https://www.cell.com/trends/microbiology/pdf/S0966-842X(15)00027-X.pdf

Towards an HIV-1 cure: measuring the latent reservoir

In the past decade, the marked expansion of human immunodeficiency virus (HIV) treatment programs in resource-limited settings has resulted in the receipt of life-saving therapy by >8 million individuals [1, 2]. In line with World Health Organization (WHO) guidelines, most countries have adopted similar approaches for initial antiretroviral treatment, with the overwhelming majority of programs choosing first-line regimens based on nonnucleoside reverse transcriptase inhibitors (NNRTIs) and 2 nucleoside reverse-transcriptase inhibitors (NRTIs). Countries are moving to phase out stavudine (d4T), used initially because of its low cost and twice-daily fixed-dose formulation with lamivudine (3TC) and nevirapine (NVP) [3], and are adopting tenofovir (TDF)–based therapy because of its more favorable long-term safety profile and once-daily fixed-dose combination with either 3TC or emtricitabine (FTC) plus efavirenz (EFV) or with zidovudine (ZDV)–based therapy [4]. Second-line therapy has consisted of a protease inhibitor (PI) with 2 NRTIs; most programs have not yet adopted third-line regimens.

As a component of antiretroviral therapy (ART) roll out, surveillance for HIV drug resistance has been a critical to WHO recommendations and includes monitoring for early indicators of poor program performance, surveillance of transmitted drug resistance, and evaluation of drug resistance acquired during therapy [5]. Alongside WHO activities, treatment programs and research groups have evaluated the emergence of drug resistance among treated populations to better inform new treatment guidelines. To date, emergence of drugs resistance varies according to initial regimen choice, treatment monitoring strategies, and individual patient adherence and program factors.

For this scientific overview, we review WHO publications, systematic reviews, and relevant abstracts and manuscripts on the topic of drug resistance and summarize presentations and expert discussions conducted at the Collaborative HIV and Drug Resistance Network workshop in Geneva, Switzerland, on 10 and 11 October 2012. Specifically, we summarize the emergence of first-line drug resistance mutations after 12 months of ART and, on the basis of monitoring strategies, describe the outcomes to second-line therapy and summarize HIV resistance among patients in whom second-line therapies have failed.

Emergence of HIV Drug Resistance During First- and Second-Line Antiretroviral Therapy in Resource-Limited Settings

Optimal adherence to antiretroviral therapy is critical to prevent HIV drug resistance (HIVDR) epidemic. The objective of the study was to investigate the best performing adherence assessment method for predicting virological failure in resource-limited settings (RLS). This study was a single-centre prospective cohort, enrolling 220 HIV-infected adult patients attending an HIV/AIDS Care and Treatment Centre in Dar es Salaam, Tanzania, in 2010. Pharmacy refill, self-report (via visual analog scale [VAS] and the Swiss HIV Cohort study-adherence questionnaire), pill count, and appointment keeping adherence measurements were taken. Univariate logistic regression (LR) was done to explore a cut-off that gives a better trade-off between sensitivity and specificity, and a higher area under the curve (AUC) based on receiver operating characteristic curve in predicting virological failure. Additionally, the adherence models were evaluated by fitting multivariate LR with stepwise functions, decision trees, and random forests models, assessing 10-fold multiple cross validation (MCV). Patient factors associated with virological failure were determined using LR. Viral load measurements at baseline and one year after recruitment were available for 162 patients, of whom 55 (34%) had detectable viral load and 17 (10.5%) had immunological failure at one year after recruitment. The optimal cut-off points significantly predictive of virological failure were 95%, 80%, 95% and 90% for VAS, appointment keeping, pharmacy refill, and pill count adherence respectively. The AUC for these methods ranged from 0.52 to 0.61, with pharmacy refill giving the best performance at AUC 0.61. Multivariate logistic regression with boost stepwise MCV had higher AUC (0.64) compared to all univariate adherence models, except pharmacy refill adherence univariate model, which was comparable to the multivariate model (AUC = 0.64). Decision trees and random forests models were inferior to boost stepwise model. Pharmacy refill adherence (<95%) emerged as the best method for predicting virological failure. Other significant predictors in multivariate LR were having a baseline CD4 T lymphocytes count < 200 cells/μl, being unable to recall the diagnosis date, and a higher weight. Pharmacy refill has the potential to predict virological failure and to identify patients to be considered for viral load monitoring and HIVDR testing in RLS.

https://link.springer.com/content/pdf/10.1186%2F1471-2458-14-1035.pdf

Pharmacy refill adherence outperforms self-reported methods in predicting HIV therapy outcome in resource-limited settings

INTRODUCTION

Patients who are lost to follow-up (LTFU) while on antiretroviral therapy (ART) pose challenges to the long-term success of ART programs. We describe the extent to which patients considered LTFU are misclassified as true disengagement from care when they are still alive on ART and explain reasons for ART discontinuation using our active tracing program to further improve ART retention programs and policies.

METHODS

We identified adult ART patients who missed clinic appointment by more than 3 weeks between January 2006 and December 2010, assuming that such patients would miss their doses of antiretroviral drugs. Patients considered LTFU who consented during ART registration were traced by phone or home visits; true ART status after tracing was documented. Reasons for ART discontinuation were also recorded for those who stopped ART.

RESULTS

Of the 4,560 suspected LTFU cases, 1,384 (30%) could not be traced. Of the 3,176 successfully traced patients, 952 (30%) were dead and 2,224 (70%) were alive, of which 2,183 (99.5%) started ART according to phone-based self-reports or physical verification during in-person interviews. Of those who started ART, 957 (44%) stopped ART and 1,226 (56%) reported still taking ART at the time of interview by sourcing drugs from another clinic, using alternative ART sources or making brief ART interruptions. Among 940 cases with reasons for ART discontinuations, failure to remember (17%), too weak/sick (12%), travel (46%), and lack of transport to the clinic (16%) were frequently cited; reasons differed by gender.

CONCLUSION

The LTFU category comprises sizeable proportions 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 decentralization efforts, increasing drug allocations for frequent travels, and improving communication on patient transfers between clinics to increase retention and adherence.

/pdf/are-they-really-lost-true-status-and-reasons-for-treatment-ze3dxd74h0.pdf

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

The global response to the HIV/AIDS epidemic has improved access to antiretroviral therapy (ART) and has contributed to decreased HIV/AIDS morbidity and mortality in sub-Saharan Africa. Patient adherence to ART is crucial to the success of HIV/AIDS treatment. However, little is known about the determinants of adherence to ART among people living with HIV/AIDS (PLWHA) in the Democratic Republic of Congo (DRC). This qualitative study used in-depth semi-structured patient interviews, a purposive sampling strategy and thematic analysis scheme to identify barriers and facilitators of adherence to ART in the DRC. We recruited three categories of participants from the Centre Hospitalier Monkole and the NGO ACS/Amo-Congo including participants on antiretroviral (ARV) treatment (n=19), on ARV re-treatment (n=13) and lost to follow-up (n=6). Among 38 participants interviewed, 24 were female and the median age was 41 years. Food insecurity as a barrier to adherence emerged as a dominant theme across the three catego...

/pdf/if-i-have-nothing-to-eat-i-get-angry-and-push-the-pills-58xe5l1an7.pdf

“If I have nothing to eat, I get angry and push the pills bottle away from me”: A qualitative study of patient determinants of adherence to antiretroviral therapy in the Democratic Republic of Congo

Background. Since 2004, Malawi has rapidly scaled up access to antiretroviral therapy (ART) in the national program following a public health approach with limited laboratory monitoring. We examined virological outcomes in patients with treatment interruption at 2 clinics of the Lighthouse Trust, Lilongwe, Malawi. Methods. We evaluated patients who resumed first-line ART after having at least 1 treatment interruption documented in the electronic data system in 2008–2009. Viral load (VL) was analyzed at least 2 months after resumption of ART. For VL ≥1000 copies/mL, drug-resistance genotype was characterized using the Stanford database. Results. Between June and November 2009, we enrolled 133 patients (58.7% female) with a mean age of 38.4 years. Mean duration of ART prior to treatment interruption was 14.3 months. After a minimum of 2 months following ART resumption, VL was undetectable in 81 (60.9%) patients, was 400–1000 copies/mL in 12 (9.0%) patients, and was ≥1000 copies/mL in 40 (30.1%) patients. Genotyping and drug-resistance testing were successfully performed for 36 of 40 patients, all carrying human immunodeficiency virus type 1 subtype C. Relevant mutations affecting nonnucleoside reverse transcriptase inhibitors were found in 32 of 133 (24.1%) patients and combined with relevant nucleoside reverse transcriptase mutations in 27 of 133 (20.3%) patients. Conclusions. Virological failure combined with drug resistance after resumption of first-line ART occurred in 24.1% of the patients with treatment interruption, requiring a switch to protease inhibitor–based second-line therapy. Patients with treatment interruption should receive VL assessment after resumption of ART to detect treatment failure and to reduce development and spread of drug resistance.

/pdf/virological-failure-and-drug-resistance-in-patients-on-1lxdf9g4x5.pdf

Johnbosco Mwafilaso

Papers

Virological Failure and Drug Resistance in Patients on Antiretroviral Therapy After Treatment Interruption in Lilongwe, Malawi