed virological suppression after 6 months of ART, 7413 (76%) of 9,794 after 12 months and 3,840 (67%) of 5,690 after 24 months.
• Resistance profiles were associated with commonly used ARVs: the lamivudine-associated M184V mutation was most frequent, followed by the NNRTI-associated K103N mutation. Thymidine-analogue mutations and the K65R mutation were less frequent.
• Conclusions: First-line ART regimens used in sub-Saharan Africa were effective. Drug-resistance profiles suggest that a PI-based regimen with a NRTI backbone is a reasonable second-line option.

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Impact of antiretroviral therapy on incidence of pregnancy among HIV-infected women in Sub-Saharan Africa: a cohort study.

Myer L et al. PLoS Med 2010;7:e1000229.

• This study investigated whether ART influences pregnancy rates by analyzing data from 11 Mother-to-Child Transmission-Plus (MTCT-Plus) Initiative programs in seven African countries.
• In total, 589 pregnancies were observed among 4,531 women (incidence: 7.8/100 person-years).
• The rate of new pregnancies was significantly higher among women receiving ART (9.0/100 person-years) than those not on ART (6.5/100 person-years) (adjusted HR: 1.74; 95% CI: 1.19–2.54).
• Conclusions: ART was associated with a significantly higher pregnancy rate among HIV+ women in sub-Saharan Africa. The results indicate the importance of pregnancy planning and management as a component of HIV care services

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Treating HIV infection with drugs for HSV-2 infection?

Buvé A, Lynen L. Lancet 2010 Feb 12.

• This multicentre study in southern and east Africa investigated the effect of acyclovir on HIV-1 progression in ARV-naïve heterosexuals with dual HSV type 2 and HIV-1 infection and a CD4 cell count ≥200 cells/mm3.
• The effect of aciclovir on HIV-1 disease progression was defined by a primary composite endpoint of first occurrence of CD4 cell counts <200 cells/mm3, ART initiation or non-trauma related death.
• Acyclovir reduced the risk of HIV-1 disease progression by 16% (HR: 0.84; 95% CI: 0.71–0.98; p=0.03). In patients with CD4 cell counts ≥350 cells/mm3, acyclovir delayed the risk of CD4 cell counts falling to <350 cells/mm3 by 19% (HR: 0.81; 95% CI: 0.71–0.93; p=0.002).
• Conclusions: The role of suppression of HSV type 2 in reducing HIV-1 disease progression before starting ART warrants consideration.

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Daily aciclovir for HIV-1 disease progression in people dually infected with HIV-1 and herpes simplex virus type 2: a randomised placebo-controlled trial.

Lingappa JR et al. Lancet 2010 Feb 12.

• This multicentre study in southern and east Africa investigated the effect of acyclovir on HIV-1 progression in ARV-naïve heterosexuals with dual HSV type 2 and HIV-1 infection and a CD4 cell count ≥200 cells/mm3.
• The effect of aciclovir on HIV-1 disease progression was defined by a primary composite endpoint of first occurrence of CD4 cell counts <200 cells/mm3, ART initiation or non-trauma related death.
• Acyclovir reduced the risk of HIV-1 disease progression by 16% (HR: 0.84; 95% CI: 0.71–0.98; p=0.03). In patients with CD4 cell counts ≥350 cells/mm3, acyclovir delayed the risk of CD4 cell counts falling to <350 cells/mm3 by 19% (HR: 0.81; 95% CI: 0.71–0.93; p=0.002).
• Conclusions: The role of suppression of HSV type 2 in reducing HIV-1 disease progression before starting ART warrants consideration.

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Nevirapine/zidovudine/lamivudine has superior immunological and virological responses not reflected in clinical outcomes in a 48-week randomized comparison with abacavir/ zidovudine/lamivudine in HIV-infected Ugandan adults with low CD4 cell counts.

Munderi P et al. HIV Med 2010 Feb 2.

• This safety study compared NVP with ABC in ARV-naïve patients with CD4 cell counts <200 cells/mm3 in two Ugandan DART centres.
• Documented WHO stage 4 events were independently reviewed and plasma HIV-1 RNA assayed retrospectively. Exploratory efficacy analyses were ITT.
• The study drug was substituted in 7% of ABC patients vs 11% of NVP patients (p=0.09). At 48 weeks, 62% of ABC patients vs 77% of NVP patients had a VL <50 copies/mL (P<0.001) and mean CD4 cell count increases from baseline were +147 vs +173 cells/mm3, respectively (p=0.006).
• Twenty ABC patients vs 32 NVP patients developed new or recurrent WHO 4 events or died (HR: 0.60; 95% CI: 0.34–1.05; p=0.07) and 48 vs 68 developed new or recurrent WHO 3/4 events or died (HR: 0.67; 95% CI: 0.46–0.96; p=0.03).
• Conclusions: The clear virological/immunological superiority of NVP over ABC was not reflected in clinical outcomes over 48 weeks. The inability of CD4 cell count/VL to predict initial efficacy is unexplained and requires further evaluation.

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Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial.

DART Trial Team. Lancet [Epub ahead of print

• This study investigated the possible long-term effects on clinical outcomes of routine toxicity and efficacy monitoring of HIV+ patients receiving ART in Uganda and Zimbabwe.
• HIV+ adults with CD4 counts >200 cells/μL starting ART were randomly assigned to laboratory and clinical monitoring or clinically driven monitoring.
• The primary endpoints were new WHO stage 4 HIV events or death and serious adverse events.
• In the clinically driven monitoring group, 459 (28%) patients versus 356 (21%) in the laboratory and clinical monitoring had a new WHO stage 4 event or died (p=0.0001) and 283 (17%) versus 260 (16%) patients had a new serious adverse event (HR 1.12 [95% CI: 0.94–1.32]; p=0.19).
• Conclusions: ART can be delivered safely without routine laboratory monitoring. Differences in disease progression suggest a role for CD4-cell count monitoring to guide the switch to second-line treatment from the second year of ART.

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ART in rural Uganda—efficient scale-up with home-based care?

Korenromp EL, Viisainen KM Lancet. 2009 Nov 23.

• This study investigated whether home-based HIV care was as effective as facility-based care.
• The primary endpoint was VF, defined as RNA >500 copies/mL after 6 months’ treatment.
• Of 729 home-care patients, 117 (16%) had VF versus 80 of 483 (17%) in facility care. VF rates per 100 person-years were 8.19 (95% CI: 6.84–9.82) for home and 8.67 (95% CI: 6.96–10.79) for facility care (rate ratio [RR] 1.04, 0.78–1.40; equivalence shown).
• Mortality rates were similar: 0.95 (0.71–1.28).
• Conclusions: Home-based HIV care was as effective as a clinic-based strategy and could enable improved and equitable access to HIV treatment, especially in areas with poor infrastructure and access to clinic care.

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Rates of virological failure in patients treated in a home-based versus a facility-based HIV-care model in Jinja, southeast Uganda: a cluster-randomised equivalence trial.

Jaffar S et al. Lancet. 2009 Nov 23.

• This study investigated whether home-based HIV care was as effective as facility-based care.
• The primary endpoint was VF, defined as RNA >500 copies/mL after 6 months’ treatment.
• Of 729 home-care patients, 117 (16%) had VF versus 80 of 483 (17%) in facility care. VF rates per 100 person-years were 8.19 (95% CI: 6.84–9.82) for home and 8.67 (95% CI: 6.96–10.79) for facility care (rate ratio [RR] 1.04, 0.78–1.40; equivalence shown).
• Mortality rates were similar: 0.95 (0.71–1.28).
• Conclusions: Home-based HIV care was as effective as a clinic-based strategy and could enable improved and equitable access to HIV treatment, especially in areas with poor infrastructure and access to clinic care.

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Trends in multidrug treatment failure and subsequent mortality among antiretroviral therapy-experienced patients with HIV infection in North America.

Deeks SG et al. Clin Infect Dis 2009;49:1582–90.

• This study used Multivariate Cox regression to assess the factors associated with time to second regimen failure and time to death after the onset of second regimen failure in patients who experienced VF (defined as an HIV RNA level >1000 copies/mL), received modified therapy and then had a second episode of VF.
• Of 42,790 patients who received therapy, 7,159 experienced a second VF. The risk of second VF decreased from 1996 (56 cases per 100 person-years) through 2005 (16 cases per 100 person-years; p<0.001). The cumulative mortality after onset of second VF was 26% at 5 years and decreased over time.
• A history of AIDS, a lower CD4+ T-cell count and a higher plasma HIV RNA level were each independently associated with mortality.
• Conclusions: Mortality rates for those who have experienced failure of two or more regimens have remained high. Plasma HIV RNA levels, CD4+ T-cell counts at time of treatment failure and a history of AIDS remain independent risk factors for death. These factors remain important targets for those in need of more aggressive therapeutic interventions.

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Operational research in low-income countries: what, why, and how?

Zachariah R, Harries AD, Ishikawa N et al. Lancet Infect Dis 2009;9:711–7.

• This article provides a definition of operational research, clarifies its relevance to infectious-disease control programmes and describes some of the factors and challenges for its integration into programmes.
• Investment in operational research is needed to enable more efficient healthcare, particularly in areas with a high disease burden and limited resources.
• Research capacity needs to be developed, specific resources allocated, and different stakeholders (e.g. academic institutions, national programme managers, and non-governmental organisations) brought together to promote operational research.

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Switching to second-line antiretroviral therapy in resource-limited settings: comparison of programmes with and without viral load monitoring.

The ART-LINC of IeDEA Study Group. AIDS 2009;23:1867–74

• This study investigated switching from NNRTI-based first-line regimens to PI-based regimens in 17 ART programmes in Africa, South America and Asia and compared times to switching, CD4 cell counts at switching and adjusted HRs for switching.
• All sites monitored CD4 cell count and had access to second-line ART and 10 sites monitored VL. A total of 20,113 patients, including 6369 (31.7%) patients from 10 programmes with access to VL monitoring, were analysed; 576 patients (2.9%) switched.
• Median time to switching was 16.3 months (interquartile range 10.1–26.6) in programmes with VL monitoring and 21.8 months (interquartile range 14.0–21.8) in those without (p<0.001).
• Median CD4 cell count at switching was 161 cells/μL (interquartile range 77–265) in programmes with VL monitoring and 102 cells/μL (interquartile range 44–181) in those without (p<0.001).
• Conclusion: In resource-limited settings, switching to second-line regimens tends to occur earlier and at higher CD4 cell counts in ART programmes with VL monitoring versus those without.

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Slow accumulation of HIV resistance mutations: implications for resource-limited settings?

Stevens WS. J Infect Dis 2009;200:670–2.

• This study investigated the effect of continuing virologically failing ART in resource-limited settings in terms of the rate of accumulation of thymidine analogue mutations (TAMs).
• The study included patients in EuroSIDA with two genotypic resistance tests ([HIV RNA >500 copies/mL in any measure between tests, the first being performed after the first VF of a TA, which was continued until the second test.
• At the first test, 1 year after VF, a median of three TAMs were detected. Overall, 126 TAMs were accumulated during 548 person-years of follow-up (1/4.3 years; 95%CI: 3.7–5.0 years).
• Greater predicted activity of the TA at t0, TAM profile 2 (versus TAM profile 1) at t0, use of a NNRTI at t0 (versus combined NNRTI and PI), and heterosexual acquisition of HIV (versus homosexual) were associated with a faster rate of TAM accumulation.
• Conclusions: Although the estimated rate of TAM accumulation was lower than anticipated, all possible efforts should be continued to increase the availability of drug options in resource-limited settings.

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Rate of accumulation of thymidine analogue mutations in patients continuing to receive virologically failing regimens containing zidovudine or stavudine: implications for antiretroviral therapy programs in resource-limited settings.

Cozzi-Lepri A, Phillips AN, Martinez-Picado J et al. J Infect Dis 2009;200:687–97.

• This study investigated the effect of continuing virologically failing ART in resource-limited settings in terms of the rate of accumulation of thymidine analogue mutations (TAMs).
• The study included patients in EuroSIDA with two genotypic resistance tests ([HIV RNA >500 copies/mL in any measure between tests, the first being performed after the first VF of a TA, which was continued until the second test.
• At the first test, 1 year after VF, a median of three TAMs were detected. Overall, 126 TAMs were accumulated during 548 person-years of follow-up (1/4.3 years; 95%CI: 3.7–5.0 years).
• Greater predicted activity of the TA at t0, TAM profile 2 (versus TAM profile 1) at t0, use of a NNRTI at t0 (versus combined NNRTI and PI), and heterosexual acquisition of HIV (versus homosexual) were associated with a faster rate of TAM accumulation.
• Conclusions: Although the estimated rate of TAM accumulation was lower than anticipated, all possible efforts should be continued to increase the availability of drug options in resource-limited settings.

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Virological monitoring and resistance to first-line highly active antiretroviral therapy in adults infected with HIV-1 treated under WHO guidelines: a systematic review and meta-analysis.

Gupta RK, Hill A, Sawyer AW, Cozzi-Lepri A et al. Lancet Infect Dis. 2009;9:409–17.

• This meta-analysis assessed the effect of variable monitoring on the emergence of resistance after therapy with commonly used drug combinations by reviewing studies reporting resistance in patients infected with HIV and a CD4 count of <200 cells/μL treated with two NRTIs and an NNRTI.
• Resistance at VF to NNRTIs at 48 weeks was 88.3% (95% CI: 82.2–92.9) in infrequently monitored patients, compared with 61.0% (95% CI: 48.9–72.2) in frequently monitored patients (p<0.001).
• Lamivudine resistance was 80.5% (95% CI: 72.9–86.8) and 40.3% (95% CI: 29.1–52.2) in infrequently and frequently monitored patients, respectively (p<0.001).
• The prevalence of at least one thymidine analogue mutation was 27.8% (95% CI: 21.2–35.2) and 12.1% (95% CI: 5.9–21.4), respectively (p<0.001).
• Genotypic resistance at 48 weeks to lamivudine, NRTIs and NNRTIs was substantially higher in patients who were less frequently monitored.
• Conclusion: There is a need for cheap point-of-care VL tests to identify early viral failures and limit the emergence of resistance.

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High frequency of clinically significant mutations after first-line generic highly active antiretroviral therapy failure: implications for second-line options in resource-limited settings.

Kumarasamy N, Madhavan V, Venkatesh KK et al. Clin Infect Dis 2009;49:306–9.

• Continuing failed ART regimens may lead to the accumulation of mutations, potentially limiting options for second-line treatment.
• This study investigated the pattern of drug-resistance mutations among 138 Indian patients who experienced failure of first-line NNRTI-based ART.
• Conclusions: There was a high frequency of drug-resistance mutations in patients who experienced immunological treatment failure. This suggests a need for VL monitoring.

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Response to zidovudine/didanosine-containing combination antiretroviral therapy among HIV-1 subtype C-infected adults in Botswana: two-year outcomes from a randomized clinical trial.

Bussmann H, Wester CW, Thomas A et al. J Acquir Immune Defic Syndr. 2009;51:37–46.

• The Tshepo study compared the efficacy and tolerability of three NRTI combinations (ZDV+3TC, ZDV+ddI and d4T+3TC) and two different NNRTIs (NVP and EFV) and two different adherence strategies (the current standard of care and an ‘intensified adherence strategy).
• The ZDV+ddI arms were discontinued due to inferiority in the primary endpoint (VF with resistance).
• VF and genotypic resistance mutations occurred in 11% of patients receiving ZDV+ddI-based ART versus 2% in patients receiving either ZDV+3TC- or d4T+3TC-based ART (p=0.002).
• The median CD4-cell count increase at 1 and 2 years was 137 and 199 cells/mm3 and the percentage of patients with plasma HIV-1 RNA level ≤400 copies/mL was 92.0% and 88.8%.
• Kaplan–Meier survival estimates at 1 and 2 years were 96.6% and 95.4%. One hundred and twenty patients (18.2%) had treatment-modifying toxicities: the most common were lipodystrophy, anaemia, neutropenia, and Stevens–Johnson syndrome.
• Conclusions: The preliminary results show overall excellent efficacy and tolerability of NNRTI-based ART among HIV-1 subtype C–infected adults. However, ZDV+ddI is inferior to d4T+3TC or ZDV+3TC when used with an NNRTI for first-line ART.

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Second-line therapy.

HIV & AIDS Treatment in Practice Issue 134, April 2009, 2009

• This newsletter reviews second-line therapy in resource-constrained settings.
• Lack of VL testing means that many patients who are failing treatment go undetected for long periods, resulting in high levels of drug resistance, especially to NRTIs.
• The WHO recommends two NRTI backbones (TDF + 3TC or FTC, or ABC/ddI) and a boosted PI (LPV/r or ATV/r) for use in second-line therapy.
• Responses to second-line regimens have been good in the small cohorts of patients reported so far, but there is very little information about the effects of these recommended regimens.
• Studies are looking at other approaches, including boosted PI monotherapy or using new classes (e.g. a PI and an integrase inhibitor).
• All second-line drugs are significantly more costly than first-line drugs, so preventing failure of first-line treatment is critical.

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HIV-related lipodystrophy in Africa and Asia.

Womack J. AIDS Read 2009;19:131–9, 148–52.

• This article reviews the literature on lipodystrophy in Africa and Asia.
• Lipodystrophy in resource-constrained settings has significant implications for patient health, QoL and long-term adherence.
• Lipoatrophy may be an important adverse effect of ART in Africa and Asia.
• Although a causative link has not been identified from the literature, the consistent evidence from the West means that it is reasonable to support the WHO’s effort to remove d4T from first-line therapy options.
• Affordability and access to alternative NRTIs and the newer ARV classes are key issues.

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The President's Emergency Plan for AIDS Relief in Africa: An Evaluation of Outcomes.

Bendavid E, Bhattacharya J. Ann Intern Med 2009 Apr 6. [Epub ahead of print]

• This study investigated the effect of the President's Emergency Plan for AIDS Relief (PEPFAR), which started in 2003, on HIV-related deaths, the number of people living with HIV, and HIV prevalence in sub-Saharan Africa.
• From 2004–2007, the difference in the annual change in the number of HIV-related deaths was 10.5% lower in the focus versus control countries (p=0.001). There was no significant difference in the annual growth in the number of people living with HIV.
• Conclusion: After 4 years of PEPFAR activity, HIV-related deaths decreased in sub-Saharan African focus versus control countries but there was no difference in trends of adult prevalence.

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Low levels of antiretroviral-resistant HIV infection in a routine clinic in Cameroon that uses the World Health Organization (WHO) public health approach to monitor antiretroviral treatment and adequacy with the WHO recommendation for second-line treatmen

Kouanfack C, Montavon C, Laurent C et al. Clin Infect Dis 2009;48:1318–22.

• This cross-sectional study was conducted at a routine HIV/AIDS clinic in Cameroon using the WHO public health approach to treatment.
• The results showed low rates of virological failure and drug resistance at 12 and 24 months after initiation of ART.
• The results also showed that the WHO recommendation for second-line treatment would be effective in almost all patients with HIV drug-resistance mutations.

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Safe substitution to zidovudine among HIV-infected patients initiated on stavudine-containing highly active antiretroviral therapy from a resource-limited setting.

Kumarasamy N, Venkatesh KK, Devaleenol B et al. Int J Infect Dis 2009 Mar 26. [Epub ahead of print]

• This retrospective study in Southern India investigated the substitution of d4T with AZT in patients who started d4T-based HAART due to the development of anaemia.
• During the study period, half of 619 patients who started d4T-based HAART subsequently received AZT. After substitution, three patients (2.7%) who substituted after <6 months and one patient (0.6%) who substituted between 6–12 months developed anemia. Patients who substituted after <6 months had significantly higher median CD4-cell counts at 1- and 6-month follow-up than patients who substituted at 6–12 months (p<0.05).
• Conclusion: In settings where TDF is either expensive or not available, starting d4T followed by prompt substitution with AZT can be a safe option for anaemic patients.

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Challenges for Scaling up ART in a Resource-Limited Setting: A Retrospective Study in Kibera, Kenya.

Unge C et al. J Acquir Immune Defic Syndr 2009 Feb 12. [Epub ahead of print]

• This retrospective cohort study investigated levels of dropout and adherence in an ART programme in Kibera, Kenya.
• The dropout rate was 23 per 100 person-years and the probability of retention in the program at 6, 12 and 24 months was 0.83, 0.74 and 0.65, respectively.
• Conclusion: Despite free drugs and low associated costs, dropout probabilities were higher and adherence lower versus other sub-Saharan Africa studies. The results show that ART programs in resource-limited settings risk low adherence and retention rates when expanding services.

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Article Index